C3a receptor antagonist compounds and their applications

Abstract

This invention provides novel C3a receptor antagonist compounds useful for preventing or improving itching by inhibiting the C3a receptor signaling pathway, and their applications. [Solution] The following general formula (I) The compound represented by JPEG2026067760000027.jpg63170 or a salt thereof.

Description

[Technical Field]

[0001] This invention relates to C3a receptor antagonist compounds and their uses. [Background technology]

[0002] Itching is a symptom not only seen in skin diseases such as atopic dermatitis, but also in internal organ diseases such as renal failure. Itching can also be triggered by dry skin, sunburn, and friction between the skin and clothing. Scratching due to itching physically damages the skin and can lead to further worsening of symptoms, so resolving itching contributes to the prevention or improvement of skin diseases. For example, it has been reported that in mice in which the claws on their hind limbs were trimmed to suppress physical damage to the skin caused by scratching, skin symptoms of atopic dermatitis were prevented or improved (Non-Patent Literature 1).

[0003] The sensation of itching in peripheral tissues such as the skin is transmitted to the brain by afferent sensory nerves that connect the periphery to the spinal cord's dorsal horn. The cell bodies of afferent sensory nerves are located in the dorsal root ganglia (DRG), and nerve fibers extend from the cell bodies to the peripheral tissues and the spinal cord's dorsal horn. Afferent sensory nerves receive sensations from the skin and transmit them to secondary neurons in the spinal cord's dorsal horn.

[0004] Itching-inducing substances trigger itching by binding to corresponding receptors. Examples of pruritic substances include histamine, serotonin, and chloroquine, while Th2 cytokines such as IL-4 and IL-13 have been reported as pruritic enhancers (sensitizers). Among these, the most representative chemical pruritic substance is histamine, primarily secreted by mast cells. Recently, it has been considered that histamine is primarily associated with some acute itching, and its involvement in many chronic itchy diseases is minimal (Non-Patent Literature 2). Therefore, antihistamines (H1 receptor antagonists) are widely used to suppress itching, but only a very limited number of itches can be adequately treated with antihistamines, and many itchy conditions are refractory itching that is difficult to alleviate with antihistamines. Here, antihistamines refer to H1 receptor antagonists such as diphenhydramine. For example, it has been reported that the treatment of atopic dermatitis and xerosis with antihistamines is insufficiently effective (Non-Patent Literature 3-4), and itching associated with many skin diseases such as atopic dermatitis and xerosis, as well as internal medicine diseases such as renal failure, is called intractable itching. The mechanisms of many intractable itches remain unclear, and there is a need to elucidate the mechanisms and develop new target molecules.

[0005] Recently, the applicant has discovered that TLQP-21, a bioactive peptide derived from the neurosecretory factor VGF (nerve growth factor inducible), induces itching, and that the C3a receptor to which TLQP-21 binds is a target for itching suppression. Itching can be suppressed by inhibiting the binding of TLQP-21 to the C3a receptor (Patent Document 1). This suppression of itching based on the inhibition of the C3a receptor signaling pathway is considered useful as a new technology for resolving itchy conditions that have not been effectively treated by conventional methods.

[0006] On the other hand, Patent Document 2 contains, for example, the following formula;

[0007] [ka]

[0008] (In the formula, X is an oxygen atom, a sulfur atom, NH, N(C) 1-3 (Alkyl) or CH2 is represented; Y represents a nitrogen atom or CH; Z represents N or CH, etc.) It has been reported that heterocyclic compounds represented by have agonist or antagonist activity at the C3a receptor. However, the compound described in Patent Document 2 is a compound containing guanidine, and Patent Document 2 does not describe heterocyclic compounds having aspartic acid, glutamic acid, serine, etc. as a basic skeleton. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] Japanese Patent Publication No. 2022-183095 [Patent Document 2] International Publication No. 2013 / 067578 [Non-patent literature]

[0010] [Non-Patent Document 1] Hashimoto Y et al. Life Sciences. 2004 Dec 31;76(7):783-94 [Non-Patent Document 2] Ikoma A et al. Nature Reviews Neuroscience. 2006 Jul;7(7):535-47 [Non-Patent Document 3] J Am Acad Dermatol. 2014 Jul; 71(1): 116-132 [Non-Patent Document 4] Future Oncol. 2018 Oct;14(24):2531-2541 [Overview of the project] [Problems that the invention aims to solve]

[0011] The present invention relates to providing a novel C3a receptor antagonist compound useful for preventing or improving itching by inhibiting the C3a receptor signaling pathway and its use.

Means for Solving the Problems

[0012] When the present inventor searched for an effective compound that inhibits the C3a receptor signaling pathway, it was found that the compound represented by the following general formula (I) has a C3a receptor antagonistic action and is useful for preventing or improving itching. The compound represented by the general formula (I) is a novel compound not described in the prior art documents and the like.

[0013] That is, the present invention relates to the following 1) to 5). 1) The following general formula (I)

[0014]

Chemical formula

[0015] (In the formula, X represents a carbon atom or a nitrogen atom; Y represents a carbon atom or a sulfur atom; R 1 and R 2 are the same or different and represent a hydrogen atom or a halogen atom; R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R 4 represents a hydrogen atom or -(CH2) m COOH; R 5 is -(CH2) n -CONH-R 6 , -(CH2) n -CON-R 6 (when forming a ring together with R 7 described later) or -(CH2) n -O-R 6 ; R 6 represents formula (II) or formula (III);

[0016] [ka]

[0017] R 7 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or -CONH2, or R 5 ga-(CH2) n -CON-R 6 When R 6 It may also form a 5-6 member nitrogen-containing saturated heterocycle with the nitrogen atom to which it is bonded; R 8 and R 9 These may be the same or different hydrogen atoms, halogen atoms, C1-C6 alkyl groups, -COOH, or -CONH2, or they may form a 5-6 membered cyclic amide with the carbon atom to which they are bonded; R 10 represents a hydrogen atom, -COOH, or -CONH2; m represents either 0 or 1; n represents an integer between 0 and 2. A compound represented by or a salt thereof. 2) A C3a receptor antagonist comprising a compound represented by the above general formula (I) or a salt thereof as an active ingredient. 3) An agent for preventing or improving itching, comprising a compound represented by the above general formula (I) or a salt thereof as an active ingredient. 4) A preventive or ameliorative agent for pruritic skin diseases exhibiting intractable itching, comprising a compound represented by the above general formula (I) or a salt thereof as an active ingredient. 5) A pharmaceutical composition containing a compound represented by the above general formula (I) or a salt thereof and a pharmaceutically acceptable carrier. [Effects of the Invention]

[0018] The present invention provides a compound represented by the above general formula (I) or a salt thereof that is useful as a C3a receptor antagonist. The compounds of the present invention have excellent C3a receptor antagonistic activity and are useful for the prevention or improvement of itchy and pruritic skin diseases. [Modes for carrying out the invention]

[0019] In this specification, "halogen atom" refers to fluorine, chlorine, bromine, and iodine atoms. The halogen atom is preferably a fluorine or chlorine atom.

[0020] In this specification, "C1-C6 alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, and the like. The C1-C6 alkyl group is preferably a C1-C3 alkyl group, and more preferably a methyl group.

[0021] In the compound represented by general formula (I) of the present invention, X represents a carbon atom or a nitrogen atom. X is preferably a nitrogen atom.

[0022] In the compound represented by general formula (I) of the present invention, Y represents a carbon atom or a sulfur atom. Y is preferably a carbon atom.

[0023] In the general formula (I) of the present invention, the combination of X and Y is preferably such that X is a carbon atom and Y is a sulfur atom, or X is a nitrogen atom and Y is a carbon atom. More preferably, X is a nitrogen atom and Y is a carbon atom.

[0024] In the compound represented by the general formula (I) of the present invention, R 1 and R 2 R represents the same or different hydrogen atom or halogen atom. 1 and R 2 R is preferably a hydrogen atom, a fluorine atom, or a chlorine atom, and more preferably a hydrogen atom or a fluorine atom. 1 and R 2 It is preferable that they are the same group.

[0025] In the compound represented by the general formula (I) of the present invention, R 3 R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.3 This is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.

[0026] In the compound represented by the general formula (I) of the present invention, R 4 is a hydrogen atom or -(CH2) m This represents COOH. Here, m is either 0 or 1. Preferably, m is 0. R 4 It is preferably -COOH.

[0027] In the compound represented by the general formula (I) of the present invention, R 5 ha-(CH2) n -CONH-R 6 ,-(CH2) n -CON-R 6 (R mentioned later) 7 (When forming a ring together with) or -(CH2) n -OR 6 This shows that n is an integer between 0 and 2. n is preferably 1 or 2, and more preferably 1. R 5 Preferably, -(CH2) n -CON-R 6 That is the case.

[0028] In the compound represented by the general formula (I) of the present invention, R 6 This represents equation (II) or equation (III).

[0029] [ka]

[0030] In the compound represented by the general formula (I) of the present invention, R 7 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or -CONH2, or R 5 ga-(CH2) n -CON-R 6 When R 6 Together with the nitrogen atom to which it is bonded, it forms a 5-6 member nitrogen-containing saturated heterocycle. R7 However, R 6 Examples of 5-6 member nitrogen-containing saturated heterocycles formed with the bonded nitrogen atom include pyrrolidine rings and piperidine rings. R 7 This is preferably a hydrogen atom or a piperidine ring.

[0031] In the compound represented by the general formula (I) of the present invention, R 8 and R 9 These atoms may be identical or distinct, each representing a hydrogen atom, a halogen atom, a C1-C6 alkyl group, -COOH, or -CONH2, or they may form a 5-6 membered cyclic amide with the carbon atom to which they are bonded. R 8 and R 9 However, examples of 5-6 membered cyclic amides formed with these atoms together include γ-lactams and δ-lactams. R 8 and R 9 Preferably, the group is the same or different hydrogen atom, fluorine atom, methyl group, -COOH, or -CONH2, and more preferably -CONH2. R 8 and R 9 Preferably, the combination is R 8 -CONH2, R 9 It is a hydrogen atom. R 8 The substitution position can be any position on the benzene ring. Preferably R 7 It is the ortho or para position.

[0032] In the compound represented by the general formula (I) of the present invention, R 10 R represents a hydrogen atom, -COOH, or -CONH2. 10 It is preferably -COOH.

[0033] In terms of C3a receptor antagonist activity, among the compounds of the present invention represented by general formula (I), preferred compounds are those in which X is a carbon atom, Y is a sulfur atom, and R 1 and R 2is the same or different and is a hydrogen atom or a halogen atom, R 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 4 is a hydrogen atom or -(CH2) m COOH, R 5 is -(CH2) n -CONH-R 6 、-(CH2) n -CON-R 6 (when forming a ring together with R 7 described later) or -(CH2) n -O-R 6 and R 6 represents formula (II) or formula (III), R 7 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or -CONH2, or R 5 is -(CH2) n -CON-R 6 and when R 6 may form a 5- to 6-membered nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which it is attached, R 8 and R 9 are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, -COOH, or -CONH2, or they may form a 5- to 6-membered cyclic amide together with the carbon atom to which they are attached, R 10 is -COOH, m is 0 or 1, and n is an integer of 0 to 2.

[0034] From the viewpoint of C3a receptor antagonism, in the compound of the present invention represented by the general formula (I), preferred compounds are those in which X is a nitrogen atom, Y is a carbon atom, R 1 and R 2 are the same or different and are a hydrogen atom or a halogen atom, R 3 is an alkyl group having 1 to 6 carbon atoms, R 4 is -(CH2) m COOH, R 5 is -(CH2) n -CON-R 6 (when forming a ring together with R 7 described later), and R 6 represents formula (II), R 7However, R 6 Together with the nitrogen atom to which it is bonded, it forms a 5-6 member nitrogen-containing saturated heterocycle, R 8 and R 9 A compound in which the atoms are identical or different, a hydrogen atom, -COOH, or -CONH2, m is 0 or 1, and n is an integer between 0 and 2.

[0035] In terms of C3a receptor antagonist activity, among the compounds of the present invention represented by general formula (I), a more preferred compound is one in which X is a carbon atom and Y is a sulfur atom, and R 1 and R 2 If R is the same or different hydrogen atom or halogen atom, 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 4 is a hydrogen atom or -(CH2) m COOH, R 5 ga-(CH2) n -CONH-R 6 ,-(CH2) n -CON-R 6 (R mentioned later) 7 (When forming a ring together with) or -(CH2) n -OR 6 And R 6 If equation (II) or equation (III) is shown, R 7 is a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms, or R 5 ga-(CH2) n -CON-R 6 When R 6 R may form a 5-6 member nitrogen-containing saturated heterocycle with the nitrogen atom to which it is bonded, 8 R is a hydrogen atom, -COOH, or -CONH2, 9 is a hydrogen atom or -CONH2, and R 10 It is a compound in which -COOH, m is 0 or 1, and n is 1 or 2.

[0036] In terms of C3a receptor antagonist activity, among the compounds of the present invention represented by general formula (I), a more preferred compound is one in which X is a nitrogen atom and Y is a carbon atom, and R 1 and R 2 is a halogen atom, R 3is an alkyl group having 1 to 6 carbon atoms, and R 4 ga-(CH2) m COOH, R 5 ga-(CH2) n -CON-R 6 (R mentioned later) 7 (When it forms a ring together with R) 6 This shows equation (II), and R 7 However, R 6 Together with the nitrogen atom to which it is bonded, it forms a 5-6 member nitrogen-containing saturated heterocycle, R 8 is -COOH or -CONH2, and R 9 It is a compound in which a hydrogen atom is m is 0 or 1 and n is 1 or 2.

[0037] Furthermore, in terms of C3a receptor antagonist activity, among the compounds of the present invention represented by general formula (I), preferred compounds are those in which X is a carbon atom and Y is a sulfur atom, or X is a nitrogen atom and Y is a carbon atom, and R 1 and R 2 If R is the same or different hydrogen atom or halogen atom, 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 4 is a hydrogen atom or -(CH2) m COOH, R 5 ga-(CH2) n -CONH-R 6 ,-(CH2) n -CON-R 6 (R mentioned later) 7 (When forming a ring together with) or -(CH2) n -OR 6 And R 6 If equation (II) or equation (III) is shown, R 7 is a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms, or R 5 ga-(CH2) n -CON-R 6 When R 6 R may form a 5-6 member nitrogen-containing saturated heterocycle with the nitrogen atom to which it is bonded, 8 and R 9 If R is the same or different hydrogen atom, -COOH, or -CONH2, 10It is a compound in which -COOH, m is 0 or 1, and n is 1 or 2.

[0038] Furthermore, in terms of C3a receptor antagonist activity, among the compounds of the present invention represented by general formula (I), more preferable compounds are those in which X is a carbon atom and Y is a sulfur atom, or X is a nitrogen atom and Y is a carbon atom, and R 1 and R 2 If R is the same or different hydrogen atom or halogen atom, 3 is an alkyl group having 1 to 6 carbon atoms, and R 4 ga-(CH2) m COOH, R 5 ga-(CH2) n -CON-R 6 (R mentioned later) 7 (When it forms a ring together with R) 6 This shows equation (II), and R 7 However, R 6 Together with the nitrogen atom to which it is bonded, it forms a 5-6 member nitrogen-containing saturated heterocycle, R 8 is -CONH2, and R 9 This is a compound in which is a hydrogen atom, m is 0, and n is 1.

[0039] Among the compounds represented by the general formula (I) of the present invention, the following compounds are particularly preferred. N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(4-carbamoylphenyl)-L-asparagine (N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(4-carbamoylphenyl)-L-asparagine) (compound 1), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoylphenyl)-L-asparagine (N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4-(3-carbamoylphenyl)-L-asparagine) (compound 2), (S)-3-(5-benzhydrylthiophene-2-carboxamido)-4-((3-carbamoylphenyl)amino)-4-oxobutanoic acid ((S)-3-(5-benzhydrylthiophene-2-carboxamido)-4-((3-carbamoylphenyl)amino)-4-oxobutanoic acid) (Compound 3), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(2-carbamoylphenyl)-L-asparagine (N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(2-carbamoylphenyl)-L-asparagine) (compound 4), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 5 -(3-carbamoylphenyl)-L-glutamine (N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 5 -(3-carbamoylphenyl)-L-glutamine) (compound 5), N-(5-benzhydrylthiophene-2-carbonyl)-O-(3-carbamoylphenyl)-L-serine (compound 6), N-(5-benzhydrylthiophene-2-carbonyl)-O-(3-carbamoylphenyl)-L-homoserine (compound 7), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4-(3-carbamoyl-2-fluorophenyl)-L-asparagine(Nyl)-L-asparagine)(compound 8), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoyl-4-fluorophenyl)-L-asparagine(Nyl)-L-asparagine)(compound 9), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoyl-4-methylphenyl)-L-asparagine(N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoyl-4-methylphenyl)-L-asparagine) (compound 10), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-oxoindolin-5-yl)-L-asparagine (N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-oxoisoindolin-5-yl)-L-asparagine) (compound 11), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)-L-asparagine (N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-L-asparagine) (compound 12), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carboxyphenyl)-L-asparagine (N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4-(3-carboxyphenyl)-L-asparagine) (compound 13), N-(5-benzhydrylthiophene-2-carbonyl)-O-(3-carboxyphenyl)-L-serine (compound 14) N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(5-carboxy-1H-pyrazole-3-yl)-L-asparagine (N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(5-carboxy-1H-pyrazole-3-yl)-L-asparagine) (compound 15), (S)-1-(3-(5-benzhydrylthiophene-2-carboxamido)-3-carboxypropagyl)indoline-6-carboxylic acid ((S)-1-(3-(5-benzhydrylthiophene-2-carboxamido)-3-carboxypropanoyl)indoline-6-carboxylic acid) (Compound 16) (S)-1-(3-(5-benzhydrylthiophene-2-carboxamido)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid ) (compound 17), 1-(3-(5-benzhydrylthiophene-2-carboxamido)propanoyl)-1,2,3,4-1,2,3,4-tetrahydroquinoline-7-carboxylic acid) (Compound 18), (S)-1-(3-(5-benzhydryl-3-methylthiophene-2-carboxamido)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid ((S)-1-(3-(5-benzhydryl-3-methylthiophene-2-carboxamido)-3-carboxypropanoyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid) (Compound 19) (S)-1-(3-(5-(bis(4-fluorophenyl)methyl)thiophene-2-carboxamido)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid ((S)-1-(3-(5-(bis(4-fluorophenyl)methyl)thiophene-2-carboxamido)-3-carboxypropanoyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid) (Compound 20), (S)-1-(3-(5-(bis(4-chlorophenyl)methyl)thiophene-2-carboxamido)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid) (Compound 21), (S)-1-(3-(5-(bis(4-fluorophenyl)methyl)thiophene-2-carboxamido)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid) (Compound 22), (S)-2-(5-benzhydryl-3-methylthiophene-2-carboxamido)-4-(7-carbamoyl-3,4-dihydroquinolin-1(2H)-yl)-4-oxobutanoic acid (Compound 23), (S)-2-(5-(bis(4-fluorophenyl)methyl)-3-methylthiophene-2-carboxamido)-4-(7-carbamoyl-3,4-dihydroquinolin-1(2H)-yl)-4-oxobutanoic acid (Compound 24), (S)-1-(3-(1-(bis(4-fluorophenyl)methyl)-4-methyl-1H-pyrrole-3-carboxamido)-3-carboxypropanoyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (Compound 25), (S)-2-(1-(bis(4-fluorophenyl)methyl)-4-methyl-1H-pyrrole-3-carboxamido)-4-(7-carbamoyl-3,4-dihydroquinolin-1(2H)-yl)-4-oxobutanoic acid (Compound 26).

[0040] In this specification, the structural formula of a compound may represent a certain isomer for convenience, but the present invention includes all geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, and other isomers and isomer mixtures generated due to the structure of the compound, and is not limited to the description of the formula for convenience, and may be either one of the isomers or a mixture. Therefore, when the compound represented by the general formula (I) of the present invention (hereinafter also referred to as "the compound of the present invention") has an asymmetric carbon atom in the molecule and there are optically active forms and racemates, it is not limited in the present invention, and all are included.

[0041] The present invention includes salts of the compounds of the present invention. The salts are not particularly limited as long as they are pharmaceutically acceptable salts. For example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and acid addition salts with organic acids such as formate, acetate, trichloroacetate, trifluoroacetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, aspartate or glutamate, and salts with inorganic bases such as sodium salt, potassium salt, magnesium salt, calcium salt, aluminum salt, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and ammonium salts, etc. are included. Preferably, it is a sodium salt.

[0042] The present invention also includes prodrugs of the compounds of the present invention or their salts. A prodrug is a compound that is converted into the compound of the present invention or its salt by reactions (oxidation, reduction, hydrolysis, etc.) by enzymes, gastric acid, etc. under physiological conditions in the living body. For example, esters produced by reaction with appropriate alcohols, amides produced by reaction with appropriate amines, etc. are included, but are not particularly limited.

[0043] The present invention may include, but is not limited to, hydrates, various solvates, and crystalline polymorphs of the compound or salt thereof, and may include a single crystalline form or a mixture of crystalline forms. Furthermore, the present invention includes isotopes (e.g., 2 H, 3 H, 14 C, 35 S, 125 This also includes compounds labeled with labels such as I.

[0044] The compounds or salts thereof of the present invention can be produced, for example, by the following synthesis schemes 1 to 3, and can be appropriately modified depending on the type of substituent, etc., and produced by any suitable method. The starting materials for each step can be commercially available or produced by methods known in the art.

[0045] First, we will explain how to produce compound (5), which is an intermediate in the synthesis of the compound of the present invention.

[0046] [ka]

[0047] (In the formula, L 1 is C 1-6 This represents an alkyl group, and the other symbols are equivalent to those in general formula (I).

