Boronophenylalanine amide derivative

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

Technical Field

[0001] The present invention relates to borono phenylalanine amide derivatives.

Background Art

[0002] As a method for treating cancer, there is boron neutron capture therapy (BNCT). Boron neutron capture therapy is a treatment method in which a boron compound containing boron-10 isotope ( 10 10B) is incorporated into cancer cells, and low-energy neutron rays (for example, thermal neutrons) are irradiated to locally destroy cancer cells by a nuclear reaction occurring inside the cells. In this treatment method, 10 selectively accumulating a boron compound containing 10B in the cells of cancer tissue is important for enhancing the treatment effect. Therefore, it is necessary to develop a boron compound that is selectively incorporated into cancer cells.

[0003] Derivatives of 4-boronophenylalanine in which a boron atom or a boron atomic group is introduced into the basic skeleton have been synthesized as drugs used in BNCT. Drugs actually used in clinical practice include derivatives of 4-boronophenylalanine (L-BPA) and mercaptoundecahydrododecaborate (BSH). 4-Boronophenylalanine is incorporated into LAT1 (L-type Amino acid Transporter 1), which is a kind of amino acid transporter, as a mimic of phenylalanine. Since the expression of LAT1 is enhanced in cancer cells, L-BPA is likely to accumulate, and its property is utilized for the treatment of cancer (see, for example, Non-Patent Document 1).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] However, depending on the type and malignancy of tumor cells, LAT1 may not be upregulated. Because 4-borono-phenylalanine is taken up via LAT1, it does not accumulate in areas where LAT1 is not upregulated, making BNCT inapplicable in such cases.

[0006] Therefore, there is a need to create new compounds that can be taken up by tumor cells even if they are not taken up via LAT1.

[0007] An object of the present invention is to provide a boronophenylalaninamide derivative. [Means for solving the problem]

[0008] As a result of extensive research into solving the above problems, the present inventors have discovered a new boronophenylalanine amide derivative, leading to the completion of the present invention.

[0009] That is, the present invention provides the following compounds: [1] A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: [ka] Here, in formula (I), R 1 , R 2 represents, together with the B atom, a substituent of a boronic acid (—B(OH)2), a boronic acid ester, or a 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 10represents a group independently selected from the group consisting of H, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 haloalkylsulfanyl, C1-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 represents 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 C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxyC1-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 non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or, R 4 R 5 together with N forms a C3-C7 heterocycloalkyl; R 6 represents H or optionally substituted C1-C6 alkyl, or may form a ring structure condensed with an adjacent methylene moiety and a benzene ring, wherein the ring structure represents unsubstituted 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, CH2X, CHX2, or CX3 (X represents F), the compound according to [1] or a pharmaceutically acceptable salt thereof. [3] Said R4 represents H or C1-C6 alkyl; said R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, the compound according to [1] or [2] or a pharmaceutically acceptable salt thereof. [4] said R 4 represents H or C1-C6 alkyl; said R 5 represents aryl-substituted C1-C6 alkyl, the compound according to [1] or [2] or a pharmaceutically acceptable salt thereof. [5] said R 4 R 5 together with N forms C3-C7 heterocycloalkyl, the compound according to [1] or [2] or a pharmaceutically acceptable salt thereof. [6] A drug for BNCT, comprising the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof. [7] R of the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof 3 at any one site of 4 R, 5 or a diagnostic agent containing a radioisotope as a substituent at any one of R. [Advantages of the Invention]

[0010] The novel compound of the present invention may be useful for further expanding the application of BNCT when used alone or in combination with other compounds. [Modes for Carrying Out the Invention]

[0011] In this specification, when representing a compound having an asymmetric carbon, unless otherwise specified, the compound may be a racemate, R-form, or S-form.

[0012] [Boronophenylalanine amide derivative] The borophenylalanine amide derivative of the present invention is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

Chemical formula

[0013] In the present specification, the halogen may be any of F, Cl, Br, I, but is particularly preferably F, Cl, Br.

[0014] In the present specification, C1-C6 alkyl refers to a linear or branched C1-C6 saturated hydrocarbon group. Examples of the C1-C6 alkyl group include methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc. Preferably, it is a linear or branched C1-C4 alkyl group, and non-limiting examples include a methyl group, an ethyl group, an isopropyl group, a butyl group, etc.

[0015] In this 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, and butenyl.

[0016] As used herein, 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, and pentyne.

[0017] As used herein, C1-C6 haloalkyl refers to a C1-C6 alkyl group having one or more halogen substituents. The C1-C6 haloalkyl group is preferably represented by C2X5, CH2X, CHX2, or CX3 (X represents Cl, F, Br, or I), and includes, but is not limited to, CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, etc.

[0018] As used herein, C1-C6 alkoxy refers to a group having a linear or branched C1-C6 alkyl group and an oxygen molecule. C1-C6 alkoxy preferably has a linear or branched C1-C4 alkyl group, including, but not limited to, methoxy, ethoxy, isopropoxy, and butoxy.

[0019] As used herein, C1-C6 alkoxyC1-C6 alkyl includes, but is not limited to, methoxyethyl, ethoxyethyl, and the like.

[0020] As used herein, C1-C6 alkylamino refers to NR 11 R 12 and R 11 R 12 each independently represent H or C1-C6 alkyl, provided 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.

[0021] As used herein, C1-C6 alkylaminocarbonyl is defined as CONR 13 R 14 and R 13 , R 14 are each independently a group such as H or C1-C6 alkyl (provided that R 13 and R 14 and are both H). Examples include, but are not limited to, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, i-propylaminocarbonyl, and the like.

[0022] As used herein, C1-C6 alkylcarbonyl includes, but is not limited to, methylcarbonyl, ethylcarbonyl and the like.

[0023] In this specification, C1-C6 alkoxycarbonyl includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

[0024] 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)) includes, but is not limited to, methyloxycarbonyl, aminooxycarbonyl, and the like.

