Cyclic peptide derivative composition for treating or preventing neuropathic pain and / or inflammatory pain

Abstract

Provided is a cyclic peptide derivative composition for treating or preventing neuropathic pain and / or inflammatory pain. The present disclosure relates to compositions comprising a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof for treating or preventing neuropathic and / or inflammatory pain. The present disclosure also relates to a method for treating or preventing neuropathic pain and / or inflammatory pain comprising administering a composition comprising a compound or a pharmaceutically acceptable salt thereof. 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 a cyclic peptide derivative composition for treating or preventing neuropathic pain and / or inflammatory pain. Background Art

[0002] Neuropathic pain is currently defined as pain that starts or is caused by a primary lesion or dysfunction of the nervous system. Nerve damage can be caused by trauma and diseases, that is, the term "neuropathic pain" includes a variety of disorders with multiple etiologies. They include peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, low back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel compression syndrome, central post-stroke pain, and chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and pain associated with vitamin deficiency, but are not limited thereto.

[0003] Inflammatory pain means pain caused by inflammation. Inflammatory pain mostly presents as increased sensitivity to mechanical stimuli (mechanical hyperalgesia or tenderness). For example, inflammatory pain is caused by conditions selected from the following: burns, sunburns, arthritis, colitis, carditis, dermatitis, myositis, neuritis, mucositis, urethritis, cystitis, gastritis, pneumonia, and collagen vascular diseases, but are not limited thereto. Summary of the Invention

[0004] Means for Solving the Problems

[0005] The present disclosure provides a cyclic peptide derivative composition for treating or preventing at least one selected from neuropathic pain and inflammatory pain.

[0006] The present inventors have conducted in-depth studies and found that the compounds represented by the following formula and its related structural formulas, or pharmaceutically acceptable salts thereof (hereinafter, sometimes also referred to as "the compounds of the present disclosure" or "the disclosure compounds") have an improving effect on neuropathic pain and / or inflammatory pain, thereby completing the technical matters of the present disclosure.

[0007] That is, the present disclosure is as follows.

[0008] (Item 1)

[0009] A composition for treating or preventing at least one selected from neuropathic pain and inflammatory pain, comprising: a compound represented by the following formula (1) or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

[0010] [Chemical Formula 1]

[0011]

[0012] In the formula,

[0013] R1, R2, R5, R6, R7, R8, R9 and R 10 are each independently:

[0014] a hydrogen atom, or

[0015] an optionally substituted hydrocarbon group, or,

[0016] R7 and R8 together with the carbon atom and nitrogen atom to which they are bonded form an optionally substituted heterocycloalkyl group,

[0017] R3 and R4 are each independently:

[0018] a hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group,

[0019] an optionally substituted alkoxycarbonyl group, or

[0020] an optionally substituted alkoxycarbonyloxy group,

[0021] R 11 , R 12 , R 13 and R 14 are each independently:

[0022] a hydrogen atom, an optionally substituted hydrocarbon group, a hydroxyl group,

[0023] an optionally substituted alkoxy group, or

[0024] an optionally substituted alkoxycarbonyloxy group,

[0025] X is:

[0026] CH2 or CO,

[0027] A is O, NH or S, where NH may be optionally substituted.

[0028] (Item 2)

[0029] The composition according to any one of the foregoing items, wherein R1 and R2 are each independently a hydrogen atom or C 1-6 alkyl.

[0030] (Item 3)

[0031] The composition according to any one of the foregoing items, wherein R1 and R2 are each independently a hydrogen atom, a methyl group or an ethyl group.

[0032] (Item 4)

[0033] The composition according to any one of the foregoing items, wherein R3 and R4 are each independently a hydrogen atom, a C alkyl group substituted with a carboxyl group or a carboxyl group. 1-6 alkyl group or a carboxyl group.

[0034] (Item 5)

[0035] The composition according to any one of the foregoing items, wherein R3 and R4 are each independently a hydrogen atom, carboxymethyl, carboxyethyl, carboxypropyl or a carboxyl group.

[0036] (Item 6)

[0037] The composition according to any one of the foregoing items, wherein R5 is a hydrogen atom or a C 1-6 alkyl group.

[0038] (Item 7)

[0039] The composition according to any one of the foregoing items, wherein R5 is a hydrogen atom.

[0040] (Item 8)

[0041] The composition according to any one of the foregoing items, wherein R6 is a hydrogen atom or a C 1-6 alkyl group.

[0042] (Item 9)

[0043] The composition according to any one of the foregoing items, wherein R6 is a hydrogen atom.

[0044] (Item 10)

[0045] The composition according to any one of the foregoing items, wherein R7 is a hydrogen atom, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a carbamoyl C 1-6 alkyl group, a C 6-10 aryl C 1-6 alkyl group, a hydroxy C 6-10 aryl C 1-6 alkyl group, a C 5-10 heteroaryl C 1-6 alkyl group, a carboxy C 1-6 alkyl group, an amino C 1-6 alkyl group, a thio C 1-6 alkyl group, a C 1-6 alkylthio C 1-6 alkyl group or an amidinoamino C 1-6 alkyl group.

[0046] (Item 11)

[0047] The composition according to any one of the foregoing items, 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 sulfanylmethyl group, a 2-methylsulfanylethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinoaminopropyl group, an indolylmethyl group or a 4-imidazolylmethyl group.

[0048] (Item 12)

[0049] The composition according to any one of the foregoing items, wherein R8 is a hydrogen atom or C 1-6 alkyl.

[0050] (Item 13)

[0051] The composition according to any one of the foregoing items, wherein R8 is a hydrogen atom.

[0052] (Item 14)

[0053] The composition according to any one of the foregoing items, 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.

[0054] (Item 15)

[0055] The composition according to any one of the foregoing items, wherein R7 and R8 together with the carbon atom and nitrogen atom to which R7 and R8 are bonded form a C 5-10 heterocycloalkyl group.

[0056] (Item 16)

[0057] The composition according to any one of the foregoing items, wherein R9 and R 10 are a hydrogen atom or C 1-6 alkyl.

[0058] (Item 17)

[0059] The composition according to any one of the foregoing items, wherein R9 and R 10 are each independently a hydrogen atom or a methyl group.

[0060] (Item 18)

[0061] The composition according to any one of the foregoing items, wherein R 11 、R 12 、R 13 and R 14 are each independently a hydrogen atom, an alkoxy group or a hydroxy group.

[0062] (Item 19)

[0063] The composition according to any one of the foregoing items, wherein R 12 is a hydrogen atom or a hydroxyl group.

[0064] (Item 20)

[0065] The composition according to any one of the foregoing items, wherein R 11 , R 12 , R 13 and R 14 are each independently a hydrogen atom or a hydroxyl group.

[0066] (Item 21)

[0067] The composition according to any one of the foregoing items, wherein X is CH2.

[0068] (Item 22)

[0069] The composition according to any one of the foregoing items, wherein A is O, NH substituted with C 1-6 alkyl, NH or S.

[0070] (Item 23)

[0071] The composition according to any one of the foregoing items, wherein A is O, NH or S.

[0072] (Item 24)

[0073] The composition according to any one of the foregoing items, wherein the foregoing composition is used for treating or preventing neuropathic pain.

[0074] (Item 25)

[0075] The composition according to any one of the foregoing items, wherein the foregoing composition is used for treating or preventing inflammatory pain.

[0076] (Item 26)

[0077] The composition according to any one of the foregoing items, wherein the foregoing composition is used for treating or preventing neuropathic pain and inflammatory pain.

[0078] (Item A1)

[0079] A composition for treating or preventing at least one selected from neuropathic pain and inflammatory pain, comprising: a compound represented by the following formula (A2) or a pharmaceutically acceptable salt, solvate or prodrug thereof,

[0080] [Chemical formula 2]

[0081]

[0082] In the formula, m is from 0 to 3, n ≥ 1, R A1 ~R A4 、R A7 ~R A11 、R A312 and R A112 are each independently a hydrogen atom or a hydrocarbon group, R A14 and R A212 are each independently hydrogen, a carboxyl group or a salt thereof, or an alkoxycarbonyl group, R A5 is a hydrocarbon group, a hydroxyl group, an alkoxy group or an alkylcarbonyloxy group, R A55 and R A66 are each independently a hydrogen atom, a hydrocarbon group or an alkylcarbonyloxy group.

[0083] In the present disclosure, one or more of the above features are intended to be further combined and provided in addition to the explicitly shown combinations. Those skilled in the art will recognize further embodiments and advantages of the present disclosure as long as they read and understand the following detailed description as needed.

[0084] Advantages of the Invention

[0085] According to the present disclosure, novel cyclic peptide derivatives and compositions etc. that can be used for treating or preventing at least one selected from neuropathic pain and inflammatory pain are provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 : Figure 1 Shows the results of measuring the neuropathic pain threshold.

[0087] Figure 2 : Figure 2 Shows the effect of Compound 23 on mechanical hyperalgesia in a carrageenan-induced paw edema model in rats. DETAILED DESCRIPTION

[0088] The present disclosure will be further described in detail below.

[0089] Throughout this specification, unless otherwise specified, singular expressions should be understood to also include their plural forms. Therefore, it should be understood that, unless otherwise stated, singular articles (e.g., "a", "an", "the" in the English case, etc.) also include the concept of their plural forms. In addition, it should be understood that, unless otherwise stated, the terms used in this specification are used in the meanings commonly used in the art. Therefore, unless otherwise defined, all technical terms and scientific and technological terms used in this specification have the same meanings as those commonly understood by those skilled in the art to which the present disclosure pertains. In case of conflict, this specification (including definitions) shall prevail.

[0090] (Definition)

[0091] First, the terms and general techniques used in the present disclosure will be described.

[0092] The compounds of the present disclosure sometimes exist in the form of hydrates and / or solvates. Therefore, the hydrates and / or solvates of the compounds of the present disclosure or their pharmaceutically acceptable salts are also included in the compounds of the present disclosure.

[0093] The compounds of the present disclosure sometimes have one or more than one asymmetric carbon atoms depending on the circumstances, and sometimes geometric isomers or axial chirality are generated, so they sometimes exist 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 described in this specification may contain one or more than two asymmetric centers, and thus may 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 individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures concentrated from one or two or more stereoisomers). In addition, the present disclosure also includes the compounds described in this specification as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0094] In addition, any one or more than two 1 H is converted to 2 H(D), and the deuterium-transformed products are also included in the compounds of the present disclosure.

[0095] Among the compounds of the present disclosure and their pharmaceutically acceptable salts that can be obtained in crystalline form, there are sometimes polymorphs, and all crystal forms are included in the compounds of the present disclosure.

[0096] Next, the terms in this specification will be described below.

[0097] In this specification, unless otherwise specified, the term "group" means a monovalent group. Examples of groups that are not monovalent groups include alkylene (divalent) and the like. In addition, in the description of the following substituents and the like, the term "group" is sometimes omitted, and sometimes it is described together in the description of the term.

[0098] In this specification, in the cases defined by "optionally substituted", "substitutable" or "substituted", the number of substituents is not particularly limited as long as substitution is possible, and is one or more without particular limitation. In addition, unless otherwise specified, the description of each substituent also applies to the case where the substituent is a part of other substituents or a substituent.

[0099] As substituents in the present disclosure, the following can be mentioned: a hydrogen atom, a hydroxyl group, a carboxyl group, a sulfinic acid group, a sulfonic acid group, a phosphoric acid group, a guanidino group, a cyano group, a halogen atom (a fluorine atom, a chlorine atom, etc.), an alkyl group, an alkylthio group, a cycloalkylthio group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkylcarbonyl group, an alkylcarbonyloxy group, an alkylsulfinyl group, a cycloalkylsulfinyl group, an alkoxy group, a cycloalkoxy group, an alkoxycarbonyl group, a cycloalkyloxycarbonyl group, an 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 heterocyclic oxycarbonyl group, a heterocyclic sulfinyl group, a heterocyclic sulfonyl group, a heterocyclic carbonyl group, an alkylsulfonyl group, a cycloalkylsulfonyl group, an arylsulfonyl group, an arylsulfinyl group, a heteroarylsulfonyl group, a heteroarylsulfinyl group, a triphenylphosphonium cation group. The above substituents may be further substituted by the above substituents.

[0100] In the present specification, the "maximum number of substituents" means the maximum number of substituents that a certain group can have, which may be different for each group. For example, it is 3 for a methyl group, 5 for an ethyl group, 7 for a benzyl group, and 11 for a naphthylethyl group.

[0101] In the present 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 be substituted in the aryl part, or in the alkyl part, or in both the aryl part and the alkyl part.

[0102] In the present specification, as substituents in the case of "substitutable" or "optionally substituted", substituent group α and substituent group β can be exemplified. As substituents in the case of "substitutable" or "optionally substituted", they may be selected from substituent group α, and in addition, they may be substituted by 1 to 5 substituents that are the same or different. The types of atoms in the substituents participating in the bonding are not particularly limited by the types of substituents. When the atom to which the substituent is bonded is an oxygen atom, a nitrogen atom, or a sulfur atom, the atom bonded by the following substituents is limited to a carbon atom.

[0103] Substituent group α can include:

[0104] 1) A halogen atom

[0105] 2) A hydroxyl group

[0106] 3) A carboxyl group

[0107] 4) A cyano group

[0108] 5) C 1-6 An alkyl group

[0109] 6) C 2-6 An alkenyl group

[0110] 7)C 2-6 alkynyl

[0111] 8)C 1-6 alkoxy

[0112] 9)C 1-6 alkylthio

[0113] 10)C 1-6 alkylcarbonyl

[0114] 11)C 1-6 alkylsulfonyl

[0115] (wherein each of the substituents in 5) to 11) may be substituted by 1 to 5 identical or different substituents selected from the substituent group β)

[0116] 12)C 3-10 cycloalkyl

[0117] 13)C 3-10 cycloalkyloxy

[0118] 14)C 6-10 aryloxy

[0119] 15)C 5-10 heteroaryloxy

[0120] 16)C 4-10 non - aryl heteroepoxy

[0121] 17)C 3-10 cycloalkylthio

[0122] 18)C 6-10 arylthio

[0123] 19)C 5-10 heteroarylthio

[0124] 20)C 4-10 non - aryl heterocyclic thio

[0125] 21)C 6-10 aryl

[0126] 22)C 5-10 heteroaryl

[0127] 23)C 4-10 non - aryl heterocycle

[0128] 24)C 3-10 cycloalkylcarbonyl

[0129] 25)C 6-10 arylcarbonyl

[0130] 26)C 5-10 heteroarylcarbonyl

[0131] 27)C 4-10 Non - aryl heterocyclic carbonyl

[0132] 28)C 3-10 Cycloalkylsulfonyl

[0133] 29)C 6-10 Arylsulfonyl

[0134] 30)C 5-10 Heteroarylsulfonyl

[0135] 31)C 4-10 Non - aryl heterocyclic sulfonyl

[0136] (wherein, each of the substituents from 12) to 31) may be substituted by 1 to 5 substituent groups β or the aforementioned 5)C 1-6 alkyl substituted)

[0137] 32)-NR 10a R 11a

[0138] 33)-SO2 - NR 10b R 11b

[0139] 34)-NR 10c -C(=O)R 11c

[0140] 35)-NR 10d -C(=O)OR 11d

[0141] 36)-NR 12a -C(=O)NR 10e R 11e

[0142] 37)-NR 10i -SO2 - R 11i

[0143] 38)-NR 12c -SO2 - NR 10j R 11j

[0144] 39)-C(=O)OR 10k

[0145] 40)-C(=O)NR 10l R 11k

[0146] 41)-C(=O)NR 10m OR 11l

[0147] 42) -C(=O)NR 12d -NR 10n R 11m

[0148] 43) -C(=NR 13a )R 10s

[0149] 44) -C(=NR 13c )NR 10t R 11q

[0150] 45) -C(=NR 13d )NR 12f -NR 10u R 11r

[0151] 46) -NR 17c -C(=NR 13k )R 17d

[0152] 47) -NR 12g -C(=NR 13e )-NR 10v R 11s

[0153] 48) -NR 14 -C(=NR 13f )-NR 12h -NR 10w R 11t

[0154] 49) -OC(=O)R 10x

[0155] 50) -OC(=O)OR 10y

[0156] 51) -OC(=O)NR 10z1 R 11u

[0157] 52) -NR 12i -NR 10z2 R 11v

[0158] 53) -NR 10z3 OR 11w

[0159] 54) Protecting group;

[0160] Substituent group β is a group consisting of,

[0161] 1) A halogen atom,

[0162] 2) Hydroxyl,

[0163] 3) Carboxyl,

[0164] 4) Cyano,

[0165] 5) C 3-10 Cycloalkyl,

[0166] 6) C 1-6 Alkoxy,

[0167] 7) C 3-10 Cycloalkyloxy,

[0168] 8) C 1-6 Alkylthio,

[0169] 9) C 5-10 Heteroarylthio,

[0170] 10) C 6-10 Aryl,

[0171] 11) C 5-10 Heteroaryl,

[0172] 12) C 4-10 Non - aryl heterocycle,

[0173] 13) C 1-6 Alkylcarbonyl,

[0174] 14) C 3-10 Cycloalkylcarbonyl,

[0175] 15) C 6-10 Arylcarbonyl,

[0176] 16) C 5-10 Heteroarylcarbonyl,

[0177] 17) C 4-10 Non - aryl heterocyclocarbonyl,

[0178] 18) - NR 15a R 16a ,

[0179] 19) - SO2 - NR 15b R 16b ,

[0180] 20) - NR 15c - C(=O)R 16c

[0181] 21) - NR 17a - C(=O)NR 15d R 16d ,

[0182] 22)-C(=O)NR 15e R 16e 、

[0183] 23)-C(=NR 13g )R 15f 、

[0184] 24)-C(=NR 13h )NR 15g R 16f

[0185] 25)-NR 16g -C(=NR 13i )R 15h

[0186] 26)-NR 17b -C(=NR 13j )-NR 15i R 16h

[0187] 27) Protecting group

[0188] (In the substituent group β, each substituent from 5) to 17) can be substituted by 1 to 5 substituents selected from halogen atoms, hydroxyl groups, cyano groups, carboxyl groups, -NR 18a R 18b ),

[0189] R 13a 、R 13a2 、R 13c 、R 13c2 、R 13d 、R 13d2 、R 13e 、R 13f 、R 13g 、R 13g2 、R 13h 、R 13h2 、R 13i 、R 13j 、R 13k are each independently the same or different and are a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 1-6 alkoxycarbonyl group,

[0190] 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 17dEach independently the same or different, and is a hydrogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one to three identical or different substituents selected from hydroxyl, cyano, C 1-6 alkoxy, -NR 18a R 18b ), or C 1-6 alkoxycarbonyl,

[0191] R 18a and R 18b each independently the same or different, and is a hydrogen atom or C 1-6 alkyl.

[0192] In an exemplary embodiment, the hydrogen of any hydroxyl and amino in the substituent groups α and β may be substituted with a protecting group.

[0193] In this specification, "C 1-6 " means having 1 to 6 carbon atoms. The same applies to other numbers. For example, "C 1-4 " means having 1 to 4 carbon atoms, and "C 1-3 " means having 1 to 3 carbon atoms. In this specification, the description of the limitation of the number of carbon atoms is only a preferred numerical range, and the intention of the present disclosure is that groups having substituents with a number of carbon atoms other than the specified number of carbon atoms are also within the scope of the present disclosure.

[0194] In this specification, "hydrocarbyl" is also referred to as "hydrocarbon radical", 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.

[0195] In this specification, "functional group" refers to any group that imparts certain functionality. In addition to carboxyl, nitrile, carbonyl, hydroxyl, amino, imino, nitro, and halogen groups, it also includes alkyl, and broadly includes groups formed by bonds such as acid anhydride, ester bond, amide bond, and ether bond.

[0196] In this specification, "heteroatom" refers to an atom other than a carbon atom and a hydrogen atom, and means, 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, heteroaryl (meaning an aryl containing at least a heteroatom)) or a hetero... group (for example, heterocyclic group (meaning a ring group (carbocyclic group) containing at least one heteroatom)), etc.

[0197] In this specification, "halogen atom" is an atom belonging to the halogen group, and means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. Preferably a fluorine atom or a chlorine atom. More preferably a fluorine atom. Sometimes "halogen atom" is also referred to as "halogen", "hal".

[0198] In this specification, "hydroxyl" refers to a monovalent group of -OH. This group is sometimes also referred to as "hydroxyl group", "hydroxyl".

[0199] In this specification, "carboxyl" refers to a monovalent group of -COOH. This group is sometimes also referred to as "carboxyl group", "carboxyl", "carboxyl".

[0200] In this specification, "amino group" refers to a monovalent group of -NH2. This group is sometimes also referred to as "amino".

[0201] In this specification, "sulfhydryl group" refers to a monovalent group of -SH. This group is sometimes also referred to as "sulfhydryl".

[0202] In this specification, "cyano group" refers to a monovalent group of -CN. This group is sometimes also referred to as "cyano".

[0203] In this specification, the "alkyl" group means a straight-chain or branched-chain saturated aliphatic hydrocarbon group. "C 1-12 alkyl" is an alkyl group having 1 to 12 carbon atoms. As examples, C 1-6 alkyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, isoundecyl, dodecyl, isododecyl, etc. can be cited, but it is not limited thereto. "C 1-6 alkyl" is an alkyl group having 1 to 6 carbon atoms. As preferred examples, "C 1-4 alkyl" can be cited, and more preferably "C 1-3 alkyl", and even more preferably "C 1-2 alkyl". As specific examples of "C 1-4 alkyl", methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc. can be cited. As specific examples of "C 1-6 alkyl", C 1-4 alkyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, n-hexyl, etc. can be cited, but it is not limited thereto.

[0204] In this specification, the "alkenyl" group means a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group containing at least 1 carbon-carbon double bond. "C 2-12 alkenyl" is an alkenyl group having 2 to 12 carbon atoms. As examples, heptenyl, isoheptenyl, octenyl, isooctenyl, nonenyl, isononenyl, decenyl, isodecenyl, undecenyl, isoundecenyl, dodecenyl, isododecenyl, etc. can be cited, but it is not limited thereto. "C 2-6 alkenyl" is an alkenyl group having 2 to 6 carbon atoms. As preferred examples, "C 2-4 alkenyl" can be cited. As "C 2-6Specific examples of “alkenyl” include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, etc., but are not limited thereto.

[0205] In this specification, the “alkynyl” group means a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least 1 carbon-carbon triple bond. “C 2-12 “alkynyl” is an alkynyl group having 2 to 12 carbon atoms. Examples include heptynyl, isoheptynyl, octynyl, isooctynyl, nonynyl, isononyl, decynyl,isodecynyl, undecynyl, isoundecynyl, dodecynyl, isododecynyl, etc., but are not limited thereto. “C 2-6 “alkynyl” is an alkynyl group having 2 to 6 carbon atoms. Preferred examples include “C 2-4 “alkynyl”. As specific examples of “C 2-6 “alkynyl”, examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, etc., but are not limited thereto.

[0206] In this specification, the “aryl” group means a monocyclic or bicyclic aromatic hydrocarbon ring monovalent group, and “C 6-10 “aryl” means an aryl group having 6 to 10 carbon atoms. Examples of “aryl” include C6 aryl, C 10 “aryl”, etc., but are not limited thereto. Specific examples of C6 aryl include phenyl, etc., but are not limited thereto. As specific examples of C 10 “aryl”, examples include 1-naphthyl, 2-naphthyl, etc., but are not limited thereto.

[0207] The aryl as a substituent or a part thereof may be fused with an alicyclic group. For example, phenyl can be fused with a cyclohexane ring to form 1,2,3,4-tetrahydronaphthyl. At this time, any of the possible carbon atoms on the benzene ring is bonded to the parent skeleton or a group or atom close to the parent skeleton. Aryl includes 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl.

[0208] In this specification, the “arylalkyl” group means an alkyl group substituted with at least 1 aryl group. “C 6-10 “arylC 1-6 “alkyl” means an alkyl group substituted with at least 1 C 6-10 “aryl-substituted C 1-6 “alkyl”. As C 6-10 “arylC 1-6Specific examples of the alkyl group include benzyl (phenyl-CH2-), phenethyl (phenyl-CH2CH2-), naphthalen-1-ylmethyl, naphthalen-2-ylmethyl, 2-(naphthalen-1-yl)ethyl, 2-(naphthalen-2-yl)ethyl, etc., but are not limited thereto.

[0209] In this specification, the group "(optionally substituted amino)-arylalkyl" means an arylalkyl substituted by an optionally substituted amino group, where the alkyl group, the aryl group, or both of them are substituted by an amino group. The amino group of the arylalkyl may be unsubstituted, and in addition, it may also be substituted by 1, 2, or 3 substituents, for example, an optionally substituted alkyl group (e.g., unsubstituted C 1-6 alkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkylcarbonyl, etc.). As an example of (optionally substituted amino)-C 6-10 aryl C 1-6 alkyl, examples include (di(alkyl)amino)benzyl, ((cycloalkylalkyl)amino)benzyl, ((cycloalkylcarbonyl)amino)benzyl, ((carbamoylalkyl)carbonylamino)benzyl, ((carboxyalkyl)carbonyl)aminobenzyl, (di(alkyl)amino)naphthylmethyl, ((cycloalkylalkyl)amino)naphthylmethyl, ((cycloalkylcarbonyl)amino)naphthylmethyl, ((carbamoylalkyl)carbonylamino)naphthylmethyl, or ((carboxyalkyl)carbonyl)aminonaphthylmethyl, etc., but are not limited thereto.

[0210] In this specification, the group "hydroxyaryl" means an aryl substituted by at least 1 hydroxy group. "Hydroxy C 6-10 aryl" means a C 6-10 aryl substituted by at least 1 hydroxy group. Specific examples of hydroxy C 6-10 aryl include 2-hydroxyphenyl, 3-hydroxynaphthalene, etc., but are not limited thereto.

[0211] In this specification, the group "hydroxyarylalkyl" means an alkyl substituted by at least 1 hydroxyaryl group. "Hydroxy C 6-10 aryl C 1-6 alkyl" means a C 6-10 alkyl substituted by at least 1 hydroxy C 1-6 aryl. Specific examples of hydroxy C 6-10 aryl C 1-6 alkyl include 2-hydroxybenzyl (2-hydroxyphenyl-CH2-), 2-hydroxy phenethyl (2-hydroxyphenyl-CH2CH2-), 3-hydroxynaphthalen-1-ylmethyl, 3-hydroxynaphthalen-2-ylmethyl, 2-(3-hydroxynaphthalen-1-yl)ethyl, 2-(3-hydroxynaphthalen-2-yl)ethyl, etc., but are not limited thereto.

[0212] In this specification, the aryl moiety of the "arylthio" group has the same meaning as the above-mentioned aryl. As "C 6-10 arylthio", preferably, "C6 or C 10 arylthio" can be cited. As specific examples of "C 6-10 arylthio", phenylthio, 1-naphthylthio, 2-naphthylthio, etc. can be cited, but it is not limited thereto.

[0213] In this specification, the "arylsulfonyl" group means a sulfonyl group substituted by the above-mentioned "aryl". As "C 6-10 arylsulfonyl", preferably, it is "arylsulfonyl of C6 or C 10 ". As specific examples of "C 6-10 arylsulfonyl", phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc. can be cited, but it is not limited thereto.

[0214] In this specification, the "heteroaryl" group means a monovalent group of a monocyclic or bicyclic aromatic heterocycle containing the same or different heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom. The number of heteroatoms can be any number up to the number of carbon atoms present in the aryl group. For example, typically, 1 to 4 can be cited, and it can also be 1, 2, 3, etc.

[0215] In this specification, the "C 5-10 heteroaryl" group means a monovalent group of a monocyclic or bicyclic aromatic heterocycle composed of 5 to 10 atoms containing the same or different typically 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom. As specific examples of "C 5-10 heteroaryl", quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, imidazopyridyl, imidazothiazolyl, imidazoxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridyl, thiophenopyridyl, furanopyridyl, benzothiadiazolyl, benzoxadiazolyl, pyridopyrimidinyl, benzofuranyl, benzothiophenyl, benzo[1,3]dioxolene, thiophenofuranyl, benzopyranyl, chromanyl, coumarinyl, quinolonyl, etc. can be cited, but it is not limited thereto.

[0216] In this specification, the "heteroarylalkyl" group means an alkyl group substituted by at least 1 heteroaryl. "C 5-10 heteroarylC 1-6 alkyl" means a C 5-10 alkyl group substituted by at least 1 C 1-6 heteroaryl. As C 5-10 heteroarylC 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.

[0217] In the present specification, a "cycloalkyl" group 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 1 or 2 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.

[0218] The cycloalkyl as a substituent or a part thereof may be fused with an aryl and / or heteroaryl ring. For example, a cyclohexyl group may be fused with a benzene ring to form a 1,2,3,4-tetrahydronaphthyl group, in which case any of the possible carbon atoms on the cyclohexane ring is bonded to a parent skeleton or a group or an atom thereof close to the parent skeleton. The cycloalkyl group includes 1,2,3,4-tetrahydronaphthalene-1-yl, 1,2,3,4-tetrahydronaphthalene-2-yl, indan-1-yl, indan-2-yl, 5,6,7,8-tetrahydroquinoline-5-yl, 5,6,7,8-tetrahydroquinoline-6-yl.

[0219] In the present specification, a "cycloalkylalkyl" group refers to an alkyl group substituted by at least one cycloalkyl group. 3-6 Cycloalkyl C 1-6 "Alkyl" means a group consisting of at least 1 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.

[0220] In this specification, a "heterocycloalkyl" group means a non-aromatic saturated or partially unsaturated heterocycle consisting of three or more atoms containing one or two or more heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms, including those having a partially cross-linked structure and those partially spiro-formed. "Heterocycloalkyl" includes "non-aromatic heterocycle". Heterocycloalkyl may have a structure in which a non-aromatic heterocycle is fused with an aryl ring and / or a heteroaryl ring.