[0048] (Step a) This step involves obtaining compound (3) from compound (1) and a benzophenone derivative (2) by an addition reaction. This step can be carried out in a solvent such as ethers (tetrahydrofuran (THF), diethyl ether, dioxane, t-butyl methyl ether, diglym, etc.), ketones (acetone, methyl ethyl ketone, etc.), or aprotic polar solvents (N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoramide, etc.) in the presence of a base such as sodium hydride, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, or lithium diisopropylamide (LDA). The reaction temperature is preferably -78°C to room temperature, and the reaction time is preferably 1 hour to 24 hours.

[0049] (Step b) This step involves obtaining compound (4) by the reduction reaction of compound (3). The reduction can be carried out by commonly known methods, for example, using a reducing agent such as triethylsilane or triisopropylsilane under acidic conditions such as hydrochloric acid, trifluoroacetic acid, sulfuric acid, or boron trifluoride. The solvent is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, etc.). The reaction temperature is 0°C to room temperature, and the reaction time is 1 hour to 24 hours.

[0050] (Step c) This step involves obtaining compound (5) from compound (4) by deprotection through hydrolysis. Hydrolysis can be carried out by commonly known methods. For example, compound (4) can be dissolved in a solvent such as alcohols (methanol, ethanol, etc.) or ethers (tetrahydrofuran (THF), dioxane, etc.), and then aqueous solutions of alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide are added. The reaction is preferably carried out at 0°C under reflux for 1 hour to 24 hours.

[0051] Furthermore, compound (5), which is an intermediate in the synthesis of the compound of the present invention, can be produced by the following manufacturing method.

[0052] [ka]

[0053] (In the formula, L 1 is C 1-6 It shows an alkyl group, L 2 The symbol indicates a halogen group, and the other symbols are equivalent to those in general formula (I).

[0054] (Step d) This step involves halogenating the hydroxyl group of compound (6) to obtain compound (7). The halogenation reaction is carried out using halogenating agents such as thionyl chloride, oxalyl chloride, and phosphorus tribromide. A solvent may be added as needed, and is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, etc.). The reaction temperature is preferably 0°C to 100°C, and the reaction time is preferably 0.5 hours to 24 hours.

[0055] (Step e) This step involves obtaining compound (4) from compound (7) and compound (8) by a nucleophilic substitution reaction. The nucleophilic substitution reaction can be carried out in a solvent such as ethers (tetrahydrofuran (THF), diethyl ether, dioxane, t-butyl methyl ether, diglym, etc.) or aprotic polar solvents (N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoramide, etc.) in the presence of a metal salt base such as sodium hydride, sodium hydroxide, potassium hydroxide, or potassium tert-butoxide. The reaction temperature is preferably -78 °C to room temperature, and the reaction time is preferably 30 minutes to 24 hours.

[0056] Next, in step c, compound (5) is obtained from compound (4) by deprotection through hydrolysis. Compound (5) can be isolated and purified by known separation and purification methods, or it can be subjected to the next step without isolation and purification.

[0057] Next, in general formula (I), R 5 is -(CH2) n -CONH-R 6 The production method of the compound (I-1) which is will be described. <Synthesis Scheme 1>

[0058]

Chemical Formula

[0059] (In the formula, L 3 represents a hydrogen atom or a carboxylic acid ester, and the other symbols are synonymous with general formula (I).)

[0060] (Step f) This step is a step of obtaining the compound (10) by a condensation reaction of the compound (9) and various amines. The condensation reaction can be carried out by mixing the compound (9), the compound (10), and a condensing agent in a solvent. Examples of the condensing agent include 1,3-dicyclohexylcarbodiimide (DCC), isobutyl chloroformate, pivalic acid chloride, isovaleric acid chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), 1-cyclohexyl-3-morpholinoethylcarbodiimide, 1-cyclohexyl-3-(4-diethylaminocyclohexyl)carboximide, N,N'-carbonyldiimidazole, 1H-benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2-chloro-1,3-dimethylimidazolinium chloride, isobutyl chloroformate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), and the like. Furthermore, activators or bases that promote the condensation reaction may be added. Examples of activators include p-nitrophenol, hydroxysuccinimide, hydroxyphthalimide, 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, and 2-hydroxyimino-2-cyanoethyl acetate. Examples of bases include organic amines (triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylmorpholine, etc.), imidazole, N-methylimidazole, alkali metal salts, and metal hydrides. The solvent used in this process is not particularly limited as long as it does not hinder the reaction, and examples include hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, 1,2-dichloroethane, etc.), nitriles (acetonitrile, etc.), ethers (tetrahydrofuran (THF), diethyl ether, dioxane, t-butyl methyl ether, diglym, etc.), alcohols (methanol, ethanol, etc.), aprotic polar solvents (N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoramide, etc.), water, or mixed solvents thereof. The reaction temperature for condensation reactions is between 0°C and room temperature, and the reaction time is between 1 hour and 24 hours.

[0061] (Step g) This step involves deprotecting compound (10) to obtain amine (11). Depending on the type of protecting group, deprotection can be carried out by commonly known methods using deprotecting agents such as hydrochloric acid, trifluoroacetic acid, acetic acid, or sulfuric acid. The solvent is not particularly limited as long as it does not affect the reaction, and the solvents mentioned above can be used. In addition, a catalyst such as palladium carbon may be added as needed. The reaction temperature is 0°C to room temperature, and the reaction time is 1 hour to 24 hours.

[0062] (Process h) This step involves condensing compound (5) and amine (11) to obtain the amide compound (12). This step is performed using the same method as in step f.

[0063] (Process i) This step involves obtaining compound (I-1) from the amide (12) by deprotection through hydrolysis under basic conditions. This step uses the same method as in step c.

[0064] Next, in general formula (I), R 5 ga-(CH2) n -OR 6 The method for producing compound (I-2) is described below. <Synthesis Scheme 2>

[0065] [ka]

[0066] (The symbols in the formula are equivalent to those in general formula (I).)

[0067] (Process j) This process involves obtaining the ether (14) from compound (13) and boronic acid by Chan-Lam-Evans coupling, or obtaining the ether (14) from compound (13) and 3-hydroxybenzamide by the Mitsunobu reaction. For the Chan-Lam-Evans coupling reaction, copper catalysts such as copper(II) acetate can be used. Examples of bases include organic amines (triethylamine, N,N-diisopropylethylamine (DIPEA)), pyridine, lutidine, colidine, and 4-dimethylaminopyridine. The reaction temperature is preferably room temperature, and the reaction time is preferably 24 hours to several days.

[0068] Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD) and diisopropyl azodicarboxylate (DIAD). Examples of phosphine reagents include triphenylphosphine, tributylphosphine, and trifurylphosphine. The reaction temperature for the Mitsunobu reaction is 0°C or higher under reflux, and the reaction time is 1 hour to 24 hours.

[0069] The solvent used in this process is not particularly limited as long as it does not hinder the reaction, and examples include hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (tetrahydrofuran (THF), diethyl ether, dioxane, t-butyl methyl ether, diglym, etc.), aprotic polar solvents (N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoramide, etc.), or mixed solvents thereof.

[0070] (Process k) This step involves deprotecting the protecting group of ether (14) to obtain amine (15). This step is performed using the same method as in step g. The amine (15) obtained by this process can be isolated and purified by known separation and purification methods, or it can be used in the next process without isolation and purification.

[0071] (Step l) This step involves condensing compound (5) and amine (15) to obtain the amide compound (16). This step is performed using the same method as in step f.

[0072] (Process m) This step involves obtaining compound (I-2) from the amide (16) by deprotection through hydrolysis under basic conditions. The same method as in step c is used for this step.

[0073] Next, we will explain how to produce compound (I-3), which has an amide cyclized form as its basic skeleton in general formula (I). <Synthesis Scheme 3>

[0074] [ka]

[0075] (In the formula, l represents either 0 or 1, and the other symbols are equivalent to those in general formula (I).)

[0076] (Process o) This step involves obtaining compound (18) through a condensation reaction between compound (17) and various amines. This step is carried out using the same method as in step f.

[0077] (Process p) This step involves deprotecting compound (18) to obtain amine (19). This step is performed using the same method as in step g. The amine (19) obtained by this process can be isolated and purified by known separation and purification methods, or it can be used in the next process without isolation and purification.

[0078] (Process q) This step involves condensing compound (5) and amine (19) to obtain the amide compound (20). This step is performed using the same method as in step f.

[0079] (Process r) This step involves obtaining compound (I-3) from the amide (20) by deprotection through hydrolysis under basic conditions. The same method as in step c is used for this step.

[0080] The compounds of the present invention obtained in this manner can be isolated and purified by known separation and purification methods such as concentration, solvent extraction, filtration, recrystallization, and column chromatography.

[0081] As shown in the examples below, the compounds of the present invention exhibit antagonistic activity against the complement factor C3a receptor, a GPCR-type receptor present on the cell membrane. It is known that the C3a receptor accepts not only C3a produced in conjunction with complement system activation, but also TLQP-21. TLQP-21 is one of the bioactive peptides derived from the neurosecretory factor VGF (nerve growth factor inducible). The applicant has shown that when TLQP-21 is injected into the posterior neck skin of healthy mice, scratching behavior is induced in the mice, indicating that TLQP-21 induces itching. Furthermore, it has been shown that the C3a receptor to which TLQP-21 binds is a target for itching suppression, and that itching and pruritic skin diseases can be prevented or improved by inhibiting the binding of TLQP-21 to the C3a receptor (Patent Document 1). Therefore, the compounds or salts thereof of the present invention are useful for inhibiting the C3a receptor signaling pathway, preventing or improving itching, and preventing or improving pruritic skin diseases. In other words, the compounds of the present invention or salts thereof can serve as C3a receptor antagonists, preventive or ameliorative agents for itching, and preventive or ameliorative agents for pruritic skin diseases, and can also be used to manufacture these. Furthermore, the compounds of the present invention can be applied to animals, including humans, for the purpose of inhibiting the C3a receptor signaling pathway, preventing or ameliorating itching, and preventing or ameliorating pruritic skin diseases.

[0082] Here, “use” can be in humans or non-human animals, and may be therapeutic or non-therapeutic. “Non-therapeutic” is a concept that does not include medical procedures, that is, methods that do not include surgery, treatment, or diagnosis of humans, and more specifically, methods that do not include surgery, treatment, or diagnosis performed on humans by a physician or a person under the direction of a physician.

[0083] In this specification, "C3a receptor antagonism" means inhibiting the action of TLQP-21 via the C3a receptor, and includes, for example, inhibiting the C3a receptor signaling pathway. "Itching" is a subjective sensation, and its cause is not particularly limited. Itching can occur in a wide area or in a specific area, such as the whole body, scalp, face, back, arms, back of the hands, fingers, or legs. The present invention is suitable for preventing or improving intractable itching. "Intractable itching" refers to itching that cannot be resolved with antihistamines (H1 receptor antagonists). Examples of intractable itching include itching in diseases such as atopic dermatitis, xerosis (including senile xerosis, asteatotic dermatitis, and asteatotic eczema), contact dermatitis, seborrheic dermatitis, nummular eczema, psoriasis, prurigo, nodular prurigo, chronic prurigo, bullous pemphigoid, dermatomyositis, pruritus (for example, pruritus associated with chronic liver disease, pruritus associated with cholestasis, pruritus associated with chronic kidney disease and its dialysis treatment [hemodialysis or peritoneal dialysis], senile pruritus, winter pruritus, etc.), and malignant neoplasms. In particular, itching in atopic dermatitis, itching in xerosis, itching in nodular prurigo, or pruritus associated with cholestasis are preferred.

[0084] "Pruritic skin diseases" refers to skin diseases accompanied by itching. Examples include urticaria, atopic dermatitis, xerosis (including senile xerosis, asteatotic dermatitis, and asteatotic eczema), contact dermatitis, seborrheic dermatitis, nummular eczema, psoriasis, prurigo, nodular prurigo, chronic prurigo, bullous pemphigoid, and dermatomyositis. Of these, all skin diseases except urticaria fall under the category of skin diseases accompanied by intractable itching. The present invention is suitable for the aforementioned skin diseases accompanied by intractable itching. The pruritic skin diseases are preferably atopic dermatitis, xerosis, or nodular prurigo.

[0085] Furthermore, in this specification, "prevention" means preventing or delaying the onset of a disease or symptom in an individual, or reducing the risk of an individual developing a disease or symptom. "Improvement" means a rise in the disease, symptoms, or condition, or a reversal, prevention, or delay in the progression of the disease, or the worsening of the disease, symptoms, or condition.

[0086] The compounds of the present invention or salts thereof can be used in pharmaceuticals (including quasi-drugs, hereinafter the same) or cosmetics for preventing or improving itching, as they inhibit the C3a receptor signaling pathway.

[0087] When using the compound or salt thereof of the present invention as a pharmaceutical, various forms of administration can be adopted depending on the purpose of treatment. These forms of administration include oral administration and parenteral administration. Dosage forms for oral administration include tablets, capsules, granules, powders, and syrups. Dosage forms for parenteral administration include various preparations for topical application, transdermal, transmucosal, nasal, enteral, injection, suppositories, inhalation, and patch application. In the case of parenteral administration, the preferred preparation form is a topical preparation, specifically in the form of ointment, emulsion, cream, lotion, gel, and aerosol.

[0088] Preferred examples of cosmetics containing the compound of the present invention or a salt thereof include cosmetics for the face and body (e.g., lotions, gels, creams, masks, etc.), makeup cosmetics, and cleansers for the face or body.

[0089] Such pharmaceutical and cosmetic formulations may also be in the form of pharmaceutical or cosmetic compositions in which the compound of the present invention is combined, as necessary, with a pharmaceutically or cosmetically acceptable carrier, other active ingredients, pharmacoactive ingredients, cosmetic ingredients, etc., and these can be manufactured according to conventional methods. Examples of pharmaceutically or cosmetically acceptable carriers include excipients, diluents, binders, disintegrants, coatings, solubilizers, lubricants, gliding agents, solubilizers, lubrication aids, lubricants, plasticizers, film-forming agents, various oils, surfactants, gelling agents, pH buffers, isotonic agents, preservatives, antioxidants, solvents, dispersants, chelating agents, thickeners, stabilizers, pH adjusters, flavoring agents, sweeteners, colorants, and fragrances. Other active ingredients, medicinal ingredients, and cosmetic ingredients include, for example, plant extracts, disinfectants, moisturizers, anti-inflammatory agents, antibacterial agents, keratolytic agents, UV absorbers, cooling agents, anti-seborrheic agents, cleansing agents, and makeup ingredients.

[0090] The content of the compound of the present invention or its salt in the above-mentioned formulation varies depending on the form of the formulation and cannot be stated in general terms, but for example, based on the total amount of the formulation, it is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, and also preferably 1.2% by mass or less, and more preferably 0.6% by mass or less. Furthermore, 0.01 to 1.2% by mass is preferred, and 0.05 to 0.6% by mass is more preferred.

[0091] The dosage or amount used of the compound or salt thereof of the present invention may be an amount sufficient to achieve the effects of the present invention. The dosage or amount used may vary depending on the species, weight, sex, age, condition, or other factors of the subject, but in the case of oral administration such as tablets or capsules, the dosage per adult (60 kg) is preferably 0.01 mg or more, more preferably 0.1 mg or more, and preferably 100 mg or less, more preferably 10 mg or less. Furthermore, 0.01 mg to 100 mg is preferred, and 0.1 mg to 10 mg is more preferred. In the present invention, such an amount may be administered or used repeatedly and continuously for one day or more, preferably seven days or more, more preferably 14 days or more, and even more preferably 42 days or more, divided into one to several doses per day.

[0092] Targets for administering or using the compounds or salts thereof of the present invention include humans and non-human animals that require or desire inhibition of the C3a receptor signaling pathway, prevention or improvement of itching, or prevention or improvement of pruritic skin diseases. Specifically, this includes humans and non-human animals that have intractable itching or suffer from pruritic skin diseases. Examples of non-human animals include great apes, other primates, and non-human mammals such as Carnivora. Furthermore, the site on which the compound or salt thereof of the present invention is administered or used is not particularly limited, as long as it is a site where itching is felt, in the case of parenteral preparations such as topical skin preparations.

[0093] With regard to the embodiments described above, the present invention further discloses the following aspects.

[0094] <1> The following general formula (I)

[0095] [ka]

[0096] (In the formula, X represents a carbon atom or a nitrogen atom; Y represents a carbon atom or a sulfur atom; R 1 and R 2 These represent the same or different hydrogen atoms or halogen atoms; R 3 This represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R 4 is a hydrogen atom or -(CH2) m Show COOH; R 5 ha-(CH2) n -CONH-R 6 ,-(CH2) n -CON-R 6 (R mentioned later) 7 (When forming a ring together with) or -(CH2) n -OR 6 Show: R 6 This represents equation (II) or equation (III);

[0097] [ka]

[0098] R 7 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or -CONH2, or R 5 ga-(CH2) n -CON-R 6 When R 6 It may also form a 5-6 member nitrogen-containing saturated heterocycle with the nitrogen atom to which it is bonded; R 8 and R 9 These may be the same or different hydrogen atoms, halogen atoms, C1-C6 alkyl groups, -COOH, or -CONH2, or they may form a 5-6 membered cyclic amide with the carbon atom to which they are bonded; R 10represents a hydrogen atom, -COOH, or -CONH2; m represents either 0 or 1; n represents an integer between 0 and 2. A compound represented by or a salt thereof.

[0099] <2> X is preferably a nitrogen atom. <1> The compounds or salts thereof described below. <3> Y is preferably a carbon atom. <1> or <2> The compounds or salts thereof described below. <4> Preferably, X and Y are either a carbon atom and Y is a sulfur atom, or X is a nitrogen atom and Y is a carbon atom, more preferably X is a nitrogen atom and Y is a carbon atom. <1> The compounds or salts thereof described below. <5> R 1 and R 2 However, it is preferably a hydrogen atom, a fluorine atom, or a chlorine atom, and more preferably a hydrogen atom or a fluorine atom. <1> ~ <4> A compound or salt thereof as described in any of the following. <6> R 3 However, it is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom. <1> ~ <5> A compound or salt thereof as described in any of the following. <7> R 4 However, preferably -(CH2) m COOH (where m is 0 or 1), and more preferably -COOH. <1> ~ <6> A compound or salt thereof as described in any of the following. <8> R 5 However, preferably -(CH2) n -CON-R 6 (where n is an integer between 0 and 2), and more preferably -(CH2) n -CON-R 6 (Here, n is either 1 or 2) <1> ~ <7> A compound or salt thereof as described in any of the following. <9> R 7 However, R 6 The 5-6 member nitrogen-containing saturated heterocycle formed with the bonded nitrogen atom is preferably a pyrrolidine ring or a piperidine ring. <1> ~ <8> A compound or salt thereof as described in any of the following. <10> R 8 and R 9 However, preferably they are the same or different hydrogen atom, fluorine atom, methyl group, -COOH, or -CONH2, and more preferably -CONH2. <1> ~ <9> A compound or salt thereof as described in any of the following. <11> R 8 The substitution position is preferably R 7 It is the ortho or para position. <1> ~ <10> A compound or salt thereof as described in any of the following. <12> R 10 However, it is preferably -COOH. <1> ~ <11> A compound or salt thereof as described in any of the following.

