Cyclic peptide derivative composition for treating or preventing ophthalmic disease

Abstract

The present disclosure provides cyclic peptide derivative compositions for the treatment or prevention of ophthalmic diseases. The present disclosure relates to compositions comprising a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof for treating or preventing ophthalmic disease. More specifically, the compositions of the present disclosure may treat or prevent diabetic retinopathy, glaucoma, or age-related macular degeneration. The technology provided by the present disclosure can be used in a cyclic peptide derivative for modulating the activity of nervous system cells and a method for producing the same.

Description

Technical Field

[0001] The present disclosure relates to cyclic peptide derivative compositions for treating or preventing ophthalmic diseases. Background Art

[0002] Various eye conditions are characterized by, cause, or result in choroidal neovascularization, retinal neovascularization, iris neovascularization, or retinal edema. One of these conditions is macular degeneration. Age-related macular degeneration (AMD) affects approximately 1 in 10 Americans over the age of 65. One form of AMD, "wet AMD," accounts for only approximately 10% of AMD cases but is responsible for approximately 90% of legal blindness due to AMD in the elderly. Another eye condition is diabetic retinopathy. Diabetic retinopathy may affect up to 80% of all patients with diabetes for 10 years or more and is the third leading cause of blindness in adults, accounting for approximately 7% of blindness cases in the United States. Other conditions include hypertensive retinopathy, central serous chorioretinopathy, cystoid macular edema, Cotz's disease, and tumors of the eye and ocular adnexa, such as choroidal hemangioma, retinal pigment epithelial carcinoma, retinal vein occlusion, and intraocular lymphoma. Summary of the Invention

[0003] Means for solving problems

[0004] The present disclosure provides cyclic peptide derivative compositions for treating or preventing ophthalmic diseases.

[0005] The present inventors conducted intensive research and discovered that compounds represented by the following formula and related structural formulae, or pharmaceutically acceptable salts thereof (hereinafter sometimes referred to as "compounds of the disclosure") exhibit significant proliferative activity, thereby completing the technical scope of the present disclosure. Specifically, the present disclosure is as follows.

[0006] (Item 1)

[0007] A composition for treating or preventing ophthalmic diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt, solvate or prodrug thereof,

[0008] [Chemistry 1]

[0009]

[0010] Where,

[0011] R1, R2, R5, R6, R7, R8, R9 and R 10 Each independently is:

[0012] hydrogen atoms, or

[0013] an optionally substituted hydrocarbon group, or

[0014] R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted heterocycloalkyl group,

[0015] R3 and R4 are each independently:

[0016] A hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group,

[0017] optionally substituted alkoxycarbonyl, or

[0018] optionally substituted alkoxycarbonyloxy,

[0019] R 11 、R 12 、R 13 and R 14 Each independently is:

[0020] a hydrogen atom, an optionally substituted hydrocarbon group, a hydroxyl group,

[0021] Optionally substituted alkoxy, or

[0022] optionally substituted alkoxycarbonyloxy,

[0023] X is CH2 or CO,

[0024] A is O, NH or S, wherein NH may be optionally substituted.

[0025] (Item 2)

[0026] The composition according to any one of the preceding items, wherein the ophthalmic disease includes a retinal disease.

[0027] (Item 3)

[0028] The composition according to any one of the preceding items, wherein the ophthalmic disease comprises at least one of diabetic retinopathy, glaucoma, or age-related macular degeneration.

[0029] (Item 4)

[0030] The composition according to any one of the preceding items, wherein R1 and R2 are each independently a hydrogen atom or a C 1-6 alkyl.

[0031] (Item 5)

[0032] The composition according to any one of the preceding items, wherein R1 and R2 are each independently a hydrogen atom, a methyl group or an ethyl group.

[0033] (Item 6)

[0034] The composition according to any one of the preceding items, wherein R3 and R4 are each independently a hydrogen atom, a C substituted by a carboxyl group, 1-6 Alkyl or carboxyl.

[0035] (Item 7)

[0036] The composition according to any one of the preceding items, wherein R3 and R4 are each independently a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group or a carboxyl group.

[0037] (Item 8)

[0038] The composition according to any one of the preceding items, wherein R5 is a hydrogen atom or C 1-6 alkyl.

[0039] (Item 9)

[0040] The composition according to any one of the preceding items, wherein R5 is a hydrogen atom.

[0041] (Item 10)

[0042] The composition according to any one of the preceding items, wherein R6 is a hydrogen atom or C 1－6 alkyl.

[0043] (Item 11)

[0044] The composition according to any one of the preceding items, wherein R6 is a hydrogen atom.

[0045] (Item 12)

[0046] The composition according to any one of the preceding items, wherein R7 is a hydrogen atom, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carbamoyl C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, hydroxyl C 6-10 Aryl C 1-6 Alkyl, C 5-10 Heteroaryl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, thio C 1-6 Alkyl, C 1-6 Alkylthio C 1-6 Alkyl or amidinoamino C 1-6 alkyl.

[0047] (Item 13)

[0048] The composition according to any one of the preceding 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 thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinoaminopropyl group, an indolylmethyl group, or a 4-imidazolylmethyl group.

[0049] (Item 14)

[0050] The composition according to any one of the preceding items, wherein R8 is a hydrogen atom or C 1-6 alkyl.

[0051] (Item 15)

[0052] The composition according to any one of the preceding items, wherein R8 is a hydrogen atom.

[0053] (Item 16)

[0054] The composition according to any one of the preceding items, wherein R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted heterocycloalkyl group.

[0055] (Item 17)

[0056] The composition according to any one of the preceding items, wherein R7 and R8 together with the carbon atom and nitrogen atom to which R7 and R8 are bonded form C 5-10 Heterocycloalkyl.

[0057] (Item 18)

[0058] The composition according to any one of the preceding items, wherein R9 and R 10 A hydrogen atom or C 1-6 alkyl.

[0059] (Item 19)

[0060] The composition according to any one of the preceding items, wherein R9 and R 10 are each independently a hydrogen atom or a methyl group.

[0061] (Item 20)

[0062] The composition according to any one of the preceding items, wherein R 11 、R 12 、R 13 and R 14 Each is independently a hydrogen atom, an alkoxy group or a hydroxyl group.

[0063] (Item 21)

[0064] The composition according to any one of the preceding items, wherein R 12 is a hydrogen atom or a hydroxyl group.

[0065] (Item 22)

[0066] The composition according to any one of the preceding items, wherein R 11 、R 12 、R 13 and R 14 are each independently a hydrogen atom or a hydroxyl group.

[0067] (Item 23)

[0068] The composition according to any one of the preceding items, wherein X is CH2 or CO.

[0069] (Item 24)

[0070] The composition according to any one of the preceding items, wherein A is O, C 1-6 NH, NH or S substituted with an alkyl group.

[0071] (Item 25)

[0072] The composition according to any one of the preceding items, wherein A is O, NH or S.

[0073] (Project A1)

[0074] A composition for treating or preventing ophthalmic diseases, comprising a compound represented by the following formula (A2) or a pharmaceutically acceptable salt, solvate or prodrug thereof,

[0075] [Chemistry 2]

[0076]

[0077] Where 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 a salt thereof, or alkoxycarbonyl, R A5 is a hydrocarbon group, a hydroxyl group, an alkoxy group or an alkylcarbonyloxy group, R A55 and R A66 Each is independently a hydrogen atom, a hydrocarbon group or an alkylcarbonyloxy group.

[0078] (Item A2)

[0079] The composition according to any one of the preceding items, wherein the ophthalmic disease includes a retinal disease.

[0080] (Item A3)

[0081] The composition according to any one of the preceding items, wherein the ophthalmic disease comprises at least one of diabetic retinopathy, glaucoma, or age-related macular degeneration.

[0082] In the present disclosure, one or more features described above are intended to be provided in further combinations in addition to the combinations explicitly stated. Those skilled in the art will recognize further embodiments and advantages of the present disclosure upon reading and understanding the following detailed description as needed.

[0083] Effects of the Invention

[0084] According to the present disclosure, novel cyclic peptide derivatives and compositions, etc., which can be used to treat or prevent diabetic retinopathy, glaucoma, or age-related macular degeneration are provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0085] Figure 1 : Figure 1 Shown is a light micrograph of a cross-section of a rat retina.

[0086] Figure 2 : Figure 2 Shown are the effects of the compounds on the retinal thickness of the inner plexiform layer of the rat retina in the aqueous humor pressure load model.

[0087] Figure 3 : Figure 3 Shown are the effects of the compounds on the retinal thickness of the inner granular layer of the rat retina in the aqueous humor pressure load model.

[0088] Figure 4 : Figure 4 Shown are the effects of compounds on the retinal thickness of the outer granular layer of the rat retina in the aqueous humor pressure load model.

[0089] Figure 5 : Figure 5 The figure shows the weight change after laser irradiation in the rat laser-induced choroidal neovascularization model.

[0090] Figure 6 : Figure 6 The CNV area is shown 14 days after laser irradiation in a rat laser-induced choroidal neovascularization model. DETAILED DESCRIPTION

[0091] The present disclosure is described in further detail below.

[0092] Throughout this specification, unless otherwise specified, expressions in the singular should be understood to also include their plural forms. Therefore, it should be understood that, unless otherwise specified, articles in the singular (e.g., "a", "an", "the", etc. in the English case) also include the concept of their plural forms. In addition, it should be understood that, unless otherwise specified, the terms used in this specification are used with the meanings commonly used in the field. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meanings as those commonly understood by those skilled in the art in the field to which this disclosure belongs. In the event of a conflict, this specification (including definitions) shall prevail.

[0093] (definition)

[0094] First, terms and general techniques used in this disclosure are explained.

[0095] The compounds of the present disclosure may sometimes exist in the form of hydrates and / or solvates, and thus the hydrates and / or solvates of the compounds of the present disclosure or pharmaceutically acceptable salts thereof are also encompassed in the compounds of the present disclosure.

[0096] The compounds of the present disclosure sometimes have one or more asymmetric carbon atoms according to the circumstances, and sometimes produce geometric isomerism or axial chirality, and therefore 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 recorded in this specification can include one or more asymmetric centers, and therefore can exist in the form of various isomers, such as enantiomers and / or diastereomers. For example, the compounds recorded in this specification can be in the form of a single enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers (a mixture comprising a racemic mixture and one or more stereoisomers concentrated). In addition, the present disclosure also includes compounds recorded in this specification as a single isomer substantially free of other isomers and alternatively as a mixture of various isomers.

[0097] In addition, any one or more of the compounds disclosed herein 1 H is converted to 2 Deuterated forms formed by H(D) are also encompassed by the compounds of the present disclosure.

[0098] The compounds of the present disclosure and pharmaceutically acceptable salts thereof that can be obtained in a crystalline form may sometimes exist in polymorphic forms, and the compounds of the present disclosure include all crystalline forms.

[0099] Next, the terms used in this specification are explained below.

[0100] In this specification, unless otherwise specified, the term "group" means a monovalent group. Examples of non-monovalent groups include alkylene (divalent) groups. In addition, the term "group" may be omitted in the following descriptions of substituents, etc.

[0101] In this specification, the number of substituents in the cases defined as "optionally substituted," "may be substituted," or "substituted" is not particularly limited, and may be one or more substituents as long as they are capable of substitution. Furthermore, unless otherwise specified, the description of each substituent also applies to the case where the substituent is part of another substituent or a substituent.

[0102] Examples of the substituent in the present disclosure include a hydrogen atom, a hydroxyl group, a carboxyl group, a sulfinic acid group, a sulfonic acid group, a phosphoric acid group, a guanidine group, a cyano group, a halogen atom (fluorine atom, chlorine atom, etc.), an alkyl group, an alkylthio group, a cycloalkylthio group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkylcarbonyl group, an alkylcarbonyloxy group, an alkylsulfinyl group, a cycloalkylsulfinyl group, an alkoxy group, a cycloalkyloxy group, an alkoxycarbonyl group, a cycloalkyloxycarbonyl group, an alkylcarbonyl group, an aryl group, an arylcarbonyl group, an arylthio group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclic group, an amino group, a cyclic amino group, an aminocarbonyl group, an aminosulfinyl group, an aminosulfonyl group, a heterocyclicoxycarbonyl group, a heterocyclicsulfinyl group, a heterocyclicsulfonyl group, a heterocycliccarbonyl group, an alkylsulfonyl group, a cycloalkylsulfonyl group, an arylsulfonyl group, an arylsulfinyl group, a heteroarylsulfonyl group, a heteroarylsulfinyl group, and a triphenylphosphonium cation group. The above-mentioned substituents may be further substituted with the above-mentioned substituents.

[0103] In this specification, the "maximum substitutable number" refers to the maximum number of substituents that a group can have, and may be different for each group. For example, the maximum number of substituents is 3 for a methyl group, 5 for an ethyl group, 7 for a benzyl group, and 11 for a naphthylethyl group.

[0104] In this specification, in a group modified by "optionally substituted," "substitutable," or "substituted," any part of the group may be substituted. For example, "optionally substituted arylalkyl" and "substituted arylalkyl" may mean that the aryl portion is substituted, the alkyl portion is substituted, or both the aryl portion and the alkyl portion are substituted.

[0105] In this specification, examples of substituents in the context of "optionally substituted" or "optionally substituted" include Substituent Group α and Substituent Group β. Substituents in the context of "optionally substituted" or "optionally substituted" may be selected from Substituent Group α and may be substituted by 1 to 5 substituents, the same or different. The type of atoms in a substituent that participate in a bond is not particularly limited by the type of the substituent. When the atom to which the substituent is bonded is an oxygen atom, a nitrogen atom, or a sulfur atom, the atoms to which the substituent is bonded are limited to carbon atoms, as described below.

[0106] Examples of the substituent group α include:

[0107] 1) Halogen atoms

[0108] 2) Hydroxyl

[0109] 3) Carboxyl

[0110] 4) Cyano

[0111] 5) C 1-6 alkyl

[0112] 6) C 2-6 alkenyl

[0113] 7) C 2-6 Alkynyl

[0114] 8) C 1-6 Alkoxy

[0115] 9)C 1-6 Alkylthio

[0116] 10) C 1-6 Alkylcarbonyl

[0117] 11)C 1-6 Alkylsulfonyl

[0118] (wherein, each substituent in 5) to 11) may be substituted by 1 to 5 substituents, the same or different, selected from substituent group β)

[0119] 12)C 3-10 Cycloalkyl

[0120] 13)C 3-10 Cycloalkyloxy

[0121] 14)C 6-10 Aryloxy

[0122] 15)C 5-10 Heteroaryloxy

[0123] 16)C 4-10 Non-aromatic heterocyclic oxy

[0124] 17)C 3-10 Cycloalkylthio

[0125] 18)C 6-10 Arylthio

[0126] 19)C 5-10 Heteroarylthio

[0127] 20)C 4-10 Non-aromatic heterocyclic thio groups

[0128] 21)C 6-10Aryl

[0129] 22)C 5-10 Heteroaryl

[0130] 23)C 4-10 Non-aromatic heterocycles

[0131] 24)C 3-10 Cycloalkylcarbonyl

[0132] 25)C 6-10 Arylcarbonyl

[0133] 26)C 5-10 Heteroarylcarbonyl

[0134] 27)C 4-10 Non-aromatic heterocyclic carbonyl

[0135] 28)C 3-10 Cycloalkylsulfonyl

[0136] 29)C 6-10 Arylsulfonyl

[0137] 30)C 5-10 Heteroarylsulfonyl

[0138] 31)C 4-10 Non-aromatic heterocyclic sulfonyl

[0139] (wherein, each substituent in 12) to 31) may be replaced by 1 to 5 substituent groups β or the aforementioned 5) C 1-6 alkyl substituted)

[0140] 32)-NR 10a R 11a

[0141] 33)-SO2-NR 10b R 11b

[0142] 34)-NR 10c -C(=O)R 11c

[0143] 35)-NR 10d -C(=O)OR 11d

[0144] 36)-NR 12a -C(=O)NR 10e R 11e

[0145] 37)-NR 10i -SO2-R 11i

[0146] 38)-NR12c -SO2-NR 10j R 11j

[0147] 39)-C(=O)OR 10k

[0148] 40)-C(=O)NR 10l R 11k

[0149] 41)-C(=O)NR 10m OR 11l

[0150] 42)-C(=O)NR 12d -NR 10n R 11m

[0151] 43)-C(=NR 13a )R 10s

[0152] 44)-C(=NR 13c )NR 10t R 11q

[0153] 45)-C(=NR 13d )NR 12f -NR 10u R 11r

[0154] 46)-NR 17c -C(=NR 13k )R 17d

[0155] 47)-NR 12g -C(=NR 13e )-NR 10v R 11s

[0156] 48)-NR 14 -C(=NR 13f )-NR 12h -NR 10w R 11t

[0157] 49)-OC(=O)R 10x

[0158] 50)-OC(=O)OR 10y

[0159] 51)-OC(=O)NR 10z1 R 11u

[0160] 52)-NR 12i -NR 10z2 R 11v

[0161] 53)-NR 10z3 OR 11w

[0162] 54) protecting groups;

[0163] Substituent group β is the group consisting of,

[0164] 1) Halogen atoms,

[0165] 2) hydroxyl groups,

[0166] 3) carboxyl,

[0167] 4) cyano,

[0168] 5) C 3-10 Cycloalkyl,

[0169] 6) C 1-6 Alkoxy,

[0170] 7) C 3-10 Cycloalkyloxy,

[0171] 8) C 1-6 Alkylthio,

[0172] 9)C 5-10 Heteroarylthio,

[0173] 10) C 6-10 Aryl,

[0174] 11)C 5-10 Heteroaryl,

[0175] 12)C 4-10 Non-aromatic heterocycles,

[0176] 13)C 1-6 Alkylcarbonyl,

[0177] 14)C 3-10 Cycloalkylcarbonyl,

[0178] 15)C 6-10 Arylcarbonyl,

[0179] 16)C 5-10 Heteroarylcarbonyl,

[0180] 17)C 4-10 Non-aromatic heterocyclic carbonyl,

[0181] 18)-NR 15a R 16a、

[0182] 19)-SO2-NR 15b R 16b 、

[0183] 20)-NR 15c -C(=O)R 16c

[0184] 21)-NR 17a -C(=O)NR 15d R 16d 、

[0185] 22)-C(=O)NR 15e R 16e 、

[0186] 23)-C(=NR 13g )R 15f 、

[0187] 24)-C(=NR 13h )NR 15g R 16f

[0188] 25)-NR 16g -C(=NR 13i )R 15h

[0189] 26)-NR 17b -C(=NR 13j )-NR 15i R 16h

[0190] 27) Protecting Group

[0191] (In the substituent group β, each substituent of 5) to 17) can be selected from halogen atoms, hydroxyl groups, cyano groups, carboxyl groups -NR 18a R 18b substituted with 1 to 5 substituents in

[0192] 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 13kEach independently the same or different, is a hydrogen atom, a hydroxyl group, a C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxycarbonyl,

[0193] R 10a 、R 10b 、R 10c 、R 10d 、R 10e 、R 10i 、R 10j 、R 10k 、R 10l 、R 10m 、R 10n 、R 10s 、R 10s2 、R 10t 、R 10t2 、R 10u 、R 10u2 、R 10v 、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 、R15g2 、R 15h 、R 15i 、R 16a 、R 16b 、R 16c 、R 16d 、R 16e 、R 16f 、R 16f2 、R 16g 、R 16h 、R 17a 、R 17b 、R 17c 、R 17d are independently the same or different and are hydrogen atoms, C 1-6 Alkyl (the C 1-6 The alkyl group may be selected from hydroxy, cyano, C 1-6 Alkoxy, -NR 18a R 18b substituted with 1 to 3 substituents which may be the same or different), or C 1-6 Alkoxycarbonyl,

[0194] R 18a and R 18b are independently the same or different and are hydrogen or C 1-6 alkyl.

[0195] In an exemplary embodiment, the hydrogen atoms of any hydroxyl group and amino group in substituent groups α and β may be substituted with a protecting group.

[0196] In this manual, “C 1-6 ” means that the number of carbon atoms is 1 to 6. The same applies to other numbers, for example, “C 1-4 " means the number of carbon atoms is 1 to 4, "C 1-3 " means that the number of carbon atoms is 1 to 3. In this specification, the description of the limitation of the number of carbon atoms is only a preferred numerical range, and the intention of this disclosure is that groups having substituents with carbon atoms other than the specified number of carbon atoms are also within the scope of this disclosure.

[0197] In this specification, a "hydrocarbon group" is also referred to as a "hydrocarbon group", and refers to a group formed by removing at least one hydrogen from a "hydrocarbon" containing at least one carbon and at least one hydrogen.

[0198] In this specification, "functional group" refers to any group that imparts certain functionality, including carboxyl, nitrile, carbonyl, hydroxyl, amino, imino, nitro, and halogen groups, as well as alkyl groups. In a broad sense, it also includes groups formed by bonds such as acid anhydrides, ester bonds, amide bonds, and ether bonds.

[0199] In this specification, "heteroatom" refers to an atom other than a carbon atom and a hydrogen atom, and includes, for example, an oxygen atom, a nitrogen atom, a sulfur atom, etc. A group containing a heteroatom is sometimes referred to as a hetero... group (for example, a heteroaryl group (meaning an aryl group containing at least a heteroatom)) or a hetero... group (for example, a heterocyclic group (meaning a cyclic group (carbocyclic group) containing at least one heteroatom)).

[0200] In this specification, a "halogen atom" is an atom belonging to the halogen family, and refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Preferably, it is a fluorine atom or a chlorine atom. More preferably, it is a fluorine atom. A "halogen atom" is sometimes referred to as "halogen" or "halogen."

[0201] In this specification, a "hydroxyl group" is a monovalent group of -OH. This group may also be referred to as a "hydroxyl group" or "hydroxyl group".

[0202] In this specification, a "carboxyl group" is a monovalent group of -COOH. This group may also be referred to as a "carboxyl group," "carboxyl group," or "carboxyl group."

[0203] In this specification, "amino group" refers to a monovalent group -NH2. This group is sometimes also referred to as an "amino group."

[0204] In this specification, a "thio group" is a monovalent group of -SH. This group is sometimes also referred to as a "sulfhydryl group."

[0205] In this specification, "cyano" is a monovalent group of -CN.

[0206] In this specification, "alkyl" means a linear or branched saturated aliphatic hydrocarbon group. 1-12 "Alkyl" refers to an alkyl group having 1 to 12 carbon atoms, and examples thereof include C 1-6 Alkyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, isundecyl, dodecyl, isododecyl, etc., but are not limited thereto. 1-6 "Alkyl" is an alkyl group having 1 to 6 carbon atoms, and as a preferred example, "C 1-4 Alkyl", more preferably "C 1-3 Alkyl", further preferably "C 1-2 Alkyl. As "C 1-4 Specific examples of "alkyl" include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc. As "C 1-6 Specific examples of "alkyl" include C 1-4 The group includes, but is not limited to, alkyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, and n-hexyl.

[0207] In this specification, "alkenyl" means a linear or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond. 2-12 The term "alkenyl" refers to an alkenyl group having 2 to 12 carbon atoms, and examples thereof include heptenyl, isoheptenyl, octenyl, isooctenyl, nonenyl, isononenyl, decenyl, isodecenyl, undecenyl, isoundecenyl, dodecenyl, and isododecenyl, but the present invention is not limited thereto. "C 2-6 "Alkenyl" is an alkenyl group having 2 to 6 carbon atoms, and preferred examples include "C 2-4 Alkenyl". As "C 2-6 Specific examples of the "alkenyl group" include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl.

[0208] In this specification, "alkynyl" means a linear or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond. 2-12 "Alkynyl" refers to an alkynyl group having 2 to 12 carbon atoms, and examples thereof include heptynyl, isoheptynyl, octynyl, isooctynyl, nonynyl, isononynyl, decynyl, isodecynyl, undecynyl, isoundecynyl, dodecynyl, and isododecynyl, but are not limited thereto. "C 2-6 "Alkynyl" is an alkynyl group having 2 to 6 carbon atoms, and preferred examples include "C 2-4 Alkynyl". As "C 2-6 Specific examples of the "alkynyl group" include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, and 1-hexynyl.

[0209] In this specification, "aryl" means a monovalent group of a monocyclic or bicyclic aromatic hydrocarbon ring, "C 6-10 "Aryl" means an aryl group having 6 to 10 carbon atoms. Examples of "aryl" include C6 aryl, C 10 As a specific example of C6 aryl, phenyl etc. can be mentioned, but it is not limited thereto. 10 Specific examples of the aryl group include 1-naphthyl and 2-naphthyl, but are not limited thereto.

[0210] An aryl group as a substituent or as part of a substituent may be fused to an alicyclic group. For example, a phenyl group may be fused to a cyclohexane ring to form a 1,2,3,4-tetrahydronaphthyl group. In this case, any carbon atom on the phenyl ring is bonded to the parent backbone or a group or atom thereof proximal to the parent backbone. Examples of aryl groups include 5,6,7,8-tetrahydronaphth-1-yl and 5,6,7,8-tetrahydronaphth-2-yl.

[0211] In this specification, "arylalkyl" means an alkyl group substituted with at least one aryl group. 6-10 Aryl C 1-6 "Alkyl" means a group consisting of at least one C 6-10 Aryl-substituted C 1-6 Alkyl. As C 6-10 Aryl C 1-6 Specific examples of the alkyl group include, but are not limited to, benzyl (phenyl-CH2-), phenethyl (phenyl-CH2CH2-), naphth-1-ylmethyl, naphth-2-ylmethyl, 2-(naphth-1-yl)ethyl, and 2-(naphth-2-yl)ethyl.

[0212] In this specification, "(optionally substituted amino)-arylalkyl" means an arylalkyl substituted by an optionally substituted amino group, wherein the alkyl group or the aryl group or both are substituted by an amino group. The amino group of the arylalkyl group may be unsubstituted or may be substituted by 1, 2 or 3 substituents, for example, an optionally substituted alkyl group (e.g., an unsubstituted C 1-6 Alkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl, C 3-6 As (amino group which may be substituted)-C 6-10 Aryl C 1-6 Examples of the alkyl group include, but are not limited to, (di(alkyl)amino)benzyl, ((cycloalkylalkyl)amino)benzyl, ((cycloalkylcarbonyl)amino)benzyl, ((carbamoylalkyl)carbonylamino)benzyl, ((carbamoylalkyl)carbonylamino)benzyl, ((carboxyalkyl)carbonyl)aminobenzyl, (di(alkyl)amino)naphthylmethyl, ((cycloalkylalkyl)amino)naphthylmethyl, ((cycloalkylcarbonyl)amino)naphthylmethyl, ((carbamoylalkyl)carbonylamino)naphthylmethyl, or ((carboxyalkyl)carbonyl)aminonaphthylmethyl.

[0213] In this specification, "hydroxyaryl" means an aryl group substituted with at least one hydroxyl group. 6-10 "Aryl" means a C 6-10 Aryl. As hydroxyl C 6-10 Specific examples of the aryl group include 2-hydroxyphenyl and 3-hydroxynaphthalene, but are not limited thereto.

[0214] In this specification, "hydroxyarylalkyl" means an alkyl group substituted with at least one hydroxyaryl group. 6-10 Aryl C 1-6 "Alkyl" means an alkyl group having at least one hydroxyl group 6-10 Aryl-substituted C 1-6 Alkyl. As hydroxyl C 6-10 Aryl C 1-6Specific examples of the alkyl group include, but are not limited to, 2-hydroxybenzyl (2-hydroxyphenyl-CH2-), 2-hydroxyphenethyl (2-hydroxyphenyl-CH2CH2-), 3-hydroxynaphth-1-ylmethyl, 3-hydroxynaphth-2-ylmethyl, 2-(3-hydroxynaphth-1-yl)ethyl, and 2-(3-hydroxynaphth-2-yl)ethyl.

[0215] In this specification, the aryl part of "arylthio" has the same meaning as the above-mentioned aryl. 6-10 Arylthio", preferably "C6 or C 10 Arylthio". As "C 6-10 Specific examples of the "arylthio group" include phenylthio, 1-naphthylthio, 2-naphthylthio, etc., but are not limited thereto.

[0216] In this specification, "arylsulfonyl" means a sulfonyl group substituted with the above-mentioned "aryl". 6-10 Arylsulfonyl", preferably "C6 or C 10 Arylsulfonyl. As "C 6-10 Specific examples of the "arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl, but are not limited thereto.

[0217] In this specification, "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic heterocyclic group containing the same or different heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms. The number of heteroatoms may be any number up to the number of carbon atoms present in the aryl group, and typically, 1 to 4 heteroatoms are included, but 1, 2, or 3 heteroatoms are also possible.

[0218] In this manual, "C 5-10 "Heteroaryl" means a monovalent group of a monocyclic or bicyclic aromatic heterocyclic ring consisting of 5 to 10 atoms containing the same or different, typically 1 to 4 heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms. 5-10 Specific examples of the “heteroaryl group” include, but are not limited to, quinolyl, isoquinolyl, naphthyridinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, imidazopyridinyl, imidazothiazolyl, imidazooxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridinyl, thienopyridinyl, furopyridinyl, benzothiadiazolyl, benzoxadiazolyl, pyridopyrimidinyl, benzofuranyl, benzothiophenyl, benzo[1,3]dioxole, thienofuranyl, benzopyranyl, chromanyl, coumarinyl, and quinolonyl.

[0219] In this specification, "heteroarylalkyl" means an alkyl group substituted by at least one heteroaryl group. 5-10 Heteroaryl C 1-6 "Alkyl" means a group consisting of at least one C 5-10 Heteroaryl-substituted C 1-6 Alkyl. As C 5-10 Heteroaryl C 1-6 Specific 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.

[0220] In this specification, "cycloalkyl" means a non-aromatic saturated hydrocarbon ring group, including those having a partially cross-linked structure, those having a partially spiro structure, and those having one, two or more carbonyl structures. 3-20 "Cycloalkyl" means a monocyclic or bicyclic cycloalkyl group having 3 to 20 carbon atoms. 3-6 "Cycloalkyl" means a monocyclic cycloalkyl group having 3 to 6 carbon atoms. 3-6 Specific examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, but are not limited thereto.

[0221] A cycloalkyl group as a substituent or part thereof may be fused to an aryl and / or heteroaryl ring. For example, a cyclohexyl group may be fused to a benzene ring to form a 1,2,3,4-tetrahydronaphthyl group, in which case any of the possible carbon atoms on the cyclohexane ring is bonded to the parent skeleton or a group or atom thereof close to the parent skeleton. Cycloalkyl groups include 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl, indan-2-yl, 5,6,7,8-tetrahydroquinolin-5-yl, and 5,6,7,8-tetrahydroquinolin-6-yl.

[0222] In this specification, "cycloalkylalkyl" means an alkyl group substituted by at least one cycloalkyl group. 3-6 Cycloalkyl C 1-6 "Alkyl" means a group consisting of at least one C 3-6 Cycloalkyl substituted C 1-6 Alkyl. As C 3-6 Cycloalkyl C 1-6 Specific examples of the alkyl group include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, and 3-cyclohexylpropyl.

[0223] In this specification, "heterocycloalkyl" refers to a non-aromatic saturated or partially unsaturated heterocyclic ring composed of three or more atoms, including one or two or more heteroatoms selected from oxygen, nitrogen, and sulfur atoms, which may be the same or different, and includes those having a partially cross-linked structure and those that are partially spiro-formed. "Heterocycloalkyl" encompasses "non-aromatic heterocyclic rings." A heterocycloalkyl group may have a structure in which a non-aromatic heterocyclic ring is fused with an aryl ring and / or a heteroaryl ring.