[0221] In this specification, the "non-aromatic heterocyclic" group means a monocyclic or bicyclic non-aromatic heterocyclic composed of more than 3 atoms containing the same or different 1 or 2 or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom, including a saturated non-aromatic heterocyclic, those having partially unsaturated bonds, those having partially crosslinked structures, and those partially spiro-fused. The non-aromatic heterocyclic can form a fused ring with an aryl or a heteroaryl. For example, the case of fusion with a C 6-10 aryl or a C 5-10 heteroaryl is also included in the heterocyclic. In addition, when forming the non-aromatic heterocyclic, 1 or 2 or more carbonyl groups, thiocarbonyl groups, sulfinyl groups, or sulfonyl groups can be included. For example, cyclic groups such as lactam, thiolactam, lactone, thiolactone, cyclic imide, cyclic carbamate, and cyclic thiocarbamate are also included in the non-aromatic heterocyclic. Among them, the oxygen atom of the carbonyl group, the sulfinyl group, and the sulfonyl group and the sulfur atom of the thiocarbonyl group are not included in the number of ring members (the size of the ring) and the number of heteroatoms constituting the ring.

[0222] In this specification, "C 4-10 non-aromatic heterocyclic" means that in the above "non-aromatic heterocyclic", the "C 4-10 non-aromatic heterocyclic" becomes a substituent of a monovalent group.

[0223] In this specification, the non-aromatic heterocyclic part of the "non-aromatic heterocyclic oxy group" has the same meaning as the above "non-aromatic heterocyclic". For example, "C 4-10 non-aromatic heterocyclic oxy group" can be cited. As the "C 4-10 non-aromatic heterocyclic oxy group", "C 4-10 non-aromatic heterocyclic oxy group" is preferred. As a specific example of the "C 4-10 non-aromatic heterocyclic oxy group", tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy, etc. can be cited, but it is not limited thereto.

[0224] In this specification, the non-aromatic heterocyclic part of the "non-aromatic heterocyclic thio group" has the same meaning as the above "non-aromatic heterocyclic". For example, "C 4-10 non-aromatic heterocyclic thio group" can be cited. As the "C 4-10 non-aromatic heterocyclic thio group", "C 4-6 non-aromatic heterocyclic thio group" is preferred. As a specific example of the "C 4-10 non-aromatic heterocyclic thio group", tetrahydropyranylthio, piperidylthio, etc. can be cited, but it is not limited thereto.

[0225] In this specification, the "non-aromatic heterocyclic carbonyl group" means a carbonyl group substituted by the above "non-aromatic heterocyclic". For example, "C 4-10 non-aromatic heterocyclic carbonyl group" can be cited. As the "C 4-10"Non - aryl heterocyclic carbonyl", preferably "C" 4-6 Non - aryl heterocyclic carbonyl". As "C" 4-10 Specific examples of "non - aryl heterocyclic carbonyl" include azetidinyl carbonyl, pyrrolidinyl carbonyl, piperidinyl carbonyl, morpholinyl carbonyl, etc., but are not limited thereto.

[0226] In this specification, the "non - aryl heterocyclic sulfonyl" group means a sulfonyl group substituted by the above - mentioned "non - aryl heterocycle". For example, "C" 4-10 Non - aryl heterocyclic sulfonyl" can be cited as "C" 4-10 Non - aryl heterocyclic sulfonyl", preferably "C" 4-6 Non - aryl heterocyclic sulfonyl". As "C" 4-10 Specific examples of "non - aryl heterocyclic sulfonyl" include azetidinyl sulfonyl, pyrrolidinyl sulfonyl, piperidinyl sulfonyl, morpholinyl sulfonyl, etc., but are not limited thereto.

[0227] In this specification, the "C" 5-10 "Heterocycloalkyl" group means a heterocycloalkyl composed of 5 - 10 ring atoms containing the same or different 1 or 2 or more heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms.

[0228] In this specification, the "heterocycloalkylalkyl" group means an alkyl group substituted by at least 1 heterocycloalkyl.

[0229] In this specification, the "alkylcarbonyl" group 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 include acetyl (CH3C(=O)-), n - propionyl (CH3CH2C(=O)-), n - butyryl (CH3CH2CH2C(=O)-), n - valeryl (CH3(CH2)3C(=O)-), n - hexanoyl (CH3(CH2)4C(=O)-), n - heptanoyl (CH3(CH2)5C(=O)-), etc., but are not limited thereto.

[0230] In this specification, the "alkoxy" group is a monovalent group of - O - alkyl. Preferred examples of alkoxy include C 1-6 Alkoxy (i.e., C 1-6 Alkyl - O -), C 1-4 Alkoxy (i.e., C 1-4 Alkyl - O -), 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-), sec-butoxy (CH3CH2CH(CH3)O-), etc. As C 1-6 Specific examples of alkoxy groups include C 1-4 alkoxy groups, n-pentyloxy (CH3(CH2)4O-), isopentyloxy ((CH3)2CHCH2CH2O-), neopentyloxy ((CH3)3CCH2O-), tert-pentyloxy (CH3CH2C(CH3)2O-), 1,2-dimethylpropoxy (CH3CH(CH3)CH(CH3)O-), etc., but are not limited thereto.

[0231] In the present specification, the "alkoxycarbonyl" group is a monovalent group of -C(=O)-O-alkyl. Examples of alkoxycarbonyl groups include C 1-6 alkoxycarbonyl groups, preferably C 1-4 alkoxycarbonyl groups, but are not limited thereto. As C 1-4 Specific examples of alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, etc. As C 1-6 Specific examples of alkoxycarbonyl groups include C 1-4 alkoxycarbonyl groups, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, 1,2-dimethylpropoxycarbonyl, n-hexyloxycarbonyl, etc., but are not limited thereto.

[0232] In the present specification, the "alkoxycarbonyloxy" group is a monovalent group of -O-C(=O)-O-alkyl. Examples of alkoxycarbonyloxy groups include C 1-6 alkoxycarbonyloxy groups, preferably C 1-4 alkoxycarbonyloxy groups, but are not limited thereto. As C 1-4 Specific examples of alkoxycarbonyloxy groups include methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-butoxycarbonyloxy, sec-butoxycarbonyloxy, tert-butoxycarbonyloxy, isobutoxycarbonyloxy, etc. As C 1-6 Specific examples of alkoxycarbonyloxy groups include C 1-4Alkoxycarbonyloxy, n-pentyloxycarbonyloxy, isopentyloxycarbonyloxy, neopentyloxycarbonyloxy, tert-pentyloxycarbonyloxy, 1,2-dimethylpropyloxycarbonyloxy, n-hexyloxycarbonyloxy, etc., but not limited thereto.

[0233] In this specification, the "alkoxycarbonylamino" group is a monovalent group of -NH-C(=O)-O-alkyl. As an example of the alkoxycarbonylamino, C 1-6 alkoxycarbonylamino, preferably C 1-4 alkoxycarbonylamino, but not limited thereto. As C 1-4 specific examples of alkoxycarbonylamino, there may be mentioned methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, sec-butoxycarbonylamino, tert-butoxycarbonylamino, isobutoxycarbonylamino, etc. As C 1-6 specific examples of alkoxycarbonylamino, there may be mentioned C 1-4 alkoxycarbonylamino, n-pentyloxycarbonylamino, isopentyloxycarbonylamino, neopentyloxycarbonylamino, tert-pentyloxycarbonylamino, 1,2-dimethylpropyloxycarbonylamino, n-hexyloxycarbonylamino, etc., but not limited thereto.

[0234] In this specification, the "haloalkyl" group is a monovalent group of halogenated alkyl in which one or more hydrogens on the alkyl are replaced by halogen. In addition, the term "perhaloalkyl" means a haloalkyl in which all hydrogens on the alkyl are replaced by halogen. For example, perfluoroethyl is -CF2CF3, and perchloro-n-propyl is -CCl2CCl2CCl3. As examples of the haloalkyl, there may be mentioned C 1-6 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl, etc. As C 1-3 specific examples of alkyl, there may be mentioned fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, fluorochloromethyl, difluorochloromethyl, fluorodichloromethyl, fluoroethyl, chloroethyl, bromoethyl, trifluoroethyl, trichloroethyl, tribromoethyl, perfluoroethyl, perchloroethyl, perbromoethyl, perfluoropropyl, perchloropropyl, perbromopropyl, perfluoroisopropyl, perchloroisopropyl, perbromoisopropyl, etc., but not limited thereto. As C 1-4 specific examples of alkyl, there may be mentioned C 1-3 haloalkyl, perfluorobutyl, perchlorobutyl, perbromobutyl, perfluoroisobutyl, perfluorotert-butyl, etc., but not limited thereto. As C 1-6 specific examples of alkyl, there may be mentioned C 1-4 haloalkyl, perfluoro-n-pentyl, perfluoro-isopentyl, perfluoro-neopentyl, perfluoro-tert-pentyl, perfluoro-1,2-dimethylpropyl, etc., but not limited thereto.

[0235] In this specification, the "haloalkoxy" group and the "haloalkyl-oxy" group are monovalent groups of -O-haloalkyl in which one or more hydrogens on the alkyl group are substituted by halogen. In addition, the term "perhaloalkoxy" means a haloalkoxy in which all hydrogens on the alkyl group are substituted by halogen. For example, perfluoroethoxy is -OCF2CF3, and perchloro-n-propoxy is -OCCl2CCl2CCl3. As preferred examples of the haloalkoxy, C 1-6 haloalkoxy, C 1-4 haloalkoxy, C 1-3 haloalkoxy, etc. As specific examples of C 1-3 alkoxy, fluoro-methoxy, chloro-methoxy, bromo-methoxy, difluoro-methoxy, dichloro-methoxy, dibromo-methoxy, trifluoro-methoxy, trichloro-methoxy, tribromo-methoxy, fluoro-chloro-methoxy, difluoro-chloro-methoxy, fluoro-dichloro-methoxy, fluoro-ethoxy, chloro-ethoxy, bromo-ethoxy, trifluoro-ethoxy, trichloro-ethoxy, tribromo-ethoxy, perfluoro-ethoxy, perchloro-ethoxy, perbromo-ethoxy, perfluoro-propoxy, perchloro-propoxy, perbromo-propoxy, perfluoro-isopropoxy, perchloro-isopropoxy, perbromo-isopropoxy, etc. may be mentioned, but are not limited thereto. As specific examples of C 1-4 alkoxy, C 1-3 haloalkoxy, perfluoro-butoxy, perchloro-butoxy, perbromo-butoxy, perfluoro-isobutoxy, perfluoro-tert-butoxy, etc. may be mentioned, but are not limited thereto. As specific examples of C 1-6 alkoxy, C 1-4 haloalkoxy, perfluoro-n-pentyloxy, perfluoro-isopentyloxy, perfluoro-neopentyloxy, perfluoro-tert-pentyloxy, perfluoro-1,2-dimethylpropoxy, etc. may be mentioned, but are not limited thereto.

[0236] In this specification, the "alkylsulfonyl" group means a sulfonyl group substituted by the above-mentioned "alkyl". As the "C 1-6 alkylsulfonyl", "C 1-4 alkylsulfonyl" is preferred. As specific examples of the "C 1-6 alkylsulfonyl", methylsulfonyl, propionylsulfonyl, butyrylsulfonyl, etc. may be mentioned, but are not limited thereto.

[0237] In this specification, the alkyl part of the "alkylthio" group has the same meaning as the above-mentioned alkyl. As an example of the "C 1-6 alkylthio", "C 1-4 alkylthio" may be mentioned, and preferably "C 1-3 alkylthio". As the "C 1-6Specific examples of "alkylthio" include methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, tert-butylthio, sec-butylthio, isopentylthio, neopentylthio, tert-pentylthio, 1,2-dimethylpropylthio, etc., but are not limited thereto.

[0238] In this specification, the "arylcarbonyl" group is a monovalent group of -C(=O)-aryl. Preferred examples of arylcarbonyl include C 6-10 arylcarbonyl. As C 6-10 Specific examples of arylcarbonyl include benzoyl (i.e., phenyl-C(=O)-), 1-naphthylcarbonyl, 2-naphthylcarbonyl, etc., but are not limited thereto.

[0239] In this specification, the aryl part of the "aryloxy" group has the same meaning as the above-mentioned aryl. As "C 6-10 aryloxy", preferably "aryloxy of C6 or C 10 " can be cited. Specific examples of "C 6-10 aryloxy" include phenoxy, 1-naphthyloxy, 2-naphthyloxy, etc., but are not limited thereto.

[0240] In this specification, the "heteroarylcarbonyl" group means a monovalent group of -C(=O)-heteroaryl, meaning a carbonyl group substituted by the above-mentioned "heteroaryl". Specific examples of "C 5-10 heteroarylcarbonyl" include pyrazolylcarbonyl, triazolylcarbonyl, thiazolylcarbonyl, thiadiazolylcarbonyl, pyridylcarbonyl, pyridazinylcarbonyl, etc., but are not limited thereto.

[0241] In this specification, the heteroaryl part of the "heteroaryloxy" group has the same meaning as the above-mentioned "heteroaryl". Specific examples of "C 5-10 heteroaryloxy" include pyrazolyloxy, triazolyloxy, thiazolyloxy, thiadiazolyloxy, pyridyloxy, pyridazinyloxy, etc., but are not limited thereto.

[0242] In this specification, the heteroaryl part of the "heteroarylthio" group has the same meaning as the above-mentioned "heteroaryl". Specific examples of "C 5-10 heteroarylthio" include pyrazolylthio, triazolylthio, thiazolylthio, thiadiazolylthio, pyridylthio, pyridazinylthio, etc., but are not limited thereto.

[0243] In this specification, the "optionally substituted carbonyl" group means a monovalent group of -C(=O)-(hydrogen or any group selected from the substituent groups described in this specification). Examples of the "optionally substituted carbonyl" group include formyl, optionally substituted carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkenylcarbonyl, alkenyloxycarbonyl, alkynylcarbonyl, alkynyloxycarbonyl, arylcarbonyl, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkyloxycarbonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkyloxycarbonyl, etc., but are not limited thereto. The carbonyl group substituted by hydrogen is formyl. The carbonyl group substituted by an amino group is carbamoyl.

[0244] In this specification, the "optionally substituted oxy" group means a monovalent group of -O-(hydrogen or any group selected from the substituent groups described in this specification). Examples of the "optionally substituted oxy" group include hydroxy, optionally substituted alkyloxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, heterocycloalkylcarbonyloxy, etc., but are not limited thereto. The oxy group substituted by hydrogen is hydroxy.

[0245] In this specification, the "carbamoyl" group is a monovalent group of -C(=O)-NH2.

[0246] In this specification, the "amidinylamino" group is a monovalent group of -NH-C(=NH)-NH2.

[0247] In this specification, the description of "a group substituted by a certain substituent" means that the group is substituted by at least 1 substituent. For example, "hydroxy-substituted C 1-6 alkyl" means that C 1-6 alkyl is substituted by at least 1 hydroxy group.

[0248] In this specification, the "carbamoyl C 1-6 alkyl" group is a C 1-6 alkyl substituted by at least 1 -C(=O)-NH2 group. Specific examples of the "carbamoyl C 1-4 alkyl" group include 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), 5-amino-5-oxopentyl (i.e., H2NC(=O)-(CH2)4-, or carbamoylbutyl), etc., but are not limited thereto. As the "carbamoyl C 1-6Specific examples of "alkyl" include carbamoyl-substituted C 1-4 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.

[0249] In the present specification, the "sulfanylalkyl" group is an alkyl group substituted by at least one sulfanyl group. As specific examples of "sulfanyl C 1-6 alkyl", sulfanylmethyl, 2-sulfanylethyl, 3-sulfanylpropyl, 4-sulfanylbutyl, etc. can be mentioned, but are not limited thereto.

[0250] In the present specification, the "alkylsulfanylalkyl" group means an alkyl group substituted by at least one alkylsulfanyl group. "C 1-6 alkylsulfanyl C 1-6 alkyl" means a C 1-6 alkyl substituted by at least one C 1-6 alkylsulfanyl group. As specific examples of C 1-6 alkylsulfanyl C 1-6 alkyl, methylsulfanylmethyl, methylsulfanylethyl, ethylsulfanylmethyl, etc. can be mentioned, but are not limited thereto.

[0251] In the present specification, the "aminoalkyl" group is an alkyl group substituted by at least one amino group. As specific examples of "amino C 1-6 alkyl", aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, etc. can be mentioned, but are not limited thereto.

[0252] In the present specification, the "amidinoaminoalkyl" group or "guanidylalkyl" group is an alkyl group substituted by at least one -NH-C(=NH)-NH2 group, where the nitrogen atom of the amidinoamino group can be protected by a nitrogen protecting group (e.g., tert-butoxycarbonyl). As an example of "amidinoamino C 1-6 alkyl", "amidinoamino C 1-4 alkyl", etc. can be mentioned, but are not limited thereto. As specific examples of "amidinoamino C 1-4 alkyl", (amidinoamino)methyl, 2-(amidinoamino)ethyl, 3-(amidinoamino)propyl, 4-(amidinoamino)butyl, etc. can be mentioned, but are not limited thereto. As specific examples of "amidinoamino C 1-6 alkyl", amidinoamino-substituted C 1-4 alkyl, 5-(amidinoamino)pentyl, 6-(amidinoamino)hexyl, etc. can be mentioned, but are not limited thereto. As examples of the amidinoamino group protected by a nitrogen protecting group, the following can be mentioned:

[0253] [Chemical Formula 3]

[0254]

[0255] In this specification, "amidinylamino" has the same meaning as "guanidyl".

[0256] In this specification, a "carboxyalkyl" group is an alkyl group substituted by at least one -COOH group. As specific examples of "carboxyC 1-4 alkyl", carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, etc. can be mentioned, but it is not limited thereto. As specific examples of "carboxyC 1-6 alkyl", carboxy-substituted C 1-4 alkyl, 5-carboxypentyl, 6-carboxyhexyl, etc. can be mentioned, but it is not limited thereto.

[0257] In this specification, a "protecting group" refers to a group of atoms that shields, reduces, or prevents the reactivity of a functional group when combined with a reactive functional group within a molecule. The compounds of the present disclosure can be appropriately or as needed substituted with a protecting group at any position of any of R1 to R4 or their substituents or other substituents, and compounds containing such protecting groups are also within the scope of the present disclosure. Typically, the protecting group can be selectively removed during the 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 - 8, John Wiley & Sons, NY, etc. As representative nitrogen protecting groups, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilylethanesulfonyl ("TES"), trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), and nitroveratryloxycarbonyl ("NVOC") etc. can be mentioned, but it is not limited thereto. As representative hydroxyl protecting groups, those in which the hydroxyl group is acylated (esterified) or alkylated can be mentioned, for example, benzyl and trityl ethers, etc., 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), diol ethers (e.g., ethylene glycol ether, propylene glycol ether, etc.) and allyl ethers, but it is not limited thereto.

[0258] The amino groups possessed by the compounds of the present disclosure (e.g., the amino groups possessed by the parent skeleton, the amino groups as substituents, the amino groups in the substituents possessed by the compound, etc.) can be protected by nitrogen protecting groups or the groups represented by "Protect". The amino groups in the substituents listed in the substituent group can be further protected by nitrogen protecting groups or the groups represented by "Protect", and the protected substituents can be used as substituents.

[0259] The hydroxyl groups possessed by the compounds of the present disclosure (e.g., the hydroxyl groups as substituents, the hydroxyl groups in the substituents possessed by the compound, the hydroxyl groups in the above-mentioned substituent group, etc.) can also be protected by protecting groups for hydroxyl groups. The hydroxyl groups in the substituents listed in the substituent group can be further protected by the hydroxyl protecting groups described in this specification, and the protected substituents can be used as substituents.

[0260] In this specification, neuropathic pain is currently defined as pain that starts or is caused by an initial lesion or dysfunction of the nervous system. Nerve injury can be caused by trauma and diseases, that is, the term "neuropathic pain" includes a variety of disorders with multiple etiologies. They include peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, low back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel compression syndrome, central post-stroke pain, and chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and pain associated with vitamin deficiency, but are not limited to them. Neuropathic pain is pathological when there is no protective effect. It often persists after the initial cause has disappeared, usually for several years, significantly reducing the quality of life of patients (Woolf and Mannion, 1999, Lancet, 353, 1959 - 1964). The symptoms of neuropathic pain are often uneven even among patients with the same disease, so it is difficult to treat (Woolf & Decosterd, 1999, Pain Supp., 6, S141 - S147; Woolf and Mannion, 1999, Lancet, 353, 1959 - 1964). They include spontaneous pain (which can be continuous), which evokes paroxysmal or abnormally induced pain, such as hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to normally harmless stimuli).

[0261] In this specification, "inflammatory pain" means pain produced by inflammation as defined in the art. Inflammatory pain mostly presents as increased sensitivity to mechanical stimuli (mechanical hyperalgesia or tenderness). For example, inflammatory pain is caused by conditions selected from but not limited to the following: burns, sunburns, arthritis, colitis, carditis, dermatitis, myositis, neuritis, mucositis, urethritis, cystitis, gastritis, pneumonia, and collagen vascular diseases, etc.

[0262] In this specification, "regulation" of activity means inhibition or promotion of activity, and the term "regulator" means an inhibitor (inhibitor) or promoter of activity. "Promoting activity" means that the activity (for example, promotion of cell division) increases by more than 1%, preferably more than 5%, more preferably more than 10%, further preferably more than 20%, and further preferably more than 30% compared to the case where no activity regulator is used. "Inhibiting activity" means that the activity (for example, promotion of cell division) decreases by more than 1%, preferably more than 5%, more preferably more than 10%, further preferably more than 20%, and further preferably more than 30% compared to the case where no activity regulator is used.

[0263] In this specification, "pharmaceutically acceptable salts" means acid addition salts and base addition salts that are pharmaceutically acceptable. Specific examples of "pharmaceutically acceptable salts" include acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethyl succinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate (tosylate), lauryl sulfate, malate, ascorbate, mandelate, saccharinate, cinchoninate, ditosylate, cinnamate, adipate, cysteinate, N-acetylcysteinate, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, polyacrylate salts, carboxyvinyl polymer and other acid addition salts; inorganic base addition salts such as lithium salt, sodium salt, potassium salt, calcium salt, etc.; organic base addition salts such as morpholine, piperidine, etc.; addition salts with amino acids such as aspartic acid, glutamic acid, etc., but are not limited thereto.

[0264] 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 (such as acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, mesylate, benzenesulfonate, formate or p-toluenesulfonate, etc.) and inorganic acid salts (such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate or phosphate, etc.), salts with amino acids (such as arginine, aspartic acid or glutamic acid, etc.), metal salts such as alkali metal salts (such as sodium salt or potassium salt, etc.) and alkaline earth metal salts (such as calcium salt or magnesium salt, etc.), ammonium salts, or organic base salts (such as trimethylamine salt, triethylamine salt, pyridine salt, methylpyridine salt, dicyclohexylamine salt or N,N'-dibenzylethylenediamine salt, etc.), those skilled in the art can also appropriately select.

[0265] When attempting to obtain a salt of the compound of the present disclosure, in the case where the compound of the present disclosure is obtained in the form of a salt, it can be directly purified. In addition, in the case where it is obtained in the free form, it can be dissolved or suspended in a suitable organic solvent, an acid or a base is added, and a salt is formed by a usual method.

[0266] In addition, the compounds of the present disclosure and their pharmaceutically acceptable salts sometimes exist in the form of adducts with water or various solvents, and these adducts are also included in the present disclosure.

[0267] Furthermore, the present disclosure includes the compounds of the present disclosure or their pharmaceutically acceptable salts. In addition, it also includes their solvates such as hydrates or ethanol solvates. Further, the present disclosure also includes all tautomers of the compounds of the present disclosure, all stereoisomers present, and all polymorphic forms of the crystals.

[0268] The phrase "compound or its enantiomer or their salt or their solvate" means a certain 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.

[0269] The compounds described in this specification may contain one or more than two asymmetric centers, and thus may 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 individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched in one or more than two stereoisomers). Isomers can be separated from the mixture by methods known to those skilled in the art (including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts). Alternatively, the preferred isomers can be prepared by asymmetric synthesis. For example, refer to Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). In addition, this disclosure also includes the compounds described in this specification as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0270] In the compounds of this disclosure, there may be optical isomers based on optically active centers, atropisomers based on axial or planar chirality generated by the restriction of intramolecular rotation, other stereoisomers, tautomers, and geometric isomers, etc. All possible isomers and their mixtures, including these, are included within the scope of this disclosure.

[0271] In particular, optical isomers and atropisomers can be obtained in the form of a racemate, or in the form of an optically active substance when using optically active starting materials or intermediates. If necessary, at appropriate stages of the following manufacturing methods, the racemate of the corresponding raw material, intermediate or final product can be physically or chemically resolved into its optical enantiomers by known separation methods such as the method using an optically active column or fractional crystallization. Specifically, for example, in the diastereoisomer method, two diastereoisomers are formed from the racemate by reaction with an optical resolving agent. These different diastereoisomers usually have different physical properties and can therefore be resolved by known methods such as fractional crystallization.

[0272] As used herein, the phrase "pharmaceutically acceptable" means a compound, material, composition and / or dosage form that, within the scope of sound medical judgment, has no excessive toxicity, irritation, allergic response or other problems or complications, meets an appropriate benefit / risk ratio, and is suitable for use in contact with the tissues of humans and animals.

[0273] As used herein, 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, etc. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers are as follows: (1) sugars, such as lactose, glucose and sucrose, etc.; (2) starches, such as corn starch and potato starch, etc.; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, etc.; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax, etc.; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, etc.; (10) diols, 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) buffering agents, 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 solution; and (21) other non-toxic and compatible substances used in pharmaceutical formulations.

[0274] Furthermore, prodrugs of the compounds of the present disclosure are also included within the scope of the present disclosure. In the present disclosure, a prodrug refers to a derivative that provides the aforementioned compound of the present disclosure by acid hydrolysis or enzymatic decomposition in vivo. For example, when the aforementioned compound of the present disclosure has a hydroxyl group, an amino group or a carboxyl group, these groups can be modified according to conventional methods to produce a prodrug.

[0275] For example, in the case of a compound having a carboxyl group, examples thereof include a compound in which the carboxyl group is an alkoxycarbonyl group, an alkylthiocarbonyl group, or an alkylaminocarbonyl group.

[0276] In addition, for example, in the case of a compound having an amino group, examples thereof include a compound in which the amino group is substituted with an alkanoyl group to form an alkanoylamino group, a compound in which the amino group is substituted with an alkoxycarbonyl group to form an alkoxycarbonylamino group, a compound in which the amino group is an alkanoyloxymethylamino group, or a compound in which the amino group is a hydroxylamine.

[0277] In addition, for example, in the case of a compound having a hydroxyl group, examples thereof include 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.

[0278] As the alkyl moiety of the group used in such prodrug formation, the aforementioned alkyl group can be mentioned, and this alkyl group can be substituted with, for example, an alkoxy group or the like. Preferred examples are as follows.

[0279] For example, as an example of a compound in which the carboxyl group is an alkoxycarbonyl group, C 1-12 alkoxycarbonyl, C4 alkoxycarbonyl, C6 alkoxycarbonyl, C8 alkoxycarbonyl, C 10 alkoxycarbonyl, C 12 alkoxycarbonyl, specifically alkoxycarbonyls such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, 1,2-dimethylpropoxycarbonyl, n-hexyloxycarbonyl, heptyloxycarbonyl, isoheptyloxycarbonyl, 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 alkoxys such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl; or alkoxycarbonyls substituted with C 1-12 alkyl PEG, C4 alkyl PEG, C6 alkyl PEG, C8 alkyl PEG, C 10 alkyl PEG, C 12 alkyl PEG. Here, PEG refers to polyethylene glycol, and the alkyl group can be straight-chain or branched-chain.

[0280] In this specification, "or" is used when "at least one or more" of the items listed in the text can be adopted. The same applies to "or". In this specification, when it is clearly stated as "within the range of two values", this range also includes the two values themselves.

[0281] All references such as scientific literature, patents, patent applications, etc. cited in this specification are incorporated herein by reference in their entirety to the same extent as their respective specific descriptions.

[0282] (Preferred Embodiment)

[0283] The preferred embodiments of the present disclosure are described below. It should be understood that the embodiments provided below are for better understanding of the present disclosure, and the scope of the present disclosure should not be limited by the following description. Therefore, those skilled in the art can obviously make appropriate changes within the scope of the present disclosure with reference to the descriptions in this specification. In addition, it should be understood that the following embodiments of the present disclosure can be used alone or in combination.

[0284] (Drug for Neuropathic Pain and / or Inflammatory Pain)

[0285] The present disclosure provides a drug or composition, etc. for treating or preventing at least one selected from neuropathic pain and inflammatory pain, which contains the compounds disclosed in this specification or their pharmaceutically acceptable salts, solvates or prodrugs.

[0286] In one aspect, the compounds utilized in the present disclosure can be exemplified by the compounds represented by the following formula or their pharmaceutically acceptable salts, solvates or prodrugs,

[0287] [Chemical Formula 4]

[0288]

[0289] In the formula,

[0290] R1, R2, R5, R6, R7, R8, R9 and R 10 are each independently:

[0291] a hydrogen atom, or

[0292] an optionally substituted hydrocarbon group, or,

[0293] R7 and R8 together with the carbon atom and 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,

[0294] R3 and R4 are each independently:

[0295] a hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group,

[0296] Optionally substituted alkoxycarbonyl, or

[0297] Optionally substituted alkoxycarbonyloxy,

[0298] R 11 、R 12 、R 13 and R 14 are each independently:

[0299] A hydrogen atom, optionally substituted hydrocarbon group, hydroxy group,

[0300] Optionally substituted alkoxy, or

[0301] Optionally substituted alkoxycarbonyloxy,

[0302] X is:

[0303] CH2 or CO,

[0304] A is O, NH or S, where NH may be optionally substituted.