[0025] In this specification, C1-C6 haloalkylsulfanyl, C1-C6 haloalkylsulfinyl, and C1-C6 haloalkylsulfonyl include, but are not limited to, trifluoromethylsulfanyl, trifluoromethylsulfinyl, and trifluoromethylsulfonyl.

[0026] In this specification, examples of C1-C6 alkylthio include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, and the like.

[0027] In this specification, examples of C1-C6 alkylsulfinyl include, but are not limited to, methylsulfinyl, ethylsulfinyl, and the like.

[0028] In this specification, examples of C1-C6 alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.

[0029] In this specification, examples of substituted C1-C6 alkyl include, but are not limited to, linear or branched C1-C6 alkyl in which one to three hydrogen atoms are substituted with other groups.

[0030] In this specification, examples of substituted C2-6 alkenyl include, but are not limited to, linear or branched C2-6 alkenyl in which one or two hydrogen atoms are substituted with other groups.

[0031] In this specification, examples of substituted C2-6 alkynyl include, but are not limited to, linear or branched C2-6 alkynyl in which one or two hydrogen atoms are substituted with other groups.

[0032] In this specification, examples of substituted C1-C6 alkoxy include, but are not limited to, linear or branched C1-C6 alkoxy in which one or two hydrogen atoms are substituted with other groups.

[0033] In this specification, examples of substituted C1-C6 alkoxy C1-C6 alkyl include, but are not limited to, linear or branched C1-C6 alkoxy C1-C6 alkyl in which one or two hydrogen atoms are substituted with other groups.

[0034] Here, in the above-mentioned substituted C1-C6 alkyl, substituted C2-6 alkenyl, substituted C2-6 alkynyl, substituted C1-C6 alkoxy, substituted C1-C6 alkoxy C1-C6 alkyl, etc., the groups substituting for the hydrogen atom are, for example, halogen, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted arylthio (such as phenylthio), substituted or unsubstituted arylamino (such as phenylamino), substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0035] In the present specification, examples of the substituted or unsubstituted amino include, optionally, amino that may be substituted with C1-C6 alkyl, etc. Although not limited, examples of the substituted or unsubstituted amino include amino, methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, cyclopropylamino, and cyclohexylamino. In addition, examples of the optionally substituted amino include hydrazine, C1-C6 alkyl-substituted hydrazine, benzylamino, acetylamino, benzoylamino, methylsulfonylamino, tetrahydropyranyl amino, tetrahydrofuranyl amino, morpholino amino, morpholinyl amino, piperidinyl amino, piperazinyl amino, etc.

[0036] Examples of the substituted or unsubstituted acyl include, for example, aliphatic acyl and aroyl having 1 to 7 carbon atoms. Specifically, although not limited, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, and benzoyl, etc. are exemplified.

[0037] Examples of the substituted or unsubstituted sulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, phenylsulfonyl, naphthylsulfonyl, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl, piperidinylsulfonyl, tetrahydrofurylsulfonyl, and the like.

[0038] Examples of the substituted or unsubstituted carbamoyl include carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-n-propylaminocarbamoyl, N-isopropylcarbamoyl, N-morpholinocarbamoyl, N-tetrahydrofurylcarbamoyl, N-piperidylcarbamoyl, N-tetrahydropyranylcarbamoyl, N-benzylcarbamoyl, N-acetylcarbamoyl, N-methylsulfonylcarbamoyl, N-(2,2,2-trifluoroethyl)carbamoyl, N-(2-hydroxy-1-methylethyl)carbamoyl, and the like. In different embodiments, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-n-propylaminocarbamoyl, N-isopropylcarbamoyl, N-morpholinocarbamoyl, N-tetrahydrofurylcarbamoyl, N-piperidylcarbamoyl, N-tetrahydropyranylcarbamoyl, N-methylsulfonylcarbamoyl, N-(2,2,2-trifluoroethyl)carbamoyl, N-(2-hydroxy-1-methylethyl)carbamoyl, and the like are included.

[0039] Examples of the substituted or unsubstituted C3-C7 cycloalkyl include cyclopropyl, cyclobutyl, cyclohexyl, and the like.

[0040] Examples of the substituted or unsubstituted C3-C7 cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.

[0041] Examples of the substituted or unsubstituted non-aromatic heterocyclic group include aziridinyl, oxiranyl, thiaranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, benzodioxane, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl, which may be optionally substituted with 1 to 3 C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen.

[0042] Examples of the substituted or unsubstituted aryl include C6-C14 aryl which may be optionally substituted with 1 to 3 C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen. More specifically, phenyl, naphthyl, azulenyl, anthryl and the like are exemplified. The aryl is preferably phenyl.

[0043] Examples of the substituted or unsubstituted heteroaryl include 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, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl.

[0044] In the derivative of the present invention, R 1 , R 2 represents any of the substituents of boric acid (—B(OH)2), boronic acid ester, or boronic acid amide. Examples of the groups of boronic acid ester or boronic acid amide in this definition include, at the positions of R 1 , R 2 , a group having a chain structure such as —B(NR 71 )2 or —B(OR 71 )2, or a group having a cyclic structure together with the atom B. Here, R 71represents a linear or branched C1-C10 alkyl group. Here, when referring to a "linear or branched C1-C10 alkyl group", any alkyl group with 1 to 10 carbon atoms may be used. Preferably, it is a linear or branched C1-C8 alkyl group, more preferably a linear or branched C1-C6 alkyl group. Examples of these groups include, but are not limited to, a methyl group, an ethyl group, an isopropyl group, a butyl group, etc.

