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 JPEG2026067759000026.jpg48170 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 compounds described in Patent Document 2 have diphenylmethyl groups or arginyl groups on the carbon atoms constituting the heterocycle, and Patent Document 2 does not describe compounds in which diphenylmethyl groups or the like are bonded to heteroatoms. Furthermore, there is no description of the activity of heterocyclic compounds containing pyrrole rings toward C3a receptors. [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 Initiative] [Problems that the invention aims to solve]

[0011] The present invention relates to providing novel C3a receptor antagonist compounds useful for preventing or improving itching by inhibiting the C3a receptor signaling pathway, and their applications. [Means for solving the problem]

[0012] The inventors searched for effective compounds that inhibit the C3a receptor signaling pathway and found that a compound represented by the general formula (I) below has C3a receptor antagonistic activity and is useful for preventing or improving itching. The compound represented by the general formula (I) is a novel compound not described in the aforementioned prior art documents.

[0013] In other words, the present invention relates to the following 1) to 5). 1) The following general formula (I)

[0014] [ka]

[0015] (In the formula, X and Z represent the same or different carbon atom or nitrogen atom; Y represents CR5, a sulfur atom, or an NH group; R1 is an o-biphenyl group or formula (II);

[0016] [ka]

[0017] It may represent a diphenylmethyl group, or, when X and Z are carbon atoms and Y is a sulfur atom, it may form a biphenyl ring with the adjacent R2 and the carbon atom to which they are bonded; R2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R3 and R4 may be the same or different, each representing a hydrogen atom or a C1-C6 alkyl group, or, when X and Z are carbon atoms and Y is a sulfur atom, R3 and R4 may form a 5-6 membered cyclic amide together with the nitrogen atom to which R4 is bonded; R5 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R6 and R7 are the same or different, representing a hydrogen atom, a halogen atom, or an alkoxy group having 1 to 6 carbon atoms; dashed lines indicate single or double bonds. However, when X and Z are carbon atoms, Y is a sulfur atom, and R1 is a diphenylmethyl group of formula (II), R3 and R4 are not hydrogen atoms or alkyl groups having 1 to 6 carbon atoms. 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. [Brief explanation of the drawing]

[0019] [Figure 1] The results of the skin sensitization test are shown below. [Modes for carrying out the invention]

[0020] In this specification, "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. The halogen atom is preferably a fluorine atom.

[0021] 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.

[0022] In this specification, "alkoxy group having 1 or more carbon atoms" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, 1-methylpropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, and the like. The alkoxy group having 1 to 6 carbon atoms is preferably an alkoxy group having 1 to 3 carbon atoms, and more preferably a methoxy group.

[0023] In the compound represented by the general formula (I) of the present invention, X and Z are the same or different carbon atoms or nitrogen atoms. Preferably, one of X and Z is a nitrogen atom and the other is a carbon atom, or both are carbon atoms, and more preferably, one of X and Z is a nitrogen atom and the other is a carbon atom.

[0024] In the compound represented by general formula (I) of the present invention, Y represents CR5, a sulfur atom, or an NH group. Y is preferably CR5 or an NH group. R5 will be described later.

[0025] In the general formula (I) of the present invention, the combinations of X, Y, and Z are preferably such that X and Z are carbon atoms and Y is a sulfur atom or an NH group, or X is a nitrogen atom, Z is a carbon atom and Y is CR5, or X is a carbon atom, Z is a nitrogen atom and Y is CR5. More preferably, X and Z are carbon atoms and Y is an NH group, or X is a nitrogen atom, Z is a carbon atom and Y is CR5, or X is a carbon atom, Z is a nitrogen atom and Y is CR5. Even more preferably, X is a nitrogen atom, Z is a carbon atom and Y is CR5.

[0026] In the compound represented by general formula (I) of the present invention, R1 represents an o-biphenyl group or a diphenylmethyl group of formula (II) above (R6 and R7 will be described later), or when X and Z are carbon atoms and Y is a sulfur atom, it forms a biphenyl ring with the adjacent R2 and the carbon atom to which they are bonded. When R1 forms a biphenyl ring with the adjacent R2 and the carbon atom to which they are bonded, 7-phenylbenzo[b]thiophene is preferred as the ring. R1 is preferably an o-biphenyl group or a diphenylmethyl group of formula (II) above, and more preferably a diphenylmethyl group of formula (II) above.

[0027] In the compound represented by general formula (I) of the present invention, R2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R2 is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.

[0028] In the compound represented by general formula (I) of the present invention, R3 and R4 are the same or different hydrogen atoms or C1-C6 alkyl groups, or when X and Z are carbon atoms and Y is a sulfur atom, R3 and R4 together with the nitrogen atom to which R4 is bonded form a 5-6 membered cyclic amide. Examples of 5-6 membered cyclic amides formed by R3 and R4 together with the nitrogen atom to which R4 is bonded include γ-lactams and δ-lactams, but γ-lactams are preferred. R3 is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom. R4 is preferably a hydrogen atom. However, in the compound represented by general formula (I) of the present invention, when X and Z are carbon atoms, Y is a sulfur atom, and R1 is a diphenylmethyl group of formula (II), R3 and R4 are not hydrogen atoms or alkyl groups having 1 to 6 carbon atoms.

[0029] In the compound represented by general formula (I) of the present invention, R5 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R5 is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.

[0030] In the compound represented by general formula (I) of the present invention, R6 and R7 are the same or different, representing a hydrogen atom, a halogen atom, or an alkoxy group having 1 to 6 carbon atoms. R6 and R7 are preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a methoxy group, and more preferably a hydrogen atom. It is preferable that R6 and R7 are the same group.

[0031] In terms of C3a receptor antagonist activity, preferred compounds among the compounds represented by general formula (I) of the present invention are those in which X and Z are the same or different carbon atoms or nitrogen atoms, Y is a CR5, sulfur atom or NH group, and R1 is an o-biphenyl group or a diphenylmethyl group of formula (II); or when X and Z are carbon atoms and Y is a sulfur atom, R3 and R4 form a biphenyl ring with the adjacent R2 and the carbon atom to which they are bonded, R2 is a hydrogen atom or a methyl group, and R3 and R4 are the same or different hydrogen atoms or methyl groups; or when X and Z are carbon atoms and Y is a sulfur atom, R3 and R4 form a 5-6 membered cyclic amide with the nitrogen atom to which R4 is bonded, R5 is a hydrogen atom or a methyl group, and R6 and R7 are the same or different hydrogen atoms, halogen atoms or methoxy groups (however, when X and Z are carbon atoms, Y is a sulfur atom and R1 is a diphenylmethyl group of formula (II), R3 and R4 are not hydrogen atoms or methyl groups).

[0032] From the viewpoint of C3a receptor antagonism, a more preferred compound among the compounds represented by general formula (I) of the present invention is a compound in which X and Z are the same or different carbon atoms or nitrogen atoms, Y is a CR5 or NH group, R1 is a diphenylmethyl group of formula (II), R2 and R3 are the same or different hydrogen atoms or methyl groups, R4 is a hydrogen atom, R5 is a hydrogen atom or methyl group, and R6 and R7 are the same or different hydrogen atoms, halogen atoms or methoxy groups.

[0033] Furthermore, in terms of C3a receptor antagonist activity, more preferred compounds among those represented by the general formula (I) of the present invention are those in which X and Z are carbon atoms, Y is a sulfur atom, R1 is an o-biphenyl group or a diphenylmethyl group of formula (II), or may form a biphenyl ring with the adjacent R2 and the carbon atom to which they are bonded, R2 is a hydrogen atom, R3 and R4 are hydrogen atoms, or R3 and R4 form a 5-6 membered cyclic amide with the nitrogen atom to which R4 is bonded, and R6 and R7 are hydrogen atoms (however, when R1 is a diphenylmethyl group of formula (II), R3 and R4 are not simultaneously hydrogen atoms).

[0034] Among the compounds represented by the general formula (I) of the present invention, the following compounds are particularly preferred. (5-([1,1'-biphenyl]-2-yl)thiophene-2-carbonyl)-L-arginine ((5-([1,1'-biphenyl]-2-yl)thiophene-2-carbonyl)-L-arginine) (Compound 1), (7-phenylbenzo[b]thiophene-2-carbonyl)-L-arginine (compound 2), (2-benzhydryl-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-L-arginine (compound 3), (2-benzhydryl-7-oxo-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-L-arginine (compound 4), (3-benzhydryl-1H-pyrrole-1-carbonyl)-L-arginine (compound 5), (5-benzhydryl-1H-pyrrole-2-carbonyl)-L-arginine (compound 6), (1-benzhydryl-1H-pyrrole-3-carbonyl)-L-arginine (compound 7), (1-(bis(4-methoxyphenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine ((1-(bis(4-methoxyphenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine) (Compound 8), (1-(bis(4-fluorophenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine (compound 9), (1-(bis(4-chlorophenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine (compound 10) (1-benzhydryl-2-methyl-1H-pyrrole-3-carbonyl)-L-arginine (compound 11), (1-benzhydryl-4-methyl-1H-pyrrole-3-carbonyl)-L-arginine (compound 12), (1-benzhydryl-5-methyl-1H-pyrrole-3-carbonyl)-L-arginine (Compound 13)

[0035] In this specification, the structural formula of a compound may represent a specific isomer for convenience. However, the present invention includes all geometric isomers, optical isomers based on chiral carbons, stereoisomers, tautomers, and other isomers and mixtures of isomers that arise from the structure of a compound, and is not limited to the description of the formula for convenience. It may be either one isomer or a mixture. Therefore, if a compound represented by the general formula (I) of the present invention (hereinafter also referred to as "the compound of the present invention") has a chiral carbon atom in its molecule and exists as both an optically active form and a racemic form, the present invention is not limited and includes both.

[0036] 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, and examples include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; 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, and aluminum salt; and salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, as well as ammonium salts. Hydrochloride salts are preferred.

[0037] The present invention also includes prodrugs of the compounds of the present invention or salts thereof. A prodrug is a compound that is converted into the compound of the present invention or a salt thereof by reactions (such as oxidation, reduction, hydrolysis, etc.) by enzymes, gastric acid, etc. under physiological conditions in vivo.

[0038] The present invention may have hydrates, various solvates and crystal polymorphs of the compounds of the present invention or salts thereof, but is not limited thereto, and any crystal form may be single or a mixture of crystal forms, and all are included. Furthermore, the present invention also includes compounds labeled with isotopes (e.g., 2 H, 3 H, 14 C, 35 S, 125 I, etc.).

[0039] The compounds of the present invention or salts thereof can be produced, for example, according to the following synthetic schemes 1 to 6, and can be appropriately modified depending on the type of substituents, etc., and can be produced by any method suitable therefor. Each starting material can be commercially available or can be produced by methods known in the art.

[0040] In the general formula (I), a compound in which R1 is the diphenylmethyl group of the above formula (II) can be synthesized according to the following synthetic scheme 1. <Synthetic Scheme 1>

[0041]

Chemical Formula

[0042] (In the formula, L 1 represents a C 1-6 alkyl group, L 2 represents a halogen atom or a hydroxy group, P 1 and P 2 represent protecting groups, and other symbols are synonymous with the general formula (I).)

[0043] (Step 1) This step involves obtaining compound (2) by a dehydrating CC coupling reaction or a nucleophilic substitution reaction using the ionic liquids of compound (1) and compound (5) as solvents. The ionic liquid used in this step consists of a cationic component and an anionic component. Examples of cationic components include 1-ethyl-3-methylimidazolium cation, 1-propyl-3-methylimidazolium cation, 1,3-dimethylimidazolium cation, 1,3-diethylimidazolium cation, N-propylpyridinium cation, N-butylpyridinium cation, 1,4-dimethylpyridinium cation, trimethylammonium cation, ethyldimethylammonium cation, and diethylmethylammonium cation. Examples of anionic components include halide ions, sulfonate anions, organic sulfonate anions, phosphate anions, and borate anions. The reaction temperature for the dehydrating CC coupling reaction is preferably 100 °C, and the reaction time is preferably 3 hours.

[0044] Nucleophilic substitution reactions can be carried out in solvents such as ethers (tetrahydrofuran (THF), diethyl ether, dioxane, t-butyl methyl ether, diglym, etc.) and aprotic polar solvents (N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoramide, etc.) in the presence of metal salt bases such as sodium hydride, sodium hydroxide, potassium hydroxide, and potassium tert-butoxide. The reaction temperature is preferably -78°C to room temperature, and the reaction time is preferably 1 hour to 24 hours. The compound (2) obtained by this process can be isolated and purified by known separation and purification methods, or it can be used in the next step without isolation and purification.

