Process for producing aromatic amino acid derivatives

Abstract

To provide aromatic amino acid derivatives useful as pharmaceutical intermediates.SOLUTION: The present invention provides an amino acid derivative represented by a formula I, a salt thereof, or a solvate thereof [where R1 is hydrogen, or a protecting group for an amino group, R2 is hydrogen, or a C1-C6 alkyl, and R3 is hydrogen, or a protecting group for a carboxyl group, or R2 and R3 together form a bivalent protecting group, R6 is an optionally substituted C6-C10 aryl or an optionally substituted heteroaryl, R7 is hydrogen, or a C1-C4 alkyl, and n is 1 or 2].SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an aromatic amino acid derivative useful as a pharmaceutical intermediate and a method for producing the same.

Background Art

[0002] Access to tough targets, typified by the inhibition of protein-protein interactions, may be superior for medium-sized compounds (molecular weight 500-2000) compared to low-molecular-weight compounds. Also, medium-sized compounds may be superior to antibodies in terms of their ability to translocate into cells. Among medium-sized compounds with biological activity, peptide pharmaceuticals are a highly valuable molecular species with more than 40 already on the market (Non-Patent Document 1). Representative examples of these peptide pharmaceuticals include cyclosporin A and polymyxin B. Looking at their structures, it can be seen that they are peptide compounds containing several unnatural amino acids. Unnatural amino acids are amino acids that are not naturally encoded on mRNA. In addition to the fact that natural-derived cyclosporin A and polymyxin B contain unnatural amino acids, it is very interesting that the structural sites of these unnatural amino acids interact with the active sites in vivo to exhibit pharmacological activity. As an example of the interaction between an unnatural amino acid and an active site in vivo, the partial structure of homophenylalanine of an angiotensin-converting enzyme inhibitor typified by delapril can be cited (Non-Patent Document 2).

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

[0004] The following methods are known for producing optically active aromatic amino acids. The following (1) to (5) are methods for obtaining an optically active aromatic amino acid by inducing an asymmetric point from a prochiral starting material or for resolving a DL-mixture of an aromatic amino acid. (1) A method for enantioselectively adding a highly reactive aralkyl halide compound represented by benzyl bromide to a glycine derivative or an alanine derivative using an optically active phase transfer catalyst (Patent Document 1). (2) A method for diastereoselectively adding a highly reactive aralkyl halide compound represented by benzyl bromide 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 by optical resolution for selectively deacetylating an N-acetyl aromatic amino acid in a DL mixture with an acylase to produce an L-aromatic amino acid (Patent Document 4). (5) A method for producing a homophenylalanine derivative from an optically active alcohol obtained by asymmetric reduction of a styryl glyoxylic acid derivative in a key reaction (Non-Patent Document 3).

[0005] The following (6) to (9) are methods for producing a target optically active aromatic amino acid by introducing a functional group using an optically active amino acid as a starting material. (6) A method for producing 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 for producing 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 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 a homophenylalanine derivative after arylating the side chain of aspartic acid by a Friedel-Crafts reaction (Non-Patent Document 6).

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

[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] [Problems 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 or Patent Document 2, the aralkyl halide compound used as an electrophilic reagent needs to be stable under basic conditions. Since the electrophilic reagents used here need to be highly reactive reagents capable of efficiently forming carbon-carbon bonds, the electrophilic reagents that can be subjected to these reaction conditions are limited, and it cannot be said to be general-purpose as a method 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 it is not suitable as a general-purpose method for producing aromatic amino acid derivatives.

[0011] In the method described in Patent Document 4, when attempting to produce a plurality of aromatic amino acid derivatives with different amino acid side chains, it is necessary to produce a racemate of the corresponding acylated aromatic amino acid derivative as a raw material. Furthermore, it is also necessary to produce a hydrolase that can selectively hydrolyze aromatic amino acid derivatives with different side chain structures. That is, both a racemic starting material and a hydrolase corresponding to the type of aromatic amino acid derivative are required, and the generality as a production method is low.

[0012] The method described in Patent Document 5 is not efficient because it requires a multi-step reaction from the raw material serine to prepare a zinc reagent.

[0013] The method described in Non-Patent Document 3 is a problem as an industrial reaction in that it requires a hydrogen gas stream at 20 atmospheres in the asymmetric reduction reaction of the key reaction. Furthermore, the styryl glyoxylic acid derivative used in the asymmetric reduction reaction is limited to the amide form, and it is also necessary to convert it to the carboxylic acid form or ester form, which is useful as a pharmaceutical intermediate, and it is not efficient.

[0014] The method described in Non-Patent Document 4 uses an N-hydroxyphthalimide ester (NHPI ester) that can be easily prepared from aspartic acid, glutamic acid, etc. and an aromatic iodide as raw materials. By changing the aromatic iodide used, various aromatic amino acid derivatives can be produced, so it can be said to be a general-purpose method. However, in the method described in this document, it is necessary to use an excessive amount of the NHPI ester form of the amino acid. Therefore, multiple amino acid derivatives derived from the excessive amino acid may be produced as by-products. These by-products may cause difficulties in obtaining high-quality aromatic amino acid derivatives because their physical properties are similar to those of the target aromatic amino acid derivatives. In addition, among aromatic halides, only aromatic iodides are applicable to this method, and there are still problems with substrate generality. Specifically, although the reaction proceeds on a laboratory scale, the production methods of phenylalanine derivatives and homophenylalanine derivatives described in this document require an excessive amount of the NHPI ester form of aspartic acid or glutamic acid with respect to the aromatic iodide. Furthermore, it has been found that the reaction does not proceed under the reaction conditions using a stirring blade used in an industrial-scale reaction.

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

[0016] The method described in Non-Patent Document 6 is limited to aryl groups with excessive electrons that can be introduced by Friedel-Crafts reaction.

[0017] As described above, an efficient and general-purpose industrial production method for optically active aromatic amino acid derivatives that also meets industrially desirable conditions has not been known to date.

[0018] The present invention aims to provide a method for efficiently and generally producing an optically active aromatic amino acid derivative using industrial equipment from readily available optically active amino acids, and an optically active aromatic amino acid derivative that can be produced by the method and can be a raw material for medium molecular weight compounds.

Means for Solving the Problems

[0019] As a result of intensive studies on a method for producing an optically active aromatic amino acid derivative, the present inventors have found reaction conditions for reacting an aromatic halide with a reducing agent in the presence of a catalyst with respect to a specific ester compound. Specifically, by using an additive, an efficient production method of an optically active aromatic amino acid derivative adaptable to reaction conditions using a stirring blade commonly used industrially has been found. Furthermore, by changing the aromatic halide used in the reaction, a highly versatile method capable of producing various optically active aromatic amino acid derivatives from a common ester compound has been found, leading to the completion of the present invention.