[0045] Furthermore, in the case of a group having a cyclic structure together with the atom B mentioned here, not only an O atom necessarily intervenes, but an N atom may also intervene. Examples include, but are not limited to, esters or ester analogs composed of any one selected from the group consisting of pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,6-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, and catechol and the atom B. These include, but are not limited to, pinacol boronate, MIDA boronate, 1,3-propanediol boronate, neopentyl glycol boronate, catechol boronate, pinandiol boronate, biscyclohexyl diol boronate, MPM boronate, trifluoroborate salt, cyclic triol borate salt, cyclic bodies of diaminonaphthalene amide and boron, etc.

[0046] Here, the boron atom is not limited, but the proportion of boron-10 is preferably 75% by mass or more, more preferably 80% by mass or more, even more preferably 90% by mass or more, and particularly preferably 95% by mass or more.

[0047] Natural boron contains boron-10 and boron-11 as isotopes, with boron-10 present at a ratio of 20% and boron-11 at 80%. Therefore, prior to the production of the borono-phenylalanine amide derivative of the present invention, it is also preferable to enrich boron with a mass number of 10 (boron-10). In the present invention, for example, commercially available products may be used as the boron atom source. As a commercially available product, for example, 10B-enriched boric acid (manufactured by Stella Chemifa Corporation) can be used.

[0048] Here, as a method for measuring boron-10, Agilent 710 (manufactured by Agilent) can be used and performed by multi-type ICP emission spectrometry (ICP-OES). The ICP-OES used for the measurement is adjusted according to JIS K0116.

[0049] In the said compound, although not limited, R 1 R 2 Preferably, together with the B atom, it is boric acid (B(OH)2) or a boronic acid ester having a linear or cyclic structure, and more preferably boric acid (B(OH)2) or the pinacol ester of boric acid.

[0050] In the said compound, although not limited, the said R 3 As any 1 to 4 of them, it is particularly preferable that they are independently H, Cl, F, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 alkylthio, CH2F, CHF2, or CF3.

[0051] In the said compound, although not limited, the said R 4 Preferably, it is H, C1-C6 alkyl.

[0052] In the said compound, R 5is H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, halogen-substituted C1-C3 alkyl, substituted or unsubstituted phenyl (in the case of substitution, it is not limited, but it is preferable that it is phenyl substituted with halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, etc.), naphthyl, C1-C6 alkyl substituted with substituted or unsubstituted phenyl (here, substituted phenyl is not limited, but it is phenyl substituted with halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, etc. C1-C6 alkoxy substituted with substituted or unsubstituted phenyl (wherein substituted phenyl is not limited, but is 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, dihydrobenzodioxine, or R 4 and R 5 Preferably, R together with the N atom is a C3-C7 heterocycloalkyl, where R 4 and R 5 When 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.

[0053] In the above compounds, the R 6 is H or C1-C6 alkyl, or R 6 and the adjacent methylene are fused to a benzene ring to form a ring structure, and the ring structure is preferably an unsubstituted C5-C7 cycloalkyl. 6 More preferably, represents H, methyl or ethyl.

[0054] Among the boronophenylalaninamide derivatives of the present invention, one selected from the group consisting of the following compounds or a salt thereof is particularly preferred: (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.

[0055] The "pharmaceutically acceptable salts" in the present invention include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Preferred examples of salts with inorganic bases include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts, ammonium salts, etc. Preferred examples of salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc. Preferred examples of salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Preferred examples of salts with organic acids include, for example, salts with 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-toluenesulfonic acid, etc. Preferred examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, etc., and preferred examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, etc.

[0056] [Method for producing borono-phenylalanine amide derivative] In the present invention, the method for producing the novel borono-phenylalanine amide derivative is not limited, and ordinary amino acid synthesis methods are used. Although not limited, particularly preferred methods can be, for example, the following methods. First, a protected amino acid is reacted with an organic halide represented by the following general formula (II) in the presence of an organic solvent, a basic aqueous solution, and a phase transfer catalyst.

[0057]

Chemical formula

[0058] 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 also be used.

[0059] Among these, for example, 4-iodobenzyl bromide and 4-bromo-2-fluorobenzyl bromide are available from Tokyo Chemical Industry 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 and 4-bromo-2,6-difluorobenzyl bromide are available from Fluorochem Ltd.

[0060] ]> 5-Bromo-2-(bromomethyl)benzonitrile can be prepared, for example, from 5-bromo-2-methylbenzonitrile available from Tokyo Chemical Industry Co., Ltd. 1-Bromo-4-(bromomethyl)-2-chloro-5-fluorobenzene and 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).

[0061] 4-(Bromomethyl)-1-iodo-2-nitrobenzene can be prepared, for example, by brominating (4-iodo-3-nitro-phenyl)-methanol available from Combi-Blocks with hydrobromic acid.

[0062] Other benzyl bromides are available commercially. Those that are not available can be prepared, for example, by reacting toluene having the corresponding substituent with N-bromosuccinimide in the presence of 2,2'-azobis(isobutyronitrile), or by reducing benzaldehyde or methyl benzoate having the corresponding substituent with sodium borohydride or lithium aluminum hydride to obtain benzyl alcohol and then brominating it with hydrobromic acid or phosphorus tribromide.

[0063] The reaction of the organic halide represented by formula (II) with the protected amino acid can be carried out in the presence of an organic solvent, a basic aqueous solution, and a phase transfer catalyst. Examples of the protected amino acid include p-chlorobenzaldehyde imine or benzophenone imine. Preferably, it can be p-chlorobenzaldehyde imine having the following structure.

Chemical formula

[0064] Here, R 6 represents H or C1-C6 alkyl which may be substituted.

[0065] Here, the organic solvent to be used is not limited, but preferably includes toluene, benzene, xylene, mesitylene, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, cyclopentyl methyl ether, methyl t-butyl ether, and the like.

[0066] The basic aqueous solution is preferably an aqueous solution of calcium hydroxide, cesium hydroxide, potassium hydroxide, or the like.

[0067] The phase transfer catalyst can be, for example, a Maruoka reagent. The Maruoka reagent is not limited, but preferably includes (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.