[0045] (Process 2) This step involves obtaining compound (3) by the ester hydrolysis reaction of compound (2). The hydrolysis reaction can be carried out by a commonly known method. For example, compound (2) can be dissolved in a solvent such as an alcohol (methanol, ethanol, etc.) or an ether (tetrahydrofuran (THF), dioxane, etc.), and then an aqueous solution of alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide is added. The reaction is preferably carried out at 0°C under reflux for 1 hour to 24 hours.

[0046] (Step 3) This step involves a condensation reaction between compound (3) and arginine (6) having a protecting group to obtain compound (4). The protecting group P of the guanidyl group of arginine (6) 1 Examples include the Pbf group, Pmc group, and nitro group, and the protecting group P of the carboxyl group. 2 Examples of these groups include the tBu group, methyl group, ethyl group, and Bz group. The condensation reaction can be carried out by mixing compound (3), arginine (6), and the condensing agent in a solvent. Examples of bonding agents 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, and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (HATU). 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 acidimide, and 2-hydroxyimino-2-cyanoethyl acetate. Examples of bases include organic amines (triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylmorpholine, etc.), 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. The compound (4) obtained by this process can be isolated and purified by known separation and purification methods, or it can be used in the next step without isolation and purification.

[0047] (Step 4) This step involves deprotecting compound (4) to obtain compound (I-1) of the present invention. Depending on the type of protecting group, the deprotection can be carried out by commonly known methods using a deprotecting agent 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.

[0048] Alternatively, compounds in which Z is a nitrogen atom and R1 is the diphenylmethyl group of formula (II) can be synthesized according to the following synthesis scheme 2. <Synthesis Scheme 2>

[0049] [ka]

[0050] (In the formula, L 2 P represents a hydrogen atom or a hydroxyl group. 1 and P 2 The symbol indicates a protecting group, and the other symbols are equivalent to those in general formula (I).

[0051] (Step 5) This step involves obtaining compound (8) through a dehydration CC coupling reaction using the ionic liquid of compound (7) and compound (5) as solvents. The same method as in step 1 is used for this step.

[0052] (Step 6) This step involves obtaining compound (9) by a ureation reaction between compound (8) and arginine (6) having a protecting group in the presence of a ureating agent and a base. Examples of ureating agents include bis(4-nitrophenyl) carbonate, bis(trichloromethyl) carbonate, and phosgene. Examples of bases include organic amines (triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylmorpholine, etc.), alkali metal salts (sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc.), metal hydrides (potassium hydride, sodium hydride, etc.), and alkali metal disilazides (lithium disilazide, sodium disilazide, potassium disilazide, etc.). The solvent used in this process is not particularly limited as long as it does not hinder the reaction, and examples include halogenated hydrocarbons (chloroform, 1,2-dichloroethane, etc.), nitriles (acetonitrile, etc.), ethers (tetrahydrofuran (THF), diethyl ether, dioxane, t-butyl methyl ether, diglym, etc.), dimethyl sulfoxide (DMSO), hexamethylphosphoramide, etc.), or mixed solvents thereof. The reaction temperature is 0°C or below under reflux, and the reaction time is 1 hour to 24 hours. The compound (9) obtained by this process can be isolated and purified by known separation and purification methods, or it can be used in the next step without isolation and purification.

[0053] (Step 7) Compound (I-2) can be produced by deprotecting the protecting group of compound (9). This step is carried out using the same method as in step 4.

[0054] Compounds in which R1 is an o-biphenyl group in general formula (I) can be synthesized according to the following synthesis scheme 3. <Synthesis Scheme 3>

[0055] [ka]

[0056] (In the formula, L 1 is C 1-6 It shows an alkyl group, L 2 indicates a halogen atom or OTf, P 1 and P 2 The symbol indicates a protecting group, and the other symbols are equivalent to those in general formula (I).

[0057] (Step 8) This step involves obtaining compound (11) from compound (10) as a raw material via a CH activation reaction. Examples of catalysts used in this step include metal catalysts combining palladium(II), rhodium(I), iridium(I), ruthenium(II), copper(II), iron(II), etc., with appropriate ligands (such as 1,4-bis(diphenylphosphino)butane and 1,1'-bis(diphenylphosphino)ferrocene). Examples of bases used in this step include alkali metal salts (such as potassium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate). The solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples include aprotic polar solvents (such as N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO)). The reaction temperature for the CH activation reaction is preferably 150°C, and the reaction time is preferably 24 hours.

[0058] The compound (11) obtained by this process can be isolated and purified by known separation and purification methods, or it can be used in the next step without isolation and purification.

[0059] (Step 9) This step can be carried out by deprotecting the protecting group of compound (11). This step is carried out using the same method as in step 2.

[0060] (Step 10) This step involves obtaining compound (13) through a condensation reaction between compound (12) and arginine (6) having a protecting group. This step is carried out using the same method as in step 3.

[0061] (Step 11) Compound (I-3) can be produced by deprotecting the protecting group of compound (13). This step is carried out using the same method as in step 4.

[0062] Compounds in which X, R1, and R2 form a fused ring structure in general formula (I) can be synthesized according to the following synthesis scheme 4. <Synthesis Scheme 4>

[0063] [ka]

[0064] (In the formula, L 1 is C 1-6 It shows an alkyl group, L 2 represents a halogen atom or OTf, L 3 P indicates a boronic acid or boronic acid ester. 1 and P 2 The symbol indicates a protecting group, and the other symbols are equivalent to those in general formula (I).

[0065] (Step 12) This process involves obtaining compound (16) from compound (15) as a raw material by Suzuki-Miyaura cross-coupling. Examples of catalysts used in this process include metal catalysts combining palladium(O), palladium(II), nickel(II), etc., with appropriate ligands (triphenylphosphine, 1,4-bis(diphenylphosphino)butane, 1,1'-bis(diphenylphosphino)ferrocene, etc.). Examples of bases used in this process include alkali metal salts (sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal hydroxides (potassium hydroxide, sodium hydroxide, etc.), and organic amines (triethylamine, N,N-diisopropylethylamine (DIPEA), etc.). The solvent used in this process is not particularly limited as long as it does not interfere with the reaction. Examples include nitriles (such as acetonitrile), ethers (such as tetrahydrofuran (THF), diethyl ether, dioxane, dimethoxyethane, t-butyl methyl ether, and diglyme), aprotic polar solvents (such as N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO)), water, alcohols (such as methanol, ethanol, and isopropanol), aromatic hydrocarbons (such as benzene, toluene, and xylene), or mixtures thereof. The reaction temperature for the Suzuki-Miyaura cross-coupling reaction is preferably 0°C under reflux, and the reaction time is preferably 1 hour to 24 hours.

[0066] The compound (16) obtained by this process can be isolated and purified by known separation and purification methods, or it can be used in the next step without isolation and purification.

[0067] (Step 13) This step can be carried out by deprotecting the protecting group of compound (16). This step is carried out using the same method as in step 2.

[0068] (Step 14) This step involves a condensation reaction between compound (17) and arginine (6) having a protecting group to obtain compound (18). This step is carried out using the same method as in step 3.

[0069] (Step 15) Compound (I-4) can be produced by deprotecting the protecting group of compound (18). This step is carried out using the same method as in step 4.

[0070] Compounds in which R3 and R4, together with the nitrogen atom to which R4 is bonded, form a five-membered cyclic amide in general formula (I) can be synthesized according to the following synthesis scheme 5. <Synthesis Scheme 5>

[0071] [ka]

[0072] (In the formula, L 1 is C 1-6 It shows an alkyl group, L 2 This indicates a halogen group, P 1 and P 2 The symbol indicates a protecting group, and the other symbols are equivalent to those in general formula (I).

[0073] (Step 16) This step involves obtaining compound (20) by a nucleophilic addition reaction between compound (19) and compound (5). This step 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, 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. The compound (20) obtained by this process can be isolated and purified by known separation and purification methods, or it can be used in the next step without isolation and purification.

[0074] (Step 17) This step involves obtaining compound (21) by a halogenation reaction of compound (20). Examples of halogenating agents include chlorine, bromine, iodine, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), and N-iodosuccinimide (NIS). Reaction initiators such as benzoyl peroxide (BPO) and azobisisobutyronitrile (AIBN), as well as light irradiation, may also be used in combination. Examples of solvents include halogenated hydrocarbons (carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane), hydrocarbons (cyclohexane, benzene), acetonitrile, THF, or mixed solvents thereof. The reaction temperature for halogenation reactions is room temperature to reflux, and the reaction time is 1 hour to 24 hours. The compound (20) obtained by this process can be isolated and purified by known separation and purification methods, or it can be used in the next step without isolation and purification.

[0075] (Step 18) This step involves obtaining compound (22) by a nucleophilic substitution reaction between compound (21) and arginine (6) having a protecting group. The protecting group P of the guanidyl group of arginine (6) 1Examples include the Pbf group, Pmc group, and nitro group, and the protecting group P of the carboxyl group. 2 Examples include the tBu group, methyl group, ethyl group, and Bz group. 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.), nitriles (acetonitrile, etc.), ethers (tetrahydrofuran (THF), diethyl ether, dioxane, t-butyl methyl ether, diglym, etc.), ketones (acetone, methyl ethyl ketone, etc.), aprotic polar solvents (N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoramide, etc.), or mixed solvents thereof. Additionally, a base may be added to accelerate the reaction. Examples of bases include organic amines (triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylmorpholine, etc.), alkali metal salts, and metal hydrides. The reaction temperature is 0°C or below under reflux, and the reaction time is 1 hour to 3 days. The compound (22) obtained by this process can be isolated and purified by known separation and purification methods, or it can be used in the next step without isolation and purification.

[0076] (Step 19) This process can be carried out by deprotecting the protecting group of compound (22). This process is carried out using the same method as in step 2.

[0077] (Step 20) This step involves obtaining compound (24) through an intramolecular condensation reaction of compound (23). The same method as in step 3 is used for this step.

[0078] (Step 21) Compound (I-5) can be produced by reduction of compound (24) and deprotection of the protecting group. The reduction and deprotection methods can be carried out by commonly known methods, depending on the type of protecting group, using, for example, deprotecting agents such as hydrochloric acid, trifluoroacetic acid, acetic acid, and sulfuric acid, and reducing agents such as triethylsilane and triisopropylsilane. The solvent is not particularly limited as long as it does not affect the reaction, and the solvents listed in step 3 may be used. The reaction temperature is 0 °C to room temperature, and the reaction time is 1 hour to 24 hours.

[0079] Compounds in which R3 and R4, together with the nitrogen atom to which R4 is bonded, form a six-membered cyclic amide in general formula (I) can be synthesized according to the following synthesis scheme 6. <Synthesis Scheme 6>

[0080] [ka]

[0081] (In the formula, L 1 , L 2 is C 1-6 It shows an alkyl group, L 3 P indicates a boronic acid or boronic acid ester. 1 and P 2 The symbol indicates a protecting group, and the other symbols are equivalent to those in general formula (I).

[0082] (Step 22) This step involves obtaining compound (26) through a nucleophilic substitution reaction between compound (25) and compound (5). This step is carried out using the same method as in step 16.

[0083] (Step 23) Compound (27) can be produced by the reduction reaction of compound (26). The reduction can be carried out by commonly known methods, for example, under acidic conditions using hydrochloric acid, trifluoroacetic acid, sulfuric acid, or boron trifluoride, and using a reducing agent such as triethylsilane or triisopropylsilane. The solvent is not particularly limited as long as it does not affect the reaction, and the solvents listed in step 3 may be used. The reaction temperature is 0 °C to room temperature, and the reaction time is 1 hour to 24 hours.

[0084] (Step 24) This step involves converting the hydroxyl group of compound (27) into a leaving group, and then obtaining compound (28) by Suzuki-Miyaura cross-coupling. Examples of leaving groups include triflate, tosyl, mesyl, chloro, bromo, and iodine groups. For example, conversion to a triflate group can be achieved by adding trifluoromethanesulfonic anhydride or trifluoromethanesulfonic chloride under basic conditions. Examples of bases include organic amines (triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylmorpholine, etc.), alkali metal salts, and metal hydrides. The solvent is not particularly limited as long as it does not affect the reaction, and the solvents listed in step 3 may be used. The reaction temperature is 0 °C to room temperature, and the reaction time is 1 hour to 24 hours. The intermediate obtained in this step can be isolated and purified by known separation and purification methods, or it can be subjected to the next coupling reaction without isolation and purification. The coupling reaction is carried out using the same method as in step (12).