[0224] In this specification, "non-aromatic heterocycle" means a monocyclic or bicyclic non-aromatic heterocycle composed of three or more atoms containing one or two or more heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms, which may be the same or different, and includes saturated non-aromatic heterocycles, those having partially unsaturated bonds, those having partially cross-linked structures and those having a portion spiro. The non-aromatic heterocycle may form a condensed ring with an aryl or heteroaryl group. For example, with C 6-10 Aryl or C 5-10 The case where a heteroaryl group is fused is also included in the heterocycle. In addition, when constituting the non-aromatic heterocycle, one or two or more carbonyl groups, thiocarbonyl groups, sulfinyl groups, or sulfonyl groups may be included. For example, cyclic groups such as lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates, and cyclic thiocarbamates are also included in the non-aromatic heterocycle. However, the oxygen atoms of the carbonyl, sulfinyl, and sulfonyl groups and the sulfur atom of the thiocarbonyl group are not included in the number of ring members (ring size) and the number of heteroatoms constituting the ring.

[0225] In this manual, "C 4-10 Non-aromatic heterocycle" means the "non-aromatic heterocycle" mentioned above, "C 4-10 The non-aromatic heterocycle" becomes a substituent of a monovalent group.

[0226] In this specification, the non-aryl heterocyclic ring part of "non-aryl heterocyclic oxy" has the same meaning as the above-mentioned "non-aryl heterocycle". For example, "C 4-10 Non-aryl heterocyclic oxy", as "C 4-10 Non-aryl heterocyclic oxy", preferably "C 4-10 Non-aromatic heterocyclic oxy group". As "C 4-10 Specific examples of the "non-aryl heterocyclic oxy group" include tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy and the like, but are not limited thereto.

[0227] In this specification, the non-aryl heterocyclic portion of the "non-aryl heterocyclic thio group" has the same meaning as the above-mentioned "non-aryl heterocyclic ring". For example, "C 4-10 Non-aromatic heterocyclic thio group", as "C 4-10 Non-aromatic heterocyclic thio group", preferably "C 4-6 Non-aromatic heterocyclic thio group". As "C4-10 Specific examples of the "non-aryl heterocyclic thio group" include tetrahydropyranylthio and piperidinylthio, but are not limited thereto.

[0228] In this specification, "non-aryl heterocyclic carbonyl" means a carbonyl group substituted by the above-mentioned "non-aryl heterocycle". For example, "C 4-10 Non-aromatic heterocyclic carbonyl", as "C 4-10 Non-aromatic heterocyclic carbonyl", preferably "C 4-6 Non-aromatic heterocyclic carbonyl. As "C 4-10 Specific examples of the "non-aryl heterocyclic carbonyl group" include, but are not limited to, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, and morpholinylcarbonyl.

[0229] In this specification, "non-aryl heterocyclic sulfonyl group" means a sulfonyl group substituted with the above-mentioned "non-aryl heterocyclic ring". For example, "C 4-10 Non-aromatic heterocyclic sulfonyl", as "C 4-10 Non-aromatic heterocyclic sulfonyl", preferably "C 4-6 Non-aromatic heterocyclic sulfonyl. As "C 4-10 Specific examples of the "non-aryl heterocyclic sulfonyl group" include, but are not limited to, azetidinylsulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, and morpholinylsulfonyl.

[0230] In this manual, "C 5-10 The term "heterocycloalkyl group" refers to a heterocycloalkyl group consisting of 5 to 10 ring atoms containing the same or different 1 or 2 or more hetero atoms selected from oxygen atoms, nitrogen atoms and sulfur atoms.

[0231] In the present specification, the "heterocycloalkylalkyl group" means an alkyl group substituted by at least one heterocycloalkyl group.

[0232] In this specification, "alkylcarbonyl" is a monovalent group of -C(=O)-alkyl. Preferred examples of alkylcarbonyl include C 1-6 Alkylcarbonyl. As C 1-6 Specific examples of alkylcarbonyl groups include, but are not limited to, acetyl (CH3C(=O)-), n-propionyl (CH3CH2C(=O)-), n-butyryl (CH3CH2CH2C(=O)-), n-pentanoyl (CH3(CH2)3C(=O)-), n-hexanoyl (CH3(CH2)4C(=O)-), and n-heptanoyl (CH3(CH2)5C(=O)-).

[0233] In this specification, "alkoxy" is a monovalent group of -O-alkyl. Preferred examples of alkoxy include C 1-6 Alkoxy (i.e., C 1-6 Alkyl-O-), C1-4 Alkoxy (i.e., C 1-4 Alkyl-O-) etc. As C 1-4 Specific examples of alkoxy groups include methoxy (CH3O-), ethoxy (CH3CH2O-), n-propoxy (CH3(CH2)2O-), isopropoxy ((CH3)2CHO-), n-butoxy (CH3(CH2)3O-), isobutoxy ((CH3)2CHCH2O-), tert-butoxy ((CH3)3CO-), and sec-butoxy (CH3CH2CH(CH3)O-). 1-6 Specific examples of alkoxy groups include C 1-4 Alkyloxy, n-pentyloxy (CH3(CH2)4O-), isopentyloxy ((CH3)2CHCH2CH2O-), neopentyloxy ((CH3)3CCH2O-), tert-pentyloxy (CH3CH2C(CH3)2O-), 1,2-dimethylpropyloxy (CH3CH(CH3)CH(CH3)O-), etc., but are not limited thereto.

[0234] In this specification, "alkoxycarbonyl" is a monovalent group of -C(=O)-O-alkyl. Examples of alkoxycarbonyl include C 1-6 Alkoxycarbonyl, preferably C 1-4 Alkoxycarbonyl, but not limited thereto. 1-4 Specific examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, and isobutoxycarbonyl. 1-6 Specific examples of the alkoxycarbonyl group include C 1-4 Examples include, but are not limited to, alkoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, 1,2-dimethylpropyloxycarbonyl, and n-hexyloxycarbonyl.

[0235] In this specification, "alkoxycarbonyloxy" is a monovalent group of -OC(=O)-O-alkyl. Examples of alkoxycarbonyloxy include C 1-6 Alkoxycarbonyloxy, preferably C 1-4 Alkoxycarbonyloxy, but not limited thereto. 1-4 Specific examples of the alkoxycarbonyloxy group include methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-butoxycarbonyloxy, sec-butoxycarbonyloxy, tert-butoxycarbonyloxy, and isobutoxycarbonyloxy. 1-6 Specific examples of the alkoxycarbonyloxy group include C 1-4Examples include, but are not limited to, an alkoxycarbonyloxy group, an n-pentyloxycarbonyloxy group, an isopentyloxycarbonyloxy group, a neopentyloxycarbonyloxy group, a tert-pentyloxycarbonyloxy group, a 1,2-dimethylpropyloxycarbonyloxy group, and an n-hexyloxycarbonyloxy group.

[0236] In this specification, "alkoxycarbonylamino" is a monovalent group of -NH-C(=O)-O-alkyl. Examples of alkoxycarbonylamino include C 1-6 Alkoxycarbonylamino, preferably C 1-4 Alkoxycarbonylamino, but not limited thereto. 1-4 Specific examples of the alkoxycarbonylamino group include methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, sec-butoxycarbonylamino, tert-butoxycarbonylamino, and isobutoxycarbonylamino. 1-6 Specific examples of the alkoxycarbonylamino group include C 1-4 Examples include, but are not limited to, alkoxycarbonylamino, n-pentyloxycarbonylamino, isopentyloxycarbonylamino, neopentyloxycarbonylamino, tert-pentyloxycarbonylamino, 1,2-dimethylpropyloxycarbonylamino, and n-hexyloxycarbonylamino.

[0237] In this specification, "haloalkyl" is a monovalent group of a halogenated alkyl group in which one or more hydrogen atoms on the alkyl group are replaced by halogen atoms. In addition, the term "perhaloalkyl" means a haloalkyl group in which all hydrogen atoms on the alkyl group are replaced by halogen atoms. For example, perfluoroethyl is -CF2CF3, and perchloro-n-propyl is -CCl2CCl2CCl3. Examples of haloalkyl groups include C 1-6 Halogenated alkyl, C 1-4 Halogenated alkyl, C 1-3 Halogenated alkyl, etc. As C 1-3 Specific examples of the alkyl group include, but are not limited to, fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, fluorochloromethyl, difluorochloromethyl, fluorodichloromethyl, fluoroethyl, chloroethyl, bromoethyl, trifluoroethyl, trichloroethyl, tribromoethyl, perfluoroethyl, perchloroethyl, perbromoethyl, perfluoropropyl, perchloropropyl, perbromopropyl, perfluoroisopropyl, perchloroisopropyl, and perbromoisopropyl. 1-4 Specific examples of the alkyl group include C 1-3 Examples of C include, but are not limited to, halogenated alkyl, perfluorobutyl, perchlorobutyl, perbromobutyl, perfluoroisobutyl, and perfluorotert-butyl. 1-6 Specific examples of the alkyl group include C 1-4 Examples include, but are not limited to, halogenated alkyl, perfluoro-n-pentyl, perfluoro-isopentyl, perfluoro-neopentyl, perfluoro-tert-pentyl, and perfluoro-1,2-dimethylpropyl.

[0238] In this specification, "haloalkoxy" and "haloalkyloxy" are monovalent groups of -O-haloalkyl in which one or more hydrogen atoms on the alkyl group are replaced by halogen atoms. In addition, the term "perhaloalkoxy" means a haloalkoxy group in which all hydrogen atoms on the alkyl group are replaced by halogen atoms. For example, perfluoroethoxy is -OCF2CF3, and perchloro-n-propoxy is -OCCl2CCl2CCl3. Preferred examples of haloalkoxy groups include C 1-6 Halogenated alkoxy, C 1-4 Halogenated alkoxy, C 1-3 Halogenated alkoxy, etc. as C 1-3 Specific examples of the alkoxy group include, but are not limited to, fluoromethoxy, chloromethoxy, bromomethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, fluorochloromethoxy, difluorochloromethoxy, fluorodichloromethoxy, fluoroethoxy, chloroethoxy, bromoethoxy, trifluoroethoxy, trichloroethoxy, tribromoethoxy, perfluoroethoxy, perchloroethoxy, perbromoethoxy, perfluoropropoxy, perchloropropoxy, perbromopropoxy, perfluoroisopropoxy, perchloroisopropoxy, and perbromoisopropoxy. 1-4 Specific examples of alkoxy groups include C 1-3 Examples of C include, but are not limited to, halogenated alkoxy, perfluorobutoxy, perchlorobutoxy, perbromobutoxy, perfluoroisobutoxy, and perfluorotert-butoxy. 1-6 Specific examples of alkoxy groups include C 1-4 Examples of the group include, but are not limited to, a halogenated alkoxy group, a perfluoro-n-pentyloxy group, a perfluoro-isopentyloxy group, a perfluoro-neopentyloxy group, a perfluoro-tert-pentyloxy group, and a perfluoro-1,2-dimethylpropoxy group.

[0239] In this specification, "alkylsulfonyl" means a sulfonyl group substituted with the above-mentioned "alkyl". 1-6 Alkylsulfonyl", preferably "C 1-4 Alkylsulfonyl. As "C 1-6 Specific examples of the "alkylsulfonyl group" include methylsulfonyl, propionylsulfonyl, butyrylsulfonyl and the like, but are not limited thereto.

[0240] In this specification, the alkyl part of "alkylthio" has the same meaning as the above-mentioned alkyl. 1-6 Examples of "alkylthio" include "C 1-4 "Alkylthio", preferably "C 1-3 Alkylthio". As "C 1-6Specific examples of the "alkylthio group" include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, tert-butylthio, sec-butylthio, isopentylthio, neopentylthio, tert-pentylthio, and 1,2-dimethylpropylthio.

[0241] In this specification, "arylcarbonyl" is a monovalent group of -C(=O)-aryl. Preferred examples of arylcarbonyl include C 6-10 Arylcarbonyl. As C 6-10 Specific examples of the arylcarbonyl group include benzoyl (ie, phenyl-C(=O)-), 1-naphthylcarbonyl, and 2-naphthylcarbonyl, but are not limited thereto.

[0242] In this specification, the aryl part of "aryloxy" has the same meaning as the above-mentioned aryl. 6-10 Aryloxy", preferably "C6 or C 10 Aryloxy". As "C 6-10 Specific examples of the "aryloxy group" include phenoxy, 1-naphthyloxy, 2-naphthyloxy, etc., but are not limited thereto.

[0243] In the present specification, the "heteroarylcarbonyl group" is a monovalent group of -C(=O)-heteroaryl.

[0244] In this specification, "heteroarylcarbonyl" means a carbonyl group substituted by the above-mentioned "heteroaryl". 5-10 Specific examples of the "heteroarylcarbonyl group" include, but are not limited to, pyrazolylcarbonyl, triazolylcarbonyl, thiazolylcarbonyl, thiadiazolylcarbonyl, pyridylcarbonyl, and pyridazinylcarbonyl.

[0245] In this specification, the heteroaryl part of "heteroaryloxy" has the same meaning as the above-mentioned "heteroaryl". 5-10 Specific examples of the "heteroaryloxy" include, but are not limited to, pyrazolyloxy, triazolyloxy, thiazolyloxy, thiadiazolyloxy, pyridyloxy, and pyridazinyloxy.

[0246] In this specification, the heteroaryl part of "heteroarylthio" has the same meaning as the above-mentioned "heteroaryl". 5-10 Specific examples of the "heteroarylthio group" include, but are not limited to, pyrazolylthio, triazolylthio, thiazolylthio, thiadiazolylthio, pyridylthio and pyridazinylthio.

[0247] In this specification, an "optionally substituted carbonyl" group refers to a monovalent group -C(=O)-(hydrogen or any group selected from the group of substituents described in this specification). Examples of "optionally substituted carbonyl" groups include, but are not limited to, formyl, optionally substituted carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkenylcarbonyl, alkenyloxycarbonyl, alkynylcarbonyl, alkynyloxycarbonyl, arylcarbonyl, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkyloxycarbonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, and heterocycloalkyloxycarbonyl. A carbonyl group substituted with hydrogen is a formyl group. A carbonyl group substituted with an amino group is a carbamoyl group.

[0248] In this specification, an "optionally substituted oxy" group refers to a monovalent group -O-(hydrogen or any group selected from the group of substituents described in this specification). Examples of "optionally substituted oxy" groups include, but are not limited to, hydroxy, optionally substituted alkyloxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, and heterocycloalkylcarbonyloxy. An oxy group substituted with hydrogen is a hydroxy group.

[0249] In the present specification, a "carbamoyl group" is a monovalent group -C(=O)-NH2.

[0250] In the present specification, "amidinoamino" is a monovalent group -NH-C(=NH)-NH2.

[0251] In this specification, the description of "a group substituted by a substituent" means that the group is substituted by at least one substituent. For example, "a C 1-6 "Alkyl" means C 1-6 The alkyl group is substituted with at least one hydroxy group.

[0252] In this specification, "carbamoyl C 1-6 "Alkyl" is a C substituted by at least one -C(=O)-NH2 group. 1-6 Alkyl. As "carbamoyl C 1-4 Specific examples of the "alkyl group" include, but are not limited to, 2-amino-2-oxoethyl (i.e., H2NC(=O)-CH2-, or carbamoylmethyl), 3-amino-3-oxopropyl (i.e., H2NC(=O)-CH2CH2-, or carbamoylethyl), 4-amino-4-oxobutyl (i.e., H2NC(=O)-(CH2)3-, or carbamoylpropyl), and 5-amino-5-oxopentyl (i.e., H2NC(=O)-(CH2)4-, or carbamoylbutyl). As "carbamoyl C 1-6 Specific examples of "alkyl" include carbamoyl-substituted C1-4 Alkyl, 6-amino-6-oxohexyl (i.e., H2NC(=O)-(CH2)5-, or carbamoylpentyl), 7-amino-7-oxoheptyl (i.e., H2NC(=O)-(CH2)6-, or carbamoylhexyl), etc., but are not limited thereto.

[0253] In this specification, "thioalkyl" is an alkyl group substituted with at least one thio group. 1-6 Specific examples of the "alkyl group" include, but are not limited to, thiomethyl, 2-thioethyl, 3-thiopropyl, and 4-thiobutyl.

[0254] In this specification, "alkylthioalkyl" means an alkyl group substituted with at least one alkylthio group. 1-6 Alkylthio C 1-6 "Alkyl" means a group consisting of at least one C 1-6 Alkylthio-substituted C 1-6 Alkyl. As C 1-6 Alkylthio C 1-6 Specific examples of the alkyl group include methylthiomethyl, methylthioethyl, and ethylthiomethyl, but are not limited thereto.

[0255] In this specification, "aminoalkyl" refers to an alkyl group substituted with at least one amino group. 1-6 Specific examples of the "alkyl group" include aminomethyl, 2-aminoethyl, 3-aminopropyl, and 4-aminobutyl, but are not limited thereto.

[0256] In this specification, "amidinoaminoalkyl" or "guanidinoalkyl" is an alkyl group substituted with at least one -NH-C(=NH)-NH2 group, wherein the nitrogen atom of the amidinoamino group may be protected by a nitrogen protecting group (e.g., tert-butoxycarbonyl). 1-6 Examples of "alkyl" include "amidinoamino C 1-4 Alkyl" etc., but not limited thereto. As "amidinoamino C 1-4 Specific examples of "alkyl" include, but are not limited to, (amidinoamino)methyl, 2-(amidinoamino)ethyl, 3-(amidinoamino)propyl, and 4-(amidinoamino)butyl. 1-6 Specific examples of "alkyl" include amidinoamino-substituted C 1-4 Examples of the amidino group protected by a nitrogen protecting group include:

[0257] [Chemistry 3]

[0258]

[0259] In this specification, "amidinoamino" and "guanidino" have the same meaning.

[0260] In this specification, "carboxyalkyl" refers to an alkyl group substituted with at least one -COOH group. 1-4 Specific examples of "alkyl" include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and 4-carboxybutyl. 1-6 Specific examples of "alkyl" include carboxyl-substituted C 1-4 The group may include, but is not limited to, an alkyl group, a 5-carboxypentyl group, a 6-carboxyhexyl group, and the like.

[0261] In this specification, "protecting group" refers to an atomic group that shields, reduces or prevents the reactivity of a functional group when combined with a reactive functional group in a molecule. The compounds disclosed herein may be appropriately or as needed substituted with a protecting group at any position such as any of R1 to R4 or its substituents or substituents other than them, and compounds containing these protecting groups are also within the scope of this disclosure. Typically, the protecting group can be selectively removed during the synthesis process as needed. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 5th edition, 2014; John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Volumes 1 to 8, John Wiley & Sons, NY, etc. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilylethanesulfonyl ("TES"), trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), and nitroveratroloxycarbonyl ("NVOC"). Representative hydroxyl protecting groups include those in which the hydroxyl group is acylated (esterified) or alkylated, for example, benzyl and trityl ether, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS, triethylsilyl, tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS)), alkyldiarylsilyl ethers (e.g., tert-butyldiphenylsilyl (TBDPS)), triarylsilyl ethers (e.g., triphenylsilyl), glycol ethers (e.g., ethylene glycol ether, propylene glycol ether, etc.) and allyl ethers, but are not limited thereto.

[0262] The amino groups possessed by the compounds of the present disclosure (e.g., amino groups possessed by the parent skeleton, amino groups as substituents, amino groups in substituents possessed by the compounds, etc.) may be protected by nitrogen protecting groups or groups represented by "Protect." The amino groups in the substituents listed in the substituent group group may be further protected by nitrogen protecting groups or groups represented by "Protect," and the protected substituents may be used as substituents.

[0263] The hydroxyl groups possessed by the compounds disclosed herein (e.g., hydroxyl groups as substituents, hydroxyl groups in substituents possessed by the compounds, hydroxyl groups in the aforementioned substituent groups, etc.) may also be protected by hydroxyl-protecting groups. The hydroxyl groups in the substituents listed in the substituent groups may be further protected by hydroxyl-protecting groups described in this specification, and the protected substituents may be used as substituents.

[0264] In this specification, " ophthalmic disease " or " eye disease " are the terms used in this field, refer to diseases related to eyes including but not limited to glaucoma, age-related macular degeneration (AMD), ischemic retinopathy, optic neuropathy, diabetic retinopathy (DR), diabetic macular edema (DME), uveitis, senile cataract. Eye disease can be diseases or abnormalities related to the damage of eyes or more specifically to retinal pigment epithelium (RPE) and photocells (photo cell) including but not limited to glaucoma, AMD, ischemic retinopathy, optic neuropathy, DR, DME, induced by oxidative stress and (or) hypoxia. Eye disease can be diseases or abnormalities related to the reduction of eye blood flow including but not limited to glaucoma, ischemic retinopathy, DR, AMD.

[0265] As used herein, the terms "ocular disease," "ocular condition," "ey disease," and "eye condition" refer to diseases / conditions of the eye that may affect vision, can cause ocular discomfort, and can signal systemic health problems.

[0266] In this specification, the present disclosure may particularly target diseases or abnormalities related to damage to the retinal pigment epithelium (RPE) and photocells, and may also target diseases or abnormalities related to a decrease in ocular blood flow.

[0267] In this specification, "retinal disease" is a term used in this field and refers to any disease, disorder or symptom related to the retina, including those caused by damage to the retina due to aging, disease, etc., including but not limited to glaucoma, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, retinal detachment, diabetic maculopathy, hypertensive retinopathy, retinal vascular occlusion, retinal arteriosclerosis, retinal holes, retinal holes, macular holes, fundus hemorrhage, posterior vitreous detachment, pigmented paravenous network choroidal atrophy, choroidal atrophy, colloid degeneration, crystalline vision Retinopathy, white dot retinopathy, cone dystrophy, central annular choroidal dystrophy, Doyne honeycomb retinal dystrophy, vitelliform macular dystrophy, cystic tissue macular edema, latent macular dystrophy, Stargardt's disease, retinal detachment, central serous chorioretinopathy, spinocerebellar ataxia type 7, familial exudative vitreoretinopathy, S cone enhancement syndrome, retinal pigment streaks, autosomal dominant optic atrophy, autosomal dominant drusen, acute regional latent outer retinopathy, cancer-related retinopathy, light damage or ischemic retinopathy.

[0268] In this specification, "glaucoma" refers to a disease characterized by functional structural abnormalities of the eye with characteristic changes in the optic nerve and visual field, which can usually be improved or suppressed by sufficiently lowering the intraocular pressure (Japan Glaucoma Society Glaucoma Diagnosis and Treatment Guidelines Preparation Committee. Glaucoma Diagnosis and Treatment Guidelines (4th Edition). Japanese Ophthalmological Society Journal. Vol. 122 No. 1. p. 5-53 (2018.01) (hereinafter referred to as "Glaucoma Diagnosis and Treatment Guidelines (4th Edition)"), which can be classified into primary glaucoma, secondary glaucoma, Primary glaucoma includes primary open-angle glaucoma (broadly defined) and primary angle-closure glaucoma. Primary open-angle glaucoma (broadly defined) includes primary open-angle glaucoma, normal-tension glaucoma, and preperipheral glaucoma. Secondary glaucoma includes secondary open-angle glaucoma and secondary angle-closure glaucoma. Pediatric glaucoma includes primary congenital glaucoma, juvenile open-angle glaucoma, glaucoma with congenital eye abnormal extinction, and glaucoma related to congenital systemic diseases.

[0269] In this specification, "diabetic retinopathy" means retinal degeneration caused by microvascular degeneration found in diabetes. The blood vessels that supply oxygen to the retina of the eye are damaged due to long-term high levels of blood sugar (hyperglycemia). The disease generally develops slowly over several months. However, over time, diabetic retinopathy becomes more serious, sometimes causing decreased vision. Diabetic retinopathy usually affects both eyes. Diabetic retinopathy progresses from mild non-proliferative abnormalities characterized by increased vascular permeability to moderate and severe non-proliferative diabetic retinopathy (NPDR) characterized by vascular occlusion, and to proliferative diabetic retinopathy (PDR) characterized by new blood vessel proliferation on the back of the retina and vitreous. Macular edema characterized by retinal hypertrophy from leaky blood vessels can occur in all stages of retinopathy. Furthermore, conditions such as pregnancy, puberty, blood sugar control, hypertension and cataract surgery can accelerate these degenerations.

[0270] In this specification, "age-related macular degeneration" refers to a disease that causes degeneration of the macula in the retina of the eye as people age. Age-related macular degeneration is classified into "exudative type" and "atrophic type" according to its cause. The present disclosure is effective for either case. In the "exudative type", abnormal choroidal neovascularization is generated from the choroid and progresses to the retinal surface. The neovascularization is fragile, so bleeding and retention of exudates are confirmed, leading to functional impairment of the macula, causing partial vision, decreased vision, etc. Ultimately, irreversible degeneration is caused in the macula, resulting in significant decreased vision. In the "atrophic type", macular degeneration is caused as people age, and rapid decreased vision is confirmed depending on the extent of the degeneration. In the atrophic type, it is also characteristic that no choroidal neovascularization is observed.

[0271] In this specification, "modulation" of an activity means inhibiting or promoting an activity, and the term "modulator" means an inhibitor (inhibitor) or promoter of an activity. "Promoting activity" means that the activity (e.g., promotion of ocular blood flow, cell division) increases by 1% or more, preferably 5% or more, more preferably 10% or more, further preferably 20% or more, further preferably 30% or more, compared to when the activity modulator is not used. "Inhibiting activity" means that the activity (e.g., promotion of ocular blood flow, cell division) decreases by 1% or more, preferably 5% or more, more preferably 10% or more, further preferably 20% or more, further preferably 30% or more, compared to when the activity modulator is not used.

[0272] In this specification, "pharmaceutically acceptable salt" means an acid addition salt and a base addition salt that are pharmaceutically acceptable. Specific examples of "pharmaceutically acceptable salt" include acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonic acid, p-toluenesulfonate (toluenesulfonate), lauryl sulfate, malate, ascorbate, mandelate, saccharinate, xinafoate Acid addition salts such as hydroxybenzoate, cinnamate, adipate, cysteine, N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, carboxyvinyl polymer; inorganic base addition salts such as lithium salt, sodium salt, potassium salt, calcium salt; organic base addition salts such as morpholine and piperidine; addition salts with amino acids such as aspartic acid and glutamic acid, etc., but are not limited thereto.

[0273] Preferred salts and pharmaceutically acceptable salts of the starting compound and the target compound are conventional non-toxic salts. As these salts, in addition to acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, or p-toluenesulfonate) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, or phosphate), salts with amino acids (e.g., arginine, aspartic acid, or glutamic acid), metal salts such as alkali metal salts (e.g., sodium salt or potassium salt) and alkaline earth metal salts (e.g., calcium salt or magnesium salt), ammonium salts, or organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridinium salt, picoline salt, dicyclohexylamine salt, or N,N'-dibenzylethylenediamine salt), those skilled in the art can also appropriately select.

[0274] When a salt of the compound of the present disclosure is desired, the compound of the present disclosure may be directly purified if it is obtained in the form of a salt. Alternatively, if it is obtained in a free form, it may be dissolved or suspended in a suitable organic solvent, and an acid or base may be added to form a salt by a conventional method.

[0275] In addition, the compounds of the present disclosure and pharmaceutically acceptable salts thereof may sometimes exist in the form of adducts with water or various solvents, and these adducts are also included in the present disclosure.

[0276] In addition, the present disclosure includes the compounds of the present disclosure or their pharmaceutically acceptable salts. In addition, it also includes solvates such as hydrates or ethanol solvates thereof. Furthermore, the present disclosure also includes all tautomers, all existing stereoisomers, and all crystalline forms of the compounds of the present disclosure.

[0277] The phrase "a compound or an enantiomer thereof or a salt thereof or a solvate thereof" means a compound, an enantiomer of the aforementioned compound, a salt of the aforementioned compound, a salt of the aforementioned enantiomer, a solvate of the aforementioned compound, a solvate of the aforementioned enantiomer, a solvate of the salt of the aforementioned compound, or a solvate of the salt of the aforementioned enantiomer.

[0278] The compounds described in this specification may contain one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described in this specification may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers (comprising a racemic mixture and a mixture concentrated from one or more stereoisomers). Isomers may be separated from the mixture by methods well known to those skilled in the art (including the formation and crystallization of chiral high performance liquid chromatography (HPLC) and chiral salts). Alternatively, preferred isomers may be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33: 2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure also encompasses the compounds described herein as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0279] The compounds of the present disclosure may contain optical isomers based on optically active centers, atropisomers based on axial or planar chirality resulting from the restraint of intramolecular rotation, other stereoisomers, tautomers and geometric isomers, and all possible isomers and mixtures thereof are included within the scope of the present disclosure.

[0280] Particularly optical isomers and atropisomers can be obtained in racemic form, or when using optically active starting materials or intermediates, can be obtained in optically active form. As required, in the appropriate stage of the following manufacture method, the racemate of the corresponding raw material, intermediate or final product can be physically or chemically split into their optical enantiomers by using a method using an optically active column, a fractional crystallization method or the like, for example. Specifically, for example, in a diastereoisomer method, two diastereomers are formed from a racemate by using a reaction using an optical resolving agent. The different diastereomers usually have different physical properties and can therefore be split by known methods such as fractional crystallization.

[0281] As used in this specification, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response or other problems or complications, meet an appropriate benefit-risk ratio, and are suitable for use in contact with the tissues of humans and animals.

[0282] As used in this specification, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and is not harmful to the patient. As some examples of materials that can function as a pharmaceutically acceptable carrier, the following can be cited: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, Corn oil and soybean oil, etc.; (10) glycols, such as propylene glycol, etc.; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol, etc.; (12) esters, such as ethyl oleate and ethyl laurate, etc.; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide, etc.; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0283] Furthermore, the scope of this disclosure also includes prodrugs of the compounds of this disclosure. In this disclosure, prodrugs refer to derivatives of the compounds of this disclosure that, upon acid hydrolysis or enzymatic decomposition in vivo, provide the compounds of this disclosure. For example, when the compounds of this disclosure have hydroxyl, amino, or carboxyl groups, these groups can be modified according to conventional methods to produce prodrugs.

[0284] For example, in the case of a compound having a carboxyl group, there may be mentioned a compound in which the carboxyl group is an alkoxycarbonyl group, a compound in which the carboxyl group is an alkylthiocarbonyl group, or a compound in which the carboxyl group is an alkylaminocarbonyl group.

[0285] For example, in the case of a compound having an amino group, examples include a compound in which the amino group is substituted with an alkanoyl group to become an alkanoylamino group, a compound in which the amino group is substituted with an alkoxycarbonyl group to become an alkoxycarbonylamino group, a compound in which the amino group becomes an alkanoyloxymethylamino group, or a compound in which the amino group becomes a hydroxylamine group.

[0286] For example, in the case of a compound having a hydroxyl group, there may be mentioned a compound in which the hydroxyl group is substituted with the aforementioned alkanoyl group to form an alkanoyloxy group, a compound in which the hydroxyl group is a phosphate ester, or a compound in which the hydroxyl group is an alkanoyloxymethyloxy group.

[0287] Examples of the alkyl moiety of the group used in these prodrug formations include the aforementioned alkyl groups, which may be substituted by, for example, an alkoxy group, etc. Preferred examples include the following.

[0288] For example, examples of compounds in which the carboxyl group is an alkoxycarbonyl group include C 1-12 Alkoxycarbonyl, C4 alkoxycarbonyl, C6 alkoxycarbonyl, C8 alkoxycarbonyl, C 10 Alkoxycarbonyl, C 12 Alkoxycarbonyl, specifically methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl, neopentoxycarbonyl, tert-pentoxycarbonyl, 1,2-dimethylpropoxycarbonyl, n-hexyloxycarbonyl, heptoxycarbonyl, isoheptoxycarbonyl, octyloxycarbonyl, isooctyloxycarbonyl, nonyloxycarbonyl, isononyloxycarbonyl, decyloxycarbonyl, isodecyloxycarbonyl, undecyloxycarbonyl, isoundecyloxycarbonyl, dodecyloxycarbonyl or isododecyloxycarbonyl; or C 1-12 Alkoxy C 1-12 Alkoxycarbonyl, C 1-12 Alkoxyethoxycarbonyl, specifically methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl; or C 1-12 Alkyl PEG, C4 alkyl PEG, C6 alkyl PEG, C8 alkyl PEG, C 10 Alkyl PEG, C 12 Alkyl PEG substituted alkoxycarbonyl. Here, PEG refers to polyethylene glycol, and the alkyl group can be a linear or branched chain.