[0020] The present invention includes the following in a non-limiting specific aspect. [1] Formula I: [Chemical formula] [In the formula, R1 is hydrogen or a protecting group for an amino 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 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, a salt thereof, or a solvate thereof, Formula II: [Chemical formula] [In the formula, R1, R2, R3, R7, and n are synonymous with R1, R2, R3, R7, and n of the compound represented by Formula I, respectively, R5 is as follows: [Chemical formula] 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, * means a bonding point.] A step of mixing a compound represented by the formula, its salt, or their solvate with a reducing agent, an additive, and R6-X (where R6 is synonymous with R6 of the compound represented by Formula I and X is halogen, OTf, or OMs) in the presence of a solvent and a catalyst to obtain a compound represented by Formula I, its salt, or their solvate is included in the said method. [2] The method according to [1], wherein R1 is a protecting group for an amino group, and the protecting group for the amino 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 protecting group for a carboxyl group, and the protecting group for the carboxyl 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 is -(CR8R9)-, and the formula I is formula IA: [Chemical formula] [wherein, R1, R6, R7, and n are respectively synonymous with R1, R6, R7, and n of the compound represented by the formula I, 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], represented by [5] The additive is of formula A: [Chemical formula] [wherein, R AX , and R AY are 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], which is a silyl compound represented by or 1,2-dibromoethane. [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 is [Chemical formula] 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 (wherein R p and R q are independently hydrogen or C1-C4 alkyl), -CONR r R s (wherein 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 is substituted with 0 to 3 substituents independently selected from the group consisting of cyclic boryl, the method according to [8]. [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 alkoxys, one C1-C4 alkoxy and one or two halogens, or one -CONR r R s and one C1-C4 alkoxy, the method according to [9-1]. [9-3] The method according to [9-2], wherein the phenyl which may be substituted or the pyridyl which may be substituted 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 and 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) a metal, (b) formed by mixing a metal and a compound capable of being its ligand, (c) a complex of a metal and its ligand, or (d) formed by further mixing a complex of a metal and its ligand with a compound capable of being the ligand of 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 according to

[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(dichloro octadienyl)nickel, or a solvate thereof.

[12] The compound capable of being a ligand is of formula B: [Chemical formula] [wherein, R BX , and R BYis independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, heterocyclyl, or C6-C 10 aryl.] compound represented by, formula C:

Chem.

Chem.

Chem.

Chem.

Chem.

[10] or

[11] , which is selected from the compounds represented by

[13] The method according to

[10] , wherein the catalyst is a complex of a metal and its ligand, and the complex of the 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]amine nickel(II) chloride, cis-[2,2'-bis(diphenylphosphino)-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) After mixing the compound represented by formula II, its salt, or their solvate, a reducing agent, and R6-X in the presence of a solvent and a catalyst, an additive is mixed, or (b) After mixing the reducing agent and the additive in the presence of a solvent and a catalyst, the compound represented by formula II, its salt, or their solvate and R6-X are mixed, or (c) After mixing the reducing agent in the presence of a solvent and a catalyst, the compound represented by formula II, its salt, or their solvate, R6-X, and the additive are mixed, The method according to any one of [1] to

[14] .[[]END]]

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

[15] , wherein 1 to 500 mol% of an additive is used with respect to 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: [Chemical formula] [In the formula, R1, R6, R7, and n are synonymous with R1, R6, R7, and n of 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 salt thereof, or a solvate thereof, comprising: a step of producing a compound represented by formula I, a salt thereof, or a solvate thereof according to the method described in any one of [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, a salt thereof, or a solvate thereof to obtain a compound represented by formula III, a salt thereof, or a solvate thereof The above method comprising.

[19] Formula IV: [Chemical formula] [In the formula, R6, R7, and n are synonymous with R6, R7, and n of 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 salt thereof, or a solvate thereof, comprising: a step of producing a compound represented by formula I, a salt thereof, or a solvate thereof according to the method described in any one of [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 as described above, which comprises

[20] Formula V: [Chemical formula] [wherein, R2, R6, R7, and n are synonymous with R2, R6, R7, and n of the compound represented by Formula IV respectively, and R 1’ is a protecting group for the amino group.] A method for producing a compound represented by the formula, a salt thereof, or a solvate thereof, comprising a step of producing a compound represented by Formula IV, a salt thereof, or a solvate thereof according to the method described in

[19] , and a step of introducing R 1’ into the compound represented by Formula IV, a salt thereof, or a solvate thereof to obtain a compound represented by Formula V, a salt thereof, or a solvate thereof The method as described above, which comprises

[21] Formula VI: [Chemical formula] [wherein, R1, R6, R7, and n are synonymous with R1, R6, R7, and n of the compound represented by Formula I respectively.] A method for producing a compound represented by the formula, a salt thereof, or a solvate thereof, comprising a step of producing a compound represented by Formula IA, a salt thereof, or a solvate thereof according to the method described in any one of [4] to

[17] , and a step of ring-opening the oxazolidinone ring of the compound represented by Formula IA to obtain a compound represented by Formula VI, a salt thereof, or a solvate thereof The method as described above, which comprises

[22] A compound, a salt thereof, or a solvate thereof produced by the method described in any one of [1] to

[21] .

[23] Formula I: [Chemical formula] [In the formula, R1 is hydrogen or a protecting group for an amino 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 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, a salt thereof, or a solvate thereof.

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

[23] , wherein R1 is a protecting group for an amino group, and the protecting group for the amino group is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl.

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

[23] or

[24] , wherein R3 is a protecting group for a carboxyl group, and the protecting group for the carboxyl group is 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, and the divalent protecting group is -(CR8R9)-, and the formula I is formula IA: [Chemical formula] [In the formula, R1, R6, R7, and n are synonymous with R1, R6, R7, and n of the compound represented by the 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 described in

[23] or

[24] , a salt thereof, or a solvate thereof, represented by

[27] The amino acid derivative described in any one of

[23] to

[26] , a salt thereof, or a solvate thereof, wherein R6 is phenyl which may be substituted or pyridyl which may be substituted.

[28] Phenyl which may be substituted or pyridyl which may be substituted is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C6 alkenyloxy, halogen, C3-C8 cycloalkyl, -NR p R q (wherein R p and R q are independently hydrogen or C1-C4 alkyl), -CONR r R s (wherein 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 the amino acid derivative described in

[27] , a salt thereof, or a solvate thereof, which is substituted with 0 to 3 substituents independently selected from the group consisting of cyclic boryl.

[29] Phenyl which may be substituted or pyridyl which may be substituted is substituted with 1 C1-C4 alkyl, 1 -CONR r R s , 1 C1-C4 haloalkyl and 1 or 2 halogens, 2 C1-C4 alkoxys, 1 C1-C4 alkoxy and 1 or 2 halogens, or 1 -CONR r R s and 1 C1-C4 alkoxy, and the amino acid derivative described in

[28] , a salt thereof, or a solvate thereof.

[30] An amino acid derivative, a salt thereof, or a solvate thereof as described in

[29] , wherein phenyl which may be substituted or pyridyl which may be substituted 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 and 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)butanoic acid, (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)butanoic acid, (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 N-(((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)propanoic acid, (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. [Advantages of the Invention]

[0021] According to the present invention, an optically active aromatic amino acid derivative useful for the search for peptide pharmaceuticals and / or the supply of drug active ingredients can be efficiently produced. In addition, since various optically active aromatic amino acid derivatives can also be produced, optically active aromatic amino acid derivatives with diverse structures can be provided. [Embodiments for Carrying Out the Invention]

[0022] [Abbreviations] The abbreviations used in the present invention are described 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’-Dimethylpropyleneurea DMSO: Dimethyl sulfoxide dtbbpy: 4,4’-Di-tert-butyl-2,2’-bipyridine EDTA·2Na: Ethylenediaminetetraacetic acid disodium salt 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 spectrum 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: valine 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.) Examples of the "halogen atom" in this specification include F, Cl, Br, or I.

[0024] As used herein, "alkyl" refers to a monovalent group derived by removing one hydrogen atom from an aliphatic hydrocarbon, having no heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in its skeleton, and having a subset of the hydrocarbyl or hydrocarbon group structure containing hydrogen and carbon atoms. The alkyl group includes linear or branched-chain ones. Examples of the alkyl group include those having 1 to 20 carbon atoms (C1-C 20 , hereinafter "C p -C q " means having p to q carbon atoms).), preferably C1-C6 alkyl groups. Specifically, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl, sec-butyl, etc. can be mentioned.

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

[0026] As used herein, "alkenyl" refers to a monovalent group having at least one double bond (two adjacent sp 2 carbon atoms). Depending on the arrangement of the double bond and the substituents (if any), the geometric form of the double bond can take an entgegen (E) or zusammen (Z), cis or trans configuration. Examples of alkenyl include linear or branched-chain ones, including straight chains containing internal olefins. Preferably C2-C 10 alkenyl, more preferably C2-C6 alkenyl, C2-C4 alkenyl. Specific examples of alkenyl include, for example, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, hexenyl, etc.

