Method for preparing aromatic amino acid derivative

Abstract

To provide methods of efficiently and universally preparing aromatic amino acid derivatives.SOLUTION: There are provided an amino acid derivative represented by formula (I) [where R1 is hydrogen or a protecting group for an amino group; R2 is hydrogen or C1-C6 alkyl; R3 is hydrogen or a protecting group for a carboxyl group; R6 is a C6-C10 aryl, optionally substituted, or a heteroaryl, optionally substituted; R7 is hydrogen or C1-C4 alkyl; and n is 1], a salt thereof, or a solvate thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to aromatic amino acid derivatives useful as pharmaceutical intermediates and methods for producing the same. [Background technology]

[0002] Compared to small molecules, medium-molecular-weight compounds (molecular weights 500-2000) may be superior in accessing tough targets, such as inhibiting protein-protein interactions. Furthermore, medium-molecular-weight compounds may be superior to antibodies in terms of their ability to be transported into cells. Among physiologically active medium-molecular-weight compounds, peptide drugs are highly valuable molecular species, with over 40 types already on the market (Non-Patent Document 1). Representative examples of these peptide drugs include cyclosporin A and polymyxin B. Focusing on their structures reveals that they contain several unnatural amino acids. Unnatural amino acids are amino acids that are not naturally encoded by mRNA. Naturally occurring cyclosporin A and polymyxin B contain unnatural amino acids, and it is intriguing that the structural moieties of these unnatural amino acids interact with in vivo sites of action to exert their pharmacological activity. An example of an unnatural amino acid interacting with an in vivo site of action is the homophenylalanine partial structure of angiotensin-converting enzyme inhibitors, such as delapril (Non-Patent Document 2).

[0003] From the above, it can be said that the establishment of an efficient and versatile method for producing aromatic amino acid derivatives, such as homophenylalanine derivatives, is important for drug discovery research and pharmaceutical manufacturing.

[0004] The following methods are known for producing optically active aromatic amino acids. The following methods (1) to (5) are methods for obtaining optically active aromatic amino acids by inducing an asymmetric center from a prochiral starting material, or methods for optically resolving a DL-mixture of aromatic amino acids. (1) A method of enantioselectively adding a highly reactive halogenated aralkyl compound, such as benzyl bromide, to a glycine derivative or an alanine derivative using an optically active phase transfer catalyst (Patent Document 1). (2) A method in which a highly reactive halogenated aralkyl compound, such as benzyl bromide, is diastereoselectively added to an optically active oxazolidinone derived from glycine (Patent Document 2). (3) A method for producing an α-amino acid from an α-keto acid by an enzymatic method (Patent Document 3). (4) A method of optical resolution in which N-acetyl aromatic amino acids in a DL-mixture are selectively deacetylated to L-aromatic amino acids using acylase (Patent Document 4). (5) A method for producing a homophenylalanine derivative from an optically active alcohol obtained by asymmetric reduction of a styrylglyoxylic acid derivative in the key reaction (Non-Patent Document 3).

[0005] The following methods (6) to (9) are methods for producing a target optically active aromatic amino acid by using an optically active amino acid as a starting material and introducing a functional group. (6) A method of producing it from a zinc reagent derived from optically active serine and an aromatic halide in the presence of a palladium catalyst (Patent Document 5). (7) A method of producing it from an N-hydroxyphthalimide ester derived from aspartic acid or glutamic acid and an aromatic iodide in the presence of a nickel catalyst (Non-Patent Document 4). (8) A method for producing it from an N-hydroxyphthalimide ester derived from aspartic acid or glutamic acid and an aromatic zinc compound in the presence of a nickel catalyst (Non-Patent Document 5). (9) A method for producing homophenylalanine derivatives after arylation of the side chain of aspartic acid by the Friedel-Crafts reaction (Non-Patent Document 6). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] JP 2001-48866 A [Patent Document 2] Patent Publication No. 2009-96791 [Patent Document 3] Japanese Patent Publication No. 62-000289 [Patent Document 4] Japanese Patent Publication No. 60-169451 [Patent Document 5] Special table number 2012-506909 [Non-patent literature]

[0007] [Non-Patent Document 1] Future Med. Chem. 2009, 1, 1289-1310. [Non-patent document 2] Chem. Pharm. Bull., 1986, 34(7), 2852-2858. [Non-patent document 3] Synlett, 2018, 29, 2203-2207. [Non-patent document 4] J. Am. Chem. Soc., 2016, 138, 5016-5019. [Non-Patent Document 5] J. Am. Chem. Soc., 2016, 138, 2174-2177. [Non-patent document 6] Tetrahedron Lett., 2008, 49, 6566-6568. Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention provides an efficient and versatile method for producing aromatic amino acid derivatives.

[0009] In the methods of Patent Document 1 and Patent Document 2, the halogenated aralkyl compound used as the electrophilic reagent must be stable under basic conditions. The electrophilic reagent used here must be a highly reactive reagent capable of efficiently forming a carbon-carbon bond, and therefore, the electrophilic reagents that can be subjected to these reaction conditions are limited, and the methods cannot be said to be versatile methods for producing aromatic amino acid derivatives.

[0010] The method described in Patent Document 3 requires that the α-ketocarboxylic acid to be subjected to the enzymatic method can be stably supplied and that an enzyme with high substrate specificity suitable for the α-ketocarboxylic acid be produced for each target aromatic amino acid derivative, and is therefore not suitable as a general-purpose method for producing aromatic amino acid derivatives.

[0011] In the method described in Patent Document 4, when multiple aromatic amino acid derivatives with different amino acid side chains are to be produced, it is necessary to produce the corresponding acylated aromatic amino acid derivatives as starting materials in their racemates. Furthermore, it is also necessary to produce a hydrolase that can selectively hydrolyze aromatic amino acid derivatives with different side chain structures. In other words, both a racemic starting material and a hydrolase appropriate for the type of aromatic amino acid derivative are required, making the method less versatile.

[0012] The method described in Patent Document 5 is inefficient because it requires multiple reactions from the starting material serine to prepare the zinc reagent.

[0013] The method described in Non-Patent Document 3 has problems as an industrial reaction in that it requires a hydrogen gas flow at 20 atmospheres for the key asymmetric reduction reaction. Furthermore, the styrylglyoxylic acid derivative used in the asymmetric reduction reaction is limited to an amide, which must be converted to a carboxylic acid or ester, which are useful as pharmaceutical intermediates, and is therefore inefficient.

[0014] The method described in Non-Patent Document 4 uses N-hydroxyphthalimide esters (NHPI esters), which are easily prepared from aspartic acid, glutamic acid, etc., and aromatic iodides as raw materials. By varying the aromatic iodide used, various aromatic amino acid derivatives can be produced, making it a versatile method. However, the method described in this document requires the use of an excess of NHPI esters of amino acids, which can result in the generation of multiple amino acid derivatives derived from the excess amino acids as by-products. These by-products have similar physical properties to the target aromatic amino acid derivatives, making it difficult to obtain high-quality aromatic amino acid derivatives. Furthermore, among aromatic halides, only aromatic iodides are applicable to this method, leaving issues with substrate generality. Specifically, although the reaction proceeds on a laboratory scale, the method for producing phenylalanine derivatives and homophenylalanine derivatives described in this document requires an excess of NHPI esters of aspartic acid or NHPI esters of glutamic acid relative to the aromatic iodide. Furthermore, it has been found that the reaction does not proceed under reaction conditions using stirring blades, which are used in industrial-scale reactions.

[0015] The method described in Non-Patent Document 5 can use, as a starting material, N-hydroxyphthalimide ester (NHPI ester), which is easily prepared from glutamic acid. However, the preparation of the aromatic zinc compound, which requires strict anhydrous conditions, is complicated, and this can be said to be a problem as an industrial production method.

[0016] In the method described in Non-Patent Document 6, the aryl group that can be introduced by the Friedel-Crafts reaction is limited to an electron-excess aryl group.

[0017] As described above, no efficient and versatile industrial method for producing optically active aromatic amino acid derivatives that satisfies industrially desirable conditions has been known to date.

[0018] An object of the present invention is to provide a method for efficiently and generally producing optically active aromatic amino acid derivatives from readily available optically active amino acids using industrial equipment, and to provide optically active aromatic amino acid derivatives that can be produced by the method and can be used as raw materials for medium-molecular compounds. [Means for solving the problem]

[0019] The present inventors have conducted extensive research into methods for producing optically active aromatic amino acid derivatives and have found reaction conditions for reacting a specific ester compound with an aromatic halide and a reducing agent in the presence of a catalyst. Specifically, by using an additive, they have found an efficient method for producing optically active aromatic amino acid derivatives that is adaptable to reaction conditions using stirring blades, which are commonly used in industry. Furthermore, they have found a highly versatile method for producing various optically active aromatic amino acid derivatives from a common ester compound by changing the aromatic halide used in the reaction, and have completed the present invention.

[0020] In one non-limiting specific embodiment, the present invention includes the following. [1] Formula I: [ka] [In the formula, R1 is hydrogen or an amino-protecting group; R2 is hydrogen or C1-C6 alkyl, and R3 is hydrogen or a protecting group for a carboxyl group, or R2 and R3 together form a divalent protecting group; R6 is an optionally substituted C6-C 10 aryl, or optionally substituted heteroaryl; R7 is hydrogen or C1-C4 alkyl; n is 1 or 2. A method for producing a compound represented by the formula: Formula II: [ka] [In the formula, R1, R2, R3, R7, and n are defined the same as R1, R2, R3, R7, and n in the compound represented by formula I, respectively; R5 is as follows: [ka] selected from the group consisting of R t、 R u、 R v、 and R w are independently hydrogen, halogen, or nitro; R x and R y are independently hydrogen, C1-C4 alkyl, or optionally substituted phenyl; R z is hydrogen, C1-C4 alkyl, or halogen; Y is CH or N; * denotes the point of attachment.] the compound represented by formula I, its salt, or a solvate thereof, is mixed with a reducing agent, an additive, and R6-X (wherein R6 has the same meaning as R6 in the compound represented by formula I, and X is a halogen, OTf, or OMs) in the presence of a solvent and a catalyst to obtain a compound represented by formula I, its salt, or a solvate thereof. [2] The method according to [1], wherein R1 is an amino-protecting group, and the amino-protecting group is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl. [3] The method according to [1] or [2], wherein R3 is a carboxyl-protecting group, and the carboxyl-protecting group is selected from the group consisting of methyl, ethyl, t-Bu, benzyl, trityl, cumyl, methoxytrityl, and 2-(trimethylsilyl)ethyl. [4] R2 and R3 together form a divalent protecting group, the divalent protecting group being -(CR8R9)-, and said formula I is formula IA: [ka] [In the formula, R1, R6, R7, and n are defined the same as R1, R6, R7, and n in the compound represented by formula I, respectively; R8 and R9 are independently hydrogen, C1-C4 alkyl, or C6-C 10 aryl, or R8 and R9 together form oxo (=O). The method according to [1] or [2], wherein the [5] The additive has the formula A: [ka] [In the formula, R AX , and R AY is independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, and phenyl; L is selected from the group consisting of -Cl, -Br, -I, and -OTf. The method according to any one of [1] to [4], wherein the compound is a silyl compound represented by the formula: [6] The method according to [5], wherein the silyl compound is selected from the group consisting of TMSCl, TMSBr, TMSI, TMSOTf, TBDMSCl, TESCl, TIPSCl, TBDPSCl, and chlorotriethoxysilane. [7] R5 [ka] The method according to any one of [1] to [6], [8] The method according to any one of [1] to [7], wherein X is iodine or bromine, and R6 is optionally substituted phenyl or optionally substituted pyridyl. [9-1] Optionally substituted phenyl or optionally substituted pyridyl is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C6 alkenyloxy, halogen, C3-C8 cycloalkyl, -NR p R q (In the formula, R p and R q are independently hydrogen or C1-C4 alkyl), -CONR r R s (In the formula, R r and R s is substituted with 0 to 3 substituents independently selected from the group consisting of hydrogen, hydroxy, protected hydroxy, C1-C4 alkyl, and C1-C4 alkylsulfonyl), and cyclic boryl. [9-2] Optionally substituted phenyl or optionally substituted pyridyl is substituted with one C1-C4 alkyl, one -CONR r R s , one C1-C4 haloalkyl and one or two halogens, two C1-C4 alkoxy, one C1-C4 alkoxy and one or two halogens, or one -CONR r R s and substituted with one C1-C4 alkoxy. [9-3] The method according to [9-2], wherein the optionally substituted phenyl or the optionally substituted pyridyl is substituted with one methyl, one methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl, one trifluoromethyl and one or two fluorines, one trifluoromethyl and one or two chlorines, one trifluoromethyl, one fluorine and one chlorine, two methoxys, one methoxy and one or two fluorines, one methylaminocarbonyl and one methoxy, or one methylsulfonylaminocarbonyl and one methoxy.

[10] The catalyst is (a) Is metallic? (b) formed by mixing a metal with a compound that can be its ligand; (c) a complex of a metal and its ligand; or (d) A complex of a metal and its ligand is formed by mixing a compound capable of serving as a ligand for the metal, The method according to any one of [1] to [9-3], wherein the metal is nickel, chromium, iron, copper, palladium, or a salt thereof, or a solvate of nickel, chromium, iron, copper, palladium, or a salt thereof.

[11] The method of claim 10, wherein the metal is selected from the group consisting of NiBr2, NiI2, NiCl2, NiF2, Ni(OAc)2, Ni(acac)2, Ni(OTf)2, NiCO3, Ni(NO3)2, NiSO4, (NH4)2Ni(SO4)2, allyl(cyclopentadienyl)nickel(II), bis(cyclopentadienyl)nickel, and bis(dicyclooctadienyl)nickel, or a solvate thereof.

[12] Potential ligands include compounds of formula B: [ka] [In the formula, R BX , and R BYare independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, heterocyclyl, or C6-C 10 aryl.] Compounds represented by formula C: [ka] [In the formula, R CX , and R CY are independently hydrogen, C1-C4 alkyl, C6-C 10 aryl, or heteroaryl. Compounds represented by formula D: [ka] [In the formula, R DX , and R DY are independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C6-C 10 aryl.] Compounds represented by formula E: [ka] [In the formula, R EX , and R EY are independently hydrogen, C1-C4 alkyl, C6-C 10 Aryl C1-C6 alkyl, or C6-C 10 aryl.] Compounds represented by formula F: [ka] [In the formula, R FX , and R FY are independently hydrogen, C1-C4 alkyl, or C6-C 10 aryl.] or a compound of formula G: [ka] [In the formula, R GX , and R GY are independently hydrogen, C1-C4 alkyl, C6-C 10 Aryl C1-C6 alkyl, or C6-C 10 aryl.] The method according to

[10] or

[11] , wherein the compound is selected from compounds represented by the formula:

[13] 11. The method according to claim 10, wherein the catalyst is a complex of a metal and its ligand, and the complex of a metal and its ligand is selected from the group consisting of tetrakis(triphenylphosphine)nickel(0), bis(triphenylphosphine)nickel(II) dichloride, bis(tricyclohexylphosphine)nickel(II) dichloride, dibromobis(triphenylphosphine)nickel(II), bis[(2-dimethylamino)phenyl]aminenickel(II) chloride, cis-[2,2'-bis(diphenylphosphine)-1,1'-binaphthyl](2-methylphenyl)nickel(II) chloride, and [1,2-bis(diphenylphosphino)ethane]dichloronickel(II).

[14] The method according to any one of [1] to

[13] , wherein the reducing agent is selected from the group consisting of zinc, manganese, iron, and magnesium.

[15] (a) mixing a compound represented by formula II, a salt thereof, or a solvate thereof, a reducing agent, and R6-X in the presence of a solvent and a catalyst, and then mixing an additive therewith; or (b) mixing a reducing agent and an additive in the presence of a solvent and a catalyst, and then mixing the compound represented by formula II, a salt thereof, or a solvate thereof and R6-X; or (c) mixing a reducing agent in the presence of a solvent and a catalyst, and then mixing the compound represented by formula II, a salt thereof, or a solvate thereof, R6-X, and an additive; The method according to any one of [1] to

[14] .

[16] The method according to any one of [1] to

[15] , wherein the additive is used in an amount of 1 to 500 mol % based on the compound represented by formula II, a salt thereof, or a solvate thereof.

[17] The method according to any one of [1] to

[16] , wherein the step is carried out at a reaction temperature of -10°C to 70°C.

[18] Formula III: [ka] [In the formula, R1, R6, R7, and n are defined as R1, R6, R7, and n in the compound represented by formula I, respectively, and R2 is hydrogen or C1-C6 alkyl.] A method for producing a compound represented by the formula: A step of producing a compound represented by formula I, a salt thereof, or a solvate thereof according to any one of the methods described in [1] to

[17] ; and When R3 is a protecting group for a carboxyl group, removing the protecting group from the compound represented by formula I, its salt, or a solvate thereof to obtain a compound represented by formula III, its salt, or a solvate thereof. The method comprising:

[19] Formula IV: [ka] [In the formula, R6, R7, and n are defined as R6, R7, and n in the compound represented by formula I, respectively, and R2 is hydrogen or C1-C6 alkyl.] A method for producing a compound represented by the formula: A step of producing a compound represented by formula I, a salt thereof, or a solvate thereof according to any one of the methods described in [1] to

[17] ; and When R1 is a protecting group for an amino group and R3 is a protecting group for a carboxyl group, removing these protecting groups to obtain a compound represented by formula IV, a salt thereof, or a solvate thereof. The method comprising:

[20] Formula V: [ka] [In the formula, R2, R6, R7, and n are the same as R2, R6, R7, and n in the compound represented by formula IV, respectively, and R 1’ is a protecting group for an amino group. A method for producing a compound represented by the formula:

[19] A step of producing a compound represented by formula IV, a salt thereof, or a solvate thereof according to the method of

[19] ; ​​and The compound represented by formula IV, a salt thereof, or a solvate thereof may further comprise R 1’ to obtain a compound represented by formula V, a salt thereof, or a solvate thereof. The method comprising: 〔twenty one〕 Formula VI: [ka] [In the formula, R1, R6, R7, and n have the same meanings as R1, R6, R7, and n in the compound represented by formula I, respectively.] A method for producing a compound represented by the formula: A step of producing a compound represented by formula IA, a salt thereof, or a solvate thereof according to any one of the methods of [4] to

[17] ; and a step of opening the oxazolidinone ring of the compound of formula IA to obtain a compound of formula VI, a salt thereof, or a solvate thereof. The method comprising: 〔twenty two〕 A compound, a salt thereof, or a solvate thereof, which is produced by the method according to any one of [1] to

[21] . 〔twenty three〕 Formula I: [ka] [In the formula, R1 is hydrogen or an amino-protecting group; R2 is hydrogen or C1-C6 alkyl, and R3 is hydrogen or a protecting group for a carboxyl group, or R2 and R3 together form a divalent protecting group; R6 is an optionally substituted C6-C 10 aryl, or optionally substituted heteroaryl; R7 is hydrogen or C1-C4 alkyl; n is 1 or 2. An amino acid derivative represented by the formula (I), a salt thereof, or a solvate thereof. 〔twenty four〕 The amino acid derivative, salt thereof, or solvate thereof according to

[23] , wherein R1 is an amino-protecting group selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl. 〔twenty five〕 The amino acid derivative, salt thereof, or solvate thereof according to

[23] or

[24] , wherein R3 is a carboxyl-protecting group selected from the group consisting of methyl, ethyl, t-Bu, benzyl, trityl, cumyl, methoxytrityl, and 2-(trimethylsilyl)ethyl.

[26] R2 and R3 together form a divalent protecting group, the divalent protecting group being -(CR8R9)-, and said formula I is formula IA: [ka] [In the formula, R1, R6, R7, and n are defined the same as R1, R6, R7, and n in the compound represented by formula I, respectively; R8 and R9 are independently hydrogen, C1-C4 alkyl, or C6-C 10 aryl, or R8 and R9 together form oxo (=O). The amino acid derivative, salt thereof, or solvate thereof according to

[23] or

[24] , which is represented by the following formula:

[27] The amino acid derivative, salt thereof, or solvate thereof according to any one of

[23] to

[26] , wherein R6 is optionally substituted phenyl or optionally substituted pyridyl.

[28] Optionally substituted phenyl or optionally substituted pyridyl is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C6 alkenyloxy, halogen, C3-C8 cycloalkyl, -NR p R q (In the formula, R p and R q are independently hydrogen or C1-C4 alkyl), -CONR r R s (In the formula, R r and R s are independently selected from the group consisting of hydrogen, hydroxy, protected hydroxy, C1-C4 alkyl, and C1-C4 alkylsulfonyl), and cyclic boryl, or a solvate thereof according to

[27] .

[29] Optionally substituted phenyl or optionally substituted pyridyl is substituted with one C1-C4 alkyl, one -CONR r R s , one C1-C4 haloalkyl and one or two halogens, two C1-C4 alkoxy, one C1-C4 alkoxy and one or two halogens, or one -CONR r R s and substituted with one C1-C4 alkoxy, a salt thereof, or a solvate thereof according to

[28] .

[30] The amino acid derivative, salt thereof, or solvate thereof according to

[29] , wherein the optionally substituted phenyl or optionally substituted pyridyl is substituted with one methyl, one methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl, one trifluoromethyl and one or two fluorines, one trifluoromethyl and one or two chlorines, one trifluoromethyl, one fluorine and one chlorine, two methoxys, one methoxy and one or two fluorines, one methylaminocarbonyl and one methoxy, or one methylsulfonylaminocarbonyl and one methoxy.

[31] An amino acid derivative, a salt thereof, or a solvate thereof selected from the group consisting of: (1-1) benzyl 2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-2) tert-butyl 2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-3) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-4) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-5) benzyl 2-(((benzyloxy)carbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-6) tert-butyl 2-(((benzyloxy)carbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-7) benzyl 2-((tert-butoxycarbonyl)(methyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-8) tert-butyl 2-((tert-butoxycarbonyl)(methyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-9) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-10) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-11) benzyl 2-(((benzyloxy)carbonyl)(methyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-12) tert-butyl 2-(((benzyloxy)carbonyl)(methyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate, (1-13) 2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoic acid, (1-14) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoic acid, (1-15) 2-(((benzyloxy)carbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoic acid, (1-16) 2-((tert-butoxycarbonyl)(methyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoic acid, (1-17) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoic acid, (1-18) 2-(((benzyloxy)carbonyl)(methyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoic acid, (1-19) 2-amino-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoic acid, (1-20) 4-(3-chloro-4-(trifluoromethyl)phenyl)-2-(methylamino)butanoic acid, (1-21) benzyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-22) tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-23) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-24) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-25) benzyl 2-(((benzyloxy)carbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-26) tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-27) benzyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-28) tert-butyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-29) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-30) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-31) benzyl 2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-32) tert-butyl 2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-33) 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-34) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-35) 2-(((benzyloxy)carbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-36) 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-37) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-38) 2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-39) 2-amino-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-40) 3-(3-chloro-4-(trifluoromethyl)phenyl)-2-(methylamino)propanoic acid, (2-1) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-phenylbutanoate, (2-2) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(o-tolyl)butanoate, (2-3) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(m-tolyl)butanoate, (2-4) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(p-tolyl)butanoate, (2-5) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-ethylphenyl)butanoate, (2-6) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-chlorophenyl)butanoate, (2-7) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-chlorophenyl)butanoate, (2-8) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-chlorophenyl)butanoate, (2-9) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-fluorophenyl)butanoate, (2-10) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-fluorophenyl)butanoate, (2-11) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-fluorophenyl)butanoate, (2-12) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-cyclopropylphenyl)butanoate, (2-13) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-cyclopropylphenyl)butanoate, (2-14) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-cyclopropylphenyl)butanoate, (2-15) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(trifluoromethyl)phenyl)butanoate, (2-16) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-(trifluoromethyl)phenyl)butanoate, (2-17) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-(trifluoromethyl)phenyl)butanoate, (2-18) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-isopropylphenyl)butanoate, (2-19) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-isopropylphenyl)butanoate, (2-20) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-isopropylphenyl)butanoate, (2-21) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-methoxyphenyl)butanoate, (2-22) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-methoxyphenyl)butanoate, (2-23) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoate, (2-24) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(allyloxy)phenyl)butanoate, (2-25) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-(allyloxy)phenyl)butanoate, (2-26) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-(allyloxy)phenyl)butanoate, (2-27) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-isopropoxyphenyl)butanoate, (2-28) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoate, (2-29) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-fluoro-4-(trifluoromethyl)phenyl)butanoate, (2-30) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,4-dimethoxyphenyl)butanoate, (2-31) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-fluoro-4-methoxyphenyl)butanoate, (2-32) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-fluoro-4-methoxyphenyl)butanoate, (2-33) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-methoxyphenyl)butanoate, (2-34) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (2-35) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-methoxy-4-(methylcarbamoyl)phenyl)butanoate, (2-36) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxy-3-(methylcarbamoyl)phenyl)butanoate, (2-37) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)butanoate, (2-38) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoate, (2-39) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoate, (2-40) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-2-yl)butanoate, (2-41) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-3-yl)butanoate, (2-42) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-4-yl)butanoate, (2-43) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(6-methylpyridin-3-yl)butanoate, (2-44) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-methylpyridin-3-yl)butanoate, (2-45) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methylpyridin-3-yl)butanoate, (2-46) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(6-methoxypyridin-3-yl)butanoate, (2-47) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-methoxypyridin-3-yl)butanoate, (2-48) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-fluoropyridin-3-yl)butanoate, (2-49) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-chloropyridin-3-yl)butanoate, (2-50) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-bromopyridin-3-yl)butanoate, (2-51) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-iodopyridin-3-yl)butanoate, (2-52) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(methylamino)pyridin-4-yl)butanoate, (2-53) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(dimethylamino)pyridin-4-yl)butanoate, (2-54) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyrimidin-5-yl)butanoate, (3-1) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-phenylbutanoate, (3-2) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(o-tolyl)butanoate, (3-3) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(m-tolyl)butanoate, (3-4) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(p-tolyl)butanoate, (3-5) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-ethylphenyl)butanoate, (3-6) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-chlorophenyl)butanoate, (3-7) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-chlorophenyl)butanoate, (3-8) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-chlorophenyl)butanoate, (3-9) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-fluorophenyl)butanoate, (3-10) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-fluorophenyl)butanoate, (3-11) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-fluorophenyl)butanoate, (3-12) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-cyclopropylphenyl)butanoate, (3-13) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-cyclopropylphenyl)butanoate, (3-14) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-cyclopropylphenyl)butanoate, (3-15) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-(trifluoromethyl)phenyl)butanoate, (3-16) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-(trifluoromethyl)phenyl)butanoate, (3-17) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-(trifluoromethyl)phenyl)butanoate, (3-18) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-isopropylphenyl)butanoate, (3-19) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-isopropylphenyl)butanoate, (3-20) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-isopropylphenyl)butanoate, (3-21) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-methoxyphenyl)butanoate, (3-22) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxyphenyl)butanoate, (3-23) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-methoxyphenyl)butanoate, (3-24) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-(allyloxy)phenyl)butanoate, (3-25) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-(allyloxy)phenyl)butanoate, (3-26) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-(allyloxy)phenyl)butanoate, (3-27) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-isopropoxyphenyl)butanoate, (3-28) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoate, (3-29) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-fluoro-4-(trifluoromethyl)phenyl)butanoate, (3-30) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,4-dimethoxyphenyl)butanoate, (3-31) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-fluoro-4-methoxyphenyl)butanoate, (3-32) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-fluoro-4-methoxyphenyl)butanoate, (3-33) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-methoxyphenyl)butanoate, (3-34) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (3-35) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxy-4-(methylcarbamoyl)phenyl)butanoate, (3-36) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-methoxy-3-(methylcarbamoyl)phenyl)butanoate, (3-37) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)butanoate, (3-38) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoate, (3-39) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoate, (3-40) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyridin-2-yl)butanoate, (3-41) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyridin-3-yl)butanoate, (3-42) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyridin-4-yl)butanoate, (3-43) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(6-methylpyridin-3-yl)butanoate, (3-44) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-methylpyridin-3-yl)butanoate, (3-45) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-methylpyridin-3-yl)butanoate, (3-46) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(6-methoxypyridin-3-yl)butanoate, (3-47) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-methoxypyridin-3-yl)butanoate, (3-48) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-fluoropyridin-3-yl)butanoate, (3-49) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-chloropyridin-3-yl)butanoate, (3-50) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-bromopyridin-3-yl)butanoate, (3-51) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-iodopyridin-3-yl)butanoate, (3-52) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-(methylamino)pyridin-4-yl)butanoate, (3-53) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-(dimethylamino)pyridin-4-yl)butanoate, (3-54) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyrimidin-5-yl)butanoate, (4-1) tert-butyl (((9H-fluoren-9-yl)methoxy)carbonyl)phenylalaninate, (4-2) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(o-tolyl)propanoate, (4-3) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(m-tolyl)propanoate, (4-4) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(p-tolyl)propanoate, (4-5) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-ethylphenyl)propanoate, (4-6) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-chlorophenyl)propanoate, (4-7) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chlorophenyl)propanoate, (4-8) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-chlorophenyl)propanoate, (4-9) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-fluorophenyl)propanoate, (4-10) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-fluorophenyl)propanoate, (4-11) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-fluorophenyl)propanoate, (4-12) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-cyclopropylphenyl)propanoate, (4-13) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-cyclopropylphenyl)propanoate, (4-14) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-cyclopropylphenyl)propanoate, (4-15) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(trifluoromethyl)phenyl)propanoate, (4-16) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(trifluoromethyl)phenyl)propanoate, (4-17) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoate, (4-18) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-isopropylphenyl)propanoate, (4-19) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-isopropylphenyl)propanoate, (4-20) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-isopropylphenyl)propanoate, (4-21) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-methoxyphenyl)propanoate, (4-22) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxyphenyl)propanoate, (4-23) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoate, (4-24) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(allyloxy)phenyl)propanoate, (4-25) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(allyloxy)phenyl)propanoate, (4-26) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(allyloxy)phenyl)propanoate, (4-27) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-isopropoxyphenyl)propanoate, (4-28) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoate, (4-29) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoate, (4-30) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,4-dimethoxyphenyl)propanoate, (4-31) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-fluoro-4-methoxyphenyl)propanoate, (4-32) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-fluoro-4-methoxyphenyl)propanoate, (4-33) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-difluoro-4-methoxyphenyl)propanoate, (4-34) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (4-35) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoate, (4-36) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoate, (4-37) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoate, (4-38) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoate, (4-39) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoate, (4-40) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-2-yl)propanoate, (4-41) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoate, (4-42) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)propanoate, (4-43) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-methylpyridin-3-yl)propanoate, (4-44) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-methylpyridin-3-yl)propanoate, (4-45) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methylpyridin-3-yl)propanoate, (4-46) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-methoxypyridin-3-yl)propanoate, (4-47) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-methoxypyridin-3-yl)propanoate, (4-48) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoropyridin-3-yl)propanoate, (4-49) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloropyridin-3-yl)propanoate, (4-50) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-bromopyridin-3-yl)propanoate, (4-51) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-iodopyridin-3-yl)propanoate, (4-52) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(methylamino)pyridin-4-yl)propanoate, (4-53) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(dimethylamino)pyridin-4-yl)propanoate, (4-54) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyrimidin-5-yl)propanoate, (5-1) tert-butyl-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylphenylalaninate, (5-2) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(o-tolyl)propanoate, (5-3) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(m-tolyl)propanoate, (5-4) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(p-tolyl)propanoate, (5-5) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-ethylphenyl)propanoate, (5-6) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-chlorophenyl)propanoate, (5-7) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-chlorophenyl)propanoate, (5-8) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-chlorophenyl)propanoate, (5-9) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluorophenyl)propanoate, (5-10) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-fluorophenyl)propanoate, (5-11) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-fluorophenyl)propanoate, (5-12) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-cyclopropylphenyl)propanoate, (5-13) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-cyclopropylphenyl)propanoate, (5-14) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-cyclopropylphenyl)propanoate, (5-15) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(trifluoromethyl)phenyl)propanoate, (5-16) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-(trifluoromethyl)phenyl)propanoate, (5-17) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoate, (5-18) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-isopropylphenyl)propanoate, (5-19) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-isopropylphenyl)propanoate, (5-20) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-isopropylphenyl)propanoate, (5-21) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-methoxyphenyl)propanoate, (5-22) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxyphenyl)propanoate, (5-23) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-methoxyphenyl)propanoate, (5-24) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(allyloxy)phenyl)propanoate, (5-25) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-(allyloxy)phenyl)propanoate, (5-26) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-(allyloxy)phenyl)propanoate, (5-27) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-isopropoxyphenyl)propanoate, (5-28) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoate, (5-29) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoate, (5-30) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,4-dimethoxyphenyl)propanoate, (5-31) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-methoxyphenyl)propanoate, (5-32) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-fluoro-4-methoxyphenyl)propanoate, (5-33) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-methoxyphenyl)propanoate, (5-34) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (5-35) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoate, (5-36) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoate, (5-37) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoate, (5-38) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoate, (5-39) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoate, (5-40) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyridin-2-yl)propanoate, (5-41) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyridin-3-yl)propanoate, (5-42) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoate, (5-43) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(6-methylpyridin-3-yl)propanoate, (5-44) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-methylpyridin-3-yl)propanoate, (5-45) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-methylpyridin-3-yl)propanoate, (5-46) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(6-methoxypyridin-3-yl)propanoate, (5-47) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-methoxypyridin-3-yl)propanoate, (5-48) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-fluoropyridin-3-yl)propanoate, (5-49) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-chloropyridin-3-yl)propanoate, (5-50) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-bromopyridin-3-yl)propanoate, (5-51) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-iodopyridin-3-yl)propanoate, (5-52) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(methylamino)pyridin-4-yl)propanoate, (5-53) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(dimethylamino)pyridin-4-yl)propanoate, (5-54) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyrimidin-5-yl)propanoate, (6-1) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-phenylbutanoic acid, (6-2) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(o-tolyl)butanoic acid, (6-3) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(m-tolyl)butanoic acid, (6-4) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(p-tolyl)butanoic acid, (6-5) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-ethylphenyl)butanoic acid, (6-6) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-chlorophenyl)butanoic acid, (6-7) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-chlorophenyl)butanoic acid, (6-8) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-chlorophenyl)butanoic acid, (6-9) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-fluorophenyl)butanoic acid, (6-10) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-fluorophenyl)butanoic acid, (6-11) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-fluorophenyl)butanoic acid, (6-12) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-cyclopropylphenyl)butanoic acid, (6-13) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-cyclopropylphenyl)butanoic acid, (6-14) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-cyclopropylphenyl)butanoic acid, (6-15) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(trifluoromethyl)phenyl)butanoic acid, (6-16) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-(trifluoromethyl)phenyl)butanoic acid, (6-17) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-(trifluoromethyl)phenyl)butanoic acid, (6-18) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-isopropylphenyl)butanoic acid, (6-19) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-isopropylphenyl)butanoic acid, (6-20) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-isopropylphenyl)butanoic acid, (6-21) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-methoxyphenyl)butanoic acid, (6-22) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-methoxyphenyl)butanoic acid, (6-23) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoic acid, (6-24) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(allyloxy)phenyl)butanoic acid, (6-25) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-(allyloxy)phenyl)butanoic acid, (6-26) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-(allyloxy)phenyl)butanoic acid, (6-27) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-isopropoxyphenyl)butanoic acid, (6-28) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (6-29) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (6-30) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,4-dimethoxyphenyl)butanoic acid, (6-31) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-fluoro-4-methoxyphenyl)butanoic acid, (6-32) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-fluoro-4-methoxyphenyl)butanoic acid, (6-33) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-methoxyphenyl)butanoic acid, (6-34) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (6-35) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-methoxy-4-(methylcarbamoyl)phenyl)butanoic acid, (6-36) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxy-3-(methylcarbamoyl)phenyl)butanoic acid, (6-37) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)butanoic acid, (6-38) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoic acid, (6-39) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoic acid, (6-40) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-2-yl)butanoic acid, (6-41) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-3-yl)butanoic acid, (6-42) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-4-yl)butanoic acid, (6-43) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(6-methylpyridin-3-yl)butanoic acid, (6-44) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-methylpyridin-3-yl)butanoic acid, (6-45) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methylpyridin-3-yl)butanoic acid, (6-46) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(6-methoxypyridin-3-yl)butanoic acid, (6-47) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-methoxypyridin-3-yl)butanoic acid, (6-48) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-fluoropyridin-3-yl)butanoic acid, (6-49) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-chloropyridin-3-yl)butanoic acid, (6-50) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-bromopyridin-3-yl)butanoic acid, (6-51) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-iodopyridin-3-yl)butanoic acid, (6-52) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(methylamino)pyridin-4-yl)butanoic acid, (6-53) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(dimethylamino)pyridin-4-yl)butanoic acid, (6-54) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyrimidin-5-yl)butanoic acid, (7-1) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-phenylbutanoic acid, (7-2) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(o-tolyl)butanoic acid, (7-3) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(m-tolyl)butanoic acid, (7-4) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(p-tolyl)butanoic acid, (7-5) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-ethylphenyl)butanoic acid, (7-6) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-chlorophenyl)butanoic acid, (7-7) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-chlorophenyl)butanoic acid, (7-8) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-chlorophenyl)butanoic acid, (7-9) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-fluorophenyl)butanoic acid, (7-10) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-fluorophenyl)butanoic acid, (7-11) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-fluorophenyl)butanoic acid, (7-12) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-cyclopropylphenyl)butanoic acid, (7-13) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-cyclopropylphenyl)butanoic acid, (7-14) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-cyclopropylphenyl)butanoic acid, (7-15) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-(trifluoromethyl)phenyl)butanoic acid, (7-16) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-(trifluoromethyl)phenyl)butanoic acid, (7-17) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-(trifluoromethyl)phenyl)butanoic acid, (7-18) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-isopropylphenyl)butanoic acid, (7-19) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-isopropylphenyl)butanoic acid, (7-20) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-isopropylphenyl)butanoic acid, (7-21) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-methoxyphenyl)butanoic acid, (7-22) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxyphenyl)butanoic acid, (7-23) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-methoxyphenyl)butanoic acid, (7-24) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-(allyloxy)phenyl)butanoic acid, (7-25) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-(allyloxy)phenyl)butanoic acid, (7-26) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-(allyloxy)phenyl)butanoic acid, (7-27) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-isopropoxyphenyl)butanoic acid, (7-28) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (7-29) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (7-30) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,4-dimethoxyphenyl)butanoic acid, (7-31) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-fluoro-4-methoxyphenyl)butanoic acid, (7-32) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-fluoro-4-methoxyphenyl)butanoic acid, (7-33) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-methoxyphenyl)butanoic acid, (7-34) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (7-35) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxy-4-(methylcarbamoyl)phenyl)butanoic acid, (7-36) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-methoxy-3-(methylcarbamoyl)phenyl)butanoic acid, (7-37) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)butanoic acid, (7-38) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoic acid, (7-39) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoic acid, (7-40) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyridin-2-yl)butanoic acid, (7-41) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyridin-3-yl)butanoic acid, (7-42) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyridin-4-yl)butanoic acid, (7-43) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(6-methylpyridin-3-yl)butanoic acid, (7-44) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-methylpyridin-3-yl)butanoic acid, (7-45) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(4-methylpyridin-3-yl)butanoic acid, (7-46) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(6-methoxypyridin-3-yl)butanoic acid, (7-47) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-methoxypyridin-3-yl)butanoic acid, (7-48) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-fluoropyridin-3-yl)butanoic acid, (7-49) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-chloropyridin-3-yl)butanoic acid, (7-50) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-bromopyridin-3-yl)butanoic acid, (7-51) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(5-iodopyridin-3-yl)butanoic acid, (7-52) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-(methylamino)pyridin-4-yl)butanoic acid, (7-53) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(2-(dimethylamino)pyridin-4-yl)butanoic acid, (7-54) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyrimidin-5-yl)butanoic acid, (8-1) (((9H-fluoren-9-yl)methoxy)carbonyl)phenylalanine, (8-2) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(o-tolyl)propanoic acid, (8-3) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(m-tolyl)propanoic acid, (8-4) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(p-tolyl)propanoic acid, (8-5) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-ethylphenyl)propanoic acid, (8-6) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-chlorophenyl)propanoic acid, (8-7) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chlorophenyl)propanoic acid, (8-8) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-chlorophenyl)propanoic acid, (8-9) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-fluorophenyl)propanoic acid, (8-10) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-fluorophenyl)propanoic acid, (8-11) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-fluorophenyl)propanoic acid, (8-12) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-cyclopropylphenyl)propanoic acid, (8-13) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-cyclopropylphenyl)propanoic acid, (8-14) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-cyclopropylphenyl)propanoic acid, (8-15) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(trifluoromethyl)phenyl)propanoic acid, (8-16) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(trifluoromethyl)phenyl)propanoic acid, (8-17) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoic acid, (8-18) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-isopropylphenyl)propanoic acid, (8-19) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-isopropylphenyl)propanoic acid, (8-20) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-isopropylphenyl)propanoic acid, (8-21) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-methoxyphenyl)propanoic acid, (8-22) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxyphenyl)propanoic acid, (8-23) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid, (8-24) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(allyloxy)phenyl)propanoic acid, (8-25) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(allyloxy)phenyl)propanoic acid, (8-26) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(allyloxy)phenyl)propanoic acid, (8-27) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-isopropoxyphenyl)propanoic acid, (8-28) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (8-29) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (8-30) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,4-dimethoxyphenyl)propanoic acid, (8-31) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-fluoro-4-methoxyphenyl)propanoic acid, (8-32) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-fluoro-4-methoxyphenyl)propanoic acid, (8-33) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-difluoro-4-methoxyphenyl)propanoic acid, (8-34) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (8-35) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoic acid, (8-36) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoic acid, (8-37) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoic acid, (8-38) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (8-39) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (8-40) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-2-yl)propanoic acid, (8-41) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid, (8-42) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)propanoic acid, (8-43) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-methylpyridin-3-yl)propanoic acid, (8-44) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-methylpyridin-3-yl)propanoic acid, (8-45) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methylpyridin-3-yl)propanoic acid, (8-46) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-methoxypyridin-3-yl)propanoic acid, (8-47) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-methoxypyridin-3-yl)propanoic acid, (8-48) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoropyridin-3-yl)propanoic acid, (8-49) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloropyridin-3-yl)propanoic acid, (8-50) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-bromopyridin-3-yl)propanoic acid, (8-51) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-iodopyridin-3-yl)propanoic acid, (8-52) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(methylamino)pyridin-4-yl)propanoic acid, (8-53) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(dimethylamino)pyridin-4-yl)propanoic acid, (8-54) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyrimidin-5-yl)propanoic acid, (9-1) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylphenylalanine, (9-2) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(o-tolyl)propanoic acid, (9-3) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(m-tolyl)propanoic acid, (9-4) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(p-tolyl)propanoic acid, (9-5) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-ethylphenyl)propanoic acid, (9-6) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-chlorophenyl)propanoic acid, (9-7) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-chlorophenyl)propanoic acid, (9-8) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-chlorophenyl)propanoic acid, (9-9) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluorophenyl)propanoic acid, (9-10) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-fluorophenyl)propanoic acid, (9-11) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-fluorophenyl)propanoic acid, (9-12) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-cyclopropylphenyl)propanoic acid, (9-13) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-cyclopropylphenyl)propanoic acid, (9-14) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-cyclopropylphenyl)propanoic acid, (9-15) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(trifluoromethyl)phenyl)propanoic acid, (9-16) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-(trifluoromethyl)phenyl)propanoic acid, (9-17) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoic acid, (9-18) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-isopropylphenyl)propanoic acid, (9-19) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-isopropylphenyl)propanoic acid, (9-20) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-isopropylphenyl)propanoic acid, (9-21) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-methoxyphenyl)propanoic acid, (9-22) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxyphenyl)propanoic acid, (9-23) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-methoxyphenyl)propanoic acid, (9-24) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(allyloxy)phenyl)propanoic acid, (9-25) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-(allyloxy)phenyl)propanoic acid, (9-26) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-(allyloxy)phenyl)propanoic acid, (9-27) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-isopropoxyphenyl)propanoic acid, (9-28) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (9-29) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (9-30) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,4-dimethoxyphenyl)propanoic acid, (9-31) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-methoxyphenyl)propanoic acid, (9-32) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-fluoro-4-methoxyphenyl)propanoic acid, (9-33) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-methoxyphenyl)propanoic acid, (9-34) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (9-35) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoic acid, (9-36) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoic acid, (9-37) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoic acid, (9-38) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (9-39) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (9-40) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyridin-2-yl)propanoic acid, (9-41) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyridin-3-yl)propanoic acid, (9-42) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoic acid, (9-43) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(6-methylpyridin-3-yl)propanoic acid, (9-44) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-methylpyridin-3-yl)propanoic acid, (9-45) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-methylpyridin-3-yl)propanoic acid, (9-46) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(6-methoxypyridin-3-yl)propanoic acid, (9-47) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-methoxypyridin-3-yl)propanoic acid, (9-48) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-fluoropyridin-3-yl)propanoic acid, (9-49) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-chloropyridin-3-yl)propanoic acid, (9-50) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-bromopyridin-3-yl)propanoic acid, (9-51) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-iodopyridin-3-yl)propanoic acid, (9-52) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(methylamino)pyridin-4-yl)propanoic acid, (9-53) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(dimethylamino)pyridin-4-yl)propanoic acid, (9-54) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyrimidin-5-yl)propanoic acid, (10-1) 2-amino-4-phenylbutanoic acid, (10-2) 2-amino-4-(o-tolyl)butanoic acid, (10-3) 2-amino-4-(m-tolyl)butanoic acid, (10-4) 2-amino-4-(p-tolyl)butanoic acid, (10-5) 2-amino-4-(4-ethylphenyl)butanoic acid, (10-6) 2-amino-4-(2-chlorophenyl)butanoic acid, (10-7) 2-amino-4-(3-chlorophenyl)butanoic acid, (10-8) 2-amino-4-(4-chlorophenyl)butanoic acid, (10-9) 2-amino-4-(2-fluorophenyl)butanoic acid, (10-10) 2-amino-4-(3-fluorophenyl)butanoic acid, (10-11) 2-amino-4-(4-fluorophenyl)butanoic acid, (10-12) 2-amino-4-(2-cyclopropylphenyl)butanoic acid, (10-13) 2-amino-4-(3-cyclopropylphenyl)butanoic acid, (10-14) 2-amino-4-(4-cyclopropylphenyl)butanoic acid, (10-15) 2-amino-4-(2-(trifluoromethyl)phenyl)butanoic acid, (10-16) 2-amino-4-(3-(trifluoromethyl)phenyl)butanoic acid, (10-17) 2-amino-4-(4-(trifluoromethyl)phenyl)butanoic acid, (10-18) 2-amino-4-(2-isopropylphenyl)butanoic acid, (10-19) 2-amino-4-(3-isopropylphenyl)butanoic acid, (10-20) 2-amino-4-(4-isopropylphenyl)butanoic acid, (10-21) 2-amino-4-(2-methoxyphenyl)butanoic acid, (10-22) 2-amino-4-(3-methoxyphenyl)butanoic acid, (10-23) 2-amino-4-(4-methoxyphenyl)butanoic acid, (10-24) 2-amino-4-(2-(allyloxy)phenyl)butanoic acid, (10-25) 2-amino-4-(3-(allyloxy)phenyl)butanoic acid, (10-26) 2-amino-4-(4-(allyloxy)phenyl)butanoic acid, (10-27) 2-amino-4-(4-isopropoxyphenyl)butanoic acid, (10-28) 2-amino-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (10-29) 2-amino-4-(2-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (10-30) 2-amino-4-(3,4-dimethoxyphenyl)butanoic acid, (10-31) 2-amino-4-(2-fluoro-4-methoxyphenyl)butanoic acid, (10-32) 2-amino-4-(3-fluoro-4-methoxyphenyl)butanoic acid, (10-33) 2-amino-4-(3,5-difluoro-4-methoxyphenyl)butanoic acid, (10-34) 2-amino-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (10-35) 2-amino-4-(3-methoxy-4-(methylcarbamoyl)phenyl)butanoic acid, (10-36) 2-amino-4-(4-methoxy-3-(methylcarbamoyl)phenyl)butanoic acid, (10-37) 2-amino-4-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)butanoic acid, (10-38) 2-amino-4-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoic acid, (10-39) 2-amino-4-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoic acid, (10-40) 2-amino-4-(pyridin-2-yl)butanoic acid, (10-41) 2-amino-4-(pyridin-3-yl)butanoic acid, (10-42) 2-amino-4-(pyridin-4-yl)butanoic acid, (10-43) 2-amino-4-(6-methylpyridin-3-yl)butanoic acid, (10-44) 2-amino-4-(5-methylpyridin-3-yl)butanoic acid, (10-45) 2-amino-4-(4-methylpyridin-3-yl)butanoic acid, (10-46) 2-amino-4-(6-methoxypyridin-3-yl)butanoic acid, (10-47) 2-amino-4-(5-methoxypyridin-3-yl)butanoic acid, (10-48) 2-amino-4-(5-fluoropyridin-3-yl)butanoic acid, (10-49) 2-amino-4-(5-chloropyridin-3-yl)butanoic acid, (10-50) 2-amino-4-(5-bromopyridin-3-yl)butanoic acid, (10-51) 2-amino-4-(5-iodopyridin-3-yl)butanoic acid, (10-52) 2-amino-4-(2-(methylamino)pyridin-4-yl)butanoic acid, (10-53) 2-amino-4-(2-(dimethylamino)pyridin-4-yl)butanoic acid, (10-54) 2-amino-4-(pyrimidin-5-yl)butanoic acid, (11-1) 2-(methylamino)-4-phenylbutanoic acid, (11-2) 2-(methylamino)-4-(o-tolyl)butanoic acid, (11-3) 2-(methylamino)-4-(m-tolyl)butanoic acid, (11-4) 2-(methylamino)-4-(p-tolyl)butanoic acid, (11-5) 2-(methylamino)-4-(4-ethylphenyl)butanoic acid, (11-6) 2-(methylamino)-4-(2-chlorophenyl)butanoic acid, (11-7) 2-(methylamino)-4-(3-chlorophenyl)butanoic acid, (11-8) 2-(methylamino)-4-(4-chlorophenyl)butanoic acid, (11-9) 2-(methylamino)-4-(2-fluorophenyl)butanoic acid, (11-10) 2-(methylamino)-4-(3-fluorophenyl)butanoic acid, (11-11) 2-(methylamino)-4-(4-fluorophenyl)butanoic acid, (11-12) 2-(methylamino)-4-(2-cyclopropylphenyl)butanoic acid, (11-13) 2-(methylamino)-4-(3-cyclopropylphenyl)butanoic acid, (11-14) 2-(methylamino)-4-(4-cyclopropylphenyl)butanoic acid, (11-15) 2-(methylamino)-4-(2-(trifluoromethyl)phenyl)butanoic acid, (11-16) 2-(methylamino)-4-(3-(trifluoromethyl)phenyl)butanoic acid, (11-17) 2-(methylamino)-4-(4-(trifluoromethyl)phenyl)butanoic acid, (11-18) 2-(methylamino)-4-(2-isopropylphenyl)butanoic acid, (11-19) 2-(methylamino)-4-(3-isopropylphenyl)butanoic acid, (11-20) 2-(methylamino)-4-(4-isopropylphenyl)butanoic acid, (11-21) 2-(methylamino)-4-(2-methoxyphenyl)butanoic acid, (11-22) 2-(methylamino)-4-(3-methoxyphenyl)butanoic acid, (11-23) 2-(methylamino)-4-(4-methoxyphenyl)butanoic acid, (11-24) 2-(methylamino)-4-(2-(allyloxy)phenyl)butanoic acid, (11-25) 2-(methylamino)-4-(3-(allyloxy)phenyl)butanoic acid, (11-26) 2-(methylamino)-4-(4-(allyloxy)phenyl)butanoic acid, (11-27) 2-(methylamino)-4-(4-isopropoxyphenyl)butanoic acid, (11-28) 2-(methylamino)-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (11-29) 2-(methylamino)-4-(2-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (11-30) 2-(methylamino)-4-(3,4-dimethoxyphenyl)butanoic acid, (11-31) 2-(methylamino)-4-(2-fluoro-4-methoxyphenyl)butanoic acid, (11-32) 2-(methylamino)-4-(3-fluoro-4-methoxyphenyl)butanoic acid, (11-33) 2-(methylamino)-4-(3,5-difluoro-4-methoxyphenyl)butanoic acid, (11-34) 2-(methylamino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (11-35) 2-(methylamino)-4-(3-methoxy-4-(methylcarbamoyl)phenyl)butanoic acid, (11-36) 2-(methylamino)-4-(4-methoxy-3-(methylcarbamoyl)phenyl)butanoic acid, (11-37) 2-(methylamino)-4-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)butanoic acid, (11-38) 2-(methylamino)-4-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoic acid, (11-39) 2-(methylamino)-4-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)butanoic acid, (11-40) 2-(methylamino)-4-(pyridin-2-yl)butanoic acid, (11-41) 2-(methylamino)-4-(pyridin-3-yl)butanoic acid, (11-42) 2-(methylamino)-4-(pyridin-4-yl)butanoic acid, (11-43) 2-(methylamino)-4-(6-methylpyridin-3-yl)butanoic acid, (11-44) 2-(methylamino)-4-(5-methylpyridin-3-yl)butanoic acid, (11-45) 2-(methylamino)-4-(4-methylpyridin-3-yl)butanoic acid, (11-46) 2-(methylamino)-4-(6-methoxypyridin-3-yl)butanoic acid, (11-47) 2-(methylamino)-4-(5-methoxypyridin-3-yl)butanoic acid, (11-48) 2-(methylamino)-4-(5-fluoropyridin-3-yl)butanoic acid, (11-49) 2-(methylamino)-4-(5-chloropyridin-3-yl)butanoic acid, (11-50) 2-(methylamino)-4-(5-bromopyridin-3-yl)butanoic acid, (11-51) 2-(methylamino)-4-(5-iodopyridin-3-yl)butanoic acid, (11-52) 2-(methylamino)-4-(2-(methylamino)pyridin-4-yl)butanoic acid, (11-53) 2-(methylamino)-4-(2-(dimethylamino)pyridin-4-yl)butanoic acid, (11-54) 2-(methylamino)-4-(pyrimidin-5-yl)butanoic acid, (12-1) Phenylalanine, (12-2) 2-amino-3-(o-tolyl)propanoic acid, (12-3) 2-amino-3-(m-tolyl)propanoic acid, (12-4) 2-amino-3-(p-tolyl)propanoic acid, (12-5) 2-amino-3-(4-ethylphenyl)propanoic acid, (12-6) 2-amino-3-(2-chlorophenyl)propanoic acid, (12-7) 2-amino-3-(3-chlorophenyl)propanoic acid, (12-8) 2-amino-3-(4-chlorophenyl)propanoic acid, (12-9) 2-amino-3-(2-fluorophenyl)propanoic acid, (12-10) 2-amino-3-(3-fluorophenyl)propanoic acid, (12-11) 2-amino-3-(4-fluorophenyl)propanoic acid, (12-12) 2-amino-3-(2-cyclopropylphenyl)propanoic acid, (12-13) 2-amino-3-(3-cyclopropylphenyl)propanoic acid, (12-14) 2-amino-3-(4-cyclopropylphenyl)propanoic acid, (12-15) 2-amino-3-(2-(trifluoromethyl)phenyl)propanoic acid, (12-16) 2-amino-3-(3-(trifluoromethyl)phenyl)propanoic acid, (12-17) 2-amino-3-(4-(trifluoromethyl)phenyl)propanoic acid, (12-18) 2-amino-3-(2-isopropylphenyl)propanoic acid, (12-19) 2-amino-3-(3-isopropylphenyl)propanoic acid, (12-20) 2-amino-3-(4-isopropylphenyl)propanoic acid, (12-21) 2-amino-3-(2-methoxyphenyl)propanoic acid, (12-22) 2-amino-3-(3-methoxyphenyl)propanoic acid, (12-23) 2-amino-3-(4-methoxyphenyl)propanoic acid, (12-24) 2-amino-3-(2-(allyloxy)phenyl)propanoic acid, (12-25) 2-amino-3-(3-(allyloxy)phenyl)propanoic acid, (12-26) 2-amino-3-(4-(allyloxy)phenyl)propanoic acid, (12-27) 2-amino-3-(4-isopropoxyphenyl)propanoic acid, (12-28) 2-amino-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (12-29) 2-amino-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (12-30) 2-amino-3-(3,4-dimethoxyphenyl)propanoic acid, (12-31) 2-amino-3-(2-fluoro-4-methoxyphenyl)propanoic acid, (12-32) 2-amino-3-(3-fluoro-4-methoxyphenyl)propanoic acid, (12-33) 2-amino-3-(3,5-difluoro-4-methoxyphenyl)propanoic acid, (12-34) 2-amino-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (12-35) 2-amino-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoic acid, (12-36) 2-amino-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoic acid, (12-37) 2-amino-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoic acid, (12-38) 2-amino-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (12-39) 2-amino-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (12-40) 2-amino-3-(pyridin-2-yl)propanoic acid, (12-41) 2-amino-3-(pyridin-3-yl)propanoic acid, (12-42) 2-amino-3-(pyridin-4-yl)propanoic acid, (12-43) 2-amino-3-(6-methylpyridin-3-yl)propanoic acid, (12-44) 2-amino-3-(5-methylpyridin-3-yl)propanoic acid, (12-45) 2-amino-3-(4-methylpyridin-3-yl)propanoic acid, (12-46) 2-amino-3-(6-methoxypyridin-3-yl)propanoic acid, (12-47) 2-amino-3-(5-methoxypyridin-3-yl)propanoic acid, (12-48) 2-amino-3-(5-fluoropyridin-3-yl)propanoic acid, (12-49) 2-amino-3-(5-chloropyridin-3-yl)propanoic acid, (12-50) 2-amino-3-(5-bromopyridin-3-yl)propanoic acid, (12-51) 2-amino-3-(5-iodopyridin-3-yl)propanoic acid, (12-52) 2-amino-3-(2-(methylamino)pyridin-4-yl)propanoic acid, (12-53) 2-amino-3-(2-(dimethylamino)pyridin-4-yl)propanoic acid, (12-54) 2-amino-3-(pyrimidin-5-yl)propanoic acid, (13-1) Methylphenylalanine, (13-2) 2-(methylamino)-3-(o-tolyl)propanoic acid, (13-3) 2-(methylamino)-3-(m-tolyl)propanoic acid, (13-4) 2-(methylamino)-3-(p-tolyl)propanoic acid, (13-5) 2-(methylamino)-3-(4-ethylphenyl)propanoic acid, (13-6) 2-(methylamino)-3-(2-chlorophenyl)propanoic acid, (13-7) 2-(methylamino)-3-(3-chlorophenyl)propanoic acid, (13-8) 2-(methylamino)-3-(4-chlorophenyl)propanoic acid, (13-9) 2-(methylamino)-3-(2-fluorophenyl)propanoic acid, (13-10) 2-(methylamino)-3-(3-fluorophenyl)propanoic acid, (13-11) 2-(methylamino)-3-(4-fluorophenyl)propanoic acid, (13-12) 2-(methylamino)-3-(2-cyclopropylphenyl)propanoic acid, (13-13) 2-(methylamino)-3-(3-cyclopropylphenyl)propanoic acid, (13-14) 2-(methylamino)-3-(4-cyclopropylphenyl)propanoic acid, (13-15) 2-(methylamino)-3-(2-(trifluoromethyl)phenyl)propanoic acid, (13-16) 2-(methylamino)-3-(3-(trifluoromethyl)phenyl)propanoic acid, (13-17) 2-(methylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid, (13-18) 2-(methylamino)-3-(2-isopropylphenyl)propanoic acid, (13-19) 2-(methylamino)-3-(3-isopropylphenyl)propanoic acid, (13-20) 2-(methylamino)-3-(4-isopropylphenyl)propanoic acid, (13-21) 2-(methylamino)-3-(2-methoxyphenyl)propanoic acid, (13-22) 2-(methylamino)-3-(3-methoxyphenyl)propanoic acid, (13-23) 2-(methylamino)-3-(4-methoxyphenyl)propanoic acid, (13-24) 2-(methylamino)-3-(2-(allyloxy)phenyl)propanoic acid, (13-25) 2-(methylamino)-3-(3-(allyloxy)phenyl)propanoic acid, (13-26) 2-(methylamino)-3-(4-(allyloxy)phenyl)propanoic acid, (13-27) 2-(methylamino)-3-(4-isopropoxyphenyl)propanoic acid, (13-28) 2-(methylamino)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (13-29) 2-(methylamino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (13-30) 2-(methylamino)-3-(3,4-dimethoxyphenyl)propanoic acid, (13-31) 2-(methylamino)-3-(2-fluoro-4-methoxyphenyl)propanoic acid, (13-32) 2-(methylamino)-3-(3-fluoro-4-methoxyphenyl)propanoic acid, (13-33) 2-(methylamino)-3-(3,5-difluoro-4-methoxyphenyl)propanoic acid, (13-34) 2-(methylamino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (13-35) 2-(methylamino)-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoic acid, (13-36) 2-(methylamino)-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoic acid, (13-37) 2-(methylamino)-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoic acid, (13-38) 2-(methylamino)-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (13-39) 2-(methylamino)-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (13-40) 2-(methylamino)-3-(pyridin-2-yl)propanoic acid, (13-41) 2-(methylamino)-3-(pyridin-3-yl)propanoic acid, (13-42) 2-(methylamino)-3-(pyridin-4-yl)propanoic acid, (13-43) 2-(methylamino)-3-(6-methylpyridin-3-yl)propanoic acid, (13-44) 2-(methylamino)-3-(5-methylpyridin-3-yl)propanoic acid, (13-45) 2-(methylamino)-3-(4-methylpyridin-3-yl)propanoic acid, (13-46) 2-(methylamino)-3-(6-methoxypyridin-3-yl)propanoic acid, (13-47) 2-(methylamino)-3-(5-methoxypyridin-3-yl)propanoic acid, (13-48) 2-(methylamino)-3-(5-fluoropyridin-3-yl)propanoic acid, (13-49) 2-(methylamino)-3-(5-chloropyridin-3-yl)propanoic acid, (13-50) 2-(methylamino)-3-(5-bromopyridin-3-yl)propanoic acid, (13-51) 2-(methylamino)-3-(5-iodopyridin-3-yl)propanoic acid, (13-52) 2-(methylamino)-3-(2-(methylamino)pyridin-4-yl)propanoic acid, (13-53) 2-(methylamino)-3-(2-(dimethylamino)pyridin-4-yl)propanoic acid, (13-54) 2-(methylamino)-3-(pyrimidin-5-yl)propanoic acid, (14-1) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-2) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-3) tert-butyl 2-((tert-butoxycarbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-4) Benzyl 2-((tert-butoxycarbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-5) tert-butyl 2-(((benzyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-6) Benzyl 2-(((benzyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-7) tert-butyl 2-(((allyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-8) Benzyl 2-(((allyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-9) tert-butyl 2-(ethyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-3-(p-tolyl)propanoate, (14-10) benzyl 2-(ethyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-3-(p-tolyl)propanoate, (14-11) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid, (14-12) 2-((tert-butoxycarbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid, (14-13) 2-(((benzyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid, (14-14) 2-(((allyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid, (14-15) 2-(ethyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-3-(p-tolyl)propanoic acid, and (14-16) 2-(Ethylamino)-3-(p-tolyl)propanoic acid. [Effects of the Invention]

[0021] According to the present invention, optically active aromatic amino acid derivatives useful for the discovery of peptide drugs and / or the supply of active pharmaceutical ingredients for pharmaceuticals can be efficiently produced. Furthermore, since various optically active aromatic amino acid derivatives can be produced, optically active aromatic amino acid derivatives with diverse structures can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0022] (abbreviation) The abbreviations used in the present invention are listed below. AA or AcONH4: Ammonium acetate AcOEt: ethyl acetate Alloc group: allyloxycarbonyl group BF3·OEt2: Boron trifluoride diethyl ether complex Bn group: benzyl group Boc group: tert-butoxycarbonyl group Cbz group: benzyloxycarbonyl group DCM: dichloromethane DIC: N,N'-diisopropylcarbodiimide DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide DMI: 1,3-dimethyl-2-imidazolidinone DMPU: N,N'-dimethylpropylene urea DMSO: dimethyl sulfoxide dtbbpy: 4,4'-di-tert-butyl-2,2'-bipyridine EDTA·2Na: Disodium ethylenediaminetetraacetic acid FA: Formic acid Fmoc-Cl: 9-fluorenylmethyl chloroformate Fmoc-OSu:N-[(9H-fluoren-9-ylmethoxy)carbonyloxy]succinimide Fmoc group: 9-fluorenylmethyloxycarbonyl group HPLC: High-performance liquid chromatography LC / MS: Liquid chromatography mass spectrometry MeCN: acetonitrile Ms group: mesyl group MTBE: Methyl tert-butyl ether NHPI: N-hydroxyphthalimide NMP: N-methylpyrrolidone NMR: Nuclear magnetic resonance spectroscopy PhSiH3: Phenylsilane Ph group: phenyl group TBDMSCl: tert-butyldimethylsilyl chloride TBDMS group: tert-butyldimethylsilyl group TBDPSCl: tert-butyldiphenylsilyl chloride TBDPS group: tert-butyldiphenylsilyl group tBu or t-Bu group: tert-butyl group Teoc group: 2-(trimethylsilyl)ethoxycarbonyl group TESCl: Triethylsilyl chloride TES group: triethylsilyl group TFA: Trifluoroacetic acid TfOH: trifluoromethanesulfonic acid Tf group: trifluoromethanesulfonyl group THF: tetrahydrofuran TIPSCl: Triisopropylsilyl chloride TIPS group: triisopropylsilyl group TMSBr: Trimethylsilyl bromide TMSCl: Trimethylsilyl chloride TMSI: Trimethylsilyl iodide TMSOTf: Trimethylsilyl trifluoromethanesulfonate TMS group: trimethylsilyl group Tr group: Trityl group Ts group: tosyl group Gly: glycine Ala: Alanine Ser: Serine Thr: Threonine Val: Valin Leu: Leucine Ile: Isoleucine Phe: phenylalanine Tyr: Tyrosine Trp: tryptophan His: histidine Glu: glutamic acid Asp: aspartic acid Gln: glutamine Asn: asparagine Cys: cysteine Met: methionine Lys: Lysine Arg: arginine Pro: Proline

[0023] (Definition of functional groups, etc.) As used herein, the term "halogen atom" includes, for example, F, Cl, Br, or I.

[0024] As used herein, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, but has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. The alkyl group includes linear and branched ones. The alkyl group may have 1 to 20 carbon atoms (C1-C 20 , hereinafter referred to as “C p -C q " means that the number of carbon atoms is p to q.) and preferably includes a C1-C6 alkyl group. Specific examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl, sec-butyl, etc.

[0025] As used herein, "alkoxy" refers to an oxy group bonded to an "alkyl" as defined above, and preferably includes C1-C4 alkoxy, C1-C3 alkoxy, etc. Specific examples of alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, etc.

[0026] As used herein, "alkenyl" refers to an alkyl group having at least one double bond (two adjacent sp 2 Alkenyl is a monovalent group having 1 to 2 carbon atoms. Depending on the configuration of the double bond and the substituents (if present), the geometry of the double bond can be in the Entgegen (E) or Zusammen (Z) configuration, in the cis or trans configuration. Alkenyl includes linear or branched chains, including linear chains containing internal olefins. Preferably, C2-C 10 Alkenyl is preferably C2-C6 alkenyl or C2-C4 alkenyl. Specific examples of alkenyl include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, and hexenyl.

[0027] As used herein, "alkenyloxy" refers to an oxy group having the above-defined "alkenyl" bonded thereto, and preferred examples include C2-C6 alkenyloxy and C2-C4 alkenyloxy.

[0028] As used herein, "alkynyl" refers to a monovalent group having at least one triple bond (two adjacent sp carbon atoms). It includes straight-chain or branched-chain alkynyl, including internal alkylene. It is preferably C2-C6. 10 Alkynyl is preferably C2-C6 alkynyl or C2-C4 alkynyl. Specific examples of alkynyl include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, and 3-methyl-(5-phenyl)-4-pentynyl.

[0029] As used herein, "alkynyloxy" refers to an oxy group having the above-defined "alkynyl" bonded thereto, and preferred examples include C2-C6 alkynyloxy and C2-C4 alkynyloxy.

[0030] As used herein, "haloalkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above are substituted with halogen atoms, and preferred examples include C1-C6 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, and C1-C2 haloalkyl.

[0031] As used herein, "haloalkoxy" refers to an oxy group bonded to the above-mentioned "haloalkyl", and preferred examples include C1-C4 haloalkoxy, C1-C3 haloalkoxy, and C1-C2 haloalkoxy.

[0032] As used herein, "fluoroalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" have been substituted with fluorine atoms, and preferred examples include C1-C6 fluoroalkyl, C1-C4 fluoroalkyl, C1-C3 fluoroalkyl, C1-C2 fluoroalkyl, etc. Specific examples of fluoroalkyl include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, heptafluoropropyl, etc.

[0033] As used herein, "fluoroalkoxy" refers to an oxy group bonded to the aforementioned "fluoroalkyl," and preferred examples include C1-C4 fluoroalkoxy, C1-C3 fluoroalkoxy, C1-C2 fluoroalkoxy, etc. Specific examples of fluoroalkoxy include trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, heptafluoropropoxy, etc.

[0034] As used herein, "alkylsulfonyl" refers to a sulfonyl group to which the "alkyl" is bonded (i.e., alkyl-SO-). Preferred examples of alkylsulfonyl include C-C alkylsulfonyl and C-C alkylsulfonyl, and specific examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, and i-propylsulfonyl.

[0035] As used herein, "alkylsulfonylamino" refers to a group in which one hydrogen atom of an amino group (-NH2) is substituted with the above-mentioned "alkylsulfonyl." Preferred examples of alkylsulfonylamino include C1-C6 alkylsulfonylamino and C1-C4 alkylsulfonylamino, and specific examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, and i-propylsulfonylamino.

[0036] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spirocyclic rings. The cycloalkyl is preferably a C3-C 10 Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicyclo[2.2.1]heptyl. The cycloalkyl may be partially unsaturated. Specific examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicyclo[2.2.1]heptyl.

[0037] As used herein, "aminocarbonyl" refers to a group in which an optionally substituted nitrogen atom is bonded to a carbonyl (i.e., -C=O-NHR), and is also referred to as a carboxamide group. The substituent represented by R is not particularly specified, but examples thereof include a hydroxy group, an alkyl group, and an alkylsulfonyl group. Specific examples of the substituent include methyl, ethyl, propyl, butyl, methanesulfonyl, and ethanesulfonyl.

[0038] As used herein, "aryl" refers to a monovalent aromatic hydrocarbon ring, preferably C6-C 10 Examples of the aryl include phenyl, 1-naphthyl, 2-naphthyl, etc. Specific examples of the aryl include phenyl, 1-naphthyl, 2-naphthyl, etc. The aryl may be substituted with any substituent, preferably with alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, or a halogen atom.

[0039] As used herein, "heteroaryl" refers to an aromatic monovalent heterocyclic group having preferably 1 to 5 heteroatoms in the ring. The heteroatom is preferably N, O, or S, and the number of heteroatoms is preferably 1 or 2. The heteroaryl may be partially saturated and may be a monocyclic or fused ring (for example, a bicyclic heteroaryl fused with a benzene ring or a monocyclic heteroaryl ring). The number of atoms constituting the ring is preferably 5 to 10 (5- to 10-membered heteroaryl). The heteroaryl may be substituted with any substituent, preferably alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, or a halogen atom. Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl, azaindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, and imidazopyridyl.

[0040] As used herein, the phrase "having a heteroatom in the ring" means that a heteroatom is contained in the atoms constituting the ring. The heteroatom is preferably N, O, or S, the number of heteroatoms is preferably 1 or 2, and the ring is preferably a 4- to 6-membered ring. Examples of such rings include aromatic heterocycles such as pyridine, and non-aromatic heterocycles such as piperidine, morpholine, pyrrolidine, and azetidine. When the heteroatom is an oxygen atom, the phrase "having an oxygen atom in the ring" is used. Examples of such rings include aromatic heterocycles such as furan, and non-aromatic heterocycles such as tetrahydrofuran and 1,4-dioxane. When the heteroatom is a sulfur atom, the phrase "having a sulfur atom in the ring" is used. Examples of such rings include aromatic heterocycles such as thiophene, and non-aromatic heterocycles such as tetrahydrothiophene. Furthermore, when the heteroatoms are a nitrogen atom and an oxygen atom, it is expressed as "having a nitrogen atom and an oxygen atom in the ring," and examples of such rings include aromatic heterocycles such as oxazole, and non-aromatic heterocycles such as oxazoline, oxazolidine, and oxazolidinone. Furthermore, when the heteroatoms are a nitrogen atom and a sulfur atom, it is expressed as "having a nitrogen atom and a sulfur atom in the ring," and examples of such rings include aromatic heterocycles such as thiazole, and non-aromatic heterocycles such as thiazoline, thiazolidine, and thiazolidinone.

[0041] As used herein, the term "heterocyclic group" or "heterocyclyl" refers to a group having at least one heteroatom (e.g., N, O, S, etc.) in the ring, and the ring may be aromatic or non-aromatic, i.e., saturated, or completely or partially unsaturated. The number of heteroatoms contained in the ring is preferably 1 or 2, and the ring is preferably 3 to 7-membered. The heterocyclic group may be substituted with any substituent, preferably alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, a halogen atom, or aryl. Specific examples of heterocyclic groups include pyridyl, piperidino, morpholino, pyrrolidino, oxadiazolonyl, oxazolidin-2-yl, oxazolin-2-yl, aziridinyl, dihydrooxazolyl, and azetidinyl.

[0042] As used herein, the term "arylalkyl (aralkyl)" refers to a group containing both the above-mentioned aryl and the above-mentioned alkyl, and means, for example, a group in which at least one hydrogen atom of the alkyl is substituted with an aryl. As the arylalkyl, a group having "C6-C 10 Specific examples include benzyl and phenethyl. The aryl group of the arylalkyl may be substituted with any substituent, preferably alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, or a halogen atom.

[0043] As used herein, the term "heteroarylalkyl (heteroaralkyl)" refers to a group containing both heteroaryl and alkyl, and refers to, for example, a group in which at least one hydrogen atom of the alkyl is substituted with heteroaryl. Preferred examples of heteroarylalkyl include "5- to 10-membered heteroaryl C1-C6 alkyl," and specific examples include pyridylmethyl and pyridylethyl. The heteroaryl group of the heteroarylalkyl may be substituted with any substituent, and preferably may be substituted with alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, or a halogen atom.

[0044] As used herein, "alkylene" refers to a divalent group derived by further removing one optional hydrogen atom from the aforementioned "alkyl." Preferred examples of alkylene include C1-C2 alkylene, C1-C3 alkylene, C1-C4 alkylene, C1-C5 alkylene, and C1-C6 alkylene. Specific examples of alkylene include -CH2-, -(CH2)2-, -(CH2)3-, CH(CH3)CH2-, -C(CH3)2-, -(CH2)4-, CH(CH3)CH2CH2-, -C(CH3)2CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2-, -CH2CH2CH(CH3)-, -(CH2)5-, and -(CH2)6-.

[0045] In this specification, "arylene" means a divalent group derived from the aryl by further removing one arbitrary hydrogen atom. The arylene may be a single ring or a condensed ring. The number of atoms constituting the ring is not particularly limited, but is preferably 6 to 10 (C6-C 10 Arylene). Specific examples of arylene include phenylene. The arylene group may be substituted with any substituent, preferably alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, or a halogen atom.

[0046] As used herein, the term "heteroarylene" refers to a divalent group derived from the heteroaryl by further removing one optional hydrogen atom. The heteroarylene may be a single ring or a fused ring. The number of atoms constituting the ring is not particularly limited, but is preferably 5 to 10 (5- to 10-membered heteroarylene). Specific examples of heteroarylene include imidazolediyl, pyridinediyl, oxadiazolediyl, thiazolidinyl, and thiadiazolediyl. The heteroarylene group may be substituted with any substituent, preferably with alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, or a halogen atom.

[0047] As used herein, the term "fused ring structure" refers to a cyclic structure in a cyclic compound having two or more rings, in which the rings share two or more atoms. The term "fused ring structure of two or more aromatic rings" refers to a cyclic structure in a cyclic compound having two or more aromatic rings, in which the aromatic rings share two or more atoms. Non-limiting examples of fused ring structures include an indole skeleton, a benzofuran skeleton, a benzimidazole skeleton, a quinoline skeleton, and a bicyclo[4.4.0]decane skeleton.

[0048] As used herein, "amino group-protecting groups" include carbamate-type protecting groups, amide-type protecting groups, arylsulfonamide-type protecting groups, alkylamine-type protecting groups, imide-type protecting groups, etc. Specific examples of amino group-protecting groups include Fmoc group, Boc group, Alloc group, Cbz group, Teoc group, trifluoroacetyl group, benzenesulfonyl group, tosyl group, nosyl group, dinitronosyl group, t-Bu group, trityl group, cumyl group, benzylidene group, 4-methoxybenzylidene group, diphenylmethylidene group, etc.

[0049] As used herein, the term "protecting group for a carboxyl group" includes alkyl ester type protecting groups, benzyl ester type protecting groups, substituted alkyl ester type protecting groups, etc. Specific examples of the protecting group for a carboxyl group include a methyl group, an ethyl group, a t-Bu group, a benzyl group, a trityl group, a cumyl group, a methoxytrityl group, a 2-(trimethylsilyl)ethyl group, a 2,2,2-trichloroethyl group, an allyl group, etc.

[0050] As used herein, "hydroxy-protecting groups" include alkyl ether-type protecting groups, aralkyl ether-type protecting groups, silyl ether-type protecting groups, carbonate-type protecting groups, etc. Specific examples of hydroxy-protecting groups include a methoxymethyl group, a benzyloxymethyl group, a tetrahydropyranyl group, a tert-butyl group, an allyl group, a 2,2,2-trichloroethyl group, a benzyl group, a 4-methoxybenzyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a methoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, etc.

[0051] As used herein, the term "protected hydroxy" refers to a hydroxy group protected by the above-mentioned hydroxy-protecting group.

[0052] In the preparation of the compounds described herein, if a defined group undergoes an undesired chemical transformation under the conditions of the method, the compound can be prepared by, for example, using means such as protection and deprotection of the functional group. Here, the selection and deprotection of the protecting group can be performed using, for example, the methods described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons 2014)," which can be used appropriately depending on the reaction conditions. Furthermore, the order of reaction steps such as the introduction of substituents can also be changed as necessary.

[0053] In the present specification, when the modifier "optionally substituted" is used, examples of the substituent include an alkyl group, an alkoxy group, a fluoroalkyl group, a fluoroalkoxy group, oxo, an aminocarbonyl group, an alkylsulfonyl group, an alkylsulfonylamino group, a cycloalkyl group, an aryl group, a heteroaryl group, a heterocyclyl group, an arylalkyl group, a heteroarylalkyl group, a halogen atom, a nitro group, an amino group, a monoalkylamino group, a dialkylamino group, a cyano group, a carboxyl group, an alkoxycarbonyl group, and a formyl group. Furthermore, each of these may be given a substituent, and the substituents are not limited, and for example, one or more may be independently selected from any substituents containing a halogen atom, an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom, or a phosphorus atom. Examples include optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, cycloalkyl, etc.

[0054] The compounds represented by each formula of the present invention can be salts or solvates thereof. Salts of the compounds represented by each formula include, for example, hydrochlorides; hydrobromides; hydroiodides; phosphates; phosphonates; sulfates; sulfonates such as methanesulfonates and p-toluenesulfonates; carboxylates such as acetates, citrates, malates, tartrates, succinates, and salicylates; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. These salts can be produced, for example, by contacting the compound with an acid or a base. A solvate of a compound represented by each formula refers to a phenomenon in which solute molecules strongly attract solvent molecules in a solution, forming a molecular cluster. If the solvent is water, it is called a hydrate. The compounds represented by each formula of the present invention can form solvates with a single solvent selected from organic solvents such as alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanol, etc.), dimethylformamide, or diglyme, or water, as well as with multiple solvents selected from these.

[0055] As used herein, "amino acid" includes natural amino acids and unnatural amino acids (sometimes referred to as amino acid derivatives). As used herein, "natural amino acids" refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro. Unnatural amino acids (amino acid derivatives) are not particularly limited, but examples include β-amino acids, D-amino acids, N-substituted amino acids, α,α-disubstituted amino acids, amino acids with side chains different from those of natural amino acids, and hydroxycarboxylic acids. As used herein, amino acids may have any stereoconfiguration. The side chain of an amino acid is not particularly limited, and may be freely selected from, in addition to a hydrogen atom, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, heteroaralkyl groups, cycloalkyl groups, and spiro-linked cycloalkyl groups. Each of these may have a substituent, and the substituents are not limited, and may be independently selected from any substituents containing, for example, a halogen atom, an O atom, an S atom, an N atom, a B atom, an Si atom, or a P atom. Examples of such substituents include optionally substituted alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, cycloalkyl groups, etc., as well as oxo, aminocarbonyl, and halogen atoms. In a non-limiting embodiment, the amino acid herein may be a compound having a carboxy group and an amino group in the same molecule (even in this case, imino acids such as proline and hydroxyproline are also included in the definition of amino acids).

[0056] Halogen-derived substituents include fluoro (-F), chloro (-Cl), bromo (-Br), iodo (-I), and the like.

[0057] Substituents derived from O atoms include hydroxy (-OH), oxy (-OR), carbonyl (-C=OR), carboxyl (-COH), oxycarbonyl (-C=O-OR), carbonyloxy (-OC=OR), thiocarbonyl (-C=O-SR), carbonylthio group (-SC=OR), aminocarbonyl (-C=O-NHR), carbonylamino (-NH-C=OR), oxycarbonylamino (-NH-C=O-OR), sulfonylamino (-NH-SO2-R), aminosulfonyl (-SO2-NHR), sulfamoylamino (-NH-SO2-NHR), thiocarboxyl (-C(=O)-SH), and carboxylcarbonyl (-C(=O)-COH).

[0058] Examples of oxy (-OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy, and the like.

[0059] Examples of carbonyl (-C=OR) include formyl (-C=OH), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, and the like.

[0060] Examples of oxycarbonyl (-C=O-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, and the like.

[0061] Examples of carbonyloxy (-OC=OR) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, aralkylcarbonyloxy, and the like.

[0062] Examples of thiocarbonyl (-C=O-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, aralkylthiocarbonyl, and the like.

[0063] Examples of carbonylthio (-SC=OR) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, aralkylcarbonylthio, and the like.

[0064] Examples of aminocarbonyl (-C=O-NHR) include alkylaminocarbonyl, cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, etc. In addition to these, compounds in which the H atom bonded to the N atom in -C=O-NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0065] Examples of carbonylamino (-NH-C=OR) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylcarbonylamino, etc. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C=OR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0066] Examples of oxycarbonylamino (-NH-C=O-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, aralkyloxycarbonylamino, etc. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C=O-OR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0067] Examples of sulfonylamino (-NH-SO2-R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, etc. In addition to these, compounds in which the H atom bonded to the N atom in -NH-SO2-R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0068] Examples of aminosulfonyl (-SO2-NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, etc. In addition to these, compounds in which the H atom bonded to the N atom in -SO2-NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0069] Examples of sulfamoylamino (-NH-SO-NHR) include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, aralkylsulfamoylamino, etc. Furthermore, the two H atoms bonded to the N atom in -NH-SO-NHR may be substituted with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents may form a ring.

[0070] Substituents derived from S atoms include thiol (-SH), thio (-SR), sulfinyl (-S=OR), sulfonyl (-S(O)2-R), sulfo (-SO3H), and pentafluorosulfanyl (-SF5).

[0071] Examples of thio (-SR) are selected from alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio, and the like.

[0072] Examples of sulfinyl (-S=OR) include alkylsulfinyl, cycloalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, and the like.

[0073] Examples of sulfonyl (-S(O)2-R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and the like.

[0074] Substituents derived from the N atom include azido (-N3, also referred to as "azido group"), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R), tertiary amino (-NR(R')), amidino (-C(=NH)-NH2), substituted amidino (-C(=NR)-NR'R''), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR''')-NR'R''), and aminocarbonylamino (-NR-CO-NR'R'').

[0075] Examples of secondary amino (-NH-R) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, aralkylamino, and the like.

[0076] Examples of tertiary amino (—NR(R′)) include an amino group having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., such as alkyl(aralkyl)amino, and these two substituents may form a ring.

[0077] Examples of substituted amidino (-C(=NR)-NR'R'') include groups in which the three substituents R, R', and R'' on the N atom are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl(aralkyl)(aryl)amidino.

[0078] Examples of substituted guanidino (-NR-C(=NR''')-NR'R'') include groups in which R, R', R'', and R''' are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these groups form a ring.

[0079] Examples of aminocarbonylamino (-NR-CO-NR'R'') include groups in which R, R', and R'' are each independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these groups form a ring.

[0080] Examples of substituents derived from the B atom include boryl (-BR(R')) and dioxyboryl (-B(OR)(OR')). These two substituents, R and R', are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., or may form a ring. Specific examples include cyclic boryl groups, and more specific examples include pinacolatoboryl, neopentanediolateboryl, and catecholateboryl groups.

[0081] Specific examples of the substituent on the nitrogen atom of the N-substituted amino acid herein include alkyl, C1-C6 alkyl, C1-C4 alkyl, methyl, and the like.

[0082] The "aromatic amino acid derivative" as used herein refers to the above-mentioned amino acid derivatives, which contain an aromatic substituent in the side chain of the amino acid. Specific examples of the aromatic substituent include an optionally substituted aryl and an optionally substituted heteroaryl.

[0083] The main chain amino group of an amino acid may be unsubstituted (-NH2) or substituted (i.e., -NHR, where R represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl, which may have a substituent, and the carbon chain bonded to the N atom and the carbon atom at the α-position may form a ring, as in proline). Such amino acids in which the main chain amino group is substituted may be referred to herein as "N-substituted amino acids." Preferred examples of "N-substituted amino acids" herein include, but are not limited to, N-alkyl amino acids, N-C1-C6 alkyl amino acids, N-C1-C4 alkyl amino acids, and N-methyl amino acids.

[0084] As used herein, "amino acid" includes all corresponding isotopes. An isotope of an "amino acid" is one in which at least one atom has been replaced with an atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons). Examples of isotopes included in "amino acids" as used herein include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each of which is 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 35 S, 18 F, 36 Includes Cl etc.

[0085] (Method of producing the compound represented by formula I) In one embodiment, the present invention provides a compound of formula I: [ka] [In the formula, R1 is hydrogen or an amino-protecting group; R2 is hydrogen or C1-C6 alkyl, and R3 is hydrogen or a protecting group for a carboxyl group, or R2 and R3 together form a divalent protecting group; R6 is an optionally substituted C6-C 10 aryl, or optionally substituted heteroaryl; R7 is hydrogen or C1-C4 alkyl; n is 1 or 2. The present invention relates to a method for producing a compound represented by formula II: [ka] [In the formula, R1, R2, R3, R7, and n are defined the same as R1, R2, R3, R7, and n in the compound represented by formula I, respectively; R5 is as follows: [ka] selected from the group consisting of R t、 R u、 R v、 and R w are independently hydrogen, halogen, or nitro; R x and R y are independently hydrogen, C1-C4 alkyl, or optionally substituted phenyl; R z is hydrogen, C1-C4 alkyl, or halogen; Y is CH or N; * denotes the point of attachment.] or a solvate thereof with a reducing agent, an additive, and R6-X (wherein R6 is the same as R6 in the compound represented by formula I, and X is a halogen, OTf, or OMs) in the presence of a solvent and a catalyst to obtain a compound represented by formula I, a salt thereof, or a solvate thereof.

[0086] In Formula I, R1 is hydrogen or a protecting group for an amino group. When R1 is a protecting group for an amino group, specific examples of the protecting group include Fmoc, Boc, Alloc, Cbz, Teoc, trifluoroacetyl, benzenesulfonyl group, tosyl group, nosyl group, dinitronosyl group, t-Bu group, trityl group, cumyl group, benzylidene group, 4-methoxybenzylidene group, and diphenylmethylidene group, and among these, Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl are preferred.

[0087] In Formula I, R2 is hydrogen or C1-C6 alkyl, and R3 is hydrogen or a protecting group for a carboxyl group, or R2 and R3 together form a divalent protecting group.

[0088] When R2 in formula I is C1-C6 alkyl, the C1-C6 alkyl is preferably methyl, ethyl, propyl, butyl, etc., and particularly preferably methyl or ethyl.

[0089] When R3 in formula I is a protecting group for a carboxyl group, specific examples of the protecting group include methyl, ethyl, t-Bu, benzyl, trityl, cumyl, methoxytrityl, 2-(trimethylsilyl)ethyl, 2,2,2-trichloroethyl, and allyl, and among these, methyl, ethyl, t-Bu, benzyl, trityl, cumyl, methoxytrityl, and 2-(trimethylsilyl)ethyl are preferred.

[0090] When R2 and R3 together form a divalent protecting group, the divalent protecting group can be methylene optionally substituted by one or two substituents, and is preferably -(CR8R9)-. When R2 and R3 together form -(CR8R9)-, the formula I can be converted to formula IA: [ka] In some embodiments, R and R are independently hydrogen, C-C alkyl, or C-C 10 aryl, i.e., R and R are both hydrogen, C-C alkyl, or C-C 10 aryl, or one is hydrogen and the other is C1-C4 alkyl or C6-C 10 aryl, or one is C1-C4 alkyl and the other is C6-C 10 When one or both of R8 and R9 is C1-C4 alkyl, the C1-C4 alkyl is preferably methyl. 10 When it is aryl, the C6-C 10 The aryl is preferably phenyl. One or both of R8 and R9 is C1-C4 alkyl or C6-C 10 When it is aryl, it is C1-C4 alkyl or C6-C 10 The aryl may have a substituent, and the C1-C4 alkyl may be methyl, the C6-C 10 Preferably, aryl is phenyl. In another embodiment, R8 and R9 together form oxo (=O).

[0091] Specific examples of compounds represented by formula IA include compounds having the following structure: [ka] wherein R, R and n are as defined herein.

[0092] In Formula I, R6 is an optionally substituted C6-C 10 R6 is an optionally substituted C6-C6 alkyl group, or an optionally substituted heteroaryl group. 10 When it is aryl, the C6-C 10 The aryl is preferably phenyl. When R6 is an optionally substituted heteroaryl, the heteroaryl is preferably pyridyl.10 Substituents for the aryl or the optionally substituted heteroaryl include C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C6 alkenyloxy, halogen, C3-C8 cycloalkyl, -NR p R q (In the formula, R p and R q are independently hydrogen or C1-C4 alkyl), -CONR r R s (In the formula, R r and R s are independently selected from the group consisting of hydrogen, hydroxy, a protected hydroxy group, C1-C4 alkyl, and C1-C4 alkylsulfonyl), cyclic boryl, etc. More specific examples of these substituents include methyl, methoxy, chloro, fluoro, isopropyl, cyclopropyl, trifluoromethyl, methylaminocarbonyl, methylsulfonylamino, hydroxycarbamoyl (including those in which the hydroxy group is protected with a protecting group, such as (tetrahydro-2H-pyran-2-yl)oxycarbamoyl, methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl, etc.), pinacolatoboryl, neopentanediolateboryl, catecholateboryl, allyloxy, etc. Optionally substituted C6-C 10 The number of substituents on the aryl or optionally substituted heteroaryl is not particularly limited, and preferably has, for example, 0 to 3 substituents. When the number of substituents is multiple, preferred combinations of substituents include one C1-C4 haloalkyl and one or two halogens, two C1-C4 alkoxy, one C1-C4 alkoxy and one or two halogens, and one -CONR r R sand one C1-C4 alkoxy. More specific examples of the combination of these substituents include combinations of trifluoromethyl and one or two fluorines, trifluoromethyl and one or two chlorines, one trifluoromethyl, one fluorine and one chlorine, two methoxys, methoxy and one or two fluorines, one methylaminocarbonyl and one methoxy, one methylsulfonylamino and one methoxy, etc.

[0093] Specific examples of R6 include the following groups: In the formula, "*" indicates the point of attachment. [ka] [ka]

[0094] In formula I, R7 is hydrogen or C1-C4 alkyl, preferably hydrogen or methyl.

[0095] In formula I, n is 1 or 2.

[0096] In formula II, R1, R2, R3, R7 and n have the same meanings as R1, R2, R3, R7 and n in formula I, respectively.

[0097] In formula II, R5 is [ka] where "*" denotes the point of attachment, and R t、 R u、 R v、 and R w are independently hydrogen, halogen, or nitro. In this case, specific examples of R5 include the following structures: [ka] Examples of the group include a group having the formula:

[0098] R5 in formula II is [ka] where "*" denotes the point of attachment, and R x and R y are independently hydrogen, C1-C4 alkyl, or optionally substituted phenyl. In this case, specific examples of R5 include the following structures: [ka] Examples of the group include a group having the formula:

[0099] R5 in formula II is [ka] where "*" denotes the point of attachment, and R z is hydrogen, C1-C4 alkyl, or halogen. In this case, specific examples of R5 include the following structures: [ka] Examples of the group include a group having the formula:

[0100] R5 in formula II is [ka] wherein "*" represents a point of attachment, and Y is CH or N. In this case, specific examples of R5 include the following structures: [ka] Examples of the group include a group having the formula:

[0101] "R6-X" used in this step is a C6-C 10 R6 is aryl or optionally substituted heteroaryl, and X is halogen, OTf, or OMs. R6 can be the same group as R6 in formula I. X is preferably iodine, bromine, or OTf.

[0102] More specific examples of R6-X include bromobenzene, 1-bromo-2-methylbenzene, 1-bromo-3-methylbenzene, 1-bromo-4-methylbenzene, 1-bromo-4-ethylbenzene, 1-bromo-2-chlorobenzene, 1-bromo-3-chlorobenzene, 1-bromo-4-chlorobenzene, 1-bromo-2-fluorobenzene, 1-bromo-3-fluorobenzene, 1-bromo-4-fluorobenzene, 1-bromo-2-cyclopropylbenzene, 1-bromo-3-cyclopropylbenzene, 1-bromo-4-cyclopropylbenzene, 1-bromo-2-(trifluoromethyl)benzene, 1-bromo-3-(trifluoromethyl)benzene, 1-bromo-4-(trifluoromethyl)benzene, 1-bromo-2-isopropylbenzene, 1-bromo-3-isopropylbenzene, 1-bromo-4-isopropylbenzene, and 1-bromo-2-methoxybenzene. , 1-bromo-3-methoxybenzene, 1-bromo-4-methoxybenzene, 1-(allyloxy)-2-bromobenzene, 1-(allyloxy)-3-bromobenzene, 1-(allyloxy)-4-bromobenzene, 1-bromo-4-isopropoxybenzene, 4-bromo-2-chloro-1-(trifluoromethyl)benzene, 4-bromo-2-fluoro-1-(trifluoromethyl)benzene, 1-bromo-2-fluoro-4-(trifluoromethyl)benzene Fluoromethyl)benzene, 4-bromo-1,2-dimethoxybenzene, 1-bromo-2-fluoro-4-methoxybenzene, 4-bromo-2-fluoro-1-methoxybenzene, 5-bromo-1,3-difluoro-2-methoxybenzene, 5-bromo-1,3-difluoro-2-(trifluoromethyl)benzene, 4-bromo-2-methoxy-N-methylbenzamide, 5-bromo-2-methoxy-N-methylbenzamide, 5-bromo-1,3-Dichloro-2-(trifluoromethyl)benzene, 5-bromo-1-chloro-3-fluoro-2-(trifluoromethyl)benzene, 4-bromo-2-methoxy-N-(methylsulfonyl)benzamide, 4-bromo-N-methyl-N-((tetrahydro-2H-pyran-2-yl)oxy)benzamide, 4-bromo-2-methoxy-N-((tetrahydro-2H-pyran-2-yl)oxy)benzamide, 2-bromopyridine, 3-bromopyridine, 4-bromopyridine, 5-bromo-2-methylpyridine, 3-bromo-5-methylpyridine, 3 -Bromo-4-methylpyridine, 5-bromo-2-methoxypyridine, 3-bromo-5-methoxypyridine, 3-bromo-5-fluoropyridine, 3-bromo-5-chloropyridine, 3,5-dibromopyridine, 4-bromo-N-methylpyridin-2-amine, 4-bromo-N,N-dimethylpyridin-2-amine, 5-bromopyrimidine, iodobenzene, 1-iodo-2-methylbenzene, 1-iodo-3-methylbenzene, 1-iodo-4-methylbenzene, 1-ethyl-4-iodobenzene, 1-chloro-2-iodobenzene, 1-chloro-3-iodobenzene Iodobenzene, 1-chloro-4-iodobenzene, 1-fluoro-2-iodobenzene, 1-fluoro-3-iodobenzene, 1-fluoro-4-iodobenzene, 1-cyclopropyl-2-iodobenzene, 1-cyclopropyl-3-iodobenzene, 1-cyclopropyl-4-iodobenzene, 1-iodo-2-(trifluoromethyl)benzene, 1-iodo-3-(trifluoromethyl)benzene, 1-iodo-4-(trifluoromethyl)benzene, 1-iodo-2-isopropylbenzene, 1-iodo-3-isopropylbenzene, 1-iodo- 4-Isopropylbenzene, 1-iodo-2-methoxybenzene, 1-iodo-3-methoxybenzene, 1-iodo-4-methoxybenzene, 1-(allyloxy)-2-iodo-benzene, 1-(allyloxy)-3-iodo-benzene, 1-(allyloxy)-4-iodo-benzene, 1-iodo-4-isopropoxybenzene, 2-chloro-4-iodo-1-(trifluoromethyl)benzene, 2-fluoro-4-iodo-1-(trifluoromethyl)benzene, 2-fluoro-1-iodo-4-(trifluoromethyl)benzene, 4-iodo-1,2-Dimethoxybenzene, 2-fluoro-1-iodo-4-methoxybenzene, 2-fluoro-4-iodo-1-methoxybenzene, 1,3-difluoro-5-iodo-2-methoxybenzene, 1,3-difluoro-5-iodo-2-(trifluoromethyl)benzene, 4-iodo-2-methoxy-N-methylbenzamide, 5-iodo-2-methoxy-N-methylbenzamide, 1,3-dichloro-5-iodo-2-(trifluoromethyl)benzene, 1-chloro-3-fluoro-5-iodo-2-(trifluoromethyl)benzene, 4-iodo-2-methoxy-N-(methylsulfonyl)benzamide, 4-iodo-N-methyl- N-((tetrahydro-2H-pyran-2-yl)oxy)benzamide, 4-iodo-2-methoxy-N-((tetrahydro-2H-pyran-2-yl)oxy)benzamide, 2-iodopyridine, 3-iodopyridine, 4-iodopyridine, 5-iodo-2-methylpyridine, 3-iodo-5-methylpyridine, 3-iodo-4-methylpyridine, 5-iodo-2-methoxypyridine, 3-iodo-5-methoxypyridine, 3-fluoro-5-iodopyridine, 3-chloro-5-iodopyridine, 3-bromo-5-iodopyridine, 3,5-diiodopyridine, 4-iodo-N-methylpyridin-2-amine, 4-iodo-N,N-Dimethylpyridin-2-amine, 5-iodopyrimidine, Phenyl trifluoromethanesulfonate, o-Tolyl trifluoromethanesulfonate, m-Tolyl trifluoromethanesulfonate, p-Tolyl trifluoromethanesulfonate, 4-Ethylphenyl trifluoromethanesulfonate, 2-Chlorophenyl trifluoromethanesulfonate, 3-Chlorophenyl trifluoromethanesulfonate, 4-Chlorophenyl trifluoromethanesulfonate, 2-Fluorophenyl trifluoromethanesulfonate, 3-Fluorophenyl trifluoromethanesulfonate, 4-Fluorophenyl trifluoromethanesulfonate, 2-Cyclopropylphenyl trifluoromethanesulfonate, 3-Cyclopropylphenyl trifluoromethanesulfonate, 4-Cyclopropylphenyl trifluoromethanesulfonate, 2-(Trifluoromethyl)phenyl trifluoromethanesulfonate, 3-(Trifluoromethyl)phenyl trifluoromethanesulfonate, Trifluoromethanesulfonic acid 4-(Trifluoromethyl)phenyl, 2-Isopropylphenyl Trifluoromethanesulfonate, 3-Isopropylphenyl Trifluoromethanesulfonate, 4-Isopropylphenyl Trifluoromethanesulfonate, 2-Methoxyphenyl Trifluoromethanesulfonate, 3-Methoxyphenyl Trifluoromethanesulfonate, 4-Methoxyphenyl Trifluoromethanesulfonate, 2-(Allyloxy)phenyl Trifluoromethanesulfonate, 3-(Allyloxy)phenyl Trifluoromethanesulfonate, 4-(Allyloxy)phenyl Trifluoromethanesulfonate, 4-Isopropoxyphenyl Trifluoromethanesulfonate, 3-Chloro-4-(trifluoromethyl)phenyl Trifluoromethanesulfonate, 3-Fluoro-4-(trifluoromethyl)phenyl Trifluoromethanesulfonate, 2-Fluoro-4-(trifluoromethyl)phenyl Trifluoromethanesulfonate, 3,4-Dimethoxyphenyl Trifluoromethanesulfonate, Trifluoromethanesulfonic Acid 2-Fluoro-4-methoxyphenyl, trifluoromethanesulfonic acid 3-Fluoro-4-methoxyphenyl, trifluoromethanesulfonic acid 3,5-Difluoro-4-methoxyphenyl, 3,5-difluoro-4-(trifluoromethyl)phenyl trifluoromethanesulfonic acid, 3-methoxy-4-(methylcarbamoyl)phenyl trifluoromethanesulfonic acid, 4-methoxy-3-(methylcarbamoyl)phenyl trifluoromethanesulfonic acid, 3,5-dichloro-4-(trifluoromethyl)phenyl trifluoromethanesulfonic acid, 3-chloro-5-fluoro-4-(trifluoromethyl)phenyl trifluoromethanesulfonic acid, 3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl trifluoromethanesulfonic acid, 4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl trifluoromethanesulfonic acid, 3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl trifluoromethanesulfonic acid, trifluoromethanesulfonic acid Examples of the fluorine-containing alkyl ester include pyridin-2-yl, pyridin-3-yl trifluoromethanesulfonate, pyridin-4-yl trifluoromethanesulfonate, 6-methylpyridin-3-yl trifluoromethanesulfonate, 5-methylpyridin-3-yl trifluoromethanesulfonate, 4-methylpyridin-3-yl trifluoromethanesulfonate, 6-methoxypyridin-3-yl trifluoromethanesulfonate, 5-methoxypyridin-3-yl trifluoromethanesulfonate, 5-fluoropyridin-3-yl trifluoromethanesulfonate, 5-chloropyridin-3-yl trifluoromethanesulfonate, 5-bromopyridin-3-yl trifluoromethanesulfonate, 2-(methylamino)pyridin-4-yl trifluoromethanesulfonate, 2-(dimethylamino)pyridin-4-yl trifluoromethanesulfonate, and pyrimidin-5-yl trifluoromethanesulfonate.

[0103] In this step, R6-X can be used in an equivalent or excess amount relative to the compound represented by formula II. Specifically, for example, 1 to 10 equivalents, preferably 1 to 5 equivalents, of R6-X can be used relative to the compound represented by formula II.

[0104] The catalyst used in this step is (a) Is metallic? (b) formed by mixing a metal with a compound that can be its ligand; (c) a complex of a metal and its ligand; or (d) It is formed by mixing a compound that can act as a ligand for the metal with a complex of the metal and its ligand.

[0105] In each of the above cases (a) to (d), the metal used may be nickel, chromium, iron, copper, palladium, or a salt thereof, or a solvate of nickel, chromium, iron, copper, palladium, or a salt thereof. Specific examples of such metals include nickel, bis(1,5-cyclooctadiene)nickel(0), NiBr, NiI, NiCl, NiF, Ni(OAc), Ni(acac), Ni(OTf), NiCO, Ni(NO), NiSO, (NH)Ni(SO), allyl(cyclopentadienyl)nickel(II), bis(cyclopentadienyl)nickel, bis(dicyclooctadienyl)nickel, or solvates thereof with water, methoxyethyl ether, diglyme, or ethylene glycol dimethyl ether.

[0106] When the catalyst is formed by mixing a metal and a compound that can serve as a ligand for the metal, the compound that can serve as a ligand for the metal is represented by, for example, formulas B to G below. Formula B: [ka] Formula C: [ka] Formula D: [ka] Formula E: [ka] Formula F: [ka] Formula G: [ka]

[0107] Formula B: [ka] In R BX , and R BY are independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, heterocyclyl, or C6-C 10 Specific examples of the compound represented by formula B include 2,2'-bipyridine, 6-methyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 4,4'-diphenyl-2,2'-bipyridine, 6,6'-bis(4,5-dihydro) oxazol-2-yl)-2,2'-bipyridine, 6,6'-bis(4-phenyl-4,5-dihydrooxazol-2-yl)-2,2'-bipyridine, 6,6'-bis(4-isopropyl-4,5-dihydrooxazol-2-yl)-2,2'-bipyridine, 6,6'-bis(4-(tert-butyl)-4,5-dihydrooxazol-2-yl)-2,2'-bipyridine, and the like.

[0108] Formula C: [ka] In R CX , and R CY are independently hydrogen, C1-C4 alkyl, C6-C 10aryl, or heteroaryl. Specific examples of the compound represented by formula C include 1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 5,6-dimethyl-1,10-phenanthroline, and 4,7-dimethoxy-1,10-phenanthroline.

[0109] Formula D: [ka] In R DX , and R DY are independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C6-C 10 aryl. Specific examples of the compound represented by formula D include 2-(pyridin-2-yl)-4,5-dihydrooxazole, 4-isopropyl-2-(pyridin-2-yl)-4,5-dihydrooxazole, 4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole, 4-isopropyl-2-(6-methylpyridin-2-yl)-4,5-dihydrooxazole, 4-(tert-butyl)-2-(6-methylpyridin-2-yl)-4,5-dihydrooxazole, 4-(tert-butyl)-2-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydrooxazole, 4-(tert-butyl)-2-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydrooxazole, and 4-phenyl-2-(pyridin-2-yl)-4,5-dihydrooxazole.

[0110] Formula E: [ka] In R EX , and R EY are independently hydrogen, C1-C4 alkyl, C6-C 10 Aryl C1-C6 alkyl, or C6-C 10Specific examples of the compound represented by formula E include 4,4',5,5'-tetrahydro-2,2'-bioxazole, 4,4'-dimethyl-4,4',5,5'-tetrahydro-2,2'-bioxazole, 4,4'-diisopropyl-4,4',5,5'-tetrahydro-2,2'-bioxazole, 4,4'-di-tert-butyl-4,4',5,5'-tetrahydro-2,2'-bioxazole, 4,4'-diphenyl-4,4',5,5'-tetrahydro-2,2'-bioxazole, and 4,4'-dibenzyl-4,4',5,5'-tetrahydro-2,2'-bioxazole.

[0111] Formula F: [ka] In R FX , and R FY are independently hydrogen, C1-C4 alkyl, or C6-C 10 Specific examples of the compound represented by formula F include 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis(4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis(4-(tert-butyl)-4,5-dihydrooxazol-2-yl)pyridine, and 2,6-bis(4-phenyl-2-oxazolin-2-yl)pyridine.

[0112] Formula G: [ka] In R GX , and R GY are independently hydrogen, C1-C4 alkyl, C6-C 10 Aryl C1-C6 alkyl, or C6-C 10Specific examples of the compound represented by formula G include 2,2'-(propane-2,2-diyl)bis(4,5-dihydrooxazole), 2,2'-(propane-2,2-diyl)bis(4-isopropyl-4,5-dihydrooxazole), 2,2'-(propane-2,2-diyl)bis(4-(tert-butyl)-4,5-dihydrooxazole), 2,2'-(propane-2,2-diyl)bis(4-benzyl-4,5-dihydrooxazole), and 2,2'-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole).

[0113] When the catalyst is a complex of a metal and its ligand, specific examples of the complex of a metal and its ligand include tetrakis(triphenylphosphine)nickel(0), bis(triphenylphosphine)nickel(II) dichloride, bis(tricyclohexylphosphine)nickel(II) dichloride, dibromobis(triphenylphosphine)nickel(II), bis[(2-dimethylamino)phenyl]aminenickel(II) chloride, cis-[2,2'-bis(diphenylphosphine)-1,1'-binaphthyl](2-methylphenyl)nickel(II) chloride, and [1,2-bis(diphenylphosphino)ethane]dichloronickel(II).

[0114] When the catalyst is formed by mixing a complex of a metal and its ligand with a compound that can serve as a ligand for the metal, specific examples of the complex of a metal and its ligand include tetrakis(triphenylphosphine)nickel(0), bis(triphenylphosphine)nickel(II) dichloride, cis-[2,2'-bis(diphenylphosphino)-1,1'-binaphthyl](2-methylphenyl)nickel(II) chloride, and [1,2-bis(diphenylphosphino)ethane]dichloronickel(II). Specific examples of the compound that can serve as a ligand include 2,2'-bipyridine, 6-methyl-2,2'-bipyridine, 4,4'-dimethyl-2,2' -bipyridine, 5,5'-dimethyl-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 4,4'-diphenyl-2,2'-bipyridine, 6,6'-bis(4,5-dihydrooxazol-2-yl)-2,2'-bipyridine, 6,6'-bis(4-phenyl-4,5-dihydrooxazol-2-yl)-2,2'-bipyridine, 6,6'-bis(4-isopropyl-4,5-dihydrooxazol-2-yl)-2,2'-bipyridine, 6,6'-bis(4-(tert-butyl)-4,5-dihydrooxazol-2-yl)-2,2'-bipyridine, and the like.

[0115] The reducing agent used in this step can be a substance that has the effect of reducing the positive charge of the catalyst used in this step. Examples of such reducing agents include metals that have a higher ionization tendency than the metals contained in the catalyst. Specific examples of such metals include zinc, manganese, iron, and magnesium. Of these, zinc and manganese are preferred, and zinc is particularly preferred.

[0116] In one embodiment, when a catalyst containing nickel is used, a metal having a higher ionization tendency than nickel, such as zinc, iron, or magnesium, can be used as the reducing agent.

[0117] The reducing agent can be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, more preferably 1 to 3 molar equivalents, relative to the compound represented by formula II.

[0118] The additive used in this step can be a substance that can efficiently convert the starting material into the target compound, for example, by shortening the time required to convert the compound represented by Formula II, the starting material of this step, into the target compound represented by Formula I, compared to when the additive is not used. Specific examples of such additives include silyl compounds and 1,2-dibromoethane. Specific examples of silyl compounds include compounds represented by Formula A: [ka] Examples of the compound include compounds represented by the following formula: R in the formula AX , and R AY is independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, and phenyl. AX , and R AY More specific examples of the alkyl group include methyl, ethyl, isopropyl, t-butyl, methoxy, ethoxy, isopropoxy, and phenyl. L is selected from the group consisting of -Cl, -Br, -I, and -OTf.

[0119] More specific examples of the compound represented by formula A include TMSCl, TMSBr, TMSI, TMSOTf, TBDMSCl, TESCl, TIPSCl, TBDPSCl, and chlorotriethoxysilane, and among these, TMSCl, TMSBr, TESCl, and TIPSCl are preferred.

[0120] The additive can be used in an amount of 1 mol % to 500 mol %, preferably 10 mol % to 500 mol %, more preferably 25 mol % to 500 mol %, based on the compound represented by formula II.

[0121] By adding an additive in this step, the conversion rate from the compound represented by formula II to the compound represented by formula I can be significantly improved compared to when no additive is added. For example, the reaction can proceed efficiently with a high conversion rate regardless of the stirring state, such as stirring using a stirring blade or a stirring bar.

[0122] The solvent used in this step may be an aprotic solvent such as an amide solvent or a urea solvent, etc. Specific examples of such solvents include DMF, DMA, NMP, DMI, and DMPU.

[0123] The reaction in this step can be carried out at a temperature from -20°C to near the boiling point of the solvent, preferably at a reaction temperature of -10 to 110°C, -10 to 90°C, more preferably -10 to 70°C.

[0124] The reaction in this step can be carried out for a reaction time of 10 minutes to 1 week, preferably 10 minutes to 6 hours, more preferably 0.5 to 4 hours.

[0125] In this step, the order of mixing the compound represented by formula II, its salt, or a solvate thereof, the reducing agent, the additive, and R6-X is not particularly limited. For example, it is preferable to (a) mix the compound represented by formula II, its salt, or a solvate thereof, the reducing agent, and R6-X in the presence of a solvent and a catalyst, and then mix the additive; (b) mix the reducing agent and the additive in the presence of a solvent and a catalyst, and then mix the compound represented by formula II, its salt, or a solvate thereof, and R6-X; or (c) mix the reducing agent in the presence of a solvent and a catalyst, and then mix the compound represented by formula II, its salt, or a solvate thereof, R6-X, and the additive. More specific embodiments of (a) above include, for example, adding a solution of a catalyst dissolved in a solvent dropwise to a solution of a compound represented by formula II, a salt thereof, or a solvate thereof, a reducing agent, and R6-X dissolved in a solvent, followed by adding the additive; and also including adding a solution of a catalyst dissolved in a solvent dropwise to a solution of a compound represented by formula II, a salt thereof, or a solvate thereof, and R6-X dissolved in a solvent, followed by adding the reducing agent, followed by adding the additive. A more specific embodiment of (b) above is, for example, a method in which a reducing agent and an additive are added to a solution in which a catalyst is dissolved in a solvent, and then a solution in which a compound represented by formula II, a salt thereof, or a solvate thereof and R6-X are dissolved in a solvent is added dropwise. A more specific embodiment of (c) above is, for example, adding a reducing agent to a solution in which a catalyst is dissolved in a solvent, and then adding a solution in which a compound represented by formula II, a salt thereof, or a solvate thereof, R6-X, and an additive are dissolved in a solvent.

[0126] When an optically active compound represented by formula II is used in this step, the configuration is maintained and an optically active compound represented by formula I can be obtained.

[0127] (Method of producing the compound represented by formula II) The compound of formula II, which serves as the starting material for the above process, can be synthesized using various methods known in the art.

[0128] In one embodiment, when R2 is hydrogen, the compound of the present invention represented by formula II can be synthesized, for example, according to the following scheme, in which R1, R3, R5, R7, and n have the same meanings as R1, R3, R5, R7, and n in formula II. [ka] This step can be carried out by mixing any alcohol (R5-OH) and a carboxylic acid with a dehydration condensation agent such as a carbodiimide compound and condensing them, for example, by the method of Albert et al. (Synthesis, 1987, 7, 635-637).

[0129] In another embodiment, when R2 is hydrogen, the compound represented by formula II of the present invention can be synthesized, for example, according to the following scheme: In the scheme, R1, R3, R5, R7, and n have the same meanings as R1, R3, R5, R7, and n in formula II, respectively, and R 10 and R 11 are independently hydrogen, C1-C4 alkyl, or C6-C 10 aryl or R 10 and R 11 together form oxo (=O). [ka] The process of removing these protecting groups can be carried out by the method described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons 2014)".

[0130] In another embodiment, the compound of the present invention represented by formula II, in which R2 is C1-C6 alkyl, can be synthesized, for example, according to the following scheme: In the scheme, R1, R3, R5, R7, and n are the same as R1, R3, R5, R7, and n in formula II, respectively, R4 is a protecting group for a carboxyl group, and "Alk" is C1-C6 alkyl. [ka] Among these steps, the protecting group removal step can be carried out by the method described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons 2014)." Furthermore, the N-alkylation step can be carried out by reacting an alkylating agent under basic conditions to produce a compound in which an alkyl group has been introduced to the nitrogen atom. The R5 introduction step can be carried out by the method of Albert et al. (Synthesis, 1987, 7, 635-637), for example, by mixing an arbitrary alcohol (R5-OH) and a carboxylic acid with a dehydration condensation agent such as a carbodiimide compound and condensing them.

[0131] In another embodiment, the compound of the present invention represented by formula II, in which R2 is C1-C6 alkyl, can be synthesized, for example, according to the following scheme: In the scheme, R1, R3, R5, R7, and n are the same as R1, R3, R5, R7, and n in formula II, respectively, R4 is a protecting group for a carboxyl group, "Alk" is C1-C6 alkyl, and R 12 is hydrogen, or C1-C5 alkyl. [ka] Among these steps, the protecting group removal step can be carried out by the method described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons 2014)." The N-alkylation step accompanied by deprotection can also be carried out by the method of Freidinger et al. (J. Org. Chem., 1983, 48, 77-81) or the method of Buba et al. (Eur. J. Org. Chem., 2013, 4509-4513). The R5 introduction step can be carried out by the method of Albert et al. (Synthesis, 1987, 7, 635-637), for example, by mixing an optional alcohol (R5-OH) and a carboxylic acid with a dehydration condensation agent such as a carbodiimide compound and condensing them.

[0132] In another embodiment, when R2 and R3 combine to form -(CR8R9)-, the compound of formula IIA of the present invention can be synthesized according to the following scheme: In the scheme, R1, R5, R7, R8, R9, and n are the same as R1, R5, R7, R8, R9, and n in formula IIA, respectively, and R4 is a protecting group for the carboxyl group. [ka] Of these reactions, the protecting group introduction step can be carried out by a method such as that of Freidinger et al. (J. Org. Chem., 1983, 48, 77-81), which involves dehydration condensation with an aldehyde compound in the presence of an acid catalyst, or by the method described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons, 2014)." The deprotection step can be carried out by the method described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons, 2014)." The side chain introduction step can be carried out by the method described in Long et al. (J. Med. Chem., 2008, 51, 6371-6380). The step of introducing R5 can be carried out by, for example, the method of Albert et al. (Synthesis, 1987, 7, 635-637), by mixing any alcohol (R5-OH) and a carboxylic acid with a dehydration condensation agent such as a carbodiimide compound and condensing them.

[0133] In another embodiment, when R2 and R3 combine to form -(CR8R9)-, the compound of formula IIA of the present invention can be synthesized according to the following scheme: In the following scheme, R1, R5, R7, R8, R9, and n have the same meanings as R1, R5, R7, R8, R9, and n in formula IIA, respectively, and R4 is a protecting group for a carboxyl group. [ka] Of these reactions, the protecting group introduction step can be carried out by dehydration condensation with an aldehyde compound in the presence of an acid catalyst, such as by the method of Freidinger et al. (J. Org. Chem., 1983, 48, 77-81), or by the method described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons, 2014)." The deprotection step can be carried out by the method described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons, 2014)." The introduction step of R5 can be carried out by condensing an arbitrary alcohol with a carboxylic acid, such as by the method of Albert et al. (Synthesis, 1987, 7, 635-637).

[0134] Modification of Compounds of Formula I According to the present invention, various amino acid analogs, salts thereof, or solvates thereof can be further prepared starting from the compound represented by formula I, a salt thereof, or a solvate thereof produced according to the above-described method.

[0135] In one embodiment, when R3 in the compound represented by formula I is a protecting group for a carboxyl group, the compound represented by formula I, a salt thereof, or a solvate thereof can be used as a starting material and the protecting group removed to produce a compound represented by formula III, a salt thereof, or a solvate thereof. [ka] The deprotection step can be carried out by the method described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons 2014)".

[0136] In one embodiment, when R1 of a compound represented by formula I, a salt thereof, or a solvate thereof is a protecting group for an amino group and R3 is a protecting group for a carboxyl group, these protecting groups can be simultaneously removed to produce a compound represented by formula IV, and then a protecting group R1' can be introduced into the amino group to produce a compound represented by formula V, as shown in the following scheme. [ka] These steps of removing the protecting groups can be carried out by the method described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons 2014)".

[0137] In one embodiment, when R2 and R3 of a compound represented by formula I are taken together to form -(CR8R9)- and the compound represented by formula I is represented by formula IA, the compound represented by formula IA, a salt thereof, or a solvate thereof can be used as a starting material to open the oxazolidinone ring by a deprotection reaction, thereby producing a compound represented by formula VI, a salt thereof, or a solvate thereof. [ka] The above deprotection step can be carried out by the method described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons 2014)".

[0138] In one embodiment, the present invention can produce an N-alkylamino acid using the compound represented by formula IA as a starting material, as shown in the following scheme. [ka] Among these steps, the step of removing the protecting group can be carried out by the method described in "Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons 2014)." Also, a compound in which an alkyl group has been introduced to the nitrogen atom can be produced by reacting an alkylating agent under basic conditions, for example, by the method of Seebach et al. (Helv. Chim. Acta, 1987, 70, 237-261).

[0139] The present invention also relates to amino acid derivatives represented by the above formula I, and amino acid derivatives of each of the above formulae obtained by modifying the amino acid derivatives.

[0140] In one embodiment, such amino acid derivatives are preferably compounds of formula (I): [ka] In the above, the respective groups may be the following combinations. (a) R1 is hydrogen, Boc, Fmoc, Cbz, Alloc, or Teoc, R2 is hydrogen or methyl, R3 is hydrogen, methyl, t-butyl, or benzyl, R6 is 3-chloro-4-(trifluoromethyl)phenyl, R7 is hydrogen, and n is 1 or 2. (b) R1 is hydrogen, Boc, Fmoc, Cbz, Alloc, or Teoc, R2 is ethyl, R3 is hydrogen, methyl, t-butyl, or benzyl, R6 is 4-methylphenyl, R7 is hydrogen, and n is 1. (c) R1 is hydrogen, Boc, Fmoc, Cbz, Alloc, or Teoc, R2 is hydrogen or methyl, R3 is hydrogen, methyl, or t-butyl, R6 is 3,5-difluoro-4-(trifluoromethyl)phenyl, R7 is hydrogen, and n is 1 or 2. (d) R1 is hydrogen, Boc, Fmoc, Cbz, Alloc, or Teoc, R2 is hydrogen or methyl, R3 is hydrogen, methyl, or t-butyl, R6 is 3-methoxy-4-(methylcarbamoyl)phenyl, R7 is hydrogen, and n is 1 or 2. (e) R1 is hydrogen, Boc, Fmoc, Cbz, Alloc, or Teoc, R2 is hydrogen or methyl, R3 is hydrogen, methyl, or t-butyl, R6 is 4-methoxy-3-(methylcarbamoyl)phenyl, R7 is hydrogen, and n is 1 or 2. (f) R1 is hydrogen, Boc, Fmoc, Cbz, Alloc, or Teoc, R2 is hydrogen or methyl, R3 is hydrogen, methyl, or t-butyl, R6 is 3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl, R7 is hydrogen, and n is 1 or 2. (g) R1 is hydrogen, Boc, Fmoc, Cbz, Alloc, or Teoc, R2 is hydrogen or methyl, R3 is hydrogen, methyl, or t-butyl, R6 is 4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl, R7 is hydrogen, and n is 1 or 2. (h) R1 is hydrogen, Boc, Fmoc, Cbz, Alloc, or Teoc, R2 is hydrogen or methyl, R3 is hydrogen, methyl, or t-butyl, R6 is 3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl, R7 is hydrogen, and n is 1 or 2. (i) R1 is hydrogen, Boc, Fmoc, Cbz, Alloc, or Teoc, R2 is hydrogen or methyl, R3 is hydrogen, methyl, or t-butyl, R6 is 6-methoxypyridin-3-yl, R7 is hydrogen, and n is 1 or 2.

[0141] More preferably, the amino acid derivative of the present invention is an amino acid derivative represented by formula (1). [ka] During the ceremony, R1 is hydrogen or an amino-protecting group selected from the group consisting of Boc, Fmoc, Cbz, Alloc, and Teoc; R2 is hydrogen or methyl; R3 is hydrogen or a carboxyl-protecting group selected from the group consisting of methyl, t-butyl, and benzyl; R7 is hydrogen; n is 1 or 2, X1, X2, and X3 are independently hydrogen or halogen; however, When X1 is halogen, X2 and X3 are hydrogen; When X1 is hydrogen, X2 and X3 are both halogen, or one of X2 and X3 is halogen.

[0142] In formula (1), when X1 is a halogen, the halogen is preferably F or Cl.

[0143] In formula (1), when both X2 and X3 are halogen, the types of halogen may be the same or different. X2 and X3 are preferably X2=F and X3=F, X2=F and X3=Cl, or X2=Cl and X3=Cl.

[0144] In formula (1), when one of X2 and X3 is a halogen, the halogen is preferably F or Cl.

[0145] Specific examples of the amino acid derivative of formula (1) include the following compounds, salts thereof, or solvates thereof: (C-001) 2-(((benzyloxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (C-002) methyl 2-(((benzyloxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-003) tert-butyl 2-(((benzyloxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-004) benzyl 2-(((benzyloxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-005) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (C-006) methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-007) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate (C-008) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-009) 2-((tert-butoxycarbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (C-010) methyl 2-((tert-butoxycarbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-011) tert-butyl 2-((tert-butoxycarbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-012) benzyl 2-((tert-butoxycarbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-013) 2-(((allyloxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (C-014) methyl 2-(((allyloxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-015) tert-butyl 2-(((allyloxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-016) benzyl 2-(((allyloxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-017) 4-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)butanoic acid, (C-018) methyl 4-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)butanoate, (C-019) tert-butyl 4-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)butanoate (C-020) benzyl 4-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)butanoate, (C-021) 2-(((benzyloxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (C-022) methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-023) tert-butyl 2-(((benzyloxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-024) benzyl 2-(((benzyloxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-025) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (C-026) methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-027) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-028) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-029) 2-((tert-butoxycarbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (C-030) methyl 2-((tert-butoxycarbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-031) tert-butyl 2-((tert-butoxycarbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-032) benzyl 2-((tert-butoxycarbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-033) 2-(((allyloxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (C-034) methyl 2-(((allyloxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-035) tert-butyl 2-(((allyloxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-036) benzyl 2-(((allyloxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-037) 4-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)butanoic acid, (C-038) methyl 4-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)butanoate, (C-039) tert-butyl 4-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)butanoate (C-040) benzyl 4-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)butanoate, (C-041) 2-(((benzyloxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (C-042) methyl 2-(((benzyloxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-043) tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-044) benzyl 2-(((benzyloxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-045) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (C-046) methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-047) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-048) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-049) 2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (C-050) methyl 2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-051) tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-052) benzyl 2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-053) 2-(((allyloxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (C-054) methyl 2-(((allyloxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-055) tert-butyl 2-(((allyloxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-056) benzyl 2-(((allyloxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-057) 3-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propanoic acid, (C-058) methyl 3-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propanoate, (C-059) tert-butyl 3-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propanoate, (C-060) benzyl 3-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propanoate, (C-061) 2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (C-062) methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-063) tert-butyl 2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-064) benzyl 2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-065) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (C-066) methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-067) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-068) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-069) 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (C-070) methyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-071) tert-butyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-072) benzyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-073) 2-(((allyloxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (C-074) methyl 2-(((allyloxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-075) tert-butyl 2-(((allyloxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-076) benzyl 2-(((allyloxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-077) 3-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)propanoic acid, (C-078) methyl 3-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)propanoate, (C-079) tert-butyl 3-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)propanoate, (C-080) Benzyl 3-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)propanoate.

[0146] In another embodiment, specific examples of the amino acid derivatives of the present invention include the compounds shown in the table below, salts thereof, or solvates thereof. In each table, R1, R2, R3, R6, R7, and n respectively represent R1, R2, R3, R6, R7, and n in the following formulas, and * represents a bonding point. [ka]

[0147] [Table 1] TIFF2025138728000061.tif224161 TIFF2025138728000062.tif224161 TIFF2025138728000063.tif224162

[0148]

Table 2

[0149]

Table 3

[0150]

Table 4

[0151]

Table 5

[0152]

Table 6

[0153]

Table 7

[0154]

Table 8

[0155]

Table 9

[0156]

Table 10

[0157]

Table 11

[0158] [Table 12] TIFF2025138728000125.tif224161 TIFF2025138728000126.tif226161 TIFF2025138728000127.tif223161 TIFF2025138728000128.tif224161 TIFF2025138728000129.tif90161

[0159] [Table 13] TIFF2025138728000131.tif225162 TIFF2025138728000132.tif226162 TIFF2025138728000133.tif224161 TIFF2025138728000134.tif224162 TIFF2025138728000135.tif90161

[0160] [Table 14] TIFF2025138728000137.tif123159

[0161] The target compounds obtained through the above-mentioned reaction steps can be isolated and purified by applying conventional chemical procedures such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.

[0162] Furthermore, the compound of the present invention, a salt thereof, or a solvate thereof includes all stereoisomers of the target compound obtained through each of the above-mentioned reaction steps (e.g., enantiomers, diastereomers (including cis- and trans-geometric isomers)), racemates of the isomers, and other mixtures thereof. For example, the compound of the present invention may have one or more asymmetric centers, and the present invention includes racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.

[0163] When the compound according to the present invention is obtained as a free form, the compound can be converted into a salt which the compound may form, or a hydrate or solvate thereof, in a conventional manner.

[0164] Furthermore, when the compound according to the present invention is obtained as a salt, hydrate, or solvate of the compound, the compound can be converted into its free form by a conventional method.

[0165] All prior art documents cited in this specification are hereby incorporated by reference. [Example]

[0166] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples.

[0167] The solvents used in the practice of the present invention, such as DMF, DMA, NMP, DMI, or DMPU, were obtained from commercial suppliers without further purification. In reactions in which water was not added as a solvent, dehydrated, super-dehydrated, or anhydrous solvents were obtained from commercial suppliers without further purification.

[0168] Reagents used in carrying out the present invention, such as silyl compounds, additives exemplified by 1,2-dibromoethane, metals, compounds that can serve as ligands, metal-ligand complexes, reducing agents, reagents used in the step of introducing a protecting group, and reagents used in the step of deprotection, were obtained from commercial suppliers and used without purification, unless otherwise specified.

[0169] The starting materials for aromatic amino acid derivatives, such as phenylalanine derivatives and homophenylalanine derivatives, used in the practice of the present invention were obtained from commercial suppliers without purification unless otherwise specified, and were also prepared by known methods as necessary.

[0170] 1 H-NMR spectra were measured using an AVANCE III HD 400 BBFO-SMART probe (Bruker). The chemical shift of Me4Si, used as an internal standard, was set at 0 ppm, and the deuterium lock signal from the sample solvent was used as the reference. Chemical shifts of the analyte signals were expressed in ppm. Signal splitting was abbreviated as follows: s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, and m = multiplet. Signal splitting width was expressed as a J value (Hz). Signal integration was calculated based on the ratio of the signal area intensities of each signal.

[0171] [High-performance liquid chromatography conditions 1] Equipment: Shimadzu Corporation Column: Ascentis Express RP-Amide (3.0mm I.D. x 50mm) Mobile phase: water containing 0.05% trifluoroacetic acid (A) and acetonitrile containing 0.05% trifluoroacetic acid (B) Elution method: Stepwise solvent gradient elution from 5% B to 95% B (5.0 min), held at 95% B (2.0 min) Flow rate: 0.7mL / min Column temperature: 30℃

[0172] [High-performance liquid chromatography conditions 2] Instrument: Waters Acquity UPLC / SQD Column: Ascentis Express C18 (2.1mm I.D. x 50mm) Mobile phase: water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) Elution method: Stepwise solvent gradient elution from 5% B to 100% B (5.0 min), held at 100% B (2.0 min) Flow rate: 1.0mL / min

[0173] [High-performance liquid chromatography conditions 3] Instrument: Waters Acquity UPLC / SQD Column: Ascentis Express C18 (2.1mm I.D. x 50mm) Mobile phase: 10 mM ammonium acetate aqueous solution (A) and 10 mM ammonium acetate acetonitrile solution (B) Elution method: Stepwise solvent gradient elution from 5% B to 100% B (1.0 min), hold at 100% B (0.4 min) Flow rate: 1.0mL / min

[0174] [High-performance liquid chromatography conditions 4] Instrument: Waters Acquity UPLC / SQD Column: Ascentis Express C18 (2.1mm I.D. x 50mm) Mobile phase: water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) Elution method: Stepwise solvent gradient elution from 5% B to 100% B (1.0 min), hold at 100% B (0.4 min) Flow rate: 1.0mL / min

[0175] [High-performance liquid chromatography conditions 5] Equipment: Shimadzu Corporation Column: Ascentis Express C18 (3.0mm I.D. x 50mm) Mobile phase: water containing 0.05% trifluoroacetic acid (A) and acetonitrile containing 0.05% trifluoroacetic acid (B) Elution method: Stepwise solvent gradient elution from 5% B to 95% B (2.0 min), hold at 95% B (0.7 min) Flow rate: 1.0mL / min

[0176] [High-performance liquid chromatography conditions 6] Equipment: Shimadzu Corporation Column: Ascentis Express C18 (3.0mm I.D. x 50mm) Mobile phase: water containing 0.05% trifluoroacetic acid (A) and acetonitrile containing 0.05% trifluoroacetic acid (B) Elution method: Stepwise solvent gradient elution from 5% B to 95% B (1.1 min), held at 95% B (0.5 min) Flow rate: 1.0mL / min

[0177] Reference Example 1: When TMSCl is not used as an additive and stirring is performed with a stirring impeller Preparation of benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate [ka] Nickel bromide trihydrate (0.12 g, 0.44 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.12 g, 0.44 mmol) were dissolved in DMA (15 mL), purged with nitrogen, and stirred for 10 minutes to prepare a catalyst solution. A flask equipped with a stirrer was charged with zinc dust (2.0 g, 31 mmol), 1-benzyl 5-(1,3-dioxoisoindolin-2-yl)(tert-butoxycarbonyl)-L-glutamate (3.0 g, 6.2 mmol), and DMA (15 mL). 4-Bromo-2-chloro-1-(trifluoromethyl)benzene (4.8 g, 19 mmol) was added, and the atmosphere was purged with nitrogen. The catalyst solution was added dropwise to the reaction mixture under a nitrogen atmosphere. The solution was stirred at 25°C for 2 hours, and the reaction mixture was analyzed by HPLC. The UV intensity ratio of the raw material to the target product was 92.5:7.5 (detection wavelength: 210 nm), confirming that more than 90% of the raw material remained. Benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate: Retention time: raw material 2.7 minutes, target product 3.4 minutes (high performance liquid chromatography condition 2) ESI (LC / MS positive mode m / z 472 (M+H) + )

[0178] Example 1: When 5 mol% TMSCl was used as an additive and stirred with a stirring blade Preparation of benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate [ka] Nickel bromide trihydrate (0.20 g, 0.73 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.20 g, 0.73 mmol) were dissolved in DMA (25 mL), purged with nitrogen, and stirred for 10 minutes to prepare a catalyst solution. A flask equipped with a stirrer was charged with zinc dust (3.4 g, 52 mmol), 1-benzyl 5-(1,3-dioxoisoindolin-2-yl)(tert-butoxycarbonyl)-L-glutamate (5.0 g, 10 mmol), and DMA (25 mL). 4-Bromo-2-chloro-1-(trifluoromethyl)benzene (8.1 g, 31 mmol) was added, and the atmosphere was purged with nitrogen. The catalyst solution was added dropwise to the reaction mixture under a nitrogen atmosphere, followed by the addition of TMSCl (56 mg, 0.52 mmol). The solution was stirred at 25°C for 2 hours, and the reaction mixture was analyzed by HPLC. The UV intensity ratio of the raw material to the target product was 67:33 (detection wavelength: 210 nm), and although the raw material remained, a significant increase in the production of the target product was confirmed compared to when TMSCl was not used (Reference Example 1). Benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate: Retention time: raw material 4.3 minutes, target product 5.0 minutes (high performance liquid chromatography condition 1) ESI (LC / MS positive mode m / z 472 (M+H) + )

[0179] Example 2: When 50 mol% TMSCl was used as an additive and stirred with a stirring blade Preparation of benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate [ka] A catalyst solution was prepared by dissolving nickel bromide trihydrate (39 mg, 0.15 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (40 mg, 0.15 mmol) in DMA (5.0 mL), purging with nitrogen, and stirring for 10 minutes. A flask equipped with a stirrer was charged with zinc dust (0.68 g, 10 mmol), 1-benzyl 5-(1,3-dioxoisoindolin-2-yl)(tert-butoxycarbonyl)-L-glutamate (1.0 g, 2.1 mmol), and DMA (5.0 mL). 4-Bromo-2-chloro-1-(trifluoromethyl)benzene (1.6 g, 6.2 mmol) was added, and the mixture was then purged with nitrogen. The catalyst solution was added dropwise to the reaction mixture under a nitrogen atmosphere, followed by the addition of TMSCl (0.11 g, 1.0 mmol). The solution was stirred at 25°C for 2 hours, and the reaction mixture was analyzed by HPLC. The UV intensity ratio of the raw material to the target product was 0:100 (detection wavelength: 210 nm), confirming that the raw material had completely disappeared and the target product was the main product. The reaction mixture was purified by chromatography to obtain (S)-2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate (0.79 g, 80% yield). Benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate: Retention time: raw material 4.0 minutes, target product 4.7 minutes (high performance liquid chromatography condition 1) 1H-NMR (DMSO-D6) δ: 7.76 (1H, d, J = 8.1Hz), 7.55 (1H, s), 7.44 (0.8H, d, J = 7.8 Hz), 7.36-7.34 (6H, m), 7.10 (0.2H,m), 5.15 (1H, d, J = 12.5 Hz), 5.08 (1H, d, J = 12.5 Hz), 3.98-3.96 (0.8H, m),3.87 (0.2H, br s), 2.71 (2H, t, J = 7.9 Hz), 2.01-1.87 (2H, m), 1.39 (8H, s),1.27 (1H, s)

[0180] Example 3: When 52 mol% TMSCl was used as an additive and stirred with a stirring blade Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoic acid [ka] Nickel bromide trihydrate (0.20 g, 0.73 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.20 g, 0.73 mmol) were dissolved in DMA (25 mL), purged with nitrogen, and stirred for 10 minutes to prepare a catalyst solution. A flask equipped with a stirrer was charged with zinc dust (3.4 g, 52 mmol), 1-benzyl 5-(1,3-dioxoisoindolin-2-yl)(tert-butoxycarbonyl)-L-glutamate (5.0 g, 10 mmol), and DMA (25 mL). 4-Bromo-2-chloro-1-(trifluoromethyl)benzene (8.1 g, 31 mmol) was added, and the atmosphere was purged with nitrogen. The catalyst solution was added dropwise to the reaction mixture under a nitrogen atmosphere, followed by the addition of TMSCl (0.56 g, 5.2 mmol). The solution was stirred at 25°C for 3 hours. HPLC analysis of the reaction mixture confirmed that the starting materials had completely disappeared, and the target product was the main product. Ethyl acetate (50 mL) and 10% EDTA·2Na aqueous solution (50 mL) were added to the reaction mixture, and the organic layer was washed with 10% NaCl aqueous solution (50 mL). The resulting organic layer was concentrated under reduced pressure, and toluene (25 mL) was added to prepare a solution, which was then divided into two portions. The solution was cooled to 0°C, and TfOH (2.3 g) was added dropwise. The temperature was raised to 25°C, and water (2.5 mL) was added. After stirring for 45 minutes, 10 mL of water was added and the mixture was separated. 40% K3PO4 aqueous solution (2.0 mL) and acetonitrile (13 mL) were added to the aqueous layer. FmocOSu (1.8 g) and 40% K3PO4 aqueous solution (3.5 mL) were added. After the lower layer was discarded, 5N HCl (2.2 mL) was added, the precipitated solid was filtered, and the obtained solid was dried to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoic acid (1.8 g, yield 68%) as a white solid. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoic acid: Retention time of target substance: 3.1 minutes (high performance liquid chromatography condition 2) 1H-NMR (DMSO-D6) δ: 12.65 (1H, s), 7.90 (2H,d, J = 7.5 Hz), 7.77-7.58 (5H, m), 7.44-7.32 (5H, m), 4.37-4.18 (3H, m),3.91-3.88 (1H, m), 2.79-2.66 (2H, m), 2.07-1.86 (2H, m).

[0181] Example 4: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-fluorophenyl)butanoate [ka] Nickel bromide trihydrate (4.0 mg, 0.015 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (3.9 mg, 0.015 mmol) were dissolved in DMA (0.50 mL), purged with nitrogen, and stirred to prepare a catalyst solution. 1-(tert-butyl) 5-(1,3-dioxoisoindolin-2-yl)(((9H-fluoren-9-yl)methoxy)carbonyl)-L-glutamate (0.12 g, 0.21 mmol) and 1-fluoro-4-iodobenzene (0.14 g, 0.62 mmol) were dissolved in DMA (0.5 mL). The catalyst solution was added dropwise under a nitrogen atmosphere, followed by zinc dust (68 mg, 1.0 mmol) and then TMSCl (11 mg, 0.1 mmol). The reaction vessel was shaken at 25°C for 2 hours. HPLC analysis of the reaction mixture confirmed that the starting material had completely disappeared and the target product was the main product. The reaction mixture was purified by chromatography to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-fluorophenyl)butanoate (70 mg, 71% yield). tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-fluorophenyl)butanoate: Retention time of target substance: 1.1 minutes (high performance liquid chromatography condition 3) ESI (LC / MS positive mode m / z 498 (M+Na) + )

[0182] Example 5: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-3-yl)butanoate [ka] A catalyst solution was prepared by dissolving nickel bromide trihydrate (0.14 g, 0.53 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.14 g, 0.53 mmol) in DMA (8.0 mL), purging with nitrogen, and stirring. A flask was charged with zinc dust (0.57 g, 8.8 mmol), 5-(1,3-dioxoisoindolin-2-yl) 1-tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-L-glutamate (1.0 g, 1.8 mmol), and DMA (8.0 mL). 3-iodopyridine (1.1 g, 5.3 mmol) was added, and the atmosphere was purged with nitrogen. The catalyst solution was added dropwise to the reaction mixture under a nitrogen atmosphere, followed by the addition of TMSCl (95 mg, 0.88 mmol) and 1,2-dibromoethane (0.33 g, 1.8 mmol). The mixture was stirred at 25°C for 3 hours. HPLC analysis of the reaction mixture confirmed the complete disappearance of the starting materials and the formation of the desired product. The reaction mixture was quenched with an aqueous solution of EDTA·2Na, extracted with MTBE, and the organic layer was washed with brine. The organic layer was dried over sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by chromatography to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-3-yl)butanoate (0.21 g, 26% yield). (S)-tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-3-yl)butanoate: Retention time of target substance: 1.0 min (high performance liquid chromatography condition 3) ESI (LC / MS positive mode m / z 459 (M+H) + )

[0183] Example 6: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate [ka] Nickel bromide trihydrate (2.9 g, 11 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (2.8 g, 11 mmol) were dissolved in DMA (175 mL), purged with nitrogen, and stirred to prepare a catalyst solution. Zinc powder (11 g, 175 mmol), 1-tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-L-glutamate 5-(1,3-dioxoisoindolin-2-yl) (20 g, 35 mmol), and DMA (175 mL) were added to a flask, and 5-bromo-1,3-difluoro-2-(trifluoromethyl)benzene (27 g, 105 mmol) was added. The atmosphere was then purged with nitrogen. The catalyst solution was added dropwise to the reaction mixture under a nitrogen atmosphere, followed by the addition of TMSCl (1.9 g, 18 mmol). The mixture was stirred at 25°C for 1 hour. HPLC analysis of the reaction mixture confirmed that the starting materials had completely disappeared and the target product was the main product. The reaction mixture was quenched with an aqueous solution of EDTA·2Na and then extracted with MTBE. The organic layer was washed with an aqueous solution of sodium bicarbonate and an aqueous solution of ammonium chloride, and then concentrated. The crude product obtained was purified by recrystallization to give (tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate (15 g, 76% yield). tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate: Retention time of target substance: 1.3 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 562 (M+H) + )

[0184] Example 7: Preparation of 5-allyl 1-(tert-butyl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-glutamate [ka] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(allyloxy)-5-oxopentanoic acid (19 g, 46 mmol) was dissolved in dichloromethane (40 mL) and a solution of tert-butyl 2,2,2-trichloroacetamidate (22 g, 100 mmol) in cyclohexane (80 mL) was added dropwise. BF3·OEt2 (0.87 mL, 6.8 mmol) was added to this solution and stirred at 25 °C for 20 min. Sodium bicarbonate was added and stirred, and the insoluble material was removed by filtration. The filtrate was diluted with MTBE and washed with aqueous Na2CO3 and brine. The organic layer was concentrated to give N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-allyl 1-(tert-butyl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-glutamate (20 g, 91% yield). 5-Allyl 1-(tert-butyl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-glutamate: Retention time of target substance: 1.1 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 502 (M+Na) + )

[0185] Example 8: Preparation of (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid [ka] 5-Allyl 1-(tert-butyl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-glutamate (22 g, 46 mmol) and tetrakistriphenylphosphine palladium (0.53 g, 0.46 mmol) were dissolved in dichloromethane (91 mL), and phenylsilane (3.4 g, 32 mmol) was added. After stirring for 2 hours, tetrakistriphenylphosphine palladium (0.53 g, 0.46 mmol) was added, and the reaction mixture was stirred at 25°C for 2.5 hours. MTBE (500 mL) and aqueous sodium carbonate solution were added to the reaction mixture, and the mixture was separated into two layers. The aqueous layer was acidified with H3PO4 (30 mL), and the target product was extracted with MTBE (500 mL). The organic layer was washed with brine and then concentrated to give (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (19 g, 97% yield). (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid: Retention time of target substance: 0.88 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 440 (M+H) + )

[0186] Example 9: Preparation of 1-(tert-butyl)5-(1,3-dioxoisoindolin-2-yl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-glutamate [ka] (S)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (7.7 g, 47 mmol) and N-hydroxyphthalimide (19 g, 43 mmol) were dissolved in THF (130 mL), and a solution of N,N'-diisopropylcarbodiimide (8.1 g, 64 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at 25°C for 1 hour, after which toluene (40 mL) was added and the solid was removed by filtration. The filtrate was concentrated, and MTBE (150 mL) was added and suspended, and the precipitate was removed by filtration. The filtrate was concentrated to give 1-(tert-butyl)5-(1,3-dioxoisoindolin-2-yl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-glutamate (26 g, 100% yield). 1-(tert-butyl)5-(1,3-dioxoisoindolin-2-yl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-glutamate: Retention time of target substance: 1.1 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 585 (M+H) + )

[0187] Example 10: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyridin-3-yl)butanoate [ka] Nickel bromide trihydrate (4.0 mg, 0.015 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (3.9 mg, 0.015 mmol) were dissolved in DMA (0.50 mL), purged with nitrogen, and stirred to prepare a catalyst solution. 1-(tert-butyl) 5-(1,3-dioxoisoindolin-2-yl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-glutamate (0.12 g, 0.21 mmol) and 3-iodopyridine (0.13 g, 0.62 mmol) were dissolved in DMA (0.5 mL). The catalyst solution prepared here was added dropwise under a nitrogen atmosphere, followed by zinc powder (68 mg, 1.0 mmol) and then TMSCl (56 mg, 0.52 mmol), and the reaction vessel was shaken at 25°C for 20 hours. HPLC analysis of the reaction mixture confirmed that the starting materials had completely disappeared and the target product had been produced. The reaction mixture was purified by chromatography to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyridin-3-yl)butanoate (20 mg, 20% yield). tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyridin-3-yl)butanoate: Retention time of target substance: 1.1 minutes (high performance liquid chromatography condition 3) ESI (LC / MS positive mode m / z 473 (M+H) + )

[0188] Example 11: Preparation of 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl)(((9H-fluoren-9-yl)methoxy)carbonyl)-L-aspartate [ka] (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (2.0 g, 4.9 mmol) and N-hydroxyphthalimide (0.87 g, 5.4 mmol) were dissolved in THF (19 mL), and N,N'-diisopropylcarbodiimide (0.92 g, 7.3 mmol) was added dropwise. The reaction mixture was stirred at 25°C for 30 minutes, then concentrated, toluene (20 mL) was added, and the solid was removed by filtration. The filtrate was concentrated and purified by chromatography to give 1-(tert-butyl)4-(1,3-dioxoisoindolin-2-yl)(((9H-fluoren-9-yl)methoxy)carbonyl)-L-aspartate (2.7 g, 100% yield). 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl)(((9H-fluoren-9-yl)methoxy)carbonyl)-L-aspartate: Retention time of target substance: 1.0 min (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 479 (M+Na) + )

[0189] Example 12: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxyphenyl)propanoate [ka] Nickel bromide trihydrate (4.0 mg, 0.015 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (3.9 mg, 0.015 mmol) were dissolved in DMA (0.50 mL), purged with nitrogen, and stirred to prepare a catalyst solution. 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl)(((9H-fluoren-9-yl)methoxy)carbonyl)-L-aspartate (0.12 g, 0.21 mmol) and 1-iodo-3-methoxybenzene (0.15 g, 0.62 mmol) were dissolved in DMA (0.5 mL). The catalyst solution was added dropwise under a nitrogen atmosphere, followed by zinc dust (68 mg, 1.0 mmol) and then TMSCl (11 mg, 0.10 mmol). The reaction vessel was shaken at 25°C for 2 hours. HPLC analysis of the reaction mixture confirmed that the starting material had completely disappeared and the target product was the main product. The reaction mixture was purified by chromatography to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxyphenyl)propanoate (70 mg, 71% yield). tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxyphenyl)propanoate: Retention time of target substance: 1.1 minutes (high performance liquid chromatography condition 3) ESI (LC / MS positive mode m / z 496 (M+Na) + )

[0190] Example 13: Preparation of 4-allyl 1-(tert-butyl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate [ka] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(allyloxy)-4-oxobutanoic acid (16 g, 39 mmol) was dissolved in dichloromethane (36 mL) and a solution of tert-butyl 2,2,2-trichloroacetamidate (14 g, 77 mmol) in cyclohexane (72 mL) was added dropwise. BF3·OEt2 (0.73 mL, 5.8 mmol) was added to this solution and stirred at 25°C for 10 min. NaHCO3 was added and stirred, and the insoluble material was removed by filtration. The filtrate was diluted with MTBE and washed with aqueous Na2CO3. The organic layer was concentrated and purified by chromatography to give 4-allyl 1-(tert-butyl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate (20 g, 95% yield). 4-Allyl 1-(tert-butyl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate: Retention time of target substance: 1.1 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 488 (M+Na) + )

[0191] Example 14: Preparation of (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid [ka] 4-Allyl 1-(tert-butyl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate (14 g, 31 mmol) and tetrakistriphenylphosphine palladium (0.36 g, 0.31 mmol) were dissolved in dichloromethane (61 mL), and phenylsilane (2.3 g, 22 mmol) was added. The reaction mixture was stirred at 25°C for 40 minutes, and then MTBE (500 mL) and aqueous sodium carbonate solution were added to separate the mixture into two layers. The aqueous layer was acidified by adding H3PO4 (80 mL), and the target product was extracted with MTBE (700 mL). The organic layer was washed with brine and then concentrated to give (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (14 g, 100% yield). (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid: Retention time of target substance: 0.90 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 448 (M+Na) + )

[0192] Example 15: Preparation of 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate [ka] (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (0.27 g, 0.6 mmol) and N-hydroxyphthalimide (0.12 g, 0.71 mmol) were dissolved in THF (2.6 mL), and N,N'-diisopropylcarbodiimide (0.12 g, 1.0 mmol) was added dropwise. The reaction mixture was stirred at 25°C for 90 minutes, then concentrated, toluene (2 mL) was added, and the solid was removed by filtration. The filtrate was concentrated and purified by chromatography to give 1-(tert-butyl)4-(1,3-dioxoisoindolin-2-yl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate (0.22 g, 59% yield). 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate: Retention time of target substance: 1.1 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 593 (M+Na) + )

[0193] Example 16: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyrimidin-5-yl)propanoate [ka] A catalyst solution was prepared by dissolving nickel bromide trihydrate (4.0 mg, 0.015 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (3.9 mg, 0.015 mmol) in DMA (0.50 mL), purging with nitrogen, and stirring. 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate (0.12 g, 0.21 mmol) and 5-bromopyrimidine (99 mg, 0.62 mmol) were added to DMA (0.50 mL) and dissolved. The catalyst solution was added dropwise to the reaction mixture under a nitrogen atmosphere, followed by zinc powder (68 mg, 1.0 mmol) and then TMSCl (34 mg, 0.31 mmol). The reaction mixture was then shaken at 25°C for 2 hours. HPLC analysis of the reaction mixture confirmed that the starting materials had completely disappeared and the target product had been produced. The reaction mixture was purified by chromatography to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyrimidin-5-yl)propanoate (32 mg, 34% yield). tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyrimidin-5-yl)propanoate: Retention time of target substance: 1.0 min (high performance liquid chromatography condition 3) ESI (LC / MS positive mode m / z 460 (M+H) + )

[0194] Example 17: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoate [ka] A catalyst solution was prepared by dissolving nickel bromide trihydrate (0.21 g, 0.77 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.25 g, 0.95 mmol) in DMA (15 mL), purging with nitrogen, and stirring. A flask was charged with zinc dust (1.0 g, 16 mmol), 1-(tert-butyl)4-(1,3-dioxoisoindolin-2-yl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate (1.8 g, 3.2 mmol), DMA (8.0 mL), and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (2.3 g, 9.5 mmol). The mixture was then purged with nitrogen. The prepared catalyst solution was added dropwise to the reaction mixture under a nitrogen atmosphere, followed by the addition of TMSCl (0.17 g, 1.6 mmol) and stirring at 25°C for 30 minutes. HPLC analysis of the reaction mixture confirmed that the starting materials had completely disappeared and the target product was the main product. The reaction mixture was quenched with an aqueous solution of EDTA·2Na and then extracted with MTBE. The organic layer was washed with brine and concentrated. The crude product obtained was purified by chromatography to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoate (0.93 g, 55% yield). tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoate: Retention time of target substance: 1.2 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 566 (M+Na) + )

[0195] Example 18: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoate [ka] A catalyst solution was prepared by dissolving nickel bromide trihydrate (0.21 g, 0.77 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.25 g, 0.95 mmol) in DMA (15 mL), purging with nitrogen, and stirring. A flask was charged with zinc dust (1.0 g, 16 mmol), 1-(tert-butyl)4-(1,3-dioxoisoindolin-2-yl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate (1.8 g, 3.2 mmol), DMA (8.0 mL), and 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (2.3 g, 9.5 mmol). The mixture was then purged with nitrogen. The prepared catalyst solution was added dropwise to the reaction mixture under a nitrogen atmosphere, followed by the addition of TMSCl (0.17 g, 1.6 mmol) and stirring at 25°C for 30 minutes. HPLC analysis of the reaction mixture confirmed that the starting materials had completely disappeared and the target product was the main product. The reaction mixture was quenched with an aqueous solution of EDTA·2Na and then extracted with MTBE. The organic layer was washed with brine and concentrated. The crude product was purified by chromatography to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoate (1.2 g, 68% yield). tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoate: Retention time of target substance: 1.1 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 566 (M+Na) + )

[0196] Example 19: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-methoxyphenyl)propanoate [ka] Nickel bromide trihydrate (0.37 g, 1.4 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.45 g, 1.7 mmol) were dissolved in DMA (25 mL), purged with nitrogen, and stirred to prepare a catalyst solution. Zinc dust (1.8 g, 28 mmol), 1-(tert-butyl)4-(1,3-dioxoisoindolin-2-yl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate (3.2 g, 5.6 mmol), and DMA (25 mL) were added to a flask. 1-Bromo-2-fluoro-4-methoxybenzene (3.5 g, 17 mmol) was added, and the mixture was purged with nitrogen. The catalyst solution was added dropwise under a nitrogen atmosphere, followed by the addition of TMSCl (0.31 g, 2.8 mmol). The mixture was stirred at 25°C for 30 minutes. HPLC analysis of the reaction mixture confirmed that the starting materials had completely disappeared and the desired product had been produced. The reaction mixture was quenched with an aqueous solution of EDTA·2Na and then extracted with MTBE. The organic layer was washed with brine and then concentrated. The crude product was purified by chromatography to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-methoxyphenyl)propanoate (0.48 g, 17% yield). tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-methoxyphenyl)propanoate: Retention time of target substance: 1.1 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 506 (M+H) + )

[0197] Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid was prepared according to the following synthetic scheme. [ka]

[0198] Example 20: Preparation of (9H-fluoren-9-yl)methyl (4S)-4-(2-(allyloxy)-2-oxoethyl)-2-methyl-5-oxooxazolidine-3-carboxylate [ka] To a suspension of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(allyloxy)-4-oxobutanoic acid (50 g, 0.13 mol), magnesium sulfate (55 g, 0.38 mol), and paraldehyde (25 g, 0.19 mol) in toluene (0.50 L) was added trifluoroacetic acid (29 g, 0.38 mol) at room temperature. The mixture was stirred at 90°C for 16 hours, then cooled to room temperature, diluted with ethyl acetate, and washed with aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give (9H-fluoren-9-yl)methyl (4S)-4(2-(allyloxy)-2-oxoethyl)-2-methyl-5-oxooxazolidine-3-carboxylate (45 g, 82% yield). (9H-Fluoren-9-yl)methyl (4S)-4(2-(allyloxy)-2-oxoethyl)-2-methyl-5-oxooxazolidine-3-carboxylate: Retention time of target substance: 1.4 minutes (high performance liquid chromatography condition 6) ESI (LC / MS positive mode m / z 422 (M+H) + )

[0199] Example 21: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-4-(allyloxy)-4-oxobutanoic acid [ka] (9H-Fluoren-9-yl)methyl (4S)-4(2-(allyloxy)-2-oxoethyl)-2-methyl-5-oxooxazolidine-3-carboxylate (46 g, 0.11 mol) and triethylsilane (38 g, 0.32 mol) were dissolved in dichloromethane (0.45 L), and trifluoroacetic acid (0.45 L) was added at 25°C. The solution was stirred at 25°C for 48 hours, and then concentrated under reduced pressure. MTBE was added to the concentrated residue, and the mixture was extracted with aqueous sodium bicarbonate solution. The aqueous layer was washed three times with hexane. The pH of the aqueous layer was adjusted to 2 with hydrochloric acid and extracted twice with MTBE. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-4-(allyloxy)-4-oxobutanoic acid (33 g, yield 71%). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-4-(allyloxy)-4-oxobutanoic acid: Retention time of target substance: 1.9 minutes (high performance liquid chromatography condition 5) ESI (LC / MS positive mode m / z 424 (M+H) + )

[0200] Example 22: Preparation of 4-allyl 1-(tert-butyl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-ethyl-L-aspartate [ka] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-4-(allyloxy)-4-oxobutanoic acid (5.0 g, 12 mmol) was dissolved in dichloromethane (10 mL) and a solution of tert-butyl 2,2,2-trichloroacetamidate (5.1 g, 24 mmol) in cyclohexane (20 mL) was added dropwise. BF3·OEt2 (17 mg, 0.12 mmol) was added to the solution and stirred at 25 °C for 16 h. Insoluble matter was removed by filtration, and the filtrate was concentrated, diluted with MTBE, and washed with aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated to give 4-allyl 1-(tert-butyl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate (4.9 g, 85% yield). 4-Allyl 1-(tert-butyl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate: Retention time of target substance: 1.6 minutes (high performance liquid chromatography condition 6) ESI (LC / MS positive mode m / z 480 (M+H) + )

[0201] Example 23: Preparation of (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid [ka] 4-Allyl 1-(tert-butyl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate (4.9 g, 10 mmol) and tetrakistriphenylphosphine palladium (0.12 g, 0.10 mmol) were dissolved in dichloromethane (25 mL), and phenylsilane (0.77 g, 7.2 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours and then concentrated. MTBE was added to the concentrate to dissolve it. The target product was extracted into the aqueous layer with aqueous sodium carbonate. This aqueous layer was acidified by adding phosphoric acid, and the target product was extracted three times with MTBE. The organic layer was washed with brine and then dried over sodium sulfate, and the concentrate was purified by chromatography to give (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (2 g, 46% yield). (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid: Retention time of target substance: 1.7 minutes (high performance liquid chromatography condition 5) ESI (LC / MS positive mode m / z 440 (M+H) + )

[0202] Example 24: Preparation of 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-ethyl-L-aspartate [ka] (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (0.65 g, 1.5 mmol) and N-hydroxyphthalimide (0.27 g, 1.6 mmol) were suspended in ethyl acetate (6.5 mL), and N,N'-diisopropylcarbodiimide (0.28 g, 2.2 mmol) was added dropwise. The reaction mixture was stirred at 25°C for 60 minutes, and the solid was removed by filtration. The filtrate was concentrated and purified by chromatography to give 1-(tert-butyl)4-(1,3-dioxoisoindolin-2-yl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-ethyl-L-aspartate (0.78 g, 90% yield). 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-ethyl-L-aspartate: Retention time of target substance: 1.1 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 607 (M+Na) + )

[0203] Example 25: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate [ka] A catalyst solution was prepared by dissolving nickel bromide trihydrate (4.0 mg, 0.015 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (3.9 mg, 0.015 mmol) in DMA (0.50 mL), purging with nitrogen, and stirring. 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl)N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-ethyl-L-aspartate (0.12 g, 0.21 mmol) and 1-iodo-4-methylbenzene (0.14 g, 0.62 mmol) were dissolved in DMA (0.50 mL). The catalyst solution was added dropwise to the reaction mixture under a nitrogen atmosphere, followed by zinc powder (68 mg, 1.0 mmol) and then TMSCl (11 mg, 0.10 mmol). The reaction vessel was then shaken at 25°C for 2 hours. HPLC analysis of the reaction mixture confirmed that the starting materials had completely disappeared and the target product had been produced. The reaction mixture was purified by chromatography to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate (66 mg, 65% yield). tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate: Retention time of target substance: 1.2 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 508 (M+Na) + )

[0204] Example 26: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid [ka] tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate (50 mg, 0.10 mmol) was dissolved in trifluoroethanol (0.50 mL), and TMSCl (17 mg, 0.15 mmol) was added at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by chromatography to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid (38 mg, 86% yield). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid: Retention time of target substance: 0.95 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 430 (M+H) + )

[0205] Example 27: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(p-tolyl)propanoate [ka] Nickel bromide trihydrate (3.8 mg, 0.014 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (3.8 mg, 0.014 mmol) were dissolved in DMA (0.50 mL), purged with nitrogen, and stirred to prepare a catalyst solution. To this solution, zinc dust (65 mg, 1.0 mmol) and TMSCl (11 mg, 0.10 mmol) were added and the mixture was shaken for 10 minutes. A solution of 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate (0.11 g, 0.20 mmol) and 1-iodo-4-methylbenzene (0.13 g, 0.60 mmol) in DMA (0.50 mL) was added dropwise to the catalyst solution under a nitrogen atmosphere, and the reaction vessel was shaken at 25°C for 2 hours. HPLC analysis of the reaction mixture confirmed that the starting materials had completely disappeared and the desired product had been produced. The reaction mixture was purified by chromatography to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(p-tolyl)propanoate (56 mg, 59% yield). tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(p-tolyl)propanoate: Retention time of target substance: 1.2 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 494 (M+Na) + )

[0206] Example 28: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxyphenyl)butanoate [ka] Nickel bromide trihydrate (3.8 mg, 0.014 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (3.8 mg, 0.014 mmol) were dissolved in DMA (0.50 mL), purged with nitrogen, and stirred. To this solution, zinc dust (65 mg, 1.0 mmol) was added to prepare a catalyst solution. 1-(tert-butyl)5-(1,3-dioxoisoindolin-2-yl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-glutamate (0.12 g, 0.20 mmol) and 1-iodo-3-methoxybenzene (0.14 g, 0.60 mmol) were dissolved in DMA (0.50 mL), followed by the addition of TMSCl (11 mg, 0.10 mmol). This solution was added dropwise to the catalyst solution under a nitrogen atmosphere, and the reaction vessel was shaken at 25°C for 2 hours. HPLC analysis of the reaction mixture confirmed that the starting materials had completely disappeared and the target product had been produced. The reaction mixture was purified by chromatography to obtain tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxyphenyl)butanoate (67 mg, 67% yield). tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxyphenyl)butanoate: Retention time of target substance: 1.1 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 524 (M+Na) + )

[0207] Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoic acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoic acid can be produced according to the following synthesis scheme, which includes a step of reacting an N-hydroxyphthalimide ester with an aromatic bromide to obtain an aromatic amino acid derivative using conditions and methods similar to those in the above examples. [ka]

[0208] Example 29: Preparation of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-glutamic acid 1-methyl 5-(1,3-dioxoisoindolin-2-yl) [ka] (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(methoxy)-5-oxopentanoic acid (1.0 g, 2.6 mmol) and N-hydroxyphthalimide (0.47 g, 2.9 mmol) were suspended in ethyl acetate (10 mL), and N,N'-diisopropylcarbodiimide (0.61 mL, 3.9 mmol) was added dropwise. The reaction mixture was stirred at 25°C for 60 minutes, and the solid was removed by filtration. The filtrate was concentrated and purified by chromatography to give (((9H-fluoren-9-yl)methoxy)carbonyl)-L-glutamic acid 1-methyl 5-(1,3-dioxoisoindolin-2-yl)ester (1.0 g, 73% yield). (((9H-Fluoren-9-yl)methoxy)carbonyl)-L-glutamic acid 1-methyl 5-(1,3-dioxoisoindolin-2-yl): Retention time of target substance: 1.0 min (high performance liquid chromatography condition 3) ESI (LC / MS positive mode m / z 529 (M+H) + )

[0209] Example 30: Preparation of methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoate [ka] A catalyst solution was prepared by dissolving nickel bromide trihydrate (4.0 mg, 0.015 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (4.0 mg, 0.015 mmol) in DMA (0.50 mL), purging with nitrogen, and stirring. In a separate vessel, zinc powder (69 mg, 1.1 mmol), 5-(1,3-dioxoisoindolin-2-yl) (((9H-fluoren-9-yl)methoxy)carbonyl)-L-glutamate (1-methyl 5-(1,3-dioxoisoindolin-2-yl)) (0.11 g, 0.21 mmol), and 1-iodo-4-methoxybenzene (0.15 g, 0.63 mmol) were dissolved in DMA (0.50 mL). The catalyst solution was added dropwise to the reaction mixture under a nitrogen atmosphere, followed by the addition of TMSCl (11 mg, 0.11 mmol). The reaction vessel was then shaken at 25°C for 1 hour. The reaction mixture was analyzed by HPLC, and it was confirmed that the starting materials had completely disappeared and the target product had been produced. The reaction mixture was purified by chromatography to give methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoate (64 mg, 68% yield). Methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoate: Retention time of target substance: 0.9 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 446 (M+H) + ).

[0210] Example 31: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoic acid [ka] Calcium chloride (0.19 g, 1.7 mmol) and lithium hydroxide hydrate (19 mg, 0.45 mmol) were added to water (0.49 mL) and 2-propanol (2.0 mL) and stirred for 15 minutes at room temperature. To this mixture, a solution of methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoate (50 mg, 0.11 mmol) in THF (0.49 mL) was added dropwise at room temperature and stirred for 20 hours. Insoluble matter was removed by filtration, and the solid was washed with THF. The filtrate was concentrated and purified by chromatography to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoic acid (35 mg, 72%). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoic acid: Retention time of target substance: 0.8 minutes (high performance liquid chromatography condition 4) ESI (LC / MS positive mode m / z 432 (M+H) + ). [Industrial Applicability]

[0211] The present invention provides a novel method for producing optically active aromatic amino acid derivatives that are useful as raw materials for pharmaceuticals. By using the production method of the present invention, optically active aromatic amino acid derivatives can be efficiently produced and supplied.

Claims

1. Formula (I): 【Chemical 1】 [In the formula, R １ is hydrogen or an amino protecting group selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; R ２ is hydrogen or C １ -C ６ is alkyl, R ３ is hydrogen or a protecting group for a carboxyl group selected from the group consisting of methyl, ethyl, t-Bu, benzyl, trityl, cumyl, methoxytrityl, and 2-(trimethylsilyl)ethyl; R ６ is an optionally substituted C ６ -C １０ aryl, or optionally substituted heteroaryl; Optionally substituted C ６ -C １０ The aryl or optionally substituted heteroaryl is C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkoxy, C ２ -C ６ Alkenyloxy, halogen, C ３ -C ８ Cycloalkyl, —NR ｐ R ｑ (In the formula, R ｐ and R ｑ are independently hydrogen or C １ -C ４ alkyl), -CONR ｒ R ｓ (In the formula, R ｒ and R ｓ are independently hydrogen, hydroxy, protected hydroxy, C １ -C ４ Alkyl, and C １ -C ４ substituted with 0 to 3 substituents independently selected from the group consisting of alkylsulfonyl, cyclic boryl, and cyclic boryl; R ７ is hydrogen or C １ -C ４ is alkyl, n is 1. An amino acid derivative represented by the formula (I), a salt thereof, or a solvate thereof.

2. Optionally substituted C ６ -C １０ The aryl or optionally substituted heteroaryl is selected from the group consisting of one C １ -C ４ alkyl, one -CONR ｒ R ｓ , 1 C １ -C ４ Haloalkyl and one or two halogens, two C １ -C ４ Alkoxy, 1 C １ -C ４ Alkoxy and one or two halogens, or one -CONR ｒ R ｓ and one C １ -C ４ The amino acid derivative, salt thereof, or solvate thereof according to claim 1, which is substituted with alkoxy.

3. Optionally substituted C ６ -C １０ The amino acid derivative, its salt, or solvate thereof according to claim 1, wherein the aryl or optionally substituted heteroaryl is substituted with one methyl, one methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl, one trifluoromethyl and one or two fluorines, one trifluoromethyl and one or two chlorines, one trifluoromethyl, one fluorine and one chlorine, two methoxys, one methoxy and one or two fluorines, one methylaminocarbonyl and one methoxy, or one methylsulfonylaminocarbonyl and one methoxy.

4. Formula (II): 【Chemistry 2】 [In formula; R １ is hydrogen or an amino-protecting group selected from the group consisting of Boc, Fmoc, Cbz, Alloc, and Teoc; R ２ is hydrogen or methyl, R ３ is hydrogen or a protecting group for a carboxyl group selected from the group consisting of methyl, t-butyl, and benzyl; R ７ is hydrogen, n is 1, X １ , X ２ , and X ３ are independently hydrogen or halogen; however, X １ is a halogen, X ２ and X ３ is hydrogen, X １ is hydrogen, X ２ and X ３ are both halogens, or X ２ and X ３ one of which is a halogen.] The amino acid derivative, salt thereof, or solvate thereof according to claim 3, represented by the formula:

5. 5. The amino acid derivative, salt thereof, or solvate thereof according to claim 1, wherein the halogen is fluorine or chlorine.

6. An amino acid derivative, a salt thereof, or a solvate thereof selected from the group consisting of: (1-21) benzyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-22) tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-23) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-24) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-25) benzyl 2-(((benzyloxy)carbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-26) tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-27) benzyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-28) tert-butyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-29) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-30) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-31) benzyl 2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-32) tert-butyl 2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate, (1-33) 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-35) 2-(((benzyloxy)carbonyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-36) 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-37) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-38) 2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3-chloro-4-(trifluoromethyl)phenyl)propanoic acid, (1-40) 3-(3-chloro-4-(trifluoromethyl)phenyl)-2-(methylamino)propanoic acid, (4-14) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-cyclopropylphenyl)propanoate, (4-34) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (4-35) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoate, (4-36) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoate, (4-37) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoate, (4-38) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoate, (4-39) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoate, (4-44) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-methylpyridin-3-yl)propanoate, (4-46) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-methoxypyridin-3-yl)propanoate, (5-12) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-cyclopropylphenyl)propanoate, (5-13) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-cyclopropylphenyl)propanoate, (5-14) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-cyclopropylphenyl)propanoate, (5-19) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-isopropylphenyl)propanoate, (5-24) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(allyloxy)phenyl)propanoate, (5-25) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-(allyloxy)phenyl)propanoate, (5-26) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-(allyloxy)phenyl)propanoate, (5-27) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-isopropoxyphenyl)propanoate, (5-28) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoate, (5-29) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoate, (5-33) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-methoxyphenyl)propanoate, (5-34) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (5-35) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoate, (5-36) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoate, (5-37) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoate, (5-38) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoate, (5-39) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoate, (5-43) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(6-methylpyridin-3-yl)propanoate, (5-44) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-methylpyridin-3-yl)propanoate, (5-45) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-methylpyridin-3-yl)propanoate, (5-46) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(6-methoxypyridin-3-yl)propanoate, (5-47) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-methoxypyridin-3-yl)propanoate, (5-48) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-fluoropyridin-3-yl)propanoate, (5-49) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-chloropyridin-3-yl)propanoate, (5-50) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-bromopyridin-3-yl)propanoate, (5-51) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-iodopyridin-3-yl)propanoate, (5-52) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(methylamino)pyridin-4-yl)propanoate, (5-53) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(dimethylamino)pyridin-4-yl)propanoate, (8-14) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-cyclopropylphenyl)propanoic acid, (8-34) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (8-35) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoic acid, (8-36) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoic acid, (8-37) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoic acid, (8-38) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (8-39) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (8-40) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-2-yl)propanoic acid, (8-45) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methylpyridin-3-yl)propanoic acid, (8-47) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-methoxypyridin-3-yl)propanoic acid, (8-48) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoropyridin-3-yl)propanoic acid, (9-12) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-cyclopropylphenyl)propanoic acid, (9-13) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-cyclopropylphenyl)propanoic acid, (9-14) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-cyclopropylphenyl)propanoic acid, (9-19) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-isopropylphenyl)propanoic acid, (9-24) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(allyloxy)phenyl)propanoic acid, (9-25) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-(allyloxy)phenyl)propanoic acid, (9-26) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-(allyloxy)phenyl)propanoic acid, (9-27) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-isopropoxyphenyl)propanoic acid, (9-28) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (9-29) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (9-30) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,4-dimethoxyphenyl)propanoic acid, (9-34) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (9-35) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoic acid, (9-36) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoic acid, (9-37) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoic acid, (9-38) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (9-39) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (9-40) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyridin-2-yl)propanoic acid, (9-44) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-methylpyridin-3-yl)propanoic acid, (9-45) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(4-methylpyridin-3-yl)propanoic acid, (9-46) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(6-methoxypyridin-3-yl)propanoic acid, (9-47) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-methoxypyridin-3-yl)propanoic acid, (9-48) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-fluoropyridin-3-yl)propanoic acid, (9-49) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-chloropyridin-3-yl)propanoic acid, (9-50) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-bromopyridin-3-yl)propanoic acid, (9-51) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-iodopyridin-3-yl)propanoic acid, (9-52) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(methylamino)pyridin-4-yl)propanoic acid, (9-53) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-(dimethylamino)pyridin-4-yl)propanoic acid, (12-14) 2-amino-3-(4-cyclopropylphenyl)propanoic acid, (12-35) 2-amino-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoic acid, (12-36) 2-amino-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoic acid, (12-37) 2-amino-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoic acid, (12-38) 2-amino-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (12-39) 2-amino-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (12-40) 2-amino-3-(pyridin-2-yl)propanoic acid, (12-47) 2-amino-3-(5-methoxypyridin-3-yl)propanoic acid, (13-12) 2-(methylamino)-3-(2-cyclopropylphenyl)propanoic acid, (13-13) 2-(methylamino)-3-(3-cyclopropylphenyl)propanoic acid, (13-14) 2-(methylamino)-3-(4-cyclopropylphenyl)propanoic acid, (13-19) 2-(methylamino)-3-(3-isopropylphenyl)propanoic acid, (13-24) 2-(methylamino)-3-(2-(allyloxy)phenyl)propanoic acid, (13-25) 2-(methylamino)-3-(3-(allyloxy)phenyl)propanoic acid, (13-26) 2-(methylamino)-3-(4-(allyloxy)phenyl)propanoic acid, (13-27) 2-(methylamino)-3-(4-isopropoxyphenyl)propanoic acid, (13-28) 2-(methylamino)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (13-29) 2-(methylamino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoic acid, (13-33) 2-(methylamino)-3-(3,5-difluoro-4-methoxyphenyl)propanoic acid, (13-34) 2-(methylamino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (13-35) 2-(methylamino)-3-(3-methoxy-4-(methylcarbamoyl)phenyl)propanoic acid, (13-36) 2-(methylamino)-3-(4-methoxy-3-(methylcarbamoyl)phenyl)propanoic acid, (13-37) 2-(methylamino)-3-(3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl)propanoic acid, (13-38) 2-(methylamino)-3-(4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (13-39) 2-(methylamino)-3-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)propanoic acid, (13-40) 2-(methylamino)-3-(pyridin-2-yl)propanoic acid, (13-44) 2-(methylamino)-3-(5-methylpyridin-3-yl)propanoic acid, (13-45) 2-(methylamino)-3-(4-methylpyridin-3-yl)propanoic acid, (13-46) 2-(methylamino)-3-(6-methoxypyridin-3-yl)propanoic acid, (13-47) 2-(methylamino)-3-(5-methoxypyridin-3-yl)propanoic acid, (13-48) 2-(methylamino)-3-(5-fluoropyridin-3-yl)propanoic acid, (13-49) 2-(methylamino)-3-(5-chloropyridin-3-yl)propanoic acid, (13-50) 2-(methylamino)-3-(5-bromopyridin-3-yl)propanoic acid, (13-51) 2-(methylamino)-3-(5-iodopyridin-3-yl)propanoic acid, (13-52) 2-(methylamino)-3-(2-(methylamino)pyridin-4-yl)propanoic acid, (13-53) 2-(methylamino)-3-(2-(dimethylamino)pyridin-4-yl)propanoic acid, (13-54) 2-(methylamino)-3-(pyrimidin-5-yl)propanoic acid, (14-1) tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-2) benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-3) tert-butyl 2-((tert-butoxycarbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-4) Benzyl 2-((tert-butoxycarbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-5) tert-butyl 2-(((benzyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-6) Benzyl 2-(((benzyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-7) tert-butyl 2-(((allyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-8) Benzyl 2-(((allyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate, (14-9) tert-butyl 2-(ethyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-3-(p-tolyl)propanoate, (14-10) benzyl 2-(ethyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-3-(p-tolyl)propanoate, (14-11) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid, (14-12) 2-((tert-butoxycarbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid, (14-13) 2-(((benzyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid, (14-14) 2-(((allyloxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid, and (14-15) 2-(ethyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-3-(p-tolyl)propanoic acid.

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