JP2023106756A - Boronophenylalanine amide derivative - Google Patents

Abstract

To provide a boronophenylalanine amide derivative.SOLUTION: There is provided a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 together with the B atom represent a substituent of boronic acid (-B(OH)2), boronic acid ester, or boronic acid amide; R3 represents a substituent such as H, halogen, hydroxy; s represents any integer of 1 to 4; R4 represents H, C1-C6 alkyl, benzyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R5 represents a substituent such as H, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 alkynyl, hydroxy; and R6 represents H or an optionally substituted C1-C6 alkyl, or may form a ring structure in which the adjacent methylene moiety and a benzene ring are fused.SELECTED DRAWING: None

Description

The present invention relates to boronophenylalanine amide derivatives.

Boron neutron capture therapy (BNCT) is a cancer treatment method. Boron neutron capture therapy involves taking a boron compound containing boron 10 isotope ( ¹⁰ B) into cancer cells, irradiating low-energy neutron beams (e.g. thermal neutrons), and localizing nuclear reactions occurring within the cells. It is a treatment method that destroys cancer cells. In this therapeutic method, it is important to selectively accumulate boron compounds containing ¹⁰ B in cancer tissue cells in order to enhance the therapeutic effect. Is required.

Derivatives of 4-borono-phenylalanine having a boron atom or a boron atomic group introduced into the basic skeleton have been synthesized as drugs for use in BNCT. Drugs used clinically include 4-borono-phenylalanine derivative (L-BPA) and mercaptoundecahydrododecaborate (BSH). 4-borono-phenylalanine is incorporated into LAT1 (L-type Amino acid Transporter 1), a kind of amino acid transporter, as a mimic of phenylalanine. Since LAT1 expression is enhanced in cancer cells, L-BPA is likely to accumulate, and this property is utilized in the treatment of cancer (see, for example, Non-Patent Document 1).

JP 2008-214319 A

However, depending on the type and degree of malignancy of tumor cells, LAT1 may not be elevated. Since 4-borono-phenylalanine is taken up via LAT1, it is not accumulated in sites where LAT1 is not enhanced, and BNCT cannot be applied in such cases.

Therefore, it is desired to create a new group of compounds that may be taken up by tumor cells even if they are not taken up via LAT1.

An object of the present invention is to provide boronophenylalanine amide derivatives.

The present inventors have made intensive studies to solve the above problems, and as a result, have found a new boronophenylalanine amide derivative and completed the present invention.

ここで、式（Ｉ）中、
Ｒ¹、Ｒ^２は、Ｂ原子と共に、ボロン酸（‐Ｂ（ＯＨ）_２）、ボロン酸エステル、又はボロン酸アミドの置換基を表し；
Ｒ³は、Ｈ、ハロゲン、ヒドロキシ、シアノ、アミノ、Ｃ１－Ｃ６アルキルアミノ、Ｃ１－Ｃ６アルキル、Ｃ１－Ｃ６アルコキシ、ベンジルオキシ、Ｃ１－Ｃ６アルコキシＣ１－Ｃ６アルキル、ニトロ、Ｃ１－Ｃ６ハロアルキル、カルバモイル、Ｃ１－Ｃ６アルキルアミノカルボニル、Ｃ１－Ｃ６アルコキシカルボニル、Ｃ１－Ｃ６アルキルカルボニル、ＣＯＯＲ^１０（Ｒ^１０は、Ｈ又はＣ１－Ｃ６アルキル、アミノ、Ｃ１－Ｃ６アルキルアミノ）、Ｃ１－Ｃ６ハロアルキルスルファニル、Ｃ１－Ｃ６ハロアルキルスルフィニル、Ｃ１－Ｃ６ハロアルキルスルホニル、Ｃ１－Ｃ６アルキルチオ、Ｃ１－Ｃ６アルキルスルフィニル、Ｃ１－Ｃ６アルキルスルホニル、アミノスルホニル、スルホ、及びスルファモイルからなる群から、独立して選択される基を表し；
ｓは、１～４のいずれかの整数を表し；
Ｒ⁴は、Ｈ、Ｃ１－Ｃ６アルキル、ベンジル、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表し；
Ｒ⁵は、Ｈ、置換もしくは非置換のＣ１－Ｃ６アルキル、置換もしくは非置換のＣ２－６アルケニル、置換もしくは非置換のＣ２－６アルキニル、ヒドロキシ、シアノ、置換もしくは非置換のアミノ、置換もしくは非置換のＣ１－Ｃ６アルコキシ、置換もしくは非置換のＣ１－Ｃ６アルコキシＣ１－Ｃ６アルキル、置換もしくは非置換のアシル、置換もしくは非置換のスルホニル、置換もしくは非置換のカルバモイル、Ｃ１－Ｃ６アルコキシカルボニル、置換もしくは非置換のＣ３－Ｃ７シクロアルキル、置換もしくは非置換のＣ３－Ｃ７シクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表すか、又は、Ｒ^４Ｒ^５がＮと共に、Ｃ３－Ｃ７ヘテロシクロアルキルを形成し；
Ｒ⁶はＨ又は置換されていてもよいＣ１－Ｃ６アルキル、又は隣接するメチレン部とベンゼン環に縮合する形の環構造を形成してもよいことを表し、ここで、環構造は、非置換のＣ５－７シクロアルキル又は非置換のＣ５－７シクロアルケニルを表す。
[２]
前記Ｒ^３は、独立して、Ｈ、Ｃｌ、Ｆ、Ｃ１－Ｃ３アルキル、Ｃ１－Ｃ３アルコキシ、Ｃ１－Ｃ６アルキルチオ、ＣＨ_２Ｘ、ＣＨＸ_２、又はＣＸ_３（ＸはＦを表わす）を表す、[１]に記載の化合物又はその薬学的に許容される塩。
[３]
前記Ｒ⁴は、Ｈ又はＣ１－Ｃ６アルキルを表し；
前記Ｒ⁵は、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表す、[１]又は[２]に記載の化合物又はその薬学的に許容される塩。
[４]
前記Ｒ⁴は、Ｈ又はＣ１－Ｃ６アルキルを表し；
前記Ｒ⁵は、アリール置換Ｃ１－Ｃ６アルキルを表す、[１]又は[２]に記載の化合物又はその薬学的に許容される塩。
[５]
前記Ｒ^４Ｒ^５がＮと共に、Ｃ３－Ｃ７ヘテロシクロアルキルを形成する、[１]又は[２]に記載の化合物又はその薬学的に許容される塩。
[６]
[１]～[５]のいずれか１項に記載の化合物又はその薬学的に許容される塩を含む、ＢＮＣＴ用薬剤。
[７]
[１]～[５]のいずれか１項に記載の化合物又はその薬学的に許容される塩のＲ^３のいずれか１つの部位、Ｒ^４、又はＲ^５のいずれかに放射性同位体を置換基として含有する診断薬。 Specifically, the present invention provides the following compounds.
[1]
A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

Here, in formula (I),
R ¹ , R ² together with the B atom represent substituents of boronic acid (-B(OH) ₂ ), boronic ester, or boronic acid amide;
R ³ is H, halogen, hydroxy, cyano, amino, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, C1-C6 alkoxyC1-C6 alkyl, nitro, C1-C6 haloalkyl, carbamoyl , C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, COOR ¹⁰ (R ¹⁰ is H or C1-C6 alkyl, amino, C1-C6 alkylamino), C1-C6 haloalkylsulfanyl, C1 - represents a group independently selected from the group consisting of C6 haloalkylsulfinyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, aminosulfonyl, sulfo, and sulfamoyl;
s represents any integer from 1 to 4;
R ⁴ represents H, C1-C6 alkyl, benzyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R ⁵ is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, hydroxy, cyano, substituted or unsubstituted amino, substituted or unsubstituted substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxy C1-C6 alkyl, substituted or unsubstituted acyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted carbamoyl, C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, substituted or unsubstituted unaromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl or R ⁴ R ⁵ together with N form C3-C7 heterocycloalkyl;
R ⁶ represents H or optionally substituted C1-C6 alkyl, or may form a fused ring structure with the adjacent methylene moiety and a benzene ring, wherein the ring structure is unsubstituted represents C5-7 cycloalkyl or unsubstituted C5-7 cycloalkenyl.
[2]
said R ³ independently represents H, Cl, F, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 alkylthio, CH ₂ X, CHX ₂ , or CX ₃ (X represents F); The compound of [1] or a pharmaceutically acceptable salt thereof.
[3]
said R ⁴ represents H or C1-C6 alkyl;
The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein R ⁵ represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
[4]
said R ⁴ represents H or C1-C6 alkyl;
The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein said R ⁵ represents an aryl-substituted C1-C6 alkyl.
[5]
The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein said R ⁴ R ⁵ together with N form C3-C7 heterocycloalkyl.
[6]
A BNCT agent comprising the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof.
[7]
Substitution of a radioactive isotope at any one site of R ³ , R ⁴ or R ⁵ of the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof A diagnostic agent containing as a group.

The novel compounds of the present invention may be useful for further expanding the application of BNCT, either alone or in combination with other compounds.

In the present specification, when a compound having an asymmetric carbon is indicated, the compound may be racemic, R-isomer, or S-isomer unless otherwise specified.

（Ｉ）
ここで、式（Ｉ）中、
Ｒ¹、Ｒ^２は、Ｂ原子と共に、ボロン酸（‐Ｂ（ＯＨ）_２）、ボロン酸エステル、又はボロン酸アミドの置換基を表し；
Ｒ³は、Ｈ、ハロゲン、ヒドロキシ、シアノ、アミノ、Ｃ１－Ｃ６アルキルアミノ、Ｃ１－Ｃ６アルキル、Ｃ１－Ｃ６アルコキシ、ベンジルオキシ、Ｃ１－Ｃ６アルコキシＣ１－Ｃ６アルキル、ニトロ、Ｃ１－Ｃ６ハロアルキル、カルバモイル、Ｃ１－Ｃ６アルキルアミノカルボニル、Ｃ１－Ｃ６アルコキシカルボニル、Ｃ１－Ｃ６アルキルカルボニル、ＣＯＯＲ^１０（Ｒ^１０は、Ｈ又はＣ１－Ｃ６アルキル、アミノ、Ｃ１－Ｃ６アルキルアミノ）、Ｃ１－Ｃ６ハロアルキルスルファニル、Ｃ１－Ｃ６ハロアルキルスルフィニル、Ｃ１－Ｃ６ハロアルキルスルホニル、Ｃ１－Ｃ６アルキルチオ、Ｃ１－Ｃ６アルキルスルフィニル、Ｃ１－Ｃ６アルキルスルホニル、アミノスルホニル、スルホ、及びスルファモイルからなる群から、独立して選択される基を表し；
ｓは、１～４のいずれかの整数を表し；
Ｒ⁴は、Ｈ、Ｃ１－Ｃ６アルキル、ベンジル、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表し；
Ｒ⁵は、Ｈ、置換もしくは非置換のＣ１－Ｃ６アルキル、置換もしくは非置換のＣ２－６アルケニル、置換もしくは非置換のＣ２－６アルキニル、ヒドロキシ、シアノ、置換もしくは非置換のアミノ、置換もしくは非置換のＣ１－Ｃ６アルコキシ、置換もしくは非置換のＣ１－Ｃ６アルコキシＣ１－Ｃ６アルキル、置換もしくは非置換のアシル、置換もしくは非置換のスルホニル、置換もしくは非置換のカルバモイル、Ｃ１－Ｃ６アルコキシカルボニル、置換もしくは非置換のＣ３－Ｃ７シクロアルキル、置換もしくは非置換のＣ３－Ｃ７シクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表すか、又は、Ｒ^４Ｒ^５がＮと共に、Ｃ３－Ｃ７ヘテロシクロアルキルを形成し；
Ｒ⁶はＨ又は置換されていてもよいＣ１－Ｃ６アルキル、又は隣接するメチレン部とベンゼン環に縮合する形の環構造を形成してもよいことを表し、ここで、環構造は、非置換のＣ５－Ｃ７シクロアルキル又は非置換のＣ５－７シクロアルケニルを表す。 [Boronophenylalanine amide derivative]
The boronophenylalanine amide derivative of the present invention is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

(I)
Here, in formula (I),
R ¹ , R ² together with the B atom represent substituents of boronic acid (-B(OH) ₂ ), boronic ester, or boronic acid amide;
R ³ is H, halogen, hydroxy, cyano, amino, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, C1-C6 alkoxyC1-C6 alkyl, nitro, C1-C6 haloalkyl, carbamoyl , C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, COOR ¹⁰ (R ¹⁰ is H or C1-C6 alkyl, amino, C1-C6 alkylamino), C1-C6 haloalkylsulfanyl, C1 - represents a group independently selected from the group consisting of C6 haloalkylsulfinyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, aminosulfonyl, sulfo, and sulfamoyl;
s represents any integer from 1 to 4;
R ⁴ represents H, C1-C6 alkyl, benzyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R ⁵ is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, hydroxy, cyano, substituted or unsubstituted amino, substituted or unsubstituted substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxy C1-C6 alkyl, substituted or unsubstituted acyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted carbamoyl, C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, substituted or unsubstituted unaromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl or R ⁴ R ⁵ together with N form C3-C7 heterocycloalkyl;
R ⁶ represents H or optionally substituted C1-C6 alkyl, or may form a fused ring structure with the adjacent methylene moiety and a benzene ring, wherein the ring structure is unsubstituted represents C5-C7 cycloalkyl or unsubstituted C5-7 cycloalkenyl.

In this specification, halogen may be any of F, Cl, Br and I, but F, Cl and Br are particularly preferred.

In the present specification, C1-C6 alkyl refers to a linear or branched C1-C6 saturated hydrocarbon group. Examples of C1-C6 alkyl groups are methyl, ethyl, propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, t-butyl), pentyl (eg n-pentyl, isopentyl, neopentyl), etc. Preferred are linear or branched C1-C4 alkyl groups, including, but not limited to, methyl, ethyl, isopropyl and butyl groups.

In the present specification, C2-C6 alkenyl refers to a linear or branched C2-C6 unsaturated hydrocarbon group containing a double bond. Examples of C2-C6 alkenyl groups include ethenyl, propenyl, butenyl, and the like.

In the present specification, C2-C6 alkynyl refers to a linear or branched C2-C6 unsaturated hydrocarbon group containing a triple bond. Examples of C2-C6 alkynyl groups include acetylene, methylacetylene, butyne, pentyne, and the like.

As used herein, C1-C6 haloalkyl refers to a C1-C6 alkyl group having one or more halogen substituents. A C1-C6 haloalkyl group is preferably represented by C ₂ X ₅ , CH ₂ X, CHX ₂ or CX ₃ (where X represents Cl, F, Br or I) and is not limited to, for example CF _{3 , C2F5} , _CHF2 , _CCl3 , _{CHCl2 , C2Cl5} and the like.

As used herein, C1-C6 alkoxy represents a group having a linear or branched C1-C6 alkyl group and an oxygen molecule. C1-C6 alkoxy preferably has linear or branched C1-C4 alkyl, including, but not limited to, methoxy, ethoxy, isopropoxy, butoxy and the like.

As used herein, C1-C6 alkoxy C1-C6 alkyl includes, but is not limited to, methoxyethyl, ethoxyethyl and the like.