[0027] "Alkenyloxy" as used herein means an oxy group to which "alkenyl" as defined above is bonded, and preferably includes C2-C6 alkenyloxy, C2-C4 alkenyloxy, and the like.

[0028] As used herein, "alkynyl" is a monovalent group having at least one triple bond (two adjacent sp carbon atoms). Examples include linear or branched alkynyl, including internal alkylene. Preferably C2-C 10 alkynyl, more preferably C2-C6 alkynyl, C2-C4 alkynyl. Specific examples of alkynyl include, for example, 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, 3-methyl-(5-phenyl)-4-pentynyl, and the like.

[0029] "Alkynyloxy" as used herein means an oxy group to which "alkynyl" as defined above is bonded, and preferably includes C2-C6 alkynyloxy, C2-C4 alkynyloxy, and the like.

[0030] "Haloalkyl" as used herein means a group in which one or more hydrogen atoms of the above "alkyl" are substituted with halogen atoms, and preferably includes C1-C6 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, C1-C2 haloalkyl, and the like.

[0031] "Haloalkoxy" as used herein means an oxy group to which the above "haloalkyl" is bonded, and preferably includes C1-C4 haloalkoxy, C1-C3 haloalkoxy, C1-C2 haloalkoxy, and the like.

[0032] "Fluoroalkyl" as used herein means a group in which one or more hydrogen atoms of the "alkyl" are replaced by fluorine atoms, and preferably C1-C6 fluoroalkyl, C1-C4 fluoroalkyl, C1-C3 fluoroalkyl, C1-C2 fluoroalkyl, etc. are exemplified. Specific examples of fluoroalkyl include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, heptafluoropropyl, etc.

[0033] "Fluoroalkoxy" as used herein means an oxy group to which the above-mentioned "fluoroalkyl" is bonded, and preferably C1-C4 fluoroalkoxy, C1-C3 fluoroalkoxy, C1-C2 fluoroalkoxy, etc. are exemplified. Specific examples of fluoroalkoxy include trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, heptafluoropropoxy, etc.

[0034] "Alkylsulfonyl" as used herein means a sulfonyl group (i.e., alkyl-SO2-) to which the above-mentioned "alkyl" is bonded. Preferred examples of alkylsulfonyl include C1-C6 alkylsulfonyl, C1-C4 alkylsulfonyl, etc., and specific examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, i-propylsulfonyl, etc.

[0035] "Alkylsulfonylamino" as used herein means a group in which one hydrogen atom of an amino group (-NH2) is replaced by the above-mentioned "alkylsulfonyl". Preferred examples of alkylsulfonylamino include C1-C6 alkylsulfonylamino, C1-C4 alkylsulfonylamino, etc., and specific examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, i-propylsulfonylamino, etc.

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

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

[0038] "Aryl" as used herein means a monovalent aromatic hydrocarbon ring, preferably C6-C 10 Examples thereof include aryl. Specific examples of the aryl include phenyl, 1-naphthyl, 2-naphthyl, and the like. Further, the aryl may be optionally substituted, preferably substituted with an alkyl, an alkoxy, a fluoroalkyl, a fluoroalkoxy, an oxo, an aminocarbonyl, or a halogen atom.

[0039] As used herein, "heteroaryl" means an aromatic monovalent heterocyclic group preferably having 1 to 5 heteroatoms in the atoms constituting the ring. Preferred heteroatoms are 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 a 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). Further, the heteroaryl may be substituted with any substituent, and is preferably substituted with 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, imidazopyridyl, and the like.

[0040] In this specification, "having a heteroatom in the ring" means containing a heteroatom among the atoms constituting the ring. As the heteroatom, N, O or S is preferable, the number of heteroatoms is preferably 1 or 2, and it 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, or azetidine. When the heteroatom is an oxygen atom, it is expressed as "having an oxygen atom in the ring", and examples of such rings include aromatic heterocycles such as furan, and non-aromatic heterocycles such as tetrahydrofuran or 1,4-dioxane. When the heteroatom is a sulfur atom, it is expressed as "having a sulfur atom in the ring", and examples of such rings include aromatic heterocycles such as thiophene, and non-aromatic heterocycles such as tetrahydrothiophene. 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, or oxazolidinone. 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, or thiazolidinone.

[0041] As used herein, the term "heterocyclic group" or "heterocyclyl" refers to a group having at least one heteroatom (such as N, O, S, etc.) in the ring, and the ring may be aromatic or non-aromatic, that is, it may be 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 also be optionally substituted, preferably with alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, a halogen atom, or aryl. Specific examples of the heterocyclic group include pyridyl, piperidino, morpholino, pyrrolidino, oxadiazolonyl, oxazolidin-2-yl, oxazolin-2-yl, aziridinyl, dihydrooxazolyl, or azetidinyl.

[0042] As used herein, the term "arylalkyl (aralkyl)" refers to a group containing both the above-mentioned aryl and the above-mentioned alkyl, for example, a group in which at least one hydrogen atom of the alkyl is substituted with aryl. Preferably, the arylalkyl is, for example, "C6-C 10 aryl C1-C6 alkyl", etc., and specific examples include, for example, benzyl, phenethyl, etc. The aryl group of the arylalkyl may be optionally substituted, preferably with alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, or a halogen atom.

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

[0044] As used herein, "alkylene" refers to a divalent group derived by further removing one arbitrary hydrogen atom from the above-mentioned "alkyl". Preferred examples of alkylene include C1-C2 alkylene, C1-C3 alkylene, C1-C4 alkylene, C1-C5 alkylene, C1-C6 alkylene, and the like. 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-, -(CH2)6-, and the like.

[0045] As used herein, "arylene" refers to a divalent group derived by further removing one arbitrary hydrogen atom from the above-mentioned aryl. The arylene may be a monocyclic 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 and the like. The arylene group may be substituted with any substituent, and is preferably substituted with an alkyl, an alkoxy, a fluoroalkyl, a fluoroalkoxy, an oxo, an aminocarbonyl, or a halogen atom.

[0046] As used herein, "heteroarylene" means a divalent group derived by further removing one arbitrary hydrogen atom from the heteroaryl. The heteroarylene may be a monocyclic 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 the heteroarylene include imidazolediyl, pyridinediyl, oxadiazolediyl, thiazolediyl, thiadiazolediyl, and the like. The heteroarylene group may be substituted with any substituent, and is preferably substituted with alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, or a halogen atom.

[0047] As used herein, the "fused ring structure" refers to a cyclic structure in a cyclic compound having two or more rings, in which a plurality of rings share two or more atoms. The "fused ring structure formed by two or more aromatic rings" refers to a cyclic structure in a cyclic compound having two or more aromatic rings, in which a plurality of aromatic rings share two or more atoms. Although not intended to be limiting, examples of the fused ring structure include an indole skeleton, a benzofuran skeleton, a benzimidazole skeleton, a quinoline skeleton, a bicyclo[4.4.0]decane skeleton, and the like.

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

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

[0050] As used herein, the “protecting group for hydroxy” includes alkyl ether type protecting groups, aralkyl ether type protecting groups, silyl ether type, carbonate ester type protecting groups, and the like. Specific examples of the protecting group for hydroxy include methoxymethyl group, benzyloxymethyl group, tetrahydropyranyl group, tert-butyl group, allyl group, 2,2,2-trichloroethyl group, benzyl group, 4-methoxybenzyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, methoxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, and the like.

[0051] As used herein, “protected hydroxy” means a hydroxy group protected by the above-mentioned protecting group for hydroxy.