[0085] (Step 25) This step involves hydrolyzing compound (28) to obtain compound (29). The hydrolysis can be carried out under acidic conditions, for example, using an acid such as hydrochloric acid, trifluoroacetic acid, or sulfuric acid, by a method commonly known. The solvent is not particularly limited as long as it does not affect the reaction, and the solvents mentioned above can be used. The reaction temperature is room temperature to reflux, and the reaction time is 1 hour to 3 days.

[0086] (Step 26) This step involves obtaining compound (30) by a reductive amination reaction between compound (29) and arginine (6) having a protecting group. The protecting group P of the guanidyl group of arginine (6) 1 Examples include the Pbf group, Pmc group, and nitro group, and the protecting group P of the carboxyl group. 2 Examples include the tBu group, methyl group, ethyl group, and Bz group. The solvent used in this process is not particularly limited as long as it does not hinder the reaction. Examples include hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, etc.), nitriles (acetonitrile, etc.), alcohols (methanol, ethanol, isopropanol, 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. An acid may also be added to promote the reaction. Examples of acids include acetic acid, formic acid, and trifluoroacetic acid. Examples of reducing agents include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, picolineborane, and pyridineborane. Additionally, a base may be added depending on the type of amine. Examples of bases include organic amines (triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylmorpholine, etc.), alkali metal salts (sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc.), metal hydrides (potassium hydride, sodium hydride, etc.), and alkali metal disilazides (lithium disilazide, sodium disilazide, potassium disilazide, etc.). The reaction temperature for the reduction reaction is 0°C or below under reflux, and the reaction time is 1 hour to 24 hours. The compound (30) obtained by this process can be isolated and purified by known separation and purification methods, or it can be used in the next step without isolation and purification.

[0087] (Step 27) This step involves cyclizing compound (30) to obtain compound (31). The cyclization can be carried out under acidic conditions, for example, with an acid such as acetic acid, formic acid, hydrochloric acid, trifluoroacetic acid, or sulfuric acid, or under basic conditions, for example, with organic amines (triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylmorpholine, etc.), alkali metal salts, or metal hydrides. The solvent is not particularly limited as long as it does not affect the reaction, and the solvents mentioned above can be used. Additives can also be added to remove the alcohol that is eliminated from the system. Examples of additives include magnesium sulfate, sodium sulfate, and molecular sieves. The reaction temperature is room temperature to reflux, and the reaction time is 1 hour to 24 hours.

[0088] (Step 28) Compound (I-6) can be produced by deprotecting the protecting group of compound (31). This step is carried out using the same method as in step 4.

[0089] 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.

[0090] As shown in the examples below, the compounds of the present invention exhibit antagonistic activity against complement factor C3a receptors, which are GPCR-type receptors present on cell membranes. Furthermore, they are expected to reduce skin sensitization compared to existing C3a receptor antagonists. C3a receptors are known to accept 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. It has also 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.

[0091] 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.

[0092] 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.

[0093] "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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] Such pharmaceutical and cosmetic formulations can be manufactured by conventional methods, combining the compound of the present invention with, as necessary, pharmaceutically or cosmetically acceptable carriers, other active ingredients, pharmacokinetic ingredients, cosmetic ingredients, etc. Examples of pharmaceutically or cosmetically acceptable carriers include excipients, diluents, binders, disintegrants, coatings, solubilizers, lubricants, gliding agents, solubilizers, various oils, surfactants, gelling agents, pH buffers, isotonic agents, preservatives, antioxidants, solvents, dispersants, chelating agents, thickeners, stabilizers, pH adjusters, pigments, 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] With regard to the embodiments described above, the present invention further discloses the following aspects.

[0103] <1> The following general formula (I)

[0104] [ka]

[0105] (In the formula, X and Z represent the same or different carbon atom or nitrogen atom; Y represents CR5, a sulfur atom, or an NH group; R1 is an o-biphenyl group or formula (II);

[0106] [ka]

[0107] It may represent a diphenylmethyl group, or, when X and Z are carbon atoms and Y is a sulfur atom, it may form a biphenyl ring with the adjacent R2 and the carbon atom to which they are bonded; R2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R3 and R4 may be the same or different, each representing a hydrogen atom or a C1-C6 alkyl group, or, when X and Z are carbon atoms and Y is a sulfur atom, R3 and R4 may form a 5-6 membered cyclic amide together with the nitrogen atom to which R4 is bonded; R5 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R6 and R7 are the same or different hydrogen atom, halogen atom, or alkoxy group having 1 to 6 carbon atoms; The dashed lines indicate single or double bonds. However, when X and Z are carbon atoms, Y is a sulfur atom, and R1 is a diphenylmethyl group of formula (II), R3 and R4 are either the same or different atoms and are not hydrogen atoms or alkyl groups having 1 to 6 carbon atoms. A compound represented by or a salt thereof.

[0108] <2> Preferably, X and Z are either one nitrogen atom and the other carbon atom, or both carbon atoms, and more preferably, one of X and Z is a nitrogen atom and the other is a carbon atom. <1> The compounds or salts thereof described below. <3> Y is preferably a CR5 or NH group. <1> or <2> The compounds or salts thereof described below. <4> Preferably, X and Z are carbon atoms and Y is a sulfur atom or an NH group, or X is a nitrogen atom, Z is a carbon atom and Y is a CR5, or X is a carbon atom, Z is a nitrogen atom and Y is a CR5, more preferably X and Z are carbon atoms and Y is an NH group, or X is a nitrogen atom, Z is a carbon atom and Y is a CR5, or X is a carbon atom, Z is a nitrogen atom and Y is a CR5, and even more preferably X is a nitrogen atom, Z is a carbon atom and Y is a CR5. <1> The compounds or salts thereof described below. <5> R1 is preferably an o-biphenyl group or a diphenylmethyl group of formula (II), and more preferably a diphenylmethyl group of formula (II). <1> ~ <4> A compound or salt thereof as described in any of the following. <6> R2 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> R3 and R4, together with the nitrogen atom to which R4 is bonded, form a 5-6 membered cyclic amide, which is preferably a γ-lactam, a δ-lactam, and more preferably a γ-lactam. <1> ~ <6> A compound or salt thereof as described in any of the following. <8> R3 is preferably a hydrogen atom or a methyl group, more preferably a hydrogen atom, and R4 is preferably a hydrogen atom. <1> ~ <6> A compound or salt thereof as described in any of the following. <9> R5 is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom. <1> ~ <8> A compound or salt thereof as described in any of the following. <10> R6 and R7 are preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a methoxy group, and more preferably a hydrogen atom. <1> ~ <9> A compound or salt thereof as described in any of the following.

[0109] <11> Preferably, the compound is such that X and Z are the same or different carbon atoms or nitrogen atoms, Y is a CR5, sulfur atom, or NH group, and R1 represents an o-biphenyl group or a diphenylmethyl group of formula (II); or when X and Z are carbon atoms and Y is a sulfur atom, R2 and the adjacent R2 form a biphenyl ring with the carbon atom to which they are bonded, R2 is a hydrogen atom or a methyl group, and R3 and R4 are the same or different hydrogen atoms or methyl groups; or when X and Z are carbon atoms and Y is a sulfur atom, R3 and R4 form a 5-6 membered cyclic amide with the nitrogen atom to which R4 is bonded, R5 is a hydrogen atom or a methyl group, and R6 and R7 are the same or different hydrogen atoms, halogen atoms, or methoxy groups (however, when X and Z are carbon atoms, Y is a sulfur atom, and R1 is a diphenylmethyl group of formula (II), R3 and R4 are not hydrogen atoms or methyl groups). <1> The compounds or salts thereof described below. <12> Preferably, the compound is such that X and Z are the same or different carbon atoms or nitrogen atoms, Y is a CR5 or NH group, R1 is a diphenylmethyl group of formula (II), R2 and R3 are the same or different hydrogen atoms or methyl groups, R4 is a hydrogen atom, R5 is a hydrogen atom or methyl group, and R6 and R7 are the same or different hydrogen atoms, halogen atoms or methoxy groups. <1> The compounds or salts thereof described below. <13> Preferably, X and Z are carbon atoms, Y is a sulfur atom, R1 represents an o-biphenyl group or a diphenylmethyl group of formula (II), or may form a biphenyl ring with the adjacent R2 and the carbon atom to which they are bonded, R2 is a hydrogen atom, R3 and R4 are hydrogen atoms, or R3 and R4 form a 5-6 membered cyclic amide with the nitrogen atom to which R4 is bonded, and R6 and R7 are hydrogen atoms (however, when R1 is a diphenylmethyl group of formula (II), R3 and R4 are not simultaneously hydrogen atoms). <1> The compounds or salts thereof described below. <14> A compound or salt thereof selected from the following. (5-([1,1'-biphenyl]-2-yl)thiophene-2-carbonyl)-L-arginine (compound 1), (7-phenylbenzo[b]thiophene-2-carbonyl)-L-arginine (compound 2), (2-benzhydryl-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-yl)-L-arginine (compound 3), (2-benzhydryl-7-oxo-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-yl)-L-arginine (compound 4), (3-benzhydryl-1H-pyrrole-1-carbonyl)-L-arginine (compound 5), (5-benzhydryl-1H-pyrrole-2-carbonyl)-L-arginine (compound 6), (1-benzhydryl-1H-pyrrole-3-carbonyl)-L-arginine (compound 7), (1-(bis(4-methoxyphenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine (compound 8), (1-(bis(4-fluorophenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine (compound 9), (1-(bis(4-chlorophenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine (compound 10), (1-benzhydryl-2-methyl-1H-pyrrole-3-carbonyl)-L-arginine (compound 11), (1-benzhydryl-4-methyl-1H-pyrrole-3-carbonyl)-L-arginine (compound 12), (1-benzhydryl-5-methyl-1H-pyrrole-3-carbonyl)-L-arginine (compound 13).

[0110] <15> <1> ~ <14> A C3a receptor antagonist comprising any of the compounds or salts thereof described in one of the above as an active ingredient. <16> <1> ~ <14> An agent for preventing or improving itching, comprising any of the compounds or salts thereof described in the above as an active ingredient. <17> The itching is preferably intractable itching, more preferably itching associated with 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 associated with atopic dermatitis, xerosis, nodular prurigo, or pruritus associated with cholestasis. <16> An agent for preventing or improving itching as described above. <18> <1> ~ <14> 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. <19> 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. <18> A preventive or ameliorative agent for pruritic skin diseases exhibiting intractable itching, as described above. <20> <1> ~ <14> A pharmaceutical composition comprising a compound or salt thereof as described in any of the above and a pharmaceutically acceptable carrier. [Examples]

[0111] All reagents and solvents were used as purchased from various vendors. NMR spectra were measured using a Bruker Avance III 600 MHz NMR spectrometer. 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 TripleTOF4600 or XR500. Column chromatography was performed using a Universal column (Yamazen, Premium) in 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 1000 ppm and then analyzing it by high-performance liquid chromatography (HPLC, Agilent) under the following conditions.

[0112] Column: L-coumn 2 ODS (CERI, 3.0×50 mm, 2 μm) Injection volume: 5 μL Solvent: A: 0.1% TFA aq. B: 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)

[0113] General procedure 1: Condensation reaction (i) A carboxylic acid (1.0 eq.) was dissolved in dimethylformamide (DMF) (5 mL / mmol) under an argon atmosphere, and then 1H-benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1.5 eq.), amine hydrochloride (1.5 eq.), and N,N-diisopropylethylamine (DIPEA) (3.0 eq.) were added. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain the compound.

[0114] General procedure 2: 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, and then saturated ammonium chloride aqueous solution was added. After extraction with ethyl acetate, the organic layer was washed with saturated brine. The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain the compound.

[0115] General procedure 3: Hydrolysis reaction (i) An ester (1.0 eq.) was dissolved in methanol (or possibly mixed with an equal amount of tetrahydrofuran (THF)) or ethanol (2.5 mL / mmol), and then a 2.5N sodium hydroxide (NaOH) aqueous solution (5.0 eq.) was added. 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.