As used herein, C1-C6 alkylamino is represented as NR ¹¹ R ¹² , and groups such that each R ¹¹ R ¹² independently represents H or C1-C6 alkyl (with the proviso that R ¹¹ and R ¹² and are both H). Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, i-propylamino, and the like.

In the present specification, C1-C6 alkylaminocarbonyl is represented as CONR ¹³ R ¹⁴ , and R ¹³ and R ¹⁴ each independently represent H or a group representing C1-C6 alkyl (with the proviso that R ¹³ and and R ¹⁴ are both H). Examples include, but are not limited to, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, i-propylaminocarbonyl, and the like.

As used herein, C1-C6 alkylcarbonyl includes, but is not limited to, methylcarbonyl, ethylcarbonyl, and the like.

As used herein, C1-C6 alkoxycarbonyl includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, hexyloxycarbonyl and the like.

As used herein, COOR ¹⁰ (R ¹⁰ is H or C1-C6 alkyl, amino, alkylamino (NR ¹¹ R ¹² (R ¹¹ R ¹² each independently represents H or C1-C6 alkyl)) Examples include, but are not limited to, methyloxycarbonyl, aminooxycarbonyl, and the like.

As used herein, C1-C6 haloalkylsulfanyl, C1-C6 haloalkylsulfinyl, and C1-C6 haloalkylsulfonyl include, but are not limited to, trifluoromethylsulfanyl, trifluoromethylsulfinyl group, or trifluoromethylsulfonyl. .

As used herein, C1-C6 alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hesylthio and the like.

As used herein, C1-C6 alkylsulfinyl includes, but is not limited to, methylsulfinyl, ethylsulfinyl and the like.

As used herein, C1-C6 alkylsulfonyl includes, but is not limited to, methylsulfonyl, ethylsulfonyl and the like.

As used herein, substituted C1-C6 alkyl includes, but is not limited to, linear or branched C1-C6 alkyl in which 1 to 3 hydrogen atoms are substituted with other groups. .

As used herein, substituted C2-6 alkenyl includes, but is not limited to, straight chain or branched C2-6 alkenyl in which one or two hydrogen atoms are substituted with other groups. .

As used herein, substituted C2-6 alkynyl includes, but is not limited to, straight chain or branched C2-6 alkynyl in which one or two hydrogen atoms are replaced with other groups.

As used herein, substituted C1-C6 alkoxy includes, but is not limited to, linear or branched C1-C6 alkoxy in which one or two hydrogen atoms are replaced with other groups.

As used herein, substituted C1-C6 alkoxy C1-C6 alkyl includes, but is not limited to, linear or branched C1-C6 alkoxy C1 having one or two hydrogen atoms replaced with other groups. -C6 alkyl is included.

Here, in the above substituted C1-C6 alkyl, substituted C2-6 alkenyl, substituted C2-6 alkynyl, substituted C1-C6 alkoxy, substituted C1-C6 alkoxy C1-C6 alkyl, etc. , a group substituted in place of a hydrogen atom is, for example, a halogen, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted arylthio (such as phenylthio), a substituted or unsubstituted arylamino (phenylamino etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

As used herein, substituted or unsubstituted amino is exemplified by amino optionally substituted with C1-C6 alkyl. Substituted or unsubstituted amino include, but are not limited to, amino, methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, cyclopropylamino, cyclohexylamino. Other optionally substituted amino include hydrazine, C1-C6 alkyl substituted hydrazine, benzylamino, acetylamino, benzoylamino, methylsulfonylamino, tetrahydropyranylamino, tetrahydrofuranylamino, morpholinoamino, morpholinyl. amino, piperidinylamino, piperazinylamino and the like.

Substituted or unsubstituted acyl includes, for example, aliphatic acyl and aroyl having 1 to 7 carbon atoms. Specific examples include, but are not limited to, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl and benzoyl.

Examples of substituted or unsubstituted sulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, phenylsulfonyl, naphthylsulfonyl, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclo hexenylsulfonyl, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like.

Substituted or unsubstituted carbamoyl includes carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, Nn-propylaminocarbamoyl, N-isopropyl Carbamoyl, N-morpholinocarbamoyl, N-tetrahydrofuranylcarbamoyl, N-piperidylcarbamoyl, N-tetrahydropyranylcarbamoyl, N-benzylcarbamoyl, N-acetylcarbamoyl, N-methylsulfonylcarbamoyl, N-(2,2,2-tri fluoroethyl)carbamoyl, N-(2-hydroxy-1-methylethyl)carbamoyl and the like. As different embodiments, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, Nn-propylaminocarbamoyl, N-isopropylcarbamoyl, N-morpholinocarbamoyl, N-tetrahydrofuranylcarbamoyl, N-piperidylcarbamoyl, N-tetrahydro pyranylcarbamoyl, N-methylsulfonylcarbamoyl, N-(2,2,2-trifluoroethyl)carbamoyl, N-(2-hydroxy-1-methylethyl)carbamoyl and the like.

Examples of substituted or unsubstituted C3-C7 cycloalkyl include cyclopropyl, cyclobutyl, cyclohexyl and the like.

Examples of substituted or unsubstituted C3-C7 cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.

Substituted or unsubstituted non-aromatic heterocyclic groups include aziridinyl optionally substituted with 1 to 3 C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen, oxiranyl , thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, benzodioxane, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroiso oxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl , diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl.

Substituted or unsubstituted aryl includes C6-C14 aryl optionally substituted with 1-3 C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen. More specific examples include phenyl, naphthyl, azulenyl, anthryl and the like. Aryl is preferably phenyl.

substituted or unsubstituted heteroaryl, optionally substituted with 1 to 3 C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen, thienyl, furyl, pyrrolyl , imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4 - thiadiazolyl, triazolyl, tetrazolyl, triazinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzodioxolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia zolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, Examples include β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl.

In the derivatives of the invention, R ¹ , R ² represent any of the substituents of boronic acid (-B(OH) ₂ ), boronic ester, or boronic amide, but in this definition boronic ester or boron Examples of acid amide groups include groups having a chain structure such as -B(NR ⁷¹ ) ₂ or -B(OR ⁷¹ ) ₂ at the positions of R ¹ and R ² , or together with atom B, cyclic represents a group having a structure. Here, R ⁷¹ represents a linear or branched C1-C10 alkyl group. Here, the term “linear or branched C1-C10 alkyl group” may be any alkyl group having 1-10 carbon atoms. A linear or branched C1-C8 alkyl group is preferred, and a linear or branched C1-C6 alkyl group is more preferred. Examples of these groups include, but are not limited to, methyl group, ethyl group, isopropyl group, butyl group, and the like.

Furthermore, in the group having a cyclic structure together with the atom B referred to here, not only O atoms but also N atoms may intervene. Examples include, but are not limited to, pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1-6-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane and catechol. These include, but are not limited to, boronic acid pinacol ester, boronic acid MIDA ester, boronic acid 1,3-propanediol ester, boronic acid neopentyl glycol ester, boronic acid catechol ester, boronic acid pinanediol ester, boron acid biscyclohexyl diol esters, boronic acid MPM esters, trifluoroborate salts, cyclic triol borate salts, diaminonaphthaleneamide-boron cyclics, and the like.

Here, the boron atom is not limited, but the ratio of boron 10 is preferably 75% by mass or more, more preferably 80% by mass or more, still more preferably 90% by mass or more, particularly preferably , 95% by mass or more.

In natural boron (boron), boron-10 and boron-11 are isotopes, and boron-10 is present at a ratio of 20% and boron-11 at a ratio of 80%. Therefore, it is also preferable to enrich boron with a mass number of 10 (boron 10) prior to the production of the boronophenylalanine amide derivative of the present invention. In the present invention, for example, a commercially available product may be used as the boron atom source. As a commercial product, for example, 10B concentrated boric acid (manufactured by Stella Chemifa Co., Ltd.) can be used.

Here, as a method for measuring boron 10, Agilent 710 (manufactured by Agilent) can be used and multi-type ICP emission spectrometry (ICP-OES) can be performed. ICP-OES used for measurement is adjusted according to JISK0116.

In the compound, although not limited, R ¹ R ² together with the B atom is preferably boronic acid (B(OH) ₂ ) or a boronic acid ester of chain or cyclic structure, and boronic acid (B(OH) ₂ ) or pinacol ester of boronic acid.

In the compound, although not limited, any one to four of R ³ are independently H, Cl, F, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 alkylthio, CH ₂ F , CHF ₂ or CF ₃ are particularly preferred.

In said compound, said R ⁴ is preferably, but not limited to, H, C1-C6 alkyl.

In the above compounds, R ⁵ is H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, halogen-substituted C1-C3 alkyl, substituted or unsubstituted phenyl (if substituted, but not limited to phenyl substituted with halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, etc.), naphthyl, C1-C6 alkyl substituted with substituted or unsubstituted phenyl (where substituted phenyl phenyl substituted with, but not limited to, halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, etc.), C1-C6 alkoxy substituted with substituted or unsubstituted phenyl (here, substituted phenyl is not limited, but preferably substituted with halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, etc.), thienyl, furyl, pyrimidine, thienyl-substituted C1-C6 alkyl , furyl-substituted C1-C6 alkyl, pyrimidine-substituted C1-C6 alkyl, phenylthio-substituted C1-C6 alkyl, phenylamino-substituted C1-C6 alkyl, benzodioxolyl, dihydrobenzodioxin, or R ⁴ and R ⁵ together with an N atom are C3 -C7 heterocycloalkyl, preferably. Here, when R ⁴ and R ⁵ together with the N atom form a C3-C7 heterocycloalkyl, the C3-C7 heterocycloalkyl includes, but is not limited to morpholino, pyrrolidine and the like.

In said compound, said R ⁶ is, but not limited to, H or C1-C6 alkyl, or together with the methylene adjacent to R ⁶ forms a ring structure in a form fused to a benzene ring, wherein the ring structure is non- Preferred is substituted C5-C7 cycloalkyl. Among these, R ⁶ more preferably represents H, methyl or ethyl.

Among the boronophenylalanine amide derivatives of the present invention, particularly preferred are one selected from the group consisting of the following compounds or a salt thereof.
(S)-(4-(2-amino-3-(ethylamino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-((2,2,2-trifluoroethyl)amino)propyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-(p-tolylamino)propyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-(m-tolylamino)propyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((3,4-dimethylphenyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((4-methoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((3,5-dimethoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((3-methoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-(benzo[d][1,3]dioxol-5-ylamino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((2,3-dihydroxybenzo[b][1,4]dioxin-6-yl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-(phenethylamino)propyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((4-methoxyphenethyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((3-methoxyphenethyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((4-fluorophenethyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-((2-phenoxyethyl)amino)propyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-((3-phenoxypropyl)amino)propyl)phenyl)boronic acid; and (S)-(4-(2-amino-3-oxo) -3-(Pyridin-2-ylamino)propyl)phenyl)boronic acid.

The "pharmaceutically acceptable salt" in the present invention includes salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. . Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts and ammonium salts. Preferable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p - salts with toluenesulfonic acid and the like. Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. be done.

[Method for producing boronophenylalanine amide derivative]
In the present invention, the method for producing the novel boronophenylalanine amide derivative is not limited, and conventional methods for synthesizing amino acids are used. Although not limited, a particularly preferred method may be, for example, the following method.
First, an organic halide represented by the following general formula (II) is reacted with a protected amino acid in the presence of an organic solvent, a basic aqueous solution, and a phase transfer catalyst.

ここで、式（ＩＩ）中、
Ｘ^１、及びＸ^２は、独立してハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）を表すものとする。
さらに、式(ＩＩ)中、ベンゼン環は、Ｘ^１が存在する箇所以外で任意に１－４個の置換基Ｒ^３で置換されていてもよい。

where in formula (II),
X ¹ and X ² shall independently represent halogen (F, Cl, Br, I).
Additionally, in formula (II), the benzene ring may optionally be substituted with 1-4 substituents R ³ , except where X ¹ occurs.

Here, as the organic halide represented by formula (II), a compound prepared by a known method can be used as it is, or a commercially available product can be used.

Among these, for example, 4-iodobenzyl bromide and 4-bromo-2-fluorobenzyl bromide are available from Tokyo Kasei Kogyo Co., Ltd. and Combi-Blocks. 4-bromo-3-fluorobenzyl bromide, 1-bromo-4-(bromomethyl)-2,3-difluorobenzene, 4-bromo-1-(bromomethyl)-2-methoxybenzene, 4-bromo-1-(bromomethyl )-2-nitrobenzene, 4-bromo-1-(bromomethyl)-2-chlorobenzene, 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene, 4-bromo-1-(bromomethyl)-2 -(trifluoromethyl)benzene, 1-bromo-4-(bromomethyl)-2-methylbenzene, are available from Combi-Blocks. 4-bromo-1-(bromomethyl)-2-methylbenzene, 4-bromo-2,6-difluorobenzyl bromide are available from Fluorochem Ltd.; more available.

5-bromo-2-(bromomethyl)benzonitrile can be prepared, for example, from 5-bromo-2-methylbenzonitrile available from Tokyo Chemical Industry Co., Ltd., followed by 1-bromo-4-(bromomethyl)-2-chloro -5-fluorobenzene, 5-bromo-2-methylthioanisole can be prepared from 4-bromo-5-chloro-2-fluorotoluene available from Combi-Blocks. These compounds can be prepared, for example, by reacting a commercially available compound with N-bromosuccinimide in the presence of 2,2'-azobis(isobutyronitrile).

4-(bromomethyl)-1-iodo-2-nitrobenzene can be obtained, for example, from (4-iodo-3-nitro-phenyl)-methanol available from Combi-Blocks by bromination with hydrobromic acid. can be prepared.

Other benzyl bromides are available from commercial products, and those that are not available are, for example, N-bromosuccinimide in the presence of 2,2'-azobis(isobutyronitrile) for toluene having a corresponding substituent. Alternatively, benzaldehyde or methyl benzoate having a corresponding substituent can be reduced with sodium borohydride or lithium aluminum hydride to give benzyl alcohol, followed by hydrobromic acid or tribromide. It can be prepared by bromination with phosphorus.

The reaction between the organic halide represented by formula (II) and the protected amino acid can proceed in the presence of an organic solvent, a basic aqueous solution, and a phase transfer catalyst. Examples of protected amino acids include p-chlorobenzaldehyde imine, benzophenone imine, and the like. Preferably, it may be p-chlorobenzaldehyde imine of the structure below.

Here, R ⁶ represents H or optionally substituted C1-C6 alkyl.

Here, the organic solvent used is not limited, but preferably toluene, benzene, xylene, mesitylene, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, cyclopentyl methyl ether, methyl t-butyl ether, etc. is mentioned.

The basic aqueous solution is preferably an aqueous solution of calcium hydroxide, cesium hydroxide, potassium hydroxide, or the like.

The phase transfer catalyst can be, for example, Maruoka's reagent. The Maruoka reagent is not limited, but preferably (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho [ 2,1-c: 1′,2′-e]azepinium bromide, (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5- Dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl )-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, (S)-4,4-dibutyl-2,6-bis(3,4 ,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepinium bromide and the like can be used.

The reaction temperature at this time is preferably between −20° C. and 10° C., and the reaction time can be about 1 hour to 60 hours.

After completion of the reaction, the product can be extracted with an organic solvent such as toluene, and subjected to washing, drying and filtration steps as appropriate.