[0052] In the production of the compounds described herein, when the defined groups undergo unwanted chemical conversions under the conditions of the implementation method, for example, the compounds can be produced by using means such as protection and deprotection of functional groups. Here, the selection of the protecting group and the desorption operation can include, for example, the methods described in “Greene’s, “Protective Groups in Organic Synthesis” (5th Edition, John Wiley & Sons 2014)”, and these can be appropriately used according to the reaction conditions. Also, if necessary, the order of reaction steps such as introduction of substituents can be changed.

[0053] In this specification, when a modifying phrase "optionally substituted" is given, examples of the substituent include, for example, 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, a formyl group, and the like. Furthermore, each of these may be optionally substituted with a substituent, and these substituents are not limited either. For example, one or more may be freely selected independently from among 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. For example, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, cycloalkyl, and the like are exemplified.

[0054] The compounds represented by the various formulas of the present invention can be their salts or their solvates. Examples of salts of the compounds represented by the various formulas include hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; sulfonates such as methanesulfonate, p-toluenesulfonate; carboxylates such as acetate, citrate, malate, tartrate, succinate, salicylate; or alkali metal salts such as sodium salt, potassium salt; alkaline earth metal salts such as magnesium salt, calcium salt; ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc. These salts are produced, for example, by bringing the compound into contact with an acid or a base. The solvate of the compound represented by the various formulas refers to the phenomenon in which solute molecules strongly attract solvent molecules in a solution to form a single molecular aggregate, and when the solvent is water, it is called a hydrate. The compounds represented by the various formulas 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, and can also form solvates with a plurality of 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 acid" refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, Pro. Unnatural amino acids (amino acid derivatives) are not particularly limited, and examples include β - amino acids, D - type amino acids, N - substituted amino acids, α,α - disubstituted amino acids, amino acids with side chains different from natural amino acids, hydroxycarboxylic acids, etc. As the amino acids herein, any configuration is acceptable. The selection of the side chain of the amino acid is not particularly restricted, and in addition to a hydrogen atom, for example, it can be freely selected from an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroaralkyl group, a cycloalkyl group, a spiro - fused cycloalkyl group. Each may be provided with a substituent, and these substituents are also not restricted and can be independently selected freely from one or more of 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. That is, examples include an optionally substituted alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a cycloalkyl group, etc., or oxo, aminocarbonyl, a halogen atom, etc. In one non - limiting aspect, the amino acids herein may be compounds having a carboxy group and an amino group within the same molecule (even in this case, imino acids such as proline and hydroxyproline are also included in amino acids).

[0056] Examples of substituents derived from halogen include fluoro (-F), chloro (-Cl), bromo (-Br), iodo (-I), etc.

[0057] Examples of substituents derived from an O atom include hydroxy (-OH), oxy (-OR), carbonyl (-C=O-R), carboxyl (-CO2H), oxycarbonyl (-C=O-OR), carbonyloxy (-O-C=O-R), thiocarbonyl (-C=O-SR), carbonylthio group (-S-C=O-R), aminocarbonyl (-C=O-NHR), carbonylamino (-NH-C=O-R), oxycarbonylamino (-NH-C=O-OR), sulfonylamino (-NH-SO2-R), aminosulfonyl (-SO2-NHR), sulfamoylamino (-NH-SO2-NHR), thiocarboxyl (-C(=O)-SH), carboxylcarbonyl (-C(=O)-CO2H).

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

[0059] Examples of carbonyl (-C=O-R) include formyl (-C=O-H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, etc.

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

[0061] Examples of carbonyloxy (-O-C=O-R) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, aralkylcarbonyloxy, etc.

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

[0063] Examples of carbonylthio (-S-C=O-R) 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, and the like. 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=O-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylcarbonylamino, and the like. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C=O-R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0066] Examples of oxicarbonylamino (-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, aralkyl are 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, aralkyl are 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, aralkyl are included.

[0069] Examples of sulfamoyl amino (-NH-SO2-NHR) include alkylsulfamoyl amino, cycloalkylsulfamoyl amino, alkenylsulfamoyl amino, alkynylsulfamoyl amino, arylsulfamoyl amino, heteroarylsulfamoyl amino, aralkylsulfamoyl amino, etc. Further, the two H atoms bonded to the N atom in -NH-SO2-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 also form a ring.

[0070] Examples of substituents derived from the S atom include thiol (-SH), thio (-S-R), sulfinyl (-S=O-R), sulfonyl (-S(O)2-R), sulfo (-SO3H), pentafluorosulfanyl (-SF5).

[0071] Examples of thio (-S-R) are selected from alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio, etc.

[0072] Examples of sulfinyl (-S=O-R) include alkylsulfinyl, cycloalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, etc.

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

[0074] As substituents derived from N atoms, azide (-N3, also referred to as "azide 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''), aminocarbonylamino (-NR-CO-NR'R'') can be mentioned.

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

[0076] Examples of tertiary amino (-NR(R')) include, for example, alkyl(aralkyl)amino, etc., an amino group having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., and any two of these 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 independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, such as alkyl(aralkyl)(aryl)amidino, etc.

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

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

[0080] Examples of substituents derived from a B atom include boryl (-BR(R')) and dioxaborolyl (-B(OR)(OR')). The two substituents R and R' are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., or they may form a ring. Specifically, cyclic boryl groups are included, and more specifically, pinacolato boryl groups, neopentanediolato boryl groups, catecholato boryl groups, etc. are included.

[0081] Specific examples of substituents on the nitrogen atom of the N-substituted amino acid in this specification include alkyl, C1-C6 alkyl, C1-C4 alkyl, methyl, etc.

[0082] The "aromatic amino acid derivative" in this specification is exemplified by those among the above amino acid derivatives that contain an aromatic substituent in the side chain of the amino acid. Specific examples of the aromatic substituent include optionally substituted aryl and optionally substituted heteroaryl.

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

[0084] The "amino acid" in this specification includes all corresponding isotopes. The isotope of the "amino acid" is one in which at least one atom is substituted with an atom having the same atomic number (number of protons) and a different mass number (sum of the number of protons and neutrons). Examples of the isotopes included in the "amino acid" of this specification include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, etc., respectively, 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 35 S, 18 F, 36 Cl, etc. are included.

[0085] (Method for producing the compound represented by formula I) In one embodiment, the present invention provides a compound of formula I:

Chemical formula

Chemical formula

Chemical formula

[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, for example, 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, diphenylmethylidene group, etc. Among these, Fmoc, Boc, Alloc, Cbz, Teoc, or trifluoroacetyl is 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, for example, methyl, ethyl, t-Bu, benzyl, trityl, cumyl, methoxytrityl, and 2-(trimethylsilyl)ethyl, 2,2,2-trichloroethyl, allyl, etc. Among these, methyl, ethyl, t-Bu, benzyl, trityl, cumyl, methoxytrityl, or 2-(trimethylsilyl)ethyl is preferred.