[0289] In this specification, "or" is used when "at least one or more" of the items listed in the text can be used. The same applies to "or". In this specification, when it is clearly stated that "within the range of two values", the range also includes the two values ​​themselves.

[0290] The scientific literature, patents, patent applications and other references cited in this specification are incorporated herein by reference in their entirety to the same extent as if each were specifically described.

[0291] (Preferred embodiment)

[0292] The preferred embodiments of the present disclosure are described below. It should be understood that the embodiments provided below are provided for a better understanding of the present disclosure, and the scope of the present disclosure should not be limited by the following description. Therefore, it is obvious that those skilled in the art can make appropriate changes within the scope of the present disclosure with reference to the description in this specification. In addition, it should be understood that the following embodiments of the present disclosure can be used alone or in combination.

[0293] (Medications for eye diseases)

[0294] The present disclosure provides a drug or composition for treating or preventing ophthalmic diseases, comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0295] In one aspect, the compounds utilized in the present disclosure can be exemplified by compounds represented by the following formula or pharmaceutically acceptable salts, solvates or prodrugs thereof,

[0296] [Chemistry 4]

[0297]

[0298] Where,

[0299] R1, R2, R5, R6, R7, R8, R9 and R 10 Each independently is:

[0300] hydrogen atoms, or

[0301] an optionally substituted hydrocarbon group, or

[0302] R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted cycloalkyl group or an optionally substituted heterocycloalkyl group,

[0303] R3 and R4 are each independently:

[0304] A hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group,

[0305] optionally substituted alkoxycarbonyl, or

[0306] optionally substituted alkoxycarbonyloxy,

[0307] R 11 、R 12 、R 13 and R 14 Each independently is:

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

[0309] Optionally substituted alkoxy, or

[0310] optionally substituted alkoxycarbonyloxy,

[0311] X is CH2 or CO,

[0312] A is O, NH or S, wherein NH may be optionally substituted.

[0313] In one embodiment, R1, R2, R5, R6, R7, R8, R9 and R 10 Each independently is:

[0314] hydrogen atoms, or

[0315] an optionally substituted hydrocarbon group, or

[0316] R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted heterocycloalkyl group,

[0317] R3 and R4 are each independently:

[0318] A hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group,

[0319] optionally substituted alkoxycarbonyl, or

[0320] optionally substituted alkoxycarbonyloxy,

[0321] R 11 、R 12 、R 13 and R 14 Each independently is:

[0322] Hydrogen atoms, hydroxyl groups,

[0323] Optionally substituted alkoxy, or

[0324] optionally substituted alkoxycarbonyloxy,

[0325] X is CH2 or CO,

[0326] A is O, NH or S, wherein NH may be optionally substituted.

[0327] In one embodiment, R1, R2, R5, R6, R7, R8, R9 and R 10 Each independently is:

[0328] hydrogen atoms, or

[0329] optionally substituted alkyl, or,

[0330] R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted heterocycloalkyl group,

[0331] R3 and R4 are each independently:

[0332] a hydrogen atom, an optionally substituted alkyl group, a carboxyl group,

[0333] optionally substituted alkoxycarbonyl, or

[0334] optionally substituted alkoxycarbonyloxy,

[0335] R 11 、R 12 、R 13 and R 14 Each independently is:

[0336] Hydrogen atoms, hydroxyl groups,

[0337] Optionally substituted alkoxy, or

[0338] optionally substituted alkoxycarbonyloxy,

[0339] X is CH2 or CO,

[0340] A is O, NH or S, wherein NH may be optionally substituted.

[0341] In one embodiment, R1, R2, R5, R6, R7, R8, R9 and R 10 Each independently is:

[0342] hydrogen atoms, or

[0343] an alkyl group substituted with the same or different substituents selected from hydrogen, alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxyl, amino, guanidino, guanidino substituted by alkoxycarbonyl, carbamoyl, and heterocycloalkyl, or

[0344] R7 and R8 together with the carbon atom and nitrogen atom to which R7 and R8 are bonded form a heterocycloalkyl group, and R3 and R4 are each independently:

[0345] hydrogen atoms,

[0346] Alkyl, carboxyl, or substituted with the same or different substituents selected from hydrogen, alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxyl, amino, guanidino, guanidino substituted by alkoxycarbonyl, carbamoyl, and heterocycloalkyl, up to the maximum number of substitutable substituents.

[0347] an alkoxycarbonyl group substituted by the same or different substituents selected from alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxyl, amino, guanidino, guanidino substituted by alkoxycarbonyl, carbamoyl, and heterocycloalkyl, up to the maximum number of substitutable substituents,

[0348] R 11 、R 12 、R 13 and R 14 Each independently is:

[0349] Hydrogen atoms, hydroxyl groups, or

[0350] an alkoxy group substituted by the same or different substituents selected from alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy and heterocycloalkyl, from one to the maximum substitutable number,

[0351] X is CH2 or CO,

[0352] A is O, NH or S, wherein NH may be substituted by the same or different substituents selected from alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, cycloalkyl, carboxyl and heterocycloalkyl, from one to the maximum substitutable number.

[0353] In one embodiment, R1 and R2 are each independently: a hydrogen atom or a C 1-6 Alkyl, R3 and R4 are each independently: a hydrogen atom, a C substituted by a carboxyl group 1-6 Alkyl or carboxyl, R5 is a hydrogen atom or C 1-6 Alkyl, R6 is a hydrogen atom or C 1-6 Alkyl, R7 is a hydrogen atom, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carbamoyl C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, hydroxyl C 6-10 Aryl C 1-6 Alkyl, C 5-10 Heteroaryl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, thio C 1-6 Alkyl, C 1-6 Alkylthio C1-6 Alkyl, or amidinoamino C 1-6 Alkyl, R8 is a hydrogen atom or C 1-6 Alkyl, wherein R7 and R8 may form an optionally substituted heterocycloalkyl together with the carbon atom and nitrogen atom to which R7 and R8 are bonded, R9 and R 10 A hydrogen atom or C 1-6 Alkyl, R 11 、R 12 、R 13 and R 14 Each independently represents: a hydrogen atom, an alkoxy group or a hydroxyl group, X represents CH2 or CO, A represents O, 1-6 NH, NH or S substituted with an alkyl group.

[0354] In one embodiment, R1 and R2 are each independently a hydrogen atom, a methyl group or an ethyl group, R3 and R4 are each independently a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group or a carboxyl group, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a carboxymethyl group, a carboxyethyl group, a 4-hydroxybenzyl group, an aminoethyl group, a 4-aminobutyl group, a thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinopropyl group, an indolylmethyl group or a 4-imidazolemethyl group, and R8 is a hydrogen atom, wherein R7 and R8 may form a C 5-10 Heterocycloalkyl, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 are each independently a hydrogen atom, R 12 is a hydrogen atom, a methoxy group or a hydroxyl group, X is CH2 or CO, and A is O, NH or S.

[0355] In one embodiment, R1 and R2 are each independently a hydrogen atom or a C 1-6 alkyl.

[0356] In one embodiment, R1 and R2 are each independently a hydrogen atom, a methyl group or an ethyl group.

[0357] In one embodiment, R3 and R4 are each independently a hydrogen atom, a C 1-6 Alkyl or carboxyl.

[0358] In one embodiment, R3 and R4 are each independently a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group or a carboxyl group.

[0359] In one embodiment, R5 is a hydrogen atom or C 1-6 alkyl.

[0360] In one embodiment, R5 is a hydrogen atom.

[0361] In one embodiment, R6 is a hydrogen atom or C 1-6 alkyl.

[0362] In one embodiment, R6 is a hydrogen atom.

[0363] In one embodiment, R7 is a hydrogen atom, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carbamoyl C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, hydroxyl C 6-10 Aryl C 1-6 Alkyl, C 5-10 Heteroaryl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, thio C 1-6 Alkyl, C 1-6 Alkylthio C 1-6 Alkyl or amidinoamino C 1-6 alkyl.

[0364] In one embodiment, R7 is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a carboxymethyl group, a carboxyethyl group, a 4-hydroxybenzyl group, an aminoethyl group, a 4-aminobutyl group, a thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinopropyl group, an indolylmethyl group or a 4-imidazolemethyl group.

[0365] In one embodiment, R8 is a hydrogen atom or C 1-6 alkyl.

[0366] In one embodiment, R8 is a hydrogen atom.

[0367] In one embodiment, R7 and R8, together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded, form an optionally substituted heterocycloalkyl group.

[0368] In one embodiment, R7 and R8 together with the carbon atom and nitrogen atom to which R7 and R8 are bonded form C 5-10 Heterocycloalkyl.

[0369] In one embodiment, R9 and R 10 A hydrogen atom or C 1-6 alkyl.

[0370] In one embodiment, R9 and R 10 are each independently a hydrogen atom or a methyl group.

[0371] In one embodiment, R 11 、R 12 、R 13 and R 14 Each is independently a hydrogen atom, an alkoxy group or a hydroxyl group.

[0372] In one embodiment, R 12 is a hydrogen atom, a methoxy group or a hydroxyl group.

[0373] In one embodiment, R 11 、R 12 、R 13 and R 14 Each is independently a hydrogen atom, a methoxy group or a hydroxyl group.

[0374] In one embodiment, X is CH2 or CO.

[0375] In one embodiment, A is O, C 1-6 NH, NH or S substituted with an alkyl group.

[0376] In one embodiment, A is O, NH or S.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[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 a hydroxymethyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[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 a 1-hydroxyethyl, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[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 a 4-hydroxybenzyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[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 is 4-aminobutyl, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[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 an amidinoaminopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

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

[0406] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a carbamoylmethyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0407] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a 4-imidazole methyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0408] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an indolylmethyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0409] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 and R8 together with the carbon atom and nitrogen atom to which they are bonded form a pyrrolidine ring, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0410] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is methoxy, X is CH2, and A is O.

[0411] In one embodiment, R1 and R2 are ethyl groups, R3 and R4 are carboxyl groups or carboxyethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0412] In one embodiment, X in the above embodiment is CO.

[0413] In one embodiment, A in the above embodiment is NH.

[0414] In one embodiment, A in the above embodiment is S.

[0415] In another aspect, a composition for treating or preventing an ophthalmic disease comprises: The compound used in the present disclosure can be exemplified by a compound represented by the following formula or a pharmaceutically acceptable salt, solvate or prodrug thereof,

[0416] [Chemistry 5]

[0417]

[0418] Where 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 a salt thereof, or alkoxycarbonyl, R A5 is a hydrocarbon group, a hydroxyl group, an alkoxy group or an alkylcarbonyloxy group, R A55 and R A66 Each is independently a hydrogen atom, a hydrocarbon group or an alkylcarbonyloxy group.

[0419] As the above-mentioned cyclic peptide derivative, in the aforementioned general formula (1), it is preferred 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.

[0420] The present disclosure may include compounds having any of the following substituents.

[0421] [Chemistry 6]

[0422]

[0423] [Table A-1]

[0424]

[0425] [Table A-2]

[0426]

[0427] In addition, the indolylmethyl group in Table 19 above independently represents a 2-indolylmethyl group or a 3-indolylmethyl group in each case.

[0428] [Table A-3]

[0429]

[0430] [Table A-4]

[0431]

[0432] [Table A-5]

[0433]

[0434] [Table A-6]

[0435]

[0436] [Table A-7]

[0437]

[0438] [Table A-8]

[0439]

[0440] [Table A-9]

[0441]

[0442] [Table A-10]

[0443]

[0444] [Table A-11]

[0445]

[0446] [Table A-12]

[0447]

[0448] [Table A-13]

[0449]

[0450] [Table A-14]

[0451]

[0452] [Table A-15]

[0453]

[0454] [Table A-16]

[0455]

[0456] [Table A-17]

[0457]

[0458] [Table A-18]

[0459]

[0460] [Table A-19]

[0461]

[0462] wherein the numbers of each X, A, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are the corresponding substituents shown in the above definition table.

[0463] The present disclosure may be a compound having any combination of substituents shown in the above definition table.

[0464] In one embodiment, the compounds disclosed in this specification are shown in the following table.

[0465] [Table 2-1]

[0466]

[0467] [Table 2-2]

[0468]

[0469] [Table 2-3]

[0470]

[0471] [Table 2-4]

[0472]

[0473] [Table 2-5]

[0474]

[0475] [Table 2-6]

[0476]

[0477] [Table 2-7]

[0478]

[0479] In addition, the following can be exemplified as the compounds of the present disclosure.

[0480] [Table 2-8]

[0481]

[0482] [Table 2-9]

[0483]

[0484] [Table 2-10]

[0485]

[0486] The present disclosure preferably uses a cyclic peptide derivative or a salt thereof as an active ingredient.

[0487] Furthermore, the present disclosure is preferably used to treat or prevent ophthalmic diseases. Preferably, the ophthalmic disease is a retinal disease, more preferably diabetic retinopathy, glaucoma or age-related macular degeneration.

[0488] Do not wish to be bound by theory, in the present disclosure, when administering control substance, tested substance and positive control to the rat of anterior chamber aqueous humor pressure load model, in general state and retinal thickness (inner plexiform layer, inner granular layer, outer granular layer), by the model of the retinal disorder induced by the ischemia of pressure load, all observe effect, therefore it can be understood that in any ophthalmological disease directly or indirectly related to them, all is effective.In addition, it can be understood that many retinal diseases are included in these.In addition, according to the content of the present disclosure, it is believed that compound of the present disclosure, medicine or composition are to the disease related to the damage of retinal pigment epithelium (RPE) and photocell (photo cell) or abnormally effective, or to the disease related to the reduction of ocular blood flow or abnormally effective.

[0489] (Medications, treatments, etc.)

[0490] General Description

[0491] In one embodiment, the compounds of the present disclosure can be directly administered orally or parenterally or can be administered as a preparation, medicine or pharmaceutical composition using an appropriate dosage form. As specific examples of these dosage forms, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, cataplasms, etc. can be cited, but are not limited thereto. In addition, these preparations can be manufactured by known methods using additives commonly used as pharmaceutical additives.

[0492] As these additives, excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavorings, etc. can be used depending on the purpose. Specific examples of these additives include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially alpha-starch, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc., but are not limited thereto.

[0493] In one embodiment, the compounds of the present disclosure are compounds that can treat or prevent ophthalmic diseases.

[0494] In one embodiment, the compounds of the present disclosure are compounds that can treat or prevent retinal diseases.

[0495] In one embodiment, the compounds of the present disclosure are compounds that can treat or prevent diabetic retinopathy, glaucoma, or age-related macular degeneration.

[0496] In one embodiment, the retinal disease targeted by the present disclosure may be a disease that causes degeneration, disorder or cell death of cells constituting the retina, or a disease caused by degeneration, disorder or cell death of cells constituting the retina, and examples thereof include glaucoma, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, retinal detachment, diabetic maculopathy, hypertensive retinopathy, retinal vascular occlusion (retinal artery occlusion; retinal vein occlusion such as central retinal vein occlusion and branch retinal vein occlusion), retinal arteriosclerosis, retinal holes, retinal holes, macular holes, fundus hemorrhage, posterior hyaloid detachment, choroidal atrophy of the pigmented paravenous network, circumflex venous stenosis, and the like. Examples of diseases that may be considered include chorioretinal atrophy, colloid degeneration, crystalline retinopathy, white dot retinopathy, cone dystrophy, central annular choroidal dystrophy, Doyne honeycomb retinal dystrophy, vitelliform macular dystrophy, cystic tissue macular edema, latent macular dystrophy, Stargardt's disease, retinal detachment, central serous chorioretinopathy (central retinopathy), spinocerebellar ataxia type 7, familial exudative vitreoretinopathy, S cone enhancement syndrome, retinal pigment streaks, autosomal dominant optic atrophy, autosomal dominant drusen, familial drusen, acute regional latent outer retinopathy, cancer-related retinopathy, light damage, and ischemic retinopathy. Suitable target diseases include glaucoma, age-related macular degeneration, and diabetic retinopathy.

[0497] In addition, the present disclosure also targets diseases in which any cell constituting the retina is damaged, or diseases caused by damage to any cell constituting the retina. Cells constituting the retina include retinal ganglion cells, amacrine cells, horizontal cells, Müller glial cells, bipolar cells, retinal photoreceptors (cones, rods), and retinal pigment epithelial cells. In particular, it is suitable to observe damage to retinal ganglion cells or retinal pigment epithelial cells, or diseases caused by damage to these cells.

[0498] In addition, the present disclosure also targets diseases in which any of the layers constituting the retina, namely, the inner limiting membrane, nerve fiber layer, ganglion cell layer, inner plexiform membrane, inner granular layer, outer plexiform layer, outer granular layer, outer limiting membrane, photoreceptor layer, and retinal pigment epithelium, is damaged, or diseases caused by damage to any of these layers. In particular, diseases in which the ganglion cell layer, inner granular layer, or outer granular layer is damaged are suitable targets.

[0499] Retinal diseases can be one or more than one.

[0500] Suitable patients who are the subject of the present disclosure are patients suffering from the above-mentioned retinal diseases.

[0501] Age-related macular degeneration and diabetic retinopathy are diseases caused by angiogenesis in the eye, resulting in damage to the macula and impaired vision. Diabetic retinopathy is presumed to be caused by inflammation of the endothelial cells within the retina caused by high blood sugar, leading to angiogenesis.

[0502] The compounds of the present disclosure inhibit the thinning of the thickness of the retina (outer granular layer). Therefore, the compounds of the present disclosure prevent, improve or treat retinal diseases.

[0503] The administration period of the compounds of the present invention and their therapeutic agents is not limited. They can be administered to the subject to be administered simultaneously or at intervals. In addition, a combination of the compounds of the present invention and their therapeutic agents can be prepared. The dosage of these therapeutic agents can be appropriately selected based on the dosage used clinically. In addition, the ratio of the compounds of the present invention and their therapeutic agents can be appropriately selected based on the subject to be administered, the route of administration, the target disease, disorder, symptoms, combination, etc.

[0504] In one embodiment of the present disclosure, when a pharmaceutical composition is used, the compounds of the present disclosure may be administered simultaneously or at different times. Such a pharmaceutical composition is also within the scope of the present disclosure.

[0505] Such drugs, preparations, and pharmaceutical compositions can be manufactured by mixing the compounds of the present invention and / or additional drugs (e.g., antibacterial drugs, antiviral agents (e.g., ribavirin, amantadine, etc.), sedatives (e.g., ketamine, midazolam, etc.) together or separately in the form of a mixture or in the form of a separate drug with any appropriate ingredients using any technology known in the art. They can be formulated into suitable preparations, such as tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and poultices using any technology known in the art. When the compound of the present disclosure and / or an additional pharmaceutical agent (e.g., an antibacterial drug, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.)) are prepared as separate pharmaceutical agents, they can be provided as a kit of two pharmaceutical agents or as a single agent of one component, and provided together with instructions (package insert, etc.) indicating whether to administer the compound of the present disclosure simultaneously or at different times in combination with the other component (the additional pharmaceutical agent in the case of the compound of the present disclosure, or the compound of the present disclosure in the case of the additional pharmaceutical agent (e.g., an antibacterial drug, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.)).

[0506] In certain embodiments, co-administration of a compound of the present disclosure with one or more additional therapeutic agents (which may be multiple) (e.g., one or more additional chemotherapeutic agents (which may be multiple)) provides improved efficacy compared to administration of a compound of the present disclosure (e.g., a compound of Formula (1), (A2), or (2)) or one or more additional therapeutic agents (which may be multiple) alone. In certain such embodiments, co-administration provides an additive effect, whereby the additive effect refers to the sum of the effects of the compound of the present disclosure and the one or more additional therapeutic agents (which may be multiple) administered alone.

[0507] For use in the methods of the present disclosure, the active compound can be provided per se, or can be provided as a pharmaceutical composition containing, for example, 0.1-99.5% (more preferably 0.5-90%) active ingredient in combination with a pharmaceutically acceptable carrier.

[0508] The dosage of the compound of the present disclosure is appropriately selected based on the animal to be administered, the route of administration, the disease, the age, weight, and symptoms of the patient. For example, in the case of oral administration, for adults, the lower limit per day is 0.01 mg and the upper limit is 10,000 mg, and this amount can be administered once a day or in divided doses.

[0509] The administration period of the compounds of the present invention and their therapeutic agents is not limited, and they can be administered to the subjects to be administered simultaneously or at intervals. In addition, a mixture of the compounds of the present invention and their therapeutic agents can be prepared. The dosage of these therapeutic agents can be appropriately selected based on the dosage used clinically. In addition, the compound of the present invention and the proportion of their therapeutic agents can be appropriately selected based on the subject to be administered, the route of administration, the target disease, disorder or symptom, the age or weight of the subject, or a combination thereof.

[0510] In one embodiment of the present disclosure, when a pharmaceutical composition is used, the compounds of the present disclosure may be administered simultaneously or at different times. Such a pharmaceutical composition is also within the scope of the present disclosure.

[0511] When the compounds of the present disclosure are used as active ingredients of medicines, they are not intended to be used only for humans but can also be used for animals other than humans (cats, dogs, cows, horses, bats, foxes, mongooses, raccoons, etc.).

[0512] (Prevention or treatment methods)

[0513] In addition, the present disclosure also provides a method for preventing or treating an ophthalmic disease, comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same to a subject in need of such prevention or treatment. In one embodiment, the method for preventing or treating an ophthalmic disease comprises administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition comprising the same to a subject in need of such prevention or treatment.

[0514] (For preventive or therapeutic use)

[0515] In one embodiment of the present disclosure, there is provided use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating an ophthalmic disease.

[0516] In addition, the present disclosure also provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in preventing or treating an ophthalmic disease.

[0517] (synthesis example)

[0518] For example, the present disclosure can be obtained by combining four compound fragments (A, B, C, and D), but is not limited thereto. The compounds used may be commercially available or synthesized.

[0519] The term "binding reaction" generally refers to all methods that can be used in organic synthetic chemistry, and includes, for example, cyclization reaction, addition reaction, ring-opening addition reaction, dehydration condensation reaction, etc. In addition to the binding reaction, protection reaction, deprotection reaction, oxidation reaction, reduction reaction, hydrogenation reaction, etc. can also be used. Reaction conditions such as reaction temperature and reaction time can be appropriately set.

[0520] In each reaction, the functional group contained in the compound used may be protected by a protecting group or the like.

[0521] The order of the reaction is not particularly limited. The cyclization reaction may be carried out after combining the four compounds, or the cyclization reaction may be carried out at the stage of combining the three compounds, and the resulting cyclized compound may be combined with the fourth compound.

[0522] The compound used in each reaction may be a purified product or a product from the previous step of the reaction may be used as it is.

[0523] 1. Method for producing cyclic peptide derivatives

[0524] In the method for producing a cyclic peptide derivative disclosed herein, a cyclic peptide derivative represented by the following general formula (2) is produced.

[0525] [Chemistry 7]

[0526]

[0527] Here, in formula (2),

[0528] R A1 represents a hydrogen atom or a hydrocarbon group,

[0529] R A2 represents a hydrogen atom or a hydrocarbon group,

[0530] R A3 represents a hydrogen atom or a hydrocarbon group,

[0531] R A4 represents a hydrogen atom or a hydrocarbon group,

[0532] R A5 Indicates -OR A51 (R A51 represents a hydrogen atom or a protecting group),

[0533] R A61 Indicates -OR A6 (R A6 represents a hydrogen atom, a hydrocarbon group or a protecting group),

[0534] R A7 represents a hydrogen atom, a hydrocarbon group or a protecting group,

[0535] R A8 represents a hydrogen atom, a hydrocarbon group or a protecting group,

[0536] R A9 represents a hydrogen atom, a hydrocarbon group or a protecting group,

[0537] R A10 represents a hydrogen atom, a hydrocarbon group or a protecting group,

[0538] R A11 represents a hydrogen atom, a hydrocarbon group or a protecting group,

[0539] R A12 represents a hydrogen atom or a protecting group,

[0540] 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 greater than or equal to 1),

[0541] Among them, R A51 、R A6 、R A12 and R A13 At least one of them is other than a hydrogen atom,

[0542] m is 1.

[0543] In particular, the production method disclosed herein includes a step of condensing a product obtained by an oxidation reaction of a compound represented by the following general formula (2') with a compound having both a carboxyl group and an amino group, or a salt or ester of the compound (hereinafter referred to as "step A" in this specification).

[0544] [Chemistry 8]

[0545]

[0546] Here, in formula (2'), R A1 、R A2 、R A3 、R A4 、R A5 、R A61 、R A7 、R A8 、R A9 、R A10 and m are respectively the same as R A1 、R A2 、R A3 、R A4 、R A5 、R A61 、R A7 、R A8 、R A9 、R A10 and m have the same meaning. In particular, R in formula (2') A1 、R A2 、R A3 、R A4 、R A5 、R A61 、R A7 、R A8 、R A9 、R A10 and m are respectively the same as R A1 、R A2 、R A3 、R A4 、R A5 、R A61 、R A7 、R A8 、R A9 、R A10 Same as m.

[0547] In the present disclosure, a hydrocarbon group may be any of an alkyl group, an alkenyl group, and an alkynyl group. The number of carbon atoms in the hydrocarbon group is not particularly limited, but is, for example, 1 to 10, preferably 1 to 5, more preferably 1 to 4, and particularly preferably 1 to 3. Specific examples of the hydrocarbon group include methyl, ethyl, vinyl, ethynyl, propyl, isopropyl, and propenyl. The hydrocarbon group may be linear or branched.

[0548] In the present disclosure, examples of the protecting group include aromatic groups other than the aforementioned hydrocarbon groups; heterocyclic groups; oxygen-containing functional groups such as alkoxyalkyl groups, carbonyl groups, and ester groups; and groups having silicon atoms such as silyl groups.

[0549] When the protecting group is an aromatic group, examples include phenyl, benzyl, oxybenzyl (-O-CH2-Ph), and 2-nitrobenzenesulfonyl (Nosyl). When the protecting group is an oxygen-containing functional group, examples include tert-butyloxycarbonyl (Boc). When the protecting group is a group containing a silicon atom, examples include tert-butyldimethylsilyl (-Si(t-Bu)(CH3)2) and tert-butyldiphenylsilyl (-Si(t-Bu)Ph2).

[0550] In formulas (2) and (2'), R A1 When it 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, further preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0551] In formulas (2) and (2'), R A1 When it is a hydrocarbon group, it is preferably an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, or an alkynyl group having 2 to 5 carbon atoms, more preferably a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms, or an alkynyl group having 2 to 3 carbon atoms, and particularly preferably an ethynyl group (-C≡C). In particular, in formula (2), R A2 In the case of an ethynyl group, since steric hindrance is smaller than that of an ethyl group or the like, the condensation reaction described later proceeds easily.

[0552] In formulas (2) and (2'), R A3 When it 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, further preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0553] In formulas (2) and (2'), R A4 When it 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, further preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0554] In formulas (2) and (2'), preferably R A5For-OR A51 (R A51 represents a hydrogen atom or a protecting group), R A51 is a protecting group, among which an aromatic group is more preferred, and an oxybenzyl group (-O-CH2-Ph) is particularly preferred.

[0555] In formulas (2) and (2'), preferably R A61 For-OR 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 When it is a hydrocarbon group, it is preferably an allyl group, and when it is a protecting group, examples thereof include tert-butyldimethylsilyl (-Si(t-Bu)(CH3)2), tert-butyldiphenylsilyl (-Si(t-Bu)Ph2), benzyl, methoxymethyl (MOM), etc. A6 Preferred is tert-butyldimethylsilyl.

[0556] In formulas (2) and (2'), R A7 A hydrogen atom or an alkyl group having 1 to 5 carbon atoms is preferred, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms is preferred, a hydrogen atom, a methyl group or an ethyl group is further preferred, and a hydrogen atom is particularly preferred.

[0557] In formulas (2) and (2'), R A8 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, further preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a hydrogen atom.

[0558] In formulas (2) and (2'), R A9 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, further preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0559] In formulas (2) and (2'), R A10 The aforementioned protecting groups are preferred, and 2-nitrobenzenesulfonyl group (Nosyl group) is particularly preferred.

[0560] In formula (2), R A11 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, further preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a hydrogen atom.

[0561] In formula (2), R A12 It is preferably a protecting group, more preferably an aromatic group, and particularly preferably a benzyl group.

[0562] 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 It is preferably a protecting group, more preferably an aromatic group, and particularly preferably a benzyl group.

[0563] In formula (2) and formula (2'), R A5 The bonding position of is not particularly limited, and for example, it can be a bonding position represented by the following formula (2”).

[0564] [Chemistry 9]

[0565]

[0566] Here, in formula (2"), R A1 ~R A5 、R A7 ~R A12 and R A14 R of the above formula (2) A1 ~R A5 、R A7 ~R A12 and R A14 Same meaning, R A61 R of the above formula (2) A61 Same meaning.

[0567] Step A includes an oxidation reaction of the compound represented by formula (2'). Specifically, the 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 into a carboxyl group.

[0568] In step A, the type of oxidation reaction is not particularly limited. For example, a wide range of known oxidation reactions of alcohol compounds can be employed. For example, the oxidation reaction can be a two-step reaction in which an alcohol is oxidized to an aldehyde, followed by oxidation of the aldehyde to a carboxylic acid. Performing the oxidation reaction in two steps can easily prevent undesired oxidation of functional groups.

[0569] In step A, the oxidation reaction preferably includes Dess-Martin oxidation and Pinnick oxidation. This facilitates suppression of racemization and facilitates oxidation under mild reaction conditions. For example, the hydroxyl group is oxidized to an aldehyde by Dess-Martin oxidation, and the aldehyde is then oxidized to a carboxylic acid by Pinnick oxidation.

[0570] In step A, when performing the oxidation reaction, it is preferred to use 1 to 5 moles of the oxidizing agent per 1 mole of the compound represented by formula (2'). The type of the oxidizing agent is not particularly limited, and a wide range of known oxidizing agents used in oxidation reactions can be used.

[0571] In the Dess-Martin oxidation, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzimidoxolan-3(1H)-one (DMP) is preferably used as the oxidizing agent. In the Dess-Martin oxidation, the oxidizing agent is preferably used in an amount of 1 to 5 moles, more preferably 1 to 3 moles, per 1 mole of the compound represented by formula (2').

[0572] In Pinnick oxidation, sodium chlorite (NaClO2) is preferably used as the oxidizing agent. In Pinnick oxidation, the oxidizing agent is preferably used in an amount of 1 to 5 moles, more preferably 2 to 5 moles, per mole of the compound represented by formula (2').

[0573] Other oxidizing agents may be used in the oxidation reaction. For example, an oxidizing agent comprising a nitroxide radical species such as 2,2,6,6-tetramethylpiperidinyl 1-oxyl and a combination of iodosobenzene diacetate may be used.

[0574] In step A, a solvent may be used in the oxidation reaction as needed. Examples of the solvent used in the oxidation reaction include chlorine-containing compounds such as dichloromethane and dichloroethane, acetonitrile, and tert-butanol.

[0575] In step A, the reaction temperature of the oxidation reaction is not particularly limited, and can be, for example, carried out at -20 to 60°C, preferably at 0 to 30°C.

[0576] In step A, after the oxidation reaction, the product obtained in the oxidation reaction (carboxylic acid compound) 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, is referred to as "Compound C."

[0577] Among compound C, the compound having both a carboxyl group and an amino group is not particularly limited, and examples thereof include amino acids, with glutamic acid or aspartic acid being preferred.