[0305] In one embodiment, R1, R2, R5, R6, R7, R8, R9 and R 10 are each independently:

[0306] A hydrogen atom, or

[0307] Optionally substituted hydrocarbon group, or,

[0308] R7 and R8 together with the carbon atom and nitrogen atom to which they are bonded form an optionally substituted heterocycloalkyl group,

[0309] R3 and R4 are each independently:

[0310] A hydrogen atom, optionally substituted hydrocarbon group, carboxyl group,

[0311] Optionally substituted alkoxycarbonyl, or

[0312] Optionally substituted alkoxycarbonyloxy,

[0313] R 11 、R 12 、R 13 and R 14 are each independently:

[0314] A hydrogen atom, hydroxy group,

[0315] Optionally substituted alkoxy, or

[0316] Optionally substituted alkoxycarbonyloxy,

[0317] X is:

[0318] CH2 or CO,

[0319] A is O, NH or S, where NH may be optionally substituted.

[0320] In one embodiment, R1, R2, R5, R6, R7, R8, R9 and R 10 are each independently:

[0321] a hydrogen atom, or

[0322] an optionally substituted alkyl group, or,

[0323] R7 and R8 together with the carbon and nitrogen atoms to which they are bonded form an optionally substituted heterocycloalkyl group,

[0324] R3 and R4 are each independently:

[0325] a hydrogen atom, an optionally substituted alkyl group, a carboxyl group,

[0326] an optionally substituted alkoxycarbonyl group, or

[0327] an optionally substituted alkoxycarbonyloxy group,

[0328] R 11 、R 12 、R 13 and R 14 are each independently:

[0329] a hydrogen atom, a hydroxyl group,

[0330] an optionally substituted alkoxy group, or

[0331] an optionally substituted alkoxycarbonyloxy group,

[0332] X is CH2 or CO,

[0333] A is O, NH or S, where NH may be optionally substituted.

[0334] In one embodiment, R1, R2, R5, R6, R7, R8, R9 and R 10 are each independently:

[0335] a hydrogen atom, or

[0336] an alkyl group substituted with 1 to the maximum number of substituents selected from hydrogen, alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxyl, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxyl, amino, guanidino, guanidino substituted with alkoxycarbonyl, carbamoyl and heterocycloalkyl, or,

[0337] R7 and R8 together with the carbon and nitrogen atoms to which they are bonded form a heterocycloalkyl group,

[0338] R3 and R4 are each independently:

[0339] a hydrogen atom,

[0340] an alkyl group, a carboxyl group, or an alkoxycarbonyl group substituted with one to the maximum number of substituents selected from hydrogen, alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxyl, amino, guanidino, guanidino substituted with alkoxycarbonyl, carbamoyl, and heterocycloalkyl,

[0341] an alkoxycarbonyl group substituted with one to the maximum number of substituents selected from alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxyl, amino, guanidino, guanidino substituted with alkoxycarbonyl, carbamoyl, and heterocycloalkyl,

[0342] R 11 、R 12 、R 13 and R 14 are each independently:

[0343] a hydrogen atom, a hydroxy group, or

[0344] an alkoxy group substituted with one to the maximum number of substituents selected from alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, and heterocycloalkyl,

[0345] X is CH2 or CO,

[0346] A is O, NH, or S, where NH may be substituted with one to the maximum number of substituents selected from alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, cycloalkyl, carboxyl, and heterocycloalkyl.

[0347] In one embodiment, R1 and R2 are each independently: a hydrogen atom or C 1-6 alkyl, R3 and R4 are each independently: a hydrogen atom, C 1-6 alkyl substituted with a carboxyl group, or a carboxyl group, 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, hydroxy C 1-6 alkyl, carbamoyl C 1-6 alkyl, C 6-10 aryl C 1-6 alkyl, hydroxy C 6-10 aryl C 1-6Alkyl, 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, where R8 is a hydrogen atom or C 1-6 Alkyl, where R7 and R8 can together with the carbon and nitrogen atoms to which R7 and R8 are bonded form an optionally substituted heterocycloalkyl, R9 and R 10 are a hydrogen atom or C 1-6 Alkyl, R 11 , R 12 , R 13 and R 14 are each independently: a hydrogen atom, an alkoxy group or a hydroxyl group, X is CH2 or CO, and A is O, NH substituted by C 1-6 alkyl, NH, NH or S.

[0348] 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, carboxymethyl, carboxyethyl, carboxypropyl or carboxyl, 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, an aminoethyl group, a 4-aminobutyl group, a thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinoaminopropyl group, an indolylmethyl group or a 4-imidazolylmethyl group, R8 is a hydrogen atom, where R7 and R8 can together with the carbon and nitrogen atoms to which R7 and R8 are bonded form a C 5-10 heterocycloalkyl, R9 and R 10 are 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.

[0349] In one embodiment, R1 and R2 are each independently a hydrogen atom or C 1-6 alkyl.

[0350] In one embodiment, R1 and R2 are each independently a hydrogen atom, a methyl group or an ethyl group.

[0351] In one embodiment, R3 and R4 are each independently a hydrogen atom, C 1-6 alkyl substituted by carboxyl or carboxyl.

[0352] In one embodiment, R3 and R4 are each independently a hydrogen atom, carboxymethyl, carboxyethyl, carboxypropyl or carboxyl.

[0353] In one embodiment, R5 is a hydrogen atom or C 1-6 alkyl.

[0354] In one embodiment, R5 is a hydrogen atom.

[0355] In one embodiment, R6 is a hydrogen atom or C 1-6 alkyl.

[0356] In one embodiment, R6 is a hydrogen atom.

[0357] In one embodiment, R7 is a hydrogen atom, C 1-6 alkyl, hydroxy C 1-6 alkyl, carbamoyl C 1-6 alkyl, C 6-10 aryl C 1-6 alkyl, hydroxy C 6-10 aryl C 1-6 alkyl, C 5-10 heteroaryl C 1-6 alkyl, carboxy 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.

[0358] In one embodiment, R7 is a hydrogen atom, methyl, isopropyl, isobutyl, sec-butyl, benzyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, carboxyethyl, 4-hydroxybenzyl, aminoethyl, 4-aminobutyl, thiomethyl, 2-methylthioethyl, carbamoylmethyl, carbamoylethyl, amidinoaminopropyl, indolylmethyl or 4-imidazolylmethyl.

[0359] In one embodiment, R8 is a hydrogen atom or C 1-6 alkyl.

[0360] In one embodiment, R8 is a hydrogen atom.

[0361] In one embodiment, R7 and R8 together with the carbon atom and nitrogen atom to which R7 and R8 are attached form an optionally substituted heterocycloalkyl.

[0362] In one embodiment, R7 and R8 together with the carbon atom and nitrogen atom to which R7 and R8 are attached form C 5-10 heterocycloalkyl.

[0363] In one embodiment, R9 and R 10is a hydrogen atom or C 1-6 alkyl group.

[0364] In one embodiment, R9 and R 10 are each independently a hydrogen atom or a methyl group.

[0365] In one embodiment, R 11 , R 12 , R 13 and R 14 are each independently a hydrogen atom, an alkoxy group or a hydroxyl group.

[0366] In one embodiment, R 12 is a hydrogen atom, a methoxy group or a hydroxyl group.

[0367] In one embodiment, R 11 , R 12 , R 13 and R 14 are each independently a hydrogen atom, a methoxy group or a hydroxyl group.

[0368] In one embodiment, X is CH2.

[0369] In one embodiment, A is O, NH substituted with C 1-6 alkyl group, NH or S.

[0370] In one embodiment, A is O, NH or S.

[0371] 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 isopropyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or a methyl group, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, X is CH2, and A is O.

[0372] 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 are a hydrogen atom or a methyl group, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, X is CH2, and A is O.

[0373] In one embodiment, R1 and R2 are hydrogen atoms, 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 10is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, X is CH2, and A is O.

[0374] 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 are hydrogen atoms or methyl groups, R 11 、R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, X is CH2, and A is O.

[0375] In one embodiment, R1 and R2 are hydrogen atoms, 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 are hydrogen atoms or methyl groups, R 11 、R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, X is CH2, and A is O.

[0376] In one embodiment, R1 and R2 are methyl or 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 are hydrogen atoms, R 11 、R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, X is CH2, and A is O.

[0377] In one embodiment, R1 and R2 are hydrogen atoms, 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 are hydrogen atoms, R 11 、R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, X is CH2, and A is O.

[0378] In one embodiment, R1 and R2 are hydrogen atoms, 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 are hydrogen atoms, R 11 、R 13 and R 14 are hydrogen atoms, R12 is a hydroxyl group, X is CH2, and A is O.

[0379] 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 isopropyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, X is CH2, and A is O.

[0380] 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 are a hydrogen atom or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, X is CH2, and A is O.

[0381] In one embodiment, R1 and R2 are hydrogen atoms, 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 are a hydrogen atom or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, X is CH2, and A is O.

[0382] In one embodiment, R1 and R2 are hydrogen atoms or methyl, 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 are a hydrogen atom or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, X is CH2, and A is O.

[0383] 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 are hydrogen atoms, X is CH2, and A is O.

[0384] 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 isopropyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or methyl, R 11 、R 12 、R 13 and R 14 are hydrogen atoms, X is CH2, and A is O.

[0385] 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 isopropyl, R8 is a hydrogen atom, R9 and R 10 are hydrogen atoms, R 11 、R 13 and R 14 are hydrogen atoms, R 12 is hydroxyl, X is CH2, and A is O.

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

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

[0389] In one embodiment, R1 and R2 are methyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is isopropyl, R8 is a hydrogen atom, R9 and R 10 are hydrogen atoms, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, 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 isopropyl, R8 is a hydrogen atom, R9 and R 10 is methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, 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 benzyl, R8 is a hydrogen atom, R9 and R 10 are hydrogen atoms or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, 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 carboxyethyl, R8 is a hydrogen atom, R9 and R 10 are hydrogen atoms or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, 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 carboxymethyl, R8 is a hydrogen atom, R9 and R 10 are hydrogen atoms or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, 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 hydroxymethyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, 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 1-hydroxyethyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, 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 4-hydroxybenzyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, 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 4-aminobutyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, 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 amidinoaminopropyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or methyl, R 11 , R 13 and R 14 are hydrogen atoms, R 12 is a hydroxyl group, 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 carbamoylethyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or methyl, R 11 、R 13 and R 14 are 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 carbamoylmethyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or methyl, R 11 、R 13 and R 14 are 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 is 4-imidazolylmethyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or methyl, R 11 、R 13 and R 14 are 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 indolylmethyl, R8 is a hydrogen atom, R9 and R 10 are a hydrogen atom or methyl, R 11 、R 13 and R 14 are a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0403] 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 are a hydrogen atom or methyl, R 11 、R 13 and R 14 are a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0404] 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 isopropyl, R8 is a hydrogen atom, R9 and R 10 are hydrogen atoms, R 11 、R 13 and R 14 are hydrogen atoms, R 12 is methoxy, X is CH2, and A is O.

[0405] In one embodiment, R1 and R2 are ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is isopropyl, R8 is a hydrogen atom, R9 and R 10 are hydrogen atoms, R 11 、R 13 and R 14 are hydrogen atoms, R 12 is hydroxy, X is CH2, and A is O.

[0406] In one embodiment, X in the above embodiment is CO.

[0407] In one embodiment, A in the above embodiment is NH.

[0408] In one embodiment, A in the above embodiment is S.

[0409] In another aspect, a composition for treating or preventing at least one selected from neuropathic pain and inflammatory pain, which comprises: a compound used in the present disclosure is a compound represented by the following formula or a pharmaceutically acceptable salt, solvate or prodrug thereof,

[0410] [Chemical Formula 5]

[0411]

[0412] In the formula, m is 0 to 3, n≥1, R A1 ~R A4 、R A7 ~R A11 、R A312 and R A112 are each independently a hydrogen atom or a hydrocarbon group, R A14 and R A212 are each independently hydrogen, carboxyl or its salt, or alkoxycarbonyl, R A5 is a hydrocarbon group, hydroxy, alkoxy or alkylcarbonyloxy, R A55 and R A66 are each independently a hydrogen atom, a hydrocarbon group or alkylcarbonyloxy.

[0413] As the cyclic peptide derivative described above, in the aforementioned general formula (1), it is preferable that R1, R2, R3 and R4 are each independently an alkyl group, n = 2 to 4, R5 and R6 are hydrogen atoms, and R7 and R8 are carboxyl groups, etc.

[0414] The present disclosure may be a compound having a substituent represented by any of the following.

[0415] [Chemical Formula 6]

[0416]

[0417] [Table A1-1]

[0418]

[0419] [Table A1-2]

[0420]

[0421] It should be noted that the indolylmethyl group at 19 in the above table independently represents 2-indolylmethyl or 3-indolylmethyl in each case.

[0422] [Table A1-3]

[0423]

[0424] [Table A1-4]

[0425]

[0426] [Table A1-5]

[0427]

[0428] [Table A1-6]

[0429]

[0430] [Table A1-7]

[0431]

[0432] [Table A1-8]

[0433]

[0434] [Table A1-9]

[0435]

[0436] [Table A1-10]

[0437]

[0438] [Table A1-11]

[0439]

[0440] [Table A1-12]

[0441]

[0442] [Table A1-13]

[0443]

[0444] [Table A1-14]

[0445]

[0446] [Table A1-15]

[0447]

[0448] [Table A1-16]

[0449]

[0450] [Table A1-17]

[0451]

[0452] [Table A1-18]

[0453]

[0454] [Table A1-19]

[0455]

[0456] Among them, the numbers of each X, A, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 are the corresponding substituents shown in the above-defined table.

[0457] The present disclosure may be a compound of any combination of the substituents shown in the above-defined table. In one embodiment, the compounds disclosed in this specification are shown in the following table.

[0458] [Table A2-1]

[0459]

[0460] [Table A2-2]

[0461]

[0462] [Table A2-3]

[0463]

[0464] [Table A2-4]

[0465]

[0466] [Table A2-5]

[0467]

[0468] [Table A2-6]

[0469]

[0470] [Table A2-7]

[0471]

[0472] In addition, the following can be exemplified as the compounds of the present disclosure.

[0473] [Table A2-8]

[0474]

[0475] [Table A2-9]

[0476]

[0477] [Table A2-10]

[0478]

[0479] The composition of the present disclosure preferably contains a cyclic peptide derivative or a salt thereof as an active ingredient.

[0480] In addition, the composition of the present disclosure preferably treats or prevents neuropathic pain and / or inflammatory pain. Therefore, the present disclosure can improve neuropathic pain and / or inflammatory pain.

[0481] Without wishing to be bound by theory, in the present disclosure, a significant decrease in the 50% withdrawal threshold was observed in the von Frey test, and thus it is understood to be effective against any neuropathic pain directly or indirectly related thereto. In addition, without wishing to be bound by theory, in the present disclosure, a significant improvement in the pain threshold based on the Randall-Selitto method was observed, and thus it is understood to be effective against any inflammatory pain directly or indirectly related thereto. In addition, according to the content of the present disclosure, it is considered that the compounds, drugs or compositions of the present disclosure are effective against diseases or abnormalities related to neuropathic pain and / or inflammatory pain.

[0482] (Drug, treatment method, etc.)

[0483] General description

[0484] In one embodiment, the compounds of the present disclosure can be administered directly by oral administration or non-oral administration or formulated into preparations, drugs or pharmaceutical compositions using appropriate dosage forms. Specific examples of these dosage forms include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, cataplasms, etc. In addition, these preparations can be manufactured by known methods using additives commonly used as pharmaceutical additives.

[0485] As these additives, excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, cosolvents, thickeners, dispersants, stabilizers, sweeteners, flavors, etc. can be used according to the purpose. Specific examples of these additives include, but are not limited to, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc.

[0486] In one embodiment, the compounds of the present disclosure are compounds that can treat or prevent at least one selected from neuropathic pain and inflammatory pain.

[0487] In one embodiment, the compounds of the present disclosure are compounds that can treat or prevent neuropathic pain.

[0488] In one embodiment, the compounds of the present disclosure are compounds that can treat or prevent inflammatory pain.

[0489] In one embodiment, the compounds of the present disclosure are compounds that can treat or prevent neuropathic pain and inflammatory pain.

[0490] In an exemplary embodiment, examples of the patients targeted by the present disclosure are patients having or expected to develop the above-mentioned neuropathic pain and / or inflammatory pain.

[0491] In an exemplary embodiment, the compounds of the present disclosure have an improving effect on neuropathic pain and / or inflammatory pain. Therefore, the compounds of the present disclosure prevent, improve or treat neuropathic pain and / or inflammatory pain.

[0492] The administration period of the compounds of the present disclosure and their therapeutic agents is not limited. They can be administered to the subject to whom they are to be administered simultaneously or with a time difference. In addition, they can be formulated into a combined preparation of the compounds of the present disclosure and their therapeutic agents. The dosage of these therapeutic agents can be appropriately selected based on the dosages used clinically. In addition, the mixing ratio of the compounds of the present disclosure and their therapeutic agents can be appropriately selected according to the subject to be administered, the administration route, the target disease, the disorder, the symptom, the combination, etc.

[0493] In one embodiment of the present disclosure, when using a pharmaceutical composition, the compounds of the present disclosure can be administered in combination, either simultaneously or not simultaneously. Such pharmaceutical compositions are also within the scope of the present disclosure.

[0494] Such drugs, preparations, and pharmaceutical compositions can be manufactured by using any technique known in the art to mix the compounds of the present disclosure and / or additional agents (e.g., antibacterial drugs, antiviral agents (e.g., ribavirin, amantadine, etc.), sedatives (e.g., ketamine, midazolam, etc.), etc.) together or alone in the form of a combined preparation or in the form of a single agent with any suitable components, and can be formulated into suitable preparations by using any technique known in the art, such as tablets, capsules, powders, granules, solutions, suspensions, injections, patches, cataplasms. When the compounds of the present disclosure and / or additional agents (e.g., antibacterial drugs, antiviral agents (e.g., ribavirin, amantadine, etc.), sedatives (e.g., ketamine, midazolam, etc.), etc.) are prepared in the form of a single agent, they can be provided in the form of a kit of two agents or in the form of a single dose of one component, and provided together with an instruction manual (package insert, etc.), which instructs to administer in combination, either simultaneously or not simultaneously, with another component (in the case of the compounds of the present disclosure, it is an additional agent, and in the case of an additional agent (e.g., antibacterial drugs, antiviral agents (e.g., ribavirin, amantadine, etc.), sedatives (e.g., ketamine, midazolam, etc.), etc.), it is the compounds of the present disclosure).

[0495] In a specific embodiment, the co - administration of the compounds of the present disclosure with one or more additional therapeutic agents (multiple possible) (e.g., one or more additional chemotherapeutic agents (multiple possible)) provides improved efficacy compared to the individual administration of the compounds of the present disclosure (e.g., the compounds of formula (1), (A2) or (2)) or one or more additional therapeutic agents (multiple possible). In certain such embodiments, the co - administration provides an additive effect, and these additive effects refer to the respective addition of the effects of the individual administrations of the compounds of the present disclosure and one or more additional therapeutic agents (multiple possible).

[0496] For use in the methods of the present disclosure, the active compound itself may be provided, or it may be provided as a pharmaceutical composition which comprises, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient and a pharmaceutically acceptable carrier.

[0497] The dosage of the compounds of the present disclosure is appropriately selected according to the animal to be administered, the administration route, the disease, the age, weight and symptoms of the patient. For example, in the case of oral administration, for an adult, 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 several divided doses.

[0498] There is no limitation on the administration period of the compounds of the present disclosure and their therapeutic agents. They can be administered to the subject to whom they are to be administered simultaneously or with a time difference. In addition, they can be formulated as a combined preparation of the compounds of the present disclosure and their therapeutic agents. The dosage of these therapeutic agents can be appropriately selected based on the dosages used clinically. In addition, the mixing ratio of the compounds of the present disclosure and their therapeutic agents can be appropriately selected according to the subject to be administered, the administration route, the target disease, disorder or symptom, the age or weight of the subject, or a combination thereof, etc.

[0499] In one embodiment of the present disclosure, when using a pharmaceutical composition, the compounds of the present disclosure can be administered in combination, either simultaneously or non-simultaneously. Such pharmaceutical compositions are also within the scope of the present disclosure.

[0500] When using the compounds of the present disclosure as the active ingredient of a drug, it is not intended for use only in humans, and it can also be used in other animals (cats, dogs, cows, horses, bats, foxes, mongooses, raccoons, etc.) other than humans.

[0501] (Prevention or treatment method)

[0502] In addition, the present disclosure also provides a method for preventing or treating neuropathic pain and / or inflammatory pain, which comprises the step of administering to a subject in need of such prevention or treatment the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In one embodiment, the method for preventing or treating neuropathic pain and / or inflammatory pain comprises the step of administering to a subject in need of such prevention or treatment a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or their solvates, or a pharmaceutical composition comprising the same.

[0503] (Use for prevention or treatment)

[0504] In one embodiment of the present disclosure, there is provided the use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a drug for preventing or treating neuropathic pain and / or inflammatory pain.

[0505] In addition, the present disclosure also provides the compounds of the present disclosure or their pharmaceutically acceptable salts for the prevention or treatment of neuropathic pain and / or inflammatory pain.

[0506] (Synthesis Example)

[0507] For example, the present disclosure can be obtained by the coupling reaction of four compound fragments (A, B, C, and D), but is not limited thereto. The compounds used can be commercially available products or synthetic products.

[0508] The coupling reaction generally refers to all methods that can be used in organic synthetic chemistry, and examples thereof include cyclization reactions, addition reactions, ring-opening addition reactions, dehydration condensation reactions, etc. In addition, in addition to the coupling reaction, protection reactions, deprotection reactions, oxidation reactions, reduction reactions, hydrogenation reactions, etc. can also be used. The reaction conditions such as the reaction temperature and reaction time can be appropriately set.

[0509] In each reaction, the functional groups contained in the compounds used can be protected by protecting groups or the like.

[0510] The order of the reactions is not particularly limited. The cyclization reaction can be carried out after the four compounds are coupled, or the cyclization reaction can be carried out at the stage where three compounds are coupled, and the resulting cyclized compound is coupled with the fourth compound.

[0511] The compounds used in each reaction can be purified products or the reaction products of the previous stage can be used directly.

[0512] 1. Method for manufacturing cyclic peptide derivatives

[0513] In the method for manufacturing the cyclic peptide derivatives of the present disclosure, the cyclic peptide derivatives represented by the following general formula (2) are manufactured.

[0514] [Chemical Formula 7]

[0515]

[0516] Here, in formula (2),

[0517] R A1 represents a hydrogen atom or a hydrocarbon group,

[0518] R A2 represents a hydrogen atom or a hydrocarbon group,

[0519] R A3 represents a hydrogen atom or a hydrocarbon group,

[0520] R A4 represents a hydrogen atom or a hydrocarbon group,

[0521] R A5 represents -O-R A51 (RA51 represents a hydrogen atom or a protecting group),

[0522] R A61 represents -O-R A6 (R A6 represents a hydrogen atom, a hydrocarbon group or a protecting group),

[0523] R A7 represents a hydrogen atom, a hydrocarbon group or a protecting group,

[0524] R A8 represents a hydrogen atom, a hydrocarbon group or a protecting group,

[0525] R A9 represents a hydrogen atom, a hydrocarbon group or a protecting group,

[0526] R A10 represents a hydrogen atom, a hydrocarbon group or a protecting group,

[0527] R A11 represents a hydrogen atom, a hydrocarbon group or a protecting group,

[0528] R A12 represents a hydrogen atom or a protecting group,

[0529] R A14 represents -(CH2) n -H or -(CH2) n -COOR A13 (R A13 represents a hydrogen atom or a protecting group, and n is a number of 1 or more),

[0530] wherein at least one of R A51 , R A6 , R A12 and R A13 is other than a hydrogen atom,

[0531] and m is 1.

[0532] In particular, the production method of the present disclosure includes a step of subjecting a product obtained by an oxidation reaction of a compound represented by the following general formula (2’) to a condensation reaction with a compound having both a carboxyl group and an amino group, or a salt or ester of the compound (hereinafter, this step will be abbreviated as “step A” in this specification).

[0533] [Chemical formula 8]

[0534]

[0535] Here, in formula (2’), R A1 , R A2 , R A3 , R A4 , R A5 , RA61 , R A7 , R A8 , R A9 , R A10 and m respectively have the same meanings as R A1 , R A2 , R A3 , R A4 , R A5 , R A61 , R A7 , R A8 , R A9 , R A10 and m in formula (2’). In particular, R A1 , R A2 , R A3 , R A4 , R A5 , R A61 , R A7 , R A8 , R A9 , R A10 and m respectively have the same meanings as R A1 , R A2 , R A3 , R A4 , R A5 , R A61 , R A7 , R A8 , R A9 , R A10 and m in formula (2).

[0536] In the present disclosure, the hydrocarbon group can be any of an alkyl group, an alkenyl group, and an alkynyl group. The number of carbon atoms of the hydrocarbon group is not particularly limited, for example, it is 1 to 10, preferably 1 to 5, more preferably 1 to 4, and particularly preferably 1 to 3. Specifically, examples of the hydrocarbon group include a methyl group, an ethyl group, a vinyl group, an ethynyl group, a propyl group, an isopropyl group, a propenyl group, etc. The hydrocarbon group can be linear or branched.

[0537] In the present disclosure, examples of the protecting group include: an aromatic group other than the aforementioned hydrocarbon group; a heterocyclic group; an oxygen-containing functional group having an alkoxyalkyl group, a carbonyl group, an ester, etc.; a group having a silicon atom such as a silyl group, etc.

[0538] When the protecting group is an aromatic group, examples include a phenyl group, a benzyl group, an oxybenzyl group (-O-CH2-Ph), a 2-nitrobenzenesulfonyl group (Nosyl group), etc. When the protecting group is an oxygen-containing functional group, examples include a tert-butoxycarbonyl group (Boc group). When the protecting group is a group having a silicon atom, examples include a tert-butyldimethylsilyl group (-Si(t-Bu)(CH3)2), a tert-butyldiphenylsilyl group (-Si(t-Bu)Ph2), etc.

[0539] In formulas (2) and (2’), when R A1 is a hydrocarbon group, it is preferably an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0540] In formulas (2) and (2’), when R A1 is a hydrocarbon group, it is preferably an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms or an alkynyl group having 2 to 5 carbon atoms, still more preferably a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms or an alkynyl group having 2 to 3 carbon atoms, and particularly preferably an ethynyl group (-C≡C). In particular, in formula (2), when R A2 is an ethynyl group, since the steric hindrance is smaller than that of an ethyl group or the like, the subsequent condensation reaction can be easily carried out.

[0541] In formulas (2) and (2’), when R A3 is a hydrocarbon group, it is preferably an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0542] In formulas (2) and (2’), when R A4 is a hydrocarbon group, it is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0543] In formulas (2) and (2’), it is preferred that R A5 is -O-R A51 (R A51 represents a hydrogen atom or a protecting group), R A51 is a protecting group, and among them, it is more preferably an aromatic group, and particularly preferably an oxybenzyl group (-O-CH2-Ph).

[0544] In formulas (2) and (2’), it is preferred that R A61 is -O-R A6 (R A6 represents a hydrogen atom, a hydrocarbon group or a protecting group), R A6 is a hydrocarbon group or a protecting group, R A6 is preferably an allyl group when it is a hydrocarbon group, and examples of the protecting group include tert-butyldimethylsilyl (-Si(t-Bu)(CH3)2), tert-butyldiphenylsilyl (-Si(t-Bu)Ph2), benzyl, methoxymethyl (MOM), etc. R A6 is preferably tert-butyldimethylsilyl.

[0545] In formulas (2) and (2’), when R A7Preferably a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a hydrogen atom.

[0546] In formulas (2) and (2’), R A8 Preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a hydrogen atom.

[0547] In formulas (2) and (2’), R A9 Preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0548] In formulas (2) and (2’), R A10 Preferably the aforementioned protecting group, and particularly preferably 2-nitrobenzenesulfonyl group (Nosyl group).

[0549] In formula (2), R A11 Preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a hydrogen atom.

[0550] In formula (2), R A12 Preferably a protecting group, still more preferably an aromatic group, and particularly preferably a benzyl group.

[0551] In formula (2), R A14 Preferably -(CH2) n -H or -(CH2) n -COOR A13 (n is 1 to 4), more preferably -(CH2)2-COOR A13 . R A13 Preferably a protecting group, still more preferably an aromatic group, and particularly preferably a benzyl group.

[0552] In formulas (2) and formula (2’), the bonding position of R A5 is not particularly limited. For example, it can be set as the bonding position shown in the following formula (2”).

[0553] [Chemical formula 9]

[0554]

[0555] Here, in formula (2”), R A1 ~R A5 , R A7 ~R A12 and R A14R as defined in the aforementioned formula (2) A1 ~R A5 、R A7 ~R A12 and R A14 have the same meanings, and R A61 has the same meaning as R in the aforementioned formula (2). A61

[0556] Step A includes an oxidation reaction of the compound represented by formula (2'). Specifically, this oxidation reaction is a reaction for oxidizing an alcohol to a carboxylic acid. Thereby, the hydroxyl group indicated by the arrow in the compound represented by formula (2') is converted to a carboxyl group.

[0557] In Step A, the type of the oxidation reaction is not particularly limited. For example, a publicly known oxidation reaction of an alcohol compound can be widely employed. The oxidation reaction can be, for example, a two-step reaction of oxidizing an alcohol to an aldehyde and then oxidizing the aldehyde to a carboxylic acid. When the oxidation reaction is carried out in two steps in this way, it is easy to prevent an oxidation reaction of an undesired functional group.