[0090] When R2 and R3 together form a divalent protecting group, the divalent protecting group can be methylene which may be substituted by one or two substituents, and is preferably -(CR8R9)-. When R2 and R3 together form -(CR8R9)-, formula I becomes formula IA:

Chemical formula

[0091] Specific examples of the compound represented by formula IA include, for example, the following structures:

Chemical formula

[0092] In formula I, R6 is optionally substituted C6-C 10 aryl, or optionally substituted heteroaryl. When R6 is optionally substituted C6-C 10 aryl, phenyl is preferred as the C6-C 10 aryl. Also, when R6 is optionally substituted heteroaryl, pyridyl is preferred as the heteroaryl. Optionally substituted C6-C10 As the substituent of aryl or the substituent of heteroaryl which may be substituted, there are C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C6 alkenyloxy, halogen, C3-C8 cycloalkyl, -NR p R q (wherein R p and R q are independently hydrogen or C1-C4 alkyl), -CONR r R s (wherein R r and R s are independently selected from the group consisting of hydrogen, hydroxy, protected hydroxy group, C1-C4 alkyl, and C1-C4 alkylsulfonyl), cyclic boryl and the like. More specifically as these substituents, there are methyl, methoxy, chloro, fluoro, isopropyl, cyclopropyl, trifluoromethyl, methylaminocarbonyl, methylsulfonylamino, hydroxycarbamoyl (including those in which the hydroxy group is protected by a protecting group, for example, (tetrahydro-2H-pyran-2-yl)oxycarbamoyl, methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl, etc.), pinacolato boryl, neopentanediolato boryl, catecholato boryl, allyloxy and the like. The number of substituents of C6-C 10 aryl which may be substituted or heteroaryl which may be substituted is not particularly limited. For example, it preferably has 0 to 3 substituents. When the number of substituents is plural, preferred combinations of substituents are 1 C1-C4 haloalkyl and 1 or 2 halogens, 2 C1-C4 alkoxys, 1 C1-C4 alkoxy and 1 or 2 halogens, 1 -CONR r R sExamples include one C1-C4 alkoxy group. More specifically, as combinations of these substituents, there are trifluoromethyl and one or two fluorine atoms, trifluoromethyl and one or two chlorine atoms, one trifluoromethyl, one fluorine atom, and one chlorine atom, two methoxy groups, methoxy and one or two fluorine atoms, one methylaminocarbonyl and one methoxy group, one methylsulfonylamino and one methoxy group, and the like.

[0093] Specific examples of R6 include, for example, the following groups. Here, "*" in the formula means a bonding point.

Chemical formula

Chemical formula

[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

Chemical formula

Chemical formula

[0098] R5 in Formula II is

Chemical formula

Chemical formula

[0099] R5 in Formula II is

Chemical formula

Chemical formula

[0100] R5 in Formula II is

Chemical formula

Chemical formula

[0101] "R6-X" used in this project, where R6 is an optionally substituted C6-C 10 aryl, or an optionally substituted heteroaryl, and X is halogen, OTf, or OMs. As R6, the same group as the aforementioned R6 in Formula I can be used. As X, iodine, bromine, or OTf is preferred.

[0102] As R6-X, more specifically, for example, 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, 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, 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, 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, 4-(trifluoromethyl)phenyl trifluoromethanesulfonate, 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, 2-fluoro-4-methoxyphenyl trifluoromethanesulfonate, 3-fluoro-4-methoxyphenyl trifluoromethanesulfonate, 3,5-difluoro-4-methoxyphenyl, 3,5-difluoro-4-(trifluoromethyl)phenyl trifluoromethanesulfonate, 3-methoxy-4-(methylcarbamoyl)phenyl trifluoromethanesulfonate, 4-methoxy-3-(methylcarbamoyl)phenyl trifluoromethanesulfonate, 3,5-dichloro-4-(trifluoromethyl)phenyl trifluoromethanesulfonate, 3-chloro-5-fluoro-4-(trifluoromethyl)phenyl trifluoromethanesulfonate, 3-methoxy-4-((methylsulfonyl)carbamoyl)phenyl trifluoromethanesulfonate, 4-(methyl((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl trifluoromethanesulfonate, 3-methoxy-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl trifluoromethanesulfonate, pyridin-2-yl trifluoromethanesulfonate, 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, pyrimidin-5-yl trifluoromethanesulfonate, etc. can be mentioned.,

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

[0104] The catalyst used in this process is (a) a metal, (b) formed by mixing a metal and a compound that can be its ligand, (c) a complex of a metal and its ligand, or (d) formed by further mixing a complex of a metal and its ligand with a compound that can be the ligand of the metal.

[0105] In each of the above cases (a) to (d), the metals used include nickel, chromium, iron, copper, palladium, or their salts, or solvates of nickel, chromium, iron, copper, palladium, or their salts. Specific examples of such metals include, for example, nickel, bis(1,5-cyclooctadiene)nickel(0), 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, bis(dichlorooctadienyl)nickel, or their solvates with water, methoxyethyl ether, diglyme, or ethylene glycol dimethyl ether, etc.

[0106] When the catalyst is formed by mixing a metal and a compound that can be its ligand, the compounds that can be the ligand of the metal are represented by, for example, the following formulas B to G. Formula B:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0107] Formula B: [Chemical formula] wherein, R BX and R BY are independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, heterocyclyl, or C6-C 10 aryl. Specific examples of the compound represented by Formula B include, for example, 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.

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

[0109] Formula D:

Chemical formula

[0110] Formula E:

Chemical formula

[0111] Formula F:

Chem.

[0112] Formula G:

Chem.

[0113] When the catalyst is a complex of a metal and its ligand, specific examples of the complex of the 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]amine nickel(II) chloride, cis-[2,2'-bis(diphenylphosphino)-1,1'-binaphthyl](2-methylphenyl)nickel(II) chloride, [1,2-bis(diphenylphosphino)ethane]dichloronickel(II), and the like.

[0114] When the catalyst is formed by mixing a complex of a metal and its ligand with a compound that can further serve as a ligand for the metal, specific examples of the complex of the 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, [1,2-bis(diphenylphosphino)ethane]dichloronickel(II), etc. 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, etc.

[0115] As the reducing agent used in this step, a substance having an effect of reducing the positive charge of the catalyst used in this step can be used. Examples of such a reducing agent include metals having a greater ionization tendency than the metal contained in the catalyst. Specific examples of such metals include, for example, zinc, manganese, iron, magnesium, etc. Among 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 greater ionization tendency than nickel, such as zinc, iron, 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, based on the compound represented by Formula II.

[0118] As the additive used in this step, a substance that can efficiently convert the starting material, the compound represented by Formula II, into the target compound, the compound represented by Formula I, can be used, such as shortening the time required for the conversion compared to the case without it. Specifically, a silyl compound or 1,2-dibromoethane can be used as such an additive. Specifically, as the silyl compound, Formula A:

Chemical formula

[0119] More specifically, as the compound represented by Formula A, TMSCl, TMSBr, TMSI, TMSOTf, TBDMSCl, TESCl, TIPSCl, TBDPSCl, and chlorotriethoxysilane can be mentioned, 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 as compared to the case without it. For example, regardless of the stirring state such as stirring using a stirring blade or stirring using a stir bar, the reaction can proceed efficiently with a high conversion rate.

[0122] As the solvent used in this step, for example, an aprotic solvent such as an amide-based solvent or a urea-based solvent can be used. Specific examples of such solvents include, for example, DMF, DMA, NMP, DMI, or DMPU.

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

[0124] The reaction of this step can be carried out with a reaction time of 10 minutes to 1 week. Preferably, the reaction can be carried out with a reaction time of 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 their solvates, a reducing agent, an additive, and R6-X is not particularly limited. For example, (a) mixing the additive after mixing the compound represented by Formula II, its salt, or their solvates, a reducing agent, and R6-X in the presence of a solvent and a catalyst; (b) mixing the compound represented by Formula II, its salt, or their solvates and R6-X after mixing a reducing agent and an additive in the presence of a solvent and a catalyst; or (c) mixing the compound represented by Formula II, its salt, or their solvates, R6-X, and an additive after mixing a reducing agent in the presence of a solvent and a catalyst is preferred. As a more specific embodiment of the above (a), for example, a solution of a catalyst dissolved in a solvent is dropped into a solution of a compound represented by Formula II, its salt, or a solvate thereof, a reducing agent, and R6-X dissolved in a solvent, and then an additive is added. Also, a solution of a catalyst dissolved in a solvent is dropped into a solution of a compound represented by Formula II, its salt, or a solvate thereof and R6-X dissolved in a solvent, and then a reducing agent is added, and then an additive is added. As a more specific embodiment of the above (b), for example, a reducing agent and an additive are added to a solution of a catalyst dissolved in a solvent, and then a solution of a compound represented by Formula II, its salt, or a solvate thereof and R6-X dissolved in a solvent is dropped. As a more specific embodiment of the above (c), for example, a reducing agent is added to a solution of a catalyst dissolved in a solvent, and then a solution of a compound represented by Formula II, its salt, or a solvate thereof, R6-X, and an additive dissolved in a solvent is added.