[0578] In particular, in step A, it is preferred to subject the product obtained in the aforementioned oxidation reaction (carboxylic acid compound) to a condensation reaction with glutamate or aspartic acid. By using glutamate in the condensation reaction, the resulting cyclic peptide derivative, i.e., the cyclic peptide derivative represented by the general formula (2), wherein R A14 -(CH2)2-COOR A13When aspartic acid ester is used in the condensation reaction, the resulting cyclic peptide derivative, that is, the cyclic peptide derivative represented by the general formula (2), R A14 -(CH2)-COOR A13 In either case, as R A13 , are preferably protecting groups, more preferably aromatic groups, and particularly preferably benzyl groups.

[0579] In the condensation reaction of step A, the amount of compound C used is preferably 1 to 5 mol, more preferably 2 to 5 mol, and even more preferably 3 to 4 mol, per 1 mol of the carboxylic acid compound obtained in the oxidation reaction.

[0580] For example, in step A, when the product obtained in the above oxidation reaction (carboxylic acid compound) is subjected to a condensation reaction with glutamate, the resulting cyclic peptide derivative represented by formula (2) is represented by the following general formula (2A).

[0581] [Chemistry 10]

[0582]

[0583] Here, in formula (2A), R A1 ~R A5 、R A61 、R A7 ~R A13 and m and R of the above formula (2) A1 ~R A5 、R A61 、R A7 ~R A13 Has the same meaning as m.

[0584] In step A, the condensation reaction method is not particularly limited, and for example, known condensation reaction conditions can be widely adopted. A condensing agent can also be used in the condensation reaction from the viewpoint of easily suppressing racemization and promoting oxidation under mild reaction conditions.

[0585] The type of the condensing agent is not particularly limited, and for example, a wide range of known condensing agents can be used. In particular, in the condensation reaction of step A, it is preferred to use a phosphorus-based condensing agent as the condensing agent. Examples of such condensing agents include 3-(diethoxyphosphoryloxy)-3H-benzo[d][1,2,3]triazin-4-one (DEPBT), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate, and N-[1-(cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate. The phosphorus-based condensing agent is preferably a phosphoric acid azide compound, and DEPBT is particularly preferred.

[0586] When a condensing agent is used, its amount is not particularly limited. For example, the amount of the condensing agent used is preferably 1 to 3 mol, more preferably 1.2 to 2.5 mol, per 1 mol of the carboxylic acid compound obtained in the oxidation reaction.

[0587] A solvent may be used in the condensation reaction of step A as needed. The solvent is not particularly limited, and examples thereof include aliphatic hydrocarbons such as hexane and heptane; alicyclic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; chlorinated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; alcohols such as methanol, ethanol, isopropyl alcohol, and tert-butyl alcohol; and amide solvents such as N,N-dimethylacrylamide.

[0588] The condensation reaction can be carried out in the presence of a base catalyst such as diisopropylethylamine or dimethylaminopyridine.

[0589] In step A, the reaction temperature of the condensation reaction is not particularly limited, and can be, for example, -20 to 60°C, preferably 0 to 30°C.

[0590] 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 high yield. In the past, a method for stereoselectively reacting a cyclic peptide derivative obtained by condensing a large lactam structure containing a structure derived from a non-natural amino acid such as a β-hydroxydopa unit and a β-hydroxyisoleucine unit with an amino acid derivative such as a glutamic acid 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.

[0591] Generally, in known biosynthesis, cyclic peptide derivatives are produced by combining all peptides and then cyclizing them. In contrast, in the method for producing cyclic peptide derivatives disclosed herein, compound C (e.g., glutamate) is combined with a compound having a cyclized structure. That is, in the method for producing cyclic peptide derivatives disclosed herein, compound C is combined last, and therefore has the advantage of being able to obtain cyclic peptide derivatives combined with various amino acids, etc., depending on the type of compound C. In addition, as disclosed herein, the path of pre-constructing a ring structure and then introducing a side chain (compound C) also has the advantage of simplifying the steps involved in the removal of the protecting group and providing the target product in high yield.

[0592] 2. Method for producing cyclic peptide compounds

[0593] The method for producing a cyclic peptide compound disclosed herein includes a step of obtaining the cyclic peptide compound by subjecting the cyclic peptide derivative obtained by the aforementioned method for producing a cyclic peptide derivative to a hydrogenation-reduction reaction. Specifically, the method for producing a cyclic peptide compound disclosed herein includes a step of conducting a hydrogenation-reduction reaction after the condensation reaction in step A of the method for producing the cyclic peptide derivative.

[0594] In the method for producing the cyclic peptide compound, the method for the hydrogenation reduction reaction is not particularly limited, and for example, known hydrogenation reduction reaction conditions can be widely adopted. For example, the hydrogenation reduction reaction can be carried out by using hydrogen in the presence of a catalyst. As the catalyst, for example, a known catalyst used in the hydrogenation reduction reaction can be used, specifically palladium carbon can be mentioned. A solvent can also be used in the hydrogenation reduction reaction as needed. As the solvent, lower alcohols such as methanol and ethanol can be mentioned.

[0595] When the cyclic peptide derivative represented by formula (2) obtained in the condensation reaction of step A has a protecting group such as a tert-butyloxycarbonyl group (Boc group), a tert-butyldimethylsilyl group (TBS group), or a 2-nitrobenzenesulfonyl group (Nosyl group), the protecting group may be deprotected before the hydrogenation reduction reaction. The deprotection method is not particularly limited, and for example, a wide range of known deprotection methods can be employed. For example, deprotection of the TBS group and deprotection of the Nosyl group may be performed sequentially.

[0596] When the cyclic peptide derivative represented by formula (2) has an alkyne group (for example, R A2 ), the alkynyl group can be converted into an alkyl group by the aforementioned hydrogenation reduction reaction. For example, when an ethynyl group exists in the cyclic peptide derivative represented by formula (2), it can be converted into an ethyl group by the aforementioned hydrogenation reduction reaction.

[0597] In one embodiment of the method for producing a cyclic peptide compound disclosed herein, for example, the cyclic peptide derivative represented by formula (2) obtained in the condensation reaction of step A is deprotected and then subjected to a hydrogenation reduction reaction. This can produce, for example, a compound represented by the following formula (10). As a specific example, a compound represented by the following formula (A) can be produced.

[0598] [Chemistry 11]

[0599]

[0600] [Chemistry 12]

[0601]

[0602] In formula (10), R A1 、R A2 、R A3 、R A4 、R A61 、R A7 、R A8 、R A9 、R A10 and R A11 Respectively with R of the above formula (2) A1 、R A2 、R A3 、R A4 、R A61 、R A7 、R A8 、R A9 、R A10 and R A11 The meaning is the same. At this time, R A61 A hydroxy group is preferred.

[0603] In addition, in formula (A), R A1 、R A3 and R A4 R of the above formula (2) A1 、R A3 and R A4 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, R A14 It should be noted that in formula (A), R A2 is ethyl, R A61 OH, R A7 、R A8 、R A9 and R A11 is a hydrogen atom, R A10 It is a methyl group, but is not limited thereto.

[0604] In the hydrogenation reduction reaction, when the cyclic peptide derivative represented by formula (2) has an alkyne group, in addition to converting it into an alkyl group, for example, the ester portion derived from compound C is converted into a carboxylic acid. A5 When there is a protecting group (for example, an ether structure-containing group such as an oxybenzyl group), R A5 It can be converted into a hydroxyl group (see the aforementioned formula (A)).

[0605] The cyclic peptide compound obtained by the hydrogenation reduction reaction is not particularly limited as long as it is a compound that can be generated by hydrogenation reduction of the compound represented by formula (2). Preferably, R in formula (2) is A5 is hydroxyl group, R A12 is a hydrogen atom, R A14 COOR A13 R in A13 In this case, R A2 The cyclic peptide compound is further preferably R A14 The cyclic peptide compound obtained by the hydrogenation reduction reaction is most preferably the compound represented by the general formula (A) R A1 、R A3 and R A4 All are methyl compounds.

[0606] In the method for producing a cyclic peptide compound disclosed herein, a cyclic peptide compound can be obtained by subjecting a cyclic peptide derivative obtained by the aforementioned method for producing a cyclic peptide derivative to a hydrogenation reduction reaction, thereby obtaining the cyclic peptide compound in high yield. Furthermore, depending on the type of compound C used in the method for producing a cyclic peptide derivative, cyclic peptide compounds bonded to various amino acids, etc., can be obtained.

[0607] 3. Preparation Methods of Raw Materials Used in the Present Disclosure

[0608] Hereinafter, an example of a method for producing the compound represented by formula (2') used in step A of the method for producing the cyclic peptide derivative disclosed herein will be described. The method for producing the compound represented by formula (2') is not particularly limited, and for example, a wide range of known production methods can be employed.

[0609] The method for producing the compound represented by formula (2') comprises the following steps: A6 When it is a protecting group, for example, there may be a step (hereinafter referred to as a cyclization step) of obtaining a compound represented by the following formula (22a) by an intramolecular cyclization reaction of a cyclization precursor represented by the following formula (21a).

[0610] [Chemistry 13]

[0611]

[0612] In formula (21a), R A1 ~R A5 and m and R of the above formula (1) A1 ~R A5 and m have the same meaning. In formula (21a), MOM represents a methoxymethyl group (the same applies hereinafter). TBS represents a tert-butyldimethylsilyl group.

[0613] [Chemistry 14]

[0614]

[0615] In formula (22a), R A1 ~R A5 and m and R of the above formula (1) A1 ~R A5 Has the same meaning as m.

[0616] In the cyclization step, an amide bond is formed between the β-hydroxyisoleucine unit and the β-hydroxydopa unit through an intramolecular cyclization reaction of the cyclization precursor represented by formula (21a), thereby forming the compound represented by formula (22a).

[0617] Conventional methods for the intramolecular cyclization reaction (e.g., P. Li, C.D. Evans, M.M. Joullie, Org. Lett., 2005, 7, 5325) have yields ranging from 10% to 20%, with the production of large amounts of dimers of the cyclization precursor as by-products. Furthermore, other methods (e.g., P. Li, C.D. Evans, Y. Wu, B. Cao, E. Hamel, M.M. Joullie, J. Am. Chem. Soc., 2008, 130, 2351) have yields of 30% to 40%, but these yields still do not exceed 40%.

[0618] In this regard, in the present disclosure, in the cyclization step, a dilute substrate solution is added dropwise to a solvent containing a coupling agent to reduce the concentration of the substrate (i.e., the compound shown in Formula (21a)), thereby suppressing the intermolecular reaction and promoting the intramolecular cyclization reaction. Thus, compared with the past, an intramolecular cyclization reaction can be performed with a high yield. By performing such an intramolecular cyclization reaction, the intermolecular reaction can be suppressed, and it is therefore presumed that the yield of the target cyclized compound (i.e., the compound shown in Formula (22a)) is increased.

[0619] In the cyclization step, the type of coupling agent is not particularly limited, and a wide range of coupling agents used in intramolecular cyclization reactions can be used. Examples of coupling agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorohexafluorophosphate, and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT).

[0620] The solvent used to dissolve the coupling agent and substrate in the cyclization step is not particularly limited, but preferably includes 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. These solvents may be used alone or in combination of two or more.

[0621] The concentration of the coupling agent can be set, for example, in the range of 1 mM to 15 mM based on the solvent used. The concentration of the substrate can be set in the range of 0.1 mM to 1.5 mM based on the solvent used.

[0622] The temperature of 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, etc. For example, the substrate can be added dropwise for 6 to 24 hours and then the reaction can be continued for 6 to 24 hours, but the reaction is not limited to this. In particular, by carrying out the reaction at a low temperature for a long time, the intramolecular cyclization reaction is promoted, and the yield of the cyclized compound (compound represented by formula (22a)) can be increased by about 1.5 to 2.5 times compared to conventional cyclization reactions.

[0623] After the compound shown in formula (22a) is obtained by intramolecular cyclization, the compound shown in formula (2) can be obtained by the deprotection of MOM. The method for the deprotection of MOM is not particularly limited, for example, can be set to the condition identical with the method for the deprotection of known MOM. Before carrying out the deprotection of MOM, for example, the protecting group in the compound shown in formula (22a) can also be substituted with other protecting groups (for example, the Boc group substituted on the N atom is replaced with a Nosyl group). Further, before carrying out the deprotection of MOM, the N atom methylation of the protecting groups such as the Nosyl group can also be performed. Methylation can widely adopt for example known method, exemplified by the methylation of methyl p-nitrobenzenesulfonate.

[0624] The method for producing 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 by a known reaction. As an example, the compound represented by formula (21a) can be obtained by reacting a compound represented by formula (7a) with a compound represented by formula (8a).

[0625] [Chemistry 15]

[0626]

[0627] In formula (7a), R A5 and m and R of the above formula (1) A5 and m have the same meaning. The compound represented by formula (7a) is a β-hydroxydopa unit.

[0628] [Chemistry 16]

[0629]

[0630] In formula (8a), R A1 and R A2 R of the above formula (2) A1 and R A2 The compound represented by formula (8a) is an aziridine compound.

[0631] The reaction between the compound represented by formula (7a) and the compound represented by formula (8a) can be carried out under the same conditions as a known ring-opening reaction. This ring-opening reaction can be carried out in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).

[0632] In formula (8a), R A2 In the case of an ethynyl group, the nucleophilic reaction rate is extremely fast, thereby rapidly accelerating the nucleophilic addition reaction between the β-hydroxydopa unit and the aziridine, and increasing the yield of the reaction product. Therefore, the production method disclosed herein also has the advantage of being able to use aziridine, which does not react with amino acids.

[0633] After the reaction of the compound represented by formula (7a) and the compound represented by formula (8a), a protecting group (MOM) is introduced to synthesize the compound represented by formula (13a). The reaction conditions for introducing the protecting group are not particularly limited and can be the same as those of known methods.

[0634] [Chemistry 17]

[0635]

[0636] In formula (13a), R A1 、R A2 、R A5 and m and R of the above formula (2) A1 、R A2 、R A5 Has the same meaning as m.

[0637] Then, the compound represented by the formula (13a) can be subjected to a deprotection reaction and an esterification reaction to obtain a compound represented by the following formula (18a). The deprotection reaction and the esterification reaction conditions are not particularly limited and can be the same as those of known methods.

[0638] [Chemistry 18]

[0639]

[0640] In formula (18a), R A1 、R A2 、R A5 and m and R of the above formula (2) A1 、R A2 、R A5 Has the same meaning as m.

[0641] After deprotecting the Troc group (2,2,2-trichloroethoxycarbonyl) of the obtained compound represented by formula (18a), a condensation reaction is carried out with a valine compound having a 9-fluorenylmethoxycarbonyl group, and then deprotected to produce the compound represented by formula (21a) (cyclization precursor). In this condensation reaction, a suitable condensing agent can be used.

[0642] It should be noted that R A2 When it is an ethynyl group, it can be reduced as needed. The reduction can be carried out after the condensation reaction in step A, in the step of carrying out the hydrogenation reduction reaction, or it can be carried out at any time as long as it is after the nucleophilic addition reaction with the aforementioned aziridine. In this regard, in R A2 In the case of an ethynyl group, the ethynyl group is less bulky than an alkyl group and is therefore less likely to inhibit the reaction. Therefore, the ethynyl group can be maintained without being reduced until the hydrogenation reduction reaction.

[0643] The method for producing the compound represented by formula (7a) is not particularly limited, and it can be produced, for example, by reacting a compound represented by the following formula (1a) and a compound represented by the following formula (2a) as starting materials.

[0644] [Chemistry 19]

[0645]

[0646] [Chemistry 20]

[0647]

[0648] In formula (2a), R A5 and m and R of the aforementioned formula (2') A5 Same meaning.

[0649] On the other hand, the compound represented by formula (8a) can be obtained, for example, by a known production method or can be obtained from a commercially available product.

[0650] (Pharmaceutical composition)

[0651] The compositions and methods of the present disclosure can be used to treat individuals in need thereof. In a specific embodiment, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal such as a human, the composition or compound is preferably administered in the form of a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or buffered saline, or other solvents or vehicles such as ethylene glycol, glycerol, oils such as olive oil, or organic esters for injection. In a preferred embodiment, such a pharmaceutical composition is administered to a human, particularly when administered by an invasive route (i.e., for example, injection or implantation to avoid transport or diffusion through an epithelial barrier), and the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to delay the release of the formulation or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be in unit dosage form, such as tablets, capsules (including Sprinkle capsules and gelatin capsules), granules, lyophilized agents for reconstitution, powders, solutions, syrups, suppositories, or injections. In addition, the composition can also be present in a transdermal delivery system, for example, a skin patch. In addition, the composition can also be present in a solution suitable for topical administration, for example, eye drops, etc.

[0652] Pharmaceutically acceptable carriers can contain physiologically acceptable agents, the effect of which is to stabilize compounds, such as compounds of the present disclosure, or to increase solubility, or to increase absorption. As such physiologically acceptable agents, for example, carbohydrates, such as glucose, sucrose or dextran, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients, etc., can be enumerated. The selection of pharmaceutically acceptable carriers comprising physiologically acceptable agents depends on, for example, the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. In addition, the pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, into which compounds of the present disclosure can be incorporated. Liposomes, such as liposomes comprising phospholipids or other lipids, etc., are physiologically acceptable metabolizable carriers that are relatively simple to make and administer, which are non-toxic.

[0653] Pharmaceutical compositions (preparations) can be administered to a subject by any of several routes of administration, including oral administration (e.g., aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, and pastes for tongue application); absorption through the oral mucosa (e.g., sublingually); anus, rectum, or vagina (e.g., as vaginal suppositories, creams, or foams); parenteral administration (including intramuscular, intravenous, subcutaneous, or intramedullary, e.g., sterile solutions or suspensions); nasal administration; intraperitoneal administration; subcutaneous administration; transdermal administration (e.g., as a skin-applicable patch); and topical administration (e.g., as a skin-applicable cream, ointment, spray, or eye drops). Furthermore, the compound can be formulated for inhalation. In certain embodiments, the compound is simply dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found in, for example, U.S. Patent No. 6,110,973, U.S. Patent No. 5,731,000, U.S. Patent No. 5,541,231, U.S. Patent No. 5,427,798, U.S. Patent No. 5,358,970, and U.S. Patent No. 4,172,896, and patents cited therein.

[0654] The formulation can be conveniently provided in unit dosage form and prepared by any method known in the art of pharmaceutical technology. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of compound that produces a therapeutic effect. Typically, this amount ranges from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0655] The method for preparing these preparations or compositions comprises the step of combining an active compound, such as a compound of the present invention, with a carrier and, if necessary, one or more auxiliary ingredients. Generally, the preparation can be prepared by uniformly and closely combining a compound of the present invention with a liquid carrier or a finely divided solid carrier, or both, and then forming the product as needed.

[0656] Formulations of the present disclosure suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (flavored bases typically use sucrose and gum arabic or tragacanth), lyophilized forms, powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as lozenges (inert bases such as gelatin and glycerin, or sucrose and gum arabic), and / or as mouthwashes, each containing a specified amount of a compound of the present disclosure as the active ingredient. Furthermore, the composition or compound may be administered as a bolus, elixir, or paste.

[0657] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, sugar-coated tablets, powders and granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, for example, sodium citrate or calcium hydrogen phosphate and / or any of the following: (1) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and / or silicic acid, etc.; (2) binders, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic, etc.; (3) humectants, for example, glycerol, etc. ; (4) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retardants, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain a buffer. In addition, the same type of solid composition may also be used as a filler in soft and hard-filled gelatin capsules using excipients such as lactose or lactose, and high molecular weight polyethylene glycol.

[0658] Tablet can be made by compression or molding together with one or more auxiliary ingredients as needed.Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant or a dispersant. Molded tablets can be made by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine.

[0659] Tablets and other solid dosage forms of pharmaceutical compositions, such as sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, can be prepared by applying engravings or using coatings and shells, such as enteric coatings and other coatings known in pharmaceutical formulation technology, as needed. In addition, these, for example, can also use hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in different proportions to provide the desired release characteristics, and be formulated to provide sustained or controlled release of the active ingredient therein. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterilized solid composition that can be dissolved in sterile water or other sterile injection medium just before use. In addition, these compositions can contain emulsifiers as needed, and can be compositions that release the active ingredient (singular or plural) only in a specific part of the digestive tract or preferentially in that part as needed in a delayed manner. As examples of embedding compositions that can be used, polymeric substances and waxes can be cited. Furthermore, the active ingredient may be in the form of microcapsules using one or more of the above-mentioned excipients, if appropriate.

[0660] Examples of liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilized formulations for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0661] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservatives.

[0662] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0663] Formulations of pharmaceutical compositions for administration to the rectum, vagina or urethra may be provided as suppositories, which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound.

[0664] Formulations of pharmaceutical compositions for administration to the mouth may be provided as a mouthwash or oral spray or oral ointment.

[0665] Alternatively or additionally, the composition can be formulated for delivery via a catheter, stent, wire or other intraluminal device. Delivery via such a device can be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0666] Additionally, formulations suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers as are known in the art to be appropriate.

[0667] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required.

[0668] Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0669] In addition to the active compound, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances, etc. Sprays may further contain customary propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0670] The use of transdermal patches also provides the advantage of providing controlled delivery of the compounds of the present disclosure to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. The flux of the compound through the skin can also be increased by using absorption enhancers. The rate of this flux can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0671] Ophthalmic preparations, eye ointments, powders and 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 and U.S. Patent No. 6,583,124 (these contents are incorporated herein by reference). If desired, liquid ophthalmic preparations have the same characteristics as tears, aqueous humor or vitreous humor, or are compatible with such fluids. A preferred route of administration is administration to a local area (e.g., topical administration, such as eye drops or administration via an implant).

[0672] The present disclosure has been described above by way of preferred embodiments for ease of understanding. The present disclosure is described below based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present disclosure is not limited to the specific embodiments or examples described in this specification, but is defined solely by the claims.

[0673] Example

[0674] In the examples, the abbreviations shown above and below may be used to simplify the description.

[0675] Ac:Acetyl

[0676] AcOH: acetic acid

[0677] aq.: aqueous solution

[0678] Arg: Arginine

[0679] Asp: Aspartic acid

[0680] BHT: Butylated hydroxytoluene

[0681] Bn: benzyl

[0682] Boc: tert-Butoxycarbonyl

[0683] Boc2O: di-tert-butyl dicarbonate

[0684] Bzl: benzyl

[0685] Cbz: benzyloxycarbonyl

[0686] CPME: Cyclopentyl Methyl Ether

[0687] DBU: diazabicycloundecene

[0688] DEPBT: 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one DIAD: diisopropyl azodicarboxylate

[0689] DIPEA: N,N-diisopropylethylamine

[0690] DMAP: 4-dimethylaminopyridine

[0691] DMEAD: bis(2-methoxyethyl)azodicarboxylate

[0692] DME: 1,2-dimethoxyethane

[0693] DMF: N,N-dimethylformamide

[0694] DMP: 2,2-dimethoxypropane

[0695] DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

[0696] DMT-MMT: 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine tetrafluoroborate

[0697] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0698] Et: ethyl

[0699] eq.: equivalent

[0700] Fmoc: 9-fluorenylmethyloxycarbonyl

[0701] Gln: glutamine

[0702] Glu: glutamate

[0703] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0704] HBTU: 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate

[0705] HOAt: 1-hydroxy-7-azabenzotriazole

[0706] HOBt: 1-hydroxybenzotriazole

[0707] m-CPBA: meta-chloroperbenzoic acid

[0708] Me:methyl

[0709] MS: molecular sieve

[0710] MTBE: Methyl tert-butyl ether

[0711] NMM: N-methylmorpholine

[0712] Ns: 2-nitrobenzenesulfonyl

[0713] PMB: p-methoxybenzyl

[0714] Ser: serine

[0715] Su: succinimide

[0716] TBAF: Tetrabutylammonium fluoride

[0717] TBAI: Tetrabutylammonium iodide

[0718] TBD: 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

[0719] TBS: tert-butyldimethylsilyl

[0720] t-Bu: tert-butyl

[0721] TFA: trifluoroacetic acid

[0722] THF: Tetrahydrofuran

[0723] Thr:Threonine

[0724] TEMPO: 2,2,6,6-tetramethylpiperidin-1-oxyl radical

[0725] Tr: trityl

[0726] Trt: trityl

[0727] Ts: p-toluenesulfonyl

[0728] TsOH: p-toluenesulfonic acid

[0729] Tyr: tyrosine

[0730] Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

[0731] Ph: phenyl

[0732] PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate

[0733] PyBrop: tripyrrolidinylphosphonium bromide hexafluorophosphate

[0734] Val: valine

[0735] It should be noted that the fragment C group and the fragment D group were obtained as follows.

[0736] [Table 2A]

[0737]

[0738] [Table 2B]

[0739]

[0740] (Example 1: Synthesis of Fragment A-2)

[0741] [Chemistry 21]

[0742]

[0743] Under ice cooling, aluminum chloride (4.0 eq., 19.1 g, 143 mmol) and acetyl chloride (1.2 eq., 3.42 g, 43.6 mmol) were added to a solution of L-tyrosine (1.0 eq., 6.51 g, 35.9 mmol) in nitrobenzene (130 mL). The mixture was stirred for 10 minutes while warming to room temperature. The reaction mixture was heated to 100°C and stirred for 8 hours, then stirred for 16 hours while cooling to room temperature. The reaction mixture was ice-cooled and water (200 mL) was added. The mixture was separated and washed once with ethyl acetate (300 mL), and the organic layer was separated and extracted once with water (100 mL). The aqueous layers were combined to obtain A2-1 as an aqueous solution (300 mL).

[0744] [Chemistry 22]

[0745]

[0746] Under ice cooling, potassium carbonate (7.5 eq., 36.9 g, 267 mmol) was added to A2-1 (1.0 eq., 300 mL of aqueous solution, calculated as 35.9 mmol), the pH was adjusted to 9, THF (150 mL) and CbzCl (1.2 eq., 7.3 g, 42.8 mmol) were added, and the mixture was stirred at room temperature for 3 hours. 2N aqueous hydrochloric acid solution (200 mL) was added to the reaction solution to adjust the pH to 3, and THF was distilled off under reduced pressure. The concentrate was extracted three times with ethyl acetate (200 mL), the organic layers were combined, washed once with saturated aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off and concentrated under reduced pressure to obtain A2-2 (11.4 g) as a brown oil.

[0747] [Chemistry 23]

[0748]

[0749] Under a nitrogen atmosphere and ice cooling, potassium carbonate (3.0 eq., 14.9 g, 108 mmol), TBAI (0.10 eq., 1.33 g, 3.59 mmol), and BnBr (2.2 eq., 13.5 g, 79.1 mmol) were added to a solution of A2-2 (1.0 eq., 11.4 g, calculated as 35.9 mmol) in DMF (50 mL). The mixture was stirred at room temperature for 3.5 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted twice with a mixture of hexane (40 mL) and ethyl acetate (80 mL). The organic layers were combined, washed once with a saturated aqueous sodium chloride solution (100 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (23.2 g). The crude product was purified by flash silica gel column purification (200 g normal phase silica gel, hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain A2-3 (9.56 g, 50% yield over three steps starting from L-tyrosine) as a yellow viscous substance. It should be noted that throughout this specification, mixed solutions are referred to as solvent A (X mL) / solvent B (Y mL) mixtures.

[0750] [Chemistry 24]

[0751]

[0752] Under a nitrogen atmosphere and ice-cooling, sodium hydride (1.2 eq., 60%, paraffin dispersion, 796 mg, 19.9 mmol) and iodomethane (3.0 eq., 7.07 g, 49.8 mmol) were added to a solution of A2-3 (1.0 eq., 8.88 g, 16.5 mmol) in DMF (80 mL). The mixture was stirred for 1.5 hours under ice-cooling. Methanol (12 mL) was added to the reaction mixture to quench it. Water (100 mL) was added, and the mixture was extracted twice with a mixture of hexane (50 mL) and ethyl acetate (100 mL). The organic layers were combined, washed once with a saturated aqueous sodium chloride solution (100 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (13.1 g). The crude product was purified by flash silica gel column (normal phase silica gel 50 g, hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain A2-4 (9.54 g) as an orange liquid.

[0753] [Chemistry 25]

[0754]

[0755] To a solution of A2-4 (1.0 eq., 10.1 g, calculated as 17.6 mmol) in chloroform (90 mL) at room temperature was added m-CPBA (3.0 eq., 35% aqueous solution, 14.0 g, 52.7 mmol), and the mixture was stirred under reflux for 5 hours. Water (50 mL) and saturated aqueous sodium bicarbonate solution (100 mL) were added to the reaction mixture at room temperature, and the chloroform was removed under reduced pressure. The reaction mixture was extracted three times with ethyl acetate (100 mL). The organic layers were combined, washed once with saturated aqueous sodium chloride solution (100 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to yield the ester (10.6 g).

[0756] At room temperature, lithium hydroxide (4.0 eq., 1.68 g, 70.3 mmol) was added to a mixture of THF (40 mL) / water (40 mL) of the ester (1.0 eq., 10.6 g, calculated as 17.6 mmol) and stirred at the same temperature for 16 hours. The reaction solution was washed twice with hexane (100 mL), and then 6N aqueous hydrochloric acid solution (11 mL) was added to the aqueous layer to adjust the pH to 2. The aqueous layer was extracted three times with ethyl acetate (100 mL), the organic layers were combined, washed once with saturated aqueous sodium chloride solution (100 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off and concentrated under reduced pressure to obtain A2-5 (9.3 g) as an orange solid.

[0757] [Chemistry 26]

[0758]

[0759] To a solution of A2-5 (1.0 eq., 9.3 g, calculated to be 17.6 mmol) in acetonitrile (80 mL) at room temperature, DBU (1.1 eq., 2.96 g, 19.4 mmol) and PMBCl (1.1 eq., 3.00 g, 19.2 mmol) were added, and the mixture was stirred at an external temperature of 60°C for 19 hours. The reaction mixture was quenched by the addition of acetic acid (3.0 eq., 3.15 g, 52.5 mmol) and then concentrated under reduced pressure to obtain a crude product (16.7 g). The crude product was purified twice by flash silica gel column purification (first: 120 g normal phase silica gel, hexane / ethyl acetate = 75 / 25 to 50 / 50, second: 30 g normal phase silica gel, hexane / ethyl acetate = 75 / 25 to 67 / 23). The resulting fragment A-2 was dissolved in ethyl acetate (50 mL) and washed once with saturated aqueous sodium bicarbonate solution (50 mL). The aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layers were washed once with saturated aqueous sodium chloride (50 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain fragment A-2 (3.54 g, 36% yield over the first three stages of A2-3) as a yellow oil.

[0760] (Example 2A: Synthesis of Fragment A-2')

[0761] [Chemistry 27]

[0762]

[0763] To a solution of A2-5 (1.0 eq., 3.4 g, calculated as 7.12 mmol) in acetonitrile (70 mL) was added DBU (1.5 eq., 1.6 mL, 10.7 mmol) and BnBr (1.2 eq., 1.0 mL, 8.54 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hours. After quenching with saturated aqueous ammonium chloride (30 mL), the mixture was separated and washed with water (30 mL) three times and saturated aqueous sodium chloride (30 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (4.83 g). The crude product was purified on a flash silica gel column (53 g of normal phase silica gel, hexane / ethyl acetate = 3 / 1 to 2 / 1) to obtain fragment A-2' (1.87 g, 50% yield over three steps) as a yellow viscous substance.

[0764] (Example 2AA: Synthesis of Fragment A-2")

[0765] [Chemistry 28]

[0766]

[0767] [Chemistry 29]

[0768]

[0769] The synthesis of L-tyrosine → A2-1 was as described in Example 1. The synthesis of A3'-3 from A2-1 via A3'-2 was as described in Example 2.