[0116] General procedure 4: 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 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℃).

[0117] Manufacturing Example 1 Synthesis of Compound 1 The synthesis scheme for compound 1 is shown below (Scheme 7). Compounds 1-1 and 1-2 were coupled by a CH activation reaction, followed by deprotection by hydrolysis to obtain compound 1-4. Next, compound 1-5 was obtained by a condensation reaction, and then compound 1 was obtained by another deprotection reaction by hydrolysis.

[0118] [ka]

[0119] (Preparation of Pd catalyst (PdCl(C3H5)(dppb))) In a Schlenk tube that had been thoroughly dried and purged with nitrogen, 1,4-bis(diphenylphosphin)butane (dppb) (431.3 mg, 2.0 eq.) and dichloromethane (10 mL, 20 mL / mmol Pd cat.) were added to Pd(C3H5)Cl2 (183.6 mg, 1.0 eq.) and the mixture was stirred at room temperature under a nitrogen atmosphere for 20 minutes. The solvent was then removed by distillation at 100 mm bar, and the mixture was dried to obtain a pale pink solid.

[0120] (Step a) Compound 1-3 Compound 1-1 (0.5 mL, 1.5 eq.), Compound 1-2 (0.5 mL, 1.0 eq.), potassium acetate (472.4 mg, 2.0 eq.), dimethylacetamide (5 mL, 2 mL / mmol), and PdCl(C3H5)(dppb) (29.4 mg, 0.02 eq.) were added to a Schlenk tube that had been thoroughly dried and nitrogen-purged beforehand. The mixture was stirred overnight at 150 °C under a nitrogen atmosphere. After confirming the completion of the reaction by TLC, the mixture was quenched with water (5 mL) and extracted with hexane / ethyl acetate (4 / 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / acetone) to obtain red oily substance 1-3 (550.3 mg, yield 74%).

[0121] 1 H-NMR (600 MHz, CDCl3) δ: 7.56-7.53 (m, 1H), 7.52 (d, 1H, J = 4.1 Hz), 7.45-7.38 (m, 3H), 7.32-7.28 (m, 3H), 7.24-7.21 (m, 2H), 6.56 (d, 1H, J = 4.1 Hz), 4.31 (q, 2H, J =7.2 Hz), 1.35 (t, 3H, J =7.2 Hz). 13 C-NMR (150 MHz, CDCl3) δ: 162.3, 150.4, 141.2, 140.8, 133.2, 133.1, 132.2, 131.0, 130.6, 129.5, 128.7, 128.2, 127.8, 127.7, 127.2, 61.1, 14.3. HRMS (ESI, m / z, [M+H] + ): calcd for C 19 H 16 O2S: 309.0943, found: 309.0948 (Δ = 1.6 ppm).

[0122] (Step b) Compound 1-4 Compounds 1-3 (223.6 mg) were purified by silica gel column chromatography (chloroform / methanol) according to general procedure 3 to obtain white solids 1-4 (147.9 mg, 73% yield).

[0123] 1 H-NMR (600 MHz, CDCl3) δ: 7.60 (d, 1H, J = 4.0 Hz), 7.57-7.54 (m, 1H), 7.47-7.39 (m, 3H), 7.32-7.29 (m, 3H), 7.24-7.21 (m, 2H), 6.62 (d, 1H, J = 4.0 Hz). 13 C-NMR (150 MHz, CDCl3) δ: 166.7, 152.2, 141.2, 140.7, 134.8, 132.0, 131.8, 131.0, 130.5, 129.5, 128.9, 128.3, 128.1, 127.7, 127.4. HRMS (ESI, m / z, [M+H] + ): calcd for C 17 H 13 O2S: 281.0630, found: 281.0623 (Δ = - 2.8 ppm).

[0124] (Step c) Compound 1-5 White solids 1-5 (150.6 mg) were obtained from compounds 1-4 (68.4 mg) according to general procedure 1.

[0125] (Step d) Compound 1 A white solid 1 was obtained using compound 1-5 (51.2 mg) according to general procedure 4 (11.8 mg, yield 27% (2 steps)).

[0126] 1H-NMR (600 MHz, CD3OD) δ: 7.56-7.54 (m, 1H), 7.52 (d, J = 3.8 Hz, 1H), 7.47-7.41 (m, 2H), 7.39-7.37 (m, 1H), 7.32-7.26 (m, 3H), 7.23-7.20 (m, 2H), 6.67 (d, J = 3.8 Hz, 1H), 4.56 (dd, J = 4.9, 4.9 Hz, 1H), 3.28-3.18 (m, 2H), 2.07-2.00 (m, 1H), 1.87-1.80 (m, 1H), 1.75-1.65 (m, 2H). 13 C-NMR (150 MHz, CD3OD) δ: 175.2, 164.4, 163.2, 163.0, 158.7, 150.4, 142.6, 142.5, 139.1, 133.6, 132.0, 131.6, 130.7, 130.0, 129.9, 129.3, 129.0, 128.9, 128.4, 53.5, 41.9, 29.8, 26.6. HRMS (ESI, m / z, [M+H] + ): calcd for C 23 H 25 N4O3S: 437.1641, found : 437.1650 (Δ = 1.9 ppm). Purity: 99.3%

[0127] Manufacturing Example 2 Synthesis of Compound 2 The synthesis scheme for compound 2 is shown below (Scheme 8). Compound 2-1 was bonded to a phenyl group by Suzuki-Miyaura cross-coupling, and then deprotected by hydrolysis to obtain compound 2-3. Next, compound 2-4 was obtained by a condensation reaction, and then compound 2 was obtained by another deprotection reaction by hydrolysis.

[0128] [ka]

[0129] (Step a) Compound 2-2 Compound 2-1 (500 mg, 1.0 eq.) was mixed with 1,4-dioxane (6.1 mL), potassium carbonate (1.00 g, 2.0 eq.), phenylboronic acid (270 mg, 1.2 eq.), tetrakis(triphenylphosphine)palladium(0) (213 mg, 0.1 eq.), and lithium chloride (156 mg, 2.0 eq.) under an argon atmosphere and stirred under reflux for 6 hours. After confirming the completion of the reaction by TLC, the mixture was allowed to cool and quenched with water (30 mL). After extraction with ethyl acetate, the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain yellow solid 2-2 (0.4931 g, 93% yield).

[0130] 1 H-NMR (600 MHz, CDCl3) δ: 8.13 (s, 1H), 7.83 (ddd, J = 9.6, 4.1, 4.1 Hz, 1H), 7.74-7.70 (m, 2H), 7.54-7.43 (m, 5H), 3.94 (s, 3H). 13 C-NMR (150 MHz, CDCl3) δ: 163.1, 141.3, 139.8, 139.4, 137.0, 133.5, 131.0, 128.9, 128.7, 128.2, 128.1, 126.7, 125.6, 124.5, 52.4.

[0131] (Step b) Compound 2-3 A white solid 2-3 (181.2 mg, 83% yield) was obtained from compound 2-2 (230.7 mg) according to general procedure 3.

[0132] 1 H-NMR (600 MHz, DMSO-d6) δ: 8.20 (s, 1H), 8.03 (dd, J = 7.6, 1.4 Hz, 1H), 7.75-7.72 (m, 2H), 7.61-7.55 (m, 4H), 7.51-7.47 (m, 1H). 13 C-NMR (150 MHz, DMSO-d6) δ: 163.3, 139.9, 139.5, 139.2, 136.1, 134.8, 130.6, 129.0, 128.3, 127.7, 126.6, 125.9, 124.9. MS (ESI, m / z, [MH] - ): calcd for C 15 H 10 O2S: 253.0, found: 252.9.

[0133] (Engineering c) Compounds 2-4 Compound 2-3 (96.2 mg) was obtained, general hand 1 was obtained, and white solid 2-4 was obtained (268.0 mg).

[0134] (Engineering d) Compound 2 Compound 2-4 (93.6 mg) was obtained, general hand 4 was obtained, and white solid 2-4 was obtained (38.8 mg, yield 35% (2 steps)).

[0135] 1 H-NMR (600 MHz, CD3OD) δ: 8.12 (s, 1H), 7.90 (dd, J = 8.0, 1.1 Hz, 1H), 7.72-7.69 (m, 2H), 7.56-7.43 (m, 5H), 4.65 (dd, J = 9.5, 4.9 Hz, 1H), 3.32-3.20 (m, 2H), 2.13-2.06 (m, 1H), 1.94-1.86 (m, 1H), 1.82-1.69 (m 2H). 13 C-NMR (150 MHz, CD3OD) δ: 174.9, 164.9, 163.0 (q, J = 34.3 Hz), 158.7, 141.6, 141.44, 141.41, 139.6, 138.3, 130.1, 129.4, 129.2, 127.6, 127.5, 127.0, 125.5, 118.4 (q, J = 293.7 Hz), 53.6, 41.9, 29.8, 26.6. MS (ESI, m / z, [M+H] + ): calcd for C 21 H 23 N4O3S: 411.1, found: 411.6. MS (ESI, m / z, [MH] - ): calcd for C 21 H 23 N4O3S: 409.1, found: 409.2. Purity: 99.5%.

[0136] Manufacturing Example 3 Synthesis of Compound 3 The synthesis scheme for compound 3 is shown below (Scheme 9). Compound 3-1 was bonded to a diphenylmethane group by nucleophilic addition, and then compound 3-3 was obtained by bromination at the benzyl position. Next, compound 3-3 was bonded to an arginine skeleton by nucleophilic substitution, and then cyclized compound 3-6 was obtained by selective deprotection and intramolecular condensation. Finally, compound 3 was obtained by simultaneously carrying out deprotection and reduction reactions.

[0137] [ka]

[0138] (Step a) Compound 3-2 Under an argon atmosphere, compound 3-1 (4.20 mL, 1.0 eq.) and THF (100 mL) were added, and 2.0 M lithium diisopropylamide (LDA) THF solution (16.0 mL) was added at -78°C, and the mixture was stirred for 30 minutes. Next, benzophenone (6.42 g, 1.1 eq.) dissolved in THF (10 mL, 10 mL, 8 mL) was added, and the mixture was stirred overnight while gradually increasing the temperature to room temperature. After confirming the completion of the reaction by TLC, the mixture was concentrated and quenched with saturated ammonium chloride aqueous solution. After extraction with ethyl acetate, the mixture was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain pale yellow solid 3-2 (5.07 g, yield 64%).

[0139] 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). 13 C-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.

[0140] (Step b) Compound 3-3 Compound 3-2 (1.00 g, 1.0 eq.) was mixed with 1,2-dichloroethane (24 mL), N-bromosuccinimide (NBS) (557.6 mg, 1.06 eq.), and benzoyl peroxide (52.8 mg, 0.06 eq.) under an argon atmosphere and stirred at room temperature for 1.5 hours and then under reflux for 3.5 hours. Subsequently, benzoyl peroxide (50.8 mg, 0.05 eq.) was added and stirred under reflux overnight. Further addition of NBS (556.8 mg, 1.06 eq.) and benzoyl peroxide (97.6 mg, 0.10 eq.) was added and stirred under reflux for 3 hours. After confirming the completion of the reaction by TLC, the mixture was allowed to cool and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain pale yellow solid 3-3 (926.1 mg, yield 75%).

[0141] 1 H-NMR (600 MHz, CDCl3) δ: 7.39-7.31 (m, 10 H), 6.89 (s, 1H), 4.82 (s, 2H), 3.86 (s, 3H), 2.98 (s, 1H). 13 C-NMR (150 MHz, CDCl3) δ: 162.3, 157.6, 145.4, 144.2, 129.9, 128.4, 128.3, 128.1, 127.2, 80.2, 52.1, 25.1. MS (ESI, m / z, [M+H] + ): calculated for C 20 H 17 BrO3S: 419.0, found: 418.8.

[0142] (Project c) Compounds 3-4 Compound 3-3 (203.3 mg, 1.0 eq.) was added with H-Arg(Pbf)-OtBu·HCl (379.4 mg, 1.5 eq.), DMF (2.4 mL), and potassium carbonate (194.8 mg, 2.9 eq.) under an argon atmosphere and stirred at room temperature for 2 days. After confirming the completion of the reaction by TLC, water (2 mL) was added for quenching. After extraction with ethyl acetate, it was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. After azeotroping with toluene, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain white solid 3-4 (340.1 mg, yield 85%).