[0558] In Step A, the aforementioned oxidation reaction preferably includes Dess-Martin oxidation and Pinnick oxidation. Thereby, racemization is easily suppressed, and in addition, oxidation easily occurs under mild reaction conditions. For example, through Dess-Martin oxidation, the aforementioned hydroxyl group is oxidized to an aldehyde, and then the aldehyde is oxidized to a carboxylic acid through Pinnick oxidation.

[0559] In Step A, when carrying out the aforementioned oxidation reaction, it is preferable to use 1 to 5 moles of an oxidizing agent relative to 1 mole of the compound represented by formula (2'). The type of the oxidizing agent is not particularly limited, and publicly known oxidizing agents used in oxidation reactions can be widely used.

[0560] In Dess-Martin oxidation, it is preferable to use 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (DMP) as the oxidizing agent. In the case of Dess-Martin oxidation, relative to 1 mole of the compound represented by formula (2'), the oxidizing agent is preferably used in an amount of 1 to 5 moles, more preferably 1 to 3 moles.

[0561] In Pinnick oxidation, it is preferable to use sodium chlorite (NaClO2) as the oxidizing agent. In the case of Pinnick oxidation, relative to 1 mole of the compound represented by formula (2'), the oxidizing agent is preferably used in an amount of 1 to 5 moles, more preferably 2 to 5 moles.

[0562] Other oxidizing agents can also be used in the aforementioned oxidation reaction. For example, an oxidizing agent composed of a combination of a nitroxide radical type such as 2,2,6,6-tetramethylpiperidine 1-oxy and iodosobenzene diacetate can be exemplified.​

[0563] In Step A, a solvent can be used as needed in the aforementioned oxidation reaction. As the solvent in the oxidation reaction, for example, chlorine-containing compounds such as dichloromethane and dichloroethane, acetonitrile, and tert-butanol can be used.

[0564] In Step A, the reaction temperature of the aforementioned oxidation reaction is not particularly limited. For example, it can be carried out at -20 to 60 °C, preferably at 0 to 30 °C.

[0565] In Step A, after the aforementioned oxidation reaction, the product (carboxylic acid compound) obtained in the oxidation reaction is subjected to a condensation reaction with a compound having both a carboxyl group and an amino group, or a salt or ester of the compound. Hereinafter, the compound having both a carboxyl group and an amino group or a salt or ester of the compound will be simply referred to as "Compound C".

[0566] In Compound C, the compound having both a carboxyl group and an amino group is not particularly limited, and examples thereof include amino acids, and among them, glutamic acid or aspartic acid is preferred.

[0567] In particular, in Step A, it is preferred to subject the product (carboxylic acid compound) obtained in the aforementioned oxidation reaction to a condensation reaction with a glutamate ester or an aspartate ester. By using a glutamate ester in the condensation reaction, in the resulting cyclic peptide derivative, that is, the cyclic peptide derivative represented by the general formula (2), R in the formula (2) A14 is -(CH2)2-COOR A13 . When an aspartate ester is used in the condensation reaction, in the resulting cyclic peptide derivative, that is, the cyclic peptide derivative represented by the general formula (2), R in the formula (2) A14 is -(CH2)-COOR A13 . In any case, as R A13 , a protecting group is preferably used, more preferably an aromatic group, and particularly preferably a benzyl group.

[0568] In the condensation reaction of Step A, the usage amount of Compound C is preferably 1 to 5 moles, more preferably 2 to 5 moles, and further preferably 3 to 4 moles relative to 1 mole of the carboxylic acid compound obtained in the oxidation reaction.

[0569] For example, in Step A, when the product (carboxylic acid compound) obtained in the aforementioned oxidation reaction is subjected to a condensation reaction with a glutamate ester, the resulting cyclic peptide derivative represented by the formula (2) is represented by the following general formula (2A).

[0570] [Chemical formula 10]

[0571]

[0572] Here, in the formula (2A), R A1 ~R A5 , R A61, R A7 ~R A13 and m have the same meanings as R A1 ~R A5 , R A61 , R A7 ~R A13 in formula (2) above.

[0573] In step A, the method of the condensation reaction is not particularly limited. For example, the conditions of the well-known condensation reaction can be widely adopted. From the viewpoints of easily suppressing racemization and easily promoting oxidation under mild reaction conditions, a condensing agent can also be used in the condensation reaction.

[0574] The type of the condensing agent is not particularly limited. For example, well-known condensing agents can be widely used. In particular, in the condensation reaction of step A, a phosphorus-based condensing agent is preferably used as the condensing agent. Examples of such a condensing agent include 3-(diethoxyphosphoryloxy)-3H-benzo[d][1,2,3]triazin-4-one (DEPBT), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate, N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]urea hexafluorophosphate, etc. The phosphorus-based condensing agent is preferably a phosphoric azide compound, and particularly preferably DEPBT.

[0575] When using a condensing agent, its usage amount is not particularly limited. For example, relative to 1 mole of the carboxylic acid compound obtained in the oxidation reaction, the usage amount of the condensing agent is preferably 1 to 3 moles, more preferably 1.2 to 2.5 moles.

[0576] A solvent can be used as needed in the condensation reaction of step A. The solvent is not particularly limited, and examples thereof include aliphatic hydrocarbons such as hexane and heptane; alicyclic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; chlorinated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; alcohols such as methanol, ethanol, isopropanol, and tert-butanol; amide solvents such as N,N-dimethylacrylamide, etc.

[0577] The condensation reaction can be carried out in the presence of a base catalyst such as diisopropylethylamine and dimethylaminopyridine.

[0578] In step A, the reaction temperature of the aforementioned condensation reaction is not particularly limited. For example, it can be carried out at -20 to 60 °C, preferably at 0 to 30 °C.

[0579] In Step A, by performing an oxidation reaction and a subsequent condensation reaction, a cyclic peptide derivative represented by formula (2) can be produced in a high yield. Conventionally, a method for stereoselectively reacting a cyclic peptide derivative, which is obtained by condensing and linking a macrocyclic lactam structure containing non-natural amino acid-derived structures such as a β-hydroxydopa unit and a β-hydroxyisoleucine unit with an amino acid derivative such as a glutamate derivative, has not been known. In contrast, in the present disclosure, by adopting Step A using a compound represented by formula (2’), a cyclic peptide derivative represented by formula (2) can be achieved. Therefore, the cyclic peptide derivative represented by formula (2) has a structure containing a β-hydroxydopa unit and a β-hydroxyisoleucine unit.

[0580] Generally, it is known that in biosynthesis, a cyclic peptide derivative is produced by cyclizing after binding all peptides. In contrast, in the method for producing a cyclic peptide derivative of the present disclosure, a compound C (for example, a glutamate ester) is bound to a compound having a cyclized structure. That is, in the method for producing a cyclic peptide derivative of the present disclosure, the compound C is finally bound, and thus has the advantage that cyclic peptide derivatives bound with various amino acids and the like can be obtained depending on the type of the compound C. In addition, a route of pre-constructing a ring structure and then introducing a side chain (compound C) as in the present disclosure also has the advantages that steps involved in removing protecting groups can be simplified and the target product can be provided in a high yield.

[0581] 2. Method for producing a cyclic peptide compound

[0582] The method for producing a cyclic peptide compound of the present disclosure includes a step of obtaining a cyclic peptide compound by subjecting the cyclic peptide derivative obtained by the method for producing the cyclic peptide derivative described above to a hydrogenation reduction reaction. That is, the method for producing a cyclic peptide compound of the present disclosure includes a step of performing a hydrogenation reduction reaction after the condensation reaction in Step A in the method for producing the cyclic peptide derivative.

[0583] In the method for producing a cyclic peptide compound, the method of the hydrogenation reduction reaction is not particularly limited. For example, well-known hydrogenation reduction reaction conditions can be widely adopted. For example, the hydrogenation reduction reaction can be carried out using hydrogen in the presence of a catalyst. As the catalyst, for example, well-known catalysts used in the hydrogenation reduction reaction can be used, and specifically, palladium on carbon can be mentioned. A solvent can also be used as needed in the hydrogenation reduction reaction. As the solvent, lower alcohols such as methanol and ethanol can be mentioned.

[0584] In the condensation reaction of Step A, when the cyclic peptide derivative represented by Formula (2) has a protecting group such as, for example, tert-butoxycarbonyl (Boc group), tert-butyldimethylsilyl (TBS group), 2-nitrobenzenesulfonyl (Nosyl group), etc., the protecting group can also be deprotected in advance and then the hydrogenation reduction reaction can be carried out. The method of deprotection is not particularly limited. For example, publicly known deprotection methods can be widely adopted. For example, the deprotection of the TBS group and the deprotection of the Nosyl group can be carried out in sequence.

[0585] When the cyclic peptide derivative represented by Formula (2) has an alkynyl group (for example, R in Formula (2) A2 ), the alkynyl group can be converted into an alkyl group by the aforementioned hydrogenation reduction reaction. For example, when there is an ethynyl group in the cyclic peptide derivative represented by Formula (2), it can be converted into an ethyl group by the aforementioned hydrogenation reduction reaction.

[0586] In one mode of the method for producing the cyclic peptide compound of the present disclosure, for example, the cyclic peptide derivative represented by Formula (2) obtained in the condensation reaction of Step A is deprotected and then the hydrogenation reduction reaction is carried out. Thereby, for example, a compound represented by the following Formula (10) can be generated, and as a specific example, a compound represented by the following Formula (A) can be generated.

[0587] [Chemical formula 11]

[0588]

[0589] [Chemical formula 12]

[0590]

[0591] In Formula (10), R A1 , R A2 , R A3 , R A4 , R A61 , R A7 , R A8 , R A9 , R A10 and R A11 are respectively the same as R in the aforementioned Formula (2) A1 , R A2 , R A3 , R A4 , R A61 , R A7 , R A8 , R A9 , R A10 and R A11 . At this time, R A61 is preferably a hydroxyl group.

[0592] In addition, in Formula (A), R A1 , RA3 and R A4 is the same as R in the aforementioned formula (2). A1 , R A3 and R A4 have the same meaning. Specifically, in the compound represented by formula (A), R in formula (2) A5 is a hydroxyl group (where m is set to 1), R A12 is a hydrogen atom, and R A14 is -(CH2)2-COOH. It should be noted that in formula (A), R A2 is an ethyl group, R A61 is OH, R A7 , R A8 , R A9 and R A11 are hydrogen atoms, and R A10 is a methyl group, but is not limited thereto.

[0593] In the hydrogenation reduction reaction, when the cyclic peptide derivative represented by formula (2) has an alkynyl group, in addition to converting it into an alkyl group, for example, the ester moiety derived from compound C is converted into a carboxylic acid. In addition, when R A5 has a protecting group (for example, a group containing an ether structure such as benzyloxy), through the hydrogenation reduction reaction, R A5 can be converted into a hydroxyl group (refer to the aforementioned formula (A)).

[0594] The cyclic peptide compound obtained by the hydrogenation reduction reaction is not particularly limited as long as it can be generated by hydrogenating the compound represented by formula (2). Preferably, R A5 in formula (2) is a hydroxyl group, R A12 is a hydrogen atom, and R A14 in COOR A13 is a hydrogen atom. At this time, it is also preferred that R A13 is an ethyl group. The cyclic peptide compound is further preferably R A2 is -(CH2)2-COOH or -CH2-COOH. The cyclic peptide compound obtained by the hydrogenation reduction reaction is most preferably the compound in which R A14 , R A1 , R A3 and R A4 in the compound represented by the aforementioned general formula (A) are all methyl groups.

[0595] In the method for producing the cyclic peptide compound of the present disclosure, by subjecting the cyclic peptide derivative obtained by the aforementioned method for producing the cyclic peptide derivative to a hydrogenation reduction reaction, a cyclic peptide compound can be obtained. Therefore, the cyclic peptide compound can be obtained in a high yield. Moreover, depending on the type of compound C used in the method for producing the cyclic peptide derivative, cyclic peptide compounds conjugated with various amino acids and the like can be obtained.

[0596] 3. Preparation method of raw materials used in the present disclosure

[0597] Hereinafter, in the method for producing the cyclic peptide derivative of the present disclosure, an example of the method for producing the compound represented by the formula (2') used in step A will be described. The method for producing the compound represented by the formula (2') is not particularly limited, and for example, a well-known production method can be widely adopted.

[0598] Regarding the method for producing the compound represented by the formula (2'), when R A6 is a protecting group, for example, it may have a step of obtaining the compound represented by the following formula (22a) through an intramolecular cyclization reaction of the cyclization precursor represented by the following formula (21a) (hereinafter, referred to as the cyclization step).

[0599] [Chemical formula 13]

[0600]

[0601] In the formula (21a), R A1 ~R A5 and m have the same meanings as R A1 ~R A5 and m in the aforementioned formula (1). In the formula (21a), MOM represents methoxymethyl (the same hereinafter). TBS represents tert-butyldimethylsilyl.

[0602] [Chemical formula 14]

[0603]

[0604] In the formula (22a), R A1 ~R A5 and m have the same meanings as R A1 ~R A5 and m in the aforementioned formula (1).

[0605] In the cyclization step, an amide bond is formed between the β-hydroxyisoleucine unit and the β-hydroxydopa unit through the intramolecular cyclization reaction of the cyclization precursor represented by the formula (21a) to form the compound represented by the formula (22a).

[0606] For the aforementioned intramolecular cyclization reaction, in the methods known in the past (for example, the method described in P. Li, C. D. Evans, M. M. Joullie, Org. Lett., 2005, 7, 5325), the yield remained at 10 - 20%, and a large amount of dimer of the cyclization precursor was produced as a by-product. In addition, in other methods (for example, P. Li, C. D. Evans, Y. Wu, B. Cao, E. Hamel, M. M. Joullie, J. Am. Chem. Soc., 2008, 130, 2351), although the yield was increased to 30 - 40%, the yield still did not exceed 40%.

[0607] Regarding this point, in the present disclosure, in the cyclization step, by dropping a dilute substrate solution into a solvent containing a coupling agent, the concentration of the substrate (that is, the compound represented by formula (21a)) is reduced, thereby suppressing the intermolecular reaction and promoting the intramolecular cyclization reaction. As a result, the intramolecular cyclization reaction can be carried out in a higher yield compared with the prior art. By carrying out such an intramolecular cyclization reaction, the intermolecular reaction can be suppressed, and thus it is speculated that the yield of the target cyclized compound (that is, the compound represented by formula (22a)) is increased.

[0608] In the cyclization step, the type of the coupling agent is not particularly limited, and coupling agents used in intramolecular cyclization reactions can be widely used. Examples of the coupling agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT).

[0609] In the cyclization step, the solvent used for dissolving the coupling agent and the substrate is not particularly limited, and polar solvents such as chlorinated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; alcohols such as methanol, ethanol, isopropanol, and tert-butanol; and amide solvents such as N,N-dimethylacrylamide are preferred. The solvent can be used alone or in combination of two or more.

[0610] As the concentration of the coupling agent, for example, it can be in the range of 1 mM to 15 mM based on the solvent used. In addition, the concentration of the substrate can be in the range of 0.1 mM to 1.5 mM based on the solvent used.

[0611] The temperature in the intramolecular cyclization reaction is not particularly limited. For example, it can be carried out at -20 to 60 °C, preferably at 0 to 30 °C. The reaction time can be appropriately set according to the reaction temperature and the like. For example, after dropping the substrate for 6 to 24 hours, the reaction can be continued for 6 to 24 hours, but it is not limited thereto. In particular, by spending time on the reaction at a low temperature, the intramolecular cyclization reaction is promoted, and the yield of the cyclized compound (the compound represented by formula (22a)) can be increased by about 1.5 to 2.5 times compared with the conventional cyclization reaction.

[0612] After obtaining the compound represented by formula (22a) through the intramolecular cyclization reaction, the compound represented by formula (2) can be obtained by deprotection of MOM. The method for deprotection of MOM is not particularly limited. For example, it can be set under the same conditions as the known method for deprotection of MOM. Before performing the deprotection of MOM, for example, the protecting group in the compound represented by formula (22a) can be replaced with other protecting groups (for example, the Boc group substituted on the N atom is replaced with a Nosyl group). Further, before performing the deprotection of MOM, the N atom bonded with a protecting group such as a Nosyl group can be methylated. Methylation can be widely carried out by, for example, a known method, and methylation with methyl p-nitrobenzenesulfonate is exemplified.

[0613] The manufacturing method for obtaining the compound represented by formula (21a) used in the cyclization step is not particularly limited. For example, the compound represented by formula (21a) can be obtained through a known reaction. As an example, the compound represented by formula (21a) can be obtained via a step of reacting the compound represented by the following formula (7a) with the compound represented by the following formula (8a).

[0614] [Chemical formula 15]

[0615]

[0616] In formula (7a), R A5 and m have the same meanings as R A5 and m in the aforementioned formula (1). The compound represented by formula (7a) is a β-hydroxydopa unit.

[0617] [Chemical formula 16]

[0618] In formula (8a), R A1 and R A2 have the same meanings as R A1 and R A2 in the aforementioned formula (2). The compound represented by formula (8a) is an aziridine compound.

[0619] The reaction between the compound represented by formula (7a) and the compound represented by formula (8a) can be carried out, for example, under the same conditions as known ring-opening reactions. In this ring-opening reaction, for example, it can be carried out in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).

[0620] In formula (8a), when R A2 is ethynyl, the nucleophilic reaction rate is extremely fast. Thereby, the nucleophilic addition reaction between the β-hydroxydopa unit and aziridine proceeds rapidly, and the yield of the reaction product also becomes high. Therefore, the production method of the present disclosure also has an advantage in that aziridine that does not react with amino acids can be used.

[0621] After the reaction between the compound represented by formula (7a) and the compound represented by formula (8a), the compound represented by the following formula (13a) is synthesized through a reaction for introducing a protecting group (MOM). The reaction conditions for introducing the protecting group are not particularly limited and can be set to be the same as known methods.

[0622] [Chemical formula 17]

[0623]

[0624] In formula (13a), R A1 , R A2 , R A5 and m have the same meanings as R A1 , R A2 , R A5 and m in the aforementioned formula (2).

[0625] Then, through the deprotection reaction and esterification reaction of the compound represented by formula (13a), the compound represented by the following formula (18a) can be obtained. The deprotection reaction and esterification reaction conditions are not particularly limited and can be set to be the same as known methods.

[0626] [Chemical formula 18]

[0627]

[0628] In formula (18a), R A1 , R A2 , R A5 and m have the same meanings as R A1 , R A2 , R A5 and m in the aforementioned formula (2).

[0629] After deprotecting the Troc group (2,2,2-trichloroethoxycarbonyl) of the compound represented by the obtained formula (18a), for example, a condensation reaction is carried out with a valine compound having 9-fluorenylmethoxycarbonyl, and then deprotection is carried out, whereby the compound represented by the formula (21a) (cyclization precursor) is produced. In this condensation reaction, a suitable condensing agent can be used.

[0630] It should be noted that R A2 When it is ethynyl, reduction can be carried out as needed. This reduction can be carried out in the step of carrying out a hydrogenation reduction reaction after the condensation reaction in step A as described above, or can be carried out at any time as long as it is after the nucleophilic addition reaction with the aforementioned aziridine. In this regard, when R A2 is ethynyl, the ethynyl group is not large in volume compared to the alkyl group, so it is difficult to inhibit the reaction. Therefore, the ethynyl group can be maintained without reduction until the hydrogenation reduction reaction.

[0631] It should be noted that the method for producing the compound represented by the formula (7a) is not particularly limited. For example, it can be produced by a reaction starting from the compound represented by the following formula (1a) and the compound represented by the following formula (2a).

[0632] [Chemical formula 19]

[0633]

[0634] [Chemical formula 20]

[0635]

[0636] In the formula (2a), R A5 and m have the same meanings as R A5 in the aforementioned formula (2').

[0637] On the other hand, the compound represented by the formula (8a) can be obtained, for example, by a known production method, or can also be obtained from commercially available products.

[0638] (Pharmaceutical composition)

[0639] The compositions and methods of the present disclosure can be used to treat individuals in need thereof. In certain embodiments, the individual is a mammal such as a human or the like, or a non-human mammal. When administering to an animal such as a human or the like, the composition or compound is preferably administered, for example, in the form of a pharmaceutical composition comprising the compound of the present disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and examples thereof include 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, when such a pharmaceutical composition is administered to a human, especially for invasive route administration (i.e., routes such as injection or implantation that avoid transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to effect delayed release of the formulation or selective targeting of 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, such as a skin patch. In addition, the composition can also be present in a solution suitable for topical administration, such as eye drops.

[0640] The pharmaceutically acceptable carrier can contain a physiologically acceptable agent that functions to stabilize a compound such as the compound of the present disclosure, or to increase solubility, or to increase absorption. Examples of such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of the pharmaceutically acceptable carrier containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. In addition, the pharmaceutical composition (preparation) can also be a liposome or other polymeric matrix, into which, for example, the compound of the present disclosure can be incorporated. Liposomes, such as liposomes containing phospholipids or other lipids, are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively simple to prepare and administer.

[0641] A pharmaceutical composition (preparation) can be administered to a subject, for example, by any one of several routes of administration including oral (e.g., medicated drinks, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for tongue application in aqueous or non-aqueous solutions or suspensions, etc.); absorption through the oral mucosa (e.g., sublingual); anal, rectal or vaginal (e.g., as vaginal suppositories, creams or foams, etc.); parenteral (including intramuscular, intravenous, subcutaneous or intramedullary, e.g., sterile solutions or suspensions); nasal; intraperitoneal; subcutaneous; transdermal (e.g., as skin-applied patches); and topical (e.g., as skin-applied creams, ointments or sprays or eye drops). In addition, the compound can be formulated into an inhalation preparation. In certain embodiments, the compound can be simply dissolved or suspended in sterile water. Details of suitable routes of administration and the compositions suitable therefor can be found, for example, in 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 the patents cited therein.

[0642] The preparations can conveniently be presented in unit dosage form and are prepared by any methods well known in the art of pharmacy. The amount of the active ingredient that can be combined with a carrier material to produce a single dosage form varies depending on the host to be treated and the particular mode of administration. The amount of the active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces a therapeutic effect. Generally, in 100%, this amount ranges from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70% of the active ingredient, and most preferably from about 10% to about 30% of the active ingredient.

[0643] The methods of preparing these preparations or compositions include the step of bringing the active compound, such as the compounds of the present disclosure, etc., into association with a carrier and one or more accessory ingredients as required. Generally, the preparations can be prepared by uniformly and intimately bringing the compounds of the present disclosure into association with a liquid carrier or a finely divided solid carrier, or with both, and then shaping the product as required.

[0644] The 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 (wherein a flavored base is usually sucrose and gum arabic or tragacanth), lyophilized products, powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as water-in-oil or oil-in-water liquid emulsions, or as elixirs or syrups, or as troches (wherein an inert base is, for example, gelatin and glycerol, or sucrose and gum arabic) and / or as mouthwashes, etc., each containing a predetermined amount of the compound of the present disclosure as an active ingredient. In addition, the composition or compound may also be administered in the form of boluses, pastilles or pastes.

[0645] To prepare solid dosage forms for oral administration (such as capsules (including Sprinkle capsules and gelatin capsules), tablets, pills, dragees, 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 one of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid, etc.; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic, etc.; (3) humectants, such as glycerol, etc.; (4) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, etc.; (5) dissolution retardants, such as paraffin wax, etc.; (6) absorption promoters, such as quaternary ammonium compounds, etc.; (7) wetting agents, such as cetyl alcohol and glycerol monostearate, etc.; (8) absorbents, such as kaolin and bentonite clay, etc.; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and their mixtures, etc.; (10) complexing agents, such as modified and unmodified cyclodextrins, etc.; and (11) coloring agents. In the case of capsules (including Sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain buffering agents. In addition, the same type of solid composition may also use excipients such as lactose or lactitol, and high molecular weight polyethylene glycol, etc., and be used as fillers in soft and hard gelatin capsules filled with the drug.

[0646] Tablets can be made by compression or molding, together with one or more accessory ingredients as required. Compressed tablets can be prepared using binders (such as gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch glycolate or croscarmellose sodium), surfactants or dispersants. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0647] Tablets and other solid dosage forms of the pharmaceutical composition, e.g., dragees, capsules (including Sprinkle capsules and gelatin capsules), pills, and granules, etc., can be prepared with scored lines or using coatings and shells as needed, such as enteric coatings and other coatings well-known in pharmaceutical formulation technology, etc. In addition, these can also be used in different proportions with hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres in order to provide desired release characteristics, and formulated to provide sustained release 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 injectable media immediately before use. In addition, these compositions can contain an emulsifier as needed and can be compositions that release the active ingredient(s) only in a specific part of the digestive tract or preferentially in that part in a delayed manner as needed. Examples of embedding compositions that can be used include polymeric substances and waxes. In addition, under appropriate circumstances, the active ingredient can be made into the form of microcapsules using one or more of the above excipients.

[0648] As liquid dosage forms useful for oral administration, there can be mentioned pharmaceutically acceptable emulsions, lyophilized products for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms can also contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizing agents, and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, etc., and mixtures thereof, etc.

[0649] In addition to the inert diluent, oral compositions can also contain adjuvants, e.g., wetting agents, emulsifying agents, and suspending agents, sweeteners, flavoring agents, coloring agents, perfumes, and preservatives, etc.

[0650] In addition to the active compound, suspending agents can also be contained in the suspension, e.g., ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, and tragacanth, and mixtures thereof, etc.

[0651] Preparations 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, etc., which are solid at room temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity to release the active compounds.

[0652] Preparations of pharmaceutical compositions for administration to the mouth may be provided as mouthwashes or oral sprays or oral ointments.

[0653] Optionally or additionally, the composition may be formulated for delivery via a catheter, stent, wire or other intravascular device. Delivery via such devices may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0654] In addition, preparations suitable for vaginal administration include vaginal suppositories, tampons, creams, gels, pastes, foams or spray preparations containing carriers known in the art as being appropriate.

[0655] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compounds may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required.

[0656] In addition to the active compound, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof, etc.

[0657] In addition to the active compound, powders and sprays may also 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 conventional propellants such as chlorofluorocarbons, etc. and volatile unsubstituted hydrocarbons such as butane and propane, etc.

[0658] With transdermal patches, the advantage of providing controlled delivery of the compounds of the present disclosure to the body is also conferred. Such dosage forms may be made by dissolving or dispersing the active compound in a suitable medium. By using absorption enhancers, the flux of the compound through the skin can also be increased. The rate of such flux can be controlled either by providing a rate controlling membrane or by dispersing the compound within a polymeric matrix or gel.

[0659] Ophthalmic preparations, eye ointments, powders, solutions, etc. are also contemplated within the scope of the present disclosure. Exemplary ophthalmic preparations are described 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, as well as U.S. Patent No. 6,583,124 (the contents of which are incorporated herein by reference). If desired, the liquid ophthalmic preparation has the same properties as, or is compatible with, tear fluid, aqueous humor, or vitreous humor. The preferred route of administration is topical (e.g., topical administration, such as eye drops, etc. or administration via an implant).

[0660] As described above, the present disclosure has been described with reference to preferred embodiments for ease of understanding. Hereinafter, the present disclosure will be described based on examples, but the above description and the following examples are provided for illustrative purposes only and not for the purpose of limiting the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described in this specification, but is defined only by the claims.

[0661] Examples

[0662] In the examples, for simplicity of description, the abbreviations shown above and the following abbreviations are sometimes used.

[0663] Ac: Acetyl

[0664] AcOH: Acetic acid

[0665] aq.: Aqueous solution

[0666] Arg: Arginine

[0667] Asp: Aspartic acid

[0668] BHT: Butylated hydroxytoluene

[0669] Bn: Benzyl

[0670] Boc: tert-Butyloxycarbonyl

[0671] Boc2O: Di-tert-butyl dicarbonate

[0672] Bzl: Benzyl

[0673] Cbz: Benzyloxycarbonyl

[0674] CPME: Cyclopentyl methyl ether

[0675] DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

[0676] DEPBT: 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one

[0677] DIAD: Diisopropyl azodicarboxylate

[0678] DIPEA: N,N-Diisopropylethylamine

[0679] DMAP: 4-Dimethylaminopyridine

[0680] DMEAD: Bis(2-methoxyethyl) azodicarboxylate

[0681] DME: 1,2-Dimethoxyethane

[0682] DMF: N,N-Dimethylformamide

[0683] DMP: 2,2-Dimethoxypropane

[0684] DMT-MM: 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

[0685] DMT-MMT: 4-(4,6-Dimethoxytriazin-2-yl)-4-methylmorpholinium tetrafluoroborate

[0686] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0687] Et: Ethyl

[0688] eq.: Equivalent

[0689] Fmoc: 9-Fluorenylmethyloxycarbonyl

[0690] Gln: Glutamine

[0691] Glu: Glutamic acid

[0692] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0693] HBTU: 1-[Bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate

[0694] HOAt: 1-Hydroxy-7-azabenzotriazole

[0695] HOBt: 1-Hydroxybenzotriazole

[0696] m-CPBA: m-Chloroperbenzoic acid

[0697] Me: Methyl

[0698] MS: Molecular sieve

[0699] MTBE: Methyl tert-butyl ether

[0700] NMM: N-Methylmorpholine

[0701] Ns: 2-Nitrobenzenesulfonyl

[0702] PMB: p-Methoxybenzyl

[0703] Ser: Serine

[0704] Su: Succinimide

[0705] TBAF: Tetrabutylammonium fluoride

[0706] TBAI: Tetrabutylammonium iodide

[0707] TBD: 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

[0708] TBS: tert-Butyldimethylsilyl

[0709] t-Bu: tert-Butyl

[0710] TFA: Trifluoroacetic acid

[0711] THF: Tetrahydrofuran

[0712] Thr: Threonine

[0713] TEMPO: 2,2,6,6-Tetramethylpiperidin-1-oxyl

[0714] Tr: Triphenylmethyl

[0715] Trt: Triphenylmethyl

[0716] Ts: p-Toluenesulfonyl

[0717] TsOH: p-Toluenesulfonic acid

[0718] Tyr: Tyrosine

[0719] Pbf: 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl

[0720] Ph: Phenyl

[0721] PyBOP: (Benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate

[0722] PyBrop: Tris(pyrrolidino)phosphonium bromide hexafluorophosphate

[0723] Val: Valine

[0724] It should be noted that the fragment C group and the fragment D group are obtained as follows.