[0100] <13> X is a carbon atom, Y is a sulfur atom, and R 1 and R 2 If R is the same or different hydrogen atom or halogen atom, 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 4 is a hydrogen atom or -(CH2) m COOH, R 5 ga-(CH2) n -CONH-R 6 ,-(CH2) n -CON-R 6 (R mentioned later) 7 (When forming a ring together with) or -(CH2) n -OR 6 And R 6 If equation (II) or equation (III) is shown, R 7 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or -CONH2, or R 5 ga-(CH2) n -CON-R 6 When R 6 R may form a 5-6 member nitrogen-containing saturated heterocycle with the nitrogen atom to which it is bonded, 8 and R 9 These may be the same or different hydrogen atoms, halogen atoms, C1-C6 alkyl groups, -COOH, or -CONH2, or they may form a 5-6 membered cyclic amide together with the carbon atom to which they are bonded, R 10The expression is -COOH, m is 0 or 1, and n is an integer between 0 and 2. <1> The compounds or salts thereof described below. <14> X is a nitrogen atom, Y is a carbon atom, and R 1 and R 2 If R is the same or different hydrogen atom or halogen atom, 3 is an alkyl group having 1 to 6 carbon atoms, and R 4 ga-(CH2) m COOH, R 5 ga-(CH2) n -CON-R 6 (R mentioned later) 7 (When it forms a ring together with R) 6 This shows equation (II), and R 7 However, R 6 Together with the nitrogen atom to which it is bonded, it forms a 5-6 member nitrogen-containing saturated heterocycle, R 8 and R 9 The atoms are identical or different, being hydrogen atoms, -COOH, or -CONH2, m is 0 or 1, and n is an integer between 0 and 2. <1> The compounds or salts thereof described below. <15> X is a carbon atom and Y is a sulfur atom, or X is a nitrogen atom and Y is a carbon atom, R 1 and R 2 If R is the same or different hydrogen atom or halogen atom, 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 4 is a hydrogen atom or -(CH2) m COOH R 5 ga-(CH2) n -CONH-R 6 ,-(CH2) n -CON-R 6 (R mentioned later) 7 (When forming a ring together with) or -(CH2) n -OR 6 And R 6 If equation (II) or equation (III), then R 7 is a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms, or R 5 ga-(CH2) n -CON-R 6 When R 6R may form a 5-6 member nitrogen-containing saturated heterocycle with the nitrogen atom to which it is bonded, 8 and R 9 These are identical or different hydrogen atoms, -COOH, or -CONH2, R 10 is -COOH, m is 0 or 1, and n is 1 or 2. <1> The compounds or salts thereof described below. <16> X is a carbon atom and Y is a sulfur atom, R 1 and R 2 If R is the same or different hydrogen atom or halogen atom, 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 4 is a hydrogen atom or -(CH2) m COOH, R 5 ga-(CH2) n -CONH-R 6 ,-(CH2) n -CON-R 6 (R mentioned later) 7 (When forming a ring together with) or -(CH2) n -OR 6 And R 6 If equation (II) or equation (III) is shown, R 7 is a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms, or R 5 ga-(CH2) n -CON-R 6 When R 6 R may form a 5-6 member nitrogen-containing saturated heterocycle with the nitrogen atom to which it is bonded, 8 R is a hydrogen atom, -COOH, or -CONH2, 9 is a hydrogen atom or -CONH2, and R 10 is -COOH, m is 0 or 1, and n is 1 or 2. <1> The compounds or salts thereof described below. <17> X is a nitrogen atom and Y is a carbon atom, R 1 and R 2 is a halogen atom, R 3 is an alkyl group having 1 to 6 carbon atoms, and R 4 ga-(CH2) m COOH, R 5 ga-(CH2) n-CON-R 6 (R mentioned later) 7 (When it forms a ring together with R) 6 This shows equation (II), and R 7 However, R 6 Together with the nitrogen atom to which it is bonded, it forms a 5-6 member nitrogen-containing saturated heterocycle, R 8 is -COOH or -CONH2, and R 9 is a hydrogen atom, m is 0 or 1, and n is 1 or 2. <1> The compounds or salts thereof described below. <18> A compound or salt thereof selected from the following. N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(4-carbamoylphenyl)-L-asparagine (compound 1), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoylphenyl)-L-asparagine (compound 2), (S)-3-(5-benzhydrylthiophene-2-carboxamide)-4-((3-carbamoylphenyl)amino)-4-oxobutanoic acid (compound 3), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(2-carbamoylphenyl)-L-asparagine (compound 4), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 5 -(3-carbamoylphenyl)-L-glutamine (compound 5), N-(5-benzhydrylthiophene-2-carbonyl)-O-(3-carbamoylphenyl)-L-serine (compound 6), N-(5-benzhydrylthiophene-2-carbonyl)-O-(3-carbamoylphenyl)-L-homoserine (compound 7), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoyl-2-fluorophenyl)-L-asparagine (compound 8), N2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoyl-4-fluorophenyl)-L-asparagine (compound 9), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoyl-4-methylphenyl)-L-asparagine (compound 10), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-oxoindolin-5-yl)-L-asparagine (compound 11), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)-L-asparagine (compound 12), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carboxyphenyl)-L-asparagine (compound 13), N-(5-benzhydrylthiophene-2-carbonyl)-O-(3-carboxyphenyl)-L-serine (compound 14), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(5-carboxy-1H-pyrazole-3-yl)-L-asparagine (compound 15), (S)-1-(3-(5-benzhydrylthiophene-2-carboxamide)-3-carboxypropagyl)-indoline-6-carboxylic acid (compound 16), (S)-1-(3-(5-benzhydrylthiophene-2-carboxamide)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 17), 1-(3-(5-benzhydrylthiophene-2-carboxamide)propanoyl)-1,2,3,4-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 18), (S)-1-(3-(5-benzhydryl-3-methylthiophene-2-carboxamide)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 19), (S)-1-(3-(5-(bis(4-fluorophenyl)methyl)thiophene-2-carboxamide)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 20), (S)-1-(3-(5-(bis(4-chlorophenyl)methyl)thiophene-2-carboxamide)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 21), (S)-1-(3-(5-(bis(4-fluorophenyl)methyl)thiophene-2-carboxamide)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 22), (S)-2-(5-benzhydryl-3-methylthiophene-2-carboxamide)-4-(7-carbamoyl-3,4-dihydroquinoline-1(2H)-yl)-4-oxobutanoic acid (compound 23), (S)-2-(5-(bis(4-fluorophenyl)methyl)-3-methylthiophen-2-carboxamide)-4-(7-carbamoyl-3,4-dihydroquinoline-1(2H)-yl)-4-oxobutanoic acid (compound 24), (S)-1-(3-(1-(bis(4-fluorophenyl)methyl)-4-methyl-1H-pyrrole-3-carboxamide)-3-carboxypropanoyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 25), (S)-2-(1-(bis(4-fluorophenyl)methyl)-4-methyl-1H-pyrrole-3-carboxamide)-4-(7-carbamoyl-3,4-dihydroquinoline-1(2H)-yl)-4-oxobutanoic acid (compound 26).

[0101] <19> <1> ~ <18> A C3a receptor antagonist comprising any of the compounds or salts thereof described in one of the above as an active ingredient. <20> <1> ~ <18> An agent for preventing or improving itching, comprising any of the compounds or salts thereof described in the above as an active ingredient. <21> The itching is preferably intractable itching, more preferably itching in atopic dermatitis, xerosis, contact dermatitis, seborrheic dermatitis, nummular eczema, psoriasis, prurigo, nodular prurigo, chronic prurigo, bullous pemphigoid, dermatomyositis, pruritus, or malignant neoplasms, and even more preferably itching in atopic dermatitis, itching in xerosis, itching in nodular prurigo, or pruritus associated with cholestasis. <20> An agent for preventing or improving itching as described above. <22> <1> ~ <18> An agent for preventing or improving pruritic skin diseases exhibiting intractable itching, comprising any of the compounds or salts thereof described in the above as an active ingredient. <23> The pruritic skin disease is preferably atopic dermatitis, xerosis, contact dermatitis, seborrheic dermatitis, nummular eczema, psoriasis, prurigo, nodular prurigo, chronic prurigo, bullous pemphigoid, or dermatomyositis, and more preferably atopic dermatitis, xerosis, or nodular prurigo. <22> A preventive or ameliorative agent for pruritic skin diseases exhibiting intractable itching, as described above. <24> <1> ~ <18> A pharmaceutical composition comprising a compound or salt thereof as described in any of the above and a pharmaceutically acceptable carrier. [Examples]

[0102] All reagents and solvents were used as purchased from various vendors. NMR spectra were measured using a Bruker Avance III 600 MHz or Bruker Avance 400 MHz NMR spectrum analyzer. 1 1H NMR and 13The chemical shift (δ) of 13C NMR is expressed in ppm relative to the tetramethylsilane (TMS) or residual solvent peak. Mass spectra (MS) were measured using TripleQuad4500, and high-performance resolved mass spectra (HRMS) were measured using XR500. Silica gel column chromatography was performed using a Universal column (Yamazen, Premium) and the solvent system indicated according to standard procedures. Analytical thin-layer chromatography (TLC) was performed on pre-coated glass silica gel plates (Supelco TLC Silica gel 60 F254). Visualization of developed TLCs was performed by UV absorbance (254 nm) or phosphomolybdate staining. Unless otherwise specified, purity analysis was performed by dissolving each sample in 1,000 ppm and then analyzing it by high-performance liquid chromatography (HPLC, Agilent) under the following conditions.

[0103] Column: L-coumn 2 ODS (CERI, 3.0×50 mm, 2 μm) Injection volume: 5 μL Solvents: A: 0.1% trifluoroacetic acid (TFA) aqueous solution (aq.) B: Acetonitrile (MeCN) B (5%, 0 min.) → B (5%, 1 min.) → B (100%, 10 min.) → B (100%, 12 min.) Flow rate: 1 mL / min. Temperature: 40℃ Detection: UV (254 nm)

[0104] General procedure 1: Addition reaction To an ester (1.0 eq.), tetrahydrofuran (THF) (3 mL / mmol) was added under an argon atmosphere. Then, 2M lithium diisopropylamide (LDA) (THF solution) (1.07 eq.) was added at -78°C and the mixture was stirred for 15 minutes at -78°C. Next, a solution of ketone (1.0 eq.) added to THF was added to the reaction solution, and the mixture was stirred overnight while gradually increasing the temperature. After confirming the completion of the reaction by TLC, the mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. After washing with saturated brine, the mixture was dried over anhydrous magnesium sulfate (MgSO4). After Kiriyama filtration, the organic layer was concentrated. The residue was purified by silica gel column chromatography to obtain the compound.

[0105] General procedure 2: Reduction reaction Under an argon atmosphere, ester (1.0 eq.) was mixed with dichloromethane (4 mL / mmol), triethylsilane (1.1 eq.), and TFA (2.2 eq.), and the mixture was stirred at room temperature for 1-2 hours. After confirming the completion of the reaction by TLC, the mixture was quenched with saturated sodium bicarbonate aqueous solution and extracted with chloroform. After washing with saturated brine, the mixture was dried over anhydrous magnesium sulfate (MgSO4). After Kiriyama filtration, the organic layer was concentrated. The residue was purified by silica gel column chromatography to obtain the compound.

[0106] General procedure 3: Condensation reaction (i) A carboxylic acid (1.0 eq.) was dissolved in DMF (2.5 mL / mmol) at room temperature under an argon atmosphere. Then, under ice cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl) (1.5 eq.), 1-hydroxybenzotriazole monohydrate (HOBt·H2O) (1.5 eq.), and amine (1.1 eq.) were added, and the mixture was stirred overnight while gradually raising the temperature to room temperature. After confirming the completion of the reaction by TLC, saturated sodium bicarbonate aqueous solution was added. After extraction with ethyl acetate, the organic layer was washed with brine. The organic layer was collected, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound.

[0107] General procedure 4: Condensation reaction (ii) A carboxylic acid (1.0 eq.) was dissolved in DMF (4 mL / mmol) under an argon atmosphere. Then, under ice cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl) (1.5 eq.), 1-hydroxybenzotriazole monohydrate (HOBt·H2O) (1.5 eq.), DIPEA (3.0 eq.), and amine hydrochloride (1.1 eq.) were added. The reaction mixture was stirred overnight while gradually increasing the temperature to room temperature. After confirming the completion of the reaction by TLC, saturated aqueous ammonium chloride solution was added. After extraction with ethyl acetate, the organic layer was washed with brine. The organic layer was collected, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound.

[0108] General procedure 5: Condensation reaction (iii) A carboxylic acid (1.0 eq.) was dissolved in acetonitrile (5.5 mL / mmol) at room temperature under an argon atmosphere, and then amine hydrochloride (1.2 eq.), N-methylimidazole (NMI) (3.1 eq.), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (1.1 eq.) were added. The reaction mixture was stirred overnight, and after confirming the completion of the reaction by TLC, water was added. After extraction with ethyl acetate, the organic layer was washed with brine. The organic layer was collected, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound.

[0109] General procedure 6: Deprotection reaction with acid To the Boc-protected compound (1.0 eq.), 4N hydrochloric acid / 1,4-dioxane solution (2 mL / mmol) was added at room temperature and the mixture was stirred at room temperature. After confirming the completion of the reaction by TLC, the solution was concentrated under reduced pressure and dried to obtain the compound.

[0110] General procedure 7: Hydrolysis reaction (i) To an ester (1.0 eq.), methanol (2.5 mL / mmol for methyl ester, mixed with an equal amount of THF depending on solubility) or ethanol (2.5 mL / mmol for ethyl ester) was added at room temperature, followed by the addition of a 2.5N sodium hydroxide (NaOH) aqueous solution (5.0 eq.). The mixture was heated as needed (40-80 °C) depending on the progress of the reaction. After confirming the completion of the reaction by TLC, 1N hydrochloric acid was added. After confirming the acidity with pH test paper, the precipitated solid was filtered, washed with water, and the compound was obtained.

[0111] General procedure 8: Hydrolysis reaction (ii) Ester (1.0 eq.) was dissolved in methanol (2 mL / mmol), and then 2.5N sodium hydroxide (NaOH) aqueous solution (10 eq.) was added. After confirming the completion of the reaction by TLC, 1N hydrochloric acid was added. After confirming acidity with pH test paper, the solution was concentrated under reduced pressure to remove the organic solvent. After lyophilization, the solution was fractionated by liquid chromatography (L-column 2 (10 × 250 mm, 5 μm), 0.1% TFA aq. / MeCN, 4.6 mL / min., 40 ℃).

[0112] Composite of the left unit The synthesis scheme for the left unit of a compound having a thiophene skeleton is shown below (Scheme 1). Compound 29a-e was synthesized from compounds 27a-c and benzophenone derivative 28a-c by addition reaction, and then compound 30a-e was synthesized by reduction reaction with triethylsilane. Subsequently, compound 31a-e was obtained by deprotection by hydrolysis.

[0113] [ka]

[0114] The synthesis scheme for the left unit of a compound having a pyrrole skeleton is shown below (Scheme 2). Compound 33 was obtained by chlorination of 4,4'-difluorobenzhydrol 32, and then compound 35 was synthesized by nucleophilic substitution with methyl 4-methyl-1H-pyrrole-3-carboxylate methyl ester 34. Subsequently, compound 36 was obtained by deprotection by hydrolysis.

[0115] [ka]

[0116] Compound synthesis The basic synthetic schemes for compounds 1-5, 8-10, and 13, which have aspartic acid or glutamic acid as their basic skeleton, are shown below (Scheme 3). Amides 39a-h were obtained by condensation of carboxylic acid 37a or 37b with various amines 38a-g, and then amine hydrochlorides 40a-h were synthesized by deprotection reaction with acid. Subsequently, amide 41a-h was synthesized by condensation of carboxylic acid 31a synthesized in Scheme 1 with amine hydrochlorides 40a-h, and then the target compounds 1-5, 8-10, and 13 were obtained by deprotection reaction by hydrolysis under basic conditions.

[0117] [ka]

[0118] The synthesis schemes for compounds 11, 12, and 15 are shown below (Scheme 4). Similar to Scheme 3, amide compounds 43a-c were obtained by condensation of carboxylic acid 37a with various amines 42a-c, and then amine hydrochlorides 44a-c were synthesized by deprotection with acid. Subsequently, amide compounds 45a-c were synthesized by condensation of carboxylic acid 31a synthesized in Scheme 1 with amine hydrochlorides 44a-c, and then the target compounds 11, 12, and 15 were obtained by deprotection by hydrolysis under basic conditions.

[0119] [ka]

[0120] The synthesis schemes for compounds 6 and 14, which have serine as their basic structure, are shown below (Scheme 5). After obtaining the ether 48a-b from serine derivative 46 and boronic acid 47a-b by Chan-Lam-Evans coupling, the amine hydrochloride salts 49a-b were synthesized by acid deprotection. Subsequently, the carboxylic acid 31a synthesized in Scheme 1 was condensed with the amine hydrochloride salts 49a-b to synthesize the amide 50a-b, and the target compounds 6 and 14 were obtained by deprotection by hydrolysis under basic conditions.

[0121] [ka]

[0122] The synthesis scheme for compound 7, which has homoserine as its basic structure, is shown below (Scheme 6). After obtaining the ether 53 from homoserine derivative 51 and 3-hydroxybenzamide 52 via the Mitsunobu reaction, the amine hydrochloride 54 was synthesized by an acidic deprotection reaction. Subsequently, the carboxylic acid 31a synthesized in Scheme 1 was condensed with the amine hydrochloride 54 to synthesize the amide 55, and the target compound 7 was obtained by a deprotection reaction by hydrolysis under basic conditions.

[0123] [ka]

[0124] The basic synthetic schemes for compounds 16-26, which have an amide cyclized form as their basic skeleton, are shown below (Scheme 7). Amide compounds 57a-d were obtained by condensing carboxylic acid 37a or 37c with various amines 56a-c, and then amine hydrochloride salts 58a-d were synthesized by deprotection reaction with acid. Subsequently, amide compounds 59a-k were synthesized by condensing carboxylic acid 31a-e synthesized in Scheme 1 with amine hydrochloride salt 58a-d, and then the target compounds 16-26 were obtained by deprotection reaction by hydrolysis under basic conditions.

[0125] [ka]

[0126] Composite of the left unit Compound 29a Ethyl 2-thiophenecarboxylate 27a (4.31 mL, 1.0 eq.) and benzophenone 28a (5.72 g, 1.0 eq.) were mixed according to general procedure 1 to obtain a pale yellow solid 29a (8.02 g, 76% yield).

[0127] 1 H-NMR (600 MHz, CDCl3) δ = 7.65 (d, J = 3.8 Hz, 1H), 7.36-7.30 (m, 10H), 6.78 (d, J = 3.8 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.00 (s, 1H), 1.34 (t, J = 7.2 Hz, 3H). 13 C-NMR (150 MHz, CDCl3) δ = 162.3, 159.3, 145.8, 133.2, 133.0, 128.2, 128.0, 127.2, 127.0, 80.3, 61.1, 14.3.

[0128] Compound 29b 3-methyl-2-thiophenecarboxylate methyl ester 27b (4.2 mL, 1.0 eq.) and benzophenone 28a (6.42 g, 1.1 eq.) were mixed according to general procedure 1 to obtain pale yellow solid 29b (6.89 g, yield 64%).

[0129] 1 H-NMR (600 MHz, CDCl3) δ = 7.37-7.29 (m, 10 H), 6.63 (s, 1H), 3.81 (s, 3H), 2.93 (s, 1H), 2.47 (s, 3H). 13C-NMR (150 MHz, CDCl3) δ = 163.3, 156.5, 146.1, 145.8, 131.0, 128.2, 128.0, 127.2, 125.9, 80.2, 51.7, 16.2.

[0130] compound 29d A pale yellow oily substance 29d was obtained from 2-thiophenecarboxylate ethyl ester 27a (3.0 mL, 1.0 eq.) and 4,4'-difluorobenzophenone 28b (5.36 g, 1.1 eq.) according to general procedure 1 (5.58 g, yield 67%).

[0131] 1 H-NMR (600 MHz, CDCl3) δ = 7.65 (d, J = 3.9 Hz, 1H), 7.33-7.30 (m, 4H), 7.05-7.00 (m, 4H), 6.76 (d, J = 3.9 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.96 (s, 1H), 1.34 (t, J = 7.1 Hz, 3H). 13 C-NMR (150 MHz, CDCl3) δ = 162.4 (d, J = 248.5 Hz), 162.2, 158.9, 141.5 (d, J = 3.3 Hz), 133.6, 133.0, 129.1 (d, J = 8.7 Hz), 127.0, 115.1 (d, J = 21.8 Hz), 79.5, 61.3, 14.3.

[0132] compound 29e A pale yellow oily substance 29e was obtained from 2-thiophenecarboxylate ethyl ester 27a (3.0 mL, 1.0 eq.) and 4,4'-dichlorobenzophenone 28c (6.14 g, 1.1 eq.) according to general procedure 1 (6.42 g, 71% yield).

[0133] 1H-NMR (600 MHz, CDCl3) δ = 7.65 (d, J = 4.0 Hz, 1H), 7.33-7.26 (m, 8H), 6.76 (d, J = 4.0 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.99 (s, 1H), 1.34 (t, J = 7.1 Hz, 3H). 13 C-NMR (150 MHz, CDCl3) δ = 162.1, 158.1, 143.9, 134.2, 133.8, 133.0, 128.6, 128.5, 127.1, 79.4, 61.3, 14.3.

[0134] Compound 30a Compound 29a (6.91 g, 1.0 eq.) was followed in the general procedure 2, and a pale yellow oil 30a was obtained (6.68 g, yield quant.).

[0135] 1 H-NMR (600 MHz, CDCl3) δ = 7.65 (d, J = 3.8 Hz, 1H), 7.34-7.29 (m, 4H), 7.28-7.24 (m, 2H), 7.23-7.19 (m, 4H), 6.73 (dd, J = 3.8, 0.8 Hz, 1H), 5.67 (s, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.00 (s, 1H), 1.33 (t, J = 7.2 Hz, 3H). 13 C-NMR (150 MHz, CDCl3) δ = 162.3, 155.7, 142.8, 133.3, 132.6, 128.8, 128.6, 127.14, 127.06, 61.0, 52.5, 14.4.

[0136] Compound 30b Compound 29b (1.82 g, 1.0 eq.) was obtained by using the usual method 2, and light yellow oil 30b was obtained (1.69 g, yield 98%).

[0137] 1H-NMR (600 MHz, CDCl3) δ = 7.33-7.29 (m, 4H), 7.27-7.23 (m, 2H), 7.22-7.19 (m, 4H), 6.57 (s, 1H), 5.59 (s, 1H), 3.79 (s, 3H), 2.47 (s, 3H). 13 C-NMR (150 MHz, CDCl3) δ = 163.2, 153.0, 146.4, 142.8, 131.2, 128.8, 128.6, 127.0, 125.2, 52.4, 51.6, 16.0.

[0138] Compound 31a Compound 30a (5.33 g, 1.0 eq.) was obtained by using the general method 7, and 31a was obtained as a white solid (4.31 g, yield 89%).

[0139] 1 H-NMR (600 MHz, CDCl3) δ = 7.73 (d, J = 3.8 Hz, 1H), 7.34-7.29 (m, 4H), 7.28-7.24 (m, 2H), 7.22-7.18 (m, 4H), 6.77 (dd, J = 3.8, 1.1 Hz, 1H), 5.68 (s, 1H). 13 C-NMR (150 MHz, CDCl3) δ = 167.3, 157.9, 142.6, 135.0, 131.3, 128.8, 128.6, 127.5, 127.2, 52.6.

[0140] Compound 31b Compound 30b (0.94 g, 1.0 eq.) was obtained by using the general method 7, and light yellow solid 31b was obtained (0.82 g, yield 91%).

[0141] 1H-NMR (600 MHz, CDCl3) δ = 7.34-7.29 (m, 4H), 7.27-7.23 (m, 2H), 7.22-7.19 (m, 4H), 6.59 (s, 1H), 5.60 (s, 1H), 2.46 (s, 3H). 13 C-NMR (150 MHz, CDCl3) δ = 167.6, 154.8, 148.0, 142.6, 131.6, 128.8, 128.6, 127.1, 124.8, 52.5, 16.3.