A solvent is then added to such reaction product and reacted with the acid. Here, as the solvent, it is preferable to use an ether solvent. Examples of the ether solvent include, but are not limited to, diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, cyclopentylmethyl ether, glyme, and diglyme. Tetrahydrofuran is particularly preferably used in the present invention.

Examples of acids include organic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, toluenesulfonic acid and methanesulfonic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. be done.

The reaction is preferably carried out at a temperature in the range 0°C to 50°C.

The reaction time is about 1 to 10 hours, preferably 2 to 8 hours, still more preferably 3 to 6 hours.

The amino group of the obtained compound is protected by a conventional method. Although the protecting group is not limited, for example, a carbamate-based protecting group, an amide-based protecting group, and an alkyl protecting group are preferably used. Such carbamate-based protective groups include tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl group (Fmoc), 2,2,2-trichloroethoxycarbonyl group (Troc) and the like, the amide-based protecting group includes acetyl group, benzoyl group and the like, and the alkyl protecting group includes benzyl group and the like.

Next, the compound obtained as described above or the amine compound having a boronic acid or borono group is condensed by reacting the amine compound with a condensing agent in a solvent.

Examples of condensing agents include, but are not limited to, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, N, N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU"), diphenyl and phosphoryl azide.

The above reaction can also be carried out in the presence of a base. Examples of bases include organic bases such as TEA, DIPEA and pyridine.

Additives can also be used in the above reaction to suppress racemization. Examples of additives include 1-hydroxybenzotriazole, 1-hydroxybenzotriazole monohydrate, 1-hydroxy-7-azabenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide, 3 ,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine, N-hydroxysuccinimide and the like.

Examples of the solvent include, but are not limited to, halogen-based solvents, ether-based solvents, amides, nitriles, or mixed solvents thereof.

Examples of halogen-based solvents include, but are not limited to, dichloromethane, chloroform, carbon tetrachloride, and the like.

Examples of ether solvents include, but are not limited to, diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, cyclopentylmethyl ether, glyme, and diglyme.

Solvents for amides include, but are not limited to, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), and the like.

Examples of nitrile solvents include acetonitrile and propionitrile.

The reaction temperature is not limited, but preferably -78°C to 200°C, more preferably -20°C to 50°C.

Although the reaction time is not limited, it is usually about 1 to 24 hours.

Next, the resulting compound is optionally reacted with a boron compound in a solvent in the presence of a palladium catalyst, an organic phosphorus compound and a base. This step can be omitted if the compound already has a boronic acid or borono group.

Here, palladium catalysts include, but are not limited to, palladium(II) acetate, palladium(II) chloride, and tris(dibenzylideneacetone)dipalladium(0), [1,1′-bis(diphenylphosphino )ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0) and the like.

Organic phosphorus compounds include, but are not limited to, triphenylphosphine, tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl and the like.

Examples of bases include, but are not limited to, potassium acetate, sodium acetate, sodium carbonate, cesium carbonate, potassium carbonate, sodium bicarbonate, and the like.

Examples of boron compounds include borate esters and borate amides, preferably B(OR) ₃ , B(NR) ₃ , B(OR) ₂ (NR), (RO) ₂ BB(OR) ₂ , or B(OR)(NR) ₂ (R is a linear or branched C1-C10 alkyl group, phenyl group, or benzyl group). Furthermore, among these, a compound represented by (RO) ₂ BB(OR) ₂ is particularly preferably used. Here, the term "linear or branched C1-C10 alkyl group" may be any alkyl group having 1 to 10 carbon atoms, but preferably linear or branched C1-C8 alkyl groups, more preferably linear or branched C1-C6 alkyl groups. Examples of these groups include, but are not limited to, methyl groups, ethyl groups, isopropyl groups, butyl groups, and the like. A representative example of the boron compound is, but not limited to, bis(pinacolato)diboron.

Examples of the solvent include, but are not limited to, ether solvents such as 1,4-dioxane, tetrahydrofuran, and 1,2-dimethoxyethane; hydrocarbon solvents such as toluene; and N,N-dimethylformamide, dimethylsulfoxide, and the like. Polar solvents are exemplified. Preferred solvents include dimethylsulfoxide. The reaction temperature is, for example, 20°C to 160°C, preferably 60°C to 120°C.

Next, the obtained compounds are sequentially deprotected or directly subjected to the next step. Deprotection can be carried out by conventional methods, such as hydrolysis, catalytic hydrogenation, decarboxylation, and oxidation.

In each step of the production method, purification follows a conventional method and can be modified as appropriate.

Especially when the compound is racemic, it can be used as is, or the optical purity of the R- or S-form can be enhanced in order to obtain the preferred compound for use, for example, in boron neutron capture therapy.

For the optical resolution, a known method may be used as appropriate. For example, a hydrolysis step, an esterification step, followed by an optical resolution (using α-chymotrypsin or the like), or a hydrolysis step followed by an acylase. A simplified method including simplified steps can also be adopted.

[Drug for BNCT (Boron Neutron Capture Therapy)]
The boronophenylalanine amide derivative of the present invention can be used as it is in the form of the above compound or a pharmaceutically acceptable salt, or mixed with a pharmaceutically acceptable carrier in the form of formulations known to those skilled in the art, or micro/nano It can be conveniently used for BNCT in the form of encapsulation in particles or the like.

Treatment with the boronophenylalanine amide derivative formulations of the present invention is effected by administration by any suitable route of administration and in such a manner that the boronophenylalanine amide derivative accumulates in the target tumor. The boronophenylalanine amide derivative is preferably concentrated in the tumor prior to irradiation and has a tumor:blood ratio of at least 1.5:1, preferably 2:1 or greater, prior to irradiation. The boronophenylalanine amide derivative can be administered once or continuously. In some cases, it can be administered separately. After the desired accumulation of the compound within the tumor, the site is irradiated with an effective dose of low energy neutrons (eg, epithermal neutrons). The site can be irradiated through the skin, or the site can be fully or partially exposed prior to irradiation. Administration of the boronophenylalanine amide derivative followed by irradiation can be repeated as necessary. If desired, treatment with the boronophenylalanine amide derivative can be followed by surgery to shrink the tumor to a surgically feasible extent. Alternatively, after surgical treatment, the remaining tumor is destroyed using the boronophenylalanine amide derivatives of the invention. In another embodiment, the patient is administered an appropriate amount of the boronophenylalanine amide derivative and irradiated with an effective amount of 252 californium, a naturally occurring neutron emitter. It is preferably inserted into the tumor and removed at the appropriate time.

Here, the type of tumor is not particularly limited, but brain tumors including glioblastoma, malignant glioma, etc., head and neck cancer, malignant melanoma, breast cancer, prostate cancer, etc. can be particularly suitable targets. . In addition, lung cancer, uterine cancer, kidney cancer, epithelial cell carcinoma such as liver cancer, various sarcomas, and the like can also be targeted.

Administration of the boronophenylalanine amide derivatives of the present invention can be oral and parenteral. Parenteral administration can be intraarterial (eg, via the carotid artery), intramuscular, subcutaneous, intramedullary, intrathecal, intracerebroventricular, intravenous, intraperitoneal, or intranasal.

Formulations can be in any form, such as powders, granules, fine granules, dry syrups, tablets, capsules, injections, and liquids. In addition, depending on the dosage form, it may be administered to the patient alone or in combination with other drugs, mixed with an appropriate additive and/or a pharmaceutically acceptable carrier, according to a pharmaceutically known method. obtain. Additives include, for example, excipients; disintegrants; binders; lubricants; diluents; emulsifiers; dispersing agents; stabilizing agents; solubilizing agents; antioxidants such as ascorbic acid; proteins (eg, serum albumin, gelatin, or immunoglobulins); hydrophilic polymers (eg, polyvinylpyrrolidone); amino acids (eg, glycine, glutamic acid, aspartic acid, or arginine); monosaccharides, disaccharides and other carbohydrates (including cellulose or its derivatives, glucose, mannose, or dextrins); chelating agents (eg, EDTA); sugar alcohols (eg, mannitol or sorbitol); counterions (eg, sodium); and/or nonionic interfaces. active agents (eg, polysorbates, poloxamers), and the like. It can be prepared by appropriately mixing, diluting and dissolving with these pharmaceutical excipients. Carriers that can be preferably used are, but are not limited to, pharmaceutically inert aqueous carriers. Such carriers include saline, buffered saline, dextrose, water and the like. In one embodiment of the invention, the pharmaceutically acceptable carrier is pharmaceutically inert. Suitable excipients and/or pharmaceutically acceptable carriers are nontoxic to recipients at the dosages and concentrations employed. A particularly preferred formulation is an injection prepared with an aqueous carrier.

Techniques for formulation and administration are described, for example, in the latest edition and latest supplement of the Japanese Pharmacopoeia, final edition of "REMINGTON'S PHARMACEUTICAL SCIENCES" (Maack Publishing Co. Easton, PA).

The formulation of the boronophenylalanine amide derivative of the present invention is a drug containing an amount effective to achieve the intended purpose of the target drug, and a "therapeutically effective amount" or "pharmacologically effective amount" is It is well recognized by those skilled in the art and refers to the amount of an agent effective to produce a pharmacological result. Determination of a therapeutically effective dose is well known to those skilled in the art.

A therapeutically effective amount, as used herein, refers to that amount of an agent that reduces the disease state upon administration followed by irradiation. Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. Dosages preferably lie within a range of circulating concentrations that include the _ED50 with little or no toxicity. The dosage will vary within this range depending on the dosage form used, patient sensitivity, and route of administration. For example, the dosage is appropriately selected depending on the age and other conditions of the patient, the type of disease, the type of conjugate to be used, and the like. A preferred dose is, but is not limited to, 5-1000 mg/kg can be administered per treatment. In particular, it may be 5-500 mg, more preferably 6-480 mg, of the derivative per kg of body weight of the subject to be treated.

[Diagnostic Agent Containing Radioisotope]
The boronophenylalanine amide derivatives of the present invention can also be prepared as a radioisotope-containing medicament. When preparing a drug containing radioactive isotope, typically, but not limited to, ¹⁸ F is used as the F atom contained in the compound, and ¹³¹ is used as the I atom contained in the compound. I, ¹²³ I can be used, or ¹¹ C can be used as the C atom contained in the compound. As for the position of these radioisotopes, they can be introduced at any position of ^R3 , or as a substituent when ^R4 or ^R5 contains aryl or heteroaryl. Compounds thus obtained can be used, for example, in RI examinations and nuclear medicine examinations. These include, but are not limited to, agents for scintigraphic tomography, SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography), i.e., injecting radioactivity into a subject. The boronophenylalanine amide derivative of the present invention containing is administered as a PET drug or SPECT drug, an image is acquired before treatment, and the distribution of the derivative in the body, the tumor tissue / normal tissue abundance ratio (T / N ratio), etc. Information can be obtained.Based on this information, it is also possible to presume the therapeutic effect of BNCT and formulate a research or treatment plan.In addition, the mode of administration and others are described in [BNCT (Boron Neutron Capture Therapy) ) drugs].

The present invention will be described in more detail by the following examples, but the invention is not limited thereto.

In the following examples, the following models and reagents were used for the analysis and separation and purification of the compounds.

・NMR spectrum:
(JEOL RESONANCE/JNM-ECZ500R/500MHz

(Example 1)
Preparation of (S)-(4-(2-amino-3-(benzo[d][1,3]dioxol-5-ylamino)-3-oxopropyl)phenyl)boronic acid

step one
Preparation of tert-butyl (S)-(1-(benzo[d][1,3]dioxol-5-ylamino)-3-(4-iodophenyl)-1-oxopropan-2-yl)carbamate Boc- 4-iodo-L-phenylalanine (4.00 g, 10.2 mmol), 1,2,3-benzotriazol-1-ol monohydrate (1.87 g, 12.2 mmol), 3,4-methylenedioxy Aniline (1.67 g, 12.2 mmol) was dissolved in DMF (80 mL). Under an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.74 g, 14.3 mmol) dissolved in DMF (27 mL) in advance was added. Then, it was returned to room temperature and stirred overnight. After completion of the reaction, ethyl acetate (27 mL) and distilled water (27 mL) were added. After stirring for about 5 minutes, it was transferred to a separatory funnel. The aqueous layer was further extracted with ethyl acetate (29 mL), and the obtained ethyl acetate layers were combined and washed with saturated brine (27 mL). After drying with anhydrous magnesium sulfate, the residue obtained by filtration was crudely purified by silica gel column chromatography to obtain 4.2 g of the desired product (yield 81%).
¹ H NMR (DMSO-d ₆ ); 1.26 (s, 9H, t-Bu), 2.75 (dd, J = 10.5, 14.0 Hz, 1H, β-H), 2.92 (dd, J = 4.0, 13.5 Hz, 1H, β-H), 3.71 (s, OC H ₂ O), 4.23-4.28 (m, 1H, α-H), 6.63 (d, J = 8.0 Hz, 1H, NH), 7.11-7.13 (m, 3H, ArH), 7.20 (t, J = 8.0 Hz, 2H, ArH), 7.24 (s, 1H, ArH), 7.63 (d, J = 8.0 Hz, 2H, ArH), 10.05 (s, 1H, NH) .

step 2
Preparation of (S)-(4-(3-(benzo[d][1,3]dioxol-5-ylamino)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)boronic acid In DMSO (42 mL) was added the Boc compound obtained in step 1 (4.20 g, 8.23 mmol) _Pd (dppf) _2.CH2Cl2 ( ₃₃₆ mg, 0.412 mmol), potassium acetate (1.60 g, 16.0 mmol). 5 mmol) was added and reacted at 100° C. for 2 hours. After completion of the reaction, the reaction solution was cooled in an ice bath, and ethyl acetate (42 mL) and distilled water (42 mL) were added. After stirring for about 5 minutes, the mixture was filtered through celite, and the resulting filtrate was transferred to a separatory funnel. The aqueous layer was further extracted with ethyl acetate (42 mL), and the obtained ethyl acetate layers were combined and washed with saturated brine (42 mL). After drying over anhydrous magnesium sulfate, the residue obtained by filtration was crudely purified by silica gel column chromatography.
The crude product obtained was dissolved in acetone (200 mL). Separately, an aqueous solution prepared by dissolving sodium periodate (4.40 g, 20.6 mmol) and ammonium acetate (2.00 g, 20.6 mmol) in distilled water (200 mL) was added to this acetone solution. Then, it was made to react for 2 days at room temperature. After completion of the reaction, acetone was distilled off under reduced pressure, and the resulting aqueous solution was extracted twice with ethyl acetate (84 mL). Then, after drying with anhydrous magnesium sulfate, this was separated by filtration, and the ethyl acetate solution was distilled off under reduced pressure. This was purified by silica gel column chromatography to obtain 1.9 g of the desired product (yield 55%).
¹ H NMR (DMSO-d ₆ ); 1.30 (s, 9H, t-Bu), 2.81 (dd, J = 10.0, 13.5 Hz, 1H, β-H), 2.96 (dd, J = 5.0, 14.0 Hz, 1H, β-H), 3.71 (s, OC H ₂ O), 4.27-4.32 (m, 1H, α-H), 6.62 (d, J = 7.5 Hz, 1H, NH), 7.08-7.13 (m, 2H, ArH), 7.20 (t, J = 8.0 Hz, 1H, ArH), 7.25-7.27 (m, 3H, ArH), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.98 (s, 2H, B(OH) ₂ ), 10.04 (s, 1H, NH).

step 3
Preparation of (S)-(4-(2-amino-3-(benzo[d][1,3]dioxol-5-ylamino)-3-oxopropyl)phenyl)boronic acid Depinacol obtained in Step 2 The compound (1.00 g, 2.34 mmol) was dissolved in trifluoroacetic acid (10 mL). After allowing to stand for about 3 hours, it was concentrated under reduced pressure. It was dissolved with a small amount of distilled water and neutralized with sodium carbonate to precipitate the desired product. This was collected by filtration and washed with cold water to obtain 0.35 g of the desired product (yield 46%).
¹ H NMR (3.5% DCl in D ₂ O); 3.22 (dd, J = 8.5, 13.0 Hz, 1H, β-H), 3.37 (dd, J = 6.5, 13.0 Hz, 1H, β-H), 4.27 (dd, J = 6.5, 9.0 Hz, 1H, α-H), 5.96 (s, 1H, OCH ₂ O), 6.60 (dd, J = 2.5, 8.5 Hz, 1H, ArH), 6.76 (d, J = 2.5 Hz, 1H, ArH). 6.81 (d, J = 8.0 Hz, 1H, ArH), 7.34 (d, J = 7.5 Hz, 1H, ArH), 7.75 (d, J = 7.5 Hz, 1H, ArH).