[0143] 1 1H-NMR (600 MHz, CDCl3) δ: 7.36-7.28 (m, 10H), 6.89 (s, 1H), 6.23 (brs, 1H), 6.01 (brs, 2H), 3.98 (d, J = 12.2 Hz, 1H), 3.87 (d, J = 13.1 Hz, 1H), 3.81 (s, 3H), 3.16-3.02 (m, 3H), 2.94 (s, 2H), 2.56 (s, 3H), 2.50 (s, 3H), 2.08 (s, 3H), 1.78-1.48 (m, 4H), 1.45 (s, 6H), 1.43 (s, 9H). 13C-NMR (150 MHz, CDCl3) δ: 173.8, 162.9, 158.6, 158.3, 155.9, 147.5, 145.72, 145.67, 138.4, 133.2, 132.3, 129.6, 128.2, 128.0, 127.2, 127.0, 124.5, 117.4, 86.3, 81.7, 80.0, 61.4, 52.1, 45.9, 43.3, 41.0, 29.7, 28.6, 28.1, 25.4, 19.3, 17.9, 12.5. MS (ESI, m / z, [M+2H) 2+ ): calcd for C 43 H 54 N4O8S2: 820.3, found: 820.9.

[0144] (Engineering d, e) Compounds 3-6 Compounds 3-4 (150.5 mg, 1.0 eq.) were mixed with 0.375 M NaOH (in THF / MeOH / H2O (1 / 1 / 1) (0.736 mL, 1.5 eq.), stirred at room temperature for 30 minutes and then at 50 °C for 45 minutes. Then, 0.375 N NaOH (in THF / MeOH / H2O (1 / 1 / 1) (0.720 mL, 1.5 eq.) was added, and the mixture was stirred at 50 °C for 2.5 hours. After confirming the completion of the reaction by TLC, the mixture was allowed to cool. The reaction mixture was concentrated and quenched with saturated ammonium chloride aqueous solution (2 mL). After extraction with ethyl acetate, the mixture was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting white solid was then mixed with dichloromethane (1.9 mL) and DIPEA (156 μL, 5.0) under an argon atmosphere. eq.) 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (210.5 mg, 3.0 eq.) was added and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction by TLC, the mixture was quenched with water (2 mL). After extraction with ethyl acetate, the mixture was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain white solids 3-6 (114.6 mg, yield 79% (2 steps)).

[0145] 1 H-NMR (600 MHz, CDCl3) δ:7.56-7.46 (m, 10H), 6.89 (s, 1H), 6.22 (brs, 3H), 4.96 (d, J = 8.6 Hz, 1H), 4.66 (d, J = 17.7 Hz, 1H), 4.30 (d, J = 17.7 Hz, 1H), 3.83 (brs, 1H), 3.46-3.34 (m, 2H), 3.11 (s, 2H), 2.73 (s, 3H), 2.66 (s, 3H), 2.25 (s, 3H), 2.18-2.12 (m, 1H), 2.02-1.94 (m, 1H), 1.76-1.56 (m, 2H), 1.63 (s, 6H), 1.62 (s, 9H) 13 13C-NMR (150 MHz, CDCl3) δ: 170.0, 166.2, 164.2, 158.7, 155.9, 151.5, 145.8, 138.3, 133.1, 132.3, 128.2, 128.0, 127.3, 127.2, 124.5, 120.7, 117.4, 86.3, 82.6, 80.4, 54.1, 46.0, 43.2, 40.6, 28.6, 28.0, 27.7, 25.6, 19.3, 17.9, 12.5. MS (ESI, m / z, [M+H] + ): calculated for C 42 H 50 N4O7S2: 787.3, found: 788.1. MS (ESI, m / z, [M-H] - ): calculated for C 42 H 50 N4O7S2: 785.3, found: 785.2.

[0146] (Project f) Compound 3 To Compound 3-6 (33.3 mg), trifluoroacetic acid / triethylsilane (20 / 1) (0.90 mL) was added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction by TLC, it was concentrated and azeotroped with toluene and chloroform. The residue was separated by liquid chromatography (L-column 2 (10×250 mm, 5 μm), 0.1% TFA aq. / MeCN, 4.6 mL / min., 40 °C) to obtain white solid 3 (18.2 mg, yield 77%).

[0147] 11H-NMR (600 MHz, CD3OD) δ: 7.34 - 7.31 (m, 4H), 7.25 - 7.23 (m, 6H), 6.82 (d, J = 0.8 Hz, 1H), 5.84 (s, 1H), 4.81 (dd, J = 11.2, 4.8 Hz, 1H), 4.55 (d, J = 18.2 Hz, 1H), 4.34 (d, J = 18.2 Hz, 1H), 3.26 - 3.20 (m, 2H), 2.18 - 2.13 (m, 1H), 1.95 - 1.88 (m, 1H), 1.62 - 1.56 (m, 2H). 13 13C-NMR (150 MHz, CD3OD) δ: 174.9, 167.9, 163.4, 163.1 (q, J = 34.6 Hz), 158.7, 154.2, 144.4, 133.6, 130.0, 129.7, 128.2, 122.2, 118.3 (q, J = 293.5 Hz), 56.0, 54.1, 47.6, 41.8, 28.2, 26.9. HRMS (ESI, m / z, [M-H] - ): calcd for C 25 H 26 N4O3S: 461.2, 460.9 found. Purity: 99.3%.

[0148] Production Example 4 Synthesis of Compound 4 The synthesis scheme of Compound 4 is shown below (Scheme 10). Through a nucleophilic addition reaction, Compound 4-1 was bonded to a diphenylmethane group, and then through a reduction reaction, Compound 4-3 was obtained. Next, after activating the hydroxyl group with a leaving group, Compound 4-4 with a vinyl ether group added by Suzuki-Miyaura cross-coupling was obtained. After obtaining the aldehyde form 4-5 by an acid hydrolysis reaction, Compound 4-6 linked to an arginine skeleton by a reductive amination reaction was obtained. Under acidic conditions, after obtaining the cyclized form 4-7, Compound 4 was obtained by a deprotection reaction.

[0149]

Chemical Structure

[0150] (Step a) Compound 4-2 Compound 4-1 (1.59 g, 1.0 eq.) was added to THF (15 mL) under an argon atmosphere, and 2.0 M lithium diisopropylamide (LDA) THF solution (9.8 mL) was added at -78°C, and the mixture was stirred for 15 minutes. Next, benzophenone (1.81 g, 1.01 eq.) was added in THF (10 mL, 7 mL, 7 mL) and the mixture was stirred overnight while gradually raising the temperature to room temperature. After confirming the completion of the reaction by TLC, the mixture was concentrated and quenched with saturated ammonium chloride aqueous solution (70 mL). After extraction with ethyl acetate, the mixture was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a white solid 4-2 (2.08 g, yield 61%).

[0151] 1 H-NMR (600 MHz, CDCl3) δ: 9.51 (s, 1H), 7.36-7.30 (m, 12H), 6.50 (s, 1H), 3.85 (s, 3H), 3.00 (s, 1H). 13 C-NMR (150 MHz, CDCl3) δ: 166.8, 163.7, 158.3, 145.2, 128.3, 128.1, 127.2, 118.7, 103.5, 80.4, 51.8. HRMS (ESI, m / z, [MH] - ): calcd for C 19 H 15 O4S: 339.0696; found: 339.0693 (Δ = - 1.0ppm)

[0152] (Step b) Compound 4-3 Compound 4-2 (7.13 g, 1.0 eq.) was mixed with dichloromethane (84 mL), triethylsilane (3.7 mL), and trifluoroacetic acid (3.5 mL) under an argon atmosphere and stirred at room temperature for 1 hour. After confirming the completion of the reaction by TLC, the mixture was quenched with saturated sodium bicarbonate solution (300 mL). After extraction with chloroform, the mixture was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a yellow oily substance 4-3 (5.92 g, yield 87%).

[0153] 1 H-NMR (600 MHz, CDCl3) δ: 9.54 (s, 1H), 7.34-7.30 (m, 4H), 7.28-7.24 (m, 2H), 7.21-7.19 (m, 4H), 6.45 (d, J = 1.1 Hz, 1H), 5.55 (s, 1H), 3.83 (s, 3H). 13 C-NMR (150 MHz, CDCl3) δ: 166.6, 164.2, 155.0, 142.1, 128.8, 128.6, 127.2, 119.0, 102.9, 52.9, 51.7. HRMS (ESI, m / z, [MH] - ): calcd for C 19 H 15 O3S : 323.0752; found:323.0755 (Δ = 0.8ppm).

[0154] (Steps c, d) Compound 4-4 Compound 4-3 (3.00 g, 1.0 eq.) was mixed with pyridine (23 mL) under an argon atmosphere and trifluoromethanesulfonic anhydride (1.80 mL, 1.2 eq.) under ice cooling, and the mixture was stirred under ice cooling for 1 hour. After confirming the completion of the reaction by TLC, the mixture was quenched with saturated sodium bicarbonate solution (40 mL). After extraction with ethyl acetate, the mixture was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. The organic layer was concentrated and azeotropically diluted with toluene. To the residue, under an argon atmosphere, 1,2-dimethoxyethane (69.2 mL), water (9.2 mL), (E)-1-ethoxyethene-2-boronic acid pinacol ester (2.94 mL, 1.5 eq.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (Pd(dppf)Cl2·CH2Cl2) (376.3 mg, 0.05 eq.), and cesium carbonate (6.03 g, 2.0 eq.) were added and the mixture was stirred at 80 °C overnight. After confirming the completion of the reaction by TLC, the mixture was allowed to cool and then quenched with saturated sodium bicarbonate solution (100 mL). After extraction with ethyl acetate, the mixture was washed with saturated brine. The organic layer was dried over magnesium sulfate and then filtered. After concentrating the organic layer, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain an orange oily substance 4-4 (3.40 g, 97% yield (2 steps)).

[0155] 1 H-NMR (600 MHz, CDCl3) δ: 7.34-7.30 (m, 4H), 7.27-7.24 (m, 2H), 7.22-7.20 (m, 4H), 7.05 (d, J = 13.3 Hz, 1H), 6.80 (d, J = 13.3 Hz, 1H), 6.79 (s, 1H), 5.59 (s, 1H), 3.92 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 1313C-NMR (150 MHz, CDCl3) δ: 163.3, 153.5, 152.0, 144.7, 142.6, 128.8, 128.6, 127.1, 124.0, 121.3, 100.4, 65.2, 52.5, 51.6, 14.6. HRMS (ESI, m / z, [M+H] + ): calcd for C 23 H 23 O3S :379.1362; found:379.1355 (Δ = - 2.0ppm).

[0156] (Engineering e) Compounds 4-5 Compound 4-4 (1.51 g, 1.0 eq.) was added to THF (22 mL) and 6N HCl aq. (5.98 mL, 9.0 eq.), and the mixture was stirred at room temperature for 2 days. Then, 6N HCl aq. (6 mL, 9.0 eq.) was added, and after stirring at room temperature for 5 hours, the reaction was confirmed to be complete by TLC and then quenched with saturated aqueous sodium bicarbonate (50 mL). After extraction with ethyl acetate, it was washed with saturated brine. The organic layer was dried over magnesium sulfate and then filtered. After concentrating the organic layer, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain yellow oily substance 4-5 (849.2 mg, yield 60%).

[0157] 1 1H-NMR (600 MHz, CDCl3) δ: 9.69 (t, J = 1.7 Hz, 1H), 7.34-7.31 (m, 4H), 7.28-7.25 (m, 2H), 7.22-7.18 (m, 4H), 6.61 (d, J = 1.0 Hz, 1H), 5.62 (s, 1H), 4.02 (d, J = 1.7 Hz, 2H), 3.80 (s, 3H). 13 13C-NMR (150 MHz, CDCl3) δ: 198.2, 162.8, 154.5, 142.5, 139.9, 130.6, 128.8, 128.7, 127.2, 127.2, 52.4, 51.9, 44.4. HRMS (ESI, m / z, [MH] - ): calcd for C 21 H 17 O3S : 349.0903; found : 349.0898 (Δ = - 1.7ppm).