[0142] Compound 31c 3-methyl-2-thiophenecarboxylic acid (1.00 g, 1.0 eq.) was mixed with ethanol (10 mL) and thionyl chloride (0.51 mL, 1.01 eq.) and stirred at 80 °C for 12 hours. After confirming the formation of ethyl ester compound 27c by LC-MS, water (50 mL) was added, and the mixture was concentrated under reduced pressure to remove the ethanol. After extraction with ethyl acetate, the mixture was washed with brine (30 mL). After drying over anhydrous sodium sulfate and filtration, the mixture was concentrated to obtain a yellow oily substance (1.00 g) containing compound 27c. The resulting oily substance (1.00 g) was reacted with 4,4'-difluorobenzophenone 28b (1.28 g, 1.0 eq.) according to general procedure 1. The residue was then separated and purified by HPLC (0.1% formic acid (FA) aqueous solution (aq.) / acetonitrile = 50 / 50 → 30 / 70, 10 min., Ultimate XB_C18 (Welch) 20-40 μm, 120 Å, 100 mL / min, 23-25 ​​℃) to obtain a yellow oily substance containing compound 29c (1.10 g). TFA (10 mL) and Et3SiH (1.00 mL, 2.43 eq.) were added to the oily substance, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, water (30 mL) and sodium bicarbonate solution were added to adjust the pH to 7-8, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily substance containing compound 30c (1.10 g). Methanol (10 mL), sodium hydroxide (1.18 g, 10 eq.), and water (2 mL) were added to the oily substance, and the mixture was stirred at 80 °C for 12 hours. After the reaction was complete, water (30 mL) and 1N hydrochloric acid were added to adjust the pH to 7-8, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative HPLC (0.1% formic acid (FA) aq. / MeCN = 40 / 60, 10 min., Ultimate XB_C18 (Welch) 20-40 μm, 120 Å, 100 mL / min, 23 °C) to obtain a white solid 31c (0.250 g, yield 11% (4 steps)).

[0143] 1H-NMR (400 MHz, DMSO-d6) δ = 12.79 (brs, 1H), 7.29-7.25 (m, 4H), 7.19-7.14 (m, 4H), 6.66 (s, 1H), 5.84 (s, 1H), 2.38 (s, 3H) 13 C-NMR (100 MHz, DMSO-d6) δ = 164.0, 161.6 (d, J = 243.4 Hz), 152.4, 145.6, 139.5 (d, J = 2.9 Hz), 131.6, 130.8 (d, J = 8.3 Hz), 126.8, 115.9 (d, J = 21.6 Hz), 49.9, 16.0.

[0144] compound 35 4,4'-Difluorobenzhydrol 32 (1.00 g, 1.0 eq.) was mixed with thionyl chloride (10 mL) and stirred at 70 °C for 1 hour. After confirming the completion of the reaction by TLC, the mixture was concentrated under reduced pressure to obtain a yellow oily substance (1.00 g) containing compound 33.

[0145] Separately, at room temperature, 1.00 g, 1.0 eq. of methyl 4-1H-pyrrole-3-carboxylate methyl ester 34 was mixed with 10 mL of DMF and 60% sodium hydride (0.432 g, 1.5 eq.), and the mixture was stirred for 30 minutes. Next, 1.71 g, 1.0 eq. of a yellow oily substance containing compound 33 was added to the reaction system, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction by LC-MS, the mixture was quenched with 20 mL of saturated ammonium chloride aqueous solution and extracted with ethyl acetate. After concentrating the organic layer, the residue was purified by preparative HPLC (0.1% FA aq. / MeCN = 90 / 10→20 / 80, 50 min., Ultimate XB_C18 (Welch) 20-40 μm, 120 Å, 100 mL / min, 23-25℃) to obtain a yellow oily substance 35 (0.600 g, yield 23% (2 steps)). 1H-NMR (400 MHz, DMSO-d6) δ = 7.29-7.19 (m, 5H), 7.18-7.09 (m, 4H), 6.76 (s, 1H), 6.63-6.57 (m, 1H), 3.64 (s, 3H), 2.14 (d, J = 0.4 Hz, 3H).

[0146] compound 36 Compound 35 (600 mg) was mixed with methanol (6 mL), sodium hydroxide (703 mg, 10 eq.), and water (1 mL), and the mixture was stirred at 80 °C for 12 hours. After confirming the completion of the reaction by LC-MS, water (20 mL) and 1N hydrochloric acid were added to adjust the pH to 7-8, and the mixture was extracted with dichloromethane. The organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate. The organic layer was then filtered and concentrated to obtain yellow solid 36 (300 mg, yield 52%).

[0147] 1 H-NMR (400 MHz, DMSO-d6) δ = 11.69 (brs, 1H), 7.25-7.16 (m, 4H), 7.15-7.12 (m, 5H), 6.74 (s, 1H), 6.55 (d, J = 1.2 Hz, 1H), 2.12 (s, 3H). 13 C-NMR (100 MHz, DMSO-d6) δ = 166.3, 162.1 (d, J = 244.7 Hz), 136.7 (d, J = 3.3 Hz), 130.5 (d, J = 8.8 Hz), 127.0, 121.1, 121.0, 116.1 (d, J = 21.5 Hz), 114.9, 64.6, 12.2.

[0148] Synthesis of Compound 1 Compound 39a N-(tert-butoxycarbonyl)-L-aspartate 1-methyl 37a (501.9 mg, 1.0 eq.) and 4-aminobenzamide 38a (306.2 mg, 1.1 eq.) were mixed according to general procedure 3 to obtain a white solid 39a (349.2 mg, 47% yield).

[0149] 1 H-NMR (600 MHz, DMSO-d6) δ = 10.21 (s, 1H), 7.85 (brs, 1H), 7.84-7.80 (m, 2H), 7.65-7.61 (m, 2H), 7.31 (d, J = 8.1 Hz, 1H), 7.24 (brs, 1H), 4.45 (dd, J = 8.1, 7.4, 5.9 Hz, 1H), 3.62 (s, 3H), 2.85 (dd, J = 15.7, 5.9 Hz, 1H), 2.71 (dd, J = 15.7, 7.4 Hz, 1H), 1.38 (s, 9H). 13 C-NMR (150 MHz, DMSO-d6) δ = 172.2, 168.3, 167.3, 155.2, 141.6, 128.7, 128.4, 118.1, 78.4, 52.0, 50.1, 38.2, 28.1.

[0150] Compound 41a Compound 39a (196.4 mg) was reacted according to general procedure 6 to obtain a pale yellow solid containing compound 40a (208.1 mg). The obtained solid (106.3 mg) and compound 31a (86.3 mg) were reacted according to general procedure 4 to obtain a white solid 41a (40.6 mg, yield 26%).

[0151] 1H-NMR (600 MHz, DMSO-d6) δ = 10.28 (s, 1H), 8.91 (d, J = 7.6 Hz, 1H), 7.85 (brs, 1H), 7.84-7.80 (m, 2H), 7.67 (d, J = 3.8 Hz, 1H), 7.64-7.60 (m, 2H), 7.38-7.32 (m, 4H), 7.28-7.20 (m, 7H), 6.77 (dd, J = 3.8, 0.8 Hz, 1H), 5.83 (s, 1H), 4.80 (ddd, J = 7.6, 7.6, 6.1 Hz, 1H), 3.63 (s, 3H), 3.02 (dd, J = 15.8, 6.1 Hz, 1H), 2.84 (dd, J = 15.8, 7.6 Hz, 1H). 13 C-NMR (150 MHz, DMSO-d6) δ = 171.6, 168.3, 167.3, 161.0, 153.3, 143.2, 141.6, 137.4, 128.8, 128.7, 128.6, 128.5, 128.4, 127.0, 126.9, 118.1, 52.2, 51.2, 49.2, 37.8.

[0152] Compound 1 Compound 41a (16.5 mg) was obtained as a white solid 1 (1.8 mg, yield 11%) using the conventional method 8.

[0153] 1H-NMR (600 MHz, DMSO-d6) δ = 10.16 (s, 1H), 8.67 (d, J = 7.7 Hz, 1H), 7.79 (brs, 1H), 7.76-7.72 (m, 2H), 7.58 (d, J = 3.9 Hz, 1H), 7.58-7.54 (m, 2H), 7.30-7.24 (m, 4H), 7.20-7.14 (m, 7H), 6.70 (dd, J = 3.9, 0.8 Hz, 1H), 5.76 (s, 1H), 4.80 (ddd, J = 7.8, 7.7, 5.9 Hz, 1H), 2.93 (dd, J = 15.8, 5.9 Hz, 1H), 2.74 (dd, J = 15.8, 7.8 Hz, 1H). 13 C-NMR (150 MHz, DMSO-d6) δ = 172.7, 168.6, 167.4, 161.0, 153.1, 143.3, 141.7, 137.8, 128.7, 128.6, 128.5, 128.4, 127.0, 126.9, 118.1, 51.2, 49.3, 38.0.

[0154] Synthesis of compounds 2 and 3 Compound 39b N-(tert-butoxycarbonyl)-L-methyl aspartate 37a (0.60 g, 1.0 eq.) and 3-aminobenzamide 38b (0.36 g, 1.1 eq.) were mixed according to general procedure 3 to obtain a white solid 39b (0.89 g, yield quant.).

[0155] 1H-NMR (600 MHz, DMSO-d6) δ = 10.15 (s, 1H), 8.05 (dd, J = 1.8, 1.4 Hz, 1H), 7.97-7.93 (m, 1H), 7.72 (dd, J = 8.0, 1.4 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.40-7.34 (m, 2H), 7.30 (d, J = 8.2 Hz, 1H), 4.46 (ddd, J = 8.2, 7.4, 5.8 Hz, 1H), 3.63 (s, 3H), 2.83 (dd, J = 15.5, 5.8 Hz, 1H), 2.70 (dd, J = 15.5, 7.4 Hz, 1H), 1.38 (s, 9H).

[0156] Compound 41b Compound 39b (220.3 mg, 1.0 eq.) was obtained as a general compound, and compound 40b was obtained as a pale yellow solid (344.0 mg). Compound 31a (51.9 mg, 1.0 eq.) and compound 41b were obtained as a solid (79.8 mg) and a light yellow solid (33.7 mg, yield 35%).

[0157] 1 H-NMR (600 MHz, DMSO-d6) δ = 10.18 (s, 1H), 8.91 (d, J = 7.6 Hz, 1H), 8.05-8.02 (m, 1H), 7.94 (s, 1H), 7.75-7.72 (m, 1H), 7.67 (d, J = 3.9 Hz, 1H), 7.54-7.51 (m, 1H), 7.38-7.32 (m, 6H), 7.27-7.22 (m, 6H), 6.78-6.76 (m, 1H), 5.83 (s, 1H), 4.84-4.79 (m, 1H), 3.63 (s, 3H), 3.00 (dd, J = 15.8, 6.2 Hz, 1H), 2.82 (dd, J = 15.8, 7.5 Hz, 1H). 13C-NMR (150 MHz, DMSO-d6) δ = 171.5, 167.9, 167.7, 160.9, 153.1, 143.1, 138.9, 137.3, 134.92, 134.89, 128.7, 128.5, 128.4, 126.9, 126.8, 121.8, 121.6, 118.5, 52.1, 51.0, 49.1, 37.6.

[0158] Compounds 2, 3 For compound 41 (15.7 mg, 1.0 eq.), according to General Procedure 8, white solid 2 (4.5 mg, yield 29%) and white solid 3 (1.0 mg, yield 7%) were obtained.

[0159] Compound 2 1 H-NMR (600 MHz, DMSO-d6) δ = 12.77 (brs, 1H), 10.14 (s, 1H), 8.76 (d, J = 7.8 Hz, 1H), 8.05 - 8.02 (m, 1H), 7.94 (s, 1H), 7.76 - 7.72 (m, 1H), 7.66 (d, J = 3.9 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.37 - 7.32 (m, 6H), 7.27 - 7.22 (m, 6H), 6.77 - 6.75 (m, 1H), 5.83 (s, 1H), 4.76 (ddd, J = 7.8, 7.8, 6.0 Hz, 1H), 2.98 (dd, J = 15.7, 6.0 Hz, 1H), 2.79 (dd, J = 15.7, 7.8 Hz, 1H). 13 C-NMR (150 MHz, DMSO-d6) δ = 172.6, 168.2, 167.7, 160.8, 152.9, 143.1, 139.0, 137.7, 134.9, 128.5, 128.42, 128.36, 126.9, 126.7, 121.7, 121.6, 118.5, 51.0, 49.1, 37.7. HRMS (ESI, m / z, [M+H] +): calcd for C 29 H 25 N3O5S: 528.1588, found: 528.1590 (Δ = 0.4 ppm). HRMS (ESI, m / z, [M-H] - ): calcd for C 29 H 25 N3O5S: 526.1442, found: 526.1433 (Δ = -1.7 ppm). Purity (HPLC, 254 nm): >99%.

[0160] Compound 3 1 H-NMR (600 MHz, DMSO-d6) δ = 12.35 (brs, 1H), 10.17 (s, 1H), 8.69 (d, J = 7.6 Hz, 1H), 8.00 - 7.98 (m, 1H), 7.87 (s, 1H), 7.71 - 7.68 (m, 1H), 7.67 - 7.64 (m, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.32 - 7.24 (m, 6H), 7.21 - 7.16 (m, 6H), 6.72 (d, J = 3.8 Hz, 1H), 5.77 (s, 1H), 4.82 - 4.77 (m, 1H), 2.75 (dd, J = 16.8, 5.7 Hz, 1H), 2.64 (dd, J = .8 Hz 1H). 13 C-NMR (150 MHz, DMSO-d6) δ = 171.7, 169.7, 168.0, 161.2, , 143.4, 139.0, 137.9, 135.1, 128.9, 128.7, 128.62, 128.59, 127.1, 127.0, 122.24, 122.23, 119.2, 51.3, 51.0, 35.9. HRMS (ESI, m / z, [M-H] - ): calcd for C 29 H 25 It should be noted that there seems to be an error in the original text where "2.64 (dd, J = 16.8, 8.8 Hz 1H)" is missing an operator between 16.8 and 8.8, and in the C-NMR data, "153.2" is followed by a comma which seems incorrect. The translation is done based on the provided text as is.N3O5S: 526.1442, found: 526.1436 (Δ = -1.2 ppm). Purity (HPLC, 254 nm): >99%.

[0161] Synthesis of Compound 4 compound 41c N-(tert-butoxycarbonyl)-L-methyl 37a (501.8 mg, 1.0 eq.) was mixed with DMF (8.4 mL), ice-cold DIPEA (0.69 mL, 2.0 eq.), and 2-aminobenzamide 38c (305.3 mg, 1.1 eq.) under an argon atmosphere. After stirring for 15 minutes, [[[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy]-4-morpholinomethylene]dimethylammonium hexafluorophosphate (COMU) (961.0 mg, 1.1 eq.) was added. The reaction mixture was stirred overnight while gradually increasing the temperature to room temperature. After confirming the completion of the reaction by TLC, saturated ammonium chloride aqueous solution (30 mL) was added. After extraction with ethyl acetate, the organic layer was washed with saturated saline solution (30 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain a yellow oily substance (591.0 mg) containing compound 39c. Compound 39c (153.5 mg, 1.0 eq.) was subjected to general procedure 6 to obtain a pale yellow paste containing compound 40c (201.3 mg). The obtained solid (54.3 mg) and compound 31a (34.4 mg, 1.0 eq.) were subjected to general procedure 4 to obtain a pale yellow oily substance 41c (33.7 mg, 53% yield).

[0162] 1H-NMR (600 MHz, CDCl3) δ = 11.30 (s, 1H), 8.54 (d, J = 8.2 Hz, 1H), 7.53-7.46 (m, 2H), 7.32-7.17 (m, 12H), 7.10 (ddd, J = 8.6, 7.6, 1.1 Hz, 1H), 6.69 (dd, J = 3.8, 1.1 Hz, 1H), 6.16 (brs, 1H), 5.67 (brs, 1H), 5.65 (s, 1H), 5.05 (ddd, J = 8.2, 4.2, 4.1 Hz, 1H), 3.78 (s, 3H), 3.28 (dd, J = 16.6, 4.1 Hz, 1H), 3.03 (dd, J = 16.6, 4.2 Hz, 1H). 13 C-NMR (150 MHz, CDCl3) δ = 171.5, 170.9, 169.1, 161.5, 153.9, 142.9, 139.6, 136.7, 133.4, 128.8, 128.7, 128.6, 127.2, 127.00, 126.99, 123.1, 121.7, 118.6, 52.9, 52.4, 49.0, 39.0.

[0163] Compound 4 Compound 41c (15.0 mg, 1.0 eq.) was obtained as a white solid, as a white solid 41c (1.9 mg, yield 13%).

[0164] 11H-NMR (600 MHz, DMSO-d6) δ = 12.30 (broad singlet, 1H), 8.83 (doublet, J = 8.0 Hz, 1H), 8.09 - 8.06 (multiplet, 1H), 7.79 - 7.74 (multiplet, 1H), 7.64 - 7.61 (multiplet, 1H), 7.56 (doublet, J = 8.1 Hz, 1H), 7.49 - 7.45 (multiplet, 1H), 7.36 - 7.31 (multiplet, 4H), 7.28 - 7.21 (multiplet, 6H), 6.76 (doublet of doublets, J = 3.8, 0.9 Hz, 1H), 5.83 (singlet, 1H), 5.04 - 4.98 (multiplet, 1H), 3.24 (doublet of doublets, J = 15.2, 6.4 Hz, 1H), 3.02 (doublet of doublets, J = 15.2, 7.9 Hz, 1H). 13 13C-NMR (150 MHz, DMSO-d6) δ = 172.4, 161.8, 161.0, 154.6, 153.2, 148.5, 143.3, 137.7, 134.5, 128.71, 128.65, 128.6, 127.1, 127.0, 126.8, 126.3, 125.8, 120.9, 51.2, 50.3, 35.8. HRMS (ESI, m / z, [M - H2O - H] - ): calculated for C 29 H 23 N3O4S: 508.1337, found: 508.1333 (Δ = -0.7 ppm). Purity (HPLC, 254 nm): >99%.

[0165] Synthesis of Compound 5 Compound 41d N-(tert-butoxycarbonyl)-L-methyl glutamate 37b (0.7136 g, 1.0 eq.) and 3-aminobenzamide 38b (0.4080 g, 1.1 eq.) were mixed according to general procedure 3 to obtain a white solid containing compound 39d (0.99 g). The obtained solid (200.9 mg) was mixed according to general procedure 6 to obtain a pale pink solid containing compound 40d (287.6 mg). The obtained solid (85.8 mg) and compound 31a (52.8 mg, 1.0 eq.) were mixed according to general procedure 4 to obtain a transparent oily substance 41d (91.8 mg, yield 92%).

[0166] 1 H-NMR (600 MHz, CDCl3) δ = 9.16 (s, 1H), 8.07-8.05 (m, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.51-7.48 (m, 1H), 7.45 (d, J = 4.0 Hz, 1H), 7.36 (dd, J = 7.9, 7.9 Hz, 1H), 7.33-7.29 (m, 4H), 7.28-7.24 (m, 2H), 7.20-7.17 (m, 4H), 6.93 (d, J = 7.8 Hz, 1H), 6.70 (dd, J = 4.0, 1.0 Hz, 1H), 6.22 (brs, 1H), 5.87 (brs, 1H), 5.64 (s, 1H), 4.79 (ddd, J = 10.4, 7.8, 3.6 Hz, 1H), 3.77 (s, 3H), 2.63-2.47 (m, 2H), 2.44-2.34 (m, 1H), 2.10-1.99 (m, 1H). 13 C-NMR (150 MHz, CDCl3) δ = 172.3, 171.0, 168.9, 162.7, 154.7, 142.7, 138.8, 136.0, 133.8, 129.3, 129.1, 128.8, 128.6, 127.2, 127.1, 123.1, 122.7, 118.5, 52.9, 52.5, 52.1, 34.1, 29.8.

[0167] Compound 5 Compound 41d (16.2 mg, 1.0 eq.) was obtained as a white solid (7.5 mg, yield 47%).

[0168] 1 H-NMR (600 MHz, CD3OD) δ = 8.00 (m, 1H), 7.70-7.66 (m, 1H), 7.61-7.58 (m, 1H), 7.57-7.53 (m, 1H), 7.35 (ddd, J = 7.9, 7.9, 2.4 Hz, 1H), 7.33-7.27 (m, 4H), 7.25-7.21 (m, 2H), 7.21-7.18 (m, 4H), 6.70-6.67 (m, 1H), 5.72 (d, J = 3.5 Hz, 1H), 4.61 (dd, J = 9.8, 4.5 Hz, 1H), 2.60-2.51 (m, 2H), 2.42-2.35 (m, 1H), 2.21-2.13 (m, 1H). 13 C-NMR (150 MHz, CD3OD) δ = 174.9, 173.5, 172.2, 164.6, 155.8, 144.7, 140.1, 138.2, 135.8, 130.2, 130.0, 129.9, 129.6, 128.2, 128.1, 124.5, 124.1, 120.5, 53.8, 53.6, 34.4, 28.1. HRMS (ESI, m / z, [M+H] + ): calcd for C 30 H 27 N3O5S: 542.1744, found: 542.1749 (Δ = 0.9 ppm). HRMS (ESI, m / z, [MH] - ): calcd for C 30 H 27 N3O5S: 540.1599, found: 540.1592 (Δ = -1.2 ppm). Purity (HPLC, 254 nm): 98.6%.

[0169] Synthesis of Compound 6 compound 48a Under an air atmosphere, N-(tert-butoxycarbonyl)-L-serine methyl ester 46 (854.8 mg, 1.0 eq.), 3-carbamoylphenylboronic acid 47a (645.5 mg, 1.0 eq.), 4-dimethylaminopyridine (DMAP) (94.5 mg, 0.2 eq.), copper(II) acetate (73.6 mg, 0.1 eq.), water (7.0 μL, 0.1 eq.), and dichloromethane (14.5 mL) were added, and the mixture was stirred at room temperature overnight. Subsequently, copper(II) acetate (992.8 mg, 1.4 eq.), DMAP (857.8 mg, 1.8 eq.), and compound 47a (643.3 mg, 1.0 eq.) were added, and the mixture was stirred again at room temperature overnight. After confirming the completion of the reaction by TLC, saturated ammonium chloride aqueous solution (20 mL) was added. After extraction with chloroform, the organic layer was washed with saturated brine (20 mL). The organic layer was collected, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a clear oily substance 48a (171.6 mg, yield 13%).