[0770] The synthesis of A2"-1 from A3'-3 is as follows.

[0771] [Chemistry 30]

[0772]

[0773] Under a nitrogen atmosphere, methyl iodide (3.0 eq., 6.8 mL, 109.23 mmol) and sodium hydride (60%, paraffin dispersion, 1.2 eq., 1.7 g, 43.45 mmol) were added to a solution of A3'-3 (1.0 eq., 18.3 g, 36.34 mmol) in DMF (150 mL) at an external temperature of -20°C. The mixture was stirred at the same temperature for 3 hours. 1N aqueous hydrochloric acid (50 mL) was added at an external temperature of -20°C, followed by water (100 mL). The mixture was extracted twice with a mixture of hexane (50 mL) and ethyl acetate (100 mL). The organic layers were combined and washed once with a saturated aqueous sodium chloride solution (150 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the crude product (20.2 g) as a yellow oil. The crude product was purified by flash silica gel column (normal phase silica gel 40 g, hexane / ethyl acetate = 9 / 1 to 3 / 1), and the resulting light yellow viscous material was washed with hexane to obtain A2"-1 (18.9 g, yield 101%).

[0774] The synthesis of A2"-2 from A2"-1 is as follows.

[0775] [Chemistry 31]

[0776]

[0777] Under a nitrogen atmosphere, to a solution of A2"-1 (1.0 eq., 18.9 g, 36.34 mmol) in chloroform (150 mL) was added m-CPBA (30% aqueous, 2.0 eq., 18.0 g, 73.01 mmol) at room temperature, and the mixture was stirred at an external temperature of 60°C for 4.5 hours. m-CPBA (0.5 eq., 4.8 g, 19.47 mmol) was further added at room temperature, and the mixture was stirred at an external temperature of 60°C for 1 hour, and then stirred at an external temperature of 40°C for 15 hours. Under ice-cooling, a 20% aqueous sodium sulfite solution (75 mL) and a saturated aqueous sodium bicarbonate solution (75 mL) were added. The organic layer of the reaction solution was recovered, and 20% aqueous sodium sulfite solution (75 mL), saturated aqueous sodium bicarbonate solution (75 mL), saturated aqueous sodium chloride solution (250 mL), and ethyl acetate (400 mL) were added to the organic layer and washed once. The aqueous layers were combined and extracted once with ethyl acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, the magnesium sulfate was filtered out, and the mixture was concentrated under reduced pressure to obtain a crude product (20.6 g) as a brown viscous substance. The crude product was purified by rapid silica gel column purification (40 g normal phase silica gel, hexane / ethyl acetate = 9 / 1 to 3 / 1) to obtain the ester (17.2 g, yield 89%) as a yellow viscous substance.

[0778] To a mixture of the ester (1.0 eq., 17.2 g, 32.17 mmol) in THF (75 mL) and water (75 mL) was added lithium hydroxide (2.5 eq., 1.9 g, 80.25 mmol) at room temperature, followed by stirring at room temperature for 3 hours. Lithium hydroxide (1.0 eq., 790 mg, 32.97 mmol) was added, followed by stirring for 1 hour, and then lithium hydroxide (0.5 eq., 392 mg, 16.37 mmol) was added, followed by stirring for 30 minutes. The reaction mixture was washed twice with hexane (75 mL), and the organic layers were combined and extracted once with water (20 mL). The aqueous layers were combined, adjusted to pH 1 with 2N aqueous hydrochloric acid (65 mL) under ice-cooling, and then extracted three times with ethyl acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain crude A2"-2 (14.3 g, crude yield 110%) as a dark brown viscous substance.

[0779] The synthesis of fragment A-2" from A2"-2 is as follows.

[0780] [Chemistry 32]

[0781]

[0782] Under nitrogen atmosphere, DIPEA (1.2 eq, 6.6 mL, 38.81 mmol) and BnBr (1.2 eq., 3.8 mL, 38.66 mmol) were added to a solution of A2"-2 (1.0 eq., 14.2 g, 32.17 mmol) in acetonitrile (150 mL) at room temperature, and the mixture was stirred for 2 hours at room temperature. DIPEA (0.2 eq, 1.1 mL, 6.47 mmol) and BnBr (0.2 eq., 650 μL, 6.61 mmol) were added, and the mixture was stirred for 1 hour before adding saturated chloride. Aqueous ammonium solution (75 mL) and water (75 mL). After recovering the organic layer of the reaction solution, the aqueous layer was separated and extracted twice with ethyl acetate (100 mL). The organic layers were combined and washed twice with saturated aqueous sodium chloride solution (100 mL). After drying the organic layer with magnesium sulfate, the magnesium sulfate was filtered out and concentrated under reduced pressure to obtain a crude product (18.0 g) in the form of a brown oil. The crude product was purified by rapid silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate = 5 / 1 to 0 / 1) to obtain fragment A-2" (7.1 g, 45% yield in 2 stages) in the form of a light yellow sticky substance.

[0783] (Example 2: Synthesis of Fragment A-3)

[0784] [Chemistry 33]

[0785]

[0786] To a solution of A2-3 (1.0 eq., 13.1 g, 24.4 mmol) in chloroform (120 mL) was added m-CPBA (2.0 eq., 35% aqueous solution, 13.0 g, 48.9 mmol) under ice cooling, and the mixture was stirred under reflux for 18 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate (100 mL) at room temperature, and the chloroform was removed under reduced pressure. The reaction mixture was extracted three times with ethyl acetate (200 mL). The organic layers were combined, washed once with saturated aqueous sodium chloride (200 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain the ester.

[0787] To a mixture of the ester (1.0 eq., calculated to be 24.4 mmol) in THF (60 mL) and water (60 mL) was added lithium hydroxide (4.0 eq., 2.34 g, 97.7 mmol) at room temperature, and the mixture was stirred at the same temperature for 19 hours. Further lithium hydroxide (2.0 eq., 1.17 g, 48.9 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 4.5 hours. Water (100 mL) was added to the reaction mixture, and the mixture was washed twice with hexane (100 mL). A 6N aqueous hydrochloric acid solution was added to the aqueous layer to adjust the pH to 3. The aqueous layer was extracted twice with ethyl acetate (200 mL), and the organic layers were combined, washed once with saturated sodium chloride aqueous solution (200 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain A3-4 (11.2 g) as a dark brown oil.

[0788] [Chemistry 34]

[0789]

[0790] To a solution of A3-4 (1.0 eq., 11.2 g, calculated as 24.4 mmol) in acetonitrile (120 mL) at room temperature were added DBU (1.1 eq., 4.09 g, 26.8 mmol) and PMBCl (1.1 eq., 4.20 g, 26.8 mmol), and the mixture was stirred at an external temperature of 60°C for 16 hours. The reaction mixture was quenched by the addition of acetic acid (3.0 eq., 4.41 g, 73.4 mmol) and concentrated under reduced pressure to obtain a crude product. The crude product was purified on a flash silica gel column (180 g of normal phase silica gel, hexane / ethyl acetate = 75 / 25 to 50 / 50) to obtain fragment A-3 (7.83 g, 59% yield over two stages starting from A2-3) as an orange oil.

[0791] [Chemistry 35]

[0792]

[0793] Under a nitrogen atmosphere, aluminum chloride (4.1 eq., 9.08 g, 68.11 mmol) and acetyl chloride (1.3 eq., 1.5 mL, 21.12 mmol) were added to a solution of L-tyrosine (1.0 eq., 3.04 g, 16.78 mmol) in nitrobenzene (70 mL) with ice cooling. The mixture was stirred for 20 minutes under ice cooling and then stirred at an external temperature of 100°C for 7 hours. The reaction mixture was allowed to cool and then quenched with ice-cold 1N aqueous hydrochloric acid (100 mL). The mixture was separated and washed three times with ethyl acetate (100 mL) to obtain A2-1 as an aqueous solution (100 mL).

[0794] [Chemistry 36]

[0795]

[0796] To A2-1 (1.0 eq., 100 mL of aqueous solution, calculated to be 16.78 mmol) was added water (100 mL) and 1,4-dioxane (100 mL). Under ice cooling, sodium bicarbonate (25.0 eq., 35.2 g, 419.05 mmol) was added to make the solution alkaline. Subsequently, Boc2O (1.2 eq., 4.6 mL, 20.02 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 4.5 hours. Sodium bicarbonate (2.1 eq., 3.03 g, 36.07 mmol) and Boc2O (1.0 eq., 4 mL, 17.41 mmol) were additionally added, and the mixture was stirred for an additional 17 hours. The reaction mixture was concentrated under reduced pressure to remove the 1,4-dioxane, and then 2N aqueous hydrochloric acid (approximately 300 mL) was added to adjust the pH to 1-2. After one fractional extraction with ethyl acetate (300 mL), the organic layer was fractionally washed once with 1N aqueous hydrochloric acid (100 mL). The aqueous layers were combined and fractionally extracted once with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain A3'-2 (5.63 g, crude yield 104%) as a brown viscous substance.

[0797] [Chemistry 37]

[0798]

[0799] Under a nitrogen atmosphere, potassium carbonate (3.0 eq., 7.03 g, 50.85 mmol), TBAI (0.1 eq., 640 mg, 1.73 mmol) and BnBr (2.2 eq., 3.6 mL, 36.62 mmol) were added to a DMF (80 mL) solution of A3'-2 (1.0 eq., 5.63 g, calculated as 16.78 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water (80 mL) was added to the reaction solution, and the mixture was extracted three times with a mixture of hexane (25 mL) and ethyl acetate (75 mL). The organic layers were combined and washed with a saturated aqueous sodium chloride solution (200 mL). After drying the organic layer over magnesium sulfate, the magnesium sulfate was filtered out and concentrated under reduced pressure to obtain a crude product (9.84 g) as a dark brown oil. The crude product was purified by flash silica gel column (normal phase silica gel 70 g, hexane / ethyl acetate = 5 / 1 to 1 / 1) to obtain A3'-3 (6.18 g, 3-stage yield 73%) as a light orange viscous substance.

[0800] [Chemistry 38]

[0801]

[0802] Under a nitrogen atmosphere and ice-cooling, m-CPBA (35% aqueous solution, 2.0 eq., 19.0 g, 77.07 mmol) was added to a chloroform (200 mL) solution of A3'-3 (1.0 eq., 19.32 g, 38.36 mmol) and stirred at an external temperature of 60°C for 6 hours. The reaction mixture was concentrated under reduced pressure until the volume was approximately half, and then saturated aqueous sodium bicarbonate solution (200 mL) was added. After separation and extraction with ethyl acetate (200 mL) and ethyl acetate (100 mL) twice, the organic layers were combined and washed with saturated aqueous sodium chloride solution (200 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the ester (24.9 g, crude yield 125%) as a pale yellow solid.

[0803] Under ice cooling, lithium hydroxide (2.5 eq., 2.31 g, 96.43 mmol) was added to a mixture of the ester (1.0 eq., 24.9 g, calculated as 38.36 mmol) in THF (100 mL) and water (100 mL), and the mixture was stirred at room temperature for 3 hours. Subsequently, lithium hydroxide (1.0 eq., 929 mg, 38.80 mmol) was added, and the mixture was stirred for a further 2 hours. Furthermore, lithium hydroxide (1.5 eq., 1.39 g, 57.87 mmol) was added, and the mixture was stirred for 1 hour. The reaction mixture was separated and washed twice with hexane (100 mL). Under ice cooling, 6N aqueous hydrochloric acid (30 mL) was added to the aqueous layer to adjust the pH to 2-3, and then the mixture was separated and extracted once with ethyl acetate (100 mL). 6N aqueous hydrochloric acid (5 mL) was added to the aqueous layer, and the pH was adjusted to 1-2. The mixture was then extracted twice with ethyl acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (21.6 g) as a brown viscous substance. The crude product was recrystallized from a hexane / ethyl acetate mixture (4 / 1 to 1 / 1) to obtain A3'-4 (12.4 g, apparent yield 83%, containing approximately 30% m-CPBA) as a white solid.

[0804] [Chemistry 39]

[0805]

[0806] Under nitrogen atmosphere, to a solution of A3"-4 (1.0 eq., 3.03 g, containing about 30% of m-CPBA, calculated as 7.83 mmol) in acetonitrile (40 mL) was added DBU (1.1 eq., 1.3 mL, 8.71 mmol) and BnBr (1.1 eq., 850 μL, 8.65 mmol) under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was separated and washed once with saturated aqueous ammonium chloride solution (40 mL). The aqueous layer was washed with ethyl acetate. The organic layers were combined and washed once with water (100 mL), and then washed once with a saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered out, and the mixture was concentrated under reduced pressure to obtain a crude product (3.7 g) as a brown oil. The crude product was purified by rapid silica gel column purification (50 g normal phase silica gel, hexane / ethyl acetate = 5 / 1 to 3 / 1) to obtain fragment A-3 (1.8 g, yield 48%) as a light yellow viscous substance.

[0807] [Chemistry 40]

[0808]

[0809] Under a nitrogen atmosphere and ice cooling, DBU (1.1 eq., 1.9 mL, 12.73 mmol) and PMBCl (1.1 eq., 1.7 mL, 12.48 mmol) were added to a solution of A3'-4 (1.0 eq., 4.42 g, containing approximately 30% of the hydrolyzate of A3'-3, calculated to be 11.43 mmol) in acetonitrile (60 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was washed once with saturated aqueous ammonium chloride (60 mL). The aqueous layer was extracted twice with ethyl acetate (60 mL). The organic layers were combined and washed once with saturated aqueous sodium chloride (100 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the crude product (6.17 g) as a brown oil. The crude product was purified by flash silica gel column (normal phase silica gel 70 g, hexane / ethyl acetate = 5 / 1 to 2 / 1) to obtain fragment A-3' (3.47 g, containing about 30% PMB ester of A3'-3, apparent yield 60%) as a light yellow sticky substance.

[0810] (Example 2A: Synthesis of Fragment A-13)

[0811] [Chemistry 41]

[0812]

[0813] The two steps of L-tyrosine to A2-2 were carried out as described in Example 2.

[0814] The syntheses of A2-2 to A13-1 are as follows.

[0815] [Chemistry 42]

[0816]

[0817] Under a nitrogen atmosphere, potassium carbonate (3.0 eq., 22.9 g, 166 mmol), TBAI (0.10 eq., 2.04 g, 5.52 mmol) and BnBr (2.0 eq., 13.1 g, 110 mmol) were added to a DMF (110 mL) solution of A2-2 (1.0 eq., 20.3 g, calculated as 55.2 mmol) under ice cooling, and stirred at room temperature for 2.5 hours. Water (200 mL) was added to the reaction solution, and the mixture was separated and extracted twice with a mixed solution of hexane (50 mL) / ethyl acetate (150 mL). The organic layers were combined and washed once with water (100 mL) and once with a saturated sodium chloride aqueous solution (100 mL). After drying the organic layer over magnesium sulfate, the magnesium sulfate was filtered off and concentrated under reduced pressure to obtain a crude product (34.3 g) as a yellow liquid. The crude product was purified by flash silica gel column (normal phase silica gel 200 g, hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain a mixture of A13-1 and A2-3 (24.3 g) as a yellow liquid.

[0818] The syntheses of A13-1 to A13-2 are as follows.

[0819] [Chemistry 43]

[0820]

[0821] Under a nitrogen atmosphere, sodium hydride (1.2 eq., 2.17 g, 54.3 mmol) and iodomethane (3.0 eq., 8.4 mL, 135 mmol) were added to a DMF (90 mL) solution of a mixture of A13-1 and A2-3 (1.0 eq., 24.3 g, calculated as 45.2 mmol) under ice cooling, and the mixture was stirred for 4 hours under ice cooling. 2N aqueous hydrochloric acid solution (20 mL) was added to the reaction solution for quenching, and water (200 mL) was added. Extraction was performed with a mixture of hexane (50 mL) / ethyl acetate (150 mL) once and with a mixture of hexane (40 mL) / ethyl acetate (120 mL) once. The organic layers were combined and washed with water (100 mL) once and with a saturated aqueous sodium chloride solution (50 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a mixture of A13-2 and A2-4 (24.6 g).

[0822] The syntheses of A13-2 to A13-3 are as follows.

[0823] [Chemistry 44]

[0824]

[0825] Under a nitrogen atmosphere, m-CPBA (35% aqueous solution, 2.0 eq., 23.7 g, 89.3 mmol) was added to a solution of a mixture of A13-2 and A2-4 (1.0 eq., 24.6 g, calculated as 44.6 mmol) in chloroform (180 mL) at room temperature. The mixture was stirred at an external temperature of 45°C for 17 hours. The reaction solution was ice-cooled and quenched by adding a mixture of 20% aqueous sodium sulfite (80 mL) and saturated aqueous sodium bicarbonate (80 mL). Ethyl acetate (500 mL) was added to the reaction solution for separation and extraction. The organic layer was then separated and washed once with a mixture of 20% aqueous sodium sulfite (80 mL) and saturated aqueous sodium bicarbonate (80 mL) and once with saturated aqueous sodium chloride (100 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the crude product (26.2 g) as a brown oil. The crude product was purified by flash silica gel column (normal phase silica gel 220 g, hexane / ethyl acetate = 83 / 17 to 50 / 50) to obtain a mixture of ester-A13 and esters (22.2 g) as a yellow liquid.

[0826] To a mixture of ester-A13 and ester (1.0 eq., 22.2 g, calculated as 39.1 mmol) in THF (80 mL) / water (80 mL) was added lithium hydroxide (4.0 eq., 3.74 g, 156 mmol) at room temperature, and the mixture was stirred at the same temperature for 3.5 hours. The reaction solution was washed three times with hexane (100 mL), and the pH was adjusted to 1 with 2N aqueous hydrochloric acid (72 mL) added to the aqueous layer. The aqueous layer was extracted three times with ethyl acetate (150 mL), and the organic layers were combined and washed once with saturated aqueous sodium chloride (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a mixture of A13-3 and A2-5 (17.9 g) as a brown viscous substance.

[0827] The synthesis of fragments A13-3 to A-13 is as follows.

[0828] [Chemistry 45]

[0829]

[0830] To a solution of a mixture of A13-3 and A2-5 (1.0 eq., 17.4 g, calculated as 39.1 mmol) in DMF (80 mL) at room temperature, potassium carbonate (3.1 eq., 16.6 g, 120 mmol) and iodomethane (1.1 eq., 2.7 mL, 43.4 mmol) were added, and the mixture was stirred at the same temperature for 1.5 hours. Water (200 mL) was added to the reaction solution, and extraction was performed once with a mixture of hexane (60 mL) / ethyl acetate (180 mL) and twice with a mixture of hexane (30 mL) / ethyl acetate (90 mL). The organic layers were combined and washed once with a saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (17.9 g) as a brown viscous substance. The crude product was purified twice by rapid silica gel column purification (first time: 200 g of normal phase silica gel, hexane / ethyl acetate = 80 / 20 to 50 / 50, second time: 25 g of normal phase silica gel, hexane / ethyl acetate = 75 / 25 to 50 / 50) to obtain fragment A-13 (2.42 g) as a brown sticky substance and fragment A-10 (11.8 g) as a light yellow sticky substance.

[0831] (Example 3: Synthesis of Fragment B-1)

[0832] [Chemistry 46]

[0833]

[0834] Under a nitrogen atmosphere, water (150 mL) and sodium carbonate (1.0 eq., 25.2 g, 0.238 mol) were added to a solution of D-serine (1.0 eq., 25.0 g, 0.238 mol) in saturated aqueous sodium bicarbonate (150 mL) at room temperature. A solution of Boc2O (1.2 eq., 62.4 g, 0.286 mol) in 1,4-dioxane (125 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 0.5 hours and then at room temperature overnight. The 1,4-dioxane was removed by distillation after concentration under reduced pressure. MTBE (200 mL) was added to the residue, and the insoluble matter was filtered off. The aqueous layer of the filtrate was recovered and washed once with MTBE (200 mL). Then, concentrated hydrochloric acid (approximately 25 mL) was added under ice-cooling to adjust the pH to 2-3. After adding sodium chloride (60 g), the mixture was extracted with ethyl acetate (200 mL) four times. Concentrated hydrochloric acid (5 mL) and sodium chloride (20 g) were added to the aqueous layer, and the mixture was extracted with ethyl acetate (200 mL) four times. Sodium chloride and concentrated hydrochloric acid were further added to the aqueous layer, and the mixture was extracted with ethyl acetate (100 mL) six times and ethyl acetate (50 mL) / THF (50 mL) six times. The organic layers were combined, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to obtain DN-Boc-serine (50.81 g, 92% yield) as a colorless oil.

[0835] Under a nitrogen atmosphere, N,O-dimethylhydroxylamine hydrochloride (1.0 eq., 50.8 g, net weight 44.9 g, 0.219 mol) was added to a solution of DN-Boc-serine (1.0 eq., 50.8 g, net weight 44.9 g, 0.219 mol) in dichloromethane (300 mL) at an internal temperature of -10°C. NMM (1.03 eq., 23.10 g, 0.228 mol), and EDCI (1.1 eq., 46.74 g, 0.244 mol) were added. The solution was stirred overnight at -10°C to room temperature. Under ice cooling, 1 M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was washed once. The aqueous layer was then extracted once with dichloromethane (100 mL). The organic layers were combined and washed once with saturated aqueous sodium bicarbonate (100 mL). The aqueous layer was extracted again with dichloromethane (50 mL), and the organic layers were combined and dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain B1-1 (50.4 g, 93% yield) as a white solid.

[0836] [Chemistry 47]

[0837]

[0838] Under a nitrogen atmosphere, 2,2-dimethoxypropane (164 mL) and boron trifluoride diethyl ether complex (0.06 eq., 1.64 mL, 0.013 mol) were added to a solution of B1-1 (1.0 eq., 50.4 g, 0.203 mol) in acetone (327 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Triethylamine (0.146 eq., 3.00 g, 29.65 mmol) was added to the reaction solution, and the mixture was concentrated under reduced pressure. THF (100 mL) was added to the concentrated residue, and the mixture was concentrated again. This operation was repeated three times to obtain B1-2 (1) (60.4 g, quant.) as a light yellow oil.

[0839] Under a nitrogen atmosphere, methyllithium (2.0 eq., 279 mL, 0.419 mmol in 1.5 M Et2O) was added to a solution of B1-2(1) (1.0 eq., 60.4 g, calculated as 0.203 mol) in THF (570 mL) at an internal temperature of -57 to -40°C over 40 minutes, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous ammonium chloride solution (130 mL) was added to the reaction mixture at the same temperature, and the mixture was warmed to room temperature and then separated and washed. The aqueous layer was extracted three times with ethyl acetate (200 mL), and the organic layers were combined and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product (51.56 g) as a light yellow oil. The crude product was purified by flash silica gel column (normal phase silica gel 750 g, hexane / ethyl acetate = 10 / 1 to 4 / 1) to obtain B1-2 (34.8 g, yield 70%) as a colorless oil.

[0840] [Chemistry 48]

[0841]

[0842] Under a nitrogen atmosphere, ethynylmagnesium bromide (2.5 eq., 715 mL, 0.358 mol in 0.5 M THF, under nitrogen atmosphere) was added to a solution of B1-2 (1.0 eq., 34.8 g, 0.143 mol) in THF (696 mL) over 1.5 hours at room temperature, followed by stirring at the same temperature for 2 hours. Saturated aqueous ammonium chloride (160 mL) was added to the reaction mixture at -55°C, and the temperature was raised to -5°C before concentration under reduced pressure. Water (300 mL) was added to the concentrated residue, and extraction was performed once with ethyl acetate (300 mL) and once with ethyl acetate (150 mL). The organic layers were combined, washed once with saturated aqueous sodium chloride (150 mL), and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain the crude product (40.36 g) as a yellow solid. The crude product was purified by flash silica gel column (normal phase silica gel 370 g, chloroform / ethyl acetate = 100 / 0 to 20 / 1) to obtain B1-3 (diastereoisomer mixture, 33.9 g, yield 88%) as a white solid.

[0843] [Chemistry 49]

[0844]

[0845] Under nitrogen atmosphere, concentrated hydrochloric acid (12 eq., 130 mL, 1.56 mol) was added to a solution of B1-3 (diastereoisomer mixture, 1.0 eq., 33.9 g, 0.126 mol) in THF (450 mL) at room temperature, and the mixture was stirred at the same temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a crude solution of B1-4(1).

[0846] Under a nitrogen atmosphere, THF (260 mL) and water (65 mL) were added to the crude solution of B1-4 (1). Sodium carbonate (5.0 eq., 66.70 g, 0.629 mol) and NsCl (1.0 eq., 27.90 g, 0.125 mol) were added to the solution, and the mixture was stirred at room temperature for 17 hours. After adding saturated sodium chloride aqueous solution (65 mL) to the reaction solution for separation and washing, the aqueous layer was separated and extracted three times with ethyl acetate (260 mL). The organic layers were combined and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product (40.01 g) as a brown viscous substance. The crude product was purified by flash silica gel column (200 g normal phase silica gel, hexane / ethyl acetate = 1 / 1 to 3 / 7) to obtain B1-4 (diastereoisomer mixture, 38.05 g, containing 4.0 wt% ethyl acetate, conversion yield 92%) as a light brown viscous substance.

[0847] [Chemistry 50]

[0848]

[0849] Under a nitrogen atmosphere, imidazole (1.5 eq., 11.71 g, 0.172 mol) and TBSCl (1.2 eq., 20.74 g, 0.138 mol) were added to a solution of B1-4 (diastereoisomer mixture, 1.0 eq., 36.0 g, containing 4.0 wt% ethyl acetate, 0.110 mol) in DMF (360 mL) at room temperature. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was fractionated with ethyl acetate (350 mL) and water (300 mL) for one extraction. The aqueous layer was fractionated twice with ethyl acetate (100 mL). The organic layers were combined and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain the crude product as a brown viscous substance. The crude product was purified by flash silica gel column (normal phase silica gel 540 g, hexane / ethyl acetate = 1 / 0 to 1 / 1) to obtain B1-5 (diastereoisomer mixture, 48.3 g, yield 98%) as a yellow sticky substance.

[0850] [Chemistry 51]

[0851]

[0852] Under a nitrogen atmosphere and ice cooling, triphenylphosphine (1.5 eq., 17.10 g, 0.085 mol) and DIAD (1.5 eq., 17.09 g, 0.084 mol) were added to a THF (560 mL) solution of B1-5 (diastereoisomer mixture, 1.0 eq., 24.1 g, 0.056 mol) and stirred at the same temperature for 2 hours. The reaction mixture was separated and extracted once with ethyl acetate (650 mL), water (300 mL), and 5% aqueous sodium bicarbonate solution (300 mL). The organic layer was then washed once with 5% aqueous sodium bicarbonate solution (300 mL) and once with saturated aqueous sodium chloride solution (300 mL), and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain the crude product as a yellow oil. The crude product was purified by flash silica gel column (normal phase silica gel 720 g, hexane / ethyl acetate = 10 / 1) to obtain fragment B-1 (12.6 g, yield 54%) as a white solid. In addition, 4.09 g was obtained as a mixture containing 16% of diastereomers.

[0853] A mixture of hexane (8.5 mL) and diisopropyl ether (8.5 mL) was added to the diastereomeric mixture (3.41 g) and dissolved by heating to an external temperature of 45°C. The solution was cooled to an internal temperature of 11°C, and the precipitated solid was collected by filtration. The solid was washed once with hexane (1.5 mL) and diisopropyl ether (1.5 mL) and once with hexane (3 mL) to obtain Fragment B-1 (2.41 g, containing 0.7% of diastereomers, yield 10%) as a white solid.

[0854] (Example 4: Synthesis of Fragment B-2)

[0855] [Chemistry 52]

[0856]

[0857] Under a nitrogen atmosphere, thionyl chloride (1.5 eq., 5 mL, 69.35 mmol) was added dropwise to methanol (47 mL) with ice cooling. L-serine (1.0 eq., 5.00 g, 47.66 mmol) was added at the same temperature, and the mixture was stirred under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure to remove the methanol, yielding B2-1 (7.61 g, crude yield 104%) as a pale yellow solid.

[0858] [Chemistry 53]

[0859]

[0860] Under a nitrogen atmosphere, triethylamine (2.1 eq., 8.3 mL, 62.01 mmol) and TrCl (1.05 eq., 8.71 g, 31.23 mmol) were added to a dichloromethane (30 mL) solution of B2-1 (1.0 eq., 4.56 g, calculated as 29.69 mmol) under ice cooling, and stirred at room temperature for 3 hours. Dichloromethane (30 mL) was added to the reaction solution and washed once with water (60 mL). The aqueous layer was extracted twice with dichloromethane (60 mL). The organic layers were combined, washed once with saturated sodium chloride aqueous solution (150 mL), and then dried over magnesium sulfate. The magnesium sulfate was filtered off and concentrated under reduced pressure to obtain a crude product (10.99 g). Ethyl acetate (20 mL) and hexane (40 mL) were added to the crude product under ice cooling. The insoluble white solid was collected by filtration to obtain Fragment B-2 (7.67 g, 71% yield over two stages).

[0861] (Example 5: Synthesis of Fragment B-3)

[0862] [Chemistry 54]

[0863]

[0864] Under a nitrogen atmosphere and ice cooling, thionyl chloride (1.5 eq., 4.5 mL, 62.03 mmol) was added dropwise to methanol (42 mL). L-threonine (1.0 eq., 5.01 g, 42.10 mmol) was added at the same temperature, and the mixture was stirred under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the methanol was distilled off to obtain B3-1 (8.29 g, crude yield 116%) as a pale yellow solid.

[0865] [Chemistry 55]

[0866]

[0867] Under a nitrogen atmosphere, triethylamine (2.1 eq., 6.9 mL, 49.50 mmol) and TrCl (1.06 eq., 6.99 g, 25.08 mmol) were added to a dichloromethane (48 mL) solution of B3-1 (1.0 eq., 4.01 g, calculated as 23.66 mmol) under ice cooling, and the mixture was stirred at room temperature for 5 hours. Triethylamine (1.1 eq., 3.6 mL, 25.83 mmol) and TrCl (0.53 eq., 3.50 g, 12.55 mmol) were added under ice cooling, and the mixture was further stirred at room temperature for 18 hours. The reaction solution was washed once with water (60 mL). The aqueous layer was extracted twice with dichloromethane (60 mL). The organic layers were combined, washed with saturated sodium chloride aqueous solution (150 mL), and then dried over magnesium sulfate. The magnesium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (13.4 g). The crude product was purified by flash silica gel column (normal phase silica gel 70 g, hexane / ethyl acetate = 2 / 1 to 1 / 1) to obtain fragment B-3 (7.27 g, 82% yield over two stages) as a white solid.

[0868] (Example 6: Synthesis of Fragment B-9)

[0869] [Chemistry 56]

[0870]

[0871] Under a nitrogen atmosphere and ice cooling, thionyl chloride (1.45 eq., 25 mL, 345 mmol) was added to methanol (240 mL). D-serine (1.0 eq., 25 g, 238 mmol) was added at the same temperature, and the mixture was stirred at 70°C for 16.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude methyl ester (37 g).

[0872] [Chemistry 57]

[0873]

[0874] Under a nitrogen atmosphere, sodium bicarbonate (2.5 eq., 49.9 g, 595 mmol) and Boc2O (1.05 eq., 65 mL, 250 mmol) were added to a mixture of methyl ester (1.0 eq., 37.0 g, calculated as 238 mmol) in water (100 mL) / methanol (100 mL) under ice cooling, and the mixture was stirred at room temperature for 5.5 hours. Water (200 mL) was added to the reaction solution, and extraction was performed twice with ethyl acetate (200 mL). The organic layer was washed twice with water (100 mL) and once with a saturated sodium chloride aqueous solution (100 mL), and then dried over magnesium sulfate. The mixture was concentrated under reduced pressure to obtain B8-1 (58.7 g) as a crude product.