[0158] (Step f) Compound 4-6 Compounds 4-5 (28.6 mg, 1.0 eq.) were mixed with methanol (0.74 mL), acetic acid (0.074 mL), and H-Arg(Pbf)-OMe·HCl (64.9 mg, 1.5 eq.) under an argon atmosphere and stirred at room temperature for 1 hour. Then, 2-picolineborane (14.0 mg, 1.5 eq.) was added and stirred at room temperature for 1.5 hours. After confirming the completion of the reaction by TLC, the mixture was quenched with saturated sodium bicarbonate solution (2 mL). After extraction with ethyl acetate, the mixture was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. After concentrating the organic layer, the residue was purified by silica gel column chromatography (chloroform / methanol), and then again by silica gel column chromatography (hexane / ethyl acetate) to obtain pale yellow oily substance 4-6 (30.6 mg, yield 48%).

[0159] 1 H-NMR (600 MHz, CDCl3) δ: 7.33-7.29 (m, 4H), 7.27-7.24 (m, 2H), 7.21-7.17 (m, 4H), 6.62 (d, J = 0.8 Hz, 1H), 6.39 (brs, 1H), 6.11 (brs, 2H), 5.59 (s, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 3.24-3.08 (m, 4H), 3.06-3.01 (m, 1H), 2.95 (s, 2H), 2.80-2.74 (m, 1H), 2.69-2.64 (m, 1H), 2.60 (s, 3H), 2.54 (s, 3H), 2.09 (s, 3H), 1.64-1.55 (m, 4H), 1.45 (s, 6H). 13C-NMR (150 MHz, CDCl3) δ: 175.2, 163.1, 158.6, 155.9, 154.3, 148.3, 142.6, 138.4, 132.3, 130.1, 128.8, 128.7, 128.6, 127.1, 125.6, 124.5, 117.3, 86.3, 60.7, 52.4, 52.0, 51.9, 48.3, 43.3, 40.9, 30.3, 29.7, 28.6, 25.9, 19.3, 17.9, 12.5. HRMS (ESI, m / z, [M+H] + ): calcd for C 41 H 51 N4O7S2: 775.3193; found: 775.3181 (Δ = - 1.6 ppm).

[0160] (Step g) Compound 4-7 Compound 4-6 (46.4 mg, 1.0 eq.) was mixed with toluene (1.3 mL) and acetic acid (35.0 μL, 10.0 eq.) under an argon atmosphere and stirred at 80 °C overnight. After confirming the completion of the reaction by TLC, the mixture was allowed to cool and then quenched with saturated sodium bicarbonate solution (3 mL). After extraction with ethyl acetate, the mixture was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. The organic layer was concentrated, and the residue was purified again by silica gel column chromatography (hexane / ethyl acetate) to obtain pale yellow solid 4-7 (23.2 mg, yield 52%).

[0161] 11H-NMR (600 MHz, CDCl3) δ: 7.34 - 7.29 (m, 4H), 7.28 - 7.24 (m, 2H), 7.23 - 7.20 (m, 4H), 6.57 (d, J = 0.9 Hz, 1H), 6.12 (brs, 1H), 5.88 (s, 2H), 5.64 (s, 1H), 5.40 - 5.30 (m, 1H), 3.73 (s, 3H), 3.59 - 3.52 (m, 1H), 3.49 - 3.43 (m, 1H), 3.40 - 3.26 (brs, 1H), 3.26 - 3.20 (brs, 1H), 2.96 (ddd, J = 16.3, 5.1, 5.1 Hz, 1H), 2.94 (s, 2H), 2.78 (ddd, J = 16.3, 6.4, 5.4 Hz, 1H), 2.57 (s, 3H), 2.51 (s, 3H), 2.08 (s, 3H), 2.03 - 1.96 (m, 1H), 1.92 - 1.85 (m, 1H), 1.69 - 1.63 (m, 1H), 1.50 - 1.40 (m, 1H), 1.45 (s, 6H). 13 13C-NMR (150 MHz, CDCl3) δ: 171.3, 162.6, 158.6, 156.5, 155.8, 144.8, 142.6, 138.4, 133.1, 132.4, 129.5, 128.8, 128.7, 127.2, 126.2, 124.5, 117.4, 86.3, 52.7, 52.5, 43.4, 43.3, 40.9, 29.7, 28.6, 24.7, 22.7, 19.2, 17.8, 14.1, 12.5. HRMS (ESI, m / z, [M+H] + ): calcd for C 40 H 47 N4O6S2: 743.2931; found: 743.2912 (Δ = - 2.6ppm).

[0162] (Engineering h, i) Compound 4 To compound 4-7 (20.9 mg), methanol (0.3 mL) and 2.5N aqueous sodium hydroxide solution (0.112 mL, 10.0 eq.) were added, and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction by TLC, the mixture was quenched with 1N hydrochloric acid (0.5 mL). After extraction with ethyl acetate, the mixture was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. After concentrating the organic layer, trifluoroacetic acid / water / triisopropylsilane (20 / 1 / 1) (0.300 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the mixture was concentrated and azeotropically diluted with toluene. The obtained residue was separated by liquid chromatography (L-column 2 (10 × 250 mm, 5 μm), 0.1% TFA aq. / MeCN, 4.6 mL / min., 40 ℃) to obtain white solid 4 (8.0 mg, yield 49% (2 steps)).

[0163] 1 H-NMR (600 MHz, DMSO-d6) δ: 7.72 (s, 1H), 7.56-7.20 (m, 11H), 6.96 (brs, 1H), 6.70 (s, 1H), 5.83 (s, 1H), 4.91-4.85 (m, 1H), 3.56-3.44 (m, 2H), 3.14-3.06 (m, 2H), 2.88-2.76 (m, 2H), 1.98-1.90 (m, 1H), 1.80-1.72 (m, 1H), 1.48-1.38 (m, 2H). 13 C-NMR (150 MHz, DMSO-d6) δ: 172.6, 160.9, 158.0 (q, J = 26.7 Hz), 156.7, 154.2, 144.8, 143.1, 143.1, 129.8, 128.6, 128.5, 127.0, 126.4, 117.3 (q, J = 299.8 Hz), 55.4, 51.3, 43.3, 41.1, 25.6, 25.2, 24.2. MS (ESI, m / z, [M+H] + ): calcd for C 26 H 28N4O3S: 477.2; found: 477.0. Purity: 96.8%.

[0164] Manufacturing Example 5 Synthesis of Compound 5 The synthesis scheme for compound 5 is shown below (Scheme 11). Compound 5-1 was bonded to a diphenylmethane group by a dehydrating CC coupling reaction using an ionic liquid as the solvent, and then compound 5-3 was obtained by urea formation. Finally, compound 5 was obtained by a deprotection reaction.

[0165] [ka]

[0166] (Step a) Compound 5-2 Under an argon atmosphere, compound 5-1 (1.91 mL, 1.02 eq.), benzhydrol (5.00 g, 1.0 eq.), and 1-ethyl-3-methylimidazolium trifluoromethanesulfonate (EMIMOTf) (5.4 mL, 1.05 eq.) were added, and the mixture was stirred at 100 °C for 3 hours. After confirming the completion of the reaction by TLC, the mixture was allowed to cool and extracted with hexane / ethyl acetate (1 / 1). The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain pale yellow solid 5-2 (346.1 mg, yield 5.5%).

[0167] 1 H-NMR (600 MHz, CDCl3) δ: 8.04 (brs, 1H), 7.30-7.16 (m, 10H), 6.77-6.75 (m, 1H), 6.34-6.32 (m, 1H), 6.05-6.03 (m, 1H), 5.38 (s, 1H). 13 C-NMR (150 MHz, CDCl3) δ: 145.2, 128.9, 128.1, 127.0, 126.0, 118.0, 117.0, 109.2, 49.9.

[0168] (Step b) Compound 5-3 To compound 5-2 (87.0 mg), add DMF (0.5 mL) and sodium hydride (6.2 mg, 1.6 eq.) under ice cooling. Stir under ice cooling for 30 minutes, then add bis(4-nitrophenyl) carbonate (33.4 mg, 1.1 eq.) and stir under ice cooling for 1 hour, then at room temperature for 2 hours. Subsequently, add H-Arg(Pbf)-OtBu·HCl (213.9 mg, 1.1 eq.) and stir for 2 hours. Then, add H-Arg(Pbf)-OtBu·HCl (387.6 mg, 2.0 eq.) and stir at room temperature overnight. After confirming the completion of the reaction by TLC, quench with saturated ammonium chloride aqueous solution (2 mL) and extract with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. After concentrating the organic layer, the residue was purified by silica gel column chromatography (chloroform / acetone) to obtain a brown oily substance 5-3 (65.9 mg, yield 24%).

[0169] 1 H-NMR (600 MHz, CDCl3) δ: 7.30-7.25 (m, 4H), 7.22-7.17 (m, 7H), 6.74 (s, 1H), 6.30 (d, J = 6.5 Hz, 1H), 6.10 (dd, J = 3.2, 1.5 Hz, 1H), 5.94 (brs, 2H), 5.30 (s, 1H), 4.47-4.41 (m, 1H), 3.38-3.28 (m, 1H), 3.24-3.10 (m, 1H), 2.94 (s, 2H), 2.57 (s, 3H), 2.51 (s, 3H), 2.08 (s, 3H), 1.93-1.86 (m, 1H), 1.77-1.70 (m, 1H), 1.68-1.54 (m, 2H), 1.47 (s, 9H), 1.45 (s, 6H). 13C-NMR (150 MHz, CDCl3) δ: 171.1, 158.7, 155.9, 151.0, 143.8, 143.7, 138.4, 132.9, 132.3, 131.2, 128.84, 128.82, 128.4, 126.4, 124.6, 119.0, 117.4, 117.1, 113.8, 86.4, 83.4, 53.0, 49.7, 43.2, 40.7, 30.8, 28.6, 28.0, 24.9, 19.3, 17.9, 12.5.

[0170] (Step c) Compound 5 To compound 5-3 (13.5 mg), trifluoroacetic acid / thioanisole / 1,2-ethanedithiol / anisole (90 / 5 / 3 / 2) (1.82 mL) was added and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction by TLC, the mixture was concentrated. After azeotropic dichloromethane filtration, the residue was fractionated by liquid chromatography (L-column 2 (10 × 250 mm, 5 μm), 0.1% TFA aq. / MeCN, 4.6 mL / min., 40 ℃) to obtain white solid 5 (5.6 mg, yield 58%).

[0171] 1 H-NMR (600 MHz, DMSO-d6) δ: 12.89 (brs, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.70-6.60 (m, 4H), 7.63-7.53 (m, 1H), 7.43 (dd, J = 3.1, 2.5 Hz, 1H), 7.33-7.23 (m, 4H), 7.24-7.18 (m, 6H), 7.01 (dd, J = 2.5, 1.6 Hz, 1H), 6.05 (dd, J = 3.1, 2.5 Hz, 1H), 5.34 (s, 1H), 4.22 (ddd, J = 10.0, 7.8, 4.8 Hz, 1H), 3.14-3.07 (m, 2H), 1.90-1.80 (m, 1H), 1.76-1.66 (m, 1H), 1.61-1.40 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ: 173.4, 156.7, 150.7, 144.34, 144.31, 129.3, 128.6, 128.4, 126.3, 119.4, 117.2, 112.3, 53.2, 49.0, 40.3, 27.5, 25.5. HRMS (ESI, m / z, [M+H] + ): calcd for: C 24 H 27 N5O3: 434.2187 ; found 434.2173 (Δ = - 3.1ppm) HRMS (ESI, m / z, [MH] - ): calcd for C 24 H 27 N5O3: 432.2041; found 432.2032 (Δ = - 2.1ppm) Purity: 95.5%.

[0172] Manufacturing Example 6 Synthesis of Compound 6 The synthesis scheme for compound 6 is shown below (Scheme 12). Compound 6-1 was bonded to a diphenylmethane group by a dehydration CC coupling reaction using an ionic liquid as the solvent, and then compound 6-3 was obtained by deprotection via hydrolysis. Next, compound 6-4 was obtained by a condensation reaction, and then compound 6 was obtained by a deprotection reaction.

[0173] [ka]

[0174] (Step a) Compound 6-2 Under an argon atmosphere, compound 6-1 (1.39 g, 1.02 eq.), benzhydrol (2.00 g, 1.0 eq.), and 1-ethyl-3-methylimidazolium trifluoromethanesulfonate (EMIMOTf) (2.3 mL, 1.1 eq.) were added, and the mixture was stirred at 100 °C for 3 hours. After confirming the completion of the reaction by TLC, the mixture was allowed to cool and extracted with hexane / ethyl acetate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (toluene / ethyl acetate) to obtain a white solid 6-2 (1.42 g, 45% yield).