[0725] [Table 2A]

[0726]

[0727] [Table 2B]

[0728]

[0729] (Example 1: Synthesis of Fragment A-2.)

[0730] [Chemical Formula 21]

[0731]

[0732] 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), and the mixture was stirred for 10 minutes while warming to room temperature. The reaction solution was heated to 100 °C and stirred for 8 hours, and then stirred for 16 hours while cooling to room temperature. The reaction solution was ice-cooled and water (200 mL) was added, and it was separated and washed once with ethyl acetate (300 mL). The organic layer was separated and extracted once with water (100 mL). The aqueous layers were combined to obtain A2-1 in the form of an aqueous solution (300 mL).

[0733] [Chemical Formula 22]

[0734]

[0735] 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 hydrochloric acid aqueous solution (200 mL) was added to the reaction solution, the pH was adjusted to 3, and THF was distilled off under reduced pressure. The concentrate was separated and extracted 3 times with ethyl acetate (200 mL), the organic layers were combined, separated and washed once with saturated sodium chloride aqueous solution (200 mL), and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the residue was concentrated under reduced pressure to obtain A2-2 (11.4 g) as a brown oil.

[0736] [Chemical Formula 23]

[0737]

[0738] Under a nitrogen atmosphere and with 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 mixture, and the mixture was extracted twice by liquid separation with a mixture of hexane (40 mL) / ethyl acetate (80 mL). The organic layers were combined, washed once by liquid separation with a saturated aqueous sodium chloride solution (100 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (23.2 g). The crude product was purified by flash silica gel column chromatography (200 g of normal-phase silica gel, hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain A2-3 (9.56 g, 50% yield in three steps starting from L-tyrosine) as a yellow viscous substance. It should be noted that in this specification, all mixtures are expressed as a mixture of solvent A (X mL) / solvent B (Y mL).

[0739] [Chemical formula 24]

[0740]

[0741] Under a nitrogen atmosphere and with ice cooling, sodium hydride (1.2 eq., 60%, paraffin liquid dispersion, 796 mg, 19.9 mmol) and methyl iodide (3.0 eq., 7.07 g, 49.8 mmol) were added to a solution of A2-3 (1.0 eq., 8.88 g, 16.5 mmol) in DMF (80 mL). The mixture was stirred at ice-cooling temperature for 1.5 hours. Methanol (12 mL) was added to quench the reaction, and then water (100 mL) was added. The mixture was extracted twice by liquid separation with a mixture of hexane (50 mL) / ethyl acetate (100 mL). The organic layers were combined, washed once by liquid separation with a saturated aqueous sodium chloride solution (100 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (13.1 g). The crude product was purified by flash silica gel column chromatography (50 g of normal-phase silica gel, hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain A2-4 (9.54 g) as an orange liquid.

[0742] [Chemical formula 25]

[0743]

[0744] At room temperature, m-CPBA (3.0 eq., 35% aqueous, 14.0 g, 52.7 mmol) was added to a chloroform (90 mL) solution of A2-4 (1.0 eq., 10.1 g, calculated as 17.6 mmol), and the mixture was stirred under reflux for 5 hours. At room temperature, after adding water (50 mL) and saturated aqueous sodium bicarbonate solution (100 mL) to the reaction solution, chloroform was distilled off under reduced pressure. The reaction solution was extracted three times by liquid separation with ethyl acetate (100 mL), the organic layers were combined, washed once by liquid separation with saturated aqueous sodium chloride solution (100 mL), and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain the ester (10.6 g).

[0745] At room temperature, lithium hydroxide (4.0 eq., 1.68 g, 70.3 mmol) was added to a mixed solution of THF (40 mL) / water (40 mL) of the ester (1.0 eq., 10.6 g, calculated as 17.6 mmol), and the mixture was stirred at the same temperature for 16 hours. After the reaction solution was washed twice by liquid separation with hexane (100 mL), 6N hydrochloric acid aqueous solution (11 mL) was added to the aqueous layer to adjust the pH to 2. The aqueous layer was extracted three times by liquid separation with ethyl acetate (100 mL), the organic layers were combined, washed once by liquid separation with saturated aqueous sodium chloride solution (100 mL), and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain A2-5 (9.3 g) as an orange solid.

[0746] [Chemical formula 26]

[0747]

[0748] 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 to a solution of A2-5 (1.0 eq., 9.3 g, calculated as 17.6 mmol) in acetonitrile (80 mL), and the mixture was stirred at an external temperature of 60 °C for 19 hours. After quenching by adding acetic acid (3.0 eq., 3.15 g, 52.5 mmol) to the reaction solution, the mixture was concentrated under reduced pressure to obtain a crude product (16.7 g). The crude product was purified by flash silica gel column chromatography twice (the first time: 120 g of normal-phase silica gel, hexane / ethyl acetate = 75 / 25 to 50 / 50; the second time: 30 g of normal-phase silica gel, hexane / ethyl acetate = 75 / 25 to 67 / 23). The obtained fragment A-2 was dissolved in ethyl acetate (50 mL) and washed once by liquid separation with a saturated aqueous sodium bicarbonate solution (50 mL). The aqueous layer was extracted twice by liquid separation with ethyl acetate (50 mL). The combined organic layers were washed once by liquid separation with a saturated aqueous sodium chloride solution (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 as a yellow oil (3.54 g, the yield of the starting three steps of A2-3 was 36%).

[0749] (Example 2A: Synthesis of fragment A-2')

[0750] [Chemical formula 27]

[0751]

[0752] At room temperature, DBU (1.5 eq., 1.6 mL, 10.7 mmol) and BnBr (1.2 eq., 1.0 mL, 8.54 mmol) were added to a solution of A2-5 (1.0 eq., 3.4 g, calculated as 7.12 mmol) in acetonitrile (70 mL), and the mixture was stirred at room temperature for 16 hours. After quenching by adding a saturated aqueous ammonium chloride solution (30 mL), the mixture was washed by liquid separation three times with water (30 mL) and once with a saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (4.83 g). The crude product was purified by flash silica gel column chromatography (53 g of normal-phase silica gel, hexane / ethyl acetate = 3 / 1 to 2 / 1) to obtain fragment A-2' as a yellow sticky substance (1.87 g, the yield of the three steps was 50%).

[0753] (Example 2AA: Synthesis of fragment A-2")

[0754] [Chemical formula 28]

[0755]

[0756] [Chemical formula 29]

[0757]

[0758] The synthesis of L-tyrosine → A2-1 was as described in Example 1. The synthesis from A2-1 via A3’-2 to A3’-3 was as described in Example 2.

[0759] The synthesis from A3’-3 to A2”-1 is described below.

[0760] [Chemical formula 30]

[0761]

[0762] Under a nitrogen atmosphere and at an external temperature of -20°C, methyl iodide (3.0 eq., 6.8 mL, 109.23 mmol) and sodium hydride (60%, paraffin liquid 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), and the mixture was stirred at the same temperature for 3 hours. After adding 1N aqueous hydrochloric acid solution (50 mL) at an external temperature of -20°C, water (100 mL) was added. After liquid-liquid extraction twice with a mixture of hexane (50 mL) / ethyl acetate (100 mL), the organic layers were combined and washed once by liquid-liquid extraction with saturated aqueous sodium chloride solution (150 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (20.2 g) in the form of a yellow oil. The crude product was purified by flash silica gel column chromatography (40 g of normal-phase silica gel, hexane / ethyl acetate = 9 / 1 to 3 / 1), and the resulting pale yellow sticky substance was washed with hexane to obtain A2”-1 (18.9 g, yield 101%).

[0763] The synthesis from A2”-1 to A2”-2 is described below.

[0764] [Chemical formula 31]

[0765]

[0766] Under a nitrogen atmosphere and at room temperature, m-CPBA (30% aqueous, 2.0 eq., 18.0 g, 73.01 mmol) was added to a chloroform (150 mL) solution of A2”-1 (1.0 eq., 18.9 g, 36.34 mmol), and the mixture was stirred at an external temperature of 60 °C for 4.5 hours. m-CPBA (0.5 eq., 4.8 g, 19.47 mmol) was added at room temperature, and after stirring at an external temperature of 60 °C for 1 hour, the mixture was stirred at an external temperature of 40 °C for 15 hours. A 20% aqueous sodium sulfite solution (75 mL) and a saturated aqueous sodium bicarbonate solution (75 mL) were added under ice cooling. The organic layer of the reaction solution was recovered, and a 20% aqueous sodium sulfite solution (75 mL), a saturated aqueous sodium bicarbonate solution (75 mL), a saturated aqueous sodium chloride solution (250 mL), and ethyl acetate (400 mL) were added to the organic layer, followed by liquid separation and washing once. The aqueous layers were combined, and liquid separation extraction was performed once with ethyl acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (20.6 g) in the form of a brown viscous substance. The crude product was purified by flash silica gel column chromatography (40 g of normal-phase silica gel, hexane / ethyl acetate = 9 / 1 to 3 / 1) to obtain the ester (17.2 g, yield 89%) in the form of a yellow viscous substance.

[0767] At room temperature, lithium hydroxide (2.5 eq., 1.9 g, 80.25 mmol) was added to a mixed solution of the ester (1.0 eq., 17.2 g, 32.17 mmol) in THF (75 mL) / water (75 mL), and the mixture was stirred at room temperature for 3 hours. Lithium hydroxide (1.0 eq., 790 mg, 32.97 mmol) was added, and after stirring for 1 hour, lithium hydroxide (0.5 eq., 392 mg, 16.37 mmol) was further added, followed by stirring for 30 minutes. The reaction solution was washed twice by liquid separation with hexane (75 mL), the organic layers were combined, and liquid separation extraction was performed once with water (20 mL). The aqueous layers were combined, and the pH was adjusted to 1 by adding a 2N hydrochloric acid aqueous solution (65 mL) under ice cooling, followed by liquid separation extraction three times with ethyl acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product of A2”-2 (14.3 g, crude yield 110%) in the form of a brownish viscous substance.

[0768] The synthesis of fragment A-2” from A2”-2 is as described below.

[0769] [Chemical formula 32]

[0770]

[0771] Under a nitrogen atmosphere, DIPEA (1.2 eq, 6.6 mL, 38.81 mmol) and BnBr (1.2 eq., 3.8 mL, 38.66 mmol) were added to a solution of A2”-2 (1.0 eq., 14.2 g, 32.17 mmol) in acetonitrile (150 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. DIPEA (0.2 eq, 1.1 mL, 6.47 mmol) and BnBr (0.2 eq., 650 μL, 6.61 mmol) were added additionally, and after stirring for 1 hour, saturated aqueous ammonium chloride solution (75 mL) and water (75 mL) were added. After recovering the organic layer of the reaction solution, the aqueous layer was extracted twice by liquid separation with ethyl acetate (100 mL). The organic layers were combined and washed twice by liquid separation with saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solution was 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 flash silica gel column chromatography (100 g of normal-phase silica gel, hexane / ethyl acetate = 5 / 1 to 0 / 1) to obtain fragment A-2” (7.1 g, 45% yield in two steps) in the form of a pale yellow sticky substance.

[0772] (Example 2: Synthesis of fragment A-3)

[0773] [Chemical formula 33]

[0774]

[0775] Under ice-cooling, m-CPBA (2.0 eq., 35% water-containing, 13.0 g, 48.9 mmol) was added to a solution of A2-3 (1.0 eq., 13.1 g, 24.4 mmol) in chloroform (120 mL), and the mixture was stirred under reflux for 18 hours. At room temperature, saturated aqueous sodium bicarbonate solution (100 mL) was added to the reaction solution for quenching, and then chloroform was distilled off under reduced pressure. The reaction solution was extracted three times by liquid separation with ethyl acetate (200 mL), the organic layers were combined, washed once by liquid separation with saturated aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain an ester.

[0776] At room temperature, lithium hydroxide (4.0 eq., 2.34 g, 97.7 mmol) was added to a THF (60 mL) / water (60 mL) mixture of the ester (1.0 eq., calculated as 24.4 mmol), and the mixture was stirred at the same temperature for 19 hours. At room temperature, lithium hydroxide (2.0 eq., 1.17 g, 48.9 mmol) was added to the reaction mixture, and the mixture was stirred at the same temperature for 4.5 hours. Water (100 mL) was added to the reaction mixture, and after liquid separation and washing twice with hexane (100 mL), 6N hydrochloric acid aqueous solution was added to the aqueous layer to adjust the pH to 3. The aqueous layer was extracted twice by liquid separation with ethyl acetate (200 mL), the organic layers were combined, washed once by liquid separation with saturated sodium chloride aqueous solution (200 mL), and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain A3-4 (11.2 g) as a dark brown oil.

[0777] [Chemical formula 34]

[0778]

[0779] At room temperature, DBU (1.1 eq., 4.09 g, 26.8 mmol) and PMBCl (1.1 eq., 4.20 g, 26.8 mmol) were added to a solution of A3-4 (1.0 eq., 11.2 g, calculated as 24.4 mmol) in acetonitrile (120 mL), and the mixture was stirred at an external temperature of 60 °C for 16 hours. After quenching by adding acetic acid (3.0 eq., 4.41 g, 73.4 mmol) to the reaction mixture, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (180 g of normal-phase silica gel, hexane / ethyl acetate = 75 / 25 to 50 / 50) to obtain fragment A-3 (7.83 g, yield of 59% for the two-step reaction starting from A2-3) as an orange oil.

[0780] [Chemical formula 35]

[0781]

[0782] Under a nitrogen atmosphere and with ice cooling, 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). After stirring for 20 minutes with ice cooling, the mixture was stirred at an external temperature of 100 °C for 7 hours. After allowing the reaction mixture to cool, it was quenched by adding it to ice-cooled 1N hydrochloric acid aqueous solution (100 mL). After washing three times by liquid separation with ethyl acetate (100 mL), A2-1 was obtained as an aqueous solution (100 mL).

[0783] [Chemical formula 36]

[0784]

[0785] After adding water (100 mL) and 1,4-dioxane (100 mL) to A2-1 (1.0 eq., 100 mL of aqueous solution, calculated as 16.78 mmol), the mixture was adjusted to be alkaline by adding sodium bicarbonate (25.0 eq., 35.2 g, 419.05 mmol) under ice-cooling. Then, 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 added, and the mixture was further stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and after distilling off 1,4-dioxane, 2N hydrochloric acid aqueous solution (about 300 mL) was added to adjust the pH to 1 - 2. After liquid-liquid extraction once with ethyl acetate (300 mL), the organic layer was washed by liquid-liquid extraction once with 1N hydrochloric acid aqueous solution (100 mL). The aqueous layers were combined and subjected to liquid-liquid extraction once with ethyl acetate (200 mL). The organic layers were combined, dried over magnesium sulfate, filtered off magnesium sulfate, and concentrated under reduced pressure to obtain A3’-2 (5.63 g, crude yield 104%) in the form of a brown viscous substance.

[0786] [Chemical formula 37]

[0787]

[0788] Under a nitrogen atmosphere and under ice-cooling, 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 solution of A3’-2 (1.0 eq., 5.63 g, calculated as 16.78 mmol) in DMF (80 mL), and the mixture was stirred at room temperature for 2 hours. Water (80 mL) was added to the reaction solution, and liquid-liquid extraction was performed 3 times with a mixture of hexane (25 mL) / ethyl acetate (75 mL). The organic layers were combined and washed by liquid-liquid extraction with saturated sodium chloride aqueous solution (200 mL). The organic layer was dried over magnesium sulfate, filtered off magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (9.84 g) in the form of a brownish oil. The crude product was purified by flash silica gel column chromatography (70 g of normal-phase silica gel, hexane / ethyl acetate = 5 / 1 - 1 / 1) to obtain A3’-3 (6.18 g, the yield of the three steps was 73%) in the form of a pale orange viscous substance.

[0789] [Chemical formula 38]

[0790]

[0791] Under a nitrogen atmosphere and with ice-cooling, m-CPBA (35% water-containing, 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 the mixture was stirred at an external temperature of 60 °C for 6 hours. After the reaction solution was concentrated under reduced pressure until the volume reached about half, saturated aqueous sodium bicarbonate solution (200 mL) was added. After liquid-liquid extraction was performed once with ethyl acetate (200 mL) and twice with ethyl acetate (100 mL), the organic layers were combined and washed by liquid-liquid separation with saturated aqueous sodium chloride solution (200 mL). After the organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain the ester (24.9 g, crude yield 125%) as a pale yellow solid.

[0792] Under ice-cooling, lithium hydroxide (2.5 eq., 2.31 g, 96.43 mmol) was added to a mixed solution of the ester (1.0 eq., 24.9 g, calculated as 38.36 mmol) in THF (100 mL) / 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 stirring was continued for 2 hours. Further, lithium hydroxide (1.5 eq., 1.39 g, 57.87 mmol) was added, and stirring was carried out for 1 hour. The reaction solution was washed by liquid-liquid separation twice with hexane (100 mL). Under ice-cooling, 6N hydrochloric acid aqueous solution (30 mL) was added to the aqueous layer, and after adjusting the pH to 2 - 3, liquid-liquid extraction was performed once with ethyl acetate (100 mL). 6N hydrochloric acid aqueous solution (5 mL) was added to the aqueous layer, and after adjusting the pH to 1 - 2, liquid-liquid extraction was performed twice with ethyl acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain the crude product (21.6 g) as a brown sticky substance. The crude product was recrystallized using a hexane / ethyl acetate mixed solution (4 / 1 - 1 / 1) to obtain A3’-4 (12.4 g, apparent yield 83%, containing approximately 30% of m-CPBA) as a white solid.

[0793] [Chemical formula 39]

[0794]

[0795] Under a nitrogen atmosphere and with ice cooling, DBU (1.1 eq, 1.3 mL, 8.71 mmol) and BnBr (1.1 eq., 850 μL, 8.65 mmol) were added to a solution of A3”-4 (1.0 eq., 3.03 g, containing approximately 30% m-CPBA, calculated as 7.83 mmol) in acetonitrile (40 mL). The mixture was stirred at room temperature for 16 hours. The reaction solution was washed once by liquid separation with a saturated aqueous ammonium chloride solution (40 mL). The aqueous layer was extracted twice by liquid separation with ethyl acetate (40 mL). The organic layers were combined, washed once by liquid separation with water (100 mL), and then washed once by liquid separation with a saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain a crude product (3.7 g) in the form of a brown oil. The crude product was purified by flash silica gel column chromatography (50 g of normal-phase silica gel, hexane / ethyl acetate = 5 / 1 to 3 / 1) to obtain fragment A-3” (1.8 g, yield 48%) in the form of a pale yellow sticky substance.

[0796] [Chemical formula 40]

[0797]

[0798] Under a nitrogen atmosphere and with 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 as 11.43 mmol) in acetonitrile (60 mL). The mixture was stirred at room temperature for 16 hours. The reaction solution was washed once by liquid separation with a saturated aqueous ammonium chloride solution (60 mL). The aqueous layer was extracted twice by liquid separation with ethyl acetate (60 mL). The organic layers were combined and washed once by liquid separation with a saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain a crude product (6.17 g) in the form of a brown oil. The crude product was purified by flash silica gel column chromatography (70 g of normal-phase silica gel, hexane / ethyl acetate = 5 / 1 to 2 / 1) to obtain fragment A-3’ (3.47 g, containing approximately 30% of the PMB ester of A3’-3, apparent yield 60%) in the form of a pale yellow sticky substance.

[0799] (Example 2A: Synthesis of Fragment A-13)

[0800] [Chemical formula 41]

[0801]

[0802] The two steps from L-tyrosine to A2-2 were carried out as described in Example 2.

[0803] The synthesis of A2-2 to A13-1 is described below.

[0804] [Chemical formula 42]

[0805]

[0806] Under a nitrogen atmosphere and with ice cooling, 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 solution of A2-2 (1.0 eq., 20.3 g, calculated as 55.2 mmol) in DMF (110 mL). The mixture was stirred at room temperature for 2.5 hours. Water (200 mL) was added to the reaction solution, and liquid-liquid extraction was performed twice with a mixture of hexane (50 mL) / ethyl acetate (150 mL). The organic layers were combined and washed once with water (100 mL) and once with saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solution was 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 chromatography (200 g of normal-phase silica gel, 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.

[0807] The synthesis of A13-1 to A13-2 is described below.

[0808] [Chemical formula 43]

[0809]

[0810] Under a nitrogen atmosphere and with ice cooling, 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 solution of the mixture of A13-1 and A2-3 (1.0 eq., 24.3 g, calculated as 45.2 mmol) in DMF (90 mL). The mixture was stirred at ice-cooling temperature for 4 hours. 2N aqueous hydrochloric acid solution (20 mL) was added to quench the reaction, and water (200 mL) was added. Liquid-liquid extraction was performed once with a mixture of hexane (50 mL) / ethyl acetate (150 mL) and once with a mixture of hexane (40 mL) / ethyl acetate (120 mL). The organic layers were combined and washed once with water (100 mL) and once with saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain a mixture of A13-2 and A2-4 (24.6 g).

[0811] The synthesis of A13-2 to A13-3 is described below.

[0812] [Chemical formula 44]

[0813]

[0814] Under a nitrogen atmosphere and at room temperature, m-CPBA (35% aqueous, 2.0 eq., 23.7 g, 89.3 mmol) was added to a chloroform (180 mL) solution of a mixture of A13-2 and A2-4 (1.0 eq., 24.6 g, calculated as 44.6 mmol), and the mixture was stirred at an external temperature of 45 °C for 17 hours. The reaction solution was cooled in ice, and a mixture of 20% aqueous sodium sulfite solution (80 mL) / saturated aqueous sodium hydrogen carbonate solution (80 mL) was added for quenching. Ethyl acetate (500 mL) was added to the reaction solution for liquid-liquid extraction once, and the organic layer was washed by liquid-liquid separation once with a mixture of 20% aqueous sodium sulfite solution (80 mL) / saturated aqueous sodium hydrogen carbonate solution (80 mL) and once with saturated aqueous sodium chloride solution (100 mL). After drying the organic layer with magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (26.2 g) in the form of a brown oil. The crude product was purified by flash silica gel column chromatography (220 g of normal-phase silica gel, hexane / ethyl acetate = 83 / 17 to 50 / 50) to obtain a mixture of ester-A13 and the ester (22.2 g) in the form of a yellow liquid.

[0815] At room temperature, lithium hydroxide (4.0 eq., 3.74 g, 156 mmol) was added to a mixture of THF (80 mL) / water (80 mL) of the mixture of ester-A13 and the ester (1.0 eq., 22.2 g, calculated as 39.1 mmol), and the mixture was stirred at the same temperature for 3.5 hours. After washing the reaction solution by liquid-liquid separation three times with hexane (100 mL), 2N aqueous hydrochloric acid solution (72 mL) was added to the aqueous layer to adjust the pH to 1. After extracting the aqueous layer by liquid-liquid separation three times with ethyl acetate (150 mL), the organic layers were combined and washed by liquid-liquid separation once with saturated aqueous sodium chloride solution (100 mL). After drying the organic layer with magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a mixture of A13-3 and A2-5 (17.9 g) in the form of a brown sticky substance.

[0816] The synthesis of A13-3 to fragment A-13 is described as follows.

[0817] [Chemical formula 45]

[0818]

[0819] At room temperature, potassium carbonate (3.1 eq., 16.6 g, 120 mmol) and methyl iodide (1.1 eq., 2.7 mL, 43.4 mmol) were added 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), and the mixture was stirred at the same temperature for 1.5 h. Water (200 mL) was added to the reaction solution, and the mixture was extracted by liquid separation once with a hexane (60 mL) / ethyl acetate (180 mL) mixture and twice with a hexane (30 mL) / ethyl acetate (90 mL) mixture. The organic layers were combined and washed by liquid separation once with a saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (17.9 g) in the form of a brown viscous substance. The crude product was purified by flash silica gel column chromatography twice (the first time: 200 g of normal-phase silica gel, hexane / ethyl acetate = 80 / 20 to 50 / 50; the 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) in the form of a brown viscous substance and fragment A-10 (11.8 g) in the form of a pale yellow viscous substance.

[0820] (Example 3: Synthesis of Fragment B-1)

[0821] [Chemical Formula 46]

[0822]

[0823] Under a nitrogen atmosphere and at room temperature, 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 a saturated aqueous sodium bicarbonate solution (150 mL). 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 h and then stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and after distilling off 1,4-dioxane, MTBE (200 mL) was added to the concentrated residue, and the insoluble matter was filtered off. The aqueous layer of the filtrate was recovered, and after liquid-liquid extraction washing once with MTBE (200 mL), concentrated hydrochloric acid (about 25 mL) was added under ice-cooling to adjust the pH to 2 - 3. After adding sodium chloride (60 g), liquid-liquid extraction was performed 4 times with ethyl acetate (200 mL). Concentrated hydrochloric acid (5 mL) and sodium chloride (20 g) were added to the aqueous layer, and liquid-liquid extraction was performed 4 times with ethyl acetate (200 mL). Further, after adding sodium chloride and concentrated hydrochloric acid to the aqueous layer, liquid-liquid extraction was performed 6 times with ethyl acetate (100 mL) and 6 times with ethyl acetate (50 mL) / THF (50 mL). The organic layers were combined, dried over sodium sulfate, and after filtering off sodium sulfate, the mixture was concentrated under reduced pressure to obtain D-N-Boc-serine (50.81 g, yield 92%) as a colorless oil.

[0824] Under a nitrogen atmosphere and with an internal temperature of -10 °C, N,O-dimethylhydroxylamine hydrochloride (1.03 eq., 22.27 g, 0.228 mol), NMM (1.03 eq., 23.10 g, 0.228 mol), and EDCI (1.1 eq., 46.74 g, 0.244 mol) were added to a solution of D-N-Boc-serine (1.0 eq., 50.8 g, net weight 44.9 g, 0.219 mol) in dichloromethane (300 mL). The solution was stirred overnight from -10 °C to room temperature. Under ice-cooling, 1 M aqueous hydrochloric acid was added to the reaction solution, and after liquid-liquid extraction washing once, the aqueous layer was extracted once with dichloromethane (100 mL). The organic layers were combined and washed once with a saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was extracted again once with dichloromethane (50 mL). After combining the organic layers, they were dried over sodium sulfate. After filtering off sodium sulfate, the mixture was concentrated under reduced pressure to obtain B1-1 (50.4 g, yield 93%) as a white solid.

[0825] [Chemical formula 47]

[0826]

[0827] 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, and this operation was repeated 3 times to obtain B1-2(1) (60.4 g, quant.) as a pale yellow oil.

[0828] Under a nitrogen atmosphere, at an internal temperature of -57 to -40 °C, methyllithium (1.5 M in Et2O, 2.0 eq., 279 mL, 0.419 mmol) was added dropwise to a solution of B1-2(1) (1.0 eq., 60.4 g, calculated to be 0.203 mol) in THF (570 mL) over 40 minutes, and the mixture was stirred at the same temperature for 2 hours. At the same temperature, saturated aqueous ammonium chloride solution (130 mL) was added to the reaction solution, and after warming to room temperature, liquid separation and washing were carried out. The aqueous layer was extracted 3 times with ethyl acetate (200 mL), the organic layers were combined, and dried over sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product (51.56 g) as a pale yellow oil. The crude product was purified by flash silica gel column chromatography (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.

[0829] [Chemical formula 48]

[0830]

[0831] Under a nitrogen atmosphere, at room temperature, ethynylmagnesium bromide (0.5 M in THF, 2.5 eq., 715 mL, 0.358 mol) was added to a solution of B1-2 (1.0 eq., 34.8 g, 0.143 mol) in THF (696 mL) over 1.5 hours, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution (160 mL) was added to the reaction mixture at -55 °C, and the temperature was raised to -5 °C, followed by concentration under reduced pressure. Water (300 mL) was added to the concentrated residue, and the mixture was extracted once with ethyl acetate (300 mL) and once with ethyl acetate (150 mL). The organic layers were combined, washed once with a saturated aqueous sodium chloride solution (150 mL), and dried over sodium sulfate. After filtering off 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 chromatography (370 g of normal-phase silica gel, chloroform / ethyl acetate = 100 / 0 to 20 / 1) to obtain B1-3 (a mixture of diastereomers, 33.9 g, 88% yield) as a white solid.

[0832] [Chemical formula 49]

[0833]

[0834] Under a nitrogen atmosphere, at room temperature, concentrated hydrochloric acid (12 eq., 130 mL, 1.56 mol) was added to a solution of B1-3 (a mixture of diastereomers, 1.0 eq., 33.9 g, 0.126 mol) in THF (450 mL), and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude solution of B1-4(1).

[0835] Under a nitrogen atmosphere, THF (260 mL) and water (65 mL) were added to the crude solution of B1-4(1). Sodium carbonate (5.0 eq., 66.70 g, 0.629 mol) and NsCl (1.0 eq., 27.90 g, 0.125 mol) were added to this solution, and the mixture was stirred at room temperature for 17 hours. A saturated aqueous sodium chloride solution (65 mL) was added to the reaction mixture for liquid-liquid washing, and the aqueous layer was extracted three times with ethyl acetate (260 mL). The organic layers were combined, dried over sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure to obtain the crude product (40.01 g) as a brown sticky substance. The crude product was purified by flash silica gel column chromatography (200 g of normal-phase silica gel, hexane / ethyl acetate = 1 / 1 to 3 / 7) to obtain B1-4 (a mixture of diastereomers, 38.05 g, containing 4.0 wt% ethyl acetate, calculated yield 92%) as a light brown sticky substance.