[0068] 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.

[0069] After completion of the reaction, extraction can be performed with an organic solvent such as toluene, and then it can be subjected to appropriate washing, drying, and filtration steps.

[0070] Next, a solvent is added to such a reaction product and reacted with an acid. Here, as the solvent, an ether-based solvent is preferably used. Here, examples of the ether-based solvent include, but are not limited to, diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, glyme, diglyme, and the like. In the present invention, tetrahydrofuran is particularly preferably used.

[0071] Examples of the acid 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.

[0072] The reaction is preferably carried out at a temperature in the range of 0°C to 50°C.

[0073] The reaction time is about 1 to 10 hours, more preferably 2 to 8 hours, and even more preferably 3 to 6 hours.

[0074] The amino group of the obtained compound is protected by a conventional method. The protecting group is not limited, and for example, a carbamate-based protecting group, an amide-based protecting group, and an alkyl protecting group are preferably used. Examples of such a carbamate-based protecting group include a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a 9-fluorenylmethyloxycarbonyl group (Fmoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), and the like. Examples of the amide-based protecting group include an acetyl group, a benzoyl group, and the like. Examples of the alkyl protecting group include a benzyl group, and the like.

[0075] Next, an amine compound is reacted with the compound, boronic acid, or amine compound having a borono group obtained as described above in a solvent together with a condensing agent for condensation.

[0076] Examples of the condensing agent 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), diphenylphosphoryl azide, and the like.

[0077] The above reaction can also be carried out in the presence of a base. Examples of the base include organic bases such as TEA, DIPEA, and pyridine.

[0078] Additives can also be used to suppress racemization in the above reaction. Examples of the additive include 1-hydroxybenzotriazole, 1-hydroxybenzotriazole monohydrate, 1-hydroxy-7-azabenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxyimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine, N-hydroxysuccinimide, and the like.

[0079] The solvent is not limited, but halogen solvents, ether solvents, amides, nitriles, or a mixed solvent thereof are used.

[0080] Examples of the halogen solvent include, but are not limited to, dichloromethane, chloroform, carbon tetrachloride, and the like.

[0081] Examples of the ether solvent include, but are not limited to, diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, glyme, diglyme, and the like.

[0082] Examples of the amide solvent include, but are not limited to, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), and the like.

[0083] Examples of nitrile solvents include acetonitrile and propionitrile.

[0084] The reaction temperature is not limited, but is preferably from -78°C to 200°C, more preferably from -20°C to 50°C.

[0085] The reaction time is not limited, but is usually about 1 to 24 hours.

[0086] Next, the resulting compound is reacted with a boron compound, if necessary, in a solvent in the presence of a palladium catalyst, an organophosphorus compound, and a base. If the compound already has a boronic acid or borono group, this step may be omitted.

[0087] Here, examples of the palladium catalyst include, but are not limited to, palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0), [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and the like.

[0088] Examples of organophosphorus 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, and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl.

[0089] Examples of bases include, but are not limited to, potassium acetate, sodium acetate, sodium carbonate, cesium carbonate, potassium carbonate, and sodium bicarbonate.

[0090] Examples of the boron compound include a borate ester or a boric acid amide, and preferably, a compound represented by B(OR)3, B(NR)3, B(OR)2(NR), (RO)2B-B(OR)2, or B(OR)(NR)2 (R is a linear or branched C1-C10 alkyl group, a phenyl group, or a benzyl group), etc. Further, among these, a compound represented by (RO)2B-B(OR)2 is particularly preferably used. Here, when referring to the "linear or branched C1-C10 alkyl group", any alkyl group having 1 to 10 carbon atoms may be used, but preferably, a linear or branched C1-C8 alkyl group, more preferably, a linear or branched C1-C6 alkyl group. Examples of these groups include, but are not limited to, a methyl group, an ethyl group, an isopropyl group, a butyl group, etc. Representative examples of the boron compound include, but are not limited to, bis(pinacolato)diboron.

[0091] Examples of the solvent include, but are not limited to, ether solvents such as 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane; hydrocarbon solvents such as toluene; and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. A preferred solvent is dimethyl sulfoxide. The reaction temperature is, for example, from 20°C to 160°C, preferably from 60°C to 120°C.

[0092] Next, the obtained compound is sequentially deprotected or directly used in the next step. The deprotection is carried out according to a conventional method, and can be carried out, for example, by hydrolysis, catalytic hydrogenation, decarboxylation, or oxidation.

[0093] In each step of the production method, purification is carried out according to a conventional method and can be appropriately modified.

[0094] Particularly when the compound is a racemate, it can be used as it is, or for example, in order to obtain a preferred compound for use in boron neutron capture therapy, the optical purity of the R-form or S-form can be increased.

[0095] Optical resolution may appropriately use known techniques. For example, in addition to the method of optical resolution (using, for example, α-chymotrypsin) through a hydrolysis step and an esterification step, a simplified method including a simplified step of using acylase through a hydrolysis step can also be adopted.

[0096] [Agent for BNCT (Boron Neutron Capture Therapy)] The boronophenylalanine amide derivative of the present invention can be conveniently used for BNCT in the form of the above compound or a pharmaceutically acceptable salt as it is, or in a form mixed with a pharmaceutically acceptable carrier in a formulation known to those skilled in the art, or in a form encapsulated in micro / nanoparticles, etc.