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

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

[0128] In one 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 are synonymous with R1, R3, R5, R7, and n of the above Formula II, respectively. [Chemical formula] This step can be carried out by mixing an arbitrary alcohol (R5-OH) and a carboxylic acid with a dehydrating condensing 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 are synonymous with R1, R3, R5, R7, and n of Formula II above, 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).

Chemical formula

[0130] In another embodiment, the compound represented by Formula II of the present invention, wherein 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 synonymous with R1, R3, R5, R7, and n of Formula II above, respectively, R4 is a protecting group for a carboxyl group, and “Alk” is C1-C6 alkyl.

Chemical formula

[0131] In another embodiment, the compound represented by Formula II of the present invention 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 respectively synonymous with R1, R3, R5, R7, and n of Formula II above, R4 is a protecting group for a carboxyl group, “Alk” is C1-C6 alkyl, and R 12 is hydrogen or C1-C5 alkyl.

Chemical formula

[0132] In another aspect, when R2 and R3 combine to form -(CR8R9)-, the compound represented by 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 respectively synonymous with R1, R5, R7, R8, R9, and n of the above formula IIA, and R4 is a protecting group for the carboxyl group.

Chemical formula

[0133] In another aspect, when R2 and R3 combine to form -(CR8R9)-, the compound represented by 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 are respectively synonymous with R1, R5, R7, R8, R9, and n of the above formula IIA, and R4 is a protecting group for the carboxyl group.

Chemical formula

[0134] (Modification of the compound represented by formula I) The present invention can further prepare various amino acid analogs, salts thereof, or solvates thereof, starting from the compound represented by formula I, a salt thereof, or a solvate thereof produced according to the above method.

[0135] In one aspect, when R3 of 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 is used as a starting material, and by removing the protecting group, the compound represented by formula III, a salt thereof, or a solvate thereof can be produced. [Chemical formula] The deprotection step can be carried out by the method described in “Greene’s, “Protective Groups in Organic Synthesis” (5th Edition, John Wiley & Sons 2014)”.

[0136] In one aspect, when R1 of the compound represented by formula I, its salt, or their solvate is a protecting group for an amino group and R3 is a protecting group for a carboxyl group, the compound represented by formula IV can be produced by simultaneously removing these protecting groups as shown in the following scheme, and further introducing a protecting group R1' to the amino group to produce a compound represented by formula V.

Chemical formula

[0137] In one aspect, when R2 and R3 of the compound represented by formula I combine to form -(CR8R9)- and the compound represented by formula I is represented by formula IA, the compound represented by formula IA, its salt, or their solvate is used as a starting material, and the oxazolidinone ring is opened by a deprotection reaction to produce a compound represented by formula VI, its salt, or their solvate.

Chemical formula

[0138] In one aspect, the present invention can produce an N-alkyl amino acid using the compound represented by formula IA as a starting material as shown in the following scheme.

Chemical formula

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

[0140] In one aspect, as such an amino acid derivative, preferably, a compound of the formula (I):

Chemical formula

[0141] More preferably, the amino acid derivative of the present invention is the amino acid derivative represented by formula (1). [Chemical formula] In the formula, 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, both X2 and X3 are halogen or one of X2 and X3 is halogen.

[0142] In formula (1), when X1 is 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. Preferably, X2 = F and X3 = F, X2 = F and X3 = Cl, or X2 = Cl and X3 = Cl for X2 and X3.

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

[0145] Specific examples of the amino acid derivative of formula (1) include, for example, the following compounds, their salts, or their solvates: (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-butoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (C-030) Methyl 2-(((tert-butoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-031) tert-Butyl 2-(((tert-butoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (C-032) Benzyl 2-(((tert-butoxy)carbonyl)(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-butoxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoic acid, (C-050) Methyl 2-(((tert-butoxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-051) tert-Butyl 2-(((tert-butoxy)carbonyl)amino)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)propanoate, (C-052) Benzyl 2-(((tert-butoxy)carbonyl)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 aspect, specific examples of the amino acid derivatives of the present invention include the compounds, salts thereof, or solvates thereof described in the following table. In each table, R1, R2, R3, R6, R7, and n respectively represent R1, R2, R3, R6, R7, and n in the following formulas. Also, * represents a bonding point. [Chemical formula]

[0147] [Table 1] TIFF0007703071000061.tif224161 TIFF0007703071000062.tif224161 TIFF0007703071000063.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

[0159]

Table 13

[0160]

Table 14

[0161] Isolation and purification of the target compound obtained through each of the above reaction steps can be carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatographies.

[0162] In addition, the compounds of the present invention, their salts, or their solvates include all stereoisomers of the target compound obtained through each of the above reaction steps (for example, enantiomers, diastereomers (including cis and trans geometric isomers)), racemates of the above isomers, and other mixtures. For example, the compounds of the present invention may have one or more asymmetric points, and the present invention includes racemic mixtures, diastereomer 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 the state of salts, hydrates, or solvates that the compound may form according to conventional methods.

[0164] In addition, 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 according to conventional methods.

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

Examples

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

[0167] Solvents exemplified such as DMF, DMA, NMP, DMI, or DMPU used in the implementation of the present invention were used without purification of commercial supplier products. Also, in reactions where water was not added as a solvent, dehydrated solvents, ultra-dehydrated solvents, or anhydrous solvents were used without purification of commercial supplier products.

[0168] Reagents such as the silyl compounds used in the implementation of the present invention, or additives exemplified by 1,2-dibromoethane, compounds that can serve as metals, ligands, metal-ligand complexes, reducing agents, reagents used in the step of introducing a protecting group, and reagents used in the deprotection step were used without purification of commercially available supplier products, except as specifically described.

[0169] Starting materials of aromatic amino acid derivatives typified by phenylalanine derivatives and homophenylalanine derivatives used in the implementation of the present invention were used without purification of commercially available supplier products, except as specifically described. Further, they were produced and used by known methods as necessary.

[0170] 1 The 1H-NMR spectrum was measured using an AVANCE III HD 400 BBFO-SMART probe (manufactured by Bruker). The chemical shift of Me4Si used as an internal standard substance was set to 0 ppm, and the deuterium lock signal from the sample solvent was referenced. The chemical shift of the signal of the compound to be analyzed was expressed in ppm. Abbreviations for signal splitting were expressed as s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, m = multiplet, and the signal splitting width was expressed as the J value (Hz). The integral value of the signal was calculated based on the ratio of the signal area intensities of each signal.