（Ｓ）－（４－（２，３－ジアミノ－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O containing K₂CO₃): δ 7.54 (d, J = 7.5 Hz, 0.8H, ArH (minor)), 7.53 (d, J = 7.5 Hz, 1.2H, ArH (major)), 7.19 (d, J = 7.5 Hz, 0.8H, ArH), 7.17 (d, J = 7.5 Hz, 1.2H, ArH (major)), 4.24 (dd, J = 6.0, 8.5 Hz, 0.4H, CH (minor)), 3.66 (t, J = 6.5 Hz, 0.6H, CH (major)), 3.04 (dd, J = 6.0, 14.0 Hz, 0.4H, CH₂), 2.97-2.91 (m, 1H, CH₂), 2.86 (dd, J = 6.5, 14.0 Hz, 0.6H, CH₂ (major)). (Example 2)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2,3-diamino-3-oxopropyl)phenyl)boronic acid
^1H NMR ( _D2O containing _K2CO3 ): δ 7.54 (d, J = 7.5 Hz, _0.8H , ArH (minor)), 7.53 (d, J = 7.5 Hz, 1.2H, ArH (major)) , 7.19 (d, J = 7.5 Hz, 0.8H, ArH), 7.17 (d, J = 7.5 Hz, 1.2H, ArH (major)), 4.24 (dd, J = 6.0, 8.5 Hz, 0.4H, CH ( minor)), 3.66 (t, J = 6.5 Hz, 0.6H, CH (major)), 3.04 (dd, J = 6.0, 14.0 Hz, 0.4H, _CH2 ), 2.97-2.91 (m, 1H, _CH2 ), 2.86 (dd, J = 6.5, 14.0 Hz, 0.6H, CH ₂ (major)).

（Ｓ）－（４－（２－アミノ－３－（メチルアミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O containing K₂CO₃): δ 7.53-7.51 (m, 2H, ArH), 7.15-7.10 (m, 2H, ArH), 4.21 (t, J = 7.0 Hz, 0.4H, CH (minor)), 3.59 (t, J = 6.5 Hz, 0.6H, CH (major)), 3.02-2.84 (m, 2H, CH₂), 2.69 (s, 1.2H, CH₃(minor)), 2.65 (s, 1.8H, CH₃ (major)). (Example 3)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(methylamino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (D ₂ O containing K ₂ CO ₃ ): δ 7.53-7.51 (m, 2H, ArH), 7.15-7.10 (m, 2H, ArH), 4.21 (t, J = 7.0 Hz, 0.4H, CH (minor)), 3.59 (t, J = 6.5 Hz, 0.6H, CH (major)), 3.02-2.84 (m, 2H, CH ₂ ), 2.69 (s, 1.2H, CH ₃ (minor)), 2.65 (s, 1.8H, _CH3 (major)).

（Ｓ）－（４－（２－アミノ－３－（ジメチルアミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O containing K₂CO₃): δ 7.63-7.60 (m, 2H, ArH), 7.23 (d. J = 8.0 Hz, 0.4H, ArH (minor)), 7.19 (d, J = 6.5 Hz, 1.6H, ArH (major)), 4.77 (t, J = 8.0 Hz, 0.2H, CH (minor)), 4.21 (t, J = 7.0 Hz, 0.8H, CH (major)), 2.99-2.72 (m, 8H, CH₂, CH₃). (Example 4)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(dimethylamino)-3-oxopropyl)phenyl)boronic acid
^1H NMR ( _D2O containing _K2CO3 ): δ 7.63-7.60 (m, 2H, ArH), 7.23 (d. J = 8.0 Hz, 0.4H, ArH (minor ₎ ), 7.19 (d, J = 6.5 Hz, 1.6H, ArH (major)), 4.77 (t, J = 8.0 Hz, 0.2H, CH (minor)), 4.21 (t, J = 7.0 Hz, 0.8H, CH (major)), 2.99- 2.72 (m, 8H, _CH2 , _CH3 ).

（Ｓ）－（４－（２－アミノ－３－（エチルアミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (3.5% DCl in D₂O); 0.93 (t, J = 7.5 Hz, 3H, OCH₂ CH ₃ ), 3.08 (dd, J = 8.0, 13.5 Hz, 1H, β-H), 3.17 (q, J = 7.5 Hz, 2H, OCH ₂ CH₃), 3.29 (dd, J = 6.5, 13.5 Hz, 1H, β-H), 4.22 (dd, J = 6.5, 8.0 Hz, 1H, α-H), 7.34 (d, J = 8.0 Hz, 2H, ArH), 7.76 (d, J = 8.0 Hz, 2H, ArH). (Example 5)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(ethylamino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (3.5% DCl in D ₂ O); 0.93 (t, J = 7.5 Hz, 3H, OCH ₂ CH ₃ ), 3.08 (dd, J = 8.0, 13.5 Hz, 1H, β-H), 3.17 ( q, J = 7.5 Hz, 2H, O CH ₂ CH ₃ ), 3.29 (dd, J = 6.5, 13.5 Hz, 1H, β-H), 4.22 (dd, J = 6.5, 8.0 Hz, 1H, α-H ), 7.34 (d, J = 8.0 Hz, 2H, ArH), 7.76 (d, J = 8.0 Hz, 2H, ArH).

（Ｓ）－（４－（２－アミノ－３－（ジエチルアミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O containing K₂CO₃): δ 7.52 (d, J = 5.0 Hz, 2H, ArH), 7.15 (dd, J = 5.0, 10.0 Hz, 2H, ArH), 4.71 (t, J = 10.0 Hz, 0.5H, CH), 4.03 (t, J = 10.0 Hz, 0.5H, CH), 3.46 (m, 1H, ArH), 3.26-2.99 (m, 3H, CH₂), 2.91-2.82 (m, 2H, CH₂), 1.07-0.99 (m, 6H, CH₃). (Example 6)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(diethylamino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (D ₂ O containing K ₂ CO ₃ ): δ 7.52 (d, J = 5.0 Hz, 2H, ArH), 7.15 (dd, J = 5.0, 10.0 Hz, 2H, ArH), 4.71 (t, J = 10.0 Hz, 0.5H, CH), 4.03 (t, J = 10.0 Hz, 0.5H, CH), 3.46 (m, 1H, ArH), 3.26-2.99 (m, 3H, CH ₂ ), 2.91-2.82 ( m, 2H, _CH2 ), 1.07-0.99 (m, 6H, _CH3 ).

（Ｓ）－（４－（２－アミノ－３－（ｔｅｒｔ－ブチルアミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O containing K₂CO₃): δ 7.52 (d, J = 7.5 Hz, 0.6H, ArH (minor)), 7.52 (d, J = 8.0 Hz, 1.4H, ArH (major)), 7.16 (d, J = 7.5 Hz, 0.6H, ArH (minor)), 7.13 (d, J = 8.0 Hz, 1.4H, ArH (major)), 4.13 (t, J = 6.5 Hz, 0.3H, CH (minor)), 3.49 (t, J = 7.0 Hz, 0.7H, CH (major)), 2.93-2.80 (m, 2H, CH₂), 1.24 (s, 2.7H, CH₃ (minor)), 1.21 (s, 6.3H, CH₃). (Example 7)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(tert-butylamino)-3-oxopropyl)phenyl)boronic acid
^1H NMR ( _D2O containing _K2CO3 ): δ 7.52 (d, J = 7.5 Hz, 0.6H, ArH (minor ₎ ), 7.52 (d, J = 8.0 Hz, 1.4H, ArH (major)) , 7.16 (d, J = 7.5 Hz, 0.6H, ArH (minor)), 7.13 (d, J = 8.0 Hz, 1.4H, ArH (major)), 4.13 (t, J = 6.5 Hz, 0.3H, CH (minor)), 3.49 (t, J = 7.0 Hz, 0.7H, CH (major)), 2.93-2.80 (m, 2H, CH ₂ ), 1.24 (s, 2.7H, CH ₃ (minor)), 1.21 (s, 6.3H, _CH3 ).

（Ｓ）－（４－（２－アミノ－３－（シクロヘキシルアミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.30 (d, J = 8.0 Hz, 2H, ArH), 4.07 (dd, J = 6.0, 9.5 Hz, 1H, CH), 3.47 (m, 1H, CH), 3.27 (dd, J = 6.0, 13.5 Hz, 1H, CH₂), 3.09 (dd, J = 9.5, 13.5 Hz, 1H, CH₂), 1.72 (m, 1H, CH₂), 1.62 (m, 1H, CH₂), 1.53-1.49 (m, 2H, CH₂), 1.41 (m, 1H, CH₂), 1.29-1.02 (m, 4H, CH₂), 0.81 (m, 1H, CH₂). (Example 8)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(cyclohexylamino)-3-oxopropyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.30 (d, J = 8.0 Hz, 2H, ArH), 4.07 (dd, J = 6.0, 9.5 Hz, 1H , CH), 3.47 (m, 1H, CH), 3.27 (dd, J = 6.0, 13.5 Hz, 1H, CH ₂ ), 3.09 (dd, J = 9.5, 13.5 Hz, 1H, CH ₂ ), 1.72 (m , 1H, CH ₂ ), 1.62 (m, 1H, CH ₂ ), 1.53-1.49 (m, 2H, CH ₂ ), 1.41 (m, 1H, CH ₂ ), 1.29-1.02 (m, 4H, CH ₂ ) , 0.81 (m, 1H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（ピロリジン－１－イル）プロピル）フェニル）ボロン酸
¹H NMR (D₂O containing K₂CO₃): δ 7.51-7.49 (m, 2H, ArH), 7.16-7.12 (m, 2H, ArH), 4.53 (dd, J = 6.5, 8.25 Hz, 0.5H, CH (A-isomer)), 3.91 (dd, J = 6.0, 8.5 Hz, 0.5H, CH (B-isomer)), 3.53-3.23 (m, 3H, CH2), 2.95-2.80 (m, 3H, CH₂), 1.81-1.59 (m, 4H, CH₂). (Example 9)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-(pyrrolidin-1-yl)propyl)phenyl)boronic acid
¹ H NMR (D ₂ O containing K ₂ CO ₃ ): δ 7.51-7.49 (m, 2H, ArH), 7.16-7.12 (m, 2H, ArH), 4.53 (dd, J = 6.5, 8.25 Hz, 0.5H , CH (A-isomer)), 3.91 (dd, J = 6.0, 8.5 Hz, 0.5H, CH (B-isomer)), 3.53-3.23 (m, 3H, CH2), 2.95-2.80 (m, 3H, _CH2 ), 1.81-1.59 (m, 4H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－モルホリノ－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.78 (d, J = 8.0 Hz, 2H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 4.76 (dd, J = 6.0, 9.5 Hz, 1H, CH), 3.71-3.62 (m, 2H, CH₂), 3.50-3.39 (m, 3H, CH₂), 3.34-3.27 (m, 2H, CH₂), 3.12 (dd, J = 9.5, 13.5 Hz, 1H, CH₂), 3.01 (m, 1H, CH₂), 2.69 (m, 1H, CH₂). (Example 10)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-morpholino-3-oxopropyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 7.78 (d, J = 8.0 Hz, 2H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 4.76 (dd, J = 6.0, 9.5 Hz, 1H , CH), 3.71-3.62 (m, 2H, CH ₂ ), 3.50-3.39 (m, 3H, CH ₂ ), 3.34-3.27 (m, 2H, CH ₂ ), 3.12 (dd, J = 9.5, 13.5 Hz , 1H, CH ₂ ), 3.01 (m, 1H, CH ₂ ), 2.69 (m, 1H, CH ₂ ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（フェニルアミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O containing K₂CO₃): δ 7.74 (dd, J = 5.0, 10.0 Hz, 2H, ArH), 7.41-7.34 (m, 4H, ArH), 7.28-7.24 (m, 3H, ArH), 4.39 (t, J = 15.0 Hz, 1H, CH), 3.38 (dd, J = 5.0, 15.0 Hz, 1H, CH₂), 3.26 (dd, J = 5.0, 15.0 Hz, 1H, CH₂). (Example 11)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-(phenylamino)propyl)phenyl)boronic acid
¹ H NMR (D ₂ O containing K ₂ CO ₃ ): δ 7.74 (dd, J = 5.0, 10.0 Hz, 2H, ArH), 7.41-7.34 (m, 4H, ArH), 7.28-7.24 (m, 3H, ArH), 4.39 (t, J = 15.0 Hz, 1H, CH), 3.38 (dd, J = 5.0, 15.0 Hz, 1H, _CH2 ), 3.26 (dd, J = 5.0, 15.0 Hz, 1H, _CH2 ) .

（Ｓ）－（４－（２－アミノ－３－（ナフタレン－１－イルアミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 10.27 (brd, J = 9.5 Hz, 1H), 8.47 (brs, 3H), 8.12 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H, ArH), 7.82-7.3 (m, 10H, ArH), 4.40 (t, J = 8.0 Hz, 1H, CH), 3.27-3.16 (m, 2H, CH₂). (Example 12)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(naphthalen-1-ylamino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (DMSO-d ₆ ): δ 10.27 (brd, J = 9.5 Hz, 1H), 8.47 (brs, 3H), 8.12 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H, ArH) , 7.82-7.3 (m, 10H, ArH), 4.40 (t, J = 8.0 Hz, 1H, CH), 3.27-3.16 (m, 2H, CH ₂ ).