[0836] [Chemical formula 50]

[0837]

[0838] Under a nitrogen atmosphere, at room temperature, 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 (a mixture of diastereomers, 1.0 eq., 36.0 g, containing 4.0 wt% ethyl acetate, 0.110 mol) in DMF (360 mL), and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate (350 mL) and water (300 mL) were added to the reaction solution for liquid-liquid extraction once, and then the aqueous layer was extracted twice with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate. After filtering off the sodium sulfate, the solution was concentrated under reduced pressure to obtain the crude product as a brown sticky substance. The crude product was purified by flash silica gel column chromatography (540 g of normal-phase silica gel, hexane / ethyl acetate = 1 / 0 to 1 / 1) to obtain B1-5 (a mixture of diastereomers, 48.3 g, 98% yield) as a yellow sticky substance.

[0839] [Chemical Formula 51]

[0840]

[0841] Under a nitrogen atmosphere, with 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 solution of B1-5 (a mixture of diastereomers, 1.0 eq., 24.1 g, 0.056 mol) in THF (560 mL), and the mixture was stirred at the same temperature for 2 hours. Ethyl acetate (650 mL), water (300 mL), and 5% aqueous sodium bicarbonate solution (300 mL) were added to the reaction solution for liquid-liquid extraction once, and then the organic layer was 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 off the sodium sulfate, the solution was concentrated under reduced pressure to obtain the crude product as a yellow oil. The crude product was purified by flash silica gel column chromatography (720 g of normal-phase silica gel, hexane / ethyl acetate = 10 / 1) to obtain fragment B-1 (12.6 g, 54% yield) as a white solid. In addition, 4.09 g was obtained as a mixture containing 16% diastereomers.

[0842] To a mixture of diastereomers (3.41 g) was added a mixture of hexane (8.5 mL) / diisopropyl ether (8.5 mL), and the mixture was heated to an external temperature of 45 °C to dissolve it. After the solution was cooled to an internal temperature of 11 °C, the precipitated solid was filtered, and the solid was washed once with hexane (1.5 mL) / diisopropyl ether (1.5 mL) and once with hexane (3 mL) to obtain Fragment B-1 (2.41 g, containing 0.7% of diastereomers, yield 10%) as a white solid.

[0843] (Example 4: Synthesis of Fragment B-2)

[0844] [Chemical formula 52]

[0845]

[0846] Under a nitrogen atmosphere and with ice cooling, thionyl chloride (1.5 eq., 5 mL, 69.35 mmol) was added dropwise to methanol (47 mL). At the same temperature, L-serine (1.0 eq., 5.00 g, 47.66 mmol) was added, and the mixture was stirred under reflux conditions for 2.5 hours. The reaction solution was concentrated under reduced pressure to distill off methanol, and thus B2-1 (7.61 g, crude yield 104%) was obtained as a pale yellow solid.

[0847] [Chemical formula 53]

[0848]

[0849] Under a nitrogen atmosphere and with ice cooling, 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 solution of B2-1 (1.0 eq., 4.56 g, calculated as 29.69 mmol) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 3 hours. Dichloromethane (30 mL) was added to the reaction solution, and it was washed once by liquid separation with water (60 mL). The aqueous layer was extracted twice by liquid separation with dichloromethane (60 mL). The organic layers were combined, washed once by liquid separation with a saturated aqueous sodium chloride solution (150 mL), and then the organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain a crude product (10.99 g). Under ice cooling, ethyl acetate (20 mL) and hexane (40 mL) were added to the crude product. The insoluble white solid was filtered to obtain Fragment B-2 (7.67 g, two-stage yield 71%).

[0850] (Example 5: Synthesis of Fragment B-3)

[0851] [Chemical formula 54]

[0852]

[0853] Under a nitrogen atmosphere and with ice-cooling, thionyl chloride (1.5 eq., 4.5 mL, 62.03 mmol) was added dropwise to methanol (42 mL). At the same temperature, after adding L-threonine (1.0 eq., 5.01 g, 42.10 mmol), the mixture was stirred under reflux conditions for 5 hours. The reaction solution was concentrated under reduced pressure, and methanol was distilled off, thereby obtaining B3-1 (8.29 g, crude yield 116%) as a pale yellow solid.

[0854] [Chemical formula 55]

[0855]

[0856] Under a nitrogen atmosphere and with ice-cooling, 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 solution of B3-1 (1.0 eq., 4.01 g, calculated as 23.66 mmol) in dichloromethane (48 mL), 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 additionally added with ice-cooling, and the mixture was further stirred at room temperature for 18 hours. The reaction solution was washed once by liquid separation with water (60 mL). The aqueous layer was extracted twice by liquid separation with dichloromethane (60 mL). The organic layers were combined, washed by liquid separation with a saturated aqueous sodium chloride solution (150 mL), and then the organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (13.4 g). The crude product was purified by flash silica gel column chromatography (70 g of normal-phase silica gel, hexane / ethyl acetate = 2 / 1 to 1 / 1), thereby obtaining fragment B-3 (7.27 g, yield of two steps 82%) as a white solid.

[0857] (Example 6: Synthesis of fragment B-9)

[0858] [Chemical formula 56]

[0859]

[0860] Under a nitrogen atmosphere and with ice-cooling, thionyl chloride (1.45 eq., 25 mL, 345 mmol) was added to methanol (240 mL). At the same temperature, D-serine (1.0 eq., 25 g, 238 mmol) was added, and the mixture was stirred at 70 °C for 16.5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude methyl ester (37 g).

[0861] [Chemical formula 57]

[0862]

[0863] Under a nitrogen atmosphere and with ice cooling, 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 water (100 mL) / methanol (100 mL) of methyl ester (1.0 eq., 37.0 g, calculated as 238 mmol), and the mixture was stirred at room temperature for 5.5 hours. After adding water (200 mL) to the reaction solution, liquid-liquid extraction was performed twice with ethyl acetate (200 mL). The organic layer was washed by liquid-liquid separation twice with water (100 mL) and once with saturated sodium chloride aqueous solution (100 mL), and then dried over magnesium sulfate. It was concentrated under reduced pressure to obtain B8-1 (58.7 g) in the form of a crude product.

[0864] [Chemical formula 58]

[0865]

[0866] Under a nitrogen atmosphere and at room temperature, 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), and the mixture was stirred at the same temperature for 1 hour. Triethylamine (0.075 eq., 2.5 mL, 17.9 mmol) was added to the reaction solution, and it was concentrated under reduced pressure to obtain B8-2 (68.0 g) in the form of a crude product as a pale yellow oil.

[0867] [Chemical formula 59]

[0868]

[0869] Under a nitrogen atmosphere and with 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. 10% ammonium chloride aqueous solution (200 mL), ethyl acetate (100 mL) and water (30 mL) were added to the reaction solution for liquid-liquid extraction once, and the aqueous layer was extracted twice by liquid-liquid separation with ethyl acetate (50 mL). The organic layers were combined, washed by liquid-liquid separation once with 5% sodium chloride aqueous solution (200 mL), dried over sodium sulfate, the sodium sulfate was filtered out, and it was concentrated under reduced pressure.

[0870] The crude product obtained from B8-2 (2.00 g) by the same operation was combined with the previous concentrated residue, and subjected to flash silica gel column purification (100 g of normal-phase silica gel, hexane / ethyl acetate = 80 / 20 to 20 / 80), to obtain B9-1 (17.22 g, containing 1.7 wt% ethyl acetate, conversion yield 95%) in the form of a pale yellow oil.

[0871] [Chemical formula 60]

[0872]

[0873] Under a nitrogen atmosphere, at room temperature, concentrated hydrochloric acid (12 eq., 62 mL, 744 mmol) was added to a solution of B9-1 (1.0 eq., 16.22 g, containing 1.7 wt% ethyl acetate, 61.5 mmol) in THF (248 mL). After stirring 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) in the form of a purple oil.

[0874] The crude product obtained from B9-1 (1.00 g) by the same operation was combined with the previous crude product, dissolved in THF (130 mL), and 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, additional NsCl (0.3 eq., 4.34 g, 19.6 mmol) was added and stirred at the same temperature for 30 minutes. Saturated aqueous sodium chloride solution (150 mL), ethyl acetate (50 mL), and water (180 mL) were added to the reaction solution for a single liquid-liquid extraction, and the aqueous layer was extracted three times with ethyl acetate (30 mL). The organic layers were combined, dried over sodium sulfate, and after filtering out the sodium sulfate, concentrated under reduced pressure. The concentrated residue was subjected to flash silica gel column purification (100 g of normal-phase silica gel, hexane / ethyl acetate = 50 / 50 to 0 / 100), to obtain B9-2 (19.70 g, containing impurities, apparent yield 99%) in the form of a brown oil.

[0875] [Chemical formula 61]

[0876]

[0877] Under a nitrogen atmosphere, at room temperature, TBSCl (1.2 eq., 11.64 g, 77.3 mmol) and imidazole (1.5 eq., 6.57 g, 96.6 mmol) were added to a solution of B9-2 (1.0 eq., 19.59 g, 64.4 mmol) in DMF (65 mL), and stirred at the same temperature for 30 minutes.

[0878] The reaction solution obtained by treating B9-2 (100 mg) in the same manner was combined with the previous reaction solution, ethyl acetate (130 mL) and water (200 mL) were added, and liquid-liquid extraction was performed once. The aqueous layer was subjected to liquid-liquid extraction twice with ethyl acetate (30 mL). The organic layers were combined, washed once by liquid-liquid extraction 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 off, and after concentration under reduced pressure, the concentrated residue was purified by flash silica gel column chromatography (100 g of normal-phase silica gel, hexane / ethyl acetate = 90 / 10 to 64 / 36) to obtain B9-3 (22.09 g, containing 3.1 wt% ethyl acetate, 79% conversion yield in three steps starting from B9-1) as a white viscous substance.

[0879] [Chemical formula 62]

[0880]

[0881] Under a nitrogen atmosphere, at room temperature, 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), and the mixture was stirred at the same temperature for 3 hours. The reaction solution obtained by treating B9-3 (130 mg) in the same manner was combined with the previous reaction solution, concentrated under reduced pressure, and the concentrated residue was purified by flash silica gel column chromatography twice (first time: 480 g of normal-phase silica gel, hexane / ethyl acetate = 10 / 0 to 5 / 1; second time: 100 g of normal-phase silica gel, hexane / ethyl acetate = 91 / 9 to 85 / 15). Hexane was added to the resulting pale red solid, ultrasonic irradiation was carried out, and after cooling in ice, the solid was filtered to obtain fragment B-9 (15.07 g, yield 74%) as a white solid.

[0882] (Example 6A: Synthesis of fragment D-8)

[0883] Fragment D-8 was synthesized as described below.

[0884] [Chemical formula 63]

[0885]

[0886] The synthesis of H-L-Asp-OBzl to D8-1 was carried out as described below.

[0887] [Chemical formula 64]

[0888]

[0889] 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 to a mixed solution of H-L-Asp-OBzl (1.0 eq., 501 mg, 2.24 mmol) in THF (3 mL) / water (6 mL), and the mixture was stirred at the same temperature for 5 hours. Ethyl acetate (50 mL) was added to the reaction solution, and liquid-liquid extraction was performed twice with water (25 mL). The aqueous layers were combined, adjusted to pH 7 by adding 1N hydrochloric acid aqueous solution (0.5 mL), and concentrated under reduced pressure. After filtering the solid precipitated by concentration, the residue was washed with DMF. The filtrate and the washings were combined and concentrated under reduced pressure to obtain D8-1 (753.3 mg, quant.) as a turbid oil.

[0890] The synthesis of D8-1 to D8-2 was carried out as described below.

[0891] [Chemical formula 65]

[0892]

[0893] 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) were added to a solution of D8-1 (1.0 eq., 753 mg, calculated as 2.24 mmol) in DMF (6 mL), and the mixture was stirred at the same temperature for 18 hours. After adding ethyl acetate (30 mL) and hexane (10 mL) to the reaction solution, liquid-liquid washing was performed twice with water (20 mL), twice with a mixture of water (10 mL) / saturated sodium bicarbonate aqueous solution (10 mL), and once with saturated sodium chloride aqueous solution (20 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and concentrated under reduced pressure to obtain D8-2 (511 mg, 65% yield in two steps) as a light brown liquid.

[0894] The synthesis of D8-2 to fragment D-8 was carried out as described below.

[0895] [Chemical formula 66]

[0896]

[0897] At room temperature, TFA (9.7 eq., 1.0 mL, 13.1 mmol) was added to a solution of D8-2 (1.0 eq., 472 mg, 1.34 mmol) in dichloromethane (2 mL), and the mixture was stirred at the same temperature for 2 hours. After adding ethyl acetate (20 mL) to the reaction solution, liquid-liquid extraction was performed twice with water (10 mL), three times with saturated aqueous sodium bicarbonate solution (10 mL), and once with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain Fragment D-8 (229 mg, yield 68%) as a colorless transparent liquid.

[0898] (Example 6B: Synthesis of Fragment D-9)

[0899] Fragment D-9 was synthesized as described below.

[0900] [Chemical formula 67]

[0901]

[0902] The synthesis of Boc-L-Asp(OBzl)-OH to D9-1 was carried out as described below.

[0903] [Chemical formula 68]

[0904]

[0905] At room temperature, 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) were added to a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 893 mg, 2.76 mmol) in DMF (8 mL), and the mixture was stirred at the same temperature for 18 hours. After adding ethyl acetate (30 mL) and hexane (10 mL) to the reaction solution, liquid-liquid extraction was performed twice with water (20 mL), twice with a mixture of water (10 mL) / saturated aqueous sodium bicarbonate solution (10 mL), and once with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain D9-1 (881 mg, yield 91%) as a pale yellow liquid.

[0906] The synthesis of D9-1 to Fragment D-9 was carried out as described below.

[0907] [Chemical formula 69]

[0908]

[0909] To a solution of D9-1 (1.0 eq., 864 mg, 2.46 mmol) in dichloromethane (3 mL) at room temperature was added TFA (10 eq., 2.83 g, 24.8 mmol), and the mixture was stirred at the same temperature for 1.5 h. 1M aqueous sodium hydroxide solution (22 mL) was added to the reaction mixture to adjust the pH to 9. After liquid-liquid extraction once with ethyl acetate (30 mL), the organic layer was washed once by liquid-liquid extraction with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give Fragment D-9 (524 mg, 85% yield) as a pale yellow liquid.

[0910] (Example 6C: Synthesis of Fragment D-10)

[0911] Fragment D-10 was synthesized as described below.

[0912] [Chemical formula 70]

[0913]

[0914] The synthesis of Boc-L-Asp(OBzl)-OH to D10-1 was carried out as described below.

[0915] [Chemical formula 71]

[0916]

[0917] At room temperature, 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), and the mixture was stirred at the same temperature for 1 h. After adding ethyl acetate (90 mL) and hexane (30 mL) to the reaction mixture, it was washed twice with water (100 mL), twice with a mixture of water (50 mL) / saturated aqueous sodium bicarbonate solution (50 mL), and once with saturated aqueous sodium chloride solution (50 mL) by liquid-liquid extraction. The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give D10-1 (6.08 mg, 96% yield) as a pale yellow liquid.

[0918] The synthesis of D10-1 to Fragment D-10 was carried out as described below.

[0919] [Chemical formula 72]

[0920]

[0921] At room temperature, TFA (10 eq., 17.0 g, 149 mmol) was added to a solution of D10-1 (1.0 eq., 6.07 g, 14.9 mmol) in dichloromethane (30 mL), and the mixture was stirred at the same temperature for 1 hour. 1M aqueous sodium hydroxide solution (140 mL) was added to the reaction solution to adjust the pH to 9. After liquid separation extraction was performed once with ethyl acetate (100 mL), the organic layer was washed by liquid separation once with water (50 mL) and once with saturated aqueous sodium chloride solution (50 mL). After drying the organic layer with magnesium sulfate, the magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain fragment D-10 (4.48 g, yield 98%) as a pale yellow liquid.

[0922] (Example 6D: Synthesis of Fragment D-11)

[0923] Fragment D-11 was synthesized as described below.

[0924] [Chemical Formula 73]

[0925]

[0926] The synthesis of Boc-L-Asp(OBzl)-OH to D11-1 was carried out as described below.

[0927] [Chemical Formula 74]

[0928]

[0929] At room temperature, 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) were added to a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.04 g, 15.6 mmol) in DMF (45 mL), and the mixture was stirred at the same temperature for 2 hours. After adding ethyl acetate (90 mL) and hexane (30 mL) to the reaction solution, liquid separation washing was performed twice with water (100 mL), twice with a mixture of water (50 mL) / saturated aqueous sodium bicarbonate solution (50 mL), and once with saturated aqueous sodium chloride solution (50 mL). After drying the organic layer with magnesium sulfate, the magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain D11-1 (7.87 mg, crude yield 103%) as a pale yellow liquid.

[0930] The synthesis of D11-1 to fragment D-11 was carried out as described below.

[0931] [Chemical Formula 75]

[0932]

[0933] At room temperature, TFA (8.0 eq., 14.2 g, 124 mmol) was added to a solution of D11-1 (1.0 eq., 7.87 g, calculated as 15.6 mmol) in dichloromethane (30 mL), and the mixture was stirred at the same temperature for 1 hour. 1 M aqueous sodium hydroxide solution (113 mL) was added to the reaction solution to adjust the pH to 9. After liquid separation extraction was performed once with ethyl acetate (100 mL), the organic layer was washed by liquid separation twice with water (50 mL) and once with saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (6.56 g) in the form of a pale yellow liquid. The crude product was purified by flash silica gel column chromatography (30 g of normal-phase silica gel, hexane / ethyl acetate = 75 / 25 to 25 / 75) to obtain Fragment D-11 (4.73 g, 77% yield in two steps starting from Boc-L-Asp(OBzl)-OH) in the form of a pale yellow liquid.

[0934] (Example 6E: Synthesis of Fragment D-12)

[0935] Fragment D-12 was synthesized as described below.

[0936] [Chemical formula 76]

[0937]

[0938] [Chemical formula 77]

[0939]

[0940] Under a nitrogen stream and with 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), and the mixture was stirred at the same temperature for 0.5 hour and then stirred for 17 hours while warming to room temperature. The reaction solution was washed by liquid separation once with water (50 mL) and 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 a crude product (14.78 g). The crude product was dissolved in ethyl acetate (100 mL), washed by liquid separation once with 5% aqueous sodium chloride solution (50 mL), and then dried over sodium sulfate. After the sodium sulfate was filtered off, the mixture was concentrated under reduced pressure to obtain D12-1 (14.55 g, containing 0.6 wt% ethyl acetate, quant.) in the form of a yellow solid.

[0941] [Chemical Formula 78]

[0942]

[0943] Under a nitrogen atmosphere and with ice cooling, potassium carbonate (2.0 eq., 7.90 g, 57.16 mmol) and methyl iodide (2.0 eq., 8.11 g, 57.14 mmol) were added to a solution of D12-1 (1.0 eq., 14.55 g, calculated as 28.58 mmol) in DMF (100 mL), and the mixture was stirred at the same temperature for 1 hour. Toluene (200 mL) was added to the reaction solution, and after liquid separation and washing once with water (200 mL) and once with 5% brine (200 mL), it was dried over sodium sulfate. The sodium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain D12-2 (14.78 g, 0.4 wt% DMF, conversion yield of 99% for the two-stage starting from fragment D-2) as a light brown viscous substance.

[0944] [Chemical Formula 79]

[0945]

[0946] Under a nitrogen atmosphere and at room temperature, cesium carbonate (1.5 eq., 13.84 g, 42.48 mmol) and 4-tert-butylbenzenethiol (1.5 eq., 7.06 g, 42.46 mmol) were added to a solution of D12-2 (1.0 eq., 14.78 g, 28.29 mmol) in DMF (140 mL), and the mixture was stirred at the same temperature for 2 hours. Toluene (300 mL) was added to the reaction solution, and after liquid separation and washing once with water (300 mL), once with 5% aqueous potassium carbonate solution (300 mL), and once with 5% aqueous sodium chloride solution (300 mL), it was dried over sodium sulfate. The sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The obtained crude product (19.66 g) was purified by flash silica gel column chromatography (100 g of normal-phase silica gel, hexane / ethyl acetate = 90 / 10 - 0 / 100) to obtain fragment D-12 (7.52 g, yield 81%) as an orange oil.

[0947] (Example 6F: Synthesis of Fragment D-13)

[0948] Fragment D-13 was synthesized as described below.

[0949] [Chemical Formula 80]

[0950]

[0951] Under a nitrogen atmosphere, at room temperature, 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), 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 solution, and liquid-liquid extraction washing was carried out twice with water (50 mL), twice with a mixture of saturated aqueous sodium bicarbonate solution (25 mL) / water (25 mL), and once with saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain D13-1 (7.09 g) as a pale yellow liquid.

[0952] [Chemical formula 81]

[0953]

[0954] Under a nitrogen atmosphere, at room temperature, to a solution of D13-1 (1.0 eq., 7.09 g, calculated as 15.5 mmol) in dichloromethane (30 mL) was added TFA (10 eq., 12.3 mL, 161 mmol), and the mixture was stirred at room temperature for 1 hour. 1 M aqueous sodium hydroxide solution (145 mL) was added to the reaction solution, and liquid-liquid extraction was carried out once with ethyl acetate (100 mL). The organic layer was washed twice with water (50 mL) and once with saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain a crude product (5.62 g) as a pale yellow liquid. The crude product was purified by flash silica gel column chromatography (41 g of normal-phase silica gel, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain fragment D-13 (4.20 g, 81% yield in two steps) as a pale yellow liquid.

[0955] (Example 6F: Synthesis of fragment D-14)

[0956] Fragment D-14 was synthesized as described below.

[0957] [Chemical formula 82]

[0958]

[0959] Under a nitrogen atmosphere, at room temperature, 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) were added to a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.00 g, 15.5 mmol) in DMF (45 mL), 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 solution, and liquid-liquid extraction was performed twice with water (50 mL), twice with a mixture of saturated aqueous sodium bicarbonate (25 mL) / water (25 mL), and once with saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain D14-1 (7.80 g) as a pale yellow liquid.

[0960] [Chemical formula 83]

[0961]

[0962] Under a nitrogen atmosphere, at room temperature, 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), and the mixture was stirred at room temperature for 2 hours. 1 M aqueous sodium hydroxide solution (130 mL) was added to the reaction solution, and liquid-liquid extraction was performed once with ethyl acetate (100 mL). The organic layer was washed twice with water (50 mL) and once with saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain a crude product (6.61 g) as a pale yellow liquid. The crude product was purified by flash silica gel column chromatography (33 g of normal-phase silica gel, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain Fragment D-14 (4.00 g, two-step yield 71%) as a pale yellow liquid.

[0963] (Example 7: Synthesis of Compound 1)

[0964] [Chemical formula 84]

[0965]

[0966] Under a nitrogen atmosphere and with 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), and the mixture was stirred for 22 hours while warming to room temperature. 5% Aqueous citric acid solution (50 mL) was added to the reaction solution for a single liquid-liquid washing, and the organic layer was washed once with a mixture of 5% aqueous sodium bicarbonate solution (50 mL) / 5% aqueous sodium chloride solution (50 mL) and once with 5% aqueous sodium chloride solution (50 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (10.90 g) in the form of a light brown viscous substance. The crude product was purified by flash silica gel column chromatography (100 g of normal-phase silica gel, hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain Compound 1-1 (8.49 g, containing Fragment A-2, PMBOH, ethyl acetate, apparent yield 90%) in the form of a yellow viscous substance.

[0967] [Chemical Formula 85]

[0968]

[0969] Under a nitrogen atmosphere and with ice cooling, 1-dodecanethiol (6.0 eq., 3.73 g, 18.43 mmol) and DBU (6.0 eq., 2.81 g, 18.46 mmol) were added to a DMF (15 mL) solution of Compound 1-1 (1.0 eq., 2.97 g, containing Fragment A-2, PMBOH, ethyl acetate, calculated as 3.07 mmol), and the mixture was stirred at room temperature for 5 hours. Toluene (30 mL) and 5% aqueous citric acid solution (40 mL) were added to the reaction solution for a single liquid-liquid extraction, and the aqueous layer was extracted again with toluene (30 mL). The organic layers were combined, washed once with a mixture of 5% aqueous sodium bicarbonate solution (30 mL) / 5% aqueous sodium chloride solution (30 mL), dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (6.54 g) in the form of a yellow oil.

[0970] 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 purified by flash silica gel column chromatography (100 g of normal-phase silica gel, hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain Compound 1-2 (2.32 g, containing PMBOH and ethyl acetate, apparent yield 71%) in the form of a pale yellow oil.

[0971] [Chemical Formula 86]

[0972]

[0973] Under a nitrogen atmosphere, 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) were added 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), and the mixture was stirred at room temperature for 3.5 hours. Toluene (50 mL) and 5% aqueous sodium bicarbonate solution (50 mL) were added to the reaction solution for liquid-liquid extraction once. After the organic layer was washed once with 5% aqueous sodium chloride solution (50 mL), it was dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (3.49 g) in the form of a yellow viscous substance. The crude product was purified by flash silica gel column chromatography (28 g of NH2 silica gel, hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain compound 1-3 (2.22 g, yield 98%) in the form of a white amorphous solid.

[0974] [Chemical formula 87]

[0975]

[0976] 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) / water (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was cooled in ice, and 5% aqueous citric acid solution (30 mL) was added to adjust the pH to 3. Liquid-liquid extraction was performed once with ethyl acetate (30 mL). After the organic layer was washed once with 5% aqueous sodium chloride solution (30 mL), it was dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (2.45 g) in the form of a pale yellow viscous substance. The crude product was purified by flash silica gel column chromatography (25 g of 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, conversion yield 85%) in the form of a white amorphous solid.

[0977] [Chemical formula 88]

[0978]

[0979] Under a nitrogen atmosphere, at room temperature, 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). Subsequently, at the same temperature, 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 over 17 hours. After the addition was complete, the mixture was stirred at room temperature for an additional 1.5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (15 mL) and 5% aqueous citric acid solution (15 mL) were added to the concentrated residue for liquid-liquid extraction and washing once. The organic layer was washed once with 5% aqueous sodium bicarbonate solution (15 mL) and once with 5% aqueous sodium chloride solution (30 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a mixture (1.05 g) of Compound 1-5 and Compound 1-6 as a light brown amorphous solid.

[0980] Under a nitrogen atmosphere, with ice-cooling, TBAF (1.1 M in THF, 8.0 eq., 5.63 mL, 6.193 mmol) was added to a solution of the mixture of Compound 1-5 and Compound 1-6 (1.0 eq., 0.95 g, calculated as 0.774 mmol) in THF (19 mL), and the mixture was stirred for 4 hours while warming to room temperature. The reaction solution was cooled with ice, 10% aqueous ammonium chloride solution (40 mL) was added, and liquid-liquid 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, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product (1.19 g) as a light brown viscous substance.

[0981] The crude product (106 mg) obtained from the 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 purified by flash silica gel column chromatography (10 g of normal-phase silica gel, hexane / ethyl acetate = 50 / 50) to obtain Compound 1-6 (0.60 g, a mixture of isomers. Containing 0.7 wt% ethyl acetate, 36.4 wt% TBAF, 70% overall yield in two steps starting from Compound 1-4) as a light orange solid.

[0982] [Chemical Formula 89]

[0983]

[0984] Under a nitrogen atmosphere and with ice cooling, Dess-Martin periodinane (1.5 eq., 0.38 g, 0.90 mmol) was added to a dichloromethane (13 mL) solution of Compound 1-6 (1.0 eq., 0.66 g, isomer mixture, containing 3.9 wt% ethyl acetate and 38.9 wt% TBAF, 0.60 mmol). The mixture was stirred for 16 hours while warming to room temperature. After adding 5% aqueous sodium bicarbonate solution (10 mL) and 5% aqueous sodium thiosulfate solution (10 mL) to the reaction solution, liquid-liquid extraction and washing were carried out once. The organic layer was washed once with 5% aqueous sodium chloride solution (20 mL), dried over sodium sulfate, the sodium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain the aldehyde (0.392 g, containing isomers) in the form of a pale orange amorphous solid.

[0985] Under a nitrogen atmosphere and at room temperature, 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 tert-butanol (16 mL) / pentene (4 mL) / water (4 mL) containing the aldehyde (1.0 eq., 0.39 g, containing isomers, calculated as 0.60 mmol). 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 solution for liquid-liquid extraction once. The organic layer was washed twice with water (20 mL) and once with 5% aqueous sodium chloride solution (20 mL), and then dried over sodium sulfate. After filtering off the sodium sulfate, the solution was concentrated under reduced pressure to obtain Compound 1-7 (0.351 g, isomer mixture, containing 12.5 wt% TBAF, 80% conversion yield in two steps starting from Compound 1-6) in the form of a pale orange solid.

[0986] [Chemical formula 90]

[0987]

[0988] Under a nitrogen atmosphere and with ice cooling, DIPEA (3.0 eq., 78 μL, 0.46 mmol) and HBTU (1.5 eq., 87 mg, 0.23 mmol) were added to a dichloromethane (1.3 mL) solution of Compound 1-7 (1.0 eq., 130 mg, isomer mixture, containing 24.8 wt% TBAF, 0.15 mmol) and dibenzyl L-glutamate hydrochloride (Fragment D-1, 1.5 eq., 83 mg, 0.23 mmol). The mixture was stirred for 3.5 hours while warming to room temperature.