[0171] [Conditions 1 for High Performance Liquid Chromatography] Apparatus: Manufactured by Shimadzu Corporation Column: Ascentis Express RP-Amide (3.0 mm I.D. x 50 mm) Mobile phase: Water (A) containing 0.05% trifluoroacetic acid and acetonitrile (B) containing 0.05% trifluoroacetic acid Elution method: Stepwise solvent gradient elution of 5% B to 95% B (5.0 minutes), held at 95% B (2.0 minutes) Flow rate: 0.7 mL / min Column temperature: 30 °C

[0172] [Conditions 2 for High Performance Liquid Chromatography] Apparatus: Waters Acquity UPLC / SQD Column: Ascentis Express C18 (2.1 mm I.D. x 50 mm) 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 minutes), held at 100% B (2.0 minutes) Flow rate: 1.0 mL / min

[0173] [Conditions 3 for High Performance Liquid Chromatography] Apparatus: Waters Acquity UPLC / SQD Column: Ascentis Express C18 (2.1 mm I.D. x 50 mm) 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 minute), held at 100% B (0.4 minute) Flow rate: 1.0 mL / min

[0174] [Conditions 4 for High Performance Liquid Chromatography] Apparatus: Waters Acquity UPLC / SQD Column: Ascentis Express C18 (2.1 mm I.D. x 50 mm) 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 minute), held at 100% B (0.4 minute) Flow rate: 1.0 mL / min

[0175] [Conditions 5 for High Performance Liquid Chromatography] Apparatus: Manufactured by Shimadzu Corporation Column: Ascentis Express C18 (3.0 mm I.D. x 50 mm) Mobile phase: Water (A) containing 0.05% trifluoroacetic acid and acetonitrile (B) containing 0.05% trifluoroacetic acid Elution method: Stepwise solvent gradient elution of 5% B to 95% B (2.0 minutes), held at 95% B (0.7 minutes) Flow rate: 1.0 mL / min

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

[0177] Reference Example 1: When stirred with a stirring blade without using TMSCl as an additive Production of benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate

Chemical formula

[0178] Example 1: When 5 mol% of TMSCl was used as an additive and stirred with a stirring blade Production of benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate

Chemical formula

[0179] Example 2: When using 50 mol% of TMSCl as an additive and stirring with a stirrer blade Production of benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoate

Chemical formula

[0180] Example 3: When 52 mol% of TMSCl was used as an additive and stirred with a stirring blade Production of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-chloro-4-(trifluoromethyl)phenyl)butanoic acid [Chemical formula] Nickel(II) 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. Zinc powder (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) were added to a flask equipped with a stirring blade. After adding 4-bromo-2-chloro-1-(trifluoromethyl)benzene (8.1 g, 31 mmol), the mixture was purged with nitrogen. The prepared catalyst solution was added dropwise to the reaction solution under a nitrogen atmosphere, followed by the addition of TMSCl (0.56 g, 5.2 mmol), and the solution was stirred at 25 °C for 3 hours. Analysis of the reaction mixture by HPLC confirmed that the raw materials had completely disappeared and the target product was the main product. Ethyl acetate (50 mL) and 10% aqueous EDTA·2Na solution (50 mL) were added to the reaction solution, and the organic layer was washed with 10% aqueous NaCl solution (50 mL). The obtained organic layer was concentrated under reduced pressure, toluene (25 mL) was added to prepare a solution, and the solution was divided into two portions. The solution was cooled to 0 °C, TfOH (2.3 g) was added dropwise, and after warming to 25 °C, water (2.5 mL) was added. After stirring for 45 minutes, 10 mL of water was added and separated. 40% aqueous K3PO4 solution (2.0 mL) and acetonitrile (13 mL) were added to the aqueous layer. FmocOSu (1.8 g) was added, and 40% aqueous K3PO4 solution (3.5 mL) was added. After discharging the lower layer, 5N HCl (2.2 mL) was added, and the precipitated solid was filtered and 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 the target product: 3.1 minutes (Condition 2 of high performance liquid chromatography) 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

Chemical formula

[0182] Example 5: Preparation of tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-3-yl)butanoate [Chemical formula] Nickel(II) bromide trihydrate (0.14 g, 0.53 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.14 g, 0.53 mmol) were dissolved in DMA (8.0 mL). After purging with nitrogen, the mixture was stirred to prepare a catalyst solution. Zinc powder (0.57 g, 8.8 mmol), N-(((9H-fluoren-9-yl)methoxy)carbonyl)-L-glutamic acid 5-(1,3-dioxoisoindolin-2-yl) 1-tert-butyl (1.0 g, 1.8 mmol), and DMA (8.0 mL) were added to a flask. After adding 3-iodopyridine (1.1 g, 5.3 mmol), the mixture was purged with nitrogen. The prepared catalyst solution was added dropwise to the reaction solution under a nitrogen atmosphere. Then, TMSCl (95 mg, 0.88 mmol) and 1,2-dibromoethane (0.33 g, 1.8 mmol) were added, and the mixture was stirred at 25 °C for 3 hours. When the reaction mixture was analyzed by HPLC, it was confirmed that the raw materials had completely disappeared and the target product had been formed. The reaction solution was quenched with an aqueous solution of EDTA·2Na, and the organic layer extracted with MTBE was washed with brine. The organic layer was dried over sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by chromatography to obtain tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-3-yl)butanoate (0.21 g, yield 26%). (S)-2-(((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(pyridin-3-yl)butanoic acid tert-butyl Retention time of the target product: 1.0 minute (Condition 3 of high performance liquid chromatography) 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 [Chemical formula] Nickel(II) 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 then stirred to prepare a catalyst solution. Zinc powder (11 g, 175 mmol), N-(((9H-fluoren-9-yl)methoxy)carbonyl)-L-glutamic acid 5-(1,3-dioxoisoindolin-2-yl) 1-tert-butyl (20 g, 35 mmol), and DMA (175 mL) were added to the flask. After adding 5-bromo-1,3-difluoro-2-(trifluoromethyl)benzene (27 g, 105 mmol), the mixture was purged with nitrogen. The prepared catalyst solution was added dropwise to the reaction solution under a nitrogen atmosphere, and then TMSCl (1.9 g, 18 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. When the reaction mixture was analyzed by HPLC, it was confirmed that the raw materials had completely disappeared and the target product was the main product. The reaction solution 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 hydrogen carbonate and an aqueous solution of ammonium chloride, and the organic layer was concentrated. The obtained crude product was purified by recrystallization to obtain (tert-butyl (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate (15 g, yield 76%). tert-Butyl (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate: Retention time of the target product: 1.3 minutes (Condition 4 of high-performance liquid chromatography) 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 [Chemical formula] (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 the mixture was stirred at 25 °C for 20 minutes. Sodium bicarbonate was added and stirred, and the insoluble matter was removed by filtration. The filtrate was diluted with MTBE and washed with an aqueous Na2CO3 solution and brine. The organic layer was concentrated to obtain N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-5-allyl 1-(tert-butyl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-glutamate (20 g, yield 91%). 5-Allyl 1-(tert-butyl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-glutamate: Retention time of the target product: 1.1 minutes (Condition 4 of high-performance liquid chromatography) 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

Chem.

[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

Chem.

[0187] Example 10: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(pyridin-3-yl)butanoate

Chemical formula

[0188] Example 11: Preparation of 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl) (((9H-fluoren-9-yl)methoxy)carbonyl)-L-aspartate

Chemical formula

[0189] Example 12: Preparation of tert-butyl (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxyphenyl)propanoate

Chemical formula

[0190] Example 13: Preparation of 4-allyl 1-(tert-butyl) N-(((9H-fluorene-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate

Chemical Structure

[0191] Example 14: Preparation of (S)-3-(((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid

Chemical formula

[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

Chemical formula

[0193] Example 16: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(pyrimidin-5-yl)propanoate

Chemical formula

[0194] Example 17: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoate [Chemical formula] Nickel(II) bromide trihydrate (0.21 g, 0.77 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.25 g, 0.95 mmol) were dissolved in DMA (15 mL), purged with nitrogen, and then stirred to prepare a catalyst solution. Zinc powder (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), and DMA (8.0 mL) were added to a flask. After adding 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (2.3 g, 9.5 mmol), the mixture was purged with nitrogen. The prepared catalyst solution was added dropwise to the reaction solution under a nitrogen atmosphere, followed by the addition of TMSCl (0.17 g, 1.6 mmol), and the mixture was stirred at 25 °C for 30 minutes. Analysis of the reaction mixture by HPLC confirmed that the starting materials had completely disappeared and the desired product was the main product. The reaction solution 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 resulting crude product was purified by chromatography to obtain tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoate (0.93 g, yield 55%). tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoate: Retention time of the target product: 1.2 minutes (Condition 4 of high-performance liquid chromatography) 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