（Ｓ）－（４－（２－アミノ－３－（メチル（フェニル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O containing K₂CO₃): δ 7.63-6.86 (m, 9H, ArH), 4.34 (t, J = 10.0 Hz, 0.6H, CH (major)), 3.62 (t, J = 10.0 Hz, 0.4H, CH (minor)), 3.20 (s, 1.8H CH₃ (major)), 3.18 (s, 1.4H, CH₃(minor)), 2.84 (m, 1H, CH₂), 2.65 (m, 1H, CH₂). (Example 13)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(methyl(phenyl)amino)-3-oxopropyl)phenyl)boronic acid
^1H NMR ( _D2O containing _K2CO3 ): δ 7.63-6.86 (m, 9H, ArH), 4.34 (t, J = 10.0 Hz, 0.6H, CH ( _major )), 3.62 (t, J = 10.0 Hz, 0.4H, CH (minor)), 3.20 (s, 1.8H _CH3 (major)), 3.18 (s, 1.4H, _CH3 (minor)), 2.84 (m, 1H, _CH2 ), 2.65 (m, 1H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－（ベンジルアミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.36-7.32 (m, 3H, ArH), 7.06-7.02 (m, 4H, ArH), 6.78-6.75 (m, 2H, ArH), 4.44 (d, J = 15.0 Hz, 1H, CH₂), 4.18 (dd, J = 6.0, 10.0 Hz, 1H, CH), 4.13 (d, J = 15.0 Hz, 1H, CH₂), 3.19 (dd, J = 6.0, 13.5 Hz, 1H, CH₂), 3.01 (dd, J = 10.0, 13.5 Hz, 1H, CH₂). (Example 14)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(benzylamino)-3-oxopropyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 7.36-7.32 (m, 3H, ArH), 7.06-7.02 (m, 4H, ArH), 6.78-6.75 (m, 2H, ArH), 4.44 (d, J = 15.0 Hz, 1H, _CH2 ), 4.18 (dd, J = 6.0, 10.0 Hz, 1H, CH), 4.13 (d, J = 15.0 Hz, 1H, _CH2 ), 3.19 (dd, J = 6.0, 13.5 Hz, 1H, CH ₂ ), 3.01 (dd, J = 10.0, 13.5 Hz, 1H, CH ₂ ).

（Ｓ）－（４－（２－アミノ－３－（ベンジル（メチル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 8.34 (brs, 1H), 7.71-7.68 (m, 2H, ArH), 7.27-6.97 (m, 7H, ArH), 4.53-4.24 (m, 3H, CH₂, CH), 2.91-2.89 (m, 2H, CH₂), 2.70 (s, 3H, CH₃ (minor)), 2.67 (s, 3H, CH₃(major)). (Example 15)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(benzyl(methyl)amino)-3-oxopropyl)phenyl)boronic acid
^1H NMR (DMSO- _d6 ): δ 8.34 (brs, 1H), 7.71-7.68 (m, 2H, ArH), 7.27-6.97 (m, 7H, ArH), 4.53-4.24 (m, 3H, _CH2 , CH), 2.91-2.89 (m, 2H, CH ₂ ), 2.70 (s, 3H, CH ₃ (minor)), 2.67 (s, 3H, CH ₃ (major)).

（Ｓ）－（４－（２－アミノ－３－（ジベンジルアミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 7.99 (brs, 2H), 7.68 (d, J = 8.0 Hz, 2H, ArH), 7.28-7.01 (m, 12H, ArH), 4.53-4.29 (m, 4H, CH₂), 3.90 (t, J = 7.0 Hz, 1H, CH), 2.90 (dd, J = 7.0, 13.0 Hz, 1H, CH₂), 2.72 (dd, J = 7.0, 13.0 Hz, 1H, CH₂). (Example 16)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(dibenzylamino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (DMSO-d ₆ ): δ 7.99 (brs, 2H), 7.68 (d, J = 8.0 Hz, 2H, ArH), 7.28-7.01 (m, 12H, ArH), 4.53-4.29 (m, 4H , CH ₂ ), 3.90 (t, J = 7.0 Hz, 1H, CH ), 2.90 (dd, J = 7.0, 13.0 Hz, 1H, CH ₂ ), 2.72 (dd, J = 7.0, 13.0 Hz, 1H, CH ₂ ).

（４－（（Ｓ）－２－アミノ－３－オキソ－３－（（（Ｓ）－１－フェニルエチル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.54 (d, J = 7.5 Hz, 2H, ArH), 7.31-7.25 (m, 3H, ArH), 7.12 (d, J = 7.5 Hz, 2H, ArH), 6.92-6.90 (m, 2H, ArH), 4.82 (m, 1H, CH), 4.15 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.25 (dd, J = 6.0, 13.5 Hz, 1H, CH₂), 3.01 (dd, J = 10.0, 13.5 Hz, 1H, CH₂), 1.35 (d, J = 7.5 Hz, 3H, CH₃). (Example 17)
The following compounds were prepared in the same manner as in Example 1.

(4-((S)-2-amino-3-oxo-3-(((S)-1-phenylethyl)amino)propyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 7.54 (d, J = 7.5 Hz, 2H, ArH), 7.31-7.25 (m, 3H, ArH), 7.12 (d, J = 7.5 Hz, 2H, ArH), 6.92. -6.90 (m, 2H, ArH), 4.82 (m, 1H, CH), 4.15 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.25 (dd, J = 6.0, 13.5 Hz, 1H, CH ₂ ), 3.01 (dd, J = 10.0, 13.5 Hz, 1H, CH ₂ ), 1.35 (d, J = 7.5 Hz, 3H, CH ₃ ).

（４－（（Ｓ）－２－アミノ－３－オキソ－３－（（（Ｒ）－１－フェニルエチル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.79 (d, J = 8.0 Hz, 2H, ArH), 7.40-7.26 (m, 7H, ArH), 4.72 (m, 1H, CH), 4.19 (m, 1H, CH), 3.32 (dd, J = 6.0, 13.5 Hz, 1H, CH₂), 3.14 (dd, J = 9.0, 13.5 Hz, 1H, CH₂), 1.12 (d, J = 7.0 Hz, 3H, CH₃). (Example 18)
The following compounds were prepared in the same manner as in Example 1.

(4-((S)-2-amino-3-oxo-3-(((R)-1-phenylethyl)amino)propyl)phenyl)boronic acid
¹ H NMR (D ₂ O): δ 7.79 (d, J = 8.0 Hz, 2H, ArH), 7.40-7.26 (m, 7H, ArH), 4.72 (m, 1H, CH), 4.19 (m, 1H, CH), 3.32 (dd, J = 6.0, 13.5 Hz, 1H, _CH2 ), 3.14 (dd, J = 9.0, 13.5 Hz, 1H, _CH2 ), 1.12 (d, J = 7.0 Hz, 3H, _CH3 ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（（２－フェニルプロパン－２－イル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.82 (d, J = 7.5 Hz, 2H, ArH), 7.36-7.26 (m, 5H, ArH), 7.12 (d, J = 7.5 Hz, 2H, ArH), 4.31 (dd, J = 6.0, 9.0 Hz, 1H, CH), 3.27 (dd, J = 6.0, 14.0 Hz, 1H, CH₂), 3.12 (dd, J = 9.0, 14.0 Hz, 1H, CH₂), 1.51 (s, 3H, CH₃), 1.43 (s, 3H, CH₃). (Example 19)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((2-phenylpropan-2-yl)amino)propyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 7.82 (d, J = 7.5 Hz, 2H, ArH), 7.36-7.26 (m, 5H, ArH), 7.12 (d, J = 7.5 Hz, 2H, ArH), 4.31. (dd, J = 6.0, 9.0 Hz, 1H, CH), 3.27 (dd, J = 6.0, 14.0 Hz _, 1H, CH2), 3.12 (dd, J = 9.0, 14.0 Hz, 1H, _CH2 ), 1.51 (s, 3H, _CH3 ), 1.43 (s, 3H, _CH3 ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（ｐ－トリルアミノ）プロピル）フェニル）ボロン酸
¹H NMR (3.5% DCl in D₂O); 2.23 (s, 3H, CH₃), 3.28 (dd, J = 8.5, 13.5 Hz, 1H, β-H), 3.40 (dd, J = 6.0, 13.5 Hz, 1H, β-H), 4.44 (dd, J = 6.5, 8.0 Hz, 1H, α-H), 7.11 (d, J = 8.0 Hz, 2H, ArH), 7.20 (d, J = 8.5 Hz, 2H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH). (Example 20)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-(p-tolylamino)propyl)phenyl)boronic acid
¹ H NMR (3.5% DCl in D ₂ O); 2.23 (s, 3H, CH ₃ ), 3.28 (dd, J = 8.5, 13.5 Hz, 1H, β-H), 3.40 (dd, J = 6.0, 13.5 Hz, 1H, β-H), 4.44 (dd, J = 6.5, 8.0 Hz, 1H, α-H), 7.11 (d, J = 8.0 Hz, 2H, ArH), 7.20 (d, J = 8.5 Hz, 2H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（ｍ－トリルアミノ）プロピル）フェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 10.37 (brs, 1H), 8.35 (brs, 3H), 8.13 (brs, 1H), 7.73 (d, J = 8.0 Hz, 1.3H, ArH (major)), 7.62 (d, J = 7.5 Hz, 0.7H, ArH (minor)), 7.34-7.20 (m, 5H, ArH), 6.93 (d, J = 7.5 Hz, 1H, ArH), 4.16 (t, J = 7.0 Hz, 1H, CH), 3.17 (m, 1H, CH₂), 3.08 (m, 1H, CH₂), 2.28 (s, 3H, CH₃). (Example 21)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-(m-tolylamino)propyl)phenyl)boronic acid
¹ H NMR (DMSO-d ₆ ): δ 10.37 (brs, 1H), 8.35 (brs, 3H), 8.13 (brs, 1H), 7.73 (d, J = 8.0 Hz, 1.3H, ArH (major)), 7.62 (d, J = 7.5 Hz, 0.7H, ArH (minor)), 7.34-7.20 (m, 5H, ArH), 6.93 (d, J = 7.5 Hz, 1H, ArH), 4.16 (t, J = 7.0 Hz, 1H, CH), 3.17 (m, 1H, _CH2 ), 3.08 (m, 1H, _CH2 ), 2.28 (s, 3H, _CH3 ).

（Ｓ）－（４－（２－アミノ－３－（（３，４－ジメチルフェニル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (3.5% DCl in D₂O); 2.18 (s, 6H, CH ₃ ×2), 3.22 (dd, J = 9.0, 13.5 Hz, 1H, β-H), 3.39 (dd, J = 6.5, 13.5 Hz, 1H, β-H), 4.32 (dd, J = 7.0, 9.0 Hz, 1H, α-H), 6.86 (d, J = 2.0 Hz, 1H, ArH), 6.96 (dd, J = 2.5, 8.5 Hz, 1H, ArH), 7.12 (d, J = 8.0 Hz, 1H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 7.74 (d, J = 8.0 Hz, 2H, ArH). (Example 22)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((3,4-dimethylphenyl)amino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (3.5% DCl in D ₂ O); 2.18 (s, 6H, CH ₃ ×2), 3.22 (dd, J = 9.0, 13.5 Hz, 1H, β-H), 3.39 (dd, J = 6.5 , 13.5 Hz, 1H, β-H), 4.32 (dd, J = 7.0, 9.0 Hz, 1H, α-H), 6.86 (d, J = 2.0 Hz, 1H, ArH), 6.96 (dd, J = 2.5 , 8.5 Hz, 1H, ArH), 7.12 (d, J = 8.0 Hz, 1H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 7.74 (d, J = 8.0 Hz, 2H, ArH) .

（Ｓ）－（４－（２－アミノ－３－（（４－（tert－ブチル）フェニル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 10.45 (brs, 0.25H (minor)), 10.42 (brs, 0.75H (major)), 8.38 (brs, 2H), 7.74 (d, J = 7.5 Hz, 1.5H, ArH (major)), 7.62 (d, J = 7.5 Hz, 0.5H, ArH (minor)), 7.43 (d, J = 6.5 Hz, 2H, ArH), 7.35 (d, J = 6.5 Hz, 2H, ArH), 7.29 (d, J = 7.5 Hz, 0.5H, ArH (minor)), 7.23 (d, J = 7.5 Hz, 1.5H, ArH (major)), 4.17 (m, 1H, CH), 3.21-3.07 (m, 2H, CH₂), 1.27 (s, 2.25H, CH₃ (minor)), 1.25 (s, 6.75H, CH₃ (major)). (Example 23)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((4-(tert-butyl)phenyl)amino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (DMSO-d ₆ ): δ 10.45 (brs, 0.25H (minor)), 10.42 (brs, 0.75H (major)), 8.38 (brs, 2H), 7.74 (d, J = 7.5 Hz, 1.5 H, ArH (major)), 7.62 (d, J = 7.5 Hz, 0.5H, ArH (minor)), 7.43 (d, J = 6.5 Hz, 2H, ArH), 7.35 (d, J = 6.5 Hz, 2H , ArH), 7.29 (d, J = 7.5 Hz, 0.5H, ArH (minor)), 7.23 (d, J = 7.5 Hz, 1.5H, ArH (major)), 4.17 (m, 1H, CH), 3.21 -3.07 (m, 2H, CH ₂ ), 1.27 (s, 2.25H, CH ₃ (minor)), 1.25 (s, 6.75H, CH ₃ (major)).

（Ｓ）－（４－（２－アミノ－３－（（２－メトキシフェニル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 9.68 (s, 1H), 8.37 (s, 3H), 8.14 (s, 2H), 7.82 (dd, J = 1.5, 8.0 Hz, 1H, ArH), 7.75 (d, J = 7.5 Hz, 2H, ArH), 7.26 (d, J = 7.5 Hz, 2H, ArH), 7.13 (dt, J = 1.5, 8.0 Hz, 1H, ArH), 7.05 (dd, J = 1.5, 8.0 Hz, 1H, ArH), 6.93 (dt, J = 1.5, 8.0 Hz, 1H, ArH), 4.44 (t, J = 7.0 Hz, 1H, CH), 3.78 (s, 3H, CH₃), 3.14 (dd, J = 7.0, 13.5 Hz, 1H, CH₂), 3.08 (dd, J = 7.0, 13.5 Hz, 1H, CH₂). (Example 24)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((2-methoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (DMSO-d ₆ ): δ 9.68 (s, 1H), 8.37 (s, 3H), 8.14 (s, 2H), 7.82 (dd, J = 1.5, 8.0 Hz, 1H, ArH), 7.75 ( d, J = 7.5 Hz, 2H, ArH), 7.26 (d, J = 7.5 Hz, 2H, ArH), 7.13 (dt, J = 1.5, 8.0 Hz, 1H, ArH), 7.05 (dd, J = 1.5, 8.0 Hz, 1H, ArH), 6.93 (dt, J = 1.5, 8.0 Hz, 1H, ArH), 4.44 (t, J = 7.0 Hz, 1H, CH), 3.78 (s, 3H, _CH3 ), 3.14 ( dd, J = 7.0, 13.5 Hz, 1H, _CH2 ), 3.08 (dd, J = 7.0, 13.5 Hz, 1H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－（（３－メトキシフェニル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (3.5% DCl in D₂O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.40 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 3.77 (s, 3H, OCH₃), 4.46 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.78-81 (m, 2H, ArH), 6.89-6.90 (m, 1H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH). (Example 25)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((3-methoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (3.5% DCl in D ₂ O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.40 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 3.77 (s, 3H, _OCH3 ), 4.46 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.78-81 (m, 2H, ArH), 6.89-6.90 (m, 1H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH).

（Ｒ）－（４－（２－アミノ－３－（（３－メトキシフェニル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (3.5% DCl in D₂O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.40 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 3.77 (s, 3H, OCH₃), 4.46 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.78-81 (m, 2H, ArH), 6.89-6.90 (m, 1H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH). (Example 26)
The following compounds were prepared in the same manner as in Example 1.