[0170] 1 H-NMR (600 MHz, CDCl3) δ = 7.42 (m, 3H), 7.05 (ddd, J = 7.9, 2.6, 1.5 Hz, 1H), 6.14 (brs, 1H), 5.66 (brs, 1H), 5.50 (d, J = 8.3 Hz, 1H), 4.72-4.65 (m, 1H), 4.45 (dd, J = 9.3, 2.8 Hz, 1H), 4.26 (dd, J = 9.3, 3.4 Hz, 1H), 3.78 (s, 3H), 1.46 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 170.5, 168.8, 158.4, 155.3, 134.8, 129.8, 120.1, 118.6, 113.5, 80.4, 68.5, 53.3, 52.8, 28.3.

[0171] Compound 50a Compound 48a (87.7 mg, 1.0 eq.) was obtained as a general 6-methane solution, and compound 49a was obtained as a light peach-colored solid (54.5 mg). A solid (30.1 mg), compound 31a (29.9 mg, 1.0 eq.) and a transparent oil 50a (54.8 mg, yield quant.) were obtained.

[0172] 1 H-NMR (600 MHz, CDCl3) δ = 7.46 (d, J = 3.8 Hz, 1H), 7.41 (dd, J = 2.4, 1.5 Hz, 1H), 7.38 (ddd, J = 7.9, 1.5, 1.2 Hz, 1H), 7.34 (dd, J = 8.0, 7.9 Hz, 1H), 7.34-7.29 (m, 4H), 7.28-7.23 (m, 2H), 7.22-7.18 (m, 4H), 7.05 (ddd, J = 8.0, 2.4, 1.2 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.72 (dd, J = 3.8, 1.0 Hz, 1H), 6.12 (brs, 1H), 5.66 (s, 1H), 5.55 (brs, 1H), 5.10 (ddd, J = 7.7, 3.4, 2.9 Hz, 1H), 4.50 (dd, J = 9.5, 3.4 Hz, 1H), 4.39 (dd, J = 9.5, 2.9 Hz, 1H), 3.81 (s, 3H). 13 C-NMR (150 MHz, CDCl3) δ = 170.1, 168.6, 161.6, 158.3, 154.3, 142.8, 136.1, 134.8, 129.8, 129.1, 128.8, 128.6, 127.12, 127.09, 120.2, 118.5, 113.7, 68.1, 53.0, 52.5, 52.4.

[0173] Compound 6 Compound 50a (17.6 mg, 1.0 eq.) was obtained as a compound, as a general compound 8 as a white solid, as a white solid 6 (3.2 mg, yield 19%).

[0174] 1 H-NMR (600 MHz, CD3OD) δ = 7.64 (d, J = 3.9 Hz, 1H), 7.47-7.44 (m, 2H), 7.36 (dd, J = 8.3, 8.2 Hz, 1H), 7.33-7.27 (m, 4H), 7.26-7.19 (m, 6H), 7.14 (ddd, J = 8.2, 2.4, 0.9 Hz, 1H), 6.72 (dd, J = 3.9, 0.8 Hz, 1H), 5.75 (s, 1H), 4.97 (dd, J = 5.7, 3.9 Hz, 1H), 4.48 (dd, J = 9.8, 5.7 Hz, 1H), 4.45 (dd, J = 9.8, 3.9 Hz, 1H). 13 C-NMR (150 MHz, CD3OD) δ = 172.7, 172.1, 164.5, 160.1, 156.0, 144.7, 138.1, 136.5, 130.8, 130.3, 129.9, 129.6, 128.3, 128.1, 121.5, 119.5, 114.8, 68.9, 54.3, 53.6. HRMS (ESI, m / z, [M+H] + ): calcd for C 28 H 24 N2O5S: 501.1479, found: 501.1482 (Δ = 0.7 ppm). HRMS (ESI, m / z, [MH] - ): calcd for C 28 H 24 N2O5S: 499.1333, found: 499.1328 (Δ = -1.0 ppm). Purity (HPLC, 254 nm): 82.5%.

[0175] Synthesis of Compound 7 compound 7 Under an argon atmosphere, triphenylphosphine (721.7 mg, 1.5 eq.), THF (18.4 mL), and diisopropyl azodicarboxylic acid (424 μL, 1.2 eq.) were added and the mixture was stirred for 5 minutes. Next, 3-hydroxybenzamide 52 (251.7 mg, 1.0 eq.), triethylamine (270 μL, 1.0 eq.), and N-(tert-butoxycarbonyl)-L-homoserine methyl ester 51 (377.5 mg, 1.0 eq.) were added and the mixture was stirred overnight at room temperature. After confirming the completion of the reaction by TLC, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a white foam (244.0 mg) containing compound 53. The obtained white foam (108.4 mg, 1.0 eq.) was subjected to general procedure 6 to obtain a white solid (98.3 mg) containing compound 54. The obtained solid (57.3 mg) was reacted with compound 31a (49.1 mg, 1.0 eq.) according to general procedure 4 to obtain a pale yellow solid (74.0 mg) containing compound 55. A white solid 7 was obtained from the obtained solid (37.7 mg) according to general procedure 8 (19.7 mg, yield 45% (2 steps)).

[0176] 1 H-NMR (600 MHz, DMSO-d6) δ = 8.67 (d, J = 7.7 Hz, 1H), 7.96 (s, 1H), 7.72 (d, J = 3.7 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.42-7.39 (m, 1H), 7.38-7.30 (m, 6H), 7.28-7.17 (m, 6H), 7.06 (dd, J = 8.0, 2.1 Hz, 1H), 6.78 (d, J = 3.7 Hz, 1H), 5.83 (s, 1H), 4.56-4.49 (m, 1H), 4.15-4.01 (m, 2H), 2.33-2.25 (m, 1H), 2.21-2.13 (m, 1H). 13C-NMR (150 MHz, DMSO-d6) δ = 173.4, 167.6, 161.4, 158.3, 153.1, 143.3, 137.8, 135.7, 129.4, 128.7, 128.6, 128.5, 127.0, 126.9, 119.9, 117.6, 113.2, 64.3, 51.2, 49.6, 30.3. HRMS (ESI, m / z, [M+H] + ): calcd for C 29 H 26 N2O5S: 515.1635, found: 515.1632 (Δ = -0.6 ppm). HRMS (ESI, m / z, [MH] - ): calcd for C 29 H 26 N2O5S: 513.1490, found: 513.1486 (Δ = -0.7 ppm). Purity (HPLC, 254 nm): >99%.

[0177] Synthesis of compound 8 Compound 41e N-(tert-butoxycarbonyl)-L-aspartate 1-methyl 37a (710.8 mg, 1.0 eq.) and 3-amino-2-fluoro-benzamide 38d (487.3 mg, 1.1 eq.) were mixed according to general procedure 3 to obtain a white solid containing compound 39e (371.3 mg). The obtained solid (180.4 mg) was mixed according to general procedure 6 to obtain a white solid containing compound 40e (217.6 mg). The obtained solid (84.5 mg) and compound 31a (52.3 mg, 1.0 eq.) were mixed according to general procedure 4 to obtain a white solid 41e (27.9 mg, yield 28%).

[0178] 1H-NMR (600 MHz, DMSO-d6) δ = 9.94 (s, 1H), 8.88 (d, J = 7.6 Hz, 1H), 7.95 (dd, J = 8.0, 0.9 Hz, 1H), 7.76 (s, 1H), 7.67 (d, J = 3.8 Hz, 1H), 7.63 (s, 1H), 7.36-7.30 (m, 5H), 7.28-7.22 (m, 6H), 7.18 (dd, J = 8.0, 7.9 Hz, 1H), 6.78 (dd, J = 3.8, 0.7 Hz, 1H), 5.84 (s, 1H), 4.82 (ddd, J = 7.6, 7.5, 6.2 Hz, 1H), 3.63 (s, 3H), 3.06 (dd, J = 15.8, 6.2 Hz, 1H), 2.88 (dd, J = 15.8, 7.5 Hz, 1H). 13 C-NMR (150 MHz, DMSO-d6) δ = 171.5, 168.5, 165.1, 160.9, 153.1, 150.5 (d, J = 250.6 Hz), 143.1, 137.3, 128.7, 128.5, 128.4, 126.9, 126.8, 126.3 (d, J = 12.4 Hz), 125.7, 124.6, 124.5 (d, J = 13.2 Hz), 123.7 (d, J = 3.6 Hz), 52.1, 51.0, 49.2, 37.3.

[0179] Compound 8 Compound 41e (10.8 mg, 1.0 eq.) was obtained as a white solid (4.7 mg, yield 45%).

[0180] 1H-NMR (600 MHz, CD3OD) δ = 7.98 (ddd, J = 8.1, 8.1, 1.6 Hz, 1H), 7.58 (d, J = 3.8 Hz, 1H), 7.51 (ddd, J = 8.0, 6.8, 1.7 Hz, 1H), 7.33 - 7.28 (m, 4H), 7.26 - 7.19 (m, 7H), 6.73 (ddd, J = 3.8, 1.1 Hz, 1H), 5.75 (s, 1H), 4.97 (dd, J = 6.9, 5.4 Hz, 1H), 3.14 (dd, J = 15.8, 5.4 Hz, 1H), 3.04 (dd, J = 15.8, 6.9 Hz, � 13 C-NMR (150 MHz, CD3OD) δ = 174.2, 171.4, 168.6, 164.3, 155.9, 153.3 (d, J = 251.1 Hz), 144.7, 138.1, 130.1, 129.9, 129.6, 128.6, 128.3, 128� HRMS (ESI, m / z, [M+H] + ): calcd for C 29 H 24 FN3O5S: 546.1493, found: 546.1495 (Δ = 0.3 ppm). HRMS (ESI, m / z, [M-H] - ): calcd for C 29 H 24 FN3O5S: 544.1348, found: 544.1340 (Δ = -1.5 ppm). Purity (HPLC, 254 nm): > 99%.

[0181] Synthesis of compound 9 Compound 39f N-(tert-butoxycarbonyl)-L-aspartate 1-methyl 37a (0.7085 g, 1.0 eq.) and 5-amino-2-fluorobenzamide 38e (0.4869 g, 1.1 eq.) were mixed according to general procedure 3 to obtain a white solid 39f (1.05 g, 96% yield).

[0182] 1 H-NMR (600 MHz, CDCl3) δ = 9.44 (s, 1H), 8.46-8.41 (m, 1H), 8.11-8.05 (m, 1H), 7.12 (dd, J = 11.4, 9.2 Hz, 1H), 6.87 (s, 1H), 6.85 (s, 1H), 5.80 (d, J = 7.0 Hz, 1H), 4.55 (ddd, J = 7.0, 5.0, 4.3 Hz, 1H), 3.81 (s, 3H), 3.17 (dd, J = 15.0, 4.3 Hz, 1H), 3.08 (dd, J = 15.0, 5.0 Hz, 1H), 1.42 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 172.1, 168.5, 164.8, 157.1 (d, J = 245.3 Hz), 155.8, 135.6, 125.3 (d, J = 8.8 Hz), 122.7, 119.6 (d, J = 13.0 Hz), 116.6 (d, J = 26.1 Hz), 80.3, 52.8, 50.9, 39.3, 28.3.

[0183] compound 41f Compound 39f (256.9 mg, 1.0 eq.) was prepared according to general procedure 6 to obtain a gray solid containing compound 40f (360.2 mg). The obtained solid (91.6 mg) and compound 31a (56.6 mg, 1.0 eq.) were prepared according to general procedure 4 to obtain a white solid 41f (90.6 mg, yield 84%).

[0184] 1H-NMR (600 MHz, CDCl3) δ = 9.64 (s, 1H), 8.44 (ddd, J = 9.0, 4.2, 2.8 Hz, 1H), 8.03 (dd, J = 6.7, 2.8 Hz, 1H), 7.39 (d, J = 3.9 Hz, 1H), 7.33-7.25 (m, 4H), 7.25-7.20 (m, 2H), 7.20-7.14 (m, 4H), 7.08 (dd, J = 11.4, 9.0 Hz, 1H), 6.83 (dd, J = 12.5, 1.6 Hz, 1H), 6.65 (dd, J = 3.9, 0.9 Hz, 1H), 5.61 (s, 1H), 4.86 (ddd, J = 9.5, 4.8, 4.7 Hz, 1H), 3.85 (s, 3H), 3.38 (dd, J = 15.4, 4.7 Hz, 1H), 3.18 (dd, J = 15.4, 4.8 Hz, 1H). 13 C-NMR (150 MHz, CDCl3) δ = 171.9, 168.5, 164.8 (d, J = 2.5 Hz), 162.3, 157.0 (d, J = 245.9 Hz), 154.5, 142.7, 136.2, 135.6, 128.9, 128.7, 128.6, 127.2, 127.1, 125.2 (d, J = 8.8 Hz), 122.6, 119.7 (d, J = 13.2 Hz), 116.6 (d, J = 26.1 Hz), 53.0, 52.4, 50.3, 38.8.

[0185] Compound 9 Compound 41f (35.9 mg, 1.0 eq.) was obtained as a compound, as a general compound 8 as a solid, and as a white solid 9 (13.5 mg, yield 39%).

[0186] 11H-NMR (600 MHz, DMSO-d6) δ = 10.21 (s, 1H), 8.63 (d, J = 7.3 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.65 - 7.54 (m, 3H), 7.31 - 7.24 (m, 4H), 7.21 - 7.15 (m, 6H), 7.14 (dd, J = 9.5, 9.5 Hz, 1H), 6.69 (dd, J = 3.8, 0.6 Hz, 1H), 5.76 (s, 1H), 4.70 - 4.60 (m, 1H), 2.90 (dd, J = 15.7, 6.1 Hz, 1H), 2.69 (dd, J = 15.7, 7.5 Hz, 1H). 13 13C-NMR (150 MHz, DMSO-d6) δ = 172.5, 168.2, 164.8, 160.8, 154.7 (d, J = 245.1 Hz), 152.9, 143.1, 137.7, 135.3 (d, J = 1.4 Hz), 128.5, 128.4 (d, J = 4.1 Hz), 126.9, 126.7, 123.6, 123.5 (d, J = 8.2 Hz), 122.6, 120.3, 116.2 (d, J = 24.2 Hz), 51.0, 49.3, 37.9. HRMS (ESI, m / z, [M+H] + ): calcd for C 29 H 24 FN3O5S: 546.1493, found: 546.1493 (Δ = 0 ppm). HRMS (ESI, m / z, [M-H] - ): calcd for C 29 H 24 FN3O5S: 544.1348, found: 544.1349 (Δ = 0.2 ppm). Purity (HPLC, 254 nm): > 99%.

[0187] Synthesis of compound 10 Compound 39g N-(tert-butoxycarbonyl)-L-aspartate 1-methyl 37a (740.1 mg, 1.0 eq.) and 5-amino-2-methylbenzamide 38f (492.7 mg, 1.1 eq.) were mixed according to general procedure 3 to obtain 39 g of a white solid (931.8 mg, 82% yield).

[0188] 1 H-NMR (600 MHz, CDCl3) δ = 8.01-7.89 (m, 1H), 7.64 (s, 1H), 7.43 (s, 1H), 7.15 (d, J = 8.1 Hz, 1H), 5.95 (brs, 1H), 5.84 (brs, 1H), 5.76 (m, 1H), 4.62-4.55 (m, 1H), 3.78 (s, 3H), 3.09 (dd, J = 15.9, 3.1 Hz, 1H), 2.93 (dd, J = 15.9, 3.4 Hz, 1H), 2.44 (s, 3H), 1.45 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 172.0, 171.3, 168.4, 155.8, 135.38, 135.35, 132.3, 131.8, 121.8, 118.7, 80.4, 52.9, 50.4, 39.3, 28.3, 19.5.

[0189] Compound 41g 39 g (240.3 mg, 1.0 eq.) of compound was prepared according to general procedure 6 to obtain a white solid containing 40 g of compound (321.4 mg). The obtained solid (96.1 mg) and compound 31a (59.5 mg, 1.0 eq.) were prepared according to general procedure 4 to obtain 41 g of white solid (116.6 mg, yield quant.).

[0190] 11H-NMR (600 MHz, CDCl3) δ = 8.31 (s, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.49 (dd, J = 8.3, 2.3 Hz, 1H), 7.42 (d, J = 3.8 Hz, 1H), 7.33 - 7.27 (m, 5H), 7.27 - 7.22 (m, 2H), 7.20 - 7.16 (m, 4H), 7.12 (d, J = 8.3 Hz, 1H), 6.69 (dd, J = 3.8, 0.8 Hz, 1H), 5.90 (brs, 1H), 5.89 (brs, 1H), 5.84 (s, 1H), 4.95 (ddd, J = 8.8, 4.5, 4.5 Hz, 1H), 3.79 (s, 3H), 3.17 (dd, J = 16.1, 4.5 Hz, 1H), 3.06 (dd, J = 16.1, 4.5 Hz, 1H), 2.42 (s, 3H). 13 13C-NMR (150 MHz, CDCl3) δ = 171.6, 171.3, 168.5, 162.0, 154.4, 142.8, 136.3, 135.5, 135.3, 132.1, 131.7, 128.9, 128.8, 128.6, 127.2, 127.1, 121.8, 118.8, 53.0, 52.4, 49.6, 38.6, 19.5.

[0191] Compound 10 Following the general procedure 8, white solid 10 was obtained (18.6 mg, yield 43%) with respect to compound 41g (44.2 mg, 1.0 eq.).

[0192] 11H-NMR (600 MHz, CD3OD) δ = 7.66 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 4.0 Hz, 1H), 7.42 (dd, J = 8.3, 2.3 Hz, 1H), 7.32 - 7.28 (m, 4H), 7.26 - 7.19 (m, 6H), 7.17 (d, J = 8.3 Hz, 1H), 6.72 (dd, J = 4.0, 1.0 Hz, 1H), 5.74 (s, 1H), 4.94 (dd, J = 6.9, 5.5 Hz, 1H), 3.06 (dd, J = 15.7, 5.5 Hz, 1H), 2.97 (dd, J = 15.7, 6.9 Hz, 1H), 2.37 (s, 3H). 13 13C-NMR (150 MHz, CD3OD) δ = 175.3, 174.2, 170.9, 164.2, 155.9, 144.6, 138.1, 137.7, 137.4, 132.5, 132.3, 130.1, 129.9, 129.6, 128.3, 128.1, 122.7, 120.1, 53.6, 51.0, 39.1, 19.3. HRMS (ESI, m / z, [M+H] + ): calcd for C 30 H 27 N3O5S: 542.1744, found: 542.1745 (Δ = 0.2 ppm). HRMS (ESI, m / z, [M-H] - ): calcd for C 30 H 27 N3O5S: 540.1599, found: 540.1595 (Δ = - 0.7 ppm). Purity (HPLC, 254 nm): >99%.

[0193] Synthesis of compound 11 Compound 43a N-(tert-butoxycarbonyl)-L-aspartate 1-methyl 37a (533.8 mg, 1.0 eq.) and 6-amino-2,3-dihydro-1H-isoindole-1-one 42a (353.9 mg, 1.1 eq.) were mixed according to general procedure 3 to obtain a pale yellow solid 43a (481.7 mg, yield 59%).

[0194] 1 H-NMR (600 MHz, CDCl3) δ = 8.90 (s, 1H), 8.21 (d, J = 7.7 Hz, 1H), 7.81 (s, 1H), 7.37 (d, J = 7.7 Hz, 1H), 6.80 (s, 1H), 5.83 (d, J = 7.5 Hz, 1H), 4.67-4.56 (m, 1H), 4.39 (s, 2H), 3.78 (s, 3H), 3.16 (dd, J = 15.8, 4.0 Hz, 1H), 2.99 (dd, J = 15.8, 2.7 Hz, 1H), 1.43 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 172.2, 171.3, 168.6, 155.8, 138.7, 138.5, 132.3, 123.72, 123.68, 114.6, 80.2, 52.8, 50.5, 45.4, 39.4, 28.3.

[0195] compound 45a Compound 43a (196.7 mg, 1.0 eq.) was prepared according to general procedure 6 to obtain a white solid containing compound 44a (170.9 mg). The obtained solid (62.1 mg) and compound 31a (54.5 mg, 1.0 eq.) were prepared according to general procedure 4 to obtain a pale yellow solid 45a (94.7 mg, 92% yield).

[0196] 1H-NMR (600 MHz, CDCl3) δ = 8.01 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.4, 2.0 Hz, 1H), 7.57 (d, J = 3.9 Hz, 1H), 7.50 (dd, J = 8.4, 0.6 Hz, 1H), 7.34-7.27 (m, 4H), 7.26-7.19 (m, 6H), 6.72 (dd, J = 3.9, 0.9 Hz, 1H), 5.74 (s, 1H), 4.96 (dd, J = 6.7, 5.8 Hz, 1H), 4.40 (s, 2H), 3.74 (s, 3H), 3.09 (dd, J = 15.6, 5.8 Hz, 1H), 3.00 (dd, J = 15.6, 6.7 Hz, 1H). 13 C-NMR (150 MHz, CDCl3) δ = 173.4, 173.1, 170.8, 164.3, 156.1, 144.6, 141.1, 140.0, 137.9, 133.9, 130.3, 129.9, 129.6, 128.3, 128.1, 125.2, 124.9, 115.7, 53.6, 53.1, 51.2, 46.6, 39.0.

[0197] Compound 11 Compound 45a (41.6 mg, 1.0 eq.) was obtained as a compound, as a general compound 8 as a white solid, and as a white solid 11 (14.7 mg, yield 36%).

