Amino acid derivative

Abstract

Provided is a new amino acid derivative. The amino acid derivative can be selectively incorporated into LAT1-expressing cells.　The present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: In formula (I), ring A represents a ring structure; R1 independently represent various groups; -X- represents a linking group; -Y- represents an arbitrary ring, an alkynyl, or a bond; -Z- represents –(CR17R18)m-, R2 represents hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, or a substituted or unsubstituted amino; R3 represents a group having a chain structure represented by -B(NR300)2 or -B(OR300)2, or, together with atom B, a group having a cyclic structure of R30R40, for example, a group represented by -BR30R40.

Description

Amino acid derivatives

[0001] The present invention relates to amino acid derivatives.

[0002] Among amino acid transporters, which are membrane proteins necessary for the intracellular uptake of amino acids, L-type amino acid transporter 1 (LAT1) is a membrane protein responsible for the uptake of amino acids into cancer cells. Because LAT1 is expressed with high specificity in cancer cells, many attempts have been made both domestically and internationally to target it for cancer diagnosis and treatment. While LAT1 is not present in normal cells in most tissues, it is specifically expressed in cancer cells and is responsible for supplying amino acids as nutrients to cancer tissues (Non-Patent Documents 1 and 2).

[0003] Boron compounds have also been developed that are taken up by cancer cells via LAT1 and used to deliver boron to cancer cells in boron neutron capture therapy (BNCT) (Non-Patent Document 2).

[0004] Kanai Y, Segawa H, Miyamoto Ki, Uchino H, Takeda E, Endou H. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J Biol Chem. 1998 Sep 11;273(37):23629-32. doi: 10.1074 / jbc.273.37.23629.Kanai Y. Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics. Pharmacol Ther 230: Feb. 2022, 107964.

[0005] There is a further need to develop drugs containing compounds that are specifically taken up into cancer cells via LAT1.

[0006] An object of the present invention is to provide amino acid derivatives that may be useful for cancer treatment or cancer diagnosis, etc. Furthermore, they may also be useful for theranostics purposes.

[0007] As a result of extensive research into solving the above problems, the present inventors discovered a new amino acid derivative and completed the present invention.

[0008] That is, one aspect of the present invention provides the following compound: [1] A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: wherein in formula (I), ring A represents a 5- to 7-membered aromatic carbocyclic ring or a 5- to 7-membered aromatic heterocyclic ring; １ are independently halogen, hydroxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyloxy, C2-6 alkynyloxy, carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted C1-6 alkoxycarbonyl, substituted or unsubstituted C2-6 alkenyloxycarbonyl, substituted or unsubstituted C2-6 alkynyloxycarbonyl, substituted or unsubstituted C1-6 alkylcarbonyl, COOR １０ (R １０is H or C1-6 alkyl, C1-6 alkylamino, or di(C1-6 alkyl)amino), a 3- to 8-membered non-aromatic heterocycle, morpholinocarbonyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C3-8 cycloalkynyl, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C2-6 alkenylthio, substituted or unsubstituted C1-6 alkynylthio, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfonyl, sulfo, substituted or unsubstituted -X- represents a group independently selected from the group consisting of substituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted borono, substituted or unsubstituted sulfanyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted non-aromatic heterocycle, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocycle-oxy, substituted or unsubstituted aromatic carbocycle-oxy, and substituted or unsubstituted aromatic heterocycle-oxy; １１ R １２ ) n-, -(CR １１ R １２ )nO(CR １３ R １４ )n'-, -(CR １１ R １２ ) nCO(CR １３ R １４ )n'-, -(CR １１ R １２ )nOCO(CR １３ R １４ ) n'-, -(CH ２ ) nS(CH ２ ) n'-, -(CH ２ ) nN(R １５ ) (CH ２ )n'-, -(CR １１ R １２ ) nCON(R １５ ) (CR １３ R １４ )n'-, -(CR １１ R １２ ) nN(R １５ ) CO(CR １３R １４ )n'-, -(CR １１ R １２ ) nSO ２ N (R １５ ) (CR １３ R １４ )n'-, -(CR １１ R １２ ) nN(R １５ ) SO ２ (CR １３ R １４ )n'-, -(CR １１ R １２ ) n-, -(CR １１ R １２ ) nN(R １５ ) CON (R １６） (CR １３ R １４ )n'-, -C(R １５ )=CH(R １６ )- or -CC-, where n and n' each independently represent an integer of 0 to 3, and where R １１ , R １２ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R １３ and R １４ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R １５、 R １６ each independently represents hydrogen or substituted or unsubstituted alkyl; -Y- optionally represents (R ５ ) represents any one of structures selected from the group consisting of a 5- to 7-membered aromatic carbocyclic group, a 5- to 7-membered aromatic heterocyclic group, and an 8- to 16-membered polycyclic group, each of which may be substituted with s′, an alkynyl, or a simple bond; R ５is halogen, hydroxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyloxy, C2-6 alkynyloxy, carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted C1-6 alkoxycarbonyl, substituted or unsubstituted C2-6 alkenyloxycarbonyl, substituted or unsubstituted C2-6 alkynyloxycarbonyl, substituted or unsubstituted C1-6 alkylcarbonyl, COOR １０ (R １０ represents H or C1-6 alkyl, C1-6 alkylamino, or di(C1-6 alkyl)amino), a 3- to 8-membered non-aromatic heterocycle, morpholinocarbonyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C3-8 cycloalkynyl, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C2-6 alkenylthio, substituted or unsubstituted C1-6 alkynylthio, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfonyl, sulfo , substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted borono, substituted or unsubstituted sulfanyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted non-aromatic heterocycle, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocycle-oxy, substituted or unsubstituted aromatic carbocycle-oxy, substituted or unsubstituted aromatic heterocycle-oxy, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F) and astatine ( ２１１ At); s and s' are integers of 0 to 3; -Z- represents a group independently selected from the group consisting of -(CR １７ R １８ )m-, where R １７and R １８ are each independently hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or taken together to form a carbonyl, and m is an integer of 0 to 3; R ２ represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino; -W- is independently -(CR １９ R ２０ ) n-, -(CR １９ R ２０ )nO(CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nCO(CR ２１ R ２２ )n'-, -(CR １９ R ２０ )nOCO(CR ２１ R ２２ ) n'-, -(CH ２ ) nS(CH ２ ) n'-, -(CH ２ ) nN(R ２３ ) (CH ２ )n'-, -(CR １９ R ２０ ) nCON(R ２３ ) (CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nN(R ２３ ) CO(CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nSO ２ N (R ２３ ) (CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nN(R ２３ ) SO ２ (CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) n-, -(CR １９ R ２０ ) nN(R １５ ) CON (R２４ ) (CR ２１ R ２２ )n'-, -C(R ２３ )=CH(R ２４ )-, R-CC-, or a simple bond, where n and n' each independently represent an integer of 0 to 3, and where R １９ , R ２０ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R ２１ and R ２２ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R ２３ , R ２４ each independently represents hydrogen or substituted or unsubstituted alkyl; R ３ are independently -BR ３０ R ４０ , oxaborole, a radioisotope, or a group containing a radioisotope; ３０ R ４０ is -B(NR ３００ ) ２ , or -B(OR ３００ ) ２ or a group having a chain structure represented by the formula: ３０ R ４０ represents a group having a cyclic structure, where R ３００ represents a linear or branched C1-C10 alkyl group, and the radioisotope is technetium ( ９９ｍ Tc), indium ( １１１ In), iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), carbon ( １１ C), Gallium ( ６８ Ga), yttrium ( ９０ Y), Rin ( ３２ P), radium ( ２２３ Ra), lutetium ( １７７ Lu), or astatine (２１１ At), and m' represents an integer of 0 to 2.

[0009] More preferred embodiments of the present invention are as follows: [2] The ring A represents a 5- to 7-membered aromatic carbocyclic ring or a 5- to 7-membered aromatic heterocyclic ring; １ are independently halogen, hydroxy, cyano, nitro, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkoxylC1-6 alkoxylC1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyloxy, carbamoyl, C1-6 alkylaminocarbonyl, di(C1-6 alkyl)aminocarbonyl, COOR １０ (R １０ represents H or C1-6 alkyl, C1-6 alkylamino, or di(C1-6 alkyl)amino), a 3- to 8-membered non-aromatic heterocycle optionally substituted with halogen, morpholinocarbonyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8 cycloalkynyl, C3-8 cycloalkylamino, a 3- to 8-membered non-aromatic heterocycle-substituted amino, C1-6 haloalkylsulfanyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 alkylthio, C2-6 alkenylthio, C1-6 alkynylthiosulfinyl, C1-6 alkylsulfinyl, sulfonyl, C1-6 alkylsulf R represents a group independently selected from the group consisting of phenyl, aminosulfonyl, sulfo, sulfamoyl, borono, sulfanyl, sulfinyl, aromatic heterocycle optionally substituted with halogen, C1-6 haloalkyl, C1-6 alkyl; aromatic carbocycle, cycloalkyloxy, cycloalkenyloxy, non-aromatic heterocycle-oxy optionally substituted with halogen, C1-6 haloalkyl, C1-6 alkyl; aromatic carbocycle-oxy optionally substituted with halogen, C1-6 haloalkyl, C1-6 alkyl; and aromatic heterocycle-oxy optionally substituted with halogen, C1-6 haloalkyl, C1-6 alkyl; R ５is halogen, hydroxy, cyano, nitro, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkoxylC1-6 alkoxylC1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyloxy, carbamoyl, C1-6 alkylaminocarbonyl, di(C1-6 alkyl)aminocarbonyl, aminocarbonyl, C1-6 alkoxycarbonyl, C2-6 alkenyloxycarbonyl, C2-6 alkynyloxycarbonyl, C1-6 alkylcarbonyl, COOR １０ (R １０ is H or C1-6 alkyl, C1-6 alkylamino, or di(C1-6 alkyl)amino), morpholinocarbonyl, C3-8 cycloalkylC3-8 cycloalkenyl, C3-8 cycloalkynyl, C3-8 cycloalkylamino, 3-8 membered non-aromatic heterocycle-substituted amino, C1-6 haloalkylsulfanyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 alkylthio, C2-6 alkenylthio, C1-6 alkynylthio, sulfinyl, C1-6 alkylsulfinyl, sulfonyl, C1-6 alkylsulfonyl, aminosulfonyl, sulfo, sulfamoyl, carbamoyl, sulfanyl, sulfinyl, non-aromatic heterocycle, aromatic heterocycle, aromatic carbocycle, cycloalkyloxy, cycloalkenyloxy, non-aromatic heterocycle-oxy, aromatic carbocycle-oxy, aromatic heterocycle-oxy, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F) and astatine ( ２１１ Item 1, wherein the A ring represents a group independently selected from the group consisting of R , R t ... １independently represent halogen, borono, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkyloxy, C1-6 alkyl-substituted phenyloxy, C1-6 alkyl-substituted pyridyloxy, C1-6 haloalkyl-substituted phenyloxy, C1-6 haloalkyl-substituted pyridyloxy, halogen-substituted phenyloxy, or halogen-substituted pyridyloxy, s represents an integer of 0 to 2, and -X- is -(CH ２ ) n-, -(CH ２ )nN(H)CO(CH ２ ) n'-, -(CH ２ )nN(CH ３ )CO(CH ２ ) n'-, -(CH ２ )nCO(CH ２ ) n'-, -(CH ２ )nOCO(CH ２ ) n'-, -(CH ２ )nO(CH ２ )n'-, -(CH(OH))n-, -CH ２ -CH(NH ２ ))-CONH- or -CC-, wherein n and n' each independently represent an integer of 0 to 2, and Y is optionally selected from the group consisting of halogen, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), or astatine ( ２１１ At), C alkyl, C alkoxy, C haloalkyl, or C haloalkyloxy, each of which may be independently substituted by one or two of benzene, naphthalene, thiophene, pyridine, alkynyl, or pyrazine; -Z- is -(CH ２ ) m-, where m is an integer of 0 to 3; R ２ represents hydrogen or 1-6 alkyl; ２ ) n-, -(CH ２ )nN(H)CO(CH ２ ) n'-, -(CH ２ )nN(CH ３ )CO(CH ２ ) n'-, -(CH ２ )nCO(CH２ ) n'-, -(CH ２ )nOCO(CH ２ ) n'-, -(CH ２ )nO(CH ２ )n'-, -(CH(OH))n-, -CH ２ -CH(NH ２ )) represents -CONH- or -CC-, where n and n' each independently represent an integer of 0 to 2, and R ３ Is -BR ３０ R ４０ and -BR ３０ R ４０ is -B(NR ３００ ) ２ , or -B(OR ３００ ) ２ or a group having a chain structure represented by the formula: ３０ R ４０ represents a group having a cyclic structure, where R ３００ represents a linear or branched C1-C10 alkyl group, or a pharmaceutically acceptable salt thereof. [4] The compound according to item 1 or 2, wherein -W- is -(CH ２ ) n-, -(CH ２ )nN(H)CO(CH ２ ) n'-, -(CH ２ )nN(CH ３ )CO(CH ２ ) n'-, -(CH ２ )nCO(CH ２ ) n'-, -(CH ２ )nOCO(CH ２ ) n'-, -(CH ２ )nO(CH ２ )n'-, -(CH(OH))n-, -CH ２ -CH(NH ２ )) represents -CONH- or -CC-, where n and n' each independently represent an integer of 0 to 2; R ３ is a radioisotope or a group containing a radioisotope, and the radioisotope is technetium ( ９９ｍ Tc), indium ( １１１ In), iodine ( １２３ I, １２５ I, １３１ I), fluorine (１８ F), carbon ( １１ C), Gallium ( ６８ Ga), yttrium ( ９０ Y), Rin ( ３２ P), radium ( ２２３ Ra), lutetium ( １７７ Lu), or astatine ( ２１１ [5] The compound or a pharmaceutically acceptable salt thereof according to item 1 or 2, wherein R is 1 or 2, R is 1 or 2, R is 1 or 2, and ... and R is 1 or 2. [6] The compound or a pharmaceutically acceptable salt thereof according to item 1 or 2, wherein R is 1 or 2, R is 1 or 2, and R is 1 or 2. or Here, the compounds represented by the above two chemical formulas have in common: R １ represents a halogen, a C1-6 alkoxyl group, or a C1-6 alkyl group; s represents 0 or 1; R ３ is B(OH) ２ , oxaborole, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), astatine ( ２１１ At) or together with atom B, R ３０ R ４０ represents a group having a cyclic structure, and the cyclic structure forms a benzoxaborole together with an adjacent benzene ring; R ５ is a halogen, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), astatine ( ２１１ At), a C1-6 alkoxyl group, or a C1-6 alkyl group, and s' represents 0 or 1. [6] A pharmaceutical composition for treatment, comprising the compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof. [7] A drug for BNCT, comprising the compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof. [8] A cancer diagnostic drug, comprising the compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof. [9] A theranostic drug, comprising the compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof.

[0010] The novel compounds of the present invention may be useful in methods for treating or diagnosing tumors, including BNCT.

[0011] The present invention relates to novel amino acid derivatives.

[0012] In this specification, when a compound having an asymmetric carbon is represented, the compound includes any of the racemic, R-form and S-form, unless otherwise specified.

[0013] [Amino Acid Derivative] The amino acid derivative of the present invention is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof. wherein in formula (I), ring A represents a 5- to 7-membered aromatic carbocyclic ring or a 5- to 7-membered aromatic heterocyclic ring; １ are independently halogen, hydroxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyloxy, C2-6 alkynyloxy, carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted C1-6 alkoxycarbonyl, substituted or unsubstituted C2-6 alkenyloxycarbonyl, substituted or unsubstituted C2-6 alkynyloxycarbonyl, substituted or unsubstituted C1-6 alkylcarbonyl, COOR １０ (R １０is H or C1-6 alkyl, C1-6 alkylamino, or di(C1-6 alkyl)amino), a 3- to 8-membered non-aromatic heterocycle, morpholinocarbonyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C3-8 cycloalkynyl, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C2-6 alkenylthio, substituted or unsubstituted C1-6 alkynylthio, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfonyl, sulfo, substituted or unsubstituted -X- represents a group independently selected from the group consisting of substituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted borono, substituted or unsubstituted sulfanyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted non-aromatic heterocycle, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocycle-oxy, substituted or unsubstituted aromatic carbocycle-oxy, and substituted or unsubstituted aromatic heterocycle-oxy; １１ R １２ ) n-, -(CR １１ R １２ )nO(CR １３ R １４ )n'-, -(CR １１ R １２ ) nCO(CR １３ R １４ )n'-, -(CR １１ R １２ )nOCO(CR １３ R １４ ) n'-, -(CH ２ ) nS(CH ２ ) n'-, -(CH ２ ) nN(R １５ ) (CH ２ )n'-, -(CR １１ R １２ ) nCON(R １５ ) (CR １３ R １４ )n'-, -(CR １１ R １２ ) nN(R １５ ) CO(CR １３R １４ )n'-, -(CR １１ R １２ ) nSO ２ N (R １５ ) (CR １３ R １４ )n'-, -(CR １１ R １２ ) nN(R １５ ) SO ２ (CR １３ R １４ )n'-, -(CR １１ R １２ ) n-, - (CR １１ R １２ ) nN(R １５ ) CON (R １６） (CR １３ R １４ )n'-, -C(R １５ )=CH(R １６ )- or -CC-, where n and n' each independently represent an integer of 0 to 3, and where R １１ , R １２ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R １３ and R １４ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R １５、 R １６ each independently represents hydrogen or substituted or unsubstituted alkyl; -Y- optionally represents (R ５ ) represents any one of structures selected from the group consisting of a 5- to 7-membered aromatic carbocyclic group, a 5- to 7-membered aromatic heterocyclic group, and an 8- to 16-membered polycyclic group, each of which may be substituted with s′, an alkynyl, or a simple bond; R ５is halogen, hydroxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyloxy, C2-6 alkynyloxy, carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted C1-6 alkoxycarbonyl, substituted or unsubstituted C2-6 alkenyloxycarbonyl, substituted or unsubstituted C2-6 alkynyloxycarbonyl, substituted or unsubstituted C1-6 alkylcarbonyl, COOR １０ (R １０ represents H or C1-6 alkyl, C1-6 alkylamino, or di(C1-6 alkyl)amino), a 3- to 8-membered non-aromatic heterocycle, morpholinocarbonyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C3-8 cycloalkynyl, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C2-6 alkenylthio, substituted or unsubstituted C1-6 alkynylthio, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfonyl, sulfo , substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted borono, substituted or unsubstituted sulfanyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted non-aromatic heterocycle, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocycle-oxy, substituted or unsubstituted aromatic carbocycle-oxy, substituted or unsubstituted aromatic heterocycle-oxy, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), and astatine ( ２１１ At); s and s' are integers of 0 to 3; -Z- represents a group independently selected from the group consisting of -(CR １７ R １８ )m-, where R １７and R １８ are each independently hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or taken together to form a carbonyl, and m is an integer of 0 to 3; R ２ represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino; -W- is independently -(CR １９ R ２０ ) n-, -(CR １９ R ２０ )nO(CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nCO(CR ２１ R ２２ )n'-, -(CR １９ R ２０ )nOCO(CR ２１ R ２２ ) n'-, -(CH ２ ) nS(CH ２ ) n'-, -(CH ２ ) nN(R ２３ ) (CH ２ )n'-, -(CR １９ R ２０ ) nCON(R ２３ ) (CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nN(R ２３ ) CO(CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nSO ２ N (R ２３ ) (CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nN(R ２３ ) SO ２ (CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) n-, -(CR １９ R ２０ ) nN(R １５ ) CON (R２４ ) (CR ２１ R ２２ )n'-, -C(R ２３ )=CH(R ２４ )-, R-CC-, or a simple bond, where n and n' each independently represent an integer of 0 to 3, and where R １９ , R ２０ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R ２１ and R ２２ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R ２３ , R ２４ each independently represents hydrogen or substituted or unsubstituted alkyl; R ３ are independently -BR ３０ R ４０ , oxaborole, a radioisotope, or a group containing a radioisotope; ３０ R ４０ is -B(NR ３００ ) ２ , or -B(OR ３００ ) ２ or a group having a chain structure represented by the formula: ３０ R ４０ represents a group having a cyclic structure, where R ３００ represents a linear or branched C1-C10 alkyl group, and the radioisotope is technetium ( ９９ｍ Tc), indium ( １１１ In), iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), carbon ( １１ C), Gallium ( ６８ Ga), yttrium ( ９０ Y), Rin ( ３２ P), radium ( ２２３ Ra), lutetium ( １７７ Lu), or astatine (２１１ At), and m' represents an integer of 0 to 2.

[0014] wherein, in one aspect, X is -(CR １１ R １２ ) nCON(R １５ ) (CR １３ R １４ )n'-, or -(CR １１ R １２ ) nN(R １５ ) CO(CR １３ R １４ ) n'- and Y is a simple bond, then R ３ Is -BR ３０ R ４０ In such a case, X and Y are preferably not R ３ independently represent a radioisotope or a group containing a radioisotope, wherein the radioisotope is technetium ( ９９ｍ Tc), indium ( １１１ In), iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), carbon ( １１ C), Gallium ( ６８ Ga), yttrium ( ９０ Y), Rin ( ３２ P), radium ( ２２３ Ra), lutetium ( １７７ Lu), or astatine ( ２１１ At), and m′ preferably represents an integer of 0 to 2.

[0015] 1. Definitions of Groups In this specification, the meanings of the following terms are commonly explained below. Even when the words "substituted or unsubstituted" are used before these explanations, the meanings of each term are the same.

[0016] The C5- to C7-membered aromatic ring group (or sometimes referred to as a C5- to C7-membered aromatic ring) refers to an aromatic ring group having 5 to 7 carbon atoms, and examples thereof include a phenyl group (benzene).

[0017] The 5- to 7-membered aromatic heterocyclic group represents a 5- to 7-membered aromatic ring group containing one or more heteroatoms selected from O, N, and S. Examples of groups formed by 5- to 7-membered aromatic heterocycles include, but are not limited to, 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, and triazinyl. When referring to a 5- to 7-membered aromatic heterocycle, it means a ring corresponding to these groups.

[0018] The 8- to 16-membered polycyclic group refers to a group formed by a substituted or unsubstituted 8- to 16-membered polycyclic compound, and examples thereof include naphthyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzodioxolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, and pyrimidinyl. Examples thereof include thiazolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydronaphthyl, as well as groups formed from acenaphthene, anthracene, phenanthrene, pyrene, and naphthacene.

[0019] In this specification, the halogen may be any of F, Cl, Br, I, and At, but is preferably F, Cl, or Br, and particularly preferably F or Cl. The halogen may also be a radioisotope, such as fluorine ( １８F), iodine ( １２３ I, １２５ I, １３１ I), or astatine ( ２１１ At), etc.

[0020] As used herein, C1-6 alkyl refers to a linear or branched C1-6 saturated hydrocarbon group. Examples of C1-6 alkyl groups 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. Preferred are linear or branched C1-C4 alkyl groups, and examples thereof include, but are not limited to, a methyl group, an ethyl group, an isopropyl group, a butyl group, etc.

[0021] As used herein, substituted C1-6 alkyl includes C1-6 alkyl groups substituted with any substituent, and an example is C1-6 haloalkyl. C1-6 haloalkyl refers to a C1-6 alkyl group having one or more halogen substituents. The C1-6 haloalkyl group is preferably C ２ X ５ , C.H. ２ X, CHX ２ , or CX ３ (X represents Cl, F, Br or I), and examples thereof include, but are not limited to, CF ３ , C ２ F ５ , CHF ２ , C.H. ２ F, CCl ３ , CHCl ２ , C ２ Cl ５ and the like. Of these, trifluoromethyl, difluoromethyl, or monofluoromethyl is particularly preferred. Another example of a substituted C1-6 alkyl includes C1-6 alkoxyC1-6 alkyl. Examples include, but are not limited to, methoxyethyl, ethoxyethyl, and the like. Substituted C1-6 alkoxyC1-6 alkyl is also possible, and includes, but is not limited to, straight-chain or branched C1-6 alkoxyC1-6 alkyl in which one or two hydrogen atoms have been replaced with other groups.

[0022] In this specification, C2-6 alkenyl refers to a linear or branched C2-C6 unsaturated hydrocarbon group containing a double bond. Examples of C2-6 alkenyl groups include ethenyl, propenyl, and butenyl.

[0023] In the present specification, substituted C2-6 alkenyl includes C2-6 haloalkenyl and the like.

[0024] As used herein, C2-6 alkynyl refers to a linear or branched C2-C6 unsaturated hydrocarbon group containing a triple bond. Examples of C2-6 alkynyl groups include acetylene, methylacetylene, butyne, and pentyne. Substituted C2-6 alkynyl groups include C2-6 haloalkynyl and the like.

[0025] Substituted or unsubstituted amino refers to unsubstituted amino as well as, for example, C1-6 alkylamino and di(C1-6 alkyl)amino. Here, C1-6 alkylamino refers to an amino having a linear or branched C1-6 saturated hydrocarbon group. Examples include methylamino, ethylamino, propyl (e.g., n-propyl and isopropyl)amino, butyl (e.g., n-butyl, isobutyl, t-butyl)amino, pentyl (e.g., n-pentyl, isopentyl, neopentyl)amino, and the like. Preferred is a linear or branched C1-C4 alkylamino group, and examples thereof include, but are not limited to, a methylamino group, an ethylamino group, an isopropylamino group, and a butylamino group. Di(C1-6 alkyl)amino refers to an amino having two linear or branched C1-6 saturated hydrocarbon groups. Examples of di(C1-6 alkyl)amino groups include dimethylamino, diethylamino, methylethylamino, dipropyl (e.g., n-propyl and isopropyl)amino, dibutyl (e.g., n-butyl, isobutyl, t-butyl)amino, dipentyl (e.g., n-pentyl, isopentyl, neopentyl)amino, etc. Preferred are amino groups having two linear or branched C1-C4 alkyl groups, and examples thereof include, but are not limited to, a dimethylamino group, a diethylamino group, a methylethylamino group, a methylisopropylamino group, a methylbutylamino group, etc. Other examples include C3-8 cycloalkylamino (for example, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, etc.), and 3-8 membered non-aromatic heterocycle-substituted amino (for example, aziridinoamino, azetidinoamino, morpholinoamino, thiomorpholinoamino, 1-pyrrolidinylamino, piperidinoamino, 4-piperidinylamino, 1-piperazinylamino, 1-pyrrolylamino, oxazolidinoamino, thiazolidinoamino, etc.).

[0026] As used herein, C1-6 alkoxy or C1-6 alkoxyl refers to a group having a linear or branched C1-6 alkyl group and an oxygen molecule. The C1-6 alkoxy or alkoxyl preferably has a linear or branched C1-C4 alkyl group, and includes, but is not limited to, methoxy, ethoxy, isopropoxy, butoxy, and other groups.

[0027] Substituted C1-6 alkoxy includes, for example, C1-6 haloalkoxy. C1-6 haloalkoxy refers to a C1-6 alkoxy group having one or more halogen substituents. The C1-6 haloalkoxy group is preferably OCX ５ , OCH ２ X or OCHX ２ (X represents Cl, F, Br or I), and examples thereof include, but are not limited to, a trifluoromethoxy group, a trichloromethoxy group, a chloromethoxy group, a bromomethoxy group, a fluoromethoxy group, an iodomethoxy group, a difluoromethoxy group, a dibromomethoxy group, a 2-chloroethoxy group, a 2,2,2-trifluoroethoxy group, a 2,2,2-trichloroethoxy group, a 3-bromopropoxy group, a 3-chloropropoxy group and a 2,3-dichloropropoxy group. Another example of a substituted C1-6 alkoxy is C1-6 alkyl-C1-6 alkoxy.

[0028] Substituted or unsubstituted C2-6 alkenyloxy refers to a group having a linear or branched C2-6 alkenyl group and an oxygen molecule. C2-6 alkenyloxy preferably has a linear or branched C2-C4 alkenyl.

[0029] The substituted or unsubstituted C2-6 alkynyloxy refers to a group having a linear or branched C2-6 alkynyl group and an oxygen molecule. The C2-6 alkynyloxy preferably has a linear or branched C2-C4 alkynyl.

[0030] Substituted or unsubstituted acyl includes, but is not limited to, a formyl group, an acetyl group, a propionyl group, a benzoyl group, an acrylyl group, and the like.

[0031] The substituted or unsubstituted aminocarbonyl includes aminocarbonyl, C1-6 alkylaminocarbonyl, or di(C1-6 alkyl)aminocarbonyl, etc. Examples include, but are not limited to, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, i-propylaminocarbonyl, etc.

[0032] In this specification, C1-6 alkylcarbonyl includes, but is not limited to, methylcarbonyl, ethylcarbonyl and the like.

[0033] In this specification, COOR １０ (R １０ is H or C1-6 alkyl, amino, alkylamino or di(C1-6 alkyl)amino) includes, but is not limited to, methyloxycarbonyl, aminooxycarbonyl, and the like.

[0034] Substituted or unsubstituted C1-6 alkoxycarbonyl includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

[0035] The substituted or unsubstituted sulfanyl includes, for example, sulfanyl, C1-6 haloalkylsulfanyl, C1-6 alkylsulfanyl, etc., and is not limited to, trifluoromethylsulfanyl, trichloromethylsulfanyl, methylsulfanyl, ethylsulfanyl, etc.

[0036] The substituted or unsubstituted sulfinyl includes, for example, sulfinyl, C1-6 haloalkylsulfinyl, C1-6 alkylsulfinyl, etc., but is not limited to, trifluoromethylsulfinyl, trichloromethylsulfinyl, methylsulfinyl, ethylsulfinyl, etc.

[0037] The substituted or unsubstituted sulfonyl includes sulfonyl, C1-6 haloalkylsulfonyl, C1-6 alkylsulfonyl, etc., including, but not limited to, methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, etc.

[0038] In this specification, examples of substituted or unsubstituted C1-6 alkylthio include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.

[0039] In this specification, C3-8 cycloalkyl refers to, but is not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

[0040] Substituted or unsubstituted C3-8 cycloalkenyl includes, but is not limited to, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, 1,3-cyclohexadiene, and the like.

[0041] Substituted or unsubstituted C3-8 cycloalkynyl includes, but is not limited to, cyclooctyne, and the like.

[0042] In this specification, the term "3- to 8-membered non-aromatic heterocycle" refers to a 3- to 8-membered saturated or unsaturated ring containing one or two heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom within the ring, but is not an aromatic ring. Examples of such rings include aziridino, azetidino, morpholino, thiomorpholino, 1-pyrrolidinyl, piperidino, 4-piperidinyl, 1-piperazinyl, 1-pyrrolyl, oxazolidino, thiazolidino, tetrahydrofuranyl, and tetrahydropyranyl.

[0043] In this specification, -BR ３０ R ４０ is -B(NR ３００ ) ２ , or -B(OR ３００ ) ２ or a group having a chain structure such as R ３０ R４０ represents a group having a cyclic structure, where R ３００ represents a linear or branched C1-C10 alkyl group. Here, the term "linear or branched C1-C10 alkyl group" refers to any alkyl group having 1 to 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, a methyl group, an ethyl group, an isopropyl group, and a butyl group. When R is formed together with atom B, ３０ R ４０ When the group having a cyclic structure is represented by the formula (I), it does not necessarily have to be one in which only an O atom is present, but may also have an N atom present. Examples include, but are not limited to, groups formed from an ester or ester analogue formed from atom B and 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. These include, but are not limited to, pinacol boronate ester, MIDA boronate ester, 1,3-propanediol boronate ester, neopentyl glycol boronate ester, catechol boronate ester, pinanediol boronate ester, biscyclohexyldiol boronate ester, MPM boronate ester, trifluoroborate salt, cyclic triol borate salt, and a cyclic compound of diaminonaphthalene amide and boron. When R is present together with atom B, ３０ R ４０ The group having a cyclic structure includes, for example, oxaborole.

[0044] Here, the boron atoms are not limited, but may include boron-10. For example, the proportion of boron-10 may be 75% by mass or more, 80% by mass or more, 90% by mass or more, or 95% by mass or more.

[0045] Natural boron (boron) contains boron-10 and boron-11 isotopes, with the ratio of boron-10 being 20% ​​and boron-11 being 80%. Therefore, prior to producing the amino acid 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. Examples of commercially available products include: １０ B Concentrated boric acid (manufactured by Stella Chemifa Co., Ltd.) can be used.

[0046] Here, the boron-10 measurement method can be performed by multi-type ICP optical emission spectroscopy (ICP-OES) using an Agilent 710 (manufactured by Agilent). The ICP-OES used for the measurement is adjusted in accordance with JIS K0116.

[0047] B atom, R ３０ , R ４０ and the fused ring formed with ring A, or atom B, R ３０ , R ４０ A fused ring can also be formed by a part of the A ring and X. ３０ , R ４０ The fused ring formed by and ring A includes, but is not limited to, for example, benzoxaborole.

[0048] In this specification, the terms "substituted" and "having a substituent" mean that the group is substituted with any of the substituents in the range of 1 to 4, 1 to 5, or 1 to 6.

[0049] In this specification, R １ and R ５ may each independently be: １ For example, when s′ is 1 or more, each R ５ may be the same or different.

[0050] That is, R １ and R ５each independently represents halogen, hydroxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyloxy, C2-6 alkynyloxy, carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted C1-6 alkoxycarbonyl, substituted or unsubstituted C2-6 alkenyloxycarbonyl, substituted or unsubstituted C2-6 alkynyloxycarbonyl, substituted or unsubstituted C1-6 alkylcarbonyl, COOR １０ (R １０ is H or C1-6 alkyl, C1-6 alkylamino, or di(C1-6 alkyl)amino), a 3- to 8-membered non-aromatic heterocycle, morpholinocarbonyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C3-8 cycloalkynyl, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C2-6 alkenylthio, substituted or unsubstituted C1-6 alkynylthio, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfonyl, sulfo, substituted or unsubstituted and R represents a group independently selected from the group consisting of substituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted borono, substituted or unsubstituted sulfanyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted non-aromatic heterocycle, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocycle-oxy, substituted or unsubstituted aromatic carbocycle-oxy, and substituted or unsubstituted aromatic heterocycle-oxy. ５ is iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), and astatine ( ２１１ At) may be a group selected from the group consisting of

[0051] R１ and R ５ When the term "substituted or unsubstituted" is used in the definition of R, it means that the group may be optionally substituted with any substituent. １ and R ５ Substituents when further substituted within the definition include, but are not limited to, halogen, hydroxy, cyano, amino, C1-6 alkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, benzyloxy, benzyl, phenyl, phenylC1-6 alkyl, C1-6 alkoxyC1-6 alkyl, nitro, C1-6 haloalkyl, carbamoyl, C1-6 alkylaminocarbonyl, di(C1-6 alkyl)aminocarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, COOR １０ (R １０ and includes groups independently selected from the group consisting of H or C1-6 alkyl, amino, C1-6 alkylamino, or di(C1-6 alkyl)amino), 3- to 8-membered non-aromatic heterocycle, morpholinocarbonyl, C3-8 cycloalkyl, C3-8 cycloalkylamino, 3- to 8-membered non-aromatic heterocycle-substituted amino, C1-6 haloalkylsulfanyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aminosulfonyl, sulfo, and sulfamoyl.

[0052] In the compound of formula (I), the A ring represents benzene, thiophene, or pyridine, and R １ independently represent halogen, borono, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkyloxy, C1-6 alkyl-substituted phenyloxy, C1-6 alkyl-substituted pyridyloxy, C1-6 haloalkyl-substituted phenyloxy, C1-6 haloalkyl-substituted pyridyloxy, halogen-substituted phenyloxy, or halogen-substituted pyridyloxy, s represents an integer of 0 to 2, and -X- is -(CH ２ ) n-, -(CH ２ )nN(H)CO(CH ２ ) n'-, -(CH２ )nN(CH ３ )CO(CH ２ ) n'-, -(CH ２ )nCO(CH ２ ) n'-, -(CH ２ )nOCO(CH ２ ) n'-, -(CH ２ )nO(CH ２ )n'-, -(CH(OH))n-, -CH ２ -CH(NH ２ ))-CONH- or -CC-, wherein n and n' each independently represent an integer of 0 to 2, Y represents benzene, naphthalene, thiophene, pyridine, alkynyl, or pyrazine optionally substituted independently with one or two of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkyloxy, -Z- represents -(CH ２ ) m-, where m is an integer of 0 to 3; R ２ represents hydrogen or 1-6 alkyl; ２ ) n-, where n is an integer of 0 to 2, and R ３ Is -BR ３０ R ４０ and -B(NR ３００ ) ２ , or -B(OR ３００ ) ２ or a group having a chain structure represented by the formula: ３０ R ４０ represents a group having a cyclic structure, where R ３００ represents a linear or branched C1-C10 alkyl group, or a pharmaceutically acceptable salt thereof.

[0053] In yet another embodiment, in the compound of formula (I), the -W- is, but is not limited to, -(CH ２ ) n-, -(CH ２ )nN(H)CO(CH ２ ) n'-, -(CH ２ )nN(CH ３ )CO(CH ２ ) n'-, -(CH ２ )nCO(CH２ ) n'-, -(CH ２ )nOCO(CH ２ ) n'-, -(CH ２ )nO(CH ２ )n'-, -(CH(OH))n-, -CH ２ -CH(NH ２ )) represents -CONH- or -CC-, where n and n' each independently represent an integer of 0 to 2; R ３ is a radioisotope or a group containing a radioisotope, and the radioisotope is technetium ( ９９ｍ Tc), indium ( １１１ In), iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), carbon ( １１ C), Gallium ( ６８ Ga), yttrium ( ９０ Y), Rin ( ３２ P), radium ( ２２３ Ra), lutetium ( １７７ Lu), or astatine ( ２１１ At), or a pharmaceutically acceptable salt thereof.

[0054] Here, examples of the group containing a radioisotope include 3-(technetium ( ９９ｍ Tc)-1,4,8,11-tetraazabicyclohexadecane)propyl, indium ( １１１ In) 2,5,8,8-tetracarboxymethyl-2,5,8-triazaoctyl, or lutetium ( １７７ Lu)-1,4,7-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-10-methylcarbonyl, etc. The following structures are included, where ● represents the bonding site with W.

[0055] Preferred examples of the amino acid derivatives of the present invention include compounds having the following structures: or

[0056] Here, the following definitions apply to both compounds represented by the above two chemical formulas: １ represents a halogen, a C1-6 alkoxyl group, or a C1-6 alkyl group; s represents 0 or 1; R ３ is B(OH) ２ , oxaborole, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), astatine ( ２１１ At) or together with atom B, R ３０ R ４０ represents a group having a cyclic structure, and the cyclic structure forms a benzoxaborole together with an adjacent benzene ring; R ５ is a halogen, a C1-6 alkoxyl group, an iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), or astatine ( ２１１ At), or a C1-6 alkyl group; and s' represents 0 or 1.

[0057] Among these, particularly preferred examples include, but are not limited to, the following compounds:

[0058] In the present invention, "pharmaceutically acceptable salts" include 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. Suitable 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; as well as aluminum salts and ammonium salts. Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like. Suitable 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 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, and the like. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc., and suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0059] The amino acid derivatives of the present invention can be specifically taken up into cancer cells via LAT1.

[0060] [Method for Producing Amino Acid Derivatives] In the present invention, the method for producing the novel amino acid derivatives is not limited, and may be, for example, the following method. As an example, a simple amino acid derivative such as nitrophenylalanine, chlorophenylalanine, aminophenylalanine, or hydroxyphenylglycine can be used as a starting material, and an appropriate protecting group can be introduced to produce an intermediate for preparing the novel amino acid derivative of the present invention, which can then be subjected to the next step. These starting materials may be commercially available. Alternatively, nitrophenylalanine or the like in which the amino group and carboxyl group are protected can be synthesized by a method known to those skilled in the art, and then subjected to the preparation of the novel amino acid derivative of the present invention.

[0061] The protecting groups for the amino and carboxyl groups are not limited, but for example, carbamate protecting groups, amide protecting groups, and alkyl protecting groups are preferably used. Examples of such carbamate protecting groups include tert-butoxycarbonyl (Boc), benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), and 2,2,2-trichloroethoxycarbonyl (Troc). Examples of amide protecting groups include acetyl and benzoyl. Examples of alkyl protecting groups include methyl, t-butyl, and benzyl.

[0062] Next, for example, a compound of the present invention containing a moiety represented by ring A is introduced into the intermediate having an appropriately highly reactive group introduced therein. A boron-containing group may be previously introduced into ring A before the reaction with the intermediate. Alternatively, the boron-containing group may be introduced after the reaction with the intermediate.

[0063] The method for introducing the compound of the present invention containing the moiety represented by ring A into the intermediate having a highly reactive group introduced therein can be appropriately selected depending on the type of the reactive group, and for example, a known dehydration condensation method for forming an amide bond can be used.

[0064] The reaction temperature is, for example, 20°C to 160°C, preferably 60°C to 120°C.

[0065] When a group containing boron has been previously introduced into the A ring, for example, boronofluorobenzoic acid, 3-amino-2-methoxypyridine-5-boronic acid pinacol, etc. can also be used.

[0066] As a method for introducing boron into a compound, a boron compound is reacted in a solvent in the presence of a palladium catalyst, an organophosphorus compound and a base.

[0067] 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(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and the like.

[0068] 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.

[0069] Examples of bases include, but are not limited to, potassium acetate, sodium acetate, sodium carbonate, cesium carbonate, potassium carbonate, and sodium bicarbonate.

[0070] Examples of the boron compound include boric acid esters and boric acid amides, and preferably B(OR) ３ , B(NR) ３ , B(OR) ２ (NR), (RO) ２ B-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). Among these, particularly preferred are compounds represented by (RO) ２ B-B (OR) ２Here, the term "linear or branched C1-C10 alkyl group" refers to any alkyl group having 1 to 10 carbon atoms, but is preferably a linear or branched C1-C8 alkyl group, and more preferably a linear or branched C1-6 alkyl group. Examples of these groups include, but are not limited to, a methyl group, an ethyl group, an isopropyl group, and a butyl group. Examples of boron compounds include, but are not limited to, bis(pinacolato)diboron.

[0071] Examples of solvents include, but are not limited to, ether solvents such as 1,4-dioxane, tetrahydrofuran, and 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, 20°C to 160°C, and preferably 60°C to 120°C.

[0072] In each step of the production method, purification may be carried out according to a conventional method, which may be modified as appropriate.

[0073] In particular, when the compound is a racemate, it can be used as is or the optical purity of the R or S isomer can be increased to obtain a compound suitable for use in, for example, boron neutron capture therapy.

[0074] For optical resolution, known techniques may be used as appropriate. For example, a method of optical resolution (using α-chymotrypsin or the like) via a hydrolysis step and an esterification step may be used, as well as a simplified method including a simplified step of using acylase via a hydrolysis step.

[0075] [Therapeutic Pharmaceutical Composition] A composition comprising the amino acid derivative of the present invention and optionally a pharmaceutically acceptable carrier can be used as a therapeutic pharmaceutical composition. The therapeutic pharmaceutical composition may be primarily a pharmaceutical composition for treating cancer.

[0076] As used herein, the term "cancer" when referring to a cancer therapeutic agent has the same meaning as "malignant tumor." Here, "cancer" or "malignant tumor" includes both epithelial ("carcinoma") tumors such as squamous cell carcinoma and non-epithelial ("sarcoma" (e.g., osteosarcoma and leukemia) tumors). Particularly suitable targets include, but are not limited to, brain tumors including glioblastoma and malignant glioma, as well as other head and neck cancers, malignant melanoma, skin cancer, breast cancer, lung cancer, uterine cancer, ovarian cancer, kidney cancer, pancreatic cancer, biliary tract cancer, liver cancer, colon cancer, esophageal cancer, stomach cancer, tongue cancer, prostate cancer, osteosarcoma, multiple myeloma, and leukemia.

[0077] Furthermore, diseases other than cancer in which LAT1 is involved in the pathogenesis, such as autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and allergic diseases such as atopic dermatitis, may also be targets for treatment.

[0078] [Drugs for BNCT] The amino acid derivatives of the present invention contain a boron-containing group, and therefore can be conveniently used for BNCT either as is or mixed with a pharmaceutically acceptable carrier in the form of a formulation known to those skilled in the art, or in the form of being encapsulated in micro / nanoparticles, etc.

[0079] In the amino acid derivatives of the present invention, the group containing boron is, for example, a boronic acid ester or boronic acid amide group, such as -B(NR ７１ ) ２ , or -B(OR ７１ ) ２ or a group having a cyclic structure together with atom B. ７１ represents a linear or branched C1-C10 alkyl group.

[0080] When the compound is used for BNCT, the proportion of boron atoms in the compound is preferably, for example, 75 mass % or more, 80 mass % or more, 90 mass % or more, or 95 mass % or more.

[0081] Prior to the production of the amino acid derivative of the present invention, it is also preferable to concentrate 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. Examples of commercially available products include: １０B Concentrated boric acid (manufactured by Stella Chemifa Co., Ltd.) can be used.

[0082] Treatment using a formulation containing the amino acid derivative of the present invention is carried out by administering it via any suitable route in such a way that the amino acid derivative accumulates in the target tumor. It is preferable that the amino acid derivative be concentrated in the tumor before irradiation, with a tumor:blood ratio of at least 1.5:1, preferably 2:1 or greater, before irradiation. The amino acid derivative can be administered all at once or over a continuous period. In some cases, it can also be administered in divided doses. After the compound has accumulated as desired in the tumor, the tumor is irradiated with an effective amount of low-energy neutrons (e.g., epithermal neutrons). The tumor can be irradiated through the skin, or the tumor can be completely or partially exposed before irradiation. Administration of the amino acid derivative followed by subsequent irradiation can be repeated as necessary. If desired, the amino acid derivative of the present invention can be used as an anticancer agent against residual tumors or metastatic tumors after BNCT treatment.

[0083] [Diagnostic agent containing a radioisotope] The amino acid derivative of the present invention can also be prepared as a drug containing a diagnostic radioisotope. When prepared as a drug containing radioisotope activity, typically, but not limited to, the F atom contained in the compound is １８ The use of F, and the use of I atoms contained in the compound １３１ I, １２３ I or as a C atom contained in the compound １１ C can be used. In addition, technetium ( ９９ mTc), indium ( １１１ In), or gallium ( ６８The compound thus obtained can be used, for example, in RI examinations and nuclear medicine examinations. These include, but are not limited to, agents for scintigraphy tomography, SPECT (Single Photon Emission Computed Tomography), and PET (Positron Emission Tomography). That is, the radioactive amino acid derivative of the present invention is administered to a subject as an agent for PET or SPECT, and images are obtained before treatment to obtain information such as the distribution of accumulated derivatives in the body and the tumor tissue / normal tissue abundance ratio (T / N ratio). Based on this information, it is possible to predict the therapeutic effect of BNCT in advance and formulate a research or treatment plan. The mode of administration and other details are as described in the section [Agent for BNCT]. The diagnostic agent may preferably be a cancer diagnostic agent such as a PET probe or a SPECT probe.

[0084] [Theranostic Drug] The amino acid derivative of the present invention can also be prepared as a theranostic drug. Here, in compound (I) or a pharmaceutically acceptable salt thereof, R ３ is a radioisotope or a group containing a radioisotope, and the radioisotope is iodine ( １２３ I, １２５ I, １３１ I), carbon ( １１ C), yttrium ( ９０ Y), Rin ( ３２ P), radium ( ２２３ Ra), lutetium ( １７７ Lu), or astatine ( ２１１ At).

[0085] (Dosage Form) The amino acid derivative of the present invention can be administered orally or parenterally. In the case of parenteral administration, it can be administered intravenously, intraarterially (e.g., via the carotid artery), intramuscularly, subcutaneously, intramedullary, intrathecally, intraventricularly, intraperitoneally, intrathoracically, intrapelvicly, or intranasally.

[0086] (Preparation) The preparation may be in any form such as powder, granules, fine granules, dry syrup, tablets, capsules, injections, liquids, etc. Depending on the dosage form, the preparation may be mixed with appropriate additives and / or pharmaceutically acceptable carriers by known pharmaceutical techniques and administered to a patient alone or in combination with other drugs. Examples of additives include excipients; disintegrants; binders; lubricants; diluents; buffers such as phosphate, citric acid, succinic acid, acetic acid, and other organic acids or their salts; isotonicity agents; preservatives; wetting agents; emulsifiers; dispersing agents; stabilizers; solubilizers; antioxidants such as ascorbic acid; low molecular weight (fewer than about 10 residues) polypeptides (e.g., polyarginine or tripeptides); proteins (e.g., serum albumin, gelatin, or immunoglobulins); hydrophilic polymers (e.g., polyvinylpyrrolidone); amino acids (e.g., glycine, glutamic acid, aspartic acid, or arginine); monosaccharides, disaccharides, and other carbohydrates (including cellulose or derivatives thereof, glucose, mannose, or dextrin); chelating agents (e.g., EDTA); sugar alcohols (e.g., mannitol or sorbitol); counterions (e.g., sodium); and / or non-ionic surfactants (e.g., polysorbates, poloxamers). These pharmaceutical additives can be mixed or diluted / dissolved to prepare a formulation. A preferred carrier is, but is not limited to, a pharmaceutically inert aqueous carrier. Examples of such carriers include saline, buffered saline, dextrose, and water. In one embodiment of the present invention, the pharmaceutically acceptable carrier is pharmaceutically inert. Suitable additives and / or pharmaceutically acceptable carriers are non-toxic to recipients at the dosages and concentrations used. A particularly preferred formulation is an injectable solution prepared with an aqueous carrier.

[0087] Techniques for formulation and administration are described, for example, in the latest edition of the Japanese Pharmacopoeia and its latest supplement, "REMINGTON'S PHARMACEUTICAL SCIENCES" (Maack Publishing Co., Easton, PA), latest edition.

[0088] The formulations containing the amino acid derivatives of the present invention are pharmaceutical preparations containing the target drug in an amount effective to achieve the intended purpose, and the terms "therapeutically effective amount" or "pharmacologically effective amount" are well recognized by those skilled in the art and refer to the amount of drug effective to produce a pharmacological result. The determination of a therapeutically effective dose is well known to those skilled in the art. The same applies to diagnostic agents.

[0089] A therapeutically effective amount, as used herein, refers to the amount of drug that alleviates a disease state after administration. The therapeutic efficacy and toxicity of such compounds can be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose is preferably selected to achieve an ED with little or no toxicity. ５０ The circulating concentration range includes the range of 0.1 to 1.0 mg / kg of the active ingredient. This dosage varies within this range depending on the dosage form used, the sensitivity of the patient, and the route of administration. For example, the dosage is selected appropriately depending on the age and other conditions of the patient, the type of disease, the type of formulation, etc.

[0090] The present invention includes the following aspects: (1) Use of compound (1) or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for treatment. (2) The use according to (1) above, wherein the pharmaceutical composition for treatment is a pharmaceutical composition for cancer treatment. (3) The use according to (2) above, wherein the cancer is one selected from the group consisting of brain tumors including glioblastoma and malignant glioma, other head and neck cancers, malignant melanoma, skin cancer, breast cancer, lung cancer, uterine cancer, ovarian cancer, kidney cancer, pancreatic cancer, biliary tract cancer, liver cancer, colon cancer, esophageal cancer, stomach cancer, tongue cancer, prostate cancer, osteosarcoma, multiple myeloma, and leukemia. (4) The use according to (1) above, wherein the pharmaceutical composition for treatment is an autoimmune disease such as multiple sclerosis or rheumatoid arthritis, or an allergic disease such as atopic dermatitis. (5) Use of compound (1) or a pharmaceutically acceptable salt thereof for producing a medicament for BNCT. (6) Use of compound (1) or a pharmaceutically acceptable salt thereof for producing a cancer diagnostic agent. (7) Use of compound (1) or a pharmaceutically acceptable salt thereof for producing a theranostics agent. (8) Compound (1) or a pharmaceutically acceptable salt thereof for use in treatment. (9) The compound or a pharmaceutically acceptable salt thereof according to (8) above, wherein the treatment is cancer treatment. (10) The compound or a pharmaceutically acceptable salt thereof according to (9), wherein the cancer is one type selected from the group consisting of brain tumors including glioblastoma and malignant glioma, other head and neck cancers, malignant melanoma, skin cancer, breast cancer, lung cancer, uterine cancer, ovarian cancer, kidney cancer, pancreatic cancer, biliary tract cancer, liver cancer, colon cancer, esophageal cancer, stomach cancer, tongue cancer, prostate cancer, osteosarcoma, multiple myeloma, and leukemia. (11) The compound or pharmaceutically acceptable salt thereof according to (8) above, wherein the treatment is treatment of an autoimmune disease such as multiple sclerosis or rheumatoid arthritis, or an allergic disease such as atopic dermatitis. (12) Compound (1) or a pharmaceutically acceptable salt thereof for use in a drug for BNCT. (13) Compound (1) or a pharmaceutically acceptable salt thereof for use in a cancer diagnostic drug. (14) Compound (1) or a pharmaceutically acceptable salt thereof for use as a theranostic drug.

[0091] The present invention will be further described in detail with reference to the following examples, but the invention is not limited thereto.

[0092] In the following examples, the following instruments and reagents were used for analysis and separation and purification of compounds.

[0093] NMR spectrum: Magritek Spinsolve 60

[0094] As a preliminary step to preparing the example compounds, several intermediates were prepared.

[0095] (Production Example 1) Synthesis of N-Boc-4-nitro-L-phenylalanine tert-butyl ester To N-(diphenylmethylene)glycine t-butyl ester (17.1 g, 57.9 mmol), 4-nitrobenzyl bromide (12.5 g, 57.9 mmol), (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepinium bromide (43.3 mg, 0.0579 mmol), and toluene (116 mL) were added. Potassium hydroxide (16.2 g, 290 mmol) in water (16 mL) was added dropwise so that the temperature did not exceed 0°C, and the mixture was stirred at -5°C for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude product containing tert-butyl (S)-2-((diphenylmethylene)amino)-3-(4-nitrophenyl)propanoate as a yellow liquid. To the crude product containing tert-butyl (S)-2-((diphenylmethylene)amino)-3-(4-nitrophenyl)propanoate was added citric acid (33.4 g, 174 mmol) in tetrahydrofuran / water (2 / 1, 193 mL). After stirring for 4 hours, the tetrahydrofuran was evaporated under reduced pressure. The aqueous phase was washed with diethyl ether and adjusted to pH 8 or higher using sodium hydroxide and potassium carbonate. After extraction with ethyl acetate, the mixture was washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The crude product (7.36 g) containing tert-butyl (S)-2-amino-3-(4-nitrophenyl)propanoate was purified by silica gel chromatography (hexane / ethyl acetate) to give 7.36 g of the crude product containing tert-butyl (S)-2-amino-3-(4-nitrophenyl)propanoate. ２O (6.63 g, 30.4 mmol), and sodium carbonate (3.51 g, 33.1 mmol) were added. After stirring for 1 hour, acetonitrile was evaporated under reduced pressure. After extraction with ethyl acetate, the organic phase was washed with saturated brine. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure. Purification was performed by silica gel chromatography (hexane / ethyl acetate) to obtain N-Boc-4-nitro-L-phenylalanine tert-butyl ester (10.2 g, 27.8 mmol, 48% in 3 steps) as a yellow oil. １ H-NMR (60MHz, CDCl ３ ) δ8.16 (d, J=8.4Hz, 2H), 7.34 (d, J=8.4Hz, 2H), 5.05 (m, 1H), 4.48 (m, 1H), 3.21-3.11 (m, 2H), 1.42 (s, 18H).

[0096] (Preparation Example 2) The following compound was prepared in the same manner: N-Boc-4-iodo-2-chloro-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ7.73-6.90 (m, 3H), 5.04 (m, 1H), 4.49 (m, 1H), 3.18-3.09 (m, 2H), 1.41 (s, 9H), 1.37 (s, 9H).

[0097] (Preparation Example 3) The following compound was prepared in the same manner: N-Boc-4-nitro-3-chloro-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ7.86 (m, 1H), 7.38-7.13 (m, 2H), 5.04 (m, 1H), 4.45 (m, 1H), 3.17-3.08 (m, 2H), 1.44 (s, 18H).

[0098] (Preparation Example 4) The following compound was prepared in the same manner: N-Boc-4-nitro-2-trifluoromethyl-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３) δ8.56-8.24 (m, 2H), 7.65 (m, 1H), 5.15 (m, 1H), 4,50 (m, 1H), 3.63-2.84 (m, 2H), 1.43 (s, 9H), 1.33 (s, 9H).

[0099] (Preparation Example 5) The following compound was prepared in the same manner: N-Boc-4-iodo-2-fluoro-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ7.47-6.77 (m, 3H), 5.03 (m, 1H), 4.46 (m, 1H), 3.07-2.96 (m, 2H), 1.41 (s, 9H), 1.37 (s, 9H).

[0100] Preparation Example 6 The following compound was prepared in the same manner: N-Boc-4-iodo-3-fluoro-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ7.65 (m, 1H), 6.99-6.65 (m, 2H), 5.01 (m, 1H), 4.40 (m, 1H), 3.07-2.97 (m, 2H), 1.42 (s, 18H).

[0101] (Preparation Example 7) The following compound was prepared in the same manner: N-Boc-4-nitro-2-chloro-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ8.28-7.97 (m, 2H), 7.45 (d, J=8.4Hz, 1H), 5.12 (m, 1H), 4.54 (m, 1H), 3.58-2.88 (m, 2H), 1.43 (s, 9H), 1.36 (s, 9H).

[0102] Preparation Example 8 The following compound was prepared in the same manner: N-Boc-4-nitro-2-fluoro-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３) δ8.08-7.27 (m, 3H), 5.13 (m, 1H), 4.47 (m, 1H), 3.48-2.86 (m, 2H), 1.42 (s, 9H), 1.40 (s, 9H).

[0103] (Preparation Example 9) The following compound was prepared in the same manner: N-Boc-4-nitro-2-methyl-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ8.04-7.88 (m, 2H), 7.31 (m, 1H), 5.01 (m, 1H), 4.46 (m, 1H), 3.17-3.00 (m, 2H), 1.40 (s, 9H), 1.37 (s, 9H).

[0104] (Production Example 10) The following compound was similarly prepared: Synthesis of N-Boc-4-amino-2-fluoro-L-phenylalanine tert-butyl ester To a solution of N-Boc-4-nitro-2-fluoro-L-phenylalanine tert-butyl ester (6.15 g, 16 mmol) and methanol (100 mL), 10% palladium-activated carbon (0.62 g) was added, and hydrogenation was carried out under approximately 4 atmospheres for 3 hours. The reaction solution was filtered through a filter aid (Celite), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to obtain N-Boc-4-amino-2-fluoro-L-phenylalanine tert-butyl ester (4.70 g, yield 83%) as a white solid. １ H-NMR (60MHz, CDCl ３ ) δ6.87 (t, J=8.0Hz, 1H), 6.43-6.30 (m, 2H), 4.95 (m, 1H), 4.30 (m, 1H), 3.68 (brs, 2H), 2.95 (d, J=6.3Hz, 2H), 1.41 (s, 18H).

[0105] (Preparation Example 11) The following compound was prepared in the same manner: N-Boc-4-amino-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３) δ7.02-6.85 (m, 2H), 6.80-6.53 (m, 2H), 4.89 (m, 1H), 4.35 (m, 1H), 3.59 (brs, 2H), 2.93 (d, J=5.9Hz, 2H), 1.42 (s, 18H).

[0106] Preparation Example 12 The following compound was prepared in the same manner: N-Boc-4-amino-3-fluoro-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ6.89-6.65 (m, 3H), 4.89 (m, 1H), 4.25 (m, 1H), 3.66 (brs, 2H), 2.97 (d, J=5.9Hz, 2H), 1.43 (s, 18H).

[0107] (Preparation Example 13) N-Boc-4-amino-2-methyl-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ6.94-6.28 (m, 3H), 4.87 (m, 1H), 4.35 (m, 1H), 3.53 (brs, 2H), 2.91 (d, J=6.6Hz, 2H), 2.26 (s, 3H), 1.39 (s, 18H).

[0108] (Preparation Example 14) The following compound was prepared in the same manner: N-Boc-4-amino-2-methoxy-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ6.94-6.81 (m, 1H), 6.12-6.29 (m, 2H), 5.11 (m, 1H), 4.32 (m, 1H), 3.82 (s, 3H), 3.68 (brs, 2H), 2.89 (d, J=6.8Hz, 2H), 1.40 (s, 18H).

[0109] (Preparation Example 15) The following compound was similarly prepared: N-Boc-4-amino-2-trifluoromethyl-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３) δ7.19-6.67 (m, 3H), 4.89 (m, 1H), 4.39 (m, 1H), 3.77 (brs, 2H), 3.08 (d, J = 6.8Hz, 2H), 1.41 (s, 9H), 1.36 (s, 9H).

[0110] (Preparation Example 16) The following compound was prepared in the same manner: Synthesis of N-Boc-4-amino-3-methyl-L-phenylalanine tert-butyl ester To N-(diphenylmethylene)glycine t-butyl ester (5.32 g, 18.0 mmol), 3-methyl-4-nitrobenzyl bromide (4.97 g, 21.6 mmol), (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepinium bromide (16.17 mg, 0.0216 mmol), and toluene (93 mL) were added. A solution of potassium hydroxide (22.22 g, 396 mmol) and water (22 mL) was added dropwise at -5°C or below, and the mixture was stirred at -5°C for 24 hours. Water was added to the reaction solution, and the mixture was extracted with toluene. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain crude tert-butyl (S)-2-((diphenylmethylene)amino)-3-(3-methyl-4-nitrophenyl)propanoate. A solution of citric acid (34.58 g, 180 mmol) and water (103 mL) in tetrahydrofuran (103 mL) was added to the crude tert-butyl (S)-2-((diphenylmethylene)amino)-3-(3-methyl-4-nitrophenyl)propanoate. The mixture was stirred for 4 hours, and then the tetrahydrofuran was distilled off under reduced pressure. The aqueous layer was washed with ethyl acetate, adjusted to pH 8 or higher using potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane / ethyl acetate) to give tert-butyl (S)-2-amino-3-(3-methyl-4-nitrophenyl)propanoate (2.83 g, yield 56%) as a yellow oil.

[0111] To a solution of tert-butyl (S)-2-amino-3-(3-methyl-4-nitrophenyl)propanoate (2.83 g, 10.1 mmol) in acetonitrile (42 mL), a solution of sodium carbonate (2.14 g, 20.19 mmol) and water (22 mL) was added, and di-t-butyl dicarbonate (2.78 mL, 12.11 mmol) was further added, followed by stirring at room temperature overnight. The acetonitrile from the reaction solution was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain N-Boc-3-methyl-4-nitro-L-phenylalanine tert-butyl ester (4.33 g) as a yellow oil (containing di-t-butyl dicarbonate). To a solution of N-Boc-3-methyl-4-nitro-L-phenylalanine tert-butyl ester (4.18 g, 11 mmol) and methanol (42 mL) was added 5% palladium on activated carbon (0.42 g), and hydrogenation was carried out at approximately 3.5 atmospheres for 3 hours. The reaction solution was filtered through a filter aid (Celite), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to obtain N-Boc-4-amino-3-methyl-L-phenylalanine tert-butyl ester (2.45 g, yield 64%) as a light brown solid. １ H-NMR (60MHz, CDCl ３ ) δ6.92-6.30 (m, 3H), 4.86 (m, 1H), 4.35 (m, 1H), 3.53 (brs, 2H), 2.92 (d, J = 5.8Hz, 2H), 2.13 (s, 3H), 1.42 (s, 18H).

[0112] Preparation Example 17 The following compound was prepared in the same manner: N-Boc-4-amino-3-methoxy-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ6.67 (m, 4H), 5.00 (m, 1H), 4.44 (m, 1H), 3.89 (s, 3H), 3.07-2.98 (m, 2H), 1.49 (s, 18H).

[0113] (Preparation Example 18) The following compound was prepared in the same manner: Synthesis of N-Boc-4-amino-3-chloro-L-phenylalanine tert-butyl ester Ethanol / water (4 / 1, 39 mL), ammonium chloride (947 mg, 17.7 mmol), and iron powder (3.29 g, 59.0 mmol) were added to tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-nitrophenyl)propanoate (4.72 g, 11.8 mmol). After stirring at 80°C for 8 hours, the mixture was filtered and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Purification was performed by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl (S)-3-(4-amino-3-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (4.11 g, 11.1 mmol, 94%) as an orange solid. １ H-NMR (60MHz, CDCl ３ ) δ7.06-6.60 (m, 3H), 4.91 (m, 1H), 4.41-3.96 (m, 3H), 2.97-2.87 (m, 2H), 1.43 (s, 18H).

[0114] Preparation Example 19 The following compound was prepared in the same manner: N-Boc-4-amino-2-chloro-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ7.08-6.43 (m, 3H), 4.94 (m, 1H), 4.44 (m, 1H), 3.66 (brs, 2H), 3.06 (d, J=5.3Hz, 2H), 1.42 (s, 18H).

[0115] (Production Example 20) The following compound was similarly prepared: Synthesis of N-Boc-4-hydroxycarbonyl-L-phenylalanine tert-butyl ester A mixture of N-Boc-4-iodo-L-phenylalanine tert-butyl ester (1.57 g, 3.5 mmol), molybdenum hexacarbonyl (0.46 g, 1.74 mmol), palladium acetate (0.08 g, 0.35 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.19 g, 0.35 mmol), 4-dimethylaminopyridine (0.86 g, 7.0 mmol), diisopropylethylamine (1.40 mL, 8.05 mmol), dioxane (3 mL), and water (1.5 mL) was stirred at 110 °C for 1 hour under microwave irradiation. The reaction mixture was adjusted to pH 10 or higher with saturated aqueous sodium carbonate, added to water (100 mL), and washed with diethyl ether (100 mL). The aqueous layer was adjusted to pH 4 with 1 M hydrochloric acid under ice-cooling and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was recrystallized (ethyl acetate / hexane) to give N-Boc-4-hydroxycarbonyl-L-phenylalanine tert-butyl ester (1.13 g, yield 88%) as a pale brown powder. １ H-NMR (60MHz, CDCl ３ ) δ8.02 (d, J=7.9Hz, 2H), 7.28 (d, J=7.9Hz, 2H), 5.09 (d, J=8.1Hz, 1H), 4.47 (m, 1H), 3.13 (d, J=6.1Hz, 2H), 1.43 (s, 9H), 1.41 (s, 9H).

[0116] Preparation Example 21 The following compound was prepared in a similar manner: N-Boc-2-fluoro-4-hydroxycarbonyl-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ7.92-7.07 (m, 3H), 5.20 (d, J=8.1Hz, 1H), 4.47 (m, 1H), 3.16 (d, J=6.3Hz, 2H), 1.42 (s, 18H).

[0117] Preparation Example 22 The following compound was similarly prepared: N-Boc-3-fluoro-4-hydroxycarbonyl-L-phenylalanine tert-butyl ester １H-NMR (60MHz, CDCl ３ ) δ7.94 (t, J=7.9Hz, 1H), 7.11-6.91 (m, 2H), 5.09 (brs, 1H), 4.43 (brs, 1H), 3.11 (d, J=6.0Hz, 2H), 1.44 (s, 9H), 1.43 (s, 9H).

[0118] (Preparation Example 23) The following compound was similarly prepared: N-Boc-2-chloro-4-hydroxycarbonyl-L-phenylalanine tert-butyl ester １ H-NMR (60MHz, CDCl ３ ) δ8.12-7.64 (m, 2H), 7.44-7.28 (m, 1H), 5.65 (brs, 1H), 5.12 (m, 1H), 4.57 (m, 1H), 3.24 (m, 2H), 1.44 (s, 9H), 1.40 (s, 9H).

[0119] (Production Example 24) The following compound was similarly prepared: Synthesis of N-Boc-4-hydroxycarbonyl-L-phenylglycine tert-butyl ester To a solution of 4-hydroxy-L-phenylglycine (11.70 g, 70 mmol), dioxane (70 mL), and 1 M aqueous sodium hydroxide (140 mL, 140 mmol), di-t-butyl dicarbonate (18.33 g, 84 mmol) in dioxane (15 mL) was added dropwise over 15 minutes under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was added to water (150 mL) and washed with diethyl ether (150 mL). The aqueous layer was adjusted to pH 4 with 1 M hydrochloric acid under ice-cooling and extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude N-Boc-4-hydroxycarbonyl-L-phenylglycine.

[0120] To the crude N-Boc-4-hydroxycarbonyl-L-phenylglycine, tert-butanol (200 mL), acetonitrile (34 mL), di-t-butyl dicarbonate (22.92 g, 105 mmol), and 4-dimethylaminopyridine (2.57 g, 21 mmol) were added and stirred at room temperature overnight. The reaction mixture was added to ice water (500 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to obtain N-Boc-4-tert-butyloxycarbonyloxy-L-