[0097] Treatment using the boronophenylalanine amide derivative preparation of the present invention is carried out by administering it by any appropriate administration route in such a way that the boronophenylalanine amide derivative accumulates in the target tumor. The boronophenylalanine amide derivative preferably concentrates in the tumor before radiation irradiation, and the tumor:blood ratio before radiation irradiation is at least 1.5 or more:1, preferably 2 or more:1. The boronophenylalanine amide derivative can be administered at once or continuously. In some cases, it can also be administered separately. After the compound has desirably accumulated in the tumor, the site is irradiated with an effective amount of low-energy neutron rays (for example, epithermal neutron rays). The site can be irradiated through the skin, or the site can be completely or partially exposed before irradiation. Administration of the boronophenylalanine amide derivative and subsequent radiation irradiation can be repeated as necessary. If desired, treatment using the boronophenylalanine amide derivative can be performed to reduce the tumor surgically to an extent possible, and then a surgical procedure can be performed. Alternatively, after a surgical procedure, the remaining tumor can be destroyed using the boronophenylalanine amide derivative of the present invention. As another aspect, an appropriate amount of the boronophenylalanine amide derivative is administered to the patient and irradiated with an effective amount of 252 Californium, a naturally occurring neutron emitter. This is preferably inserted into the tumor and removed at an appropriate time.

[0098] Here, the type of tumor is not particularly limited, but brain tumors including glioblastoma and malignant glioma, other head and neck cancers, malignant melanoma, breast cancer, or prostate cancer, etc. can be particularly suitable targets. In addition, epithelial cell cancers such as lung cancer, uterine cancer, kidney cancer, liver cancer, etc., various sarcomas, etc. can also be targets.

[0099] Administration of the borono-phenylalanine amide derivative of the present invention can be performed orally and parenterally. In the case of parenteral administration, it can be performed intra-arterially (e.g., via the carotid artery), intramuscularly, subcutaneously, intramedullary, intrathecal, intraventricularly, intravenously, intraperitoneally, or intranasally.

[0100] The preparation can be in any form such as powder, granule, fine granule, dry syrup, tablet, capsule, injection, solution, etc. Also, depending on the dosage form, it can be mixed with appropriate additives and / or pharmaceutically acceptable carriers by pharmaceutically known methods and administered to patients alone or in combination with other drugs. Additives include, for example, excipients; disintegrants; binders; lubricants; diluents; buffers such as phosphoric acid, citric acid, succinic acid, acetic acid, and other organic acids or their salts; isotonic agents; preservatives; wetting agents; emulsifiers; dispersants; stabilizers; solubilizing agents; antioxidants such as ascorbic acid; low molecular weight (less than about 10 residues) polypeptides (e.g., polyarginine or tripeptide); proteins (e.g., serum albumin, gelatin, or immunoglobulin); hydrophilic polymers (e.g., polyvinylpyrrolidone); amino acids (e.g., glycine, glutamic acid, aspartic acid, or arginine); monosaccharides, disaccharides and other carbohydrates (including cellulose or its derivatives, glucose, mannose, or dextrin); chelating agents (e.g., EDTA); sugar alcohols (e.g., mannitol or sorbitol); counter ions (e.g., sodium); and / or nonionic surfactants (e.g., polysorbate, poloxamer), etc. These pharmaceutical additives can be formulated by appropriately mixing, diluting or dissolving them. Preferred carriers that can be used include, but are not limited to, pharmaceutically inert aqueous carriers. Such carriers include physiological saline, buffered physiological saline, dextrose, and water, etc. In one embodiment of the present invention, the pharmaceutically acceptable carrier is pharmaceutically inert. Appropriate additives and / or pharmaceutically acceptable carriers are non-toxic to the recipient at the dosage and concentration used. Particularly preferred formulations are injections prepared with an aqueous carrier.

[0101] Techniques for formulation and administration are described, for example, in the latest edition and latest supplement of the Japanese Pharmacopoeia, and the final edition of "REMINGTON’S PHARMACEUTICAL SCIENCES" (Maack Publishing Co. Easton, PA).

[0102] The formulation of the borono-phenylalanine amide derivative of the present invention is a medicament containing an effective amount of the medicament for achieving the intended purpose of the target medicament. The "therapeutically effective amount" or "pharmacologically effective amount" is well recognized by those skilled in the art and refers to the amount of the medicament effective for producing pharmacological results. The determination of the therapeutically effective dosage is well known to those skilled in the art.

[0103] The therapeutically effective amount herein refers to the amount of the medicament that reduces the disease state by radiation irradiation after administration. The therapeutic effect and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell culture or experimental animals. The dosage is preferably within a range of circulating concentrations including ED 50 This dosage varies within this range depending on the dosage form used, the sensitivity of the patient, and the route of administration. As an example, the dosage can be appropriately selected according to the age and other patient conditions, the type of disease, the type of complex used, etc. The preferred dosage can be, but is not limited to, 5 - 1000 mg / kg for a single treatment. In particular, it can also be 5 - 500 mg, more preferably 6 - 480 mg of the derivative per kg of the body weight of the subject to be treated.

[0104] [Diagnostic agent containing a radioisotope] The borono-phenylalanine amide derivative of the present invention can also be prepared as a medicament containing a radioisotope. When prepared as a medicament containing radioisotope radioactivity, typically, but not limited to, as the F atom contained in the compound, 18 use 131 F, as the I atom contained in the compound, 123 use 11 I, or as the C atom contained in the compound 3 use 4 C. As the position of these radioisotopes, it can be any position of R 5When it contains aryl or heteroaryl, it can be introduced as a substituent. The compounds thus obtained can be used, for example, in RI tests and nuclear medicine tests. These include, but are not limited to, agents for tomography of scintigraphy, SPECT (Single Photon Emission Computed Tomography), and PET (Positron Emission Tomography). That is, the boronophenylalanine amide derivative of the present invention containing radioactivity is administered to a subject as an agent for PET or SPECT, an image is acquired before treatment, and information such as the in-vivo accumulation distribution of the derivative and the tumor tissue / normal tissue presence ratio (T / N ratio) can be obtained. Based on this information, it is also possible to predict the treatment effect of BNCT in advance and formulate research or treatment plans. The administration mode and others shall conform to the content described in the section of [Agents for BNCT (Boron Neutron Capture Therapy)].