(R)-(4-(2-amino-3-((3-methoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (3.5% DCl in D ₂ O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.40 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 3.77 (s, 3H, _OCH3 ), 4.46 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.78-81 (m, 2H, ArH), 6.89-6.90 (m, 1H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH).

（Ｓ）－（４－（２－アミノ－３－（（３，４－ジメトキシフェニル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (3.5% DCl in D₂O); 3.23 (dd, J = 8.5, 13.0 Hz, 1H, β-H), 3.41 (dd, J = 6.0, 13.5 Hz, 1H, β-H), 3.75 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃), 4.42 (dd, J = 6.0, 8.5 Hz, 1H, α-H), 6.63 (d, J = 2.5 Hz, 1H, ArH), 6.79 (dd, J = 2.5, 8.5 Hz, 1H, ArH), 6.87 (d, J = 8.5 Hz, 1H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.75 (d, J = 8.0 Hz, 2H, ArH). (Example 27)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((3,4-dimethoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (3.5% DCl in D ₂ O); 3.23 (dd, J = 8.5, 13.0 Hz, 1H, β-H), 3.41 (dd, J = 6.0, 13.5 Hz, 1H, β-H), 3.75 (s, 3H, _OCH3 ), 3.78 (s, 3H, _OCH3 ), 4.42 (dd, J = 6.0, 8.5 Hz, 1H, α-H), 6.63 (d, J = 2.5 Hz, 1H, ArH) , 6.79 (dd, J = 2.5, 8.5 Hz, 1H, ArH), 6.87 (d, J = 8.5 Hz, 1H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.75 (d, J = 8.0Hz, 2H, ArH).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（（３，４，５－トリメトキシフェニル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.76 (d, J = 8.0 Hz, 2H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 6.42 (s, 2H, ArH), 4.31 (dd, J = 6.5, 9.5 Hz, 1H, CH), 3.80 (s, 6H, CH₃), 3.74 (s, 3H, CH₃), 3.44 (dd, J = 6.5, 13.5 Hz, 1H, CH₂), 3.18 (dd, J = 9.5, 13.5 Hz, 1H, CH₂). (Example 28)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((3,4,5-trimethoxyphenyl)amino)propyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 7.76 (d, J = 8.0 Hz, 2H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 6.42 (s, 2H, ArH), 4.31 (dd , J = 6.5, 9.5 Hz, 1H, CH), 3.80 (s, 6H, _CH3 ), 3.74 (s, 3H, _CH3 ), 3.44 (dd, J = 6.5, 13.5 Hz, 1H, _CH2 ), 3.18 (dd, J = 9.5, 13.5Hz, 1H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－（（２，３－ジヒドロキシベンゾ［ｂ］［１，４］ジオキシン－６－イル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (3.5% DCl in D₂O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.38 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 4.24 (s, 4H, OCH₂CH₂O), 4.44 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.69 (dd, J = 2.0 Hz, 8.5, 1H, Ar), 6.78 (d, J = 2.0 Hz, 1H, ArH), 6.81 (d, J = 8.5 Hz, 1H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH). (Example 29)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((2,3-dihydroxybenzo[b][1,4]dioxin-6-yl)amino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (3.5% DCl in D ₂ O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.38 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 4.24 (s, 4H, _OCH2CH2O ), 4.44 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.69 (dd _, J = 2.0 Hz, 8.5, 1H, Ar), 6.78 (d, J = 2.0 Hz, 1H, ArH), 6.81 (d, J = 8.5 Hz, 1H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH ).

（Ｓ）－（４－（２－アミノ－３－（（４－ニトロフェニル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (3.5% DCl in D₂O); 3.12 (dd, J = 7.5, 13.5 Hz, 1H, β-H), 3.19 (dd, J = 6.5, 13.5 Hz, 1H, β-H), 4.26 (dd, J = 6.5, 8.0 Hz, 1H, α-H), 7.15 (d, J = 8.0 Hz, 2H, ArH), 7.32 (d, J = 9.0 Hz, 2H, ArH), 7.54 (d, J = 8.0 Hz, 2H, ArH), 7.92 (d, J = 9.5 Hz, 2H, ArH). (Example 30)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((4-nitrophenyl)amino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (3.5% DCl in D ₂ O); 3.12 (dd, J = 7.5, 13.5 Hz, 1H, β-H), 3.19 (dd, J = 6.5, 13.5 Hz, 1H, β-H), 4.26. (dd, J = 6.5, 8.0 Hz, 1H, α-H), 7.15 (d, J = 8.0 Hz, 2H, ArH), 7.32 (d, J = 9.0 Hz, 2H, ArH), 7.54 (d, J = 8.0 Hz, 2H, ArH), 7.92 (d, J = 9.5 Hz, 2H, ArH).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（フェネチルアミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.73 (d, J = 7.5 Hz, 2H, ArH), 7.34 (t, J = 7.5 Hz, 2H, ArH), 7.28 (dd, J = 6.0, 7.5 Hz, 1H, ArH), 7.21 (d, J = 7.5 Hz, 2H, ArH), 7.14 (d, J = 7.5 Hz, 2H, ArH), 4.13 (t, J = 8.0 Hz, 1H, CH), 3.55 (ddd, J = 7.0, 8.0, 13.5 Hz, 1H, CH₂), 3.31 (ddd, J = 7.0, 8.0, 13.5 Hz, 1H, CH₂), 3.15 (dd, J = 8.0, 13.5 Hz, 1H, CH₂), 3.08 (dd, J = 8.0, 13.5 Hz, 1H, CH₂), 2.71-2.61 (m, 2H, ArH). (Example 31)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-(phenethylamino)propyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 7.73 (d, J = 7.5 Hz, 2H, ArH), 7.34 (t, J = 7.5 Hz, 2H, ArH), 7.28 (dd, J = 6.0, 7.5 Hz, 1H , ArH), 7.21 (d, J = 7.5 Hz, 2H, ArH), 7.14 (d, J = 7.5 Hz, 2H, ArH), 4.13 (t, J = 8.0 Hz, 1H, CH), 3.55 (ddd, J = 7.0, 8.0, 13.5 Hz, 1H, _CH2 ), 3.31 (ddd, J = 7.0, 8.0, 13.5 Hz, 1H, _CH2 ), 3.15 (dd, J = 8.0, 13.5 Hz, 1H, _CH2 ) , 3.08 (dd, J = 8.0, 13.5 Hz, 1H, CH ₂ ), 2.71-2.61 (m, 2H, ArH).

（Ｓ）－（４－（２－アミノ－３－（（４－メトキシフェネチル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.70 (dd, J = 2.5, 8.5 Hz, 2H, ArH), 7.16 (dd, J = 2.5, 8.0 Hz, 2H, ArH), 7.04 (dd, J = 2.5, 8.5 Hz, 2H, ArH), 6.89 (dd, J = 2.5, 8.0 Hz, 2H, ArH), 4.12 (dd, J = 6.5, 8.0 Hz, 1H, CH), 3.79 (s, 3H, CH₃), 3.53 (ddd, J = 6.5, 7.0, 13.5 Hz, 1H, CH₂), 3.25 (ddd, J = 6.5, 7.0, 13.5 Hz, 1H, CH₂), 3.13 (dd, J = 6.5, 14.0 Hz, 1H, CH₂), 3.06 (dd, J = 8.0, 14.0 Hz, 1H, CH₂), 2.60 (m, 2H, CH₂). (Example 32)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((4-methoxyphenethyl)amino)-3-oxopropyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 7.70 (dd, J = 2.5, 8.5 Hz, 2H, ArH), 7.16 (dd, J = 2.5, 8.0 Hz, 2H, ArH), 7.04 (dd, J = 2.5, 8.5 Hz, 2H, ArH), 6.89 (dd, J = 2.5, 8.0 Hz, 2H, ArH), 4.12 (dd, J = 6.5, 8.0 Hz, 1H, CH), 3.79 (s, 3H, _CH3 ), 3.53 (ddd, J = 6.5, 7.0, 13.5 Hz, 1H, _CH2 ), 3.25 (ddd, J = 6.5, 7.0, 13.5 Hz, 1H, _CH2 ), 3.13 (ddd, J = 6.5, 14.0 Hz, 1H , CH ₂ ), 3.06 (dd, J = 8.0, 14.0 Hz, 1H, CH ₂ ), 2.60 (m, 2H, CH ₂ ).

（Ｓ）－（４－（２－アミノ－３－（（３－メトキシフェネチル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.68 (d, J = 8.0 Hz, 2H, ArH), 7.26 (t, J = 8.0 Hz, 1H, ArH), 7.15 (d, J = 8.0 Hz, 2H, ArH), 6.85 (m, 1H, ArH), 6.76-6.74 (m, 2H, ArH), 4.12 (dd, J = 6.5, 8.5 Hz, 1H, CH), 3.79 (s, 3H, CH₃), 3.56 (m, 1H, CH₂), 3.29 (m, 1H, CH₂), 3.12 (dd, J = 6.5, 13.5 Hz, 1H, CH₂), 3.05 (dd, J = 8.5, 13.5 Hz, 1H, CH₂), 2.66-2.63 (m, 2H, CH₂). (Example 33)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((3-methoxyphenethyl)amino)-3-oxopropyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 7.68 (d, J = 8.0 Hz, 2H, ArH), 7.26 (t, J = 8.0 Hz, 1H, ArH), 7.15 (d, J = 8.0 Hz, 2H, ArH ), 6.85 (m, 1H, ArH), 6.76-6.74 (m, 2H, ArH), 4.12 (dd, J = 6.5, 8.5 Hz, 1H, CH), 3.79 (s, 3H, CH ₃ ), 3.56 ( m, 1H, CH ₂ ), 3.29 (m, 1H, CH ₂ ), 3.12 (dd, J = 6.5, 13.5 Hz, 1H, CH ₂ ), 3.05 (dd, J = 8.5, 13.5 Hz, 1H, CH ₂ ), 2.66-2.63 (m, 2H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－（（４－フルオロフェネチル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 8.48 (t, J = 5.5 Hz, 1H), 8.22 (brs, 3H), 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.16-7.06 (m, 6H, ArH), 3.93 (m, 1H, CH), 3.39 (m, 1H, CH₂), 3.18 (m, 1H, CH₂), 2.99 (dd, J = 6.5, 13.5 Hz, 1H, CH₂), 2.92 (dd, J = 7.0, 13.5 Hz, 1H, CH₂), 2.60 (m, 2H, CH₂). (Example 34)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((4-fluorophenethyl)amino)-3-oxopropyl)phenyl)boronic acid
¹ H NMR (DMSO-d ₆ ): δ 8.48 (t, J = 5.5 Hz, 1H), 8.22 (brs, 3H), 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.16-7.06 (m, 6H, ArH), 3.93 (m, 1H, CH), 3.39 (m, 1H, _CH2 ), 3.18 (m, 1H, _CH2 ), 2.99 (dd, J = 6.5, 13.5 Hz, 1H, _CH2 ) , 2.92 (dd, J = 7.0, 13.5 Hz, 1H, CH ₂ ), 2.60 (m, 2H, CH ₂ ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（（３－フェニルプロピル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 8.05-8.03 (m, 2H), 7.72 (d, J = 7.5 Hz, 2H, ArH), 7.28-7.11 (m, 9H, ArH, NH₂), 3.58 (t, J = 7.0 Hz, 1H, CH), 3.10-2.97 (m, 2H, CH₂), 2.94 (dd, J = 7.0, 13.5 Hz, 1H, CH₂), 2.76 (dd, J = 7.0, 13.5 Hz, 1H, CH₂), 2.49-2.46 (m, 2H, CH₂), 1.65-1.59 (m, 2H, CH₂). (Example 35)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((3-phenylpropyl)amino)propyl)phenyl)boronic acid
¹ H NMR (DMSO-d ₆ ): δ 8.05-8.03 (m, 2H), 7.72 (d, J = 7.5 Hz, 2H, ArH), 7.28-7.11 (m, 9H, ArH, NH ₂ ), 3.58 ( t, J = 7.0 Hz, 1H, CH), 3.10-2.97 (m, 2H, _CH2 ), 2.94 (dd, J = 7.0, 13.5 Hz, 1H, _CH2 ), 2.76 (dd, J = 7.0, 13.5 Hz, 1H, _CH2 ), 2.49-2.46 (m, 2H, _CH2 ), 1.65-1.59 (m, 2H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（（２－フェノキシエチル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.51 (d, J = 8.0 Hz, 2H, ArH), 7.35 (dd, J = 7.5, 9.0 Hz, 2H, ArH), 7.24 (d, J = 7.5 Hz, 2H, ArH), 7.04 (t, J = 7.5 Hz, 1H, ArH), 6.81 (d, J = 8.0 Hz, 2H, ArH), 4.19 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.83 (m, 1H, CH₂), 3.75 (m, 1H, CH₂), 3.55 (m, 1H, CH₂), 3.28 (dd, J = 6.0, 13.5 Hz, 1H, CH₂), 3.22 (m, 1H, CH₂), 3.05 (dd, J = 10.0, 13.5 Hz, 1H, CH₂). (Example 36)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((2-phenoxyethyl)amino)propyl)phenyl)boronic acid
¹ H NMR (D ₂ O): δ 7.51 (d, J = 8.0 Hz, 2H, ArH), 7.35 (dd, J = 7.5, 9.0 Hz, 2H, ArH), 7.24 (d, J = 7.5 Hz, 2H , ArH), 7.04 (t, J = 7.5 Hz, 1H, ArH), 6.81 (d, J = 8.0 Hz, 2H, ArH), 4.19 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.83 ( m, 1H, CH ₂ ), 3.75 (m, 1H, CH ₂ ), 3.55 (m, 1H, CH ₂ ), 3.28 (dd, J = 6.0, 13.5 Hz, 1H, CH ₂ ), 3.22 (m, 1H , CH ₂ ), 3.05 (dd, J = 10.0, 13.5 Hz, 1H, CH ₂ ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（（４－フェノキシブチル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 8.42 (brs, 2H), 8.21 (t, J = 6.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H, ArH), 7.27-7.24 (m, 2H, ArH), 7.16-7.13 (m, 5H, ArH), 3.71 (t, J = 7.0 Hz, 1H, CH), 3.09 (m, 1H, CH₂), 3.00-2.92 (m, 2H, CH₂), 2.84 (dd, J = 7.0, 13.5 Hz, 1H, CH₂), 1.47-1.41 (m, 2H, CH₂), 1.34-1.26 (m, 2H, CH₂), 1.05 (t, J = 7.0 Hz, 2H, CH₂). (Example 37)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((4-phenoxybutyl)amino)propyl)phenyl)boronic acid
¹ H NMR (DMSO-d ₆ ): δ 8.42 (brs, 2H), 8.21 (t, J = 6.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H, ArH), 7.27-7.24 (m, 2H, ArH), 7.16-7.13 (m, 5H, ArH), 3.71 (t, J = 7.0 Hz, 1H, CH), 3.09 (m, 1H, _CH2 ), 3.00-2.92 (m, 2H, _CH2 ), 2.84 (dd, J = 7.0, 13.5 Hz, 1H, _CH2 ), 1.47-1.41 (m, 2H, _CH2 ), 1.34-1.26 (m, 2H, _CH2 ), 1.05 (t, J = 7.0 Hz, 2H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（（３－フェノキシプロピル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (3.5% DCl in D₂O); 1.66-1.71 (m, 2H, CH₂ CH ₂ CH₂), 3.04-3.11 (m, 2H, CH ₂ CH₂CH₂), 3.31 (dd, J = 5.5, 13.0 Hz, 1H, β-H), 3.44-3.53 (m, 3H, β-H+CH₂CH₂ CH ₂ ), 4.25 (dd, J = 6.0, 10.0 Hz, 1H, α-H), 6.85 (d, J = 8.0 Hz, 2H, ArH), 7.05 (t, J = 7.5 Hz, 1H, ArH), 7.30 (d, J = 8.0 Hz, 2H, ArH), 7.36 (t, J = 7.0 Hz, 2H, ArH), 7.66 (d, J = 7.5 Hz, 2H, ArH). (Example 38)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((3-phenoxypropyl)amino)propyl)phenyl)boronic acid
^1H NMR (3.5% _DCl in _D2O ); 1.66-1.71 (m, _2H , CH2CH2CH2 ₎ , 3.04-3.11 (m, _2H , _{CH2CH2CH2 )} , 3.31 ( dd, J = 5.5, 13.0 Hz, 1H, β-H), 3.44-3.53 (m, 3H, β-H+CH ₂ CH ₂ CH ₂ ), 4.25 (dd, J = 6.0, 10.0 Hz, 1H, α-H) , 6.85 (d, J = 8.0 Hz, 2H, ArH), 7.05 (t, J = 7.5 Hz, 1H, ArH), 7.30 (d, J = 8.0 Hz, 2H, ArH), 7.36 (t, J = 7.0 Hz, 2H, ArH), 7.66 (d, J = 7.5 Hz, 2H, ArH).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（（３－（フェニルアミノ）プロピル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (3.5% DCl in D₂O); 1.66-1.72 (m, 2H, CH₂ CH ₂ CH₂), 2.99-3.10 (m, 4H, CH ₂ CH₂ CH ₂ ), 3.27 (dd, J = 6.5 Hz, 14.0, 1H, β-H), 3.35 (d, J = 10.5, 14.0 Hz, 1H, β-H), 4.17 (dd, J = 6.0, 10.5 Hz, 1H, α-H), 7.26 (d, J = 8.0 Hz, 2H, Ar), 7.38-7.40 (m, 2H, ArH), 7.58-7.62 (m, 5H, ArH). (Example 39)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((3-(phenylamino)propyl)amino)propyl)phenyl)boronic acid
^1H NMR (3.5% _DCl in _D2O ); 1.66-1.72 ( m , 2H _, CH2CH2CH2 ₎ , 2.99-3.10 (m, 4H _{, CH2CH2CH2 )} , 3.27 (dd, J = 6.5 Hz, 14.0, 1H, β-H), 3.35 (d, J = 10.5, 14.0 Hz, 1H, β-H), 4.17 (dd, J = 6.0, 10.5 Hz, 1H, α-H), 7.26 (d, J = 8.0 Hz, 2H, ArH), 7.38-7.40 (m, 2H, ArH), 7.58-7.62 (m, 5H, ArH).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（（３－（フェニルチオ）プロピル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (3.5% DCl in D₂O); 1.42-1.50 (m, 2H, CH₂ CH ₂ CH₂), 2.39-2.47 (m, 2H, CH₂ CH ₂ CH₂), 2.96 (dd, J = 6.0, 13.5 Hz, 1H, β-H), 3.06 (dd, J = 10.0, 13.5 Hz, 1H, β-H), 3.31-3.39 (m, 2H, CH ₂ CH₂CH₂), 4.24 (dd, J = 6.0, 10.0 Hz, 1H, α-H), 7.26-7.31 (m, 5H, ArH), 7.35-7.38 (m, 2H, ArH), 7.68 (d, J = 8.0 Hz, 2H, ArH). (Example 40)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((3-(phenylthio)propyl)amino)propyl)phenyl)boronic acid
^1H NMR (3.5% DCl in _D2O ); 1.42-1.50 ( m , _2H , CH2CH2CH2 ₎ , 2.39-2.47 ₍ m, 2H _{, CH2CH2CH2 )} , 2.96 ( dd, J = 6.0, 13.5 Hz, 1H, β-H), 3.06 (dd, J = 10.0, 13.5 Hz, 1H, β-H), 3.31-3.39 (m, 2H, CH ₂ CH ₂ CH ₂ ), 4.24 (dd , J = 6.0, 10.0 Hz, 1H, α-H), 7.26-7.31 (m, 5H, ArH), 7.35-7.38 (m, 2H, ArH), 7.68 (d, J = 8.0 Hz, 2H, ArH) .