[0198] 11H-NMR (600 MHz, DMSO-d6) δ = 12.67 (brs, 1H), 10.12 (s, 1H), 8.67 (d, J = 7.8 Hz, 1H), 8.46 (s, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.61 (dd, J = 8.1, 1.9 Hz, 1H), 7.58 (d, J = 3.9 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.29 - 7.24 (m, 4H), 7.20 - 7.15 (m, 6H), 6.69 (dd, J = 3.9, 0.8 Hz, 1H), 5.76 (s, 1H), 4.69 (ddd, J = 7.8, 7.6, 5.8 Hz, 1H), 4.23 (s, 2H), 2.93 (dd, J = 15.6, 5.8 Hz, 1H), 2.74 (dd, J = 15.6, 7.6 Hz, 1H). 13 13C-NMR (150 MHz, DMSO-d6) δ = 171.5, 168.7, 167.3, 159.8, 151.9, 142.13, 142.12, 137.7, 137.4, 136.7, 132.0, 127.5, 127.4, 125.9, 125.7, 122.8, 121.2, 111.8, 50.1, 48.2, 43.5, 36.8. HRMS (ESI, m / z, [M+H] + ): calcd for C 30 H 25 N3O5S: 540.1586, found: 540.1577 (Δ = -1.6 ppm). HRMS (ESI, m / z, [M-H] - ): calcd for C 30 H 25 N3O5S: 538.1442, found: 538.1430 (Δ = -2.3 ppm). Purity (HPLC, 254 nm): 97.3%.

[0199] Synthesis of compound 12 Compound 43b N-(tert-butoxycarbonyl)-L-aspartate 1-methyl 37a (541.2 mg, 1.0 eq.) and 7-amino-3,4-dihydroisoquinoline-1(2H)-one 42b (391.7 mg, 1.1 eq.) were prepared according to general procedure 3 to obtain white form 43b (804.5 mg, 94% yield). 1 H-NMR (600 MHz, CDCl3) δ = 9.54 (s, 1H), 8.36 (dd, J = 8.3, 1.5 Hz, 1H), 8.06 (s, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.81 (s, 1H), 5.88 (d, J = 7.2 Hz, 1H), 4.58 (ddd, J = 7.2, 5.6, 5.1 Hz, 1H), 3.80 (s, 3H), 3.62-3.53 (m, 2H), 3.14 (dd, J = 15.3, 5.2 Hz, 1H), 3.09 (dd, J = 15.3, 5.6 Hz, 1H), 3.04-2.92 (m, 2H), 1.41 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 172.4, 168.5, 166.2, 155.8, 138.0, 133.9, 128.9, 128.0, 123.6, 118.8, 80.1, 52.8, 51.0, 40.4, 39.4, 28.3, 27.5.

[0200] Compound 45b A white solid containing compound 44b was obtained from compound 43b (232.0 mg, 1.0 eq.) according to general procedure 6 (113.9 mg). A white solid 45b was obtained from the obtained solid (60.2 mg) and compound 31a (49.3 mg, 1.0 eq.) according to general procedure 4 (101.9 mg, yield quant.).

[0201] 1H-NMR (600 MHz, CDCl3) δ = 9.86 (s, 1H), 8.42 (dd, J = 8.3, 2.3 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 6.4 Hz, 1H), 7.35 (d, J = 3.9 Hz, 1H), 7.27-7.19 (m, 7H), 7.15-7.11 (m, 5H), 6.62 (dd, J = 3.9, 0.9 Hz, 1H), 5.57 (s, 1H), 4.86 (ddd, J = 6.4, 5.3, 4.8 Hz, 1H), 3.86 (s, 3H), 3.49-3.42 (m, 1H), 3.42 (dd, J = 15.3, 4.8 Hz, 1H), 3.39-3.32 (m, 1H), 3.18 (dd, J = 15.3, 5.3 Hz, 1H), 2.93-2.86 (m, 1H), 2.80-2.74 (m, 1H). 13 C-NMR (150 MHz, CDCl3) δ = 172.2, 168.4, 166.1, 162.3, 154.5, 142.8, 138.0, 136.5, 134.0, 128.9, 128.8, 128.7, 128.5, 127.9, 127.1, 127.0, 123.3, 118.6, 53.0, 52.4, 50.5, 40.4, 38.9, 27.4.

[0202] Compound 12 Compound 45b (43.9 mg, 1.0 eq.) was obtained as a white solid 12 (8.2 mg, yield 19%) using a conventional method.

[0203] 11H-NMR (600 MHz, DMSO-d6) δ = 12.85 (brs, 1H), 10.03 (s, 1H), 8.64 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 2.7, 2.7 Hz, 1H), 7.62 (dd, J = 8.2, 2.3 Hz, 1H), 7.58 (d, J = 3.8 Hz, 1H), 7.30 - 7.24 (m, 4H), 7.22 - 7.13 (m, 6H), 7.15 (d, J = 8.2 Hz, 1H), 6.69 (dd, J = 3.8, 1.0 Hz, 1H), 5.76 (s, 1H), 4.68 (ddd, J = 7.8, 7.7, 5.8 Hz, 1H), 2.89 (dd, J = 15.6, 5.8 Hz, 1H), 2.76 (m, 2H), 2.71 (dd, J = 15.6, 7.7 Hz, 1H), 2.46 - 2.42 (m, 2H). 13 13C-NMR (150 MHz, DMSO-d6) δ = 172.7, 168.2, 164.3, 160.9, 153.0, 143.2, 137.79, 137.76, 133.9, 129.6, 128.6, 128.56, 128.54, 127.8, 127.0, 126.8, 122.3, 117.7, 51.2, 49.3, 40.1, 37.9, 27.1. HRMS (ESI, m / z, [M+H] + ): calcd for C 31 H 27 N3O5S: 554.1744, found: 554.1743 (Δ = -0.2 ppm). HRMS (ESI, m / z, [M-H] - ): calcd for C 31 H 27 N3O5S: 552.1599, found: 552.1587 (Δ = -2.1 ppm). Purity (HPLC, 254 nm): >99%.

[0204] Synthesis of compound 13 compound 39h A white solid 39h (916.3 mg, 83% yield) was obtained from N-(tert-butoxycarbonyl)-L-aspartate 1-methyl 37a (718.6 mg, 1.0 eq.) and m-aminobenzoate methyl 38 g (487.8 mg, 1.1 eq.) according to general procedure 3.

[0205] 1 H-NMR (600 MHz, CDCl3) δ = 8.05 (s, 1H), 7.90 (s, 1H), 7.86 (dd, J = 8.0, 1.0 Hz, 1H), 7.80-7.76 (m, 1H), 7.39 (dd, J = 8.0, 8.0 Hz, 1H), 5.76 (d, J = 7.4 Hz, 1H), 4.60 (ddd, J = 7.4, 4.3, 3.8 Hz, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.12 (dd, J = 16.2, 3.8 Hz, 1H), 2.96 (dd, J = 16.2, 4.3 Hz, 1H), 1.45 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 171.8, 168.4, 166.7, 155.8, 137.8, 130.9, 129.2, 125.6, 124.4, 120.7, 80.4, 52.9, 52.3, 50.3, 39.4, 28.3.

[0206] compound 41h A pale yellow foam containing compound 40h was obtained from compound 39h (206.8 mg, 1.0 eq.) according to general procedure 6 (210.4 mg). A white solid 41h (106.0 mg, yield quant.) was obtained from the obtained foam (75.1 mg) and compound 31a (54.6 mg, 1.0 eq.) according to general procedure 4 (106.0 mg).

[0207] 1H-NMR (600 MHz, CDCl3) δ = 8.06 (dd, J = 1.6, 1.6 Hz, 1H), 8.02 (s, 1H), 7.83-7.79 (m, 1H), 7.79-7.75 (m, 1H), 7.43 (d, J = 3.9 Hz, 1H), 7.37 (dd, J = 7.9, 7.9 Hz, 1H), 7.32-7.27 (m, 4H), 7.26-7.22 (m, 3H), 7.20-7.16 (m, 4H), 6.70 (dd, J = 3.9, 1.0 Hz, 1H), 5.64 (s, 1H), 4.97 (ddd, J = 8.2, 4.3, 4.3 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.21 (dd, J = 16.3, 4.3 Hz, 1H), 3.08 (dd, J = 16.3, 4.3 Hz, 1H). 13 C-NMR (150 MHz, CDCl3) δ = 171.4, 168.5, 166.7, 161.9, 154.4, 142.8, 137.7, 136.3, 130.9, 129.1, 128.9, 128.8, 128.6, 127.13, 127.06, 125.6, 124.5, 120.8, 53.1, 52.4, 52.3, 49.4, 38.7.

[0208] Compound 13 Compound 41h (22.2 mg, 1.0 eq.) was obtained as a white solid 13 (9.0 mg, yield 43%).

[0209] 11H-NMR (600 MHz, CD3OD) δ = 8.19 (dd, J = 1.8, 1.6 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.74 (ddd, J = 7.8, 1.6, 1.3 Hz, 1H), 7.58 (d, J = 3.9 Hz, 1H), 7.39 (dd, J = 7.9, 7.8 Hz, 1H), 7.34 - 7.15 (m, 10H), 6.73 - 6.70 (m, 1H), 5.74 (s, 1H), 4.95 (dd, J = 6.8, 5.6 Hz, 1H), 3.08 (dd, J = 15.7, 5.6 Hz, 1H), 3.00 (dd, J = 15.7, 6.8 Hz, 1H). 13 13C-NMR (150 MHz, CD3OD) δ = 174.2, 171.0, 169.5, 164.3, 155.9, 144.6, 140.1, 138.1, 132.6, 130.1, 130.0, 129.9, 129.6, 128.3, 128.1, 126.3, 125.5, 122.3, 53.6, 51.0, 39.1. HRMS (ESI, m / z, [M + H] + ): calcd for C 29 H 24 N2O6S: 529.1428, found: 529.1428 (Δ = 0 ppm). HRMS (ESI, m / z, [M - H] - ): calcd for C 29 H 24 N2O6S: 527.1282, found: 527.1280 (Δ = -0.4 ppm). Purity (HPLC, 254 nm): >99%.

[0210] Synthesis of compound 14 Compound 48b Under an air atmosphere, N-(tert-butoxycarbonyl)-L-serine methyl ester 46 (498.3 mg, 1.0 eq.), dichloromethane (15.2 mL), water (4.1 μL, 0.1 eq.), 3-(methoxycarbonyl)phenylboronic acid 47b (409.7 mg, 1.0 eq.), DMAP (41.0 mg, 0.15 eq.), and copper(II) acetate (55.5 mg, 0.13 eq.) were added, and the mixture was stirred at room temperature overnight. Subsequently, copper(II) acetate (576.8 mg, 1.4 eq.) and DMAP (499.1 mg, 1.8 eq.) were added, and the mixture was stirred again at room temperature overnight. After confirming the completion of the reaction by TLC, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a clear oily substance 48b (262.2 mg, yield 33%).

[0211] 1 H-NMR (600 MHz, CDCl3) δ = 7.66 (ddd, J = 7.9, 1.4, 1.3 Hz, 1H), 7.54 (dd, J = 2.3, 1.4 Hz, 1H), 7.35 (dd, J = 8.1, 7.9 Hz, 1H), 7.08 (dd, J = 8.1, 2.3 Hz, 1H), 5.50 (d, J = 8.5 Hz, 1H), 4.69 (ddd, J = 8.5, 2.9, 2.7 Hz, 1H), 4.45 (dd, J = 9.1, 2.7 Hz, 1H), 4.26 (dd, J = 9.1, 2.9 Hz, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 1.46 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 170.4, 166.7, 158.2, 155.3, 131.5, 129.5, 122.8, 119.8, 115.0, 80.4, 68.5, 53.4, 52.8, 52.3, 28.3.

[0212] compound 50b Compound 48b (76.5 mg, 1.0 eq.) was obtained as a general compound, and compound 49b was obtained as a pale yellow solid (53.5 mg). A solid (42.2 mg), compound 31a (41.1 mg, 1.0 eq.), a general compound 4, and a transparent oil 50b (82.9 mg, yield quant.) were obtained.

[0213] 1 H-NMR (600 MHz, CDCl3) δ = 7.66 (ddd, J = 7.8, 1.4, 1.3 Hz, 1H), 7.54 (dd, J = 2.7, 1.4 Hz, 1H), 7.46 (d, J = 3.8 Hz, 1H), 7.33 (dd, J = 8.1, 7.8 Hz, 1H), 7.33-7.28 (m, 4H), 7.26-7.23 (m, 2H), 7.22-7.18 (m, 4H), 7.08 (ddd, J = 8.1, 2.7, 1.0 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.72 (dd, J = 3.8, 1.1 Hz, 1H), 5.66 (s, 1H), 5.11 (ddd, J = 7.7, 3.0, 2.8 Hz, 1H), 4.50 (dd, J = 9.3, 2.8 Hz, 1H), 4.38 (dd, J = 9.3, 3.0 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H). 13 C-NMR (150 MHz, CDCl3) δ = 170.0, 166.7, 161.6, 158.1, 154.2, 142.8, 136.2, 131.6, 129.5, 129.1, 128.8, 128.6, 127.1, 122.8, 119.7, 115.2, 68.2, 53.0, 52.52, 52.47, 52.2.

[0214] Compound 14 Compound 50b (41.6 mg, 1.0 eq.) was obtained as a white solid 14 (3.2 mg, yield 8%) using a conventional method.

[0215] 1 1H-NMR (600 MHz, CD3OD) δ = 7.64 (d, J = 3.9 Hz, 1H), 7.62 (ddd, J = 7.8, 1.1, 1.1 Hz, 1H), 7.59 (dd, J = 2.5, 1.4 Hz, 1H), 7.37 (dd, J = 7.9, 7.8 Hz, 1H), 7.33 - 7.28 (m, 4H), 7.26 - 7.17 (m, 7H), 6.72 (dd, J = 3.9, 0.8 Hz, 1H), 5.75 (s, 1H), 4.98 (dd, J = 5.9, 3.7 Hz, 1H), 4.48 (dd, J = 9.8, 5.9 Hz, 1H), 4.44 (dd, J = 9.8, 3.7 Hz, 1H). 13 13C-NMR (150 MHz, CD3OD) δ = 172.6, 169.6, 164.6, 160.0, 156.0, 144.7, 138.0, 133.4, 130.7, 130.3, 129.9, 129.6, 128.3, 128.1, 123.8, 120.9, 116.6, 68.9, 54.3, 53.6. HRMS (ESI, m / z, [M+H] + ): calcd for C 28 H 23 NO6S: 502.1319, found: 502.1321 (Δ = 0.4 ppm). HRMS (ESI, m / z, [M - H] - ): calcd for C 28 H 23 NO6S: 500.1173, found: 500.1165 (Δ = -1.7 ppm). Purity (HPLC, 254 nm): >99%.

[0216] Synthesis of Compound 15 Compound 43c White solid 43c (307.6 mg, 41% yield) was obtained from N-(tert-butoxycarbonyl)-L-aspartate 1-methyl 37a (497.4 mg, 1.0 eq.) and 5-amino-1H-pyrazole-3-carboxylate methyl ester 42c (311.8 mg, 1.1 eq.) according to general procedure 3.

[0217] 1 H-NMR (600 MHz, CDCl3) δ = 5.85 (s, 1H), 5.60-5.52 (m, 2H), 5.46 (d, J = 8.5 Hz, 1H), 4.78 (ddd, J = 8.5, 4.6, 4.6 Hz, 1H), 3.92 (s, 3H), 3.83 (dd, J = 18.4, 4.6 Hz, 1H), 3.76 (s, 3H), 3.70 (dd, J = 18.4, 4.6 Hz, 1H), 1.45 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 174.3, 171.6, 162.3, 155.3, 150.9, 147.1, 90.0, 80.3, 52.8, 52.5, 49.2, 38.5, 28.3.

[0218] compound 45c A pale yellow gum containing compound 44c was obtained from compound 43c (138.6 mg, 1.0 eq.) according to general procedure 6. A clear oily substance 45c (77.0 mg, 82% yield) was obtained from the obtained solid (80.7 mg) and compound 31a (50.7 mg, 1.0 eq.) according to general procedure 4.

[0219] 1H-NMR (600 MHz, CDCl3) δ = 10.23 (s, 1H), 7.43 (d, J = 3.8 Hz, 1H), 7.30 (m, 5H), 7.25 (m, 3H), 7.18-7.15 (m, 4H), 6.67 (dd, J = 3.8, 0.8 Hz, 1H), 5.82 (s, 1H), 4.96-4.91 (m, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.26 (d, J = 3.9 Hz, 2H). 13 C-NMR (150 MHz, CDCl3) δ = 171.4, 167.9, 162.2, 160.7, 154.5, 147.4, 142.8, 136.1, 134.4, 129.1, 128.8, 128.6, 127.2, 127.1, 100.4, 53.0, 52.7, 52.5, 49.8, 37.9.

[0220] Compound 15 Compound 45c (27.8 mg, 1.0 eq.) was obtained as a white solid 15 (6.0 mg, yield 23%) using a conventional method.

[0221] 1 H-NMR (600 MHz, DMSO-d6) δ = 13.27 (brs, 1H), 12.84 (brs, 1H), 10.65 (s, 1H), 8.68 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 3.8 Hz, 1H), 7.40-7.31 (m, 4H), 7.30-7.22 (m, 6H), 6.88 (s, 1H), 6.76 (dd, J = 3.8, 0.8 Hz, 1H), 5.83 (s, 1H), 4.74 (ddd, J = 7.8, 7.7, 5.7 Hz, 1H), 2.92 (dd, J = 15.8, 5.7 Hz, 1H), 2.77 (dd, J = 15.8, 7.8 Hz, 1H). 13C-NMR (150 MHz, DMSO-d6) δ = 172.7, 167.5, 160.9, 160.4, 153.0, 147.5, 143.2, 137.8, 134.5, 128.6, 128.50, 128.48, 127.0, 126.8, 99.1, 51.2, 49.2, 37.1. HRMS (ESI, m / z, [M+H] + ): calcd for C 26 H 22 N4O6S: 519.1333, found: 519.1322 (Δ = -2.1 ppm). HRMS (ESI, m / z, [MH] - ): calcd for C 26 H 22 N4O6S: 517.1187, found: 517.1195 (Δ = 1.5 ppm). Purity (HPLC, 254 nm): >99%.

[0222] Synthesis of compound 16 Compound 57a White form 57a was obtained from N-(tert-butoxycarbonyl)-L-aspartate 1-methyl 37a (696.2 mg, 1.0 eq.) and indoline-6-carboxylate methyl ester 56a (555.1 mg, 1.1 eq.) according to general procedure 3 (851.9 mg, yield 72%).

[0223] 1H-NMR (600 MHz, CDCl3) δ = 8.75 (d, J = 1.4 Hz, 1H), 7.76 (dd, J = 7.8, 1.4 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 5.86 (d, J = 9.0 Hz, 1H), 4.64 (ddd, J = 9.0, 4.0, 3.7 Hz, 1H), 4.13-4.06 (m, 2H), 3.90 (s, 3H), 3.78 (s, 3H), 3.30-3.20 (m, 3H), 2.92 (dd, J = 17.0, 4.0 Hz, 1H), 1.45 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 172.0, 168.6, 167.0, 155.8, 142.8, 136.4, 129.9, 126.1, 124.4, 117.6, 80.0, 52.8, 52.1, 49.8, 48.1, 38.3, 28.3, 28.1.

[0224] Compound 59a A pale yellow solid containing compound 58a was obtained from compound 57a (361.4 mg, 1.0 eq.) according to general procedure 6 (319.6 mg). A white solid 59a was obtained from the obtained solid (71.9 mg) and compound 31a (56.7 mg, 1.0 eq.) according to general procedure 4 (93.5 mg, yield 83%).

[0225] 1H-NMR (600 MHz, CDCl3) δ = 8.73 (d, J = 1.4 Hz, 1H), 7.76 (dd, J =7.8, 1.4 Hz, 1H), 7.44 (d, J = 3.8 Hz, 1H), 7.33-7.18 (m, 12H), 6.71 (dd, J = 3.8, 1.1 Hz, 1H), 5.65 (s, 1H), 5.07 (ddd, J = 8.0, 3.9, 3.7 Hz, 1H), 4.14-4.04 (m, 2H), 3.90 (s, 3H), 3.80 (s, 3H), 3.25 (dd, J = 17.2, 3.7 Hz, 1H), 3.26-3.21 (m, 2H), 3.04 (dd, J = 17.2, 3.9 Hz, 1H). 13 C-NMR (150 MHz, CDCl3) δ = 171.6, 168.5, 167.0, 161.6, 154.0, 142.9, 142.7, 136.7, 136.5, 129.9, 128.8, 128.7, 128.6, 127.0, 126.1, 124.5, 117.7, 53.0, 52.5, 52.1, 48.8, 48.1, 37.9, 28.1.

[0226] Compound 16 Compound 59a (41.9 mg, 1.0 eq.) was obtained as a white solid 16 (22.3 mg, yield 56%) using a conventional method.

[0227] 11H-NMR (600 MHz, CD3OD) δ = 8.74 (d, J = 0.9 Hz, 1H), 7.72 (dd, J = 7.7, 0.9 Hz, 1H), 7.58 (d, J = 3.8 Hz, 1H), 7.32 - 7.27 (m, 5H), 7.25 - 7.18 (m, 6H), 6.72 (d, J = 3.8 Hz, 1H), 5.74 (s, 1H), 5.00 (dd, J = 5.8, 5.3 Hz, 1H), 4.20 - 4.15 (m, 2H), 3.27 - 3.22 (m, 2H), 3.19 (dd, J = 16.9, 5.8 Hz, 1H), 3.15 (dd, J = 16.9, 5.3 Hz, 1H). 13 13C-NMR (150 MHz, CD3OD) δ = 174.4, 170.7, 169.8, 164.2, 155.9, 144.7, 144.3, 139.0, 138.1, 131.2, 130.1, 129.9, 129.6, 128.3, 128.1, 127.1, 125.7, 119.0, 53.6, 50.6, 49.4, 38.4, 29.0. HRMS (ESI, m / z, [M+H] + ): calculated for C 31 H 26 N2O6S: 555.1584, found: 555.1570 (Δ = -2.6 ppm). HRMS (ESI, m / z, [M-H] - ): calculated for C 31 H 26 N2O6S: 553.1439, found: 553.1432 (Δ = -1.2 ppm). Purity (HPLC, 254 nm): >99%.