[0989] The reaction solution obtained by treating Compounds 1-7 (100 mg) through the same operation was combined with the previous reaction solution, and toluene (20 mL), 5% aqueous citric acid solution (20 mL), and 5% aqueous sodium chloride solution (10 mL) were added for liquid-liquid extraction washing once. The organic layer was subjected to liquid-liquid extraction washing once with 5% aqueous citric acid solution (20 mL), once with 5% aqueous sodium bicarbonate solution (20 mL), and once with 5% aqueous sodium chloride solution (20 mL). After drying with sodium sulfate, the sodium sulfate was filtered out. It was concentrated under reduced pressure, and the crude product (290 mg) obtained as a light brown viscous substance was subjected to flash silica gel column purification (6.5 g of NH2 silica gel, hexane / ethyl acetate = 50 / 50) to obtain Compound 1-8 (37 mg, yield 14%) as a yellow viscous substance.

[0990] [Chemical Formula 91]

[0991]

[0992] Under a nitrogen atmosphere and at room temperature, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 11.1 mg) was added to a mixed solution of THF (1.85 mL) / water (1.85 mL) of Compound 1-8 (1.0 eq., 37 mg, 0.039 mmol). After purging the system with hydrogen, it was stirred at the same temperature for 16 hours. The catalyst was filtered out through diatomaceous earth filtration. After the filtrate was concentrated under reduced pressure, a mixed solution of THF (1.85 mL) / water (1.85 mL) was added to the concentrated residue. After purging the system with nitrogen, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 11.1 mg) was added at room temperature. After purging the system with hydrogen, it was stirred at the same temperature for 3 hours. As the reaction proceeded, the target product precipitated as a solid, so TFA (2.0 eq., 6.0 μL, 0.078 mmol) was added to dissolve the target product. Then the catalyst was filtered out through diatomaceous earth filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product (27 mg) in a light orange amorphous form.

[0993] The crude product (15.5 mg) obtained from Compound 1-8 (21 mg) through the same operation was combined with the previous crude product and subjected to flash silica gel column purification twice (60 g of reverse-phase silica gel, first time: 0.05% aqueous TFA solution / acetonitrile = 99 / 1 to 90 / 10, second time: 0.05% aqueous TFA 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.

[0994] 1H-NMR (400 MHz, D2O) δ 6.94 - 6.87 (m, 3H), 4.86 (s, 1H), 4.37 (dd, J = 9.2, 4.8 Hz, 1H), 4.12 (d, J = 10.0 Hz, 1H), 4.05 (dd, J = 8.8, 4.8 Hz, 1H), 3.23 (dd, J = 13.2, 4.8 Hz, 1H), 2.92 (dd, J = 13.2, 8.8 Hz, 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 = 7.2 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.78 (d, J = 6.4 Hz, 3H).

[0995] (Example 8: Synthesis of Compound 9)

[0996] [Chemical Formula 92]

[0997]

[0998] Under a nitrogen atmosphere and with 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 L - aspartic acid dibenzyl ester 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), and the mixture was stirred at the same temperature for 6 hours. 5% Aqueous citric acid solution (10 mL) was added to the reaction solution for a single liquid - liquid extraction and washing. After the organic layer was washed once with a mixture of 5% aqueous sodium bicarbonate solution (10 mL) / 5% aqueous sodium chloride solution (10 mL), it was dried over sodium sulfate. After filtering out the sodium sulfate, the crude product (496 mg) obtained by concentration under reduced pressure, which was a light - brown viscous substance, was purified by flash silica gel column chromatography twice (normal - phase silica gel 10 g, first time: chloroform / ethyl acetate = 90 / 10 - 50 / 50, second time: chloroform / ethyl acetate = 90 / 10 - 85 / 15) to obtain low - purity Compound 9 - 1 (129 mg).

[0999] The low - purity Compound 9 - 1 was dissolved in toluene (10 mL), washed 5 times with 5% aqueous sodium chloride solution (10 mL), and then dried over sodium sulfate. After filtering out the sodium sulfate, it was concentrated under reduced pressure to obtain Compound 9 - 1 (93 mg, yield 28%) in the form of a yellow amorphous solid.

[1000] [Chemical Formula 93]

[1001]

[1002] Under a nitrogen atmosphere and at room temperature, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 2.5 mg) and TFA (2.0 eq., 8.2 μL, 0.107 mmol) were added to a mixed solution of THF (2.5 mL) / water (2.5 mL) of compound 9-1 (1.0 eq., 50 mg, 0.053 mmol). After hydrogen displacement in the system, the mixture was stirred at the same temperature for 23 hours. 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 2.5 mg) was added and stirred for 27 hours. 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 2.5 mg) was added again and stirred for a further 24 hours.

[1003] The reaction solution obtained by treating compound 9-1 (10 mg) through the same operation was combined with the previous reaction solution. After filtering out the catalyst through diatomaceous earth filtration, the filtrate was concentrated under reduced pressure to obtain a crude product (58 mg) in the form of an orange viscous substance. The crude product was purified by flash silica gel column (reverse-phase silica gel 30 g, 0.05% aqueous TFA / acetonitrile = 95 / 5 - 90 / 10), and then freeze-dried to obtain the TFA salt of compound 9 (30.5 mg, yield 73%, purity 97.8%) in the form of a white solid.

[1004] 1 H-NMR (400 MHz, D2O) δ 6.94 - 6.87 (m, 3H), 4.66 (dd, J = 7.2, 5.2 Hz, 1H), 4.11 (d, J = 10.0 Hz, 1H), 4.05 (dd, J = 8.8, 4.8 Hz, 1H), 3.24 (dd, J = 13.6, 4.8 Hz, 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 = 7.2 Hz, 3H), 0.86 (d, J = 7.2 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H).

[1005] (Example 9: Synthesis of Compound 2)

[1006] [Chemical Formula 94]

[1007]

[1008] 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, containing PMBOH, ethyl acetate, calculated as 2.97 mmol) in DMF (35 mL), and the mixture was stirred at room temperature for 2 hours. Toluene (70 mL) and 5% aqueous sodium bicarbonate solution (70 mL) were added to the reaction solution for a single liquid-liquid extraction. The organic layer was washed once with 5% aqueous sodium chloride solution (70 mL) and then dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (4.56 g) as a white solid. Ethyl acetate (45 mL) was added to the crude product, and the insoluble matter was filtered off after ultrasonic irradiation. 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 solid.

[1009] [Chemical formula 95]

[1010]

[1011] Under a nitrogen atmosphere, lithium hydroxide monohydrate (4.0 eq., 0.50 g, 11.92 mmol) was added to a mixture of compound 2-9 (1.0 eq., 3.50 g, 2.97 mmol) in THF (28 mL) / water (14 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was cooled in ice, and 5% aqueous citric acid solution (45 mL) was added to adjust the pH to 3. A single liquid-liquid extraction was performed with ethyl acetate (45 mL). The organic layer was washed once with 5% aqueous sodium chloride solution (45 mL) and then dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate 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 chromatography (25 g of 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 in the 4 steps starting from fragment B-1) as a pale orange amorphous solid.

[1012] [Chemical formula 96]

[1013]

[1014] 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, at the same temperature, 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 over 17 hours. After the addition was complete, the mixture was stirred at room temperature for an additional 1 hour. The reaction solution was concentrated under reduced pressure until it reached several mL.

[1015] Under a nitrogen atmosphere, the concentrated residue was stirred at an external temperature of 50 °C for 17 hours, and then 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 a single liquid-liquid extraction. The organic layer was 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 off, and the filtrate was concentrated under reduced pressure to obtain the crude product (0.98 g) as a light brown viscous substance. The crude product was purified by flash silica gel column chromatography (10 g of normal-phase silica gel, chloroform / ethyl acetate = 90 / 10 to 5 / 95) to obtain Compound 2-12 (0.168 g, containing isomers and impurities, 2-step apparent yield of 34% starting from Compound 2-10) as an orange solid.

[1016] [Chemical formula 97]

[1017]

[1018] Under a nitrogen atmosphere and with 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 to be 0.282 mmol) in dichloromethane (3.3 mL). The mixture was stirred for 2 hours while warming to room temperature. 5% aqueous sodium bicarbonate solution (3 mL) and 5% aqueous sodium thiosulfate solution (3 mL) were added to the reaction solution, followed by a single liquid-liquid extraction. The organic layer was washed once with 5% aqueous sodium chloride solution (3 mL), dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the aldehyde (133 mg, containing isomers, apparent yield 81%) as a pale orange amorphous solid.

[1019] Under a nitrogen atmosphere, at room temperature, 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 tert-butyl alcohol (5.6 mL) / pentene (1.4 mL) / water (1.4 mL) of aldehyde (1.0 eq., 131 mg, containing isomers, calculated as 0.224 mmol), and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate (15 mL) and water (15 mL) were added to the reaction solution for liquid-liquid extraction once. The organic layer was washed by liquid-liquid extraction once with a 5% aqueous sodium chloride solution (15 mL) and then dried over sodium sulfate. After filtering out the sodium sulfate, the solution was concentrated under reduced pressure to obtain compound 2-13 (97 mg, containing isomers, 2-step conversion yield starting from compound 2-12: 58%) as a yellow solid.

[1020] [Chemical formula 98]

[1021]

[1022] Under a nitrogen atmosphere and with ice cooling, DIPEA (1.5 eq., 34 μL, 0.197 mmol) and HATU (1.5 eq., 75 mg, 0.200 mmol) were added to a dichloromethane (2 mL) solution of compound 2-13 (1.0 eq., 79 mg, containing isomers, 0.132 mmol) and dibenzyl L-glutamate hydrochloride (fragment D-1, 1.5 eq., 72 mg, 0.198 mmol), and 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 solution for liquid-liquid extraction once. The organic layer was washed by liquid-liquid extraction once with a 5% aqueous sodium bicarbonate solution (10 mL) and once with a 5% aqueous sodium chloride solution (10 mL), and then dried over sodium sulfate. After filtering out the sodium sulfate, the solution was concentrated under reduced pressure, and the crude product (160 mg) obtained as a light brown viscous substance was purified by flash silica gel column chromatography twice (first and second time: 10 g of normal-phase silica gel, chloroform / ethyl acetate = 90 / 10 - 60 / 40) to obtain compound 2-6 (67 mg, containing fragment D-1, ethyl acetate, apparent yield: 56%) as a yellow amorphous solid.

[1023] [Chemical formula 99]

[1024]

[1025] Under a nitrogen atmosphere, at room temperature, to a mixed solution of THF (3.2 mL) / water (3.2 mL) of Compound 2-6 (1.0 eq., 64 mg, containing Fragment D-1, ethyl acetate, calculated as 0.070 mmol) was added 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 3.2 mg) and TFA (2.0 eq., 10.7 μL, 0.140 mmol). After hydrogen displacement in the system, the mixture was stirred at the same temperature for 66 hours. An additional 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 3.2 mg) was added, and after stirring for 21.5 hours, the catalyst was filtered out through diatomaceous earth. The filtrate was concentrated under reduced pressure and then subjected to a re-reaction. To the concentrated residue was added a mixed solution of THF (3.2 mL) / 3.2 mL), and after nitrogen displacement in the system, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 5.8 mg) and TFA (2.0 eq., 10.7 μL, 0.140 mmol) were added at room temperature. After hydrogen displacement in the system, the mixture was stirred at the same temperature for 23 hours. The catalyst was filtered out through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product (59 mg) in the form of a light brown viscous substance. The crude product was purified by flash silica gel column (reverse-phase silica gel 30 g, 0.05% aqueous TFA / acetonitrile = 95 / 5), and then freeze-dried to obtain the TFA salt of Compound 2 (5.2 mg, yield 12%, purity 97.1%) in the form of a white solid.

[1026] 1 1H-NMR (400 MHz, D2O) δ 7.45 (s, 1H), 7.05 - 7.03 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.63 (s, 1H), 4.45 (dd, J = 8.8, 5.2 Hz, 1H), 4.26 (d, J = 16.8 Hz, 1H), 3.98 (dd, J = 10.4, 3.6 Hz, 1H), 3.54 (d, J = 16.4 Hz, 1H), 3.25 (dd, J = 13.2, 4.0 Hz, 1H), 3.07 - 3.01 (m, 1H), 2.72 (s, 3H), 2.47 (t, J = 7.2 Hz, 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 = 7.2 Hz, 3H).

[1027] (Example 9A: Synthesis of Compound 9A)

[1028] The steps up to Compound 1-7 are the same as the synthesis method of Compound 1.

[1029] Compound 1-7 to Compound 9A-1

[1030] [Chemical Formula 100]

[1031]

[1032] Under a nitrogen atmosphere and with ice-cooling, DEPBT (1.5 eq., 57.5 mg, 0.192 mmol) and 2,4,6-trimethylpyridine (3.0 eq., 46.7 mg, 0.383 mmol) were added to a solution of Compound 1-7 (1.0 eq., 82.2 mg, 0.128 mmol) and diethyl L-aspartate hydrochloride (Fragment D-7, 1.5 eq., 43.2 mg, 0.191 mmol) in THF (1.2 mL). After stirring at the same temperature for 7 hours, the mixture was stirred at room temperature for 15 hours. After adding ethyl acetate (10 mL) to the reaction mixture, liquid separation and washing were carried out once with a mixture of water (5 mL) / saturated aqueous sodium bicarbonate solution (5 mL) and once with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (162 mg) in the form of a green oil. The crude product was purified by flash silica gel column chromatography (6 g of NH2 silica gel, hexane / ethyl acetate = 75 / 25 to 50 / 50) to obtain Compound 9A-1 (48.5 mg, yield 47%) in the form of a white amorphous solid.

[1033] The synthesis of Compound 9A from Compound 9A-1 was carried out as described below.

[1034] [Chemical Formula 101]

[1035]

[1036] Under a nitrogen atmosphere and at room temperature, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 2.0 mg) and TFA (2.0 eq., 3.7 μL, 0.048 mmol) were added to a mixture of Compound 9A-1 (1.0 eq., 20 mg, 0.025 mmol) in THF (800 μL) / water (40 μL). The system was purged with hydrogen, and after stirring at the same temperature for 23 hours, the catalyst was filtered off through diatomaceous earth filtration to obtain a filtrate.

[1037] The filtrate obtained identically from Compound 9A-1 (1.0 eq., 15 mg, 0.018 mmol) was combined with the above-mentioned filtrate and concentrated under reduced pressure to obtain the crude product. The obtained crude product (36.6 mg) was purified by flash silica gel column (reverse-phase silica gel 30 g, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 75 / 25). Lyophilization was carried out to obtain the TFA salt of Compound 9A as a white solid (16.3 mg, yield 54%, purity 94.4%).

[1038] 1 H-NMR (400 MHz, D2O) δ 6.98 - 6.82 (m, 3H), 4.24 - 4.09 (m, 5H), 4.04 (dd, J = 8.8, 4.4 Hz, 1H), 3.22 (dd, J = 13.2, 4.4 Hz, 1H), 3.00 - 2.80 (m, 3H), 2.71 (s, 3H), 2.07 - 1.87 (m, 2H), 1.79 - 1.62 (m, 1H), 1.57 (s, 3H), 1.24 (m, 6H), 1.05 (t, J = 7.2 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H).

[1039] (Example 9B: Synthesis of Compound 9B)

[1040] The steps up to Compound 1-7 were carried out as described in Example 7.

[1041] The synthesis of Compound 1-7 to Compound 9B-1 was carried out as described below.

[1042] [Chemical formula 102]

[1043]

[1044] Under a nitrogen atmosphere and with ice cooling, DEPBT (1.5 eq., 55.0 mg, 0.184 mmol) and 2,4,6-collidine (3.0 eq., 44.2 mg, 0.364 mmol) were added to a 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) in THF (1.2 mL). After stirring at the same temperature for 6 hours, the mixture was stirred at room temperature for 16 hours. After adding ethyl acetate (10 mL) to the reaction solution, it was separated and washed once with a mixture of water (5 mL) / saturated aqueous sodium bicarbonate solution (5 mL) and once with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (166 mg) in the form of a green oil. The crude product was purified by flash silica gel column chromatography (6 g of NH2 silica gel, hexane / ethyl acetate = 75 / 25 to 0 / 100) to obtain Compound 9B-1 (54.5 mg, yield 51%) in the form of a white amorphous solid.

[1045] The synthesis of Compound 9B-1 for Compound 9B was carried out as described below.

[1046] [Chemical Formula 103]

[1047]

[1048] Under a nitrogen atmosphere and at room temperature, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 3.9 mg) and TFA (5.0 eq., 17 μL, 0.223 mmol) were added to a mixture of Compound 9B-1 (1.0 eq., 39 mg, 0.045 mmol) in THF (1560 μL) / water (78 μL). After purging the system with hydrogen, the mixture was stirred at the same temperature for 4 hours. The catalyst was filtered off through diatomaceous earth, 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 operation was combined with the above crude product and purified by flash silica gel column chromatography (30 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 80 / 20). Lyophilization was carried out to obtain the TFA salt of Compound 9B (24.3 mg, yield 58%, purity 95.2%) in the form of a white solid.

[1049] 1H-NMR (400 MHz, D2O) δ 6.97 - 6.86 (m, 3H), 4.69 (dd, J = 7.2, 5.2 Hz, 1H), 4.18 - 4.10 (m, 3H), 4.06 (dd, J = 9.2, 4.8 Hz, 1H), 3.24 (dd, J = 13.6, 4.8 Hz, 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 = 7.2 Hz, 3H), 1.05 (t, J = 7.2 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H).

[1050] (Example 9C: Synthesis of Compound 9C)

[1051] The synthesis of Compound 1-7 to Compound 9C-1 was carried out as described below.

[1052] [Chemical Formula 104]

[1053]

[1054] Under a nitrogen atmosphere and with ice cooling, DEPBT (1.5 eq., 42.7 mg, 143 μmol) and 2,4,6-collidine (3.0 eq., 34.0 mg, 281 μmol) were added to a THF (1 mL) solution of Compound 1-7 (1.0 eq., 59.7 mg, 93.0 μmol) and Fragment D-9 (1.5 eq., 34.6 mg, 138 μmol). After stirring at the same temperature for 5 hours, the mixture was stirred at room temperature for 15.5 hours. After adding ethyl acetate (20 mL) to the reaction solution, liquid-liquid extraction was performed once with a mixture of water (5 mL) / saturated aqueous sodium bicarbonate solution (5 mL) and once with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was 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 chromatography (NH2 silica gel 6 g, hexane / ethyl acetate = 75 / 25 - 0 / 100) to obtain Compound 9C-1 (42.3 mg, yield 56%) as a white amorphous solid.

[1055] The synthesis of Compound 9-1 to Compound 9C was carried out as described below.

[1056] [Chemical Formula 105]

[1057]

[1058] Under a nitrogen atmosphere, at room temperature, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 4.1 mg) and TFA (2.0 eq., 7.2 μL, 0.094 mmol) were added to a mixed solution of THF (1640 μL) / water (82 μL) of compound 9C-1 (1.0 eq., 41 mg, 0.047 mmol). After hydrogen displacement in the system, the mixture was stirred at the same temperature for 6 hours. The catalyst was filtered out through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product (35 mg). The crude product was purified by flash silica gel column (reverse-phase silica gel 30 g, 0.05% aqueous TFA / acetonitrile = 95 / 5 - 80 / 20). Freeze-drying was carried out to obtain the TFA salt of compound 9C as a white solid (29.0 mg, yield 91%, purity 96.0%).

[1059] 1 1H-NMR (400 MHz, D2O) δ 6.98 - 6.85 (m, 3H), 4.24 - 4.17 (m, 2H), 4.10 (d, J = 9.6 Hz, 1H), 4.05 (dd, J = 9.2, 4.8 Hz, 1H), 3.23 (dd, J = 13.6, 4.8 Hz, 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 = 7.2 Hz, 3H), 1.05 (t, J = 7.2 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 0.78 (d, J = 6.4 Hz, 3H).

[1060] (Example 9D: Synthesis of Compound 9D)

[1061] Compounds 1 - 7 were synthesized as described in Example 7. The synthesis of compounds 1 - 7 to compound 9D-1 was carried out as described below.

[1062] [Chemical Formula 106]

[1063]

[1064] Under a nitrogen atmosphere and with ice cooling, DEPBT (1.5 eq., 48.8 mg, 163 μmol) and 2,4,6-collidine (3.0 eq., 38.6 mg, 319 μmol) were added to a 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) in THF (1 mL). After stirring at the same temperature for 6 hours, the mixture was stirred at room temperature for 16 hours. Ethyl acetate (10 mL) was added to the reaction solution, and the mixture was separated and washed once with a mixture of water (5 mL) / saturated aqueous sodium bicarbonate solution (5 mL) and once with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate 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 chromatography (6 g of NH2 silica gel, hexane / ethyl acetate = 75 / 25 to 0 / 100) to obtain Compound 9D-1 (54.0 mg, yield 54%) as a white amorphous solid.

[1065] The synthesis of Compound 9D-1 from Compound 9D was carried out as described below.

[1066] [Chemical Formula 107]

[1067]

[1068] At room temperature, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 3.8 mg) and TFA (2.0 eq., 6.3 μL, 0.082 mmol) were added to a mixture of Compound 9D-1 (1.0 eq., 38.0 mg, 0.041 mmol) in THF (1600 μL) / water (80 μL). The system was purged with hydrogen, and after stirring at the same temperature for 19 hours, the catalyst was filtered off through diatomaceous earth to obtain a filtrate. The resulting crude product (32 mg) was purified by flash silica gel column chromatography (30 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 70 / 30). Lyophilization was carried out to obtain the TFA salt of Compound 9D (14.9 mg, yield 50%, purity 95.6%) as a white solid.

[1069] 1H-NMR (400 MHz, D2O) δ 6.96 - 6.86 (m, 3H), 4.22 - 4.09 (m, 3H), 4.04 (dd, J = 9.2, 4.8 Hz, 1H), 3.23 (dd, J = 13.6, 4.8 Hz, 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 = 7.2 Hz, 3H), 0.90 - 0.80 (m, 6H), 0.78 (d, J = 6.4 Hz, 3H).

[1070] (Example 9E: Synthesis of Compound 9E)

[1071] The synthesis of Compound 9E was carried out.

[1072] [Chemical Formula 108]

[1073]

[1074] Under a nitrogen atmosphere and with ice cooling, 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 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) in THF (1.4 mL). After stirring for 7 hours under ice cooling, the mixture was stirred for 16.5 hours at room temperature. After adding Fragment D-11 (0.5 eq., 27.1 mg, 69 μmol) at room temperature, DEPBT (0.5 eq., 22.5 mg, 75 μmol) was added under ice cooling. After stirring for 2 hours under ice cooling, the mixture was stirred for 1.5 hours at room temperature. After adding saturated aqueous ammonium chloride solution (1.5 mL) to the reaction solution, liquid-liquid extraction was carried out once with ethyl acetate (8 mL) and once with ethyl acetate (4 mL). The organic layers were combined and washed by liquid-liquid separation twice with saturated aqueous sodium bicarbonate solution (2 mL), once with water (2 mL), and once with saturated aqueous sodium chloride solution (2 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and concentration under reduced pressure was carried out, thereby obtaining a crude product (244 mg) in the form of a dark green viscous substance. The crude product was purified by flash silica gel column chromatography (4.9 g of NH2 silica gel, hexane / ethyl acetate = 3 / 1 - 1 / 1), and Compound 9E-1 (71.3 mg, yield 50%) was obtained in the form of a pale yellow transparent viscous substance.

[1075] [Chemical Formula 109]

[1076]

[1077] At room temperature, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 5.3 mg) and TFA (2.0 eq., 8.0 μL, 0.104 mmol) were added to a mixed solution of THF (2200 μL) / water (110 μL) of compound 9E-1 (1.0 eq., 53 mg, 0.052 mmol). Hydrogen replacement was carried out in the system, and after stirring at the same temperature for 23 hours, the catalyst was filtered out through diatomaceous earth filtration to obtain a filtrate. The crude product (44 mg) obtained by concentrating the filtrate under reduced pressure was purified by flash silica gel column (reverse-phase silica gel 30 g, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 50 / 50). Lyophilization was carried out to obtain the TFA salt of compound 9E (36.6 mg, yield 86%, purity 94.3%) in the form of a white solid.

[1078] 1 H-NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.77 (d, J = 8.4 Hz, 1H), 8.63 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 6.80 - 6.72 (m, 3H), 4.86 (d, J = 9.6 Hz, 1H), 4.57 (dd, J = 13.2, 7.2 Hz, 1H), 4.23 (dd, J = 9.2, 9.2 Hz, 1H), 4.05 - 3.95 (m, 2H), 3.89 (brs, 1H), 3.05 - 2.95 (m, 1H), 2.88 (dd, J = 14.4, 6.0 Hz, 1H), 2.73 (dd, J = 16.8, 6.0 Hz, 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 = 7.2 Hz, 3H), 0.92 - 0.73 (m, 9H)

[1079] (Example 9F: Synthesis of Compound 9F)

[1080] [Chemical Formula 110]

[1081]

[1082] Under a nitrogen atmosphere and with ice-cooling, 2,4,6-collidine (3.0 eq., 57 μL, 433 μmol) and DEPBT (1.5 eq., 65.8 mg, 220 μmol) were added to a solution of Compound 1-7 (1.0 eq., 93.3 mg, 141 μmol) and Fragment D-13 (1.6 eq, 75.6 mg, 225 μmol) in THF (1.45 mL). After stirring for 6 hours under ice-cooling, the mixture was stirred at room temperature for 16 hours. After adding saturated aqueous ammonium chloride solution (2.0 mL) to the reaction solution, liquid-liquid extraction was performed twice with ethyl acetate (6 mL). The organic layers were combined and washed by liquid-liquid separation twice with saturated aqueous sodium bicarbonate solution (3 mL), twice with water (3 mL), and once with saturated aqueous sodium chloride solution (2 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (238 mg) in the form of a dark green viscous substance. The crude product was purified by flash silica gel column chromatography (5.2 g of NH2 silica gel, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain Compound 9F-1 (73.3 mg, yield 53%) in the form of a white amorphous solid.

[1083] [Chemical Formula 111]

[1084]

[1085] Under a nitrogen atmosphere and at room temperature, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 7 mg) and TFA (2.0 eq., 25.5 μL, 0.15 mmol) were added to a mixed solution of Compound 9F-1 (1.0 eq., 72 mg, 0.075 mmol) in THF (2880 μL) / water (144 μL). The system was purged with hydrogen, and after stirring at the same temperature for 7 hours, the catalyst was filtered off through diatomaceous earth filtration. The filtrate was concentrated under reduced pressure to obtain a crude product (59 mg). The crude product was purified by flash silica gel column chromatography (30 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 55 / 45). Lyophilization was performed to obtain the TFA salt of Compound 9F (31.4 mg, yield 55%, purity 95.4%) in the form of a white solid.

[1086] 1H-NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.77 (d, J = 8.4 Hz, 1H), 8.62 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 9.6 Hz, 1H), 6.80 - 6.75 (m, 3H), 4.86 (d, J = 10.4 Hz, 1H), 4.57 (dd, J = 13.6, 7.2 Hz, 1H), 4.23 (dd, J = 9.2, 9.2 Hz, 1H), 4.07 - 3.85 (m, 3H), 3.05 - 2.95 (m, 1H), 2.89 (dd, J = 14.4, 5.6 Hz, 1H), 2.73 (dd, J = 16.8, 6.0 Hz, 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 = 7.2 Hz, 3H), 0.92 - 0.75 (m, 9H).

[1087] (Example 9G: Synthesis of Compound 9G)

[1088] [Chemical Formula 112]

[1089]

[1090] The two steps from Fragment A-2" to Compound 25-2 are as described in Example 29B below.

[1091] The synthesis of Compound 25-2 to Compound 9G-1 is carried out as described below.

[1092] [Chemical Formula 113]

[1093]

[1094] At room temperature, 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) were added to a solution of compound 25-2 (1.0 eq., 1.03 g, 1.44 mmol) in DMF (15 mL), and the mixture was stirred at room temperature for 5 hours. A mixture of hexane (15 mL) / ethyl acetate (45 mL) was added to the reaction solution, and liquid separation and washing were carried out twice with water (40 mL), twice with saturated aqueous sodium bicarbonate solution (40 mL), and once with saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain compound 9G-1 (1.71 g, crude yield 115%) in the form of a light brown amorphous solid.

[1095] The synthesis of compound 9G-2 from compound 9G-1 was carried out as described below.

[1096] [Chemical formula 114]

[1097]

[1098] At room temperature, lithium hydroxide (6.0 eq., 207 mg, 8.62 mmol) was added to a mixture of compound 9G-1 (1.0 eq., 1.71 g, calculated as 1.44 mmol) in THF (10 mL) / water (5 mL), and the mixture was stirred at room temperature for 4 hours. 1N hydrochloric acid aqueous solution (5.0 mL) was added to the reaction solution to adjust the pH to 7. Water (10 mL) was added to the reaction solution, and liquid separation extraction was carried out three times with ethyl acetate (20 mL). The organic layers were combined and washed once with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (1.84 g) in the form of a brown viscous substance. The crude product was purified by flash silica gel column chromatography (20 g of normal-phase silica gel, ethyl acetate / methanol = 100 / 0 to 40 / 60) to obtain compound 9G-2 (1.06 g, two-stage yield 102%) in the form of a light brown amorphous solid.

[1099] The synthesis of compound 9G-3 from compound 9G-2 was carried out as described below.

[1100] [Chemical formula 115]

[1101]

[1102] A mixture of acetonitrile (14.5 mL) / THF (14.5 mL) of compound 9G-2 (1.0 eq., 1.05 mg, calculated as 1.44 mmol) was added dropwise 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 over 5 hours at a rate of approximately 100 μL / min, and then stirred at room temperature for 15.5 hours. After the reaction mixture was concentrated under reduced pressure to approximately 250 mL, ethyl acetate (200 mL) was added, and liquid-liquid extraction and washing were carried out twice with a mixture of water (50 mL) / saturated aqueous ammonium chloride solution (100 mL), twice with saturated aqueous sodium bicarbonate solution (100 mL), and once with saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (1.92 g) in the form of a reddish-brown viscous substance. The crude product was purified by flash silica gel column chromatography (25 g of normal-phase silica gel, hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain compound 9G-3 (231 mg, 23% yield in three steps) in the form of a white amorphous solid.