（Ｓ）－（４－（２－アミノ－３－（（３－（ベンジルオキシ）プロピル）アミノ）－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.45-7.34 (m, 5H, ArH), 7.28 (d, J = 8.0 Hz, 2H, ArH), 4.42-4.37 (m, 2H, CH₂), 4.11 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.31 (m, 1H, CH₂), 3.25 (dd, J = 6.0, 13.5 Hz, 1H, CH₂), 3.17 (m, 1H, CH₂), 3.07-2.94 (m, 3H, CH₂), 1.58-1.46 (m, 2H, CH₂). (Example 41)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((3-(benzyloxy)propyl)amino)-3-oxopropyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.45-7.34 (m, 5H, ArH), 7.28 (d, J = 8.0 Hz, 2H, ArH), 4.42. -4.37 (m, 2H, _CH2 ), 4.11 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.31 (m, 1H, _CH2 ), 3.25 (dd, J = 6.0, 13.5 Hz, 1H, CH ₂ ), 3.17 (m, 1H, CH ₂ ), 3.07-2.94 (m, 3H, CH ₂ ), 1.58-1.46 (m, 2H, CH ₂ ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（ピリジン－２－イルアミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 8.47-8.43 (m, 2H, ArH), 7.75 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 7.70 (dt, J = 2.5, 8.0 Hz, 1H, ArH), 7.50 (d, J = 9.0 Hz, 1H, ArH), 7.38 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 4.60 (dd, J = 7.0, 8.0 Hz, 1H, CH), 3.45 (dd, J = 7.0, 14.0 Hz, 1H, CH₂), 3.36 (dd, J = 8.0, 14.0 Hz, 1H, CH₂). (Example 42)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-(pyridin-2-ylamino)propyl)phenyl)boronic acid
¹ H NMR (D ₂ O): δ 8.47-8.43 (m, 2H, ArH), 7.75 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 7.70 (dt, J = 2.5, 8.0 Hz, 1H, ArH), 7.50 (d, J = 9.0 Hz, 1H, ArH), 7.38 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 4.60 (dd, J = 7.0, 8.0 Hz, 1H, CH), 3.45 (dd, J = 7.0, 14.0 Hz, 1H, _CH2 ), 3.36 (dd, J = 8.0, 14.0 Hz, 1H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－オキソ‐３－（（ピリジン－２－イルメチル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 8.65 (dd, J = 2.0, 5.5 Hz, 1H, ArH), 8.45 (dt, J = 2.0, 8.5 Hz, 1H, ArH), 7.97 (dt, J = 2.0, 7.5 Hz, 1H, ArH), 7.63 (d, J = 8.0 Hz, 2H, ArH), 7.41 (d, J = 8.5 Hz, 1H, ArH), 7.22 (d, J = 8.0 Hz, 2H, ArH), 4.80 (d, J = 16.5 Hz, 1H, CH₂), 4.49 (d, J = 16.5 Hz, 1H, CH₂), 4.34 (dd, J = 6.5, 9.5 Hz, 1H, CH), 3.33 (dd, J = 6.5, 13.5 Hz, 1H, CH₂), 3.12 (dd, J = 9.5, 13.5 Hz, 1H, CH₂). (Example 43)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((pyridin-2-ylmethyl)amino)propyl)phenyl)boronic acid
¹ H NMR (D ₂ O): δ 8.65 (dd, J = 2.0, 5.5 Hz, 1H, ArH), 8.45 (dt, J = 2.0, 8.5 Hz, 1H, ArH), 7.97 (dt, J = 2.0, 7.5 Hz, 1H, ArH), 7.63 (d, J = 8.0 Hz, 2H, ArH), 7.41 (d, J = 8.5 Hz, 1H, ArH), 7.22 (d, J = 8.0 Hz, 2H, ArH), 4.80 (d, J = 16.5 Hz, 1H, _CH2 ), 4.49 (d, J = 16.5 Hz, 1H, _CH2 ), 4.34 (dd, J = 6.5, 9.5 Hz, 1H, CH), 3.33 (dd, J = 6.5, 13.5 Hz, 1H, _CH2 ), 3.12 (dd, J = 9.5, 13.5 Hz, 1H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（ピリジン－３－イルアミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 9.19 (s, 1H, ArH), 8.59 (d, J = 3.0 Hz, 1H, ArH), 8.36 (d, J = 9.0 Hz, 1H, ArH), 8.04 (dd, J = 3.0, 9.0 Hz, 1H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 4.50 (t, J = 7.5 Hz, 1H, CH), 3.37 (d, J = 7.5 Hz, 2H, CH₂). (Example 44)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-(pyridin-3-ylamino)propyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 9.19 (s, 1H, ArH), 8.59 (d, J = 3.0 Hz, 1H, ArH), 8.36 (d, J = 9.0 Hz, 1H, ArH), 8.04 (dd , J = 3.0, 9.0 Hz, 1H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 4.50 (t, J = 7.5 Hz, 1H, CH), 3.37 (d, J = 7.5 Hz, 2H, CH ₂ ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（（ピリジン－３－イルメチル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 8.71 (d, J = 8.0 Hz, 1H, ArH), 8.52 (s, 1H, ArH), 8.07 (d, J = 8.0 Hz, 1H, ArH), 7.95 (t, J = 8.0 Hz, 1H, ArH), 7.58 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 7.20 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 4.67 (m, 1H, CH), 4.28-4.23 (m, 2H, CH₂), 3.33 (dd, J = 6.0, 13.5 Hz, 1H, CH₂), 3.06 (t, J = 10.0 Hz, 1H, CH₂). (Example 45)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((pyridin-3-ylmethyl)amino)propyl)phenyl)boronic acid
¹ H NMR (D ₂ O): δ 8.71 (d, J = 8.0 Hz, 1H, ArH), 8.52 (s, 1H, ArH), 8.07 (d, J = 8.0 Hz, 1H, ArH), 7.95 (t , J = 8.0 Hz, 1H, ArH), 7.58 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 7.20 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 4.67 (m, 1H, CH ), 4.28-4.23 (m, 2H, CH ₂ ), 3.33 (dd, J = 6.0, 13.5 Hz, 1H, CH ₂ ), 3.06 (t, J = 10.0 Hz, 1H, CH ₂ ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（ピリジン－４－イルアミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 8.59 (m, 2H, ArH), 8.01 (m, 2H, ArH), 7.71 (m, 2H, ArH), 7.34 (m, 2H, ArH), 4.51 (t, J = 7.5 Hz, 1H, CH), 3.37 (d, J = 7.5 Hz, 2H, CH₂). (Example 46)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-(pyridin-4-ylamino)propyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 8.59 (m, 2H, ArH), 8.01 (m, 2H, ArH), 7.71 (m, 2H, ArH), 7.34 (m, 2H, ArH), 4.51 (t, J = 7.5 Hz, 1H, CH), 3.37 (d, J = 7.5 Hz, 2H, CH ₂ ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（（ピリジン－４－イルメチル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 8.43 (d, J = 5.5 Hz, 2H, ArH), 7.56 (d, J = 7.5 Hz, 2H, ArH), 7.19-7.16 (m, 4H, ArH), 4.43-4.33 (m, 3H, CH₂, CH), 3.04-2.95 (m, 2H, CH₂). (Example 47)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((pyridin-4-ylmethyl)amino)propyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 8.43 (d, J = 5.5 Hz, 2H, ArH), 7.56 (d, J = 7.5 Hz, 2H, ArH), 7.19-7.16 (m, 4H, ArH), 4.43. -4.33 (m, 3H, _CH2 , CH), 3.04-2.95 (m, 2H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－オキソ－３－（（チオフェン－２－イルメチル）アミノ）プロピル）フェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 8.96 (t, J = 6.0 Hz, 1H), 8.41 (brs, 2H), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.38 (dd, J = 1.0, 5.0 Hz, 1H, ArH), 7.15 (d, J = 8.0 Hz, 2H, ArH), 6.92 (dd, J = 3.5, 5.0 Hz, 1H, ArH), 6.83 (d, J = 1.5 Hz, 1H, ArH), 4.47 (dd, J = 6.0, 15.0 Hz, 1H, CH₂), 4.39 (dd, J = 6.0, 15.0 Hz, 1H, CH₂), 3.86 (t, J = 6.5 Hz, 1H, CH), 3.02 (dd, J = 6.5, 14.0 Hz, 1H, CH₂), 2.90 (dd, J = 6.5, 14.0 Hz, 1H, CH₂). (Example 48)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-oxo-3-((thiophen-2-ylmethyl)amino)propyl)phenyl)boronic acid
¹ H NMR (DMSO-d ₆ ): δ 8.96 (t, J = 6.0 Hz, 1H), 8.41 (brs, 2H), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.38 (dd, J = 1.0, 5.0 Hz, 1H, ArH), 7.15 (d, J = 8.0 Hz, 2H, ArH), 6.92 (dd, J = 3.5, 5.0 Hz, 1H, ArH), 6.83 (d, J = 1.5 Hz, 1H , ArH), 4.47 (dd, J = 6.0, 15.0 Hz, 1H, _CH2 ), 4.39 (dd, J = 6.0, 15.0 Hz, 1H, _CH2 ), 3.86 (t, J = 6.5 Hz, 1H, CH2) ), 3.02 (dd, J = 6.5, 14.0 Hz, 1H, CH ₂ ), 2.90 (dd, J = 6.5, 14.0 Hz, 1H, CH ₂ ).

（Ｓ）－（４－（２－アミノ－３－（（３－メトキシフェニル）アミノ）－２－メチル－３－オキソプロピル）フェニル）ボロン酸
¹H NMR (D₂O): δ 7.71 (d, J = 8.0 Hz, 2H, ArH), 7.33 (t, J = 8.5 Hz, 1H, ArH), 7.26 (d, J = 8.0 Hz, 2H, ArH), 6.92-6.84 (m, 3H, ArH), 3.78 (s, 3H, CH₃), 3.39 (d, J = 14.0 Hz, 1H, CH₂), 3.25 (d, J = 14.0 Hz, 1H, CH₂), 1.79 (s, 3H, CH₃). (Example 49)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((3-methoxyphenyl)amino)-2-methyl-3-oxopropyl)phenyl)boronic acid
^1H NMR ( _D2O ): δ 7.71 (d, J = 8.0 Hz, 2H, ArH), 7.33 (t, J = 8.5 Hz, 1H, ArH), 7.26 (d, J = 8.0 Hz, 2H, ArH ), 6.92-6.84 (m, 3H, ArH), 3.78 (s, 3H, _CH3 ), 3.39 (d, J = 14.0 Hz, 1H, _CH2 ), 3.25 (d, J = 14.0 Hz, 1H, CH ₂ ), 1.79 (s, 3H, _CH3 ).