[0228] Synthesis of Compound 17 Compound 57b White form 57b was obtained from N-(tert-butoxycarbonyl)-L-aspartate 1-methyl 37a (1.20 g, 1.0 eq.) and 1,2,3,4-tetrahydroquinoline-7-carboxylate methyl ester 56b (1.12 g, 1.2 eq.) according to general procedure 5 (1.90 g, 93% yield).

[0229] 1 H-NMR (600 MHz, CDCl3) δ = 8.70-7.58 (m, 2H), 7.30-7.15 (m, 1H), 5.80 (s, 1H), 4.57 (s, 1H), 3.92 (s, 3H), 3.83-3.70 (m, 1H), 3.75 (s, 3H), 3.40-3.16 (m, 2H), 2.95 (dd, J = 16.4, 2.0 Hz, 1H), 2.79 (s, 2H), 1.99 (s, 2H), 1.44 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 172.1, 170.1, 166.5, 155.7, 139.2 (br), 138.7 (br), 128.8, 128.5 (br), 126.8 (br), 125.7 (br), 79.9, 52.6, 52.3, 50.4, 42.6 (br), 37.3, 28.3, 27.0, 23.6.

[0230] Compound 59b Compound 57b (741.0 mg, 1.0 eq.) was prepared according to general procedure 6 to obtain a pale yellow solid containing compound 58b (684.6 mg). The obtained solid (38.8 mg) and compound 31a (54.0 mg, 1.0 eq.) were prepared according to general procedure 4 to obtain a clear oily substance 59b (43.5 mg, 40% yield).

[0231] 1H-NMR (600 MHz, CDCl3) δ = 8.60-7.60 (m, 2H), 7.42 (d, J = 3.8 Hz, 1H), 7.34-7.28 (m, 5H), 7.28-7.18 (m, 7H), 6.71 (dd, J = 3.8, 0.9 Hz, 1H), 5.66 (s, 1H), 5.02 (s, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.80-3.68 (m, 2H), 3.37 (d, J = 15.0 Hz, 1H), 3.00 (s, 1H), 2.76 (s, 2H), 1.96 (s, 2H). 13 C-NMR (150 MHz, CDCl3) δ = 171.6, 170.5, 166.4, 161.5, 153.9, 142.9, 139.2 (br), 138.5 (br), 136.8, 128.9, 128.8, 128.60, 128.58, 127.03, 127.02, 126.1 (br), 125.5 (br), 52.8, 52.5, 52.3, 49.2, 42.6 (br), 37.0, 27.0, 23.6.

[0232] Compound 17 Compound 59b (29.9 mg, 1.0 eq.) was obtained as a white solid 17 (11.6 mg, yield 41%).

[0233] 1 H-NMR (600 MHz, DMSO-d6) δ = 12.78 (brs, 2H), 8.59 (d, J = 7.9 Hz, 1H), 8.50-7.50 (m, 3H), 7.38-7.22 (m, 11H), 6.76 (d, J = 3.5 Hz, 1H), 5.83 (s, 1H), 4.82 (m, 1H), 3.75-3.65 (m, 2H), 3.14-3.04 (m, 1H), 2.94 (s, 1H), 2.80-2.68 (m, 2H), 1.94-1.83 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ = 172.6, 169.2, 167.0, 160.6, 152.8, 143.1, 138.3 (br), 137.7, 128.6, 128.4, 128.4, 128.3, 126.8, 126.7, 125.5, 51.1, 49.5, 44.3 (br), 35.7, 26.4, 23.0. HRMS (ESI, m / z, [M+H] + ): calcd for C 32 H 28 N2O6S: 569.1741, found: 569.1742 (Δ = 0.2 ppm). HRMS (ESI, m / z, [MH] - ): calcd for C 32 H 28 N2O6S: 567.1595, found: 567.1591 (Δ = -0.8 ppm). Purity (HPLC, 254 nm): >99%.

[0234] Synthesis of compound 18 compound 57c N-(tert-butoxycarbonyl)-β-alanine 37c (332.0 mg, 1.0 eq.) and 1,2,3,4-tetrahydroquinoline-7-carboxylate methyl ester 56b (401.0 mg, 1.2 eq.) were mixed according to general procedure 5 to obtain a pale yellow oily substance 57c (577.9 mg, yield 91%).

[0235] 1H-NMR (600 MHz, CDCl3) δ = 8.43 (brs, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 5.32 (s, 1H), 3.91 (s, 3H), 3.77 (s, 2H), 3.45 (s, 2H), 2.86-2.73 (m, 2H), 2.70 (t, J = 5.5 Hz, 2H), 1.98 (tt, J = 6.4, 6.4 Hz, 2H), 1.42 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 171.5, 166.6, 156.0, 138.5 (br), 128.8, 128.4, 126.4 (br), 125.8, 79.1, 52.2, 42.6 (br), 36.6, 35.0, 28.4, 27.1, 23.7.

[0236] Compound 59c Compound 57c (236.9 mg, 1.0 eq.) was obtained as a general compound, and compound 58c was obtained as a pale yellow solid (186.8 mg). A solid (80.9 mg), compound 31a (75.1 mg, 1.0 eq.), a general compound 4, and a white solid 59c (119.9 mg, yield 87%) were obtained.

[0237] 1 H-NMR (600 MHz, CDCl3) δ = 8.46 (brs, 1H), 7.79 (d, J = 6.6 Hz, 1H), 7.34 (d, J = 3.8 Hz, 1H), 7.33-7.28 (m, 4H), 7.28-7.17 (m, 7H), 6.91 (s, 1H), 6.67 (dd, J = 3.8, 0.7 Hz, 1H), 5.64 (s, 1H), 3.90 (s, 3H), 3.76 (s, 2H), 3.72 (s, 2H), 2.85-2.70 (m, 4H), 2.03-1.90 (m, 2H). 13C-NMR (150 MHz, CDCl3) δ = 171.7, 166.5, 161.9, 153.2, 143.0, 139.2 (br), 138.5 (br), 137.6, 129.0, 128.84, 128.79, 128.6, 128.0, 127.1, 127.0, 126.9, 125.7 (br), 52.4, 52.3, 42.6 (br), 35.8, 34.6, 27.1, 23.6.

[0238] Compound 18 Compound 59c (50.9 mg, 1.0 eq.) was obtained as a white solid 18 (24.7 mg, yield 50%).

[0239] 1 H-NMR (600 MHz, CD3OD) δ = 8.60-7.65 (m, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.45 (s, 1H), 7.35-7.27 (m, 4H), 7.26-7.18 (m, 7H), 6.69 (dd, J = 3.7, 0.8 Hz, 1H), 5.73 (s, 1H), 3.80-3.74 (m, 2H), 3.65-3.55 (m, 2H), 2.87 (t, J = 6.4 Hz, 2H), 2.72 (s, 2H), 1.98-1.88 (m, 2H). 13 C-NMR (150 MHz, CD3OD) δ = 173.2, 169.4, 164.4, 155.4, 144.7, 140.8 (br), 139.8 (br), 138.6, 129.9, 129.6, 128.2, 128.1, 127.4 (br), 53.6, 44.5 (br), 37.7, 35.1, 27.9, 24.8. HRMS (ESI, m / z, [M+H] + ): calcd for C 31 H 28 N2O4S: 525.1843, found: 525.1852 (Δ = 1.8 ppm). HRMS (ESI, m / z, [MH] - ): calcd for C 31 H 28 N2O4S: 523.1697, found: 523.1677 (Δ = -3.8 ppm). Purity (HPLC, 254 nm): >99%.

[0240] Synthesis of compound 19 Compound 59d Compound 31b (75.4 mg, 1.0 eq.) and compound 58b (91.2 mg, 1.05 eq.) were generally processed together, and a white solid 59d was obtained (116.1 mg, yield 78%).

[0241] 1 H-NMR (600 MHz, CDCl3) δ = 8.36 (brs, 1H), 7.80 (m, 1H), 7.33-7.28 (m, 4H), 7.27-7.19 (m, 7H), 7.16 (d, J = 8.2 Hz, 1H), 6.52 (s, 1H), 5.58 (s, 1H), 5.02 (s, 1H), 3.90 (s, 3H), 3.82-3.69 (m, 2H), 3.76 (s, 3H), 3.36 (d, J = 16.4 Hz, 1H), 3.00 (s, 1H), 2.75 (s, 2H), 2.46 (s, 3H), 1.94 (s, 2H). 13 C-NMR (150 MHz, CDCl3) δ = 171.8, 170.4, 166.4, 162.6, 150.3, 142.9, 140.9, 139.1 (br), 138.5 (br), 131.5, 130.0, 128.9, 128.8, 128.6, 127.0, 126.0 (br), 125.5 (br), 52.8, 52.3, 49.2, 45.4, 42.6, 37.1, 27.0, 23.6, 16.0.

[0242] Compound 19 Compound 59d (49.1 mg, 1.0 eq.) was obtained as a white solid 19 (20.4 mg, yield 44%).

[0243] 1 H-NMR (600 MHz, CD3OD) δ = 8.35 (brs, 1H), 7.78 (s, 1H), 7.33-7.27 (m, 4H), 7.27 (d, J = 7.8 Hz, 1H), 7.25-7.19 (m, 6H), 6.57 (s, 1H), 5.67 (s, 1H), 4.93 (s, 1H), 3.88-3.78 (m, 1H), 3.72 (s, 1H), 3.30-3.10 (m, 2H), 2.76 (s, 2H), 2.40 (s, 3H), 1.95 (s, 2H). 13 C-NMR (150 MHz, CD3OD) δ = 174.2, 172.2, 169.3, 165.0, 152.3, 144.6, 142.5, 140.9 (br), 139.9 (br), 132.5, 130.8, 130.0, 129.9, 129.6, 128.1, 127.2 (br), 53.4, 51.1, 44.1, 37.4, 27.9, 24.8, 16.0. HRMS (ESI, m / z, [MH] - ): calcd for C 33 H 30 N2O6S: 581.1752, found: 581.1745 (Δ = -1.2 ppm). Purity (HPLC, 254 nm): 98.7%.

[0244] Synthesis of compound 20 Compound 59e A pale yellow oily substance containing compound 30d was obtained from compound 29d (2.68 g, 1.0 eq.) according to general procedure 2 (2.80 g). A purple gum containing compound 31d was obtained from the obtained oily substance (1.08 g) according to general procedure 7 (0.900 g). A white solid 59e was obtained from the obtained gum (75.1 mg) and compound 58b (85.4 mg) according to general procedure 5 (94.3 mg, yield 64% (3 steps)).

[0245] 1 H-NMR (600 MHz, CDCl3) δ = 8.41 (brs, 1H), 7.80 (s, 1H), 7.43 (d, J = 3.8 Hz, 1H), 7.40-7.29 (m, 1H), 7.28-7.19 (m, 1H), 7.17-7.10 (m, 4H), 7.04-6.97 (m, 4H), 6.68 (dd, J = 3.8, 1.1 Hz, 1H), 5.83 (s, 1H), 5.02 (s, 1H), 3.91 (s, 3H), 3.76 (s, 3H), 3.74-3.67 (m, 2H), 3.38 (d, J = 12.8 Hz, 1H), 3.00 (s, 1H), 2.77 (s, 2H), 1.97 (s, 2H). 13 C-NMR (150 MHz, CDCl3) δ = 171.6, 170.5 (br), 166.4 (br), 161.9 (d, J = 246.3 Hz), 161.3, 153.4, 139.2 (br), 138.5 (d, J = 3.3 Hz), 137.2, 130.2 (d, J = 8.4 Hz), 128.9, 128.6, 127.2, 127.0, 126.1 (br), 125.4 (br), 115.5 (d, J = 21.5 Hz), 52.8, 52.3, 50.9, 49.2, 42.7 (br), 36.9, 27.0, 23.6.

[0246] compound 20 Compound 59e (49.0 mg, 1.0 eq.) was obtained as a white solid 20 ml using a conventional method (25.8 mg, yield 55%).

[0247] 1 H-NMR (600 MHz, CD3OD) δ = 8.60-7.64 (m, 2H), 7.54 (s, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.25-7.16 (m, 4H), 7.11-7.00 (m, 4H), 6.72 (dd, J = 3.9, 1.0 Hz, 1H), 5.79 (s, 1H), 5.04-4.95 (m, 1H), 3.85-3.73 (m, 2H), 3.25-3.05 (m, 2H), 2.78 (s, 2H), 1.96 (s, 2H). 13 C-NMR (150 MHz, CD3OD) δ = 174.2, 172.0, 169.4, 163.9, 163.3 (d, J = 244.1 Hz), 155.4, 140.5 (d, J = 3.2 Hz), 139.9 (br), 138.4, 131.6 (d, J = 7.6 Hz), 130.2, 130.0, 128.3, 128.1 (br), 127.3 (br), 116.3 (d, J = 21.8 Hz), 51.9, 51.3, 44.2 (br), 37.3, 27.9, 24.7. HRMS (ESI, m / z, [M+H] + ): calcd for C 32 H 26 F2N2O6S: 605.1552, found: 605.1567 (Δ = 2.4 ppm). HRMS (ESI, m / z, [MH] - ): calcd for C 32 H 26 F2N2O6S: 603.1407, found: 603.1403 (Δ = -0.6 ppm). Purity (HPLC, 254 nm): 98.8%.

[0248] Synthesis of Compound 21 compound 59f A pale yellow oily substance containing compound 30e was obtained from compound 29e (3.05 g, 1.0 eq.) according to general procedure 2 (3.20 g). A pale orange solid containing compound 31e was obtained from the obtained oily substance (1.14 g) according to general procedure 7 (0.936 g). A white solid 59f was obtained from the obtained solid (88.4 mg) and compound 58b (92.1 mg) according to general procedure 5 (116.4 mg, yield 69% (3 steps)).

[0249] 1 H-NMR (600 MHz, CDCl3) δ = 8.39 (brs, 1H), 7.80 (s, 1H), 7.43 (d, J = 3.8 Hz, 1H), 7.36 (s, 1H), 7.31-7.27 (m, 4H), 7.23 (s, 1H), 7.13-7.08 (m, 4H), 6.68 (dd, J = 3.8, 1.0 Hz, 1H), 5.60 (s, 1H), 5.02 (s, 1H), 3.91 (s, 3H), 3.76 (s, 3H), 3.74-3.68 (m, 2H), 3.38 (d, J = 14.2 Hz, 1H), 3.00 (s, 1H), 2.77 (s, 2H), 1.97 (m, 2H). 13 C-NMR (150 MHz, CDCl3) δ = 171.5, 170.5 (br), 166.4 (br), 161.3, 152.4, 140.9, 139.2 (br), 138.5 (br), 137.4, 133.2, 130.0, 128.9, 128.9, 128.6, 127.2, 126.1 (br), 125.5 (br), 52.8, 52.3, 51.1, 49.2, 42.6 (br), 36.9, 27.0, 23.6.

[0250] compound 21 Compound 59f (50.7 mg, 1.0 eq.) was obtained as a white solid 21 (25.5 mg, yield 52%).

[0251] 1 H-NMR (600 MHz, CD3OD) δ = 8.70-7.64 (m, 2H), 7.55 (s, 1H), 7.40-7.28 (m, 4H), 7.27 (d, J = 7.7 Hz, 1H), 7.23-7.15 (m, 4H), 6.73 (dd, J = 3.7, 0.8 Hz, 1H), 5.78 (s, 1H), 5.05-4.95 (m, 1H), 3.86-3.72 (m, 2H), 3.26-3.00 (m, 2H), 2.77 (s, 2H), 1.95 (s, 2H). 13 C-NMR (150 MHz, CD3OD) δ = 174.2, 172.0, 169.4, 163.8, 154.5, 143.0, 141.1 (br), 139.9 (br), 138.6, 134.1, 131.5, 130.2, 130.0, 129.8, 128.5, 128.1 (br), 127.3 (br), 52.0, 51.3, 44.2 (br), 37.3, 27.9, 24.7. HRMS (ESI, m / z, [MH] - ): calcd for C 32 H 26 Cl2N2O6S: 635.0816, found: 635.0803 (Δ = -2.0 ppm). Purity (HPLC, 254 nm): >99%.

[0252] Synthesis of compound 22 59g of compound Compound 31c (42.1 mg, 1.0 eq.) and compound 58b (45.8 mg, 1.05 eq.) were obtained as a white solid 59g (68.9 mg, yield 87%).

[0253] 1 H-NMR (600 MHz, CDCl3) δ = 8.60-7.56 (m, 2H), 7.30-7.16 (m, 2H), 7.16-7.10 (m, 4H), 7.04-6.96 (m, 4H), 6.49 (d, J = 0.5 Hz, 1H), 5.56 (s, 1H), 5.02 (s, 1H), 3.91 (s, 3H), 3.76 (s, 3H), 3.74-3.68 (m, 2H), 3.37 (d, J = 16.3 Hz, 1H), 2.96 (s, 1H), 2.76 (s, 2H), 2.47 (s, 3H), 1.95 (s, 2H). 13 C-NMR (150 MHz, CDCl3) δ = 171.7, 170.5 (br), 166.4 (br), 162.4, 161.8 (d, J = 246.4 Hz), 149.9, 140.9, 139.1 (br), 138.48 (d, J = 2.7 Hz), 138.46 (d, J = 2.4 Hz), 131.4, 130.4, 130.2 (d, J = 8.4 Hz), 128.9, 128.7 (br), 127.1 (br), 125.5 (br), 115.5 (d, J = 20.7 Hz), 52.8, 52.3, 50.7, 49.2, 42.7 (br), 37.0, 27.0, 23.6, 16.0.

[0254] Compound 22 Compound 59g (33.2 mg, 1.0 eq.) was obtained by using a normal method of 8% and 22% as a white solid (19.5 mg, yield 61%).

[0255] 11H-NMR (600 MHz, CD3OD) δ = 8.70 - 7.60 (m, 2H), 7.27 (d, J = 4.3 Hz, 1H), 7.24 - 7.19 (m, 4H), 7.07 - 7.01 (m, 4H), 6.57 (d, J = 2.1 Hz, 1H), 5.71 (d, J = 3.6 Hz, 1H), 4.93 (s, 1H), 3.90 - 3.77 (m, 1H), 3.72 (s, 1H), 3.29 - 3.05 (m, 2H), 2.76 (s, 2H), 2.40 (s, 3H), 1.95 (s, 2H). 13 13C-NMR (150 MHz, CD3OD) δ = 174.2, 172.2, 169.4, 164.8, 163.3 (d, J = 244.7 Hz), 151.9, 142.6, 140.5 (d, J = 3.2 Hz), 140.0 (br), 132.5, 131.6 (d, J = 7.6 Hz), 131.1, 130.3, 130.0, 128.2 (br), 127.2 (br), 116.3 (d, J = 21.8 Hz), 51.7, 51.1, 44.1 (br), 37.4, 27.9, 24.7, 16.0. HRMS (ESI, m / z, [M + H] + ): calcd for C 33 H 28 F2N2O6S:​​​​​​​​​​​​​​​​​N-(tert-butoxycarbonyl)-L-aspartate 1-methyl 37a (602.5 mg, 1.0 eq.) and 1,2,3,4-tetrahydroquinoline-7-carboxamide 56c (514.6 mg, 1.2 eq.) were mixed according to general procedure 5 to obtain a white solid 57d (931.4 mg, yield 94%).

[0257] 1 H-NMR (600 MHz, CDCl3) δ = 8.16 (brs, 1H), 7.64 (d, J = 4.9 Hz, 1H), 7.28-7.20 (m, 1H), 6.65 (brs, 1H), 5.82 (d, J = 8.0 Hz, 1H), 5.72 (s, 1H), 4.70-4.35 (m, 1H), 3.84 (s, 1H), 3.77 (s, 3H), 3.73-3.66 (m, 1H), 3.23 (s, 1H), 3.16 (s, 1H), 2.85-2.70 (m, 2H), 2.10-1.90 (m, 2H), 1.45 (s, 9H). 13 C-NMR (150 MHz, CDCl3) δ = 172.1, 169.9, 168.7 (br), 155.8, 138.2 (br), 131.6, 129.1, 124.8 (br), 123.5, 80.2, 52.8, 50.6, 42.9, 36.9, 28.4, 26.9, 23.7.

[0258] compound 59h Compound 57d (475.1 mg, 1.0 eq.) was prepared according to general procedure 6 to obtain a pale yellow solid containing compound 58d (412.9 mg). From the obtained solid (52.2 mg) and compound 31b (50.5 mg, 1.0 eq.), a yellow solid 59h was obtained according to general procedure 4 (71.5 mg, yield 73%).

[0259] 1H-NMR (600 MHz, CDCl3) δ = 7.71 (brs, 1H), 7.51 (brs, 1H), 7.35-7.29 (m, 5H), 7.28-7.13 (m, 8H), 6.53 (s, 1H), 5.61 (brs, 1H), 5.58 (s, 1H), 4.82 (brs, 1H), 4.02 (brs, 1H), 3.80 (s, 3H), 3.53 (brs, 2H), 3.19 (brs, 1H), 2.74 (brs, 2H), 2.47 (s, 3H), 2.16-1.80 (m, 2H). 13 C-NMR (150 MHz, CDCl3) δ = 171.8, 169.9, 168.5 (br), 163.2 (br), 151.1 (br), 142.8, 142.7, 141.1, 138.4 (br), 131.9 (br), 131.7, 129.8, 129.0, 128.8, 128.8, 128.6, 127.1, 125.8 (br), 123.4, 53.0, 52.3, 50.2 (br), 42.7 (br), 35.9 (br), 26.8, 23.7, 16.1.

[0260] Compound 23 Compound 59h (30.6 mg, 1.0 eq.) was obtained as a white solid 23 (14.5 mg, yield 48%).