[1103] The synthesis of compound 9G-4 from compound 9G-3 was carried out as described below.

[1104] [Chemical formula 116]

[1105]

[1106] At room temperature, TBAF (1 M in THF, 2.5 eq., 0.81 mL, 0.810 mmol) was added to a solution of compound 9G-3 (1.0 eq., 230 mg, 0.324 mmol) in THF (3.2 mL), and the mixture was stirred at the same temperature for 2 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and liquid-liquid extraction and washing were carried out three times with saturated aqueous ammonium chloride solution (20 mL) and once with saturated aqueous sodium chloride solution (10 mL), and then dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (214 mg) in the form of a pale yellow amorphous solid. The crude product was purified by flash silica gel column chromatography (5 g of normal-phase silica gel, hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain compound 9G-4 (191 mg, 99% yield) in the form of a white amorphous solid.

[1107] The synthesis of compound 9G-5 from compound 9G-4 was carried out as described below.

[1108] [Chemical formula 117]

[1109]

[1110] Under a nitrogen atmosphere, at room temperature, 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), and the mixture was stirred at the same temperature for 1 hour. A mixture of 10% aqueous sodium sulfite solution (10 mL) / saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture to quench it, and the mixture was extracted by liquid separation once with dichloromethane (20 mL) and twice with dichloromethane (10 mL). The organic layers were combined and washed by liquid separation once with saturated aqueous sodium chloride solution (10 mL). After drying the organic layer with magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the aldehyde as a white amorphous solid (187 mg, quant.).

[1111] At room temperature, sodium dihydrogen phosphate dihydrate (3.4 eq., 167 mg, 1.07 mmol) and an aqueous solution (1 mL) of 80% sodium chlorite (4.5 eq., 160 mg, 1.42 mmol) were added to a mixture of aldehyde (1.0 eq., 186 mg, 0.314 mmol) in pentene (1 mL) / tert-butyl alcohol (4 mL), and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, and the mixture was extracted by liquid separation once with ethyl acetate (20 mL) and twice with ethyl acetate (10 mL). The organic layers were combined and washed by liquid separation once with saturated aqueous sodium chloride solution (20 mL). After drying with magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product as a white amorphous solid (215 mg, yield 99%). The crude product was purified by flash silica gel column chromatography (5 g of normal-phase silica gel, hexane / ethyl acetate = 33 / 67) to obtain compound 9G-5 as a white amorphous solid (178 mg, yield 93%).

[1112] The synthesis of compound 9G-6 from compound 9G-5 was carried out as described below.

[1113] [Chemical formula 118]

[1114]

[1115] At room temperature, to a mixture of ethyl acetate (1.8 mL) / water (540 μL) of compound 9G-5 (1.0 eq., 177 mg, 0.291 mmol) was added fragment D-14 (1.5 eq., 164 mg, 0.435 mmol). Under ice-cooling, DIPEA (2.4 eq., 0.12 mL, 0.706 mmol) was added, and after stirring for 10 minutes, DMT-MM (1.7 eq., 138 mg, 0.497 mmol) was 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 liquid separation washing was carried out once with water (15 mL), once with a mixture of water (10 mL) / saturated ammonium chloride aqueous solution (10 mL), once with water (10 mL) / saturated sodium bicarbonate aqueous solution (10 mL), and once with saturated sodium chloride aqueous solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (360 mg) in the form of a yellow oil. The crude product was purified by flash silica gel column chromatography twice (the first time: 6 g of NH2 silica gel, hexane / ethyl acetate = 75 / 25 to 67 / 33; the second time: 4 g of normal-phase silica gel, hexane / ethyl acetate = 50 / 50) to obtain compound 9G-6 (235 mg, yield 83%) in the form of a white amorphous solid.

[1116] The synthesis of compound 9G-6 to compound 9G-7 was carried out as described below.

[1117] [Chemical formula 119]

[1118]

[1119] At room temperature, to a solution of compound 9G-6 (1.0 eq., 235 mg, 0.243 mmol) in dichloromethane (2.4 mL) was added TFA (9.7 eq., 0.18 mL, 2.35 mmol), and the mixture was stirred at the same temperature for 1 hour. Then, additional TFA (9.7 eq., 0.18 mL, 2.35 mmol) was added, and the mixture was stirred at the same temperature for 7 hours. The reaction mixture was cooled in ice, and saturated sodium bicarbonate aqueous solution (15 mL) was added to adjust the pH to 8. The reaction mixture was extracted by liquid separation once with ethyl acetate (20 mL) and twice with ethyl acetate (10 mL), and the combined organic layers were washed by liquid separation once with saturated sodium chloride aqueous solution (20 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain compound 9G-7 (210 mg, yield 99%) in the form of a pale yellow amorphous solid.

[1120] The synthesis of compound 9G-7 to compound 9G was carried out as described below.

[1121] [Chemical formula 120]

[1122]

[1123] Under a nitrogen atmosphere and at room temperature, TFA (5.0 eq., 83 μL, 1.085 mmol) was added to a mixed solution of THF (7.4 mL) / water (370 μL) of compound 9G-7 (1.0 eq., 186 mg, 0.218 mmol), and the mixture was stirred at the same temperature for 1 hour. 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 18.6 mg) was added, and after hydrogen displacement in the system, the mixture was stirred at the same temperature for 6.5 hours. After filtering out the catalyst through diatomaceous earth, 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 operation was combined with the above crude product, and subjected to flash silica column purification (reverse-phase silica gel 30 g, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 55 / 45). Lyophilization was carried out to obtain the TFA salt of compound 9G as a white solid (107 mg, yield 51%, purity 96.4%).

[1124] 1 1H-NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.79 (d, J = 8.8 Hz, 1H), 8.62 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 10.0 Hz, 1H), 6.80 - 6.75 (m, 3H), 4.87 (d, J = 10.0 Hz, 1H), 4.57 (dd, J = 13.6, 7.2 Hz, 1H), 4.23 (dd, J = 9.2, 9.2 Hz, 1H), 4.05 - 3.85 (m, 3H), 3.05 - 2.95 (m, 1H), 2.89 (dd, J = 14.4, 5.6 Hz, 1H), 2.73 (dd, J = 16.8, 6.0 Hz, 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 = 7.2 Hz, 3H), 0.92 - 0.74 (m, 9H).

[1125] (Example 10: Synthesis of Compound 10)

[1126] [Chemical Formula 121]

[1127]

[1128] Under a nitrogen atmosphere and with ice cooling, 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 dibenzyl L-aspartate hydrochloride (fragment D-2, 1.5 eq., 83 mg, 0.237 mmol) in dichloromethane (2.4 mL), and the mixture was stirred for 3 hours while warming to room temperature. 5% Aqueous citric acid solution (3 mL) was added to the reaction solution for a single liquid-liquid washing, then the organic layer was 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 off the sodium sulfate, the solution was concentrated under reduced pressure, and the crude product obtained as a light brown viscous substance (197 mg) was subjected to two flash silica gel column purifications (first time: 10 g of normal-phase silica gel, hexane / ethyl acetate = 40 / 60; second time: 6.5 g of NH2 silica gel, hexane / ethyl acetate = 40 / 60 to 0 / 100) to obtain compound 10-1 as a white solid (54 mg, containing 5.0 wt% hexane, conversion yield 36%).

[1129] [Chemical formula 122]

[1130]

[1131] Under a nitrogen atmosphere and at room temperature, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 2.6 mg) and TFA (2.0 eq., 8.4 μL, 0.110 mmol) were added to a mixture of THF (2.5 mL) / water (2.5 mL) of compound 10-1 (1.0 eq., 52 mg, containing 5.0 wt% hexane, 0.055 mmol). After purging the system with hydrogen, the mixture was stirred at the same temperature for 25 hours. THF (2.5 mL) was added, and stirring was continued for 64 hours. 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 2.6 mg) was added, and stirring was carried out for 24 hours. After filtering off the catalyst through diatomaceous earth filtration, the filtrate was concentrated under reduced pressure to obtain a crude product as a light orange viscous substance (41 mg). The crude product was subjected to flash silica gel column purification (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 10 as a white solid (18.3 mg, yield 54%, purity 99.3%).

[1132] 1H-NMR (400 MHz, D2O) δ 7.44 (s, 1H), 7.05 (dd, J = 8.0, 2.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 4.65 (s, 1H), 4.25 (d, J = 16.4 Hz, 1H), 3.99 (dd, J = 10.4, 4.0 Hz, 1H), 3.55 (d, J = 16.4 Hz, 1H), 3.26 (dd, J = 13.2, 4.0 Hz, 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 = 7.2 Hz, 3H).

[1133] (Example 11: Synthesis of Compound 5)

[1134] [Chemical Formula 123]

[1135]

[1136] Under a nitrogen atmosphere, at room temperature, 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). Stirring was carried out for 15 minutes at the same temperature and then for 2 hours with an external temperature of 75 °C. Triphenylphosphine (0.75 eq., 0.99 g, 3.77 mmol) and DIAD (1.5 eq., 0.81 mL, 3.77 mmol) were added for further stirring for 0.5 hour. After allowing the reaction solution to cool, it was concentrated under reduced pressure. The concentrated residue was purified by flash silica gel column chromatography (50 g of normal-phase silica gel, hexane / ethyl acetate = 90 / 10 - 67 / 33) to obtain Compound 5-1 (5.95 g, containing impurities, apparent yield 130%) as a pale yellowish-brown oil.

[1137] [Chemical Formula 124]

[1138]

[1139] Under a nitrogen atmosphere and with ice cooling, 1M aqueous hydrochloric acid solution (1.1 eq., 5.00 mL, 5.00 mmol) was added to a solution of Compound 5-1 (1.0 eq., 5.35 g, containing impurities, calculated as 4.55 mmol) in acetonitrile (45 mL). 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 mixture to adjust the pH to 5 - 7, and then 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 by liquid separation with ethyl acetate (25 mL). The organic layers were combined, washed once by liquid separation with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, and then the sodium sulfate was filtered off. The filtrate was concentrated under reduced pressure to obtain the crude product (5.42 g) as a light yellowish brown oil. The crude product was purified by flash silica gel column chromatography (normal-phase silica gel 50 g, chloroform / acetonitrile = 90 / 10 - 80 / 20) to obtain Compound 5-2 (1.59 g, containing impurities, apparent yield 75%) as a light yellow oil.

[1140] [Chemical formula 125]

[1141]

[1142] 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 as 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 mixture, and the mixture was extracted three times by liquid separation with ethyl acetate (25 mL). The organic layers were combined, washed once by liquid separation with saturated aqueous sodium bicarbonate solution (25 mL) and once by liquid separation with saturated aqueous sodium chloride solution (25 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product (1.50 g) as a light yellow oil. The crude product was purified by flash silica gel column chromatography twice (First time: normal-phase silica gel 50 g, hexane / ethyl acetate = 90 / 10 - 50 / 50; Second time: reverse-phase silica gel 120 g, 0.05% aqueous TFA solution / acetonitrile = 90 / 10 - 0 / 100) to obtain Compound 5-3 (0.74 g, yield of the starting 3 stages of Fragment A-2 38%) as a white amorphous solid.

[1143] [Chemical formula 126]

[1144]

[1145] Under a nitrogen atmosphere and with ice cooling, 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), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure. To the concentrated residue, a 0.05 M hydrochloric acid / 1,4-dioxane solution (20 mL) was added and concentrated under reduced pressure, and this operation was carried out 2 times. 1,4-Dioxane was added to the concentrated residue and concentrated under reduced pressure, and this operation was carried out 3 times to obtain compound 5-4 (1.39 g) as a colorless oil.

[1146] [Chemical formula 127]

[1147]

[1148] Under a nitrogen atmosphere and at room temperature, a solution of compound 5-4 (1.0 eq., 1.39 g, calculated as 0.865 mmol) in DMF (65 mL) was added dropwise over 2 hours 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). After the addition was complete, the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. Ethyl acetate (20 mL) and water (20 mL) were added to the concentrated residue for liquid-liquid extraction once. The organic layer was washed once with a saturated sodium chloride aqueous solution (10 mL) and then dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (0.71 g) as a yellowish-brown solid. The crude product was purified by flash silica gel column chromatography (25 g of normal-phase silica gel, chloroform / ethyl acetate = 90 / 10 to 80 / 20) to obtain compound 5-5 (226 mg, containing impurities, the apparent yield of the two-step reaction starting from compound 5-3 was 42%).

[1149] [Chemical formula 128]

[1150]

[1151] 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 solution was allowed to cool, and ethyl acetate (20 mL) and 1 M aqueous hydrochloric acid solution (20 mL) were added for liquid-liquid extraction once. The organic layer was washed once with 10% aqueous sodium chloride solution (20 mL), dried over sodium sulfate, and then the sodium sulfate was filtered off. After filtering off the sodium sulfate, the solution was concentrated under reduced pressure to obtain a crude product (169 mg) as a white solid.

[1152] A crude product (20 mg) was obtained from compound 5-5 (20 mg) by the same operation. It was combined with the previous crude product and purified by flash silica gel column chromatography (10 g of normal-phase silica gel, ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain compound 5-6 (147 mg, containing impurities, apparent yield 93%).

[1153] [Chemical formula 129]

[1154]

[1155] Under a nitrogen atmosphere and at room temperature, 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) were added to a solution of compound 5-6 (1.0 eq., 73 mg, containing impurities, 0.12 mmol) and dibenzyl L-glutamate hydrochloride (fragment D-1, 1.5 eq., 65 mg, 0.18 mmol) in DMF (0.73 mL), and the mixture was stirred at the same temperature for 1.5 hours.

[1156] Toluene (3 mL) was added to the reaction solution, and it was washed twice with 5% aqueous sodium bicarbonate solution (3 mL) and once with 5% aqueous sodium chloride solution (3 mL) by liquid-liquid extraction. The organic layer was dried over sodium sulfate, and after filtering off the sodium sulfate, the solution was concentrated under reduced pressure to obtain a crude product (115 mg) as a pale yellow solid. The crude product was purified by flash silica gel column chromatography (6.5 g of NH2 silica gel, 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 this solid, and after ultrasonic irradiation, the mixture 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.

[1157] [Chemical formula 130]

[1158]

[1159] Under a nitrogen atmosphere and at room temperature, 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 8.8 mg) was added to a mixed solution of THF (1.2 mL) / water (1.2 mL) of compound 5-7 (1.0 eq., 35 mg, 0.038 mmol). After hydrogen displacement in the system, the mixture was stirred at the same temperature for 22 hours. The catalyst was filtered out through diatomaceous earth, and the solid was washed with a 0.05% aqueous TFA solution. Then the filtrate was concentrated under reduced pressure to obtain a crude product (20 mg) in the form of a white solid. The crude product was purified by flash silica gel column chromatography twice (reverse-phase silica gel 60 g, first time: 0.05% aqueous TFA solution / acetonitrile = 99 / 1 - 90 / 10, second time: 0.05% aqueous TFA solution / acetonitrile = 99 / 1 - 0 / 100), and then freeze-dried to obtain the TFA salt of compound 5 (14 mg, yield 59%, purity 99.7%) in the form of a white solid.

[1160] 1 H-NMR (400 MHz, D2O) δ 6.89 (d, J = 8.0 Hz, 1H), 6.81 (dd, J = 8.0, 2.0 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 4.65 (dd, J = 13.2, 2.4 Hz, 1H), 4.56 (dd, J = 13.2, 6.0 Hz, 1H), 4.37 (dd, J = 8.8, 4.8 Hz, 1H), 4.11 (d, J = 10.8 Hz, 1H), 3.95 (dd, J = 8.8, 4.8 Hz, 1H), 3.21 (dd, J = 13.2, 4.8 Hz, 1H), 2.95 (dd, J = 13.2, 8.8 Hz, 1H), 2.70 (s, 3H), 2.45 (t, J = 7.2 Hz, 2H), 2.24 - 2.15 (m, 1H), 2.03 - 1.85 (m, 2H), 0.84 (t, J = 6.8 Hz, 6H).

[1161] (Example 12: Synthesis of Compound 3)

[1162] [Chemical Formula 131]

[1163]

[1164] Under a nitrogen atmosphere, to a solution of Compound 5-2 (1.0 eq., 0.79 g, containing impurities, calculated as 1.20 mmol) in DMF (12 mL) was added 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), and the mixture was stirred at room temperature for 2 hours. Water (30 mL) and toluene (30 mL) were added to the reaction solution for liquid-liquid extraction once. The organic layer was washed by liquid-liquid extraction once with water (30 mL) and once with 10% aqueous sodium chloride solution (30 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product (1.175 g) as a yellow viscous substance. The crude product was purified by flash silica gel column chromatography (14 g of 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, conversion yield 86%) as a pale yellow viscous substance.

[1165] [Chemical formula 132]

[1166]

[1167] Under a nitrogen atmosphere and under ice-cooling, 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) was added triethylsilane (25 eq., 3.01 g, 25.89 mmol) and TFA (4.35 mL), and the mixture was stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and 0.05 M hydrochloric acid / 1,4-dioxane solution (15 mL) was added to the concentrated residue, followed by concentration under reduced pressure again to obtain Compound 3-2 (1.196 g, containing 1,4-dioxane) as a colorless viscous substance.

[1168] [Chemical formula 133]

[1169]

[1170] Under a nitrogen atmosphere, at room temperature, 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 dropwise over 18.5 hours 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). After the addition was complete, the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (15 mL) and 5% aqueous citric acid solution (15 mL) were added to the concentrated residue for liquid-liquid extraction once. 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 filtrate was concentrated under reduced pressure to obtain the crude product (0.81 g) in the form of a light brown amorphous solid. The crude product was purified by flash silica gel column chromatography (10 g of NH2 silica gel, hexane / ethyl acetate = 50 / 50) to obtain compound 3-3 (190 mg, yield 46%) in the form of a white solid. Compound 3-3 (89 mg) obtained by the same operation was combined, purified by flash silica gel column chromatography (14 g of NH2 silica gel, hexane / ethyl acetate = 50 / 50), and the fractions containing the target compound were combined and concentrated under reduced pressure. The concentrated residue was dissolved in 1,2-dichloroethane (3 mL) and concentrated under reduced pressure, and this operation was carried out twice to obtain compound 3-3 (118 mg, containing 16.5 wt% 1,2-dichloroethane, yield 35%) in the form of a colorless viscous substance.

[1171] [Chemical formula 134]

[1172]

[1173] Under a nitrogen atmosphere, trimethyltin hydroxide (4.0 eq., 124 mg, 0.69 mmol) was added to a solution of compound 3-3 (1.0 eq., 118 mg, containing 16.5 wt% 1,2-dichloroethane, 0.17 mmol) in 1,2-dichloroethane (2.7 mL), and the mixture was stirred at an external temperature of 80 °C for 3.5 hours. After the reaction solution was cooled, ethyl acetate (20 mL) and 1 M aqueous hydrochloric acid solution (20 mL) were added for liquid-liquid extraction once. The organic layer was washed once with 5% aqueous sodium chloride solution (20 mL), dried over sodium sulfate, and then the sodium sulfate was filtered off. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure to obtain compound 3-4 (104 mg, containing impurities, quant.) in the form of a white solid.

[1174] [Chemical formula 135]

[1175]

[1176] Under a nitrogen atmosphere, at room temperature, to a solution of compound 3-4 (1.0 eq., 50 mg, containing impurities, calculated as 0.082 mmol) and dibenzyl L-glutamate hydrochloride (fragment D-1, 1.5 eq., 45 mg, 0.124 mmol) in DMF (0.5 mL) were added 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), and the mixture was stirred at the same temperature for 1.5 hours. Toluene (10 mL) and 5% aqueous citric acid solution (10 mL) were added to the reaction solution for a single liquid-liquid extraction, and the organic layer was washed by liquid-liquid extraction 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, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product (82 mg) in the form of a pale yellow viscous substance.

[1177] A crude product (60 mg) was obtained from compound 3-4 (1.0 eq., 50 mg) by the same operation. After combining with the previous crude product, flash silica column purification was carried out (6.5 g of NH2 silica, hexane / ethyl acetate = 40 / 60) to obtain compound 3-5 (69 mg, yield 48%) in the form of a white amorphous solid.

[1178] [Chemical formula 136]

[1179]

[1180] Under a nitrogen atmosphere, at room temperature, to a mixture of THF (3.35 mL) / water (3.35 mL) of compound 3-5 (1.0 eq., 67 mg, 0.077 mmol) was added 10% palladium-carbon (N.E.Chemcat NX type, 50% water-containing product, 17 mg). After hydrogen displacement of the system, the mixture was stirred at the same temperature for 19.5 hours. After adding TFA (2.0 eq., 12 μL, 0.157 mmol) to the reaction solution, the catalyst was filtered off through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product (45 mg). After flash silica column purification of the crude product (60 g of reverse-phase silica, 0.05% aqueous TFA solution / acetonitrile = 99 / 1 to 0 / 100), lyophilization was carried out to obtain the TFA salt of compound 3 (34 mg, yield 76%, purity 99.9%) in the form of a white solid.

[1181] 1H-NMR (400 MHz, D2O) δ 7.00 - 6.85 (m, 3H), 4.67 (dd, J = 13.6, 5.6 Hz, 1H), 4.53 (dd, J = 13.2, 1.6 Hz, 1H), 4.42 (dd, J = 8.8, 5.2 Hz, 1H), 4.36 (d, J = 15.2 Hz, 1H), 3.96 (dd, J = 10.0, 4.8 Hz, 1H), 3.36 - 3.29 (m, 2H), 2.98 (dd, J = 13.2, 10.0 Hz, 1H), 2.73 (s, 3H), 2.50 (t, J = 7.2 Hz, 2H), 2.28 - 2.19 (m, 1H), 2.08 - 1.90 (m, 1H).

[1182] (Example 13: Synthesis of Compound 11)

[1183] [Chemical Formula 137]

[1184]

[1185] Under a nitrogen atmosphere and with 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), 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) was added. Then 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.

[1186] The reaction solution using Compound 3 - 4 (30 mg) under the same conditions was combined with the previous reaction solution. Ethyl acetate (40 mL) and 1 M aqueous hydrochloric acid solution (20 mL) were added for a single liquid - liquid extraction. The aqueous layer was extracted three times with ethyl acetate (5 mL). The organic layers were combined, washed once with 5% aqueous sodium chloride solution (20 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the solution was concentrated under reduced pressure to obtain a crude product as a yellow oil (633.8 mg). The crude product was purified by flash silica gel column chromatography (NH2 silica gel 80 g, hexane / ethyl acetate = 43 / 57 - 0 / 100). Toluene was added to the obtained white solid (294.0 mg), and after pulverization by ultrasonic irradiation, the solid was filtered to obtain Compound 11 - 1 as a white solid (234.3 mg, containing 1.9 wt% ethyl acetate, 2 - stage conversion yield starting from Compound 3 - 3 is 61%).

[1187] [Chemical Formula 138]

[1188]

[1189] Under a nitrogen atmosphere and at room temperature, 10% palladium-carbon (N.E. Chemcat NX type, 50% water-containing product, 57 mg) was added to a mixed solution of THF (10 mL) / water (10 mL) of compound 11-1 (1.0 eq., 234 mg, containing 1.9 wt% ethyl acetate, 0.268 mmol). After hydrogen displacement in the system, stirring was carried out at the same temperature for 2 hours. TFA (2.0 eq., 41 μL, 0.536 mmol) was added, and after stirring at the same temperature for 1 hour, the catalyst was filtered out through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product (189.5 mg) in the form of a pale orange solid. Ethyl acetate was added to the obtained crude product, and it was pulverized by ultrasonic irradiation. The insoluble matter was filtered off and dried under reduced pressure. The obtained solid was dissolved in water, the insoluble matter was filtered out, and the filtrate was concentrated, whereby the TFA salt of compound 11 (150.9 mg, yield 99.6%, purity 99.4%) was obtained in the form of a pale orange solid.

[1190] 1 1H-NMR (400 MHz, D2O) δ 6.89 - 6.76 (m, 3H), 4.58 (dd, J = 13.2, 5.2 Hz, 1H), 4.40 (d, J = 13.2, 1H), 4.21 (d, J = 15.2 Hz, 1H), 3.86 (dd, J = 9.6, 4.4 Hz, 1H), 3.26 (d, J = 15.2 Hz, 1H), 3.21 (dd, J = 13.2, 4.4 Hz, 1H), 2.95 - 2.82 (m, 3H), 2.63 (s, 3H).

[1191] (Example 14: Synthesis of Compound 6)

[1192] [Chemical Formula 139]

[1193]

[1194] Under a nitrogen atmosphere and with 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), and stirring was carried out at room temperature for 3 hours. Toluene was distilled off by concentration under reduced pressure to obtain a crude product in the form of a tea-colored amorphous substance. The crude product was purified by flash silica gel column chromatography (normal-phase silica gel 70 g, hexane / ethyl acetate = 5 / 1 - 2 / 1) to obtain compound 6-1 (3.84 g, yield 70%) in the form of a pale yellow amorphous substance.

[1195] [Chemical formula 140]

[1196]

[1197] Under a nitrogen atmosphere, at room temperature, cesium carbonate (1.5 eq., 781 mg, 2.21 mmol) and benzenethiol (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), and the mixture was stirred at room temperature for 3 hours. After adding saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous sodium chloride solution (10 mL), and water (20 mL) to the reaction solution, liquid-liquid extraction was performed 3 times with a mixture of hexane (10 mL) / ethyl acetate (30 mL). The organic layers were combined, washed once by liquid-liquid extraction with saturated aqueous sodium chloride solution (60 mL), and then dried over magnesium sulfate. The magnesium sulfate was filtered off, and the solution was concentrated under reduced...

Claims

1. A composition for treating or preventing at least one selected from neuropathic pain and inflammatory pain, comprising: a compound represented by the following formula (1) or a pharmaceutically acceptable salt, solvate or prodrug thereof, [Chemical Formula 1] In the formula, R1, R2, R5, R6, R7, R8, R9 and R 10 are each independently: a hydrogen atom, or an optionally substituted hydrocarbon group, or, R7 and R8 together with the carbon atom and nitrogen atom to which they 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, an optionally substituted alkoxycarbonyl group, or an optionally substituted alkoxycarbonyloxy group, R 11 , R 12 , R 13 and R 14 are each independently: a hydrogen atom, an optionally substituted hydrocarbon group, a hydroxyl group, an optionally substituted alkoxy group, or an optionally substituted alkoxycarbonyloxy group, X is CH2 or CO, A is O, NH or S, where NH can be optionally substituted.

2. The composition according to claim 1, wherein, R1 and R2 are each independently a hydrogen atom or a C 1-6 alkyl group.

3. The composition according to claim 1 or 2, wherein, R1 and R2 are each independently a hydrogen atom, a methyl group or an ethyl group.

4. The composition according to any one of claims 1-3, wherein, R3 and R4 are each independently a hydrogen atom, a C 1-6 alkyl group substituted with a carboxyl group, or a carboxyl group.

5. The composition according to any one of claims 1-4, 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 composition according to any one of claims 1-5, wherein, R5 is a hydrogen atom or a C 1-6 alkyl group.

7. The composition according to any one of claims 1-6, wherein, R5 is a hydrogen atom.

8. The composition according to any one of claims 1-7, wherein, R6 is a hydrogen atom or a C 1-6 alkyl group.

9. The composition according to any one of claims 1-8, wherein, R6 is a hydrogen atom.

10. The composition according to any one of claims 1-9, wherein R7 is a hydrogen atom, C 1-6 alkyl, hydroxy C 1-6 alkyl, carbamoyl C 1-6 alkyl, C 6-10 aryl C 1-6 alkyl, hydroxy C 6-10 aryl C 1-6 alkyl, C 5-10 heteroaryl C 1-6 alkyl, carboxy 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 composition according to any one of claims 1-10, 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 sulfanylmethyl group, a 2-methylsulfanylethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinoaminopropyl group, an indolylmethyl group or a 4-imidazolylmethyl group.

12. The composition according to any one of claims 1-11, wherein R8 is a hydrogen atom or a C 1-6 alkyl group.

13. The composition according to any one of claims 1-12, wherein R8 is a hydrogen atom.

14. The composition according to any one of claims 1-13, 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.

15. The composition according to any one of claims 1-14, wherein R7 and R8 together with the carbon and nitrogen atoms to which R7 and R8 are bonded form a C 5-10 heterocycloalkyl group.

16. The composition according to any one of claims 1-15, wherein R9 and R 10 are a hydrogen atom or a C 1-6 alkyl group.

17. The composition according to any one of claims 1-16, wherein R9 and R 10 are each independently a hydrogen atom or a methyl group.

18. The composition according to any one of claims 1-17, wherein R 11 、R 12 、R 13 and R 14 are each independently a hydrogen atom, an alkoxy group or a hydroxyl group.

19. The composition according to any one of claims 1-18, wherein R 12 is a hydrogen atom or a hydroxyl group.

20. The composition according to any one of claims 1-19, wherein R 11 、R 12 、R 13 and R 14 each independently represents a hydrogen atom or a hydroxyl group.

21. The composition according to any one of claims 1-20, wherein X is CH2.

22. The composition according to any one of claims 1-21, wherein A is O, NH, NH or S substituted by C 1-6 alkyl groups.

23. The composition according to any one of claims 1-22, wherein A is O, NH or S.

24. The composition according to any one of claims 1-23, wherein The foregoing composition is used for treating or preventing neuropathic pain.

25. The composition according to any one of claims 1-23, wherein The foregoing composition is used for treating or preventing inflammatory pain.

26. The composition according to any one of claims 1-23, wherein The foregoing composition is used for treating or preventing neuropathic pain and inflammatory pain.

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