（Ｓ）－（４－（２－アミノ－３－（（３－メトキシフェニル）アミノ）－３－オキソプロピル）－３－クロロフェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 10.29 (s, 1H), 8.67 (brs, 4H), 7.79 (s, 1H, ArH), 7.63 (d, J = 8.0 Hz, 1H, ArH), 7.30 (d, J = 7.5 Hz, 1H, ArH), 7.22 (t, J = 8.0 Hz, 1H, ArH), 7.10 (t, J = 4.5 Hz, 1H, ArH), 7.00 (dd, J = 2.0, 8.0 Hz, 1H, ArH), 6.69 (dd, J = 3.0, 8.5 Hz, 1H, ArH), 4.14 (brs, 1H, CH), 3.71 (s, 3H, CH₃), 3.29 (dd, J = 5.5, 14.0 Hz, 1H, CH₂), 3.22 (d, J = 9.0, 14.0 Hz, 1H, CH₂). (Example 50)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-((3-methoxyphenyl)amino)-3-oxopropyl)-3-chlorophenyl)boronic acid
¹ H NMR (DMSO-d ₆ ): δ 10.29 (s, 1H), 8.67 (brs, 4H), 7.79 (s, 1H, ArH), 7.63 (d, J = 8.0 Hz, 1H, ArH), 7.30 ( d, J = 7.5 Hz, 1H, ArH), 7.22 (t, J = 8.0 Hz, 1H, ArH), 7.10 (t, J = 4.5 Hz, 1H, ArH), 7.00 (dd, J = 2.0, 8.0 Hz , 1H, ArH), 6.69 (dd, J = 3.0, 8.5 Hz, 1H, ArH), 4.14 (brs, 1H, CH), 3.71 (s, 3H, _CH3 ), 3.29 (dd, J = 5.5, 14.0 Hz, 1H, _CH2 ), 3.22 (d, J = 9.0, 14.0 Hz, 1H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－（ベンゾ［ｄ］［１，３］ジオキソル－５－イルアミノ）－３－オキソプロピル）－３－クロロフェニル）ボロン酸
¹H NMR (DMSO-d₆): δ 10.18 (s, 1H), 8.52 (brs, 4H), 7.80 (d, J = 1.0 Hz, 1H, ArH), 7.64 (dd, J = 0.5, 7.5 Hz, 1H, ArH), 7.29 (d, J = 7.5 Hz, 1H, ArH), 7.12 (d, J = 2.0 Hz, 1H, ArH), 6.86 (d, J = 8.0 Hz, 1H, ArH), 6.78 (dd, J = 2.0, 8.0 Hz, 1H, ArH), 6.00 (s, 2H, CH₂), 4.07 (brs, 1H, CH), 3.27 (dd, J = 8.0, 13.5 Hz, 1H, CH₂), 3.20 (dd, J = 7.5, 13.5 Hz, 1H, CH₂). (Example 51)
The following compounds were prepared in the same manner as in Example 1.

(S)-(4-(2-amino-3-(benzo[d][1,3]dioxol-5-ylamino)-3-oxopropyl)-3-chlorophenyl)boronic acid
¹ H NMR (DMSO-d ₆ ): δ 10.18 (s, 1H), 8.52 (brs, 4H), 7.80 (d, J = 1.0 Hz, 1H, ArH), 7.64 (dd, J = 0.5, 7.5 Hz, 1H, ArH), 7.29 (d, J = 7.5 Hz, 1H, ArH), 7.12 (d, J = 2.0 Hz, 1H, ArH), 6.86 (d, J = 8.0 Hz, 1H, ArH), 6.78 (dd , J = 2.0, 8.0 Hz, 1H, ArH), 6.00 (s, 2H, CH ₂ ), 4.07 (brs, 1H, CH), 3.27 (dd, J = 8.0, 13.5 Hz, 1H, CH ₂ ), 3.20 (dd, J = 7.5, 13.5Hz, 1H, _CH2 ).

（Ｓ）－（４－（２－アミノ－３－（（３－メトキシフェニル）アミノ）－３－オキソプロピル）－３－フルオロフェニル）ボロン酸の製造
（Ｓ）－３－（４－ボロノ－２－フルオロフェニル）－２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）プロパン酸（１．００ｇ，３．０６ｍｍｏｌ）にＮ，Ｎ－ジメチルホルムアミド（３．１ｍＬ）を加えた。この溶液にトリエチルアミン（３４１ｍｇ，３．３７ｍｍｏｌ）、ｍ－アニシジン（４１５ｍｇ，３．３７ｍｍｏｌ）、１－ヒドロキシベンゾトリアゾール（４５４ｍｇ，３．３７ｍｍｏｌ）、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（６４６ｍｇ，３．３７ｍｍｏｌ）を氷浴下で加え、室温に昇温した。２０時間攪拌後、水（１０ｍＬ）を加え反応を停止し、酢酸エチル（５０ｍＬ）で抽出した。有機相を飽和重曹水（１０ｍＬ）、１％塩酸（１０ｍＬ）、飽和食塩水（１０ｍＬ）で順次洗浄し、無水硫酸ナトリウムで乾燥後濾過し、濾液を減圧濃縮した。得られた粗生成物にジイソプロピルエーテル（３０ｍＬ）を加え結晶化させ吸引濾過後、ジイソプロピルエーテル（３０ｍＬ）で洗浄することで（Ｓ）－（４－（２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－３－（（３－メトキシフェニル）アミノ）－３－オキソプロピル）－３－フルオロフェニル）ボロン酸（７００ ｍｇ）を白色固体として得た。
得られた縮合体（７００ｍｇ）にトリフルオロ酢酸（３．６９ｇ，３２．４ｍｍｏｌ）を加えた。１６時間後、減圧濃縮し、さらにトルエン（２０ｍＬｘ３）を加えて減圧共沸させることでトリフルオロ酢酸を留去した。得られた固体をクロロホルム（５０ｍＬ）を洗浄溶媒に用いて濾過し、洗浄することで（Ｓ）－（４－（２－アミノ－３－（（３－メトキシフェニル）アミノ）－３－オキソプロピル）－３－フルオロフェニル）ボロン酸（７５４ｍｇ，１．６８ｍｍｏｌ，５５％ｆｏｒ ２ ｓｔｅｐｓ）を淡黄色固体として得た。
¹H NMR (D₂O): δ 7.43-7.37 (m, 2H, ArH), 7.25-7.19 (m, 2H, ArH), 6.77-6.75 (m, 2H, ArH), 6.69 (m, 1H, ArH), 4.26 (m, 1H, CH), 3.71 (s, 3H, CH₃), 3.36 (m, 1H, CH₂), 3.20 (m, 1H, CH₂). (Example 52)

Preparation of (S)-(4-(2-amino-3-((3-methoxyphenyl)amino)-3-oxopropyl)-3-fluorophenyl)boronic acid (S)-3-(4-borono- To 2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.00 g, 3.06 mmol) was added N,N-dimethylformamide (3.1 mL). To this solution were added triethylamine (341 mg, 3.37 mmol), m-anisidine (415 mg, 3.37 mmol), 1-hydroxybenzotriazole (454 mg, 3.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Hydrochloride (646 mg, 3.37 mmol) was added under an ice bath and warmed to room temperature. After stirring for 20 hours, water (10 mL) was added to stop the reaction, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed successively with saturated aqueous sodium bicarbonate (10 mL), 1% hydrochloric acid (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Diisopropyl ether (30 mL) was added to the obtained crude product to crystallize, filtered by suction, and washed with diisopropyl ether (30 mL) to give (S)-(4-(2-((tert-butoxycarbonyl)amino) -3-((3-Methoxyphenyl)amino)-3-oxopropyl)-3-fluorophenyl)boronic acid (700 mg) was obtained as a white solid.
Trifluoroacetic acid (3.69 g, 32.4 mmol) was added to the resulting condensate (700 mg). After 16 hours, the mixture was concentrated under reduced pressure, and toluene (20 mL×3) was further added and azeotroped under reduced pressure to distill off trifluoroacetic acid. The resulting solid was filtered using chloroform (50 mL) as a washing solvent and washed to give (S)-(4-(2-amino-3-((3-methoxyphenyl)amino)-3-oxopropyl )-3-Fluorophenyl)boronic acid (754 mg, 1.68 mmol, 55% for 2 steps) was obtained as a pale yellow solid.
^1H NMR ( _D2O ): δ 7.43-7.37 (m, 2H, ArH), 7.25-7.19 (m, 2H, ArH), 6.77-6.75 (m, 2H, ArH), 6.69 (m, 1H, ArH ), 4.26 (m, 1H, CH), 3.71 (s, 3H, _CH3 ), 3.36 (m, 1H, _CH2 ), 3.20 (m, 1H, _CH2 ).

[Uptake test 1]
(1) Preparation of human LAT1 and LAT2 high expression HEK293 cell lines Khunweeraphong, N et al.'s paper (Journal of Pharmacology Science, 2012, vol. 119, pp 368-380) according to the method described in, human LAT1 and LAT2 stably Each HEK293 cell that highly expresses is generated.
Shuttle vector DNA (LAT1: EX-H4509-M02, LAT2: EX-U0514-M02, GeneCopoeia). This vector is transfected into HEK293 cells by a method using Lipofectamine (registered trademark) 2000 (Invitrogen) according to the manufacturer's instructions. After that, cell clones stably expressing the transgene were selected by limiting dilution in the presence of 0.9 mg/mL Geneticin (registered trademark), and L-boronophenylalanine (L-BPA) uptake was compared to HEK293 cells before gene transfer. Cell clones with 2- to 5-fold enhancement are obtained. The cells are passaged and used to assess LAT1 and LAT2 selective uptake.

(2) Evaluation of LAT1 and LAT2 Selective Uptake As a method for evaluating cellular uptake, the same method as described in Khunweeraphong, N et al. (Journal of Pharmacology Science, 2012, vol.119, pp 368-380) is used. Each cell obtained in (1) is used for evaluation. However, no radioisotope was used, the substrate concentration was 0.1 mM, 2 mM BCH (2-amino-2-norbonnanecarboxylic acid) was used as LAT1 and LAT2 inhibitors, and the cells after the reaction were added to 0.05%. The concentration of the boronophenylalanine amide derivative in the cell fluid obtained by collecting with Tween 20 is determined.
Boronophenylalanine amide derivatives in cells are quantified according to the method described in Hattori, Y et al. (Sensors 2017, 17, 2436), using 2-(2-hydroxyphenyl)pyridine (boron sensor 5) as a boron sensor. to implement.
Cellular uptake is evaluated as a relative value (LAT1 selectivity) with respect to the uptake of L-BPA, which is a comparative control, performed on the same day, taking into consideration inter-experimental variability.
LAT1 selectivity = (quantitative compound uptake in LAT1 cells/quantitative control LBPA uptake in LAT1 cells)/(quantitative compound uptake in LAT2 cells/quantitative control LBPA uptake in LAT2 cells)

[Uptake test 2]
(1) Evaluation test for uptake into tumor cells (biological evaluation 2)
1.5×10 ⁶ human tongue cancer cells (SAS cells), human glioma cells (A172 cells) or human breast cancer cells (MCF-7) were seeded in a 100 mm dish and incubated at 37° C. in a 5% CO ₂ atmosphere for 24 hours. , was pre-cultured. The culture solution was removed by aspiration, a culture solution containing 1 mM of the drug of each example or reference example was added, and exposure culture was carried out at 37° C. in a 5% CO ₂ atmosphere for 3 hours. After removing the culture medium by aspiration, the cells were washed once with PBS and then trypsinized to collect the cells. After counting the number of harvested cells and packing by centrifugation, HClO ₄ (60%, 0.3 mL) and H ₂ O ₂ (31%, 0.6 mL) were added and heated to 75° C. overnight. to prepare an ashing solution. After filling up the ashing solution with pure water to 5 mL, it was filtered using 5C filter paper, and the boron concentration in the solution was measured using Agilent 710 ICP-OES to determine the amount of boron per 10 ⁷ cells. (μg) was obtained. In the evaluation of cell uptake, taking account of inter-experimental variation, the value is evaluated relative to the uptake of L-BPA of Reference Example, which is a comparative example performed on the same day.

The results of the uptake test are shown in the table. Here, 4-borono-L-phenylalanine (L-BPA), which is used in clinical studies of BNCT, was set as a control for comparison.

As a result, it was found that many of the compounds of the present invention were taken up into cells at the same concentration or higher than BPA when treated at the same concentration.

Results for other uptakes of the main compounds are shown in the table below. In the table, uptake A: 3-fold higher than BPA, B: equal to less than 3-fold higher than BPA, C: uptake but lower than BPA.
(In the following tables, unless otherwise specified, the L form is represented)

In Tables 1 to 8, each substituent of the compounds shown below is shown for each substituent.

As is clear from the table, the compounds of Examples were shown to have excellent uptake ability into tumor cells. The compounds shown in Table 9 are particularly capable of being taken up by PC3 and LNCap cells. LAT1 is highly expressed in PC3 cells, LNCap cells are known to not express LAT1 (reference: The Prostate 77: 222-233 (2017)), from this result, these compounds, LAT1 It was suggested that it may be taken up by other mechanisms without going through

Claims (7)

A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

Here, in formula (I),
R ¹ , R ² together with the B atom represent substituents of boronic acid (-B(OH) ₂ ), boronic ester, or boronic acid amide;
R ³ is H, halogen, hydroxy, cyano, amino, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, C1-C6 alkoxyC1-C6 alkyl, nitro, C1-C6 haloalkyl, carbamoyl , C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, COOR ¹⁰ (R ¹⁰ is H or C1-C6 alkyl, amino, C1-C6 alkylamino), C1-C6 haloalkylsulfanyl, C1 - represents a group independently selected from the group consisting of C6 haloalkylsulfinyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, aminosulfonyl, sulfo, and sulfamoyl;
s represents any integer from 1 to 4;
R ⁴ represents H, C1-C6 alkyl, benzyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R ⁵ is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, hydroxy, cyano, substituted or unsubstituted amino, substituted or unsubstituted substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxy C1-C6 alkyl, substituted or unsubstituted acyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted carbamoyl, C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, substituted or unsubstituted unaromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl or R ⁴ R ⁵ together with N form a substituted or unsubstituted C3-C7 heterocycloalkyl;
R ⁶ represents H or optionally substituted C1-C6 alkyl, or may form a fused ring structure with the adjacent methylene moiety and a benzene ring, wherein the ring structure is unsubstituted represents C5-7 cycloalkyl or unsubstituted C5-7 cycloalkenyl. said R ³ independently represents H, Cl, F, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 alkylthio, CH ₂ X, CHX ₂ , or CX ₃ (X represents F); A compound according to claim 1 or a pharmaceutically acceptable salt thereof. said R ⁴ represents H or C1-C6 alkyl;
3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein said ^R5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. said R ⁴ represents H or C1-C6 alkyl;
3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein said R ⁵ represents aryl-substituted C1-C6 alkyl. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein said R ⁴ R ⁵ together with N form a substituted or unsubstituted C3-C7 heterocycloalkyl. A medicament for BNCT comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof. A radioactive isotope as a substituent at any one site of R ³ , R ⁴ or R ⁵ of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof Containing diagnostic agents.