[0875] [Chemistry 58]

[0876]

[0877] Under a nitrogen atmosphere, 2,2-dimethoxypropane (268 mL) and boron trifluoride / diethyl ether complex (0.05 eq., 1.5 mL, 11.9 mmol) were added to a solution of B8-1 (1.0 eq., 58.7 g, calculated as 238 mmol) in acetone (350 mL) at room temperature. The mixture was stirred at the same temperature for 1 hour. Triethylamine (0.075 eq., 2.5 mL, 17.9 mmol) was added to the reaction solution, and the mixture was concentrated under reduced pressure to obtain B8-2 (68.0 g) as a crude pale yellow oil.

[0878] [Chemistry 59]

[0879]

[0880] Under a nitrogen atmosphere and ice cooling, methylmagnesium bromide (12.4%, 3.0 eq., 176.06 g, 183 mmol) was added to a solution of B8-2 (1.0 eq., 16.02 g, calculated as 61.0 mmol) in THF (300 mL) over 14 minutes, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was fractionated and extracted once with 10% aqueous ammonium chloride (200 mL), ethyl acetate (100 mL), and water (30 mL). The aqueous layer was fractionated and extracted twice with ethyl acetate (50 mL). The combined organic layers were fractionated and washed once with 5% aqueous sodium chloride (200 mL), dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure.

[0881] The crude product obtained from B8-2 (2.00 g) by the same operation was combined with the previous concentrated residue and subjected to rapid silica gel column purification (100 g normal phase silica gel, hexane / ethyl acetate = 80 / 20 to 20 / 80) to obtain B9-1 (17.22 g, containing 1.7 wt% of ethyl acetate, converted yield 95%) as a light yellow oil.

[0882] [Chemistry 60]

[0883]

[0884] Under a nitrogen atmosphere, concentrated hydrochloric acid (12 eq., 62 mL, 744 mmol) was added to a THF (248 mL) solution of B9-1 (1.0 eq., 16.22 g, containing 1.7 wt% of ethyl acetate, 61.5 mmol) at room temperature. The mixture was stirred at the same temperature for 2 hours and then at an external temperature of 50°C for 3 hours. The reaction solution was concentrated to obtain a crude product (14.04 g) as a purple oil.

[0885] The crude product obtained from B9-1 (1.00 g) by the same procedure was combined with the previous crude product and dissolved in THF (130 mL). Water (33 mL) and sodium carbonate (5.0 eq., 34.59 g, 326 mmol) were added at room temperature to adjust the pH to 9. NsCl (1.0 eq., 14.46 g, 65.3 mmol) was added, and after stirring at the same temperature for 16 hours, NsCl (0.3 eq., 4.34 g, 19.6 mmol) was added and stirred at the same temperature for 30 minutes. Saturated sodium chloride aqueous solution (150 mL), ethyl acetate (50 mL), and water (180 mL) were added to the reaction solution for one liquid separation. The aqueous layer was separated and extracted three times with ethyl acetate (30 mL). The organic layers were combined, dried over sodium sulfate, filtered to remove the sodium sulfate, and then concentrated under reduced pressure. The concentrated residue was purified by flash silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain B9-2 (19.70 g, containing impurities, apparent yield 99%) as a brown oil.

[0886] [Chemistry 61]

[0887]

[0888] Under nitrogen atmosphere, TBSCl (1.2 eq., 11.64 g, 77.3 mmol) and imidazole (1.5 eq., 6.57 g, 96.6 mmol) were added to a DMF (65 mL) solution of B9-2 (1.0 eq., 19.59 g, 64.4 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 minutes.

[0889] The reaction mixture obtained by treating B9-2 (100 mg) in the same manner was combined with the previous reaction mixture, and ethyl acetate (130 mL) and water (200 mL) were added for separation and extraction. The aqueous layer was separated and extracted twice with ethyl acetate (30 mL). The organic layers were combined and separated and washed once with 5% aqueous sodium chloride solution (150 mL) and saturated aqueous sodium chloride solution (30 mL), and then dried over sodium sulfate. The sodium sulfate was filtered out, and the mixture was concentrated under reduced pressure. The concentrated residue was purified on a flash silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate = 90 / 10 to 64 / 36) to obtain B9-3 (22.09 g, containing 3.1 wt% ethyl acetate, a 79% yield based on the three steps starting from B9-1) as a white viscous material.

[0890] [Chemistry 62]

[0891]

[0892] Under a nitrogen atmosphere, DIAD (90%, 1.5 eq., 17.12 g, 76.2 mmol) was added to a solution of B9-3 (1.0 eq., 21.95 g, containing 3.1 wt% ethyl acetate, 50.8 mmol) and triphenylphosphine (1.5 eq., 19.99 g, 76.2 mmol) in THF (508 mL) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture obtained by similarly treating B9-3 (130 mg) was combined with the previous reaction mixture and concentrated under reduced pressure. The residue was purified twice by flash silica gel column chromatography (first: 480 g normal phase silica gel, hexane / ethyl acetate = 10 / 0 to 5 / 1; second: 100 g normal phase silica gel, hexane / ethyl acetate = 91 / 9 to 85 / 15). Hexane was added to the obtained light red solid, and the mixture was irradiated with ultrasonic waves. After ice cooling, the mixture was collected by filtration to obtain Fragment B-9 (15.07 g, yield 74%) as a white solid.

[0893] (Example 6A: Synthesis of Fragment D-8)

[0894] Fragment D-8 was synthesized as follows.

[0895] [Chemistry 63]

[0896]

[0897] The synthesis of HL-Asp-OBzl to D8-1 was performed as follows.

[0898] [Chemistry 64]

[0899]

[0900] To a mixture of HL-Asp-OBzl (1.0 eq., 501 mg, 2.24 mmol) in THF (3 mL) / water (6 mL) at room temperature, sodium carbonate (2.0 eq., 477 mg, 4.50 mmol) and Boc2O (1.9 eq., 1.0 mL, 4.35 mmol) were added, and the mixture was stirred at the same temperature for 5 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was extracted twice with water (25 mL). The aqueous layers were combined, the pH was adjusted to 7 by adding 1N aqueous hydrochloric acid (0.5 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was filtered, and the residue was washed with DMF. The filtrate and washings were combined and concentrated under reduced pressure to obtain D8-1 (753.3 mg, quant.) as a white oil.

[0901] The synthesis of D8-1 to D8-2 was carried out as follows.

[0902] [Chemistry 65]

[0903]

[0904] To a solution of D8-1 (1.0 eq., 753 mg, calculated as 2.24 mmol) in DMF (6 mL) were added HOBt·H₂O (1.2 eq., 413 mg, 2.69 mmol), EDCI (1.2 eq., 516 mg, 2.69 mmol), ethanol (2.0 eq., 0.26 mL, 4.45 mmol), and DMAP (1.0 eq., 274 mg, 2.24 mmol), and the mixture was stirred at the same temperature for 18 hours. Ethyl acetate (30 mL) and hexane (10 mL) were added to the reaction mixture, and the mixture was then separated and washed with water (20 mL) twice, a mixture of water (10 mL) and saturated aqueous sodium bicarbonate (10 mL) twice, and a saturated aqueous sodium chloride solution (20 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain D8-2 (511 mg, 65% yield over two stages) as a light brown liquid.

[0905] The synthesis of D8-2 to fragment D-8 was performed as follows.

[0906] [Chemistry 66]

[0907]

[0908] To a solution of D8-2 (1.0 eq., 472 mg, 1.34 mmol) in dichloromethane (2 mL) at room temperature was added TFA (9.7 eq., 1.0 mL, 13.1 mmol), and the mixture was stirred at the same temperature for 2 hours. Ethyl acetate (20 mL) was added to the reaction mixture, and the mixture was then separated and washed with water (10 mL) twice, saturated aqueous sodium bicarbonate solution (10 mL) three times, and saturated aqueous sodium chloride solution (10 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain fragment D-8 (229 mg, 68% yield) as a colorless, transparent liquid.

[0909] (Example 6B: Synthesis of Fragment D-9)

[0910] Fragment D-9 was synthesized as follows.

[0911] [Chemistry 67]

[0912]

[0913] The synthesis of Boc-L-Asp(OBzl)-OH to D9-1 was performed as follows.

[0914] [Chemistry 68]

[0915]

[0916] To a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 893 mg, 2.76 mmol) in DMF (8 mL) was added HOBt·H₂O (1.2 eq., 510 mg, 3.33 mmol), EDCI (1.2 eq., 639 mg, 3.34 mmol), ethanol (1.2 eq., 150 mg, 3.26 mmol), and DMAP (1.0 eq., 339 mg, 2.77 mmol) at room temperature, and the mixture was stirred at the same temperature for 18 hours. Ethyl acetate (30 mL) and hexane (10 mL) were added to the reaction mixture, and the mixture was washed with water (20 mL) twice, a mixture of water (10 mL) / saturated aqueous sodium bicarbonate (10 mL) twice, and a saturated aqueous sodium chloride solution (10 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain D9-1 (881 mg, yield 91%) as a light yellow liquid.

[0917] The synthesis of D9-1 to fragment D-9 was performed as follows.

[0918] [Chemistry 69]

[0919]

[0920] To a solution of D9-1 (1.0 eq., 864 mg, 2.46 mmol) in dichloromethane (3 mL) was added TFA (10 eq., 2.83 g, 24.8 mmol) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. A 1M aqueous sodium hydroxide solution (22 mL) was added to the reaction mixture to adjust the pH to 9. After extraction with ethyl acetate (30 mL), the organic layer was separated and washed with a saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain fragment D-9 (524 mg, 85% yield) as a pale yellow liquid.

[0921] (Example 6C: Synthesis of Fragment D-10)

[0922] Fragment D-10 was synthesized as follows.

[0923] [Chemistry 70]

[0924]

[0925] The synthesis of Boc-L-Asp(OBzl)-OH to D10-1 was performed as follows.

[0926] [Chemistry 71]

[0927]

[0928] To a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.01 g, 15.5 mmol) in DMF (45 mL) were added HOBt·H₂O (1.2 eq., 2.85 g, 18.6 mmol), EDCI (1.2 eq., 3.57 g, 18.6 mmol), hexanol (1.2 eq., 1.89 g, 18.5 mmol), and DMAP (1.0 eq., 1.90 g, 15.6 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate (90 mL) and hexane (30 mL) were added to the reaction mixture, and the mixture was then separated and washed with water (100 mL) twice, a mixture of water (50 mL) and saturated aqueous sodium bicarbonate (50 mL) twice, and a saturated aqueous sodium chloride solution (50 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain D10-1 (6.08 mg, yield 96%) as a light yellow liquid.

[0929] The synthesis of D10-1 to fragment D-10 was performed as follows.

[0930] [Chemistry 72]

[0931]

[0932] To a solution of D10-1 (1.0 eq., 6.07 g, 14.9 mmol) in dichloromethane (30 mL) was added TFA (10 eq., 17.0 g, 149 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was adjusted to pH 9 by adding 1 M aqueous sodium hydroxide solution (140 mL). After separation and extraction with ethyl acetate (100 mL), the organic layer was separated and washed once with water (50 mL) and once with saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain fragment D-10 (4.48 g, 98% yield) as a pale yellow liquid.

[0933] (Example 6D: Synthesis of Fragment D-11)

[0934] Fragment D-11 was synthesized as follows.

[0935] [Chemistry 73]

[0936]

[0937] The synthesis of Boc-L-Asp(OBzl)-OH to D11-1 was performed as follows.

[0938] [Chemistry 74]

[0939]

[0940] To a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.04 g, 15.6 mmol) in DMF (45 mL) were added HOBt·H₂O (1.2 eq., 2.87 g, 18.7 mmol), EDCI (1.2 eq., 3.59 g, 18.7 mmol), dodecanol (1.2 eq., 3.49 g, 18.7 mmol), and DMAP (1.0 eq., 1.91 g, 15.6 mmol) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Ethyl acetate (90 mL) and hexane (30 mL) were added to the reaction mixture, and the mixture was then separated and washed with water (100 mL) twice, a mixture of water (50 mL) and saturated aqueous sodium bicarbonate (50 mL) twice, and a saturated aqueous sodium chloride solution (50 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain D11-1 (7.87 mg, crude yield 103%) as a light yellow liquid.

[0941] The synthesis of fragment D11-1 to fragment D-11 was carried out as follows.

[0942] [Chemistry 75]

[0943]

[0944] To a solution of D11-1 (1.0 eq., 7.87 g, calculated as 15.6 mmol) in dichloromethane (30 mL) was added TFA (8.0 eq., 14.2 g, 124 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A 1 M aqueous sodium hydroxide solution (113 mL) was added to the reaction solution to adjust the pH to 9. After one liquid separation with ethyl acetate (100 mL), the organic layer was separated and washed twice with water (50 mL) and once with a saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (6.56 g) as a light yellow liquid. The crude product was purified by flash silica gel column (normal phase silica gel 30 g, hexane / ethyl acetate = 75 / 25 to 25 / 75) to obtain fragment D-11 (4.73 g, 77% yield in two stages starting from Boc-L-Asp(OBzl)-OH) as a light yellow liquid.

[0945] (Example 6E: Synthesis of Fragment D-12)

[0946] Fragment D-12 was synthesized as follows.

[0947] [Chemistry 76]

[0948]

[0949] [Chemistry 77]

[0950]

[0951] Under a nitrogen stream and ice cooling, triethylamine (2.5 eq., 7.23 g, 71.44 mmol) and NsCl (1.2 eq., 7.60 g, 34.29 mmol) were added to a solution of fragment D-2 (1.0 eq., 10.00 g, 28.58 mmol) in dichloromethane (100 mL). The mixture was stirred at the same temperature for 0.5 hours and then stirred for 17 hours while warming to room temperature. The reaction mixture was washed once with water (50 mL) and once with a 5% aqueous sodium chloride solution (50 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (14.78 g). This crude product was dissolved in ethyl acetate (100 mL), washed once with a 5% aqueous sodium chloride solution (50 mL), and then dried over sodium sulfate. Sodium sulfate was filtered out and the mixture was concentrated under reduced pressure to obtain D12-1 (14.55 g, containing 0.6 wt% ethyl acetate, quant.) as a yellow solid.

[0952] [Chemistry 78]

[0953]

[0954] Under a nitrogen atmosphere and ice-cooling, potassium carbonate (2.0 eq., 7.90 g, 57.16 mmol) and iodomethane (2.0 eq., 8.11 g, 57.14 mmol) were added to a solution of D12-1 (1.0 eq., 14.55 g, calculated as 28.58 mmol) in DMF (100 mL). The mixture was stirred at the same temperature for 1 hour. Toluene (200 mL) was added to the reaction solution, and the mixture was washed once with water (200 mL) and once with 5% saline (200 mL). The mixture was then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain D12-2 (14.78 g, 0.4 wt% DMF, 99% yield based on two steps starting from fragment D-2) as a light brown viscous product.

[0955] [Chemistry 79]

[0956]

[0957] Under a nitrogen atmosphere, cesium carbonate (1.5 eq., 13.84 g, 42.48 mmol) and 4-tert-butylbenzenethiol (1.5 eq., 7.06 g, 42.46 mmol) were added to a DMF (140 mL) solution of D12-2 (1.0 eq., 14.78 g, 28.29 mmol) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Toluene (300 mL) was added to the reaction solution, and the mixture was separated and washed with water (300 mL), 5% aqueous potassium carbonate solution (300 mL), and 5% aqueous sodium chloride solution (300 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The resulting crude product (19.66 g) was purified by flash silica gel column purification (normal phase silica gel 100 g, hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain fragment D-12 (7.52 g, yield 81%) as an orange oil.

[0958] (Example 6F: Synthesis of Fragment D-13)

[0959] Fragment D-13 was synthesized as follows.

[0960] [Chemistry 80]

[0961]

[0962] Under a nitrogen atmosphere, to a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.00 g, 15.5 mmol) in DMF (45 mL) were added HOBt·H₂O (1.2 eq., 2.85 g, 18.6 mmol), EDCI (1.2 eq., 3.57 g, 18.6 mmol), 1-octanol (1.2 eq., 3.0 mL, 19.1 mmol), and DMAP (1.0 eq., 1.89 g, 15.5 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Hexane (25 mL) and ethyl acetate (75 mL) were added to the reaction mixture, and the mixture was separated and washed with water (50 mL) twice, a mixture of saturated aqueous sodium bicarbonate (25 mL) and water (25 mL) twice, and a saturated aqueous sodium chloride solution (30 mL) once. The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain D13-1 (7.09 g) as a light yellow liquid.

[0963] [Chemistry 81]

[0964]

[0965] Under a nitrogen atmosphere, TFA (10 eq., 12.3 mL, 161 mmol) was added to a solution of D13-1 (1.0 eq., 7.09 g, calculated as 15.5 mmol) in dichloromethane (30 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. A 1M aqueous sodium hydroxide solution (145 mL) was added to the reaction mixture, and the mixture was separated and extracted once with ethyl acetate (100 mL). The organic layer was washed twice with water (50 mL) and once with a saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (5.62 g) as a pale yellow liquid. The crude product was purified on a flash silica gel column (41 g normal phase silica gel, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain fragment D-13 (4.20 g, 81% yield over two stages) as a pale yellow liquid.

[0966] (Example 6F: Synthesis of Fragment D-14)

[0967] Fragment D-14 was synthesized as follows.

[0968] [Chemistry 82]

[0969]

[0970] Under a nitrogen atmosphere, to a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.00 g, 15.5 mmol) in DMF (45 mL) were added HOBt·H₂O (1.2 eq., 2.85 g, 18.6 mmol), EDCI (1.2 eq., 3.57 g, 18.6 mmol), 1-decanol (1.2 eq., 3.5 mL, 18.4 mmol), and DMAP (1.0 eq., 1.90 g, 15.5 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Hexane (25 mL) and ethyl acetate (75 mL) were added to the reaction mixture, and the mixture was separated and washed with water (50 mL) twice, a mixture of saturated aqueous sodium bicarbonate (25 mL) and water (25 mL) twice, and a saturated aqueous sodium chloride solution (25 mL) once. The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain D14-1 (7.80 g) as a light yellow liquid.

[0971] [Chemistry 83]

[0972]

[0973] Under a nitrogen atmosphere, TFA (10 eq., 12.0 mL, 157 mmol) was added to a solution of D14-1 (1.0 eq., 7.80 g, calculated as 15.5 mmol) in dichloromethane (30 mL) at room temperature, and the mixture was stirred for 2 hours. A 1M aqueous sodium hydroxide solution (130 mL) was added to the reaction mixture, and the mixture was separated and extracted once with ethyl acetate (100 mL). The organic layer was washed twice with water (50 mL) and once with a saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (6.61 g) as a pale yellow liquid. The crude product was purified on a flash silica gel column (33 g of normal phase silica gel, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain fragment D-14 (4.00 g, 71% yield over two steps) as a pale yellow liquid.

[0974] (Example 7: Synthesis of Compound 1)

[0975] [Chemistry 84]

[0976]

[0977] Under a nitrogen atmosphere and ice cooling, TBD (1.05 eq., 1.42 g, 10.20 mmol) was added to a toluene (111 mL) solution of Fragment A-2 (1.05 eq., 5.81 g, containing 2.2 wt% ethyl acetate, 10.23 mmol) and Fragment B-1 (1.0 eq., 4.00 g, 9.74 mmol). The mixture was stirred for 22 hours while warming to room temperature. A 5% aqueous citric acid solution (50 mL) was added to the reaction mixture and the mixture was washed once. The organic layer was washed once with a mixture of a 5% aqueous sodium bicarbonate solution (50 mL) and a 5% aqueous sodium chloride solution (50 mL) and once with a 5% aqueous sodium chloride solution (50 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (10.90 g) as a light brown viscous substance. The crude product was purified by flash silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain compound 1-1 (8.49 g, containing fragment A-2, PMBOH, ethyl acetate, apparent yield 90%) as a yellow sticky substance.

[0978] [Chemistry 85]

[0979]

[0980] Under a nitrogen atmosphere and ice-cooling, to a solution of compound 1-1 (1.0 eq., 2.97 g, containing fragment A-2, PMBOH, ethyl acetate, calculated as 3.07 mmol) in DMF (15 mL) were added 1-dodecanethiol (6.0 eq., 3.73 g, 18.43 mmol) and DBU (6.0 eq., 2.81 g, 18.46 mmol), followed by stirring at room temperature for 5 hours. The reaction mixture was fractionated and extracted once with toluene (30 mL) and 5% aqueous citric acid solution (40 mL). The aqueous layer was fractionated again with toluene (30 mL). The combined organic layers were fractionated and washed once with a mixture of 5% aqueous sodium bicarbonate solution (30 mL) and 5% aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to obtain a crude product (6.54 g) as a yellow oil.

[0981] The crude product (2.47 g) obtained from compound 1-1 (1.03 g) by the same operation was combined with the previous crude product and subjected to rapid silica gel column purification (normal phase silica gel 100 g, hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain compound 1-2 (2.32 g, containing PMBOH and ethyl acetate, apparent yield 71%) as a light yellow oil.

[0982] [Chemistry 86]

[0983]

[0984] Under a nitrogen atmosphere, to a solution of compound 1-2 (1.0 eq., 2.32 g, containing 2.1 wt% ethyl acetate, 2.06 mmol) in DMF (24 mL) were added N-Fmoc-L-valine (fragment C-1, 2.0 eq., 1.39 g, 4.10 mmol), EDCI (2.0 eq., 0.79 g, 4.12 mmol), and HOBt·H₂O (2.0 eq., 0.63 g, 4.11 mmol), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was separated and extracted once with toluene (50 mL) and 5% aqueous sodium bicarbonate solution (50 mL). The organic layer was separated and washed once with 5% aqueous sodium chloride solution (50 mL) and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain the crude product (3.49 g) as a yellow viscous substance. The crude product was purified by flash silica gel column (NH2 silica gel 28 g, hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain compound 1-3 (2.22 g, yield 98%) as a white amorphous substance.

[0985] [Chemistry 87]

[0986]

[0987] Under a nitrogen atmosphere, lithium hydroxide monohydrate (4.0 eq., 0.34 g, 8.10 mmol) was added to a mixture of compound 1-3 (1.0 eq., 2.22 g, 2.01 mmol) in THF (20 mL) and water (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was ice-cooled, and the pH was adjusted to 3 by adding 5% aqueous citric acid (30 mL). The mixture was then separated and extracted once with ethyl acetate (30 mL). The organic layer was washed once with 5% aqueous sodium chloride (30 mL) and dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (2.45 g) as a pale yellow viscous substance. The crude product was purified on a flash silica gel column (25 g normal phase silica gel, ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain compound 1-4 (1.36 g, containing 4.4 wt% ethyl acetate, equivalent yield 85%) as a white amorphous product.

[0988] [Chemistry 88]

[0989]

[0990] Under a nitrogen atmosphere, DIPEA (10.0 eq., 1.11 g, 8.59 mmol) was added to a solution of HATU (5.0 eq., 1.63 g, 4.29 mmol) in DMF (842 mL) at room temperature. Subsequently, a solution of compound 1-4 (1.0 eq., 0.68 g, containing 4.4 wt% ethyl acetate, 0.855 mmol) in DMF (8 mL) was added at the same temperature over 17 hours. After the addition was complete, the mixture was stirred at room temperature for a further 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed once with ethyl acetate (15 mL) and 5% aqueous citric acid solution (15 mL). The organic layer was washed once with 5% aqueous sodium bicarbonate solution (15 mL) and once with 5% aqueous sodium chloride solution (30 mL), then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a mixture of compounds 1-5 and 1-6 (1.05 g) as a light brown amorphous substance.

[0991] Under a nitrogen atmosphere, TBAF (8.0 eq., 5.63 mL, 6.193 mmol in 1.1 M THF, 0.95 g, calculated as 0.774 mmol) was added to a THF (19 mL) solution of a mixture of compounds 1-5 and 1-6 under ice cooling. The mixture was stirred for 4 hours while warming to room temperature. The reaction mixture was ice-cooled, 10% aqueous ammonium chloride solution (40 mL) was added, and extraction was performed once with ethyl acetate (40 mL). The organic layer was washed once with 5% aqueous sodium chloride solution (40 mL), dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to obtain a crude product (1.19 g) as a light brown viscous substance.

[0992] The crude product (106 mg) obtained from a mixture of compound 1-5 and compound 1-6 (0.10 g, calculated as 0.081 mmol) by the same operation was combined with the previous crude product and subjected to rapid silica gel column purification (normal phase silica gel 10 g, hexane / ethyl acetate = 50 / 50) to obtain compound 1-6 (0.60 g, isomer mixture. Contains 0.7 wt% of ethyl acetate, 36.4 wt% of TBAF, and a 2-stage conversion yield of 70% starting from compound 1-4) as a light orange solid.

[0993] [Chemistry 89]

[0994]

[0995] Under a nitrogen atmosphere and ice-cooling, Dess-Martin periodinane (1.5 eq., 0.38 g, 0.90 mmol) was added to a solution of compound 1-6 (1.0 eq., 0.66 g, isomer mixture, containing 3.9 wt% ethyl acetate, 38.9 wt% TBAF, 0.60 mmol) in dichloromethane (13 mL). The mixture was stirred for 16 hours while warming to room temperature. A 5% aqueous sodium bicarbonate solution (10 mL) and a 5% aqueous sodium thiosulfate solution (10 mL) were added to the reaction solution, followed by a single wash. The organic layer was washed once with a 5% aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to obtain the aldehyde (0.392 g, containing isomers) as a pale orange amorphous form.

[0996] Under a nitrogen atmosphere, sodium dihydrogen phosphate dihydrate (3.5 eq., 0.33 g, 2.12 mmol) and 80% sodium chlorite (4.5 eq., 0.30 g, 2.65 mmol) were added to a mixture of aldehyde (1.0 eq., 0.39 g, containing isomers, calculated as 0.60 mmol) in tert-butyl alcohol (16 mL), pentene (4 mL), and water (4 mL) at room temperature. The mixture was stirred at the same temperature for 1.5 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture for separation and extraction. The organic layer was washed twice with water (20 mL) and once with a 5% aqueous sodium chloride solution (20 mL), and then dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain compound 1-7 (0.351 g, isomer mixture, containing 12.5 wt% TBAF, 80% yield based on the two steps starting from compound 1-6) as a light orange solid.

[0997] [Chemistry 90]

[0998]

[0999] Under a nitrogen atmosphere, under ice cooling, to a dichloromethane (1.3 mL) solution of compound 1-7 (1.0 eq., 130 mg, isomer mixture, containing TBAF 24.8 wt%, 0.15 mmol) and L-glutamic acid dibenzyl ester hydrochloride (fragment D-1, 1.5 eq., 83 mg, 0.23 mmol) were added DIPEA (3.0 eq., 78 μL, 0.46 mmol) and HBTU (1.5 eq., 87 mg, 0.23 mmol), and the mixture was stirred for 3.5 hours while warming to room temperature.

[1000] The reaction solution obtained by treating compound 1-7 (100 mg) with the same operation was combined with the previous reaction solution, and toluene (20 mL), 5% citric acid aqueous solution (20 mL) and 5% sodium chloride aqueous solution (10 mL) were added for separation and washing. The organic layer was washed once with 5% citric acid aqueous solution (20 mL), once with 5% sodium bicarbonate aqueous solution (20 mL), and once with 5% sodium chloride aqueous solution (20 mL), dried over sodium sulfate, and the sodium sulfate was filtered out. The mixture was concentrated under reduced pressure, and the crude product (290 mg) obtained as a light brown sticky substance was purified by rapid silica gel column purification (NH2 silica gel 6.5 g, hexane / ethyl acetate = 50 / 50) to obtain compound 1-8 (37 mg, yield 14%) as a yellow sticky substance.

[1001] [Chemistry 91]

[1002]

[1003] Under a nitrogen atmosphere, to a mixture of compound 1-8 (1.0 eq., 37 mg, 0.039 mmol) in THF (1.85 mL) / water (1.85 mL) was added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 11.1 mg) at room temperature. After hydrogen was purged from the system, the mixture was stirred at the same temperature for 16 hours. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. To the concentrated residue was added a mixture of THF (1.85 mL) / water (1.85 mL). After nitrogen was purged from the system, 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 11.1 mg) was added at room temperature. After hydrogen was purged from the system, the mixture was stirred at the same temperature for 3 hours. As the reaction proceeded, the target product precipitated as a solid. TFA (2.0 eq., 6.0 μL, 0.078 mmol) was added to dissolve the target product. The catalyst was filtered off through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (27 mg) as a pale orange amorphous substance.

[1004] The crude product (15.5 mg) obtained from compound 1-8 (21 mg) by the same operation was combined with the previous crude product and subjected to two rapid silica gel column purifications (60 g of reverse phase silica gel, first time: 0.05% TFA aqueous solution / acetonitrile = 99 / 1 to 90 / 10, second time: 0.05% TFA aqueous solution / acetonitrile = 95 / 5), and then freeze-dried to obtain the TFA salt of compound 1 (18 mg, yield 45%, purity 97.1%) as a white solid.

[1005] 1H-NMR(400MHz,D2O)δ6.94-6.87(m,3H),4.86(s,1H),4.37(dd,J=9.2,4.8Hz,1H),4.12(d, J=10.0Hz,1H),4.05(dd,J=8.8,4.8Hz,1H),3.23(dd,J=13.2,4.8Hz,1H),2.92(dd,J=13.2, 8.8Hz,1H),2.72(s,3H),2.48-2.35(m,2H),2.22-2.14(m,1H),2.03-1.90(m,3H),1.77-1. 63(m,1H),1.57(s,3H),1.04(t,J=7.2Hz,3H),0.85(d,J=6.4Hz,3H),0.78(d,J=6.4Hz,3H).

[1006] (Example 8: Synthesis of Compound 9)

[1007] [Chemistry 92]

[1008]

[1009] Under a nitrogen atmosphere and ice cooling, to a solution of compound 1-7 (1.0 eq., 264 mg, isomer mixture, containing 12.5 wt% TBAF, 0.36 mmol) and dibenzyl L-aspartate hydrochloride (fragment D-2, 1.5 eq., 188 mg, 0.54 mmol) in dichloromethane (6.6 mL) were added DIPEA (1.5 eq., 91 μL, 0.54 mmol) and HATU (1.5 eq., 204 mg, 0.54 mmol). The mixture was stirred at the same temperature for 6 hours. The reaction mixture was washed once with 5% aqueous citric acid solution (10 mL). The organic layer was washed once with a mixture of 5% aqueous sodium bicarbonate solution (10 mL) and 5% aqueous sodium chloride solution (10 mL), and then dried over sodium sulfate. After filtering out the sodium sulfate, the crude product (496 mg) of the pale brown viscous substance obtained by concentration under reduced pressure was purified twice by flash silica gel column purification (normal phase silica gel 10 g, first time: chloroform / ethyl acetate = 90 / 10 to 50 / 50, second time: chloroform / ethyl acetate = 90 / 10 to 85 / 15) to obtain low-purity compound 9-1 (129 mg).

[1010] The low-purity compound 9-1 was dissolved in toluene (10 mL), washed five times with 5% aqueous sodium chloride solution (10 mL), and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain compound 9-1 (93 mg, 28% yield) as a yellow amorphous form.

[1011] [Chemistry 93]

[1012]

[1013] Under a nitrogen atmosphere, to a mixture of compound 9-1 (1.0 eq., 50 mg, 0.053 mmol) in THF (2.5 mL) / water (2.5 mL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.5 mg) and TFA (2.0 eq., 8.2 μL, 0.107 mmol) at room temperature. After hydrogen substitution, the mixture was stirred at the same temperature for 23 hours. 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.5 mg) was added, and the mixture was stirred for 27 hours. 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.5 mg) was added again, and the mixture was stirred for a further 24 hours.