[0261] 1 H-NMR (600 MHz, CD3OD) δ = 8.30-7.44 (m, 2H), 7.32-7.28 (m, 4H), 7.27 (d, J = 7.9 Hz, 1H), 7.25-7.19 (m, 6H), 6.57 (s, 1H), 5.67 (s, 1H), 4.93 (s, 1H), 3.82 (s, 1H), 3.70 (s, 1H), 3.23-3.17 (m, 2H), 2.75 (s, 2H), 2.40 (s, 3H), 1.95 (s, 2H). 13C-NMR (150 MHz, CD3OD) δ = 174.3, 172.3, 171.6 (br), 165.0, 152.3, 144.6, 142.6, 139.9 (br), 133.2 (br), 132.5, 130.8, 130.0, 129.9, 129.6, 128.1, 126.2 (br), 125.2, 53.4, 51.1 (br), 44.1 (br), 37.4 (br), 27.7, 24.8, 16.0. HRMS (ESI, m / z, [M+H] + ): calcd for C 33 H 31 N3O5S: 582.2057, found: 582.2044 (Δ = -2.3 ppm). HRMS (ESI, m / z, [MH] - ): calcd for C 33 H 31 N3O5S: 580.1912; found: 580.1893 (Δ = -3.2 ppm). Purity (HPLC, 254 nm): >99%.

[0262] Synthesis of Compound 24 Compound 59i Compound 31c (51.4 mg, 1.0 eq.) and compound 58d (52.2 mg, 1.0 eq.) were obtained as a light yellow solid 59i (78.8 mg, yield 84%).

[0263] 1H-NMR (600 MHz, CDCl3) δ = 7.80-7.36 (m, 2H), 7.28-7.20 (m, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.17-7.12 (m, 4H), 7.03-6.98 (m, 4H), 6.50 (s, 1H), 5.57 (brs, 1H), 5.56 (s, 1H), 4.83 (brs, 1H), 4.02 (brs, 1H), 3.80 (s, 3H), 3.51 (brs, 2H), 3.23 (brs ,1H), 2.75 (s, 2H), 2.47 (s, 3H), 2.05-1.97 (m, 1H), 1.89 (brs, 1H). 13 C-NMR (150 MHz, CDCl3) δ = 171.8, 169.9, 168.4 (br), 163.0 (br), 161.9 (d, J = 246.3 Hz), 150.5 (br), 141.0, 138.3 (d, J = 3.0 Hz), 131.8 (br), 131.6, 130.3, 130.22 (d, J = 7.6 Hz), 130.21, 129.08, 129.06, 125.6 (br), 123.4, 115.5 (d, J = 21.8 Hz), 53.0, 50.7, 50.2 (br), 42.7 (br), 35.9 (br), 26.8, 23.7, 16.1.

[0264] Compound 24 Compound 59i (31.1 mg, 1.0 eq.) was obtained as a white solid 24 (15.8 mg, yield 51%) using a conventional method.

[0265] 11H-NMR (600 MHz, CD3OD) δ = 8.40 - 7.40 (m, 2H), 7.28 (d, J = 7.7 Hz, 1H), 7.24 - 7.20 (m, 4H), 7.07 - 7.02 (m, 4H), 6.58 (s, 1H), 5.72 (s, 1H), 4.93 (s, 1H), 3.90 - 3.78 (m, 1H), 3.71 (s, 1H), 3.30 - 3.17 (m, 2H), 2.76 (s, 2H), 2.41 (s, 3H), 1.96 (s, 2H). 13 13C-NMR (150 MHz, CD3OD) δ = 174.2, 172.3, 171.6 (br), 164.9, 163.3 (d, J = 244.1 Hz), 151.9, 142.7, 140.5 (d, J = 3.3 Hz), 139.8 (br), 133.2 (br), 132.5, 131.6 (d, J = 8.7 Hz), 131.1, 130.0, 126.2 (br), 125.2, 116.3 (d, J = 21.5 Hz), 51.7, 51.1 (br), 44.1 (br), 37.3 (br), 27.7, 24.8, 16.0. HRMS (ESI, m / z, [M+H] + ): calcd for C 33 H 29 F2N3O5S: 618.1869, found: 618.1850 (Δ = -3.0 ppm). HRMS (ESI, m / z, [M-H] - ): calcd for C 33 H 29 F2N3O5S: 616.1723, found: 616.1723 (Δ = 0.0 ppm). Purity (HPLC, 254 nm): 98.2%.

[0266] Synthesis of Compound 25 Compound 59j Compound 36 (39.9 mg, 1.0 eq.) and compound 58b (45.7 mg, 1.0 eq.) were obtained as a white solid 59j (68.4 mg, yield 89%).

[0267] 1 H-NMR (600 MHz, CDCl3) δ = 8.60-7.56 (m, 2H), 7.21 (d, J = 6.2 Hz, 1H), 7.14-6.97 (m, 10H), 6.34-6.32 (m, 2H), 5.07 (s, 1H), 3.90 (s, 3H), 3.80-3.70 (m, 2H), 3.75 (s, 3H), 3.37 (d, J = 15.4 Hz, 1H), 3.03 (brs, 1H), 2.87-2.60 (m, 2H), 2.30 (s, 3H), 1.95 (s, 2H). 13 C-NMR (150 MHz, CDCl3) δ = 172.3, 170.6 (br), 166.5 (br), 164.9, 162.5 (d, J = 248.2 Hz), 138.8 (br), 135.33 (d, J = 3.0 Hz), 135.31 (d, J = 3.3 Hz), 129.84 (d, J = 7.9 Hz), 129.82 (d, J = 8.4 Hz), 128.9, 128.5 (br), 126.9 (br), 125.6 (br), 124.3, 120.7, 119.0, 118.2, 115.8 (d, J = 21.8 Hz), 65.7, 52.7, 52.2, 48.7, 42.6 (br), 37.3, 27.0, 23.6, 12.1.

[0268] Compound 25 Compound 59j (30.0 mg, 1.0 eq.) was obtained as a white solid (18.2 mg, yield 63%) using a conventional method of 8%.

[0269] 1H-NMR (600 MHz, CD3OD) δ = 8.70 - 7.56 (m, 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.19 - 7.06 (m, 9H), 6.57 (s, 1H), 6.48 (dd, J = 2.3, 1.1 Hz, 1H), 4.93 (s, 1H), 3.81 - 3.72 (m, 2H), 3.28 - 3.08 (m, 2H), 2.75 (s, 2H), 2.22 (s, 3H), 1.94 (s, 2H). 13 C-NMR (150 MHz, CD3OD) δ = 174.7, 172.4, 169.4 (br), 167.7, 163.9 (d, J = 245.8 Hz), 139.9 (br), 137.51 (d, J = 3.3 Hz), 137.49 (d, J = 2.2 Hz), 131.28 (d, J = 7.9 Hz), 131.26 (d, J = 8.5 Hz), 130.2 (br), 130.0, 128.2 (br), 127.3 (br), 125.3, 122.3, 120.9, 118.6, 116.6 (d, J = 22.0 Hz), 66.6, 50.5 (br), 44.1 (br), 37.7, 27.9, 24.8, 12.1. HRMS (ESI, m / z, [M+H] + ): calcd for C 33 H 29 F2N3O6: 602.2097, found: 602.2079 (Δ = -3.0 ppm). HRMS (ESI, m / z, [M-H] - ): calcd for C 33 H 29 F2N3O6: 600.1952, found: 600.1940 (Δ = -1.9 ppm). Purity (HPLC, 254 nm): 92.8%.

[0270] Synthesis of Compound 26 Compound 59k Compound 36 (49.7 mg, 1.0 eq.) and compound 58d (54.9 mg, 1.0 eq.) were obtained as a regular 4-color solid and a green color solid 59k (62.8 mg, yield 67%).

[0271] 1 H-NMR (600 MHz, CDCl3) δ = 7.82-7.30 (m, 2H), 7.24 (d, J = 7.7 Hz, 1H), 7.12-6.97 (m, 10H), 6.36-6.30 (m, 2H), 5.51 (brs, 1H), 4.80 (brs, 1H), 4.13 (s, 1H), 3.82 (s, 3H), 3.80-3.59 (m, 1H), 3.41 (brs, 1H), 3.12 (brs, 1H), 2.84-2.60 (m, 2H), 2.29 (d, J = 0.7 Hz, 3H), 2.09-1.94 (m, 1H), 1.86 (brs, 1H). 13 C-NMR (150 MHz, CDCl3) δ = 172.3, 170.0, 168.5 (br), 165.8 (br), 162.52 (d, J = 247.6 Hz), 162.51 (d, J = 248.7 Hz), 138.5 (br), 135.2 (d, J = 3.0 Hz), 135.1 (d, J = 2.7 Hz), 131.9 (br), 129.85 (d, J = 7.9 Hz), 129.77 (d, J = 7.9 Hz), 129.0, 126.0 (br), 124.6, 123.4, 121.0, 118.9, 117.8, 115.9 (d, J = 21.8 Hz), 65.8, 52.9, 49.9 (br), 42.5 (br), 35.9 (br), 26.8, 23.8, 12.1.

[0272] Compound 26 Compound 59k (28.9 mg, 1.0 eq.) was obtained as a white solid 26 (14.6 mg, yield 52%).

[0273] 1 1H-NMR (600 MHz, CD3OD) δ = 8.40 - 7.44 (m, 2H), 7.27 (d, J = 7.9 Hz, 1H), 7.14 (s, 1H), 7.14 - 7.06 (m, 8H), 6.57 (s, 1H), 6.47 (dd, J = 2.5, 1.1 Hz, 1H), 4.92 (s, 1H), 3.83 - 3.68 (m, 2H), 3.25 - 3.13 (m, 2H), 2.74 (s, 2H), 2.22 (s, 3H), 1.94 (s, 2H). 13 13C-NMR (150 MHz, CD3OD) δ = 174.8, 172.4, 171.7 (br), 167.7, 163.9 (d, J = 245.5 Hz), 139.8 (br), 137.50 (d, J = 3.0 Hz), 137.5 (d, J = 2.5 Hz), 133.2 (br), 131.28 (d, J = 7.9 Hz), 131.25 (d, J = 8.8 Hz), 130.0, 126.1 (br), 125.3, 122.4, 120.9, 118.6, 116.6 (d, J = 22.1 Hz), 66.6, 50.6 (br), 44.1 (br), 37.6 (br), 27.7, 24.8, 12.1. HRMS (ESI, m / z, [M + H] + ): calcd for C 33 H 30 F2N4O5: 601.2257, found: 601.2248 (Δ = -1.5 ppm). HRMS (ESI, m / z, [M - H] - ): calcd for C 33 H 30 F2N4O5: 599.2111, found: 599.2108 (Δ = -0.6 ppm). Purity (HPLC, 254 nm): 93.8%.

[0274] Test Example 1 Activity Evaluation cell culture Human Embryonic Kidney cells 293 (HEK293) obtained from Cell Lines Service were used for activity evaluation. Conventional culture was performed in DMEM High Glucose medium (Life Technologies) containing 10% FBS (Nichirei Bioscience) and 1% Pen-Strep (Life Technologies) at a temperature of 37 °C, humidity of 95%, and CO2 concentration of 5%.

[0275] Preparation of cells for evaluating C3aR response Expression vectors necessary for evaluating C3aR responsiveness (C3aR1-pCMV6, GNA16-pCMV6) were introduced into HEK293. Plasmid solutions were prepared at 1 μg / μL. Each plasmid solution and a pH 7.4 aqueous solution of PEI-MAX (Polysciences, Inc.) were sequentially mixed into serum-free DMEM medium with the composition shown in Table 1 below, and then allowed to stand at room temperature for 20 minutes. Place HEK293 suspended in normal culture medium into a 6-well plate in a 2.5 × 10⁶ container. 6 Cells were seeded at a rate of cells / well, and 100 μL of the above prepared solution was added per well and cultured for 24 hours. After washing with Dulbecco's Phosphate-Buffered Saline (DPBS, Thermo Fisher Scientific), the cells were treated for 30 seconds with 0.25% Trypsin / EDTA (Life Technologies) diluted 5-fold with DPBS to prevent damage to the expressed receptors, and the harvested cells were then treated with the following Ca 2+ - Subjected to a flux assay.

[0276] [Table 1]

[0277] Ca 2+ -flux assay The cells prepared above for evaluating the C3aR response were suspended in standard culture medium, re-seeded in a 96-well poly-D-lysine coated microplate (CORNING), and incubated for at least 1 hour. Intracellular Ca during C3aR response 2+ Calcium Kit-Fluo 4 (DOJINDO) was used to measure the concentration change. ATP (SIGMA-ALDRICH) prepared to a final concentration of 10 μM was used as a positive control. Loading buffer and recording buffer were prepared according to the kit protocol. After washing with Hank's Balanced Salt Solution (HBSS, Thermo Fisher Scientific), 100 μL / well of loading buffer was added and incubated at 37 °C for 1 hour. After removing the loading buffer and washing with HBSS, 85 μL / well of recording buffer was added. An additional 15 μL / well of 100 μM C3aR antagonist (candidate compound) solution was added to obtain a final 100 μL / well inhibitor-containing recording buffer. In this assay, the known C3aR antagonist JR10a (L-arginine, N) was used. 2-[[5-(diphenylmethyl)-2-thienyl]carbonyl]-)) was used as a control. Subsequently, a 96-well microplate (Thermo Fisher Scientific) containing HBSS solutions of TLQP-21 and ATP was placed in an FDSS / μ CELL (Hamamatsu Photonics) chamber, and the solution was automatically dispensed into cell plates containing the candidate compounds using a dedicated 96-well black tip (Hamamatsu Photonics). The intracellular fluorescence intensity was measured over time. The values ​​for each group were calculated by subtracting the values ​​without ligand (TLQP-21) from the values ​​with ligand (TLQP-21: Tocris Bioscience, C3a: R&D Systems). At this time, the AUC values ​​for each group were graphed with the value of the group without candidate compound added set to 100. The final concentrations of the candidate compound solution and ligand solution obtained by mixing were: compound: 10 or 1 μM, JR 10a: 1 μM, TLQP-21: 1 μM. The measurement conditions for FDSS / μCELL are shown in Table 2 below.

[0278] [Table 2]

[0279] Data Analysis The data obtained from the assay were graphed using the mean ± standard deviation (SD). For each group, the relative value (%) was calculated with the AUC of the non-treatment group set to 100 (n=3). A smaller AUC (%) value indicates suppression of the TLQP-21 response, meaning that the antagonist activity is higher. 50 This was calculated using the Curve Fitting Tool in the ImageJ analysis tool. The results are shown in Table 3.

[0280] [Table 3-1]

[0281] Table 3-2

[0282] Table 3-3

[0283] Table 3-4

Claims

1. The following general formula (I) 【Chemistry 1】 (In the formula, X represents a carbon atom or a nitrogen atom; Y represents a carbon atom or a sulfur atom; R 1 and R 2 These represent the same or different hydrogen atoms or halogen atoms; R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R 4 is a hydrogen atom or -(CH 2 ) m Show COOH; R 5 is -(CH 2 ) n -CONH-R 6 , -(CH 2 ) n -CON-R 6 (when forming a ring together with R 7 described below) or -(CH 2 ) n -O-R 6 and indicates: R 6 This represents equation (II) or equation (III); 【Chemistry 2】 R 7 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or -CONH 2 To show, or R 5 ga- (CH 2 ) n -CON-R 6 At that time, R 6 It may also form a 5-6 member nitrogen-containing saturated heterocycle with the nitrogen atom to which it is bonded; R 8 and R 9 These are the same or different hydrogen atoms, halogen atoms, C1-C6 alkyl groups, -COOH, or -CONH 2 They may either show a cyclic amide with a 5-6 membered carbon atom to which they are bonded; R 10 is a hydrogen atom, -COOH, or -CONH 2 Show; m represents 0 or 1; n represents an integer between 0 and 2. A compound represented by or a salt thereof.

2. X is a carbon atom, Y is a sulfur atom, R 1 and R 2 If they are the same or different hydrogen atoms or halogen atoms, R 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 4 is a hydrogen atom or -(CH 2 ) m COOH, R 5 ga- (CH 2 ) n -CONH-R 6 ,-(CH 2 ) n -CON-R 6 (R, as described later) 7 (When forming a ring together with) or - (CH 2 ) n -O-R 6 And R 6 If R represents equation (II) or equation (III), 7 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or -CONH 2 is it R 5 ga- (CH 2 ) n -CON-R 6 At that time, R 6 R may form a 5-6 member nitrogen-containing saturated heterocycle with the nitrogen atom to which it is bonded, 8 and R 9 The same or different hydrogen atoms, halogen atoms, C1-C6 alkyl groups, -COOH, or -CONH 2 Alternatively, they may form a 5-6 membered cyclic amide together with the carbon atoms to which they are bonded, R 10 The compound or salt thereof according to claim 1, wherein is -COOH, m is 0 or 1, and n is an integer from 0 to 2.

3. X is a nitrogen atom, Y is a carbon atom, R 1 and R 2 If they are the same or different hydrogen atoms or halogen atoms, R 3 is an alkyl group having 1 to 6 carbon atoms, and R 4 ga- (CH 2 ) m COOH, R 5 ga- (CH 2 ) n -CON-R 6 (R, as described later) 7 (When it forms a ring together with R) 6 This shows equation (II), and R 7 However, R 6 Together with the nitrogen atom to which it is bonded, it forms a 5-6 member nitrogen-containing saturated heterocycle, R 8 and R 9 The hydrogen atom, -COOH, or -CONH is the same or different. 2 The compound or salt thereof according to claim 1, wherein m is 0 or 1 and n is an integer from 0 to 2.

4. X is a carbon atom and Y is a sulfur atom, or X is a nitrogen atom and Y is a carbon atom, and R 1 and R 2 are the same or different and are a hydrogen atom or a halogen atom, R 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 4 is a hydrogen atom or -(CH 2 ) m COOH, R 5 is -(CH 2 ) n -CONH-R 6 , -(CH 2 ) n -CON-R 6 (when forming a ring together with R 7 described later) or -(CH 2 ) n -O-R 6 , R 6 is formula (II) or formula (III), R 7 [[ID=3�]]is a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms, or R 5 is -(CH 2 ) n -CON-R 6 when, R 6 may form a 5- to 6-membered nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which it is bonded, R 8 and R 9 are the same or different and are a hydrogen atom, -COOH, or -CONH 2 , R 10 is -COOH, m is 0 or 1, n is 1 or 2, the compound according to claim 1 or a salt thereof.

5. A compound or salt thereof selected from the following. N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(4-carbamoylphenyl)-L-asparagine (compound 1), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoylphenyl)-L-asparagine (compound 2), (S)-3-(5-benzhydrylthiophene-2-carboxamide)-4-((3-carbamoylphenyl)amino)-4-oxobutanoic acid (compound 3), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(2-carbamoylphenyl)-L-asparagine (compound 4), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 5 -(3-carbamoylphenyl)-L-glutamine (compound 5), N-(5-benzhydrylthiophen-2-carbonyl)-O-(3-carbamoylphenyl)-L-serine (compound 6), N-(5-benzhydrylthiophene-2-carbonyl)-O-(3-carbamoylphenyl)-L-homoserine (compound 7), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoyl-2-fluorophenyl)-L-asparagine (compound 8), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoyl-4-fluorophenyl)-L-asparagine (compound 9), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carbamoyl-4-methylphenyl)-L-asparagine (compound 10), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-oxoindolin-5-yl)-L-asparagine (compound 11), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)-L-asparagine (compound 12), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(3-carboxyphenyl)-L-asparagine (compound 13), N-(5-benzhydrylthiophene-2-carbonyl)-O-(3-carboxyphenyl)-L-serine (compound 14), N 2 -(5-benzhydrylthiophene-2-carbonyl)-N 4 -(5-carboxy-1H-pyrazole-3-yl)-L-asparagine (compound 15), (S)-1-(3-(5-benzhydrylthiophene-2-carboxamide)-3-carboxypropagyl)-indoline-6-carboxylic acid (compound 16), (S)-1-(3-(5-benzhydrylthiophene-2-carboxamide)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 17), 1-(3-(5-benzhydrylthiophene-2-carboxamide)propanoyl)-1,2,3,4-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 18), (S)-1-(3-(5-benzhydryl-3-methylthiophene-2-carboxamide)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 19), (S)-1-(3-(5-(bis(4-fluorophenyl)methyl)thiophene-2-carboxamide)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 20), (S)-1-(3-(5-(bis(4-chlorophenyl)methyl)thiophene-2-carboxamide)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 21), (S)-1-(3-(5-(bis(4-fluorophenyl)methyl)thiophene-2-carboxamide)-3-carboxypropagyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 22), (S)-2-(5-benzhydryl-3-methylthiophene-2-carboxamide)-4-(7-carbamoyl-3,4-dihydroquinoline-1(2H)-yl)-4-oxobutanoic acid (compound 23), (S)-2-(5-(bis(4-fluorophenyl)methyl)-3-methylthiophen-2-carboxamide)-4-(7-carbamoyl-3,4-dihydroquinoline-1(2H)-yl)-4-oxobutanoic acid (compound 24), (S)-1-(3-(1-(bis(4-fluorophenyl)methyl)-4-methyl-1H-pyrrole-3-carboxamide)-3-carboxypropanoyl)-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (compound 25), (S)-2-(1-(bis(4-fluorophenyl)methyl)-4-methyl-1H-pyrrole-3-carboxamide)-4-(7-carbamoyl-3,4-dihydroquinoline-1(2H)-yl)-4-oxobutanoic acid (compound 26).

6. A C3a receptor antagonist comprising a compound or salt thereof according to any one of claims 1 to 5 as an active ingredient.

7. An agent for preventing or improving itching, comprising the compound or salt thereof according to any one of claims 1 to 5 as an active ingredient.

8. An agent for preventing or improving pruritic skin diseases exhibiting intractable itching, comprising a compound or salt thereof according to any one of claims 1 to 5 as an active ingredient.

9. A pharmaceutical composition comprising a compound or salt thereof according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

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