[0175] 1 H-NMR (600 MHz, CDCl3) δ: 8.68 (s, 1H), 7.34-7.14 (m, 10H), 6.84 (dd, J = 3.7, 2.6 Hz, 1H), 5.89-5.86 (m, 1H), 5.47 (s, 1H), 3.80 (s, 3H). 13 C-NMR (150 MHz, CDCl3) δ: 161.5, 141.8, 139.4, 128.8, 128.7, 127.1, 121.9, 115.7, 110.5, 51.4, 50.5.

[0176] (Step b) Compound 6-3 A white solid 6-3 (216.9 mg, yield quant.) was obtained from compound 6-2 (219.6 mg) according to general procedure 3.

[0177] 1 H-NMR (600 MHz, CDCl3) δ: 8.71 (s, 1H), 7.36-7.14 (m, 10H), 6.97 (dd, J = 3.6, 2.6 Hz, 1H), 5.94-5.90 (m, 1H), 5.48 (s, 1H). 13 C-NMR (150 MHz, CDCl3) δ: 165.1, 141.6, 140.7, 128.8, 127.1, 120.9, 117.8, 111.1, 50.6.

[0178] (Step c) Compound 6-4 To compound 6-3 (88.5 mg), following General Procedure 2, white foam 6-4 was obtained (250.6 mg, quant. yield).

[0179] 1 1H-NMR (600 MHz, CDCl3) δ: 10.31 (s, 1H), 7.28 - 7.14 (m, 6H), 7.10 - 7.01 (m, 2H), 7.02 - 6.99 (m, 2H), 6.52 (dd, J = 2.8, 2.8 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 6.33 (s, 1H), 6.18 (s, 2H), 5.74 (dd, J = 2.8, 2.8 Hz, 1H), 5.28 (s, 1H), 4.42 (ddd, J = 9.0, 8.0, 4.2 Hz, 1H), 3.25 - 3.15 (m, 1H), 2.98 - 2.90 (m, 1H), 2.93 (s, 2H), 2.54 (s, 3H), 2.47 (s, 3H), 2.08 (s, 3H), 1.87 - 1.77 (m, 1H), 1.66 - 1.40 (m, 3H), 1.48 (s, 9H), 1.45 (s, 3H), 1.44 (s, 3H). 13 13C-NMR (150 MHz, CDCl3) δ: 171.5, 161.7, 158.6, 156.1, 142.2, 138.3, 132.2, 128.7, 128.6, 128.5, 128.4, 126.8, 126.7, 124.5, 117.4, 110.9, 110.3, 86.3, 83.0, 51.2, 50.3, 43.2, 40.7, 31.7, 28.6, 28.0, 24.9, 19.3, 17.9, 12.5.

[0180] (Step d) Compound 6 To compound 6-4 (24.7 mg), trifluoroacetic acid / water / triisopropylsilane (95 / 2.5 / 2.5) (768 μL) was added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction by TLC, the mixture was concentrated under nitrogen. The residue was fractionated by liquid chromatography (L-column 2 (10 × 250 mm, 5 μm), 0.1% TFA aq. / MeCN, 4.6 mL / min., 40 ℃) to obtain white solid 6 (9.5 mg, yield 54%).

[0181] 1 H-NMR (600 MHz, DMSO-d6) δ: 12.69 (brs, 1H), 11.40 (s, 1H), 8.12-8.07 (m, 1H), 7.48 (dd, J = 5.6, 5.6 Hz, 1H), 7.33-7.28 (m, 4H), 7.24-7.20 (m, 2H), 7.15-7.12 (m,4H), 6.82-6.79 (m, 1H), 5.68 (dd, J = 3.0, 3.0 Hz, 1H), 5.53 (s, 1H), 4.39-4.32 (m, 1H), 3.15-3.05 (m, 2H), 1.86-1.78 (m, 1H), 1.71-1.63 (m, 1H), 1.59-1.46 (m, 2H). 13 C-NMR (150 MHz, DMSO-d6) δ: 173.8, 160.5, 157.8 (q, J = 30.5 Hz), 156.4, 143.1, 137.7, 128.41, 128.38, 128.2, 126.24, 126.23, 124.9, 117.2 (q, J = 300.9 Hz), 111.0, 108.2, 51.1, 49.1, 40.2, 27.9, 25.3. HRMS (ESI, m / z, [M+H] + ): calcd for C 24 H 27 N5O3: 434.2187; found 434.2169 (Δ = - 4.1ppm). HRMS (ESI, m / z, [MH] -: calcd for C 24 H 27 N5O3: 432.2041 found 432.2036 (Δ = - 1.2ppm). Purity: 98.9%

[0182] Manufacturing example 7 Synthesis of Compound 7 The synthesis scheme for compound 7 is shown below (Scheme 13). Compound 7-1 was bonded to a diphenylmethane group by a nucleophilic substitution reaction, and then compound 7-3 was obtained by deprotection via hydrolysis. Next, compound 7-4 was obtained by a condensation reaction, and then compound 7 was obtained by a deprotection reaction.

[0183] [ka]

[0184] (Steps a, b) Compound 7-3 Compound 7-1 (1.02 g, 1.0 eq.) was mixed with DMF (24.5 mL), and under ice cooling, sodium hydride (0.47 g, 1.5 eq.) and α-bromodiphenylmethane (2.42 g, 1.2 eq.) were added. The mixture was stirred for 3.5 hours while gradually increasing the temperature to room temperature. After confirming the completion of the reaction by TLC, the mixture was quenched with water (20 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine (20 mL) and dried over magnesium sulfate. After filtration, the organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a yellow oily substance (2.51 g). The yellow oily substance (1.33 g) was purified by silica gel column chromatography (chloroform / methanol) according to general procedure 3 to obtain a white solid 7-3 (0.9638 g, yield 80% (2 steps)).

[0185] 1H-NMR (600 MHz, CDCl3) δ: 7.37-7.31 (m, 6H), 7.28 (dd, J =1.8, 1.8 Hz, 1H), 7.10-7.06 (m, 4H), 6.66 (dd, J =2.7, 1.8 Hz, 1H), 6.60 (dd, J =2.7, 1.8 Hz, 1H), 6.47 (s, 1H). 13 C-NMR (150 MHz, CDCl3) δ: 169.7, 139.2, 128.8, 128.3, 128.2, 127.4, 122.6, 115.0, 110.7, 67.4.

[0186] (Engineering c) Compound 7-4 Compound 7-3 (153.8 mg) was obtained, general compound 2 was obtained, and white solid 7-4 was obtained (381.5 mg, yield 93%).

[0187] 1 H-NMR (600 MHz, CDCl3) δ: 7.37-7.32 (m, 6H), 7.14 (dd, J = 2.2, 1.9 Hz, 1H), 7.12-7.05 (m, 4H), 6.60 (dd, J = 2.7, 2.2 Hz, 1H), 6.50 (brd, J = 7.9 Hz, 1H), 6.46 (s, 1H), 6.44 (dd, J = 2.7, 1.9 Hz, 1H), 6.13 (brs, 2H), 4.57 (m, 1H), 3.43 (brs, 1H), 3.20 (brs, 1H), 2.94 (s, 2H), 2.58 (s, 3H), 2.52 (s, 3H), 2.08 (s, 3H), 1.90-1.83 (m, 1H), 1.72-1.58 (m, 3H), 1.47 (s, 9H), 1.45 (s, 6H). 13C-NMR (150 MHz, CDCl3) δ: 171.8, 165.2, 158.5, 156.1, 139.3, 139.2, 138.4, 133.3, 132.3, 128.8, 128.32, 128.31, 128.2, 128.1, 124.5, 124.2, 122.6, 118.5, 117.3, 107.4, 86.2, 82.8, 67.4, 51.2, 43.2, 40.7, 31.8, 28.6, 28.0, 24.7, 19.3, 17.9, 12.5.

[0188] (Step d) Compound 7 To compound 7-4 (34.2 mg), trifluoroacetic acid / water / triethylsilane (80 / 20 / 5) (4.8 mL) was added and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction by TLC, the mixture was concentrated. After azeotropic dilution with toluene, the residue was fractionated by liquid chromatography (L-column 2 (10 × 250 mm, 5 μm), 0.1% TFA aq. / MeCN, 4.6 mL / min., 40 ℃) to obtain white solid 7 (15.6 mg, yield 64%).

[0189] 1 H-NMR (600 MHz, DMSO-d6) δ: 12.62 (brs, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.59-7.53 (m, 1H), 7.43-7.37 (m, 4H), 7.36-7.32 (m, 2H), 7.30 (dd, J = 2.2, 1.7 Hz, 1H), 7.16-7.08 (m, 4H), 6.78 (s, 1H), 6.76 (dd, J = 2.7, 2.2 Hz, 1H), 6.58 (dd, J = 2.7, 1.7 Hz, 1H), 4.35-4.28 (m, 1H), 3.14-3.04 (m, 2H), 1.84-1.76 (m, 1H), 1.69-1.61 (m, 1H), 1.58-1.44 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ: 173.9, 163.6, 157.8 (q, J = 30.5 Hz), 156.5, 140.12, 140.06, 128.6, 127.9, 127.83, 127.81, 127.76, 123.2, 121.7, 119.2, 117.2 (q, J = 300.7 Hz), 108.1, 65.6, 51.1, 40.2, 27.8, 25.3. HRMS (ESI, m / z, [M+H] + ): calcd for: C 24 H 27 N5O3: 434.2187; found: 431.2167 (Δ = - 4.5 ppm). HRMS (ESI, m / z, [M - H] - ): calcd for C 24 H 27 N5O3: 432.2041; found: 432.2036 (Δ = 1.2 ppm). Purity: >99%.

[0190] Manufacturing examples 8-13 Synthesis of compounds 8-13 Examples of the synthesis of compounds 8-13 are shown below. Carboxylic acids 8-13-1 were synthesized using the same method as in the synthesis of 7-3.

[0191] [ka]

[0192] Synthesis of compound 8-2 Compound 8-2 was synthesized using carboxylic acid compound 8-1 and H-Arg(Pbf)-OtBu·HCl (Watanabe Chemical Industry Co., Ltd., K00619) in the same manner as in general procedure 2.

[0193] Synthesis of compound 8 Compound 8 was synthesized by performing the same reaction on compound 8-2 as the method used to obtain compound 3 from compound 3-6.

[0194] Synthesis of compounds 9-13 Compounds 9 to 13 were synthesized using compounds 9 to 13-1 as raw materials, in the same manner as the synthesis methods for compounds 8-2 and 8.

[0195] Compound 8:(1-(bis(4-methoxyphenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine Appearance: White solid 1 H-NMR (600 MHz, DMSO-d6) δ: 12.52 (brs, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.48-7.58 (m, 1H), 7.24-7.26 (m, 1H), 6.99-7.03 (m, 4H), 6.92-6.96 (m, 4H), 6.69-6.71 (m, 1H), 6.62 (s, 1H), 6.54-6.56 (m, 1H), 4.30-4.35 (m, 1H), 3.75 (s, 3H), 3.75 (s, 3H), 3.04-3.14 (m, 2H), 1.76-1.84 (m, 1H), 1.61-1.70 (m, 1H), 1.44-1.58 (m, 2H). 13 C-NMR (150 MHz, DMSO-d6) δ: 174.0, 163.7, 158.7, 158.7, 156.6, 132.5, 132.5, 129.0, 129.0, 123.1, 121.5, 119.1, 114.0, 108.0, 64.7, 55.1, 51.2, 40.3, 28.0, 25.4.

[0196] Compound 9:(1-(bis(4-fluorophenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine Appearance: White solid 1H-NMR (600 MHz, DMSO-d6) δ: 12.51 (brs, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.48-7.58 (m, 1H), 7.28-7.30 (m, 1H), 7.21-7.27 (m, 4H), 7.12-7.17 (m, 4H), 6.82 (s, 1H), 6.73-6.76 (m, 1H), 6.57-6.61 (m, 1H), 4.29-4.37 (m, 1H), 3.04-3.15 (m, 2H), 1.76-1.85 (m, 1H), 1.61-1.70 (m, 1H), 1.44–1.58 (m, 2H). 13 C-NMR (150 MHz, DMSO-d6) δ: 174.3, 163.5, 161.6 (d, J = 244.7 Hz), 156.7, 136.4 (d, J = 3.3 Hz), 136.3 (d, J = 3.2 Hz), 130.0 (d, J = 8.7 Hz), 129.9 (d, J = 9.6 Hz), 123.1, 121.5, 119.6, 115.6 (d, J = 21.5 Hz), 108.4, 64.2, 51.6, 40.3, 28.2, 25.3.

[0197] Compound 10:(1-(bis(4-chlorophenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine Appearance: white solid 1H-NMR (600 MHz, DMSO-d6) δ: 12.55 (brs, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.51-7.56 (m, 1H), 7.46-7.50 (m, 4H), 7.28-7.31 (m, 1H), 7.10-7.14 (m, 4H), 6.83 (s, 1H), 6.74-6.78 (m, 1H), 6.58-6.61 (m, 1H), 4.30-4.37 (m, 1H), 3.04-3.15 (m, 2H), 1.76-1.85 (m, 1H), 1.61-1.70 (m, 1H), 1.44–1.59 (m, 2H). 13 C-NMR (150 MHz, DMSO-d6) δ: 174.0, 163.5, 156.6, 138.8, 138.8, 132.8, 132.7, 129.8, 129.7, 128.8, 123.1, 121.7, 119.6, 108.6, 64.2, 51.3, 40.3, 28.0, 25.4.

[0198] Compound 11:(1-benzhydryl-2-methyl-1H-pyrrole-3-carbonyl)-L-arginine Appearance: white solid 1 H-NMR (600 MHz, DMSO-d6) δ: 12.47 (brs, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.50-7.56 (m, 1H), 7.37-7.41 (m, 4H), 7.32-7.36 (m, 2H), 7.03-7.09 (m, 4H), 6.74 (s, 1H), 6.60 (d, J = 3.3 Hz, 1H), 6.21 (d, J = 3.3 Hz, 1H), 4.30-4.36 (m, 1H), 3.05-3.16 (m, 2H), 2.41(s, 3H), 1.78-1.87 (m, 1H), 1.65-1.74 (m, 1H), 1.45-1.61 (m, 2H). 13C-NMR (150 MHz, DMSO-d6) δ: 174.1, 165.1, 156.6, 139.8, 139.8, 133.5, 128.7, 128.3, 128.2, 127.8, 127.8, 118.3, 114.8, 106.8, 62.3, 51.2, 40.4, 27.9, 25.5, 10.7.

[0199] Compound 12:(1-benzhydryl-4-methyl-1H-pyrrole-3-carbonyl)-L-arginine Appearance: white solid 1 H-NMR (600 MHz, DMSO-d6) δ: 12.50 (brs, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.48-7.55 (m, 1H), 7.37-7.42 (m, 4H), 7.32-7.36 (m, 2H), 7.10-7.14 (m, 4H), 6.66 (s, 1H), 6.49-6.52 (m, 1H), 4.27-4.34 (m, 1H), 3.04-3.14 (m, 2H), 2.13 (d, J = 0.8 Hz, 3H), 1.73-1.82 (m, 1H), 1.58-1.68 (m, 1H), 1.43–1.57 (m, 2H). 13 C-NMR (150 MHz, DMSO-d6) δ: 174.1, 164.7, 156.6, 140.3, 140.2, 128.6, 128.0, 127.9, 127.8, 123.1, 120.5, 119.3, 117.0, 65.6, 51.2, 40.3, 28.1, 25.4, 11.8.

[0200] Compound 13:(1-benzhydryl-5-methyl-1H-pyrrole-3-carbonyl)-L-arginine Appearance: white solid 1H-NMR (600 MHz, DMSO-d6) δ: 12.50 (brs, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.46-7.51 (m, 1H), 7.38-7.43 (m, 4H), 7.33-7.37 (m, 2H), 7.04-7.09 (m, 4H), 6.83 (d, J = 1.9 Hz, 1H), 6.70 (s, 1H), 6.36-6.40 (m, 1H), 4.26-4.33 (m, 1H), 3.03-3.14 (m, 2H), 2.09 (s, 3H), 1.74-1.83 (m, 1H), 1.60-1.68 (m, 1H), 1.42-1.56 (m, 2H). 13 C-NMR (150 MHz, DMSO-d6) δ: 174.0, 163.7, 156.6, 139.8, 129.8, 128.7, 128.2, 128.1, 127.9, 122.0, 117.6, 107.0, 62.7, 51.2, 40.3, 27.9, 25.4, 11.9.

[0201] Test Example 1: Activity Evaluation Human Embryonic Kidney Cells 293 (HEK293) obtained from Cell Lines Service were used. 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%.

[0202] 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 in a single well, and 100 μL of the above-mentioned prepared solution was added per well for 24 hours of incubation. After washing with Dulbecco's Phosphate-Buffered Saline (DPBS, Thermo Fisher Scientific), the expressed receptors were treated with 0.25% Trypsin / EDTA (Life Technologies), diluted 5-fold with DPBS, for 30 seconds to prevent damage to the receptors before harvesting.

[0203] [Table 1]

[0204] 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. JR10a (L-arginine, N) was used as the known and potent C3aR antagonist in this assay. 2 -[[5-(diphenylmethyl)-2-thienyl]carbonyl]-) and JR14a(L-arginine, N 2-[[5-[bis(4-chlorophenyl)methyl]-3-methyl-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 candidate compounds were automatically dispensed into cell plates using a dedicated 96-well black tip (Hamamatsu Photonics). The intracellular fluorescence intensity at this time was measured over time. The value for each group was calculated by subtracting the value without ligand (TLQP-21) from the value with ligand (TLQP-21: Tocris Bioscience, C3a: R&D Systems). At this time, the AUC value for each group was graphed with the value of the group without candidate compound added set to 100. The final concentrations obtained by mixing the candidate compound solution and ligand solution are as follows: candidate compound: 10 or 1 μM, JR 10a, JR14a: 1 μM, TLQP-21: 1 μM. The measurement conditions for FDSS / μCELL are shown in Table 2 below.

[0205] [Table 2]

[0206] The inhibition rate was calculated by first determining the relative value (%) when the AUC of the non-treatment sample was set to 100, and then subtracting the relative value from 100 (n=3). The IC50 was calculated using the Curve Fitting Tool in the ImageJ analysis tool. The results are shown in Table 3.

[0207] [Table 3]

[0208] Test Example 2: Skin Sensitization Test (h-CLAT) 500 μL of the sample solution was added to each well of a 24-well plate seeded with human monocyte-derived cell line (THP-1 cells) and mixed. The cells were then cultured for 24 ± 0.5 hours. For the untreated control group, 500 μL of culture medium was added. At the start and end of the treatment, the presence or absence of precipitation of the test substance, changes in the color of the culture medium, and corrosion of the culture vessel were observed visually. The mixture of the treatment solution and cell suspension was collected, transferred to a 2 mL tube, and centrifuged (300 × g, 4°C, 5 min). The supernatant was discarded, and the mixture was suspended in 200 μL of Staining Buffer and centrifuged (300 × g, 4°C, 5 min). This procedure was repeated once more. The supernatant was discarded, and the mixture was suspended in 600 μL of globulin solution and allowed to stand at 4°C for 15 minutes. The suspension was dispensed in 180 μL portions (n ​​= 3) into a 96-well U-bottom plate (Corning) and centrifuged (300×g, 4°C, 5 min). The supernatant was discarded, and 50 μL of each antibody solution was added to each well. After suspension, the mixture was allowed to stand at 4°C and protected from light for 30 minutes. 150 μL of Staining Buffer was added and the mixture was centrifuged (300×g, 4°C, 5 min). The supernatant was discarded, the mixture was suspended in 200 μL of Staining Buffer, and centrifuged (300×g, 4°C, 5 min). This procedure was repeated once more. The supernatant was discarded, the mixture was suspended in 200 μL of Staining Buffer, and the entire volume was transferred to a test tube containing 180 μL of Staining Buffer. 20 μL of PI solution (12.5 μg / mL) was added (final concentration: PI = 0.625 μg / mL).

[0209] Measurements were performed using a flow cytometer. A total of 10,000 live cells were used to calculate cell viability and mean fluorescence intensity (MFI, geometric mean fluorescence intensity). FITC was measured using channel FL-1, and PI was measured using channel FL-3. If the number of detectable cells was small, the measurement was terminated 5 minutes after the start of measurement. The cell viability of each treatment group was defined as the cell viability of the isotype control (IgG1). The RFI was calculated using the following formula based on the MFI of each treatment group. For the negative control group, the RFI was calculated using the MFI value of the untreated control group as 100%. For the test substance group (compound 7, JR14a) and the positive control (2,4-dinitrochlorobenzene), the RFI was calculated using the MFI value of the negative control group (DMSO) as 100%. The results are shown in Figure 1.

[0210]

number

Claims

1. The following general formula (I) 【Chemistry 1】 (In the formula, X and Z represent the same or different carbon atoms or nitrogen atoms; Y is CR 5 , representing a sulfur atom or an NH group; R 1 is an o-biphenyl group or formula (II); 【Chemistry 2】 The diphenylmethyl group is shown, or when X and Z are carbon atoms and Y is a sulfur atom, adjacent R 2 These may also form a biphenyl ring with the carbon atoms to which they are bonded; R 2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R 3 and R 4 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or when X and Z are carbon atoms and Y is a sulfur atom, R 3 and R 4 together with the nitrogen atom to which R 4 is attached may form a 5- to 6-membered cyclic amide; R 5 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R 6 and R 7 These represent the same or different hydrogen atom, halogen atom, or alkoxy group having 1 to 6 carbon atoms; The dashed line indicates a single or double bond. Here, X and Z are carbon atoms, Y is a sulfur atom, and R 1 When is a diphenylmethyl group of formula (II), R 3 and R 4 (These are not the same or different hydrogen atoms or alkyl groups having 1 to 6 carbon atoms.) A compound represented by or a salt thereof.

2. X and Z are the same or different carbon atoms or nitrogen atoms, and Y is CR 5 , a sulfur atom or an NH group, R 1 If is an o-biphenyl group or a diphenylmethyl group of formula (II), or if X and Z are carbon atoms and Y is a sulfur atom, then adjacent R 2 These, together with the carbon atoms to which they are bonded, form a biphenyl ring, R 2 is a hydrogen atom or a methyl group, R 3 and R 4 If R is the same or different hydrogen atom or methyl group, or if X and Z are carbon atoms and Y is a sulfur atom, 3 and R 4 is R 4 Together with the nitrogen atom to which it is bonded, it forms a 5-6 membered cyclic amide, R 5 is a hydrogen atom or a methyl group, R 6 and R 7 The compound or salt thereof according to claim 1, wherein the hydrogen atom, halogen atom, or methoxy group is the same or different.

3. A compound or salt thereof selected from the following. (5-([1,1'-biphenyl]-2-yl)thiophene-2-carbonyl)-L-arginine (compound 1), (7-phenylbenzo[b]thiophene-2-carbonyl)-L-arginine (compound 2), (2-benzhydryl-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-yl)-L-arginine (compound 3), (2-benzhydryl-7-oxo-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-yl)-L-arginine (compound 4), (3-benzhydryl-1H-pyrrole-1-carbonyl)-L-arginine (compound 5), (5-benzhydryl-1H-pyrrole-2-carbonyl)-L-arginine (compound 6), (1-benzhydryl-1H-pyrrole-3-carbonyl)-L-arginine (compound 7), (1-(bis(4-methoxyphenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine (compound 8), (1-(bis(4-fluorophenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine (compound 9), (1-(bis(4-chlorophenyl)methyl)-1H-pyrrole-3-carbonyl)-L-arginine (compound 10), (1-benzhydryl-2-methyl-1H-pyrrole-3-carbonyl)-L-arginine (compound 11), (1-benzhydryl-4-methyl-1H-pyrrole-3-carbonyl)-L-arginine (compound 12), (1-benzhydryl-5-methyl-1H-pyrrole-3-carbonyl)-L-arginine (compound 13).

4. A C3a receptor antagonist comprising a compound or salt thereof according to any one of claims 1 to 3 as an active ingredient.

5. An agent for preventing or improving itching, comprising the compound or salt thereof according to any one of claims 1 to 3 as an active ingredient.

6. An agent for preventing or improving pruritic skin diseases exhibiting intractable itching, comprising the compound or a salt thereof according to any one of claims 1 to 3 as an active ingredient.

7. A pharmaceutical composition comprising a compound or salt thereof according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

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