Example

[0105] The present invention will be described in more detail by the following examples, but the invention is not limited thereto.

[0106] In the following examples, the analysis, separation, and purification of the compounds were carried out using the following models and reagents.

[0107] ·NMR spectrum: (JEOL RESONANCE / JNM-ECZ500R / 500MHz

[0108] (Example 1) Production of (S)-(4-(2-amino-3-(benzo[d][1,3]dioxol-5-ylamino)-3-oxopropyl)phenyl)boronic acid

Chemical formula

[0109] Step 1 Production 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), and 3,4-Methylenedioxyaniline (1.67 g, 12.2 mmol) were dissolved in DMF (80 mL). To this solution, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.74 g, 14.3 mmol), which had been previously dissolved in DMF (27 mL), was added under an ice bath. Then, the mixture 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, the mixture was transferred to a separatory funnel. The aqueous layer was further extracted with ethyl acetate (29 mL), and the combined ethyl acetate layers were washed with saturated brine (27 mL). After drying over anhydrous magnesium sulfate, the residue obtained by filtration was roughly purified by silica gel column chromatography to obtain 4.2 g of the target product (yield 81%). 1 H NMR (DMSO-d6); 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 2O), 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).

[0110] Step 2 Production of (S)-(4-(3-(Benzo[d][1,3]dioxol-5-ylamino)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)boronic acid To DMSO (42 mL), the Boc compound (4.20 g, 8.23 mmol) obtained in Step 1, Pd(dppf)2·CH2Cl2 (336 mg, 0.412 mmol), and potassium acetate (1.60 g, 16.5 mmol) were added, and the mixture was 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, it was filtered through celite, and the obtained 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 roughly purified by silica gel column chromatography. The obtained crude product 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, the reaction was carried out at room temperature for 2 days. After completion of the reaction, acetone was distilled off under reduced pressure, and the obtained aqueous solution was extracted twice with ethyl acetate (84 mL). Then, after drying over anhydrous magnesium sulfate, this was filtered off, 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 target product (yield 55%). 1 H NMR (DMSO-d6); 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 2O), 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).

[0111] Step 3 Production of (S)-(4-(2-amino-3-(benzo[d][1,3]dioxol-5-ylamino)-3-oxopropyl)phenyl)boronic acid The de-pinacolized product (1.00 g, 2.34 mmol) obtained in Step 2 was dissolved in trifluoroacetic acid (10 mL). After standing for about 3 hours, it was concentrated under reduced pressure. It was dissolved in a small amount of distilled water and neutralized with sodium carbonate to precipitate the target product. This was collected by filtration and washed with cold water to obtain 0.35 g of the target product (yield 46%). 1 H NMR (3.5% DCl in D2O); 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, OCH2O), 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).

[0112] (Example 2) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2,3-diamino-3-oxopropyl)phenyl)boronic acid 11H 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)).

[0113] (Example 3) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(amino-3-(methylamino)-3-oxopropyl)phenyl)boronic acid 1 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)).

[0114] (Example 4) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-(dimethylamino)-3-oxopropyl)phenyl)boronic acid 1 H 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).

[0115] (Example 5) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-(ethylamino)-3-oxopropyl)phenyl)boronic acid 1 H 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, O CH 2CH3), 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).

[0116] (Example 6) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-(diethylamino)-3-oxopropyl)phenyl)boronic acid 1 H 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).

[0117] (Example 7) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-(tert-butylamino)-3-oxopropyl)phenyl)boronic acid 1 H 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).

[0118] (Example 8) The following compound was prepared in the same manner as in Example 1. [Chemistry] (S)-(4-(2-Amino-3-(cyclohexylamino)-3-oxopropyl)phenyl)boronic acid 1 H 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).

[0119] (Example 9) The following compound was prepared in the same manner as in Example 1. [Chemistry] (S)-(4-(2-Amino-3-oxo-3-(pyrrolidin-1-yl)propyl)phenyl)boronic acid 1 H 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).

[0120] (Example 10) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-morpholino-3-oxopropyl)phenyl)boronic acid 1 H 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).

[0121] (Example 11) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-(phenylamino)propyl)phenyl)boronic acid 1 H 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).

[0122] (Example 12) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-(naphthalen-1-ylamino)-3-oxopropyl)phenyl)boronic acid 1 H 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).

[0123] (Example 13) The following compound was prepared in the same manner as in Example 1.

Chemical Structure

[0124] (Example 14) The following compound was prepared in the same manner as in Example 1.

Chemical Structure

[0125] (Example 15) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-(benzyl(methyl)amino)-3-oxopropyl)phenyl)boronic acid 1 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)).

[0126] (Example 16) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-(dibenzylamino)-3-oxopropyl)phenyl)boronic acid 11H 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).

[0127] (Example 17) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (4 - ((S)-2 - Amino - 3 - oxo - 3 - (((S)-1 - phenylethyl)amino)propyl)phenyl)boronic acid 1 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).

[0128] (Example 18) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (4 - ((S)-2 - Amino - 3 - oxo - 3 - (((R)-1 - phenylethyl)amino)propyl)phenyl)boronic acid 11H 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).

[0129] (Example 19) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-((2-phenylpropan-2-yl)amino)propyl)phenyl)boronic acid 1 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).

[0130] (Example 20) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-(p-tolylamino)propyl)phenyl)boronic acid 11H 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).

[0131] (Example 21) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-(m-tolylamino)propyl)phenyl)boronic acid 1 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).

[0132] (Example 22) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((3,4-dimethylphenyl)amino)-3-oxopropyl)phenyl)boronic acid 1 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).

[0133] (Example 23) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((4-(tert-butyl)phenyl)amino)-3-oxopropyl)phenyl)boronic acid 1 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)).

[0134] (Example 24) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((2-methoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid 1 H 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).

[0135] (Example 25) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((3-methoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid 11H 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).

[0136] (Example 26) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (R)-(4-(2-Amino-3-((3-methoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid 1 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).

[0137] (Example 27) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((3,4-dimethoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid 11H 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).

[0138] (Example 28) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-((3,4,5-trimethoxyphenyl)amino)propyl)phenyl)boronic acid 1 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).

[0139] (Example 29) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (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 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).

[0140] (Example 30) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((4-nitrophenyl)amino)-3-oxopropyl)phenyl)boronic acid 1 H 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).

[0141] (Example 31) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-(phenethylamino)propyl)phenyl)boronic acid 1 H 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).

[0142] (Example 32) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((4-methoxyphenethyl)amino)-3-oxopropyl)phenyl)boronic acid 11H 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).

[0143] (Example 33) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((3-methoxyphenethyl)amino)-3-oxopropyl)phenyl)boronic acid 1 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).

[0144] (Example 34) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((4-fluorophenethyl)amino)-3-oxopropyl)phenyl)boronic acid 1 H 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).

[0145] (Example 35) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-((3-phenylpropyl)amino)propyl)phenyl)boronic acid 1 H 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).

[0146] (Example 36) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-((2-phenoxyethyl)amino)propyl)phenyl)boronic acid 1 H 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).

[0147] (Example 37) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-((4-phenoxybutyl)amino)propyl)phenyl)boronic acid 11H 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).

[0148] (Example 38) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-((3-phenoxypropyl)amino)propyl)phenyl)boronic acid 1 1H NMR (3.5% DCl in D2O); 1.66 - 1.71 (m, 2H, CH2 CH 2CH2), 3.04 - 3.11 (m, 2H, CH 2CH2CH2), 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).

[0149] (Example 39) The following compound was prepared in the same manner as in Example 1.

Chem.

[0150] (Example 40) The following compound was prepared in the same manner as in Example 1.

Chem.

[0151] (Example 41) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((3-(benzyloxy)propyl)amino)-3-oxopropyl)phenyl)boronic acid 1 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).

[0152] (Example 42) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-(pyridin-2-ylamino)propyl)phenyl)boronic acid 11H 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).

[0153] (Example 43) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-((pyridin-2-ylmethyl)amino)propyl)phenyl)boronic acid 1 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).

[0154] (Example 44) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-(pyridin-3-ylamino)propyl)phenyl)boronic acid 1 H 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).

[0155] (Example 45) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-oxo-3-((pyridin-3-ylmethyl)amino)propyl)phenyl)boronic acid 1 H 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).

[0156] (Example 46) The following compound was prepared in the same manner as in Example 1.

Chem.

[0157] (Example 47) The following compound was prepared in the same manner as in Example 1.

Chem.

[0158] (Example 48) The following compound was prepared in the same manner as in Example 1.

Chem.

[0159] (Example 49) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((3-methoxyphenyl)amino)-2-methyl-3-oxopropyl)phenyl)boronic acid 1 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).

[0160] (Example 50) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-((3-methoxyphenyl)amino)-3-oxopropyl)-3-chlorophenyl)boronic acid 1 H 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).

[0161] (Example 51) The following compound was prepared in the same manner as in Example 1. [Chemical formula] (S)-(4-(2-Amino-3-(benzo[d][1,3]dioxol-5-ylamino)-3-oxopropyl)-3-chlorophenyl)boronic acid 11H 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).

[0162] (Example 52) [Chemical formula] Production of (S)-(4-(2-amino-3-((3-methoxyphenyl)amino)-3-oxopropyl)-3-fluorophenyl)boronic acid (S)-3-(4-Borono-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.00 g, 3.06 mmol) was added to N,N-dimethylformamide (3.1 mL). Triethylamine (341 mg, 3.37 mmol), m-anisidine (415 mg, 3.37 mmol), 1-hydroxybenzotriazole (454 mg, 3.37 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (646 mg, 3.37 mmol) were added to this solution under an ice bath, and the temperature was raised 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, filtered, and the filtrate was concentrated under reduced pressure. Diisopropyl ether (30 mL) was added to the obtained crude product for crystallization, and after suction filtration, it was washed with diisopropyl ether (30 mL) to obtain (S)-(4-(2-((tert-butoxycarbonyl)amino)-3-((3-methoxyphenyl)amino)-3-oxopropyl)-3-fluorophenyl)boronic acid (700 mg) as a white solid. Trifluoroacetic acid (3.69 g, 32.4 mmol) was added to the obtained condensate (700 mg). After 16 hours, it was concentrated under reduced pressure, and toluene (20 mL x 3) was further added and azeotroped under reduced pressure to distill off trifluoroacetic acid. The obtained solid was filtered using chloroform (50 mL) as a washing solvent and washed to obtain (S)-(4-(2-amino-3-((3-methoxyphenyl)amino)-3-oxopropyl)-3-fluorophenyl)boronic acid (754 mg, 1.68 mmol, 55% for 2 steps) as a pale yellow solid. 1 H 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).

[0163] [Uptake Test 1] (1) Preparation of HEK293 cell lines highly expressing human LAT1 and LAT2 According to the method described in the paper by Khunweeraphong, N et al. (Journal of Pharmacology Science, 2012, vol. 119, pp 368 - 380), HEK293 cells stably and highly expressing human LAT1 and LAT2 are prepared respectively. Construct a shuttle vector DNA (LAT1: EX - H4509 - M02, LAT2: EX - U0514 - M02, manufactured by GeneCopoeia) having ampicillin and neomycin resistance markers and inserting the full - length cDNA of human LAT1 or LAT2 under the promoter of CMV (cytomegalovirus). This vector is transfected into HEK293 cells by the method using Lipofectamine (registered trademark) 2000 (Invitrogen) according to the manufacturer's instructions. Then, stable expression cell clones of the introduced gene are selected by the limiting dilution method in the presence of 0.9 mg / mL Geneticin (registered trademark), and cell clones with a 2 - to 5 - fold increase in the uptake of L - borono - phenylalanine (L - BPA) compared to HEK293 cells before gene transfection are obtained. These cells are passaged and used for the evaluation of selective uptake of LAT1 and LAT2.

[0164] (2) Evaluation of selective uptake of LAT1 and LAT2 The method for evaluating cell uptake uses the same method as described in the paper by Khunweeraphong, N et al. (Journal of Pharmacology Science, 2012, vol. 119, pp 368 - 380). Using each of the cells obtained in (1), evaluation is carried out. However, radioactive isotopes are not used. A substrate concentration of 0.1 mM and 2 mM BCH (2 - amino - 2 - norbornanecarboxylic acid) as an inhibitor of LAT1 and LAT2 are used, and the concentration of the borono - phenylalanine amide derivative in the cell lysate obtained by recovering the cells after the reaction with 0.05% Tween20 is determined. Quantification of the borono-phenylalanine amide derivative inside cells is carried out according to the method described in the paper by Hattori, Y et al. (Sensors 2017, 17, 2436), using 2-(2-hydroxyphenyl)pyridine (boron sensor 5) as the boron sensor. When evaluating cell uptake, considering the variation between experiments, it is evaluated as the relative value (LAT1 selectivity) with respect to the uptake of L-BPA, which is the comparison target carried out on the same day. LAT1 selectivity = (Quantification value of compound uptake in LAT1 cells / Quantification value of control LBPA uptake in LAT1 cells) / (Quantification value of compound uptake in LAT2 cells / Quantification value of control LBPA uptake in LAT2 cells)

[0165] [Uptake Test 2] (1) Uptake evaluation test into tumor cells (Biological Evaluation 2) 1.5x10 6 Individual 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 pre-cultured at 37 °C in a 5% CO2 atmosphere for 24 hours. The culture medium was aspirated and removed, and a culture medium 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% CO2 atmosphere for 3 hours. After aspirating and removing the culture medium, the cells were washed once with PBS, then trypsinized, and the cells were collected. The number of collected cells was counted, packed by centrifugation, then HClO4 (60%, 0.3 mL) and H2O2 (31%, 0.6 mL) were added, and heated at 75 °C overnight to prepare an ashing solution. After filling up the ashing solution to 5 mL with pure water, it was filtered using a 5C filter paper, and the boron concentration in the solution was measured using an Agilent 710 ICP-OES to determine the amount of boron (μg) per 10 7 cells. When evaluating cell uptake, considering the variation between experiments, it is evaluated as the relative value with respect to the uptake of L-BPA in the reference example, which is the comparison target carried out on the same day.

[0166] The results of the uptake test are shown in a table. Here, 4-boronono-L-phenylalanine (L-BPA) used in the clinical research of BNCT was set as the comparison control.

[0167] As a result, it was found that many of the compounds of the present invention are incorporated into cells at the same concentration or more equivalently than BPA.

[0168] The results of other incorporations of the main compounds are shown in the following table. In the table, Incorporation A: more than 3 times higher than BPA, B: equivalent to BPA to less than 3 times, C: incorporated but lower than BPA are represented. (In the following table, unless otherwise specified, the L-form is represented.)

[0169] Regarding Tables 1 to 8, each substituent of the compounds shown below is shown by substituent.

Chemical formula

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

[0170]

Table 9

[0171] As is clear from the table, the compounds of the examples were shown to have excellent uptake ability for tumor cells. The compounds shown in Table 9, in particular, have a high ability to be taken up by PC3 cells and LNCap cells. It is known that PC3 cells highly express LAT1 and LNCap cells do not express LAT1 (Reference: The Prostate 77:222-233 (2017)), and from this result, it was suggested that these compounds are taken up by other mechanisms without going through LAT1.

Claims

1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: 【化1】 Here, in formula (I), R １ 、 R ２ together with the B atom, represents a substituent of boric acid (—B(OH) ２ ), boronic acid 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 represents a group independently selected from the group consisting of H or C1-C6 alkyl, amino, C1-C6 alkylamino), C1-C6 haloalkylsulfanyl, C1-C6 haloalkylsulfinyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, aminosulfonyl, sulfo, and sulfamoyl; s represents an integer of 1 to 4; R ４ represents H, C1-C6 alkyl, or benzyl; R ５ represents H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxy C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted C6-C14 aryl, or substituted or unsubstituted heteroaryl, or R ４ R ５ together with N forms a C3-C7 heterocycloalkyl (wherein, in the substituted C1-C6 alkyl, substituted C1-C6 alkoxy, or substituted C1-C6 alkoxy C1-C6 alkyl, the group substituted in place of the hydrogen atom is a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted arylthio, substituted or unsubstituted arylamino, substituted or unsubstituted C6-C14 aryl, or substituted or unsubstituted heteroaryl, wherein the substituents of the non-aromatic heterocyclic group, arylthio, arylamino, aryl, or heteroaryl are optionally selected from 1 to 3 C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen); R ６ represents H or C1-C6 alkyl.

2. Said R ３ is, independently, H, Cl, F, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 alkylthio, CH ２ X, CHX ２ , or CX ３ (wherein X represents F), the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. Said R ４ represents H or C1-C6 alkyl; Said R ５ is optionally aryl which may be substituted with 1 to 3 C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen, or optionally heteroaryl which may be substituted with 1 to 3 C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. Said R ４ represents H or C1-C6 alkyl; Said R ５ represents C1-C6 alkyl optionally substituted with 1 to 3 aryl groups which may be substituted with C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

5. said R ４ R ５ The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R, together with N, forms a C3-C7 heterocycloalkyl.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is one selected from the group consisting of the following compounds or a pharmaceutically acceptable 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. Claim 7 A BNCT agent comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. Claim 8 An R of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof ３ of any one site, R ４ , or R ５ A diagnostic agent containing a radioisotope as a substituent in any of them.

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