[1014] The reaction mixture obtained by treating compound 9-1 (10 mg) with the same procedure was combined with the previous reaction mixture. After filtering the catalyst through celite, the filtrate was concentrated under reduced pressure to obtain a crude product (58 mg) as an orange viscous substance. The crude product was purified on a flash silica gel column (30 g of reverse-phase silica gel, 0.05% TFA aqueous solution / acetonitrile = 95 / 5 to 90 / 10) and freeze-dried to obtain the TFA salt of compound 9 (30.5 mg, yield 73%, purity 97.8%) as a white solid.

[1015] 1 H-NMR (400MHz, D2O) δ6.94-6.87 (m, 3H), 4.66 (dd, J = 7.2, 5.2Hz, 1H), 4.11 ( d,J=10.0Hz,1H),4.05(dd,J=8.8,4.8Hz,1H),3.24(dd,J=13.6,4.8Hz,1H), 2.96-2.84(m,3H),2.72(s,3H),2.05-1.91(m,2H),1.78-1.69(m,1H),1.58 (s,3H),1.05(t,J=7.2Hz,3H),0.86(d,J=7.2Hz,3H),0.78(d,J=6.8Hz,3H).

[1016] (Example 9: Synthesis of Compound 2)

[1017] [Chemistry 94]

[1018]

[1019] 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 and ethyl acetate, calculated to be 2.97 mmol) in DMF (35 mL). 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 mixture for separation and extraction. The organic layer was separated and washed once with 5% aqueous sodium chloride solution (70 mL) and then dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (4.56 g) as a white solid. Ethyl acetate (45 mL) was added to the crude product, insoluble matter was filtered off after ultrasonic irradiation, and the filtrate was concentrated under reduced pressure. The concentrated residue was dissolved in THF and concentrated under reduced pressure to obtain compound 2-9 (3.50 g, containing impurities, THF and DMF) as a white amorphous form.

[1020] [Chemistry 95]

[1021]

[1022] Under a nitrogen atmosphere, lithium hydroxide monohydrate (4.0 eq., 0.50 g, 11.92 mmol) was added to a mixture of compound 2-9 (1.0 eq., 3.50 g, 2.97 mmol) in THF (28 mL) and water (14 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was ice-cooled, and the pH was adjusted to 3 by adding 5% aqueous citric acid solution (45 mL). Extraction was performed once with ethyl acetate (45 mL). The organic layer was washed once with 5% aqueous sodium chloride solution (45 mL) and dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (3.55 g) as a pale yellow viscous substance. The crude product was purified by flash silica gel column (25 g normal phase silica gel, ethyl acetate / methanol = 100 / 0 to 70 / 30) to obtain compound 2-10 (1.63 g, containing 7.3 wt% ethyl acetate, 42% conversion yield of 4 stages starting from fragment B-1) as a light orange amorphous form.

[1023] [Chemistry 96]

[1024]

[1025] Under a nitrogen atmosphere, DIPEA (10.0 eq., 1.11 g, 8.59 mmol) was added to a solution of HATU (5.0 eq., 1.63 g, 4.29 mmol) in DMF (842 mL) at room temperature. Subsequently, a solution of compound 2-10 (1.0 eq., 0.66 g, containing 7.3 wt% ethyl acetate, 0.852 mmol) in DMF (8 mL) was added at the same temperature over 17 hours. After the addition was complete, the mixture was stirred at room temperature for an additional hour. The reaction mixture was concentrated under reduced pressure until the volume was reduced to several mL.

[1026] Under a nitrogen atmosphere, the concentrated residue was stirred at an external temperature of 50°C for 17 hours, followed by stirring at an external temperature of 70°C for 2 hours. Ethyl acetate (20 mL) and 5% aqueous citric acid solution (20 mL) were added to the reaction solution for separation and extraction. The organic layer was separated and washed once with 5% aqueous sodium bicarbonate solution (20 mL) and once with 5% aqueous sodium chloride solution (20 mL), and then dried over sodium sulfate. The sodium sulfate was filtered out and concentrated under reduced pressure to obtain a crude product (0.98 g) as a light brown viscous substance. The crude product was purified on a flash silica gel column (normal phase silica gel 10 g, chloroform / ethyl acetate = 90 / 10 to 5 / 95) to obtain compound 2-12 (0.168 g, containing isomers and impurities, apparent yield of 34% for the two stages starting from compound 2-10) as an orange solid.

[1027] [Chemistry 97]

[1028]

[1029] Under a nitrogen atmosphere and ice-cooling, Dess-Martin periodinane (1.5 eq., 179 mg, 0.422 mmol) was added to a solution of compound 2-12 (1.0 eq., 165 mg, containing isomers and impurities, calculated as 0.282 mmol) in dichloromethane (3.3 mL). The mixture was stirred for 2 hours while warming to room temperature. A 5% aqueous sodium bicarbonate solution (3 mL) and a 5% aqueous sodium thiosulfate solution (3 mL) were added to the reaction solution, followed by a single separation. The organic layer was washed once with a 5% aqueous sodium chloride solution (3 mL), dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to obtain the aldehyde (133 mg, containing isomers, apparent yield 81%) as a pale orange amorphous product.

[1030] Under a nitrogen atmosphere, sodium dihydrogen phosphate dihydrate (3.5 eq., 123 mg, 0.788 mmol) and 80% sodium chlorite (4.5 eq., 114 mg, 1.008 mmol) were added to a mixture of aldehyde (1.0 eq., 131 mg, containing isomers, calculated as 0.224 mmol) in tert-butyl alcohol (5.6 mL), pentene (1.4 mL), and water (1.4 mL) at room temperature. The mixture was stirred at the same temperature for 1 hour. Ethyl acetate (15 mL) and water (15 mL) were added to the reaction mixture for a single separation. The organic layer was washed once with a 5% aqueous sodium chloride solution (15 mL) and then dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain compound 2-13 (97 mg, containing isomers, a 58% yield based on the two steps starting from compound 2-12) as a yellow solid.

[1031] [Chemistry 98]

[1032]

[1033] Under a nitrogen atmosphere and ice cooling, to a solution of compound 2-13 (1.0 eq., 79 mg, containing isomers, 0.132 mmol) and L-glutamic acid dibenzyl ester hydrochloride (fragment D-1, 1.5 eq., 72 mg, 0.198 mmol) in dichloromethane (2 mL) were added DIPEA (1.5 eq., 34 μL, 0.197 mmol) and HATU (1.5 eq., 75 mg, 0.200 mmol). The mixture was stirred for 6 hours while warming to room temperature. Ethyl acetate (10 mL) and 5% aqueous citric acid solution (10 mL) were added to the reaction mixture for separation and extraction. The organic layer was washed with 5% aqueous sodium bicarbonate solution (10 mL) and 5% aqueous sodium chloride solution (10 mL) respectively, and then dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure, and the crude product (160 mg) obtained as a light brown sticky substance was subjected to two rapid silica gel column purifications (first and second times: 10 g of normal phase silica gel, chloroform / ethyl acetate = 90 / 10 to 60 / 40) to obtain compound 2-6 (67 mg, containing fragment D-1, ethyl acetate, apparent yield 56%) as a yellow amorphous substance.

[1034] [Chemistry 99]

[1035]

[1036] Under a nitrogen atmosphere, to a mixture of compound 2-6 (1.0 eq., 64 mg, containing fragment D-1, calculated as 0.070 mmol in ethyl acetate) in THF (3.2 mL) / water (3.2 mL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 3.2 mg) and TFA (2.0 eq., 10.7 μL, 0.140 mmol) at room temperature. After hydrogen exchange, the reaction mixture was stirred at the same temperature for 66 hours. An additional 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 3.2 mg) was added, and the mixture was stirred for 21.5 hours. The catalyst was then filtered off through celite, and the filtrate was concentrated under reduced pressure and then subjected to further reaction. To the concentrated residue was added a mixture of THF (3.2 mL) and 3.2 mL. After nitrogen was purged, 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 5.8 mg) and TFA (2.0 eq., 10.7 μL, 0.140 mmol) were added at room temperature. After hydrogen was purged, the reaction mixture was stirred at the same temperature for 23 hours. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (59 mg) as a light brown viscous substance. The crude product was purified on a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5) and then freeze-dried to obtain the TFA salt of compound 2 (5.2 mg, 12% yield, 97.1% purity) as a white solid.

[1037] 1 H-NMR (400MHz, D2O) δ7.45 (s, 1H), 7.05-7.03 (m, 1H), 6.96 (d, J = 8.4Hz, 1H), 4.63 (s, 1H), 4.4 5(dd,J=8.8,5.2Hz,1H),4.26(d,J=16.8Hz,1H),3.98(dd,J=10.4,3.6Hz,1H),3.54(d,J=16. 4Hz,1H),3.25(dd,J=13.2,4.0Hz,1H),3.07-3.01(m,1H),2.72(s,3H),2.47(t,J=7.2Hz,2H) ,2.25-2.20(m,1H),2.01-1.97(m,2H),1.76-1.70(m,1H),1.61(s,3H),0.87(t,J=7.2Hz,3H).

[1038] (Example 9A: Synthesis of Compound 9A)

[1039] The steps up to compound 1-7 were the same as the synthesis method of compound 1.

[1040] Compounds 1-7 to 9A-1

[1041] [Chemistry 100]

[1042]

[1043] Under a nitrogen atmosphere and ice-cooling, DEPBT (1.5 eq., 57.5 mg, 0.192 mmol) and 2,4,6-collidine (3.0 eq., 46.7 mg, 0.383 mmol) were added to a THF (1.2 mL) solution of compound 1-7 (1.0 eq., 82.2 mg, 0.128 mmol) and L-aspartic acid diethyl ester hydrochloride (fragment D-7, 1.5 eq., 43.2 mg, 0.191 mmol). The mixture was stirred at the same temperature for 7 hours and then at room temperature for 15 hours. Ethyl acetate (10 mL) was added to the reaction solution, and the mixture was then separated and washed with a mixture of water (5 mL) and saturated aqueous sodium bicarbonate (5 mL) and then with saturated aqueous sodium chloride (10 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the crude product (162 mg) as a green oil. The crude product was purified by flash silica gel column (NH2 silica gel 6 g, hexane / ethyl acetate = 75 / 25 to 50 / 50) to obtain compound 9A-1 (48.5 mg, yield 47%) as a white amorphous substance.

[1044] The synthesis of compound 9A-1 to compound 9A was carried out as follows.

[1045] [Chemistry 101]

[1046]

[1047] Under a nitrogen atmosphere, to a mixture of compound 9A-1 (1.0 eq., 20 mg, 0.025 mmol) in THF (800 μL) / water (40 μL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.0 mg) and TFA (2.0 eq., 3.7 μL, 0.048 mmol) at room temperature. The system was purged with hydrogen, and after stirring at the same temperature for 23 hours, the catalyst was filtered off through Celite to obtain a filtrate.

[1048] The filtrate obtained similarly from compound 9A-1 (1.0 eq., 15 mg, 0.018 mmol) was combined with the above filtrate and concentrated under reduced pressure to yield a crude product. The resulting crude product (36.6 mg) was purified on a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 75 / 25). Freeze-dried, the TFA salt of compound 9A (16.3 mg, 54% yield, 94.4% purity) was obtained as a white solid.

[1049] 1 H-NMR(400MHz,D2O)δ6.98-6.82(m,3H),4.24-4.09(m,5H),4.04(dd,J=8.8,4.4Hz,1H),3.22(dd,J=13.2,4.4Hz,1H),3.00-2.80(m,3H),2.7 1(s,3H),2.07-1.87(m,2H),1.79-1.62(m,1H),1.57(s,3H),1.24(m,6 H), 1.05 (t, J = 7.2Hz, 3H), 0.85 (d, J = 6.4Hz, 3H), 0.79 (d, J = 6.8Hz, 3H).

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

[1051] The steps up to compound 1-7 were carried out as described in Example 7.

[1052] The synthesis of compound 1-7 to compound 9B-1 was carried out as follows.

[1053] [Chemistry 102]

[1054]

[1055] Under a nitrogen atmosphere and ice-cooling, DEPBT (1.5 eq., 55.0 mg, 0.184 mmol) and 2,4,6-trimethylpyridine (3.0 eq., 44.2 mg, 0.364 mmol) were added to a THF (1.2 mL) solution of compound 1-7 (1.0 eq., 78.0 mg, 0.122 mmol) and fragment D-8 (1.5 eq., 47.2 mg, 0.188 mmol). The mixture was stirred at the same temperature for 6 hours and then at room temperature for 16 hours. Ethyl acetate (10 mL) was added to the reaction solution, and the mixture was then separated and washed with a mixture of water (5 mL) and saturated aqueous sodium bicarbonate (5 mL) (partially) and saturated aqueous sodium chloride (10 mL) (partially). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (166 mg) as a green oil. The crude product was purified by flash silica gel column (NH2 silica gel 6 g, hexane / ethyl acetate = 75 / 25 to 0 / 100) to obtain compound 9B-1 (54.5 mg, yield 51%) as a white amorphous substance.

[1056] The synthesis of compound 9B-1 to compound 9B was carried out as follows.

[1057] [Chemistry 103]

[1058]

[1059] Under a nitrogen atmosphere, to a mixture of compound 9B-1 (1.0 eq., 39 mg, 0.045 mmol) in THF (1560 μL) / water (78 μL) at room temperature were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 3.9 mg) and TFA (5.0 eq., 17 μL, 0.223 mmol). After hydrogen exchange, the mixture was stirred at the same temperature for 4 hours. The catalyst was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (35 mg). The crude product (17 mg) obtained from compound 9B-1 (15 mg, 0.017 mmol) by the same procedure was combined with the above crude product and purified on a flash silica gel column (30 g of reverse phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 80 / 20). The residue was freeze-dried to obtain the TFA salt of compound 9B (24.3 mg, yield 58%, purity 95.2%) as a white solid.

[1060] 1H-NMR(400MHz,D2O)δ6.97-6.86(m,3H),4.69(dd,J=7.2,5.2Hz,1H),4.18-4.10 (m,3H),4.06(dd,J=9.2,4.8Hz,1H),3.24(dd,J=13.6,4.8Hz,1H),3.00-2.85(m ,3H),2.73(s,3H),2.08-1.88(m,2H),1.79-1.65(m,1H),1.58(s,3H),1.24(t,J =7.2Hz, 3H), 1.05 (t, J = 7.2Hz, 3H), 0.86 (d, J = 6.8Hz, 3H), 0.79 (d, J = 6.8Hz, 3H).

[1061] (Example 9C: Synthesis of Compound 9C)

[1062] The synthesis of compound 1-7 to compound 9C-1 was carried out as follows.

[1063] [Chemistry 104]

[1064]

[1065] Under a nitrogen atmosphere and ice-cooling, DEPBT (1.5 eq., 42.7 mg, 143 μmol) and 2,4,6-trimethylpyridine (3.0 eq., 34.0 mg, 281 μmol) were added to a THF (1 mL) solution of compound 1-7 (1.0 eq., 59.7 mg, 93.0 μmol) and fragment D-9 (1.5 eq., 34.6 mg, 138 μmol). The mixture was stirred at the same temperature for 5 hours and then at room temperature for 15.5 hours. Ethyl acetate (20 mL) was added to the reaction mixture, and the mixture was then separated and washed with a mixture of water (5 mL) and saturated aqueous sodium bicarbonate (5 mL) and then with saturated aqueous sodium chloride (10 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (171 mg) as a green oil. The crude product was purified by flash silica gel column (NH2 silica gel 6 g, hexane / ethyl acetate = 75 / 25 to 0 / 100) to obtain compound 9C-1 (42.3 mg, yield 56%) as a white amorphous substance.

[1066] The synthesis of compound 9-1 to compound 9C was carried out as follows.

[1067] [Chemistry 105]

[1068]

[1069] Under a nitrogen atmosphere, to a mixture of compound 9C-1 (1.0 eq., 41 mg, 0.047 mmol) in THF (1640 μL) / water (82 μL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 4.1 mg) and TFA (2.0 eq., 7.2 μL, 0.094 mmol) at room temperature. After hydrogen exchange, the system was stirred at the same temperature for 6 hours. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (35 mg). The crude product was purified on a flash silica gel column (30 g reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 80 / 20). Freeze-dried to obtain the TFA salt of compound 9C (29.0 mg, 91% yield, 96.0% purity) as a white solid.

[1070] 1 H-NMR(400MHz,D2O)δ6.98-6.85(m,3H),4.24-4.17(m,2H),4.10(d,J=9.6Hz,1 H),4.05(dd,J=9.2,4.8Hz,1H),3.23(dd,J=13.6,4.8Hz,1H),2.99-2.87(m,3H ),2.71(s,3H),2.08-1.88(m,2H),1.81-1.68(m,1H),1.57(s,3H),1.24(t,J=7 .2Hz,3H),1.05(t,J=7.2Hz,3H),0.85(d,J=6.8Hz,3H),0.78(d,J=6.4Hz,3H).

[1071] (Example 9D: Synthesis of Compound 9D)

[1072] Compound 1-7 was synthesized as described in Example 7. The synthesis of compound 1-7 to compound 9D-1 was carried out as follows.

[1073] [Chemistry 106]

[1074]

[1075] Under a nitrogen atmosphere and ice-cooling, DEPBT (1.5 eq., 48.8 mg, 163 μmol) and 2,4,6-trimethylpyridine (3.0 eq., 38.6 mg, 319 μmol) were added to a THF (1 mL) solution of compound 1-7 (1.0 eq., 69.0 mg, 108 μmol) and fragment D-10 (1.5 eq., 50.1 mg, 163 μmol). The mixture was stirred at the same temperature for 6 hours and then at room temperature for 16 hours. Ethyl acetate (10 mL) was added to the reaction mixture, and the mixture was washed with a mixture of water (5 mL) and saturated aqueous sodium bicarbonate (5 mL) once and with saturated aqueous sodium chloride (10 mL) once. The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (152 mg) as a green oil. The crude product was purified by flash silica gel column (NH2 silica gel 6 g, hexane / ethyl acetate = 75 / 25 to 0 / 100) to obtain compound 9D-1 (54.0 mg, yield 54%) as a white amorphous substance.

[1076] The synthesis of compound 9D-1 to compound 9D was carried out as follows.

[1077] [Chemistry 107]

[1078]

[1079] To a mixture of compound 9D-1 (1.0 eq., 38.0 mg, 0.041 mmol) in THF (1600 μL) and water (80 μL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 3.8 mg) and TFA (2.0 eq., 6.3 μL, 0.082 mmol) at room temperature. The system was purged with hydrogen and stirred at the same temperature for 19 hours. The catalyst was then filtered through Celite to obtain a filtrate. The resulting crude product (32 mg) was purified on a flash silica gel column (30 g reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 70 / 30). Freeze-dried, the TFA salt of compound 9D was obtained as a white solid (14.9 mg, 50% yield, 95.6% purity).

[1080] 1H-NMR(400MHz,D2O)δ6.96-6.86(m,3H),4.22-4.09(m,3H),4.04(dd,J=9.2,4.8Hz,1H),3.23(dd,J=13.6,4.8Hz,1H),2.95-2.88(m,3H),2.71(s, 3H),2.08-1.88(m,2H),1.80-1.68(m,1H),1.67-1.53(m,5H),1.38-1.19 (m,6H),1.04(t,J=7.2Hz,3H),0.90-0.80(m,6H),0.78(d,J=6.4Hz,3H).

[1081] (Example 9E: Synthesis of Compound 9E)

[1082] The synthesis of compound 9E was carried out.

[1083] [Chemistry 108]

[1084]

[1085] Under a nitrogen atmosphere, 2,4,6-trimethylpyridine (3.0 eq., 55 μL, 418 μmol) and DEPBT (1.5 eq., 62.9 mg, 210 μmol) were added to a THF (1.4 mL) solution of compound 1-7 (1.0 eq., 90.3 mg, 141 μmol) and fragment D-11 (1.4 eq., 78.5 mg, 200 μmol) under ice-cooling. The mixture was stirred under ice-cooling for 7 hours and then at room temperature for 16.5 hours. Fragment D-11 (0.5 eq., 27.1 mg, 69 μmol) was added at room temperature, followed by DEPBT (0.5 eq., 22.5 mg, 75 μmol) under ice-cooling. The mixture was stirred under ice-cooling for 2 hours and then at room temperature for 1.5 hours. After adding saturated aqueous ammonium chloride solution (1.5 mL) to the reaction solution, it was separated and extracted once with ethyl acetate (8 mL) and once with ethyl acetate (4 mL). The organic layers were combined and washed twice with saturated aqueous sodium bicarbonate solution (2 mL), once with water (2 mL), and once with saturated aqueous sodium chloride solution (2 mL). After the organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered out and concentrated under reduced pressure to obtain a crude product (244 mg) as a dark green sticky substance. The crude product was purified by rapid silica gel column purification (NH2 silica gel 4.9 g, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 9E-1 (71.3 mg, yield 50%) as a light yellow transparent sticky substance.

[1086] [Chemistry 109]

[1087]

[1088] To a mixture of compound 9E-1 (1.0 eq., 53 mg, 0.052 mmol) in THF (2200 μL) and water (110 μL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 5.3 mg) and TFA (2.0 eq., 8.0 μL, 0.104 mmol) at room temperature. The system was purged with hydrogen and stirred at the same temperature for 23 hours. The catalyst was then filtered off through Celite to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain a crude product (44 mg) which was purified on a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 50 / 50). Freeze-dried to obtain the TFA salt of compound 9E (36.6 mg, 86% yield, 94.3% purity) as a white solid.

[1089] 1 H-NMR (400MHz, DMSO-d6) δ9.12(s,1H),8.77(d,J=8.4Hz,1H),8.63(d,J=7.6Hz,1H),7.86(d,J=8.8Hz,1H),6.80-6.72( m,3H),4.86(d,J=9.6Hz,1H),4.57(dd,J=13.2,7.2Hz,1H),4.23(dd,J=9.2,9.2Hz,1H),4.05-3.95(m,2H),3.89(brs,1 H),3.05-2.95(m,1H),2.88(dd,J=14.4,6.0Hz,1H),2.73(dd,J=16.8,6.0Hz,1H),2.60-2.52(m,1H),2.09-1.93(m,1H) ,1.87-1.74(m,1H),1.73-1.61(m,1H),1.58-1.46(m,2H),1.44-1.14(m,21H),1.00(t,J=7.2Hz,3H),0.92-0.73(m,9H)

[1090] (Example 9F: Synthesis of Compound 9F)

[1091] [Chemistry 110]

[1092]

[1093] Under a nitrogen atmosphere, 2,4,6-trimethylpyridine (3.0 eq., 57 μL, 433 μmol) and DEPBT (1.5 eq., 65.8 mg, 220 μmol) were added to a THF (1.45 mL) solution of compound 1-7 (1.0 eq., 93.3 mg, 141 μmol) and fragment D-13 (1.6 eq., 75.6 mg, 225 μmol) under ice-cooling. The mixture was stirred under ice-cooling for 6 hours and then at room temperature for 16 hours. Saturated aqueous ammonium chloride (2.0 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (6 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate (3 mL) twice, water (3 mL) twice, and saturated aqueous sodium chloride (2 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (238 mg) as a dark green viscous substance. The crude product was purified on a flash silica gel column (5.2 g of NH2 silica gel, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 9F-1 (73.3 mg, 53% yield) as a white amorphous substance.

[1094] [Chemistry 111]

[1095]

[1096] Under a nitrogen atmosphere, 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 7 mg) and TFA (2.0 eq., 25.5 μL, 0.15 mmol) were added to a mixture of compound 9F-1 (1.0 eq., 72 mg, 0.075 mmol) in THF (2880 μL) and water (144 μL) at room temperature. The system was replaced with hydrogen and stirred at the same temperature for 7 hours. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (59 mg). The crude product was purified on a flash silica gel column (30 g reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 55 / 45). Freeze-dried, the TFA salt of compound 9F was obtained as a white solid (31.4 mg, 55% yield, 95.4% purity).

[1097] 1H-NMR (400MHz, DMSO-d6) δ9.11(s,1H),8.77(d,J=8.4Hz,1H),8.62(d,J=7.6Hz,1H),7.86(d,J=9.6Hz,1H),6.80-6. 75(m,3H),4.86(d,J=10.4Hz,1H),4.57(dd,J=13.6,7.2Hz,1H),4.23(dd,J=9.2,9.2Hz,1H),4.07-3.85(m,3H),3.0 5-2.95(m,1H),2.89(dd,J=14.4,5.6Hz,1H),2.73(dd,J=16.8,6.0Hz,1H),2.59-2.52(m,1H),2.10-1.93(m,1H),1. 86-1.75(m,1H),1.74-1.61(m,1H),1.59-1.46(m,2H),1.37-1.16(m,13H),1.00(t,J=7.2Hz,3H),0.92-0.75(m,9H).

[1098] (Example 9G: Synthesis of Compound 9G)

[1099] [Chemistry 112]

[1100]

[1101] The two steps from fragment A-2" to compound 25-2 are described in Example 29B below.

[1102] The synthesis of compound 25-2 to compound 9G-1 was carried out as follows.

[1103] [Chemistry 113]

[1104]

[1105] To a solution of compound 25-2 (1.0 eq., 1.03 g, 1.44 mmol) in DMF (15 mL) were added HOBt·H₂O (1.2 eq., 265 mg, 1.73 mmol), EDCI (1.2 eq., 333 mg, 1.74 mmol), and N-Fmoc-L-valine (fragment C-1, 1.2 eq., 587 mg, 1.73 mmol) at room temperature, and the mixture was stirred at room temperature for 5 hours. A mixture of hexane (15 mL) and ethyl acetate (45 mL) was added, and the mixture was separated and washed with water (40 mL) twice, saturated aqueous sodium bicarbonate (40 mL) twice, and saturated aqueous sodium chloride (20 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain compound 9G-1 (1.71 g, crude yield 115%) as a light brown amorphous form.

[1106] The synthesis of compound 9G-1 to compound 9G-2 was carried out as follows.

[1107] [Chemistry 114]

[1108]

[1109] To a mixture of compound 9G-1 (1.0 eq., 1.71 g, calculated as 1.44 mmol) in THF (10 mL) and water (5 mL) was added lithium hydroxide (6.0 eq., 207 mg, 8.62 mmol) at room temperature, and the mixture was stirred for 4 hours. A 1N aqueous hydrochloric acid solution (5.0 mL) was added to the reaction mixture to adjust the pH to 7. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined and washed once with a saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (1.84 g) as a brown viscous substance. The crude product was purified on a flash silica gel column (20 g normal phase silica gel, ethyl acetate / methanol = 100 / 0 to 40 / 60) to obtain compound 9G-2 (1.06 g, 102% yield over two stages) as a light brown amorphous substance.

[1110] The synthesis of compound 9G-2 to compound 9G-3 was carried out as follows.

[1111] [Chemistry 115]

[1112]

[1113] A mixture of compound 9G-2 (1.0 eq., 1.05 mg, calculated as 1.44 mmol) in acetonitrile (14.5 mL) and THF (14.5 mL) was added dropwise at approximately 100 μL / min over 5 hours to a solution of HATU (2.0 eq., 1.10 g, 2.88 mmol), HOAt (2.0 eq., 391 mg, 2.87 mmol), and DIPEA (2.0 eq., 0.49 mL, 2.89 mmol) in acetonitrile (718 mL) at room temperature. The mixture was then stirred at room temperature for 15.5 hours. The reaction mixture was concentrated under reduced pressure to approximately 250 mL, and ethyl acetate (200 mL) was added. The mixture was then washed with a mixture of water (50 mL) and saturated aqueous ammonium chloride (100 mL) twice, saturated aqueous sodium bicarbonate (100 mL) twice, and saturated aqueous sodium chloride (50 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (1.92 g) as a reddish-brown viscous substance. The crude product was purified on a flash silica gel column (25 g normal phase silica gel, hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain compound 9G-3 (231 mg, 3-stage yield 23%) as a white amorphous substance.

[1114] The synthesis of compound 9G-3 to compound 9G-4 was carried out as follows.

[1115] [Chemistry 116]

[1116]

[1117] To a solution of compound 9G-3 (1.0 eq., 230 mg, 0.324 mmol) in THF (3.2 mL) at room temperature was added TBAF (2.5 eq. in 1M THF, 0.81 mL, 0.810 mmol), and the mixture was stirred at the same temperature for 2 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed three times with saturated aqueous ammonium chloride (20 mL) and once with saturated aqueous sodium chloride (10 mL), followed by drying over magnesium sulfate. The magnesium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (214 mg) as a pale yellow amorphous form. The crude product was purified on a flash silica gel column (5 g normal phase silica gel, hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain compound 9G-4 (191 mg, 99% yield) as a white amorphous form.

[1118] The synthesis of compound 9G-4 to compound 9G-5 was carried out as follows.

[1119] [Chemistry 117]

[1120]

[1121] Under a nitrogen atmosphere, Dess-Martin periodate (1.5 eq., 203 mg, 0.477 mmol) was added to a solution of compound 9G-4 (1.0 eq., 189 mg, 0.318 mmol) in dichloromethane (3 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched by adding a mixture of 10% aqueous sodium sulfite (10 mL) and saturated aqueous sodium bicarbonate (10 mL). Extraction was performed once with dichloromethane (20 mL) and twice with dichloromethane (10 mL). The organic layers were combined and washed once with saturated aqueous sodium chloride (10 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the aldehyde (187 mg, quant.) as a white amorphous product.

[1122] To a mixture of aldehyde (1.0 eq., 186 mg, 0.314 mmol) in pentene (1 mL) / tert-butyl alcohol (4 mL) at room temperature, sodium dihydrogen phosphate dihydrate (3.4 eq., 167 mg, 1.07 mmol) and 80% sodium chlorite (4.5 eq., 160 mg, 1.42 mmol) in water (1 mL) were added, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, and extraction was performed once with ethyl acetate (20 mL) and twice with ethyl acetate (10 mL). The organic layers were combined, washed once with saturated aqueous sodium chloride (20 mL), dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the crude product (215 mg, 99% yield) as a white amorphous solid. The crude product was purified by flash silica gel column (normal phase silica gel 5 g, hexane / ethyl acetate = 33 / 67) to obtain compound 9G-5 (178 mg, yield 93%) as a white amorphous substance.

[1123] The synthesis of compound 9G-5 to compound 9G-6 was carried out as follows.

[1124] [Chemistry 118]

[1125]

[1126] To a mixture of compound 9G-5 (1.0 eq., 177 mg, 0.291 mmol) in ethyl acetate (1.8 mL) and water (540 μL) at room temperature, fragment D-14 (1.5 eq., 164 mg, 0.435 mmol) was added. DIPEA (2.4 eq., 0.12 mL, 0.706 mmol) was added under ice cooling, and the mixture was stirred for 10 minutes. DMT-MM (1.7 eq., 138 mg, 0.497 mmol) was then added, and the mixture was stirred at the same temperature for 2.5 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed with water (15 mL) (partially), a mixture of water (10 mL) and saturated aqueous ammonium chloride (10 mL) (partially), water (10 mL) and saturated aqueous sodium bicarbonate (10 mL) (partially), and saturated aqueous sodium chloride (10 mL) (partially). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (360 mg) as a yellow oil. The crude product was purified twice by flash silica gel column purification (first: 6 g NH2 silica gel, hexane / ethyl acetate = 75 / 25 to 67 / 33, second: 4 g normal phase silica gel, hexane / ethyl acetate = 50 / 50) to obtain compound 9G-6 (235 mg, 83% yield) as a white amorphous product.

[1127] The synthesis of compound 9G-6 to compound 9G-7 was carried out as follows.

[1128] [Chemistry 119]

[1129]

[1130] At room temperature, TFA (9.7 eq., 0.18 mL, 2.35 mmol) was added to a solution of compound 9G-6 (1.0 eq., 235 mg, 0.243 mmol) in dichloromethane (2.4 mL), and the mixture was stirred at the same temperature for 1 hour. Then, TFA (9.7 eq., 0.18 mL, 2.35 mmol) was added and stirred at the same temperature for 7 hours. The reaction solution was ice-cooled and a saturated aqueous sodium bicarbonate solution (15 mL) was added to adjust the pH to 8. The reaction solution was extracted once with ethyl acetate (20 mL) and twice with ethyl acetate (10 mL). The organic layers were combined and washed once with a saturated aqueous sodium chloride solution (20 mL). After drying the organic layer over magnesium sulfate, the magnesium sulfate was filtered out and concentrated under reduced pressure to obtain compound 9G-7 (210 mg, 99% yield) as a light yellow amorphous form.

[1131] The synthesis of compound 9G-7 to compound 9G was carried out as follows.

[1132] [Chemistry 120]

[1133]

[1134] Under a nitrogen atmosphere, TFA (5.0 eq., 83 μL, 1.085 mmol) was added to a mixture of compound 9G-7 (1.0 eq., 186 mg, 0.218 mmol) in THF (7.4 mL) and water (370 μL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After hydrogen exchange, the system was replaced with 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 18.6 mg), and the mixture was stirred at the same temperature for 6.5 hours. The catalyst was filtered off through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (171 mg). The crude product (40 mg) obtained from compound 9G-7 (40 mg) by the same procedure was combined with the above crude product and purified on a flash silica gel column (30 g of reverse phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 55 / 45). The residue was freeze-dried to obtain the TFA salt of compound 9G (107 mg, yield 51%, purity 96.4%) as a white solid.

[1135] 1 H-NMR (400MHz, DMSO-d6) δ9.11(s,1H),8.79(d,J=8.8Hz,1H),8.62(d,J=7.6Hz,1H),7.87(d,J=10.0Hz,1H),6. 80-6.75(m,3H),4.87(d,J=10.0Hz,1H),4.57(dd,J=13.6,7.2Hz,1H),4.23(dd,J=9.2,9.2Hz,1H),4.05-3.85(m ,3H),3.05-2.95(m,1H),2.89(dd,J=14.4,5.6Hz,1H),2.73(dd,J=16.8,6.0Hz,1H),2.60-2.50(m,1H),2.10-1 .94(m,1H),1.87-1.61(m,2H),1.59-1.45(m,2H),1.36-1.15(m,17H),1.01(t,J=7.2Hz,3H),0.92-0.74(m,9H).

[1136] (Example 10: Synthesis of Compound 10)

[1137] [Chemistry 121]

[1138]

[1139] Under a nitrogen atmosphere, DIPEA (1.5 eq., 40 μL, 0.235 mmol) and HATU (1.5 eq., 90 mg, 0.237 mmol) were added to a solution of compound 2-13 (1.0 eq., 95 mg, containing isomers, 0.158 mmol) and L-aspartic acid dibenzyl ester hydrochloride (fragment D-2, 1.5 eq., 83 mg, 0.237 mmol) in dichloromethane (2.4 mL) under ice cooling. The mixture was stirred for 3 hours while warming to room temperature. The reaction mixture was washed once with 5% aqueous citric acid solution (3 mL). The organic layer was then washed once with 5% aqueous sodium bicarbonate solution (3 mL) and once with 5% aqueous sodium chloride solution (3 mL), and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure, and the crude product (197 mg) obtained as a light brown sticky substance was subjected to two rapid silica gel column purifications (first: 10 g normal phase silica gel, hexane / ethyl acetate = 40 / 60, second: 6.5 g NH2 silica gel, hexane / ethyl acetate = 40 / 60 to 0 / 100) to obtain compound 10-1 (54 mg, containing 5.0 wt% hexane, converted yield 36%) as a white solid.

[1140] [Chemistry 122]

[1141]

[1142] Under a nitrogen atmosphere, to a mixture of compound 10-1 (1.0 eq., 52 mg, containing 5.0 wt% hexane, 0.055 mmol) in THF (2.5 mL) / water (2.5 mL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.6 mg) and TFA (2.0 eq., 8.4 μL, 0.110 mmol) at room temperature. After hydrogen substitution, the mixture was stirred at the same temperature for 25 hours. THF (2.5 mL) was added, and the mixture was stirred for a further 64 hours. 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.6 mg) was added, and the mixture was stirred for another 24 hours. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product (41 mg) as a pale orange viscous substance. The crude product was purified by flash silica gel column (30 g reverse phase silica gel, 0.05% aqueous TFA solution / acetonitrile = 95 / 5) and freeze-dried to obtain the TFA salt of compound 10 (18.3 mg, yield 54%, purity 99.3%) as a white solid.

[1143] 1H-NMR(400MHz,D2O)δ7.44(s,1H),7.05(dd,J=8.0,2.0Hz,1H),6.98(d,J=8.0 Hz,1H),4.65(s,1H),4.25(d,J=16.4Hz,1H),3.99(dd,J=10.4,4.0Hz,1H),3.5 5(d,J=16.4Hz,1H),3.26(dd,J=13.2,4.0Hz,1H),3.08-2.99(m,1H),2.73(s, 3H),2.03-1.97(m,1H),1.78-1.70(m,1H),1.63(s,3H),0.86(t,J=7.2Hz,3H).

[1144] (Example 11: Synthesis of Compound 5)

[1145] [Chemistry 123]

[1146]

[1147] Under a nitrogen atmosphere, triphenylphosphine (1.5 eq., 1.99 g, 7.59 mmol) and DIAD (1.5 eq., 1.63 mL, 7.58 mmol) were added to a toluene (28 mL) solution of Fragment A-2 (1.0 eq., 2.81 g, 5.06 mmol) and Fragment B-2 (1.5 eq., 2.74 g, 7.58 mmol) at room temperature. The mixture was stirred at the same temperature for 15 minutes and then at an external temperature of 75°C for 2 hours. Triphenylphosphine (0.75 eq., 0.99 g, 3.77 mmol) and DIAD (1.5 eq., 0.81 mL, 3.77 mmol) were added and stirred for a further 0.5 hour. The reaction solution was cooled and then concentrated under reduced pressure. The concentrated residue was purified by flash silica gel column (normal phase silica gel 50 g, hexane / ethyl acetate = 90 / 10 to 67 / 33) to obtain compound 5-1 (5.95 g, containing impurities, apparent yield 130%) as a light yellow-brown oil.

[1148] [Chemistry 124]

[1149]

[1150] Under a nitrogen atmosphere and ice cooling, a solution of compound 5-1 (1.0 eq., 5.35 g, containing impurities, calculated as 4.55 mmol) in acetonitrile (45 mL) was added with 1 M aqueous hydrochloric acid (1.1 eq., 5.00 mL, 5.00 mmol). The mixture was stirred for 2 hours while warming to room temperature. A few drops of saturated aqueous sodium bicarbonate solution were added to the reaction solution to adjust the pH to 5-7, and the mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the concentrated residue, and the mixture was extracted three times with ethyl acetate (25 mL). The organic layers were combined, washed once with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to obtain the crude product (5.42 g) as a light yellow-brown oil. The crude product was purified by flash silica gel column (normal phase silica gel 50 g, chloroform / acetonitrile = 90 / 10 to 80 / 20) to obtain compound 5-2 (1.59 g, containing impurities, apparent yield 75%) as a light yellow oil.

[1151] [Chemistry 125]

[1152]

[1153] Under a nitrogen atmosphere, N-Boc-L-valine (fragment C-1', 2.0 eq., 528 mg, 2.43 mmol), EDCI (2.0 eq., 466 mg, 2.43 mmol), and HOBt·H2O (2.0 eq., 372 mg, 2.43 mmol) were added to a solution of compound 5-2 (1.0 eq., 0.80 g, containing impurities, calculated to be 1.22 mmol) in DMF (12 mL). The mixture was stirred at room temperature for 20 hours. Water (50 mL) was added to the reaction solution, and extraction was performed three times with ethyl acetate (25 mL). The organic layers were combined, washed once with saturated aqueous sodium bicarbonate (25 mL) and once with saturated aqueous sodium chloride (25 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain the crude product (1.50 g) as a pale yellow oil. The crude product was purified by flash silica gel column twice (first: 50 g normal phase silica gel, hexane / ethyl acetate = 90 / 10 to 50 / 50, second: 120 g reverse phase silica gel, 0.05% TFA aqueous solution / acetonitrile = 90 / 10 to 0 / 100) to obtain compound 5-3 (0.74 g, 38% yield of the first three stages of fragment A-2) as a white amorphous product.

[1154] [Chemistry 126]

[1155]

[1156] Under a nitrogen atmosphere, triethylsilane (25 eq., 3.35 mL, 21.03 mmol) and TFA (3.75 mL) were added to a solution of compound 5-3 (1.0 eq., 0.74 g, 0.87 mmol) in dichloromethane (7.5 mL) under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and a 0.05 M hydrogen chloride / 1,4-dioxane solution (20 mL) was added to the concentrated residue and concentrated under reduced pressure. This operation was repeated twice. 1,4-dioxane was added to the concentrated residue and concentrated under reduced pressure. This operation was repeated three times to obtain compound 5-4 (1.39 g) as a colorless oil.

[1157] [Chemistry 127]

[1158]

[1159] Under a nitrogen atmosphere, a solution of compound 5-4 (1.0 eq., 1.39 g, calculated as 0.865 mmol) in DMF (65 mL) was added to a solution of EDCI (5.0 eq., 830 mg, 4.33 mmol), HOBt·H2O (5.0 eq., 663 mg, 7.33 mmol), and sodium bicarbonate (10.0 eq., 726 mg, 8.64 mmol) in DMF (800 mL) over 2 hours at room temperature. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was separated and extracted once with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and washed once with saturated aqueous sodium chloride solution (10 mL) and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (0.71 g) as an ochre-colored solid. The crude product was purified by flash silica gel column (normal phase silica gel 25 g, chloroform / ethyl acetate = 90 / 10 to 80 / 20) to obtain compound 5-5 (226 mg, containing impurities, apparent yield of 42% in the two stages starting from compound 5-3) as a white solid.

[1160] [Chemistry 128]

[1161]

[1162] Under a nitrogen atmosphere, trimethyltin hydroxide (4.0 eq., 159 mg, 0.88 mmol) was added to a solution of compound 5-5 (1.0 eq., 138 mg, containing impurities, calculated as 0.22 mmol) in 1,2-dichloroethane (3.45 mL), and the mixture was stirred at an external temperature of 80°C for 4 hours. The reaction mixture was cooled, and ethyl acetate (20 mL) and 1M aqueous hydrochloric acid (20 mL) were added for separation and extraction. The organic layer was washed once with 10% aqueous sodium chloride (20 mL), dried over sodium sulfate, and the sodium sulfate was filtered off. The sodium sulfate was filtered off and concentrated under reduced pressure to obtain a crude product (169 mg) as a white solid.

[1163] The same procedure was followed to obtain a crude product (20 mg) from compound 5-5 (20 mg). This crude product was combined with the previous crude product and purified on a flash silica gel column (normal phase silica gel 10 g, ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain compound 5-6 (147 mg, containing impurities, apparent yield 93%).

[1164] [Chemistry 129]

[1165]

[1166] Under a nitrogen atmosphere, to a solution of compound 5-6 (1.0 eq., 73 mg, containing impurities, 0.12 mmol) and L-glutamic acid dibenzyl ester hydrochloride (fragment D-1, 1.5 eq., 65 mg, 0.18 mmol) in DMF (0.73 mL) were added EDCI (1.5 eq., 34 mg, 0.18 mmol), HOBt·H2O (1.5 eq., 27 mg, 0.18 mmol) and sodium bicarbonate (3.0 eq., 30 mg, 0.36 mmol) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours.

[1167] Toluene (3 mL) was added to the reaction solution, and the mixture was separated and washed twice with 5% aqueous sodium bicarbonate solution (3 mL) and once with 5% aqueous sodium chloride solution (3 mL). The organic layer was dried over sodium sulfate, and after filtering out the sodium sulfate, it was concentrated under reduced pressure to obtain a crude product (115 mg) as a light yellow solid. The crude product was subjected to rapid silica gel column purification (NH2 silica gel 6.5 g, hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain a white solid (52 mg). Hexane (4 mL) and toluene (2 mL) were added to the solid, and after ultrasonic irradiation, it was stirred at room temperature for 15 minutes. The suspension was filtered to obtain compound 5-7 (37 mg, yield 34%) as a white solid.

[1168] [Chemistry 130]

[1169]

[1170] Under a nitrogen atmosphere, 10% palladium on carbon (NEChemcat NX, 50% aqueous solution, 8.8 mg) was added to a mixture of compound 5-7 (1.0 eq., 35 mg, 0.038 mmol) in THF (1.2 mL) and water (1.2 mL) at room temperature. After hydrogen exchange, the mixture was stirred at the same temperature for 22 hours. The catalyst was filtered through celite, and the solid was washed with 0.05% aqueous TFA. The filtrate was concentrated under reduced pressure to obtain the crude product (20 mg) as a white solid. The crude product was purified twice by flash silica gel column purification (60 g reverse phase silica gel, first pass: 0.05% aqueous TFA / acetonitrile = 99 / 1 to 90 / 10, second pass: 0.05% aqueous TFA / acetonitrile = 99 / 1 to 0 / 100) and freeze-dried to obtain the TFA salt of compound 5 (14 mg, 59% yield, 99.7% purity) as a white solid.

[1171] 1 H-NMR(400MHz,D2O)δ6.89(d,J=8.0Hz,1H),6.81(dd,J=8.0,2.0Hz,1H),6.70(d,J=2.0Hz,1H),4. 65(dd,J=13.2,2.4Hz,1H),4.56(dd,J=13.2,6.0Hz,1H),4.37(dd,J=8.8,4.8Hz,1H),4.11(d,J=1 0.8Hz,1H),3.95(dd,J=8.8,4.8Hz,1H),3.21(dd,J=13.2,4.8Hz,1H),2.95(dd,J=13.2,8.8Hz,1H ),2.70(s,3H),2.45(t,J=7.2Hz,2H),2.24-2.15(m,1H),2.03-1.85(m,2H),0.84(t,J=6.8Hz,6H).

[1172] (Example 12: Synthesis of Compound 3)

[1173] [Chemistry 131]

[1174]

[1175] Under a nitrogen atmosphere, N-Boc-L-glycine (fragment C-3', 2.0 eq., 0.42 g, 2.40 mmol), EDCI (2.0 eq., 0.46 mg, 2.40 mmol), and HOBt·H2O (2.0 eq., 0.37 mg, 2.40 mmol) were added to a DMF (12 mL) solution of compound 5-2 (1.0 eq., 0.79 g, containing impurities, calculated to be 1.20 mmol). The mixture was stirred at room temperature for 2 hours. Water (30 mL) and toluene (30 mL) were added to the reaction mixture for separation and extraction. The organic layer was washed once with water (30 mL) and once with a 10% aqueous sodium chloride solution (30 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (1.175 g) as a yellow viscous substance. The crude product was purified by flash silica gel column (14 g NH2 silica gel, hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain compound 3-1 (0.87 g, containing 3.2 wt% ethyl acetate, equivalent yield 86%) as a light yellow sticky substance.

[1176] [Chemistry 132]

[1177]

[1178] Under a nitrogen atmosphere and ice cooling, triethylsilane (25 eq., 3.01 g, 25.89 mmol) and TFA (4.35 mL) were added to a solution of compound 3-1 (1.0 eq., 0.87 g, containing 3.2 wt% ethyl acetate, 1.03 mmol) in dichloromethane (8.7 mL). The mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and a 0.05 M hydrogen chloride / 1,4-dioxane solution (15 mL) was added to the residue. The mixture was concentrated under reduced pressure again to obtain compound 3-2 (1.196 g, containing 1,4-dioxane) as a colorless viscous substance.

[1179] [Chemistry 133]

[1180]

[1181] Under a nitrogen atmosphere, a solution of compound 3-2 (1.0 eq., 0.83 g, containing 1,4-dioxane, calculated as 0.72 mmol) in DMF (8 mL) was added to a solution of HATU (5.0 eq., 1.36 g, 3.58 mmol) and DIPEA (10.0 eq., 0.92 g, 7.12 mmol) in DMF (704 mL) over 18.5 hours at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated and extracted once with ethyl acetate (15 mL) and 5% aqueous citric acid solution (15 mL). The organic layer was washed once with 5% aqueous sodium bicarbonate solution (15 mL) and once with 5% aqueous sodium chloride solution (15 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (0.81 g) as a pale brown amorphous substance. The crude product was purified by rapid silica gel column purification (NH2 silica gel 10g, hexane / ethyl acetate = 50 / 50) to obtain compound 3-3 (190mg, yield 46%) as a white solid. Compound 3-3 (89mg) obtained by the same operation was combined and purified by rapid silica gel column purification (NH2 silica gel 14g, hexane / ethyl acetate = 50 / 50), and the fractions containing the target were combined and concentrated under reduced pressure. The concentrated residue was dissolved in 1,2-dichloroethane (3mL) and concentrated under reduced pressure. This operation was performed twice to obtain compound 3-3 (118mg, containing 16.5wt% 1,2-dichloroethane, yield 35%) as a colorless sticky substance.

[1182] [Chemistry 134]

[1183]

[1184] Under a nitrogen atmosphere, trimethyltin hydroxide (4.0 eq., 124 mg, 0.69 mmol) was added to a solution of compound 3-3 (1.0 eq., 118 mg, containing 16.5 wt% 1,2-dichloroethane, 0.17 mmol) in 1,2-dichloroethane (2.7 mL). The mixture was stirred at an external temperature of 80°C for 3.5 hours. After cooling, the reaction solution was separated and extracted once with ethyl acetate (20 mL) and 1M aqueous hydrochloric acid (20 mL). The organic layer was separated and washed once with 5% aqueous sodium chloride (20 mL), dried over sodium sulfate, and the sodium sulfate was filtered off. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain compound 3-4 (104 mg, containing impurities, quant.) as a white solid.

[1185] [Chemistry 135]

[1186]

[1187] Under a nitrogen atmosphere, EDCI (1.5 eq., 24 mg, 0.125 mmol), HOBt·H₂O (1.5 eq., 19 mg, 0.124 mmol), and sodium bicarbonate (1.5 eq., 10 mg, 0.119 mmol) were added to a DMF (0.5 mL) solution of compound 3-4 (1.0 eq., 50 mg, containing impurities, calculated as 0.082 mmol) and L-glutamic acid dibenzyl ester hydrochloride (fragment D-1, 1.5 eq., 45 mg, 0.124 mmol) at room temperature. The mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was then separated and extracted once with toluene (10 mL) and 5% aqueous citric acid solution (10 mL). The organic layer was then separated and washed once with 5% aqueous sodium bicarbonate solution (10 mL) and once with 5% aqueous sodium chloride solution (10 mL). The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and then concentrated under reduced pressure to obtain a crude product (82 mg) as a light yellow viscous substance.

[1188] The same procedure was followed to obtain a crude product (60 mg) from compound 3-4 (1.0 eq., 50 mg). After combining with the previous crude product, the product was purified by flash silica gel column (NH2 silica gel 6.5 g, hexane / ethyl acetate = 40 / 60) to obtain compound 3-5 (69 mg, 48% yield) as a white amorphous product.

[1189] [Chemistry 136]

[1190]

[1191] Under a nitrogen atmosphere, 10% palladium on carbon (NEChemcat NX, 50% aqueous solution, 17 mg) was added to a mixture of compound 3-5 (1.0 eq., 67 mg, 0.077 mmol) in THF (3.35 mL) and water (3.35 mL) at room temperature. After hydrogen exchange, the reaction mixture was stirred at the same temperature for 19.5 hours. TFA (2.0 eq., 12 μL, 0.157 mmol) was added to the reaction mixture, and the catalyst was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain a crude product (45 mg). The crude product was purified on a flash silica gel column (60 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 99 / 1 to 0 / 100) and then freeze-dried to obtain the TFA salt of compound 3 (34 mg, 76% yield, 99.9% purity) as a white solid.

[1192] 1H-NMR(400MHz,D2O)δ7.00-6.85(m,3H),4.67(dd,J=13.6,5.6Hz,1H),4.53( dd,J=13.2,1.6Hz,1H),4.42(dd,J=8.8,5.2Hz,1H),4.36(d,J=15.2Hz,1H), 3.96(dd,J=10.0,4.8Hz,1H),3.36-3.29(m,2H),2.98(dd,J=13.2,10.0Hz,1 H), 2.73 (s, 3H), 2.50 (t, J = 7.2Hz, 2H), 2.28-2.19 (m, 1H), 2.08-1.90 (m, 1H).

[1193] (Example 13: Synthesis of Compound 11)

[1194] [Chemistry 137]

[1195]

[1196] Under a nitrogen atmosphere and ice cooling, to a solution of compound 3-4 (1.0 eq., 366.6 mg, calculated as 0.408 mmol) in dichloromethane (3.7 mL) were added a solution of L-aspartic acid dibenzyl ester hydrochloride (fragment D-2, 2.0 eq., 286 mg, 0.816 mmol) and DIPEA (1.9 eq., 135 μL, 0.775 mmol) in dichloromethane (2.5 mL). Subsequently, HOBt·H₂O (2.0 eq., 125 mg, 0.816 mmol) and EDCI (2.0 eq., 156 mg, 0.816 mmol) were added, and the mixture was stirred at the same temperature for 3 hours.

[1197] The reaction solution using compound 3-4 (30 mg) under the same conditions was combined with the previous reaction solution, and ethyl acetate (40 mL) and 1M hydrochloric acid aqueous solution (20 mL) were added for one liquid separation and extraction. The aqueous layer was separated and extracted three times with ethyl acetate (5 mL). The organic layers were combined, washed once with 5% sodium chloride aqueous solution (20 mL), and then dried over sodium sulfate. The sodium sulfate was filtered out and concentrated under reduced pressure to obtain a crude product (633.8 mg) as a yellow oil. The crude product was purified by flash silica gel column (80 g of NH2 silica gel, hexane / ethyl acetate = 43 / 57 to 0 / 100). Toluene was added to the resulting white solid (294.0 mg), and after pulverization by ultrasonic irradiation, the solid was filtered to obtain compound 11-1 (234.3 mg, containing 1.9 wt% ethyl acetate, a 61% yield based on the two stages starting from compound 3-3) as a white solid.

[1198] [Chemistry 138]

[1199]

[1200] Under a nitrogen atmosphere, 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 57 mg) was added to a mixture of compound 11-1 (1.0 eq., 234 mg, containing 1.9 wt% ethyl acetate, 0.268 mmol) in THF (10 mL) / water (10 mL) at room temperature. After hydrogen exchange, the mixture was stirred at the same temperature for 2 hours. TFA (2.0 eq., 41 μL, 0.536 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product (189.5 mg) as a pale orange solid. Ethyl acetate was added to the crude product, and the mixture was triturated by ultrasonic irradiation. The insoluble matter was filtered off and dried under reduced pressure. The resulting solid was dissolved in water, the insoluble matter was filtered off, and the filtrate was concentrated to obtain the TFA salt of compound 11 (150.9 mg, 99.6% yield, 99.4% purity) as a pale orange solid.

[1201] 1 H-NMR(400MHz,D2O)δ6.89-6.76(m,3H),4.58(dd,J=13.2,5.2Hz,1H),4.40(d,J=13.2,1H),4.21(d,J=15.2Hz,1H) ,3.86(dd,J=9.6,4.4Hz,1H),3.26(d,J=15.2Hz,1H),3.21(dd,J=13.2,4.4Hz,1H),2.95-2.82(m,3H),2.63(s,3H).

[1202] (Example 14: Synthesis of Compound 6)

[1203] [Chemistry 139]

[1204]

[1205] Under a nitrogen atmosphere and ice cooling, TBD (1.08 eq., 857 mg, 6.16 mmol) was added to a toluene (57 mL) solution of Fragment A-3 (1.0 eq., 3.10 g, 5.72 mmol) and Fragment B-1 (1.2 eq., 3.17 g, containing 20 mol% DIAD, 6.87 mmol). The mixture was stirred at room temperature for 3 hours. The toluene was evaporated by concentration under reduced pressure to obtain a crude product as a dark brown amorphous substance. The crude product was purified on a flash silica gel column (70 g of normal phase silica gel, hexane / ethyl acetate = 5 / 1 to 2 / 1) to obtain compound 6-1 (3.84 g, 70% yield) as a pale yellow amorphous substance.

[1206] [Chemistry 140]

[1207]

[1208] Under a nitrogen atmosphere, cesium carbonate (1.5 eq., 781 mg, 2.21 mmol) and thiophenol (1.5 eq., 230 μL, 2.25 mmol) were added to a DMF (20 mL) solution of compound 6-1 (1.0 eq., 1.41 g, 1.48 mmol) at room temperature, and the mixture was stirred at room temperature for 3 hours. After adding saturated sodium bicarbonate aqueous solution (10 mL), saturated sodium chloride aqueous solution (10 mL), and water (20 mL), the reaction solution was extracted three times with a mixture of hexane (10 mL) and ethyl acetate (30 mL). The organic layers were combined, washed once with saturated sodium chloride aqueous solution (60 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off and concentrated under reduced pressure to obtain a crude product (2.01 g) as a yellow oil. The crude product was purified by flash silica gel column (normal phase silica gel 20 g, hexane / ethyl acetate = 5 / 1 to 1 / 1) to obtain compound 6-2 (1.02 g, yield 90%) as a light yellow sticky substance.

[1209] [Chemistry 141]

[1210]

[1211] Under a nitrogen atmosphere and ice cooling, EDCI (2.0 eq. 2.23 g, 11.65 mmol), HOBt·H₂O (2.0 eq., 1.77 g, 11.59 mmol), and N-Fmoc-L-Val (2.0 eq., 3.97 g, 11.69 mmol) were added to a DMF (58 mL) solution of compound 6-2 (1.0 eq., 4.44 g, 5.79 mmol) and stirred at room temperature for 2 hours. Water (60 mL) was added to the reaction solution, and the mixture was extracted three times with a mixture of hexane (15 mL) and ethyl acetate (45 mL). The organic layers were combined and washed twice with a saturated aqueous sodium bicarbonate solution (100 mL) and once with a saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (9.01 g). The crude product was purified by flash silica gel column (normal phase silica gel 70 g, hexane / ethyl acetate = 5 / 1 to 2 / 1) to obtain compound 6-3 (5.69 g, yield 90%) as a white amorphous substance.

[1212] [Chemistry 142]

[1213]

[1214] To a mixture of compound 6-3 (1.0 eq., 2.07 g, 1.90 mmol) in THF (12 mL) and water (6 mL) was added lithium hydroxide (4.0 eq., 181 mg, 7.58 mmol) at room temperature, and the mixture was stirred at room temperature for 3.5 hours. Under ice cooling, the reaction mixture was adjusted to pH 7 with 1N aqueous hydrochloric acid (5 mL), and then extracted three times with ethyl acetate (10 mL). The organic layers were combined and washed twice with saturated aqueous sodium chloride (30 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (2.21 g). The crude product was purified on a flash silica gel column (25 g normal phase silica gel, ethyl acetate / methanol = 20 / 1 to 5 / 1) to obtain compound 6-4 (1.03 g, 73% yield) as a white amorphous product.

[1215] [Chemistry 143]

[1216]

[1217] A solution of compound 6-4 (1.0 eq., 2.80 g, 3.75 mmol) in THF (375 mL) was added dropwise at approximately 80 μL / min over 4 days to a solution of PyBOP (5.0 eq., 9.76 g, 18.76 mmol), HOBt·H₂O (5.0 eq., 2.87 g, 18.76 mmol), and DIPEA (5.0 eq., 3.2 mL, 18.82 mmol) in THF (1.5 L) at room temperature. The reaction mixture was concentrated under reduced pressure until the volume was approximately one-tenth that of the original volume, and then washed twice with saturated aqueous sodium bicarbonate (100 mL). The aqueous layers were combined and extracted twice with ethyl acetate (100 mL). The organic layers were combined and washed once with saturated aqueous sodium chloride (100 mL). The organic layers were dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to yield a crude product (16.80 g). The crude product was purified by flash silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 6-5 (1.18 g, yield 43%) as a white amorphous substance.

[1218] [Chemistry 144]

[1219]

[1220] Under a nitrogen atmosphere, TBAF (1.88 eq., 1.6 mL, 1.60 mmol in 1M THF) was added to a solution of compound 6-5 (1.0 eq., 619 mg, 850 μmol) in THF (9 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined and washed once with saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered out, and the mixture was concentrated under reduced pressure to obtain a crude product (677 mg). The crude product was purified on a flash silica gel column (7 g...

Claims

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

2. The composition according to claim 1, wherein The aforementioned ophthalmic diseases include retinal diseases.

3. The composition according to claim 1, wherein The aforementioned ophthalmic disease comprises at least one of diabetic retinopathy, glaucoma or age-related macular degeneration.

4. The composition according to any one of claims 1 to 3, wherein R1 and R2 are each independently a hydrogen atom or a C 1-6 alkyl.

5. The composition according to any one of claims 1 to 4, wherein R1 and R2 are each independently a hydrogen atom, a methyl group or an ethyl group.

6. The composition according to any one of claims 1 to 5, wherein R3 and R4 are each independently a hydrogen atom, a C substituted by a carboxyl group 1-6 Alkyl or carboxyl.

7. The composition according to any one of claims 1 to 6, wherein R3 and R4 are each independently a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group or a carboxyl group.

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

9. The composition according to any one of claims 1 to 8, wherein R5 is a hydrogen atom.

10. The composition according to any one of claims 1 to 9, wherein R6 is a hydrogen atom or C 1-6 alkyl.

11. The composition according to any one of claims 1 to 10, wherein R6 is a hydrogen atom.

12. The composition according to any one of claims 1 to 11, wherein R7 is a hydrogen atom, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carbamoyl C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, hydroxyl C 6-10 Aryl C 1-6 Alkyl, C 5-10 Heteroaryl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, thio C 1-6 Alkyl, C 1-6 Alkylthio C 1-6 Alkyl or amidinoamino C 1-6 alkyl.

13. The composition according to any one of claims 1 to 12, wherein R7 is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a carboxymethyl group, a carboxyethyl group, a 4-hydroxybenzyl group, a 4-aminobutyl group, a thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinoaminopropyl group, an indolylmethyl group or a 4-imidazolemethyl group.

14. The composition according to any one of claims 1 to 13, wherein R8 is a hydrogen atom or C 1-6 alkyl.

15. The composition according to any one of claims 1 to 14, wherein R8 is a hydrogen atom.

16. The composition according to any one of claims 1 to 15, wherein R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted heterocycloalkyl group.

17. The composition according to any one of claims 1 to 16, wherein R7 and R8 together with the carbon atom and nitrogen atom to which R7 and R8 are bonded form C 5-10 Heterocycloalkyl.

18. A composition according to any one of claims 1 to 17, wherein R9 and R 10 A hydrogen atom or C 1-6 alkyl.

19. The composition according to any one of claims 1 to 18, wherein R9 and R 10 Each is independently a hydrogen atom or a methyl group.

20. The composition according to any one of claims 1 to 19, wherein R 11 , R 12 , R 13 and R 14 Each is independently a hydrogen atom, an alkoxy group or a hydroxyl group.

21. The composition according to any one of claims 1 to 20, wherein R 12 A hydrogen atom or a hydroxyl group.

22. The composition according to any one of claims 1 to 21, wherein R 11 , R 12 , R 13 and R 14 Each is independently a hydrogen atom or a hydroxyl group.

23. A composition according to any one of claims 1 to 22, wherein X is CH2 or CO.

24. A composition according to any one of claims 1 to 23, wherein A is O, C 1-6 NH, NH or S substituted with alkyl.

25. A composition according to any one of claims 1 to 24, wherein A is O, NH or S.

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