Chemical formula

[0196] Example 19: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(2-fluoro-4-methoxyphenyl)propanoate

Chemical formula

[0197] Production of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid Following the synthetic scheme below, (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoic acid was produced. [Chemical formula]

[0198] Example 20: Preparation of (9H-Fluoren-9-yl)methyl (4S)-4-(2-(allyloxy)-2-oxoethyl)-2-methyl-5-oxooxazolidine-3-carboxylate [Chemical formula] (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 paraformaldehyde (25 g, 0.19 mol) were suspended in toluene (0.50 L), and trifluoroacetic acid (29 g, 0.38 mol) was added at room temperature. After stirring at 90 °C for 16 hours, it was cooled to room temperature, diluted with ethyl acetate, and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain (9H-Fluoren-9-yl)methyl (4S)-4(2-(allyloxy)-2-oxoethyl)-2-methyl-5-oxooxazolidine-3-carboxylate (45 g, yield 82%). (9H-Fluoren-9-yl)methyl (4S)-4(2-(allyloxy)-2-oxoethyl)-2-methyl-5-oxooxazolidine-3-carboxylate: Retention time of the target product: 1.4 minutes (Condition 6 of high performance liquid chromatography) 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 [Chemical formula] ((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 aqueous layer was extracted with an aqueous sodium hydrogen carbonate solution, and the aqueous layer was washed 3 times with hexane. The aqueous layer was adjusted to pH 2 with hydrochloric acid and extracted twice with MTBE. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain (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 the target product: 1.9 minutes (Condition 5 of high performance liquid chromatography) 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 [Chemical formula] (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-trichloroacetimidate (5.1 g, 24 mmol) in cyclohexane (20 mL) was added dropwise. BF3·OEt2 (17 mg, 0.12 mmol) was added to this solution, and the mixture was stirred at 25 °C for 16 hours. The insoluble material was removed by filtration, and the filtrate was concentrated, diluted with MTBE, and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and concentrated to obtain 4-allyl 1-(tert-butyl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate (4.9 g, yield 85%). 4-allyl 1-(tert-butyl) N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-aspartate: Retention time of the target product: 1.6 minutes (Condition 6 of high performance liquid chromatography) 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 [Chemical formula] 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 h and then concentrated. MTBE was added to the concentrate and dissolved. The target product was extracted into the aqueous layer with an aqueous sodium carbonate solution. Phosphoric acid was added to this aqueous layer to acidify the aqueous layer, and the target product was extracted three times with MTBE. The organic layer was washed with brine and then dried over sodium sulfate. The concentrate was purified by chromatography to obtain (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (2 g, yield 46%). (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid: Retention time of the target product: 1.7 min (Condition 5 of high performance liquid chromatography) 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

Chemical Structure

[0203] Example 25: Preparation of tert-butyl (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate [Chemical formula] Nickel(II) 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 then stirred to prepare a catalyst solution. DMA (0.50 mL) was added to 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) and dissolved. The prepared catalyst solution was added dropwise to the reaction solution under a nitrogen atmosphere, zinc powder (68 mg, 1.0 mmol) and then TMSCl (11 mg, 0.10 mmol) were added, and the reaction vessel was shaken at 25 °C for 2 hours. When the reaction mixture was analyzed by HPLC, it was confirmed that the raw materials had completely disappeared and the target product was formed. The reaction solution was purified by chromatography to obtain tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate (66 mg, yield 65%). tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(ethyl)amino)-3-(p-tolyl)propanoate: Retention time of the target product: 1.2 minutes (Condition 4 of high performance liquid chromatography) 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

Chemical formula

[0205] Example 27: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(p-tolyl)propanoate

Chemical formula

[0206] Example 28: Preparation of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxyphenyl)butanoate [Chemical formula] Nickel(II) 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. Then, zinc powder (65 mg, 1.0 mmol) was added to this solution 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), and then TMSCl (11 mg, 0.10 mmol) was added. 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. When the reaction mixture was analyzed by HPLC, it was confirmed that the raw materials had completely disappeared and the target product was formed. The reaction solution was purified by chromatography to obtain tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxyphenyl)butanoate (67 mg, yield 67%). tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-methoxyphenyl)butanoate: Retention time of the target product: 1.1 min (Condition 4 of high performance liquid chromatography) ESI (LC / MS positive mode m / z 524 (M+Na) + )

[0207] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoic acid production Using the same conditions and method as in the above example, a step of reacting an N-hydroxyphthalimide ester with an aromatic bromide to obtain an aromatic amino acid derivative is included. Along the following synthetic scheme, (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoic acid can be produced.

Chemical formula

[0208] Example 29: Preparation of (((9H-Fluoren-9-yl)methoxy)carbonyl)-L-glutamic acid 1-methyl 5-(1,3-dioxoisoindolin-2-yl) [Chemical formula] (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. After stirring the reaction mixture at 25 °C for 60 minutes, the solid was removed by filtration. The filtrate was concentrated and purified by chromatography to obtain (((9H-Fluoren-9-yl)methoxy)carbonyl)-L-glutamic acid 1-methyl 5-(1,3-dioxoisoindolin-2-yl) (1.0 g, yield 73%). (((9H-Fluoren-9-yl)methoxy)carbonyl)-L-glutamic acid 1-methyl 5-(1,3-dioxoisoindolin-2-yl): Retention time of the target product: 1.0 minute (Condition 3 of high performance liquid chromatography) 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 [Chemical formula] Nickel(II) bromide trihydrate (4.0 mg, 0.015 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (4.0 mg, 0.015 mmol) were dissolved in DMA (0.50 mL), purged with nitrogen, and then stirred to prepare a catalyst solution. In another container, zinc powder (69 mg, 1.1 mmol), (((9H-fluoren-9-yl)methoxy)carbonyl)-L-glutamic acid 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 added with DMA (0.50 mL) and dissolved. The prepared catalyst solution was added dropwise to the reaction solution under a nitrogen atmosphere, then TMSCl (11 mg, 0.11 mmol) was added, and the reaction vessel was shaken at 25 °C for 1 hour. When the reaction mixture was analyzed by HPLC, it was confirmed that the raw materials had completely disappeared and the target product was formed. The reaction solution was purified by chromatography to obtain methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoate (64 mg, yield 68%). Methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-methoxyphenyl)butanoate: Retention time of the target product: 0.9 min (Condition 4 of high-performance liquid chromatography) 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

Chemical Structure

Industrial Applicability

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

Claims

**Claim 1** Formula I: 【Chemical 1】 [wherein, R １ is a protecting group for an amino group selected from the group consisting of hydrogen, or Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl, R ２ is hydrogen or C １ -C ６ alkyl, and R ３ is a protecting group for a carboxyl group selected from the group consisting of hydrogen, methyl, ethyl, t-Bu, benzyl, trityl, cumyl, methoxytrityl, and 2-(trimethylsilyl)ethyl. X2 is hydrogen or halogen, X3 is halogen.] An amino acid derivative represented thereby, a salt thereof, or a solvate thereof. **Claim 2** The amino acid derivative, a salt thereof, or a solvate thereof according to Claim 1, wherein the halogen is fluorine or chlorine. **Claim 3** 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, (2-28) tert-Butyl 2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoate, (2-34) tert-Butyl 2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (3-28) tert-Butyl 2-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoate, (3-34) tert-Butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoate, (6-28) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (6-34) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (7-28) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (7-34) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (10-28) 2-Amino-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (10-34) 2-Amino-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid, (11-28) 2-(Methylamino)-4-(3-fluoro-4-(trifluoromethyl)phenyl)butanoic acid, (11-34) 2-(Methylamino)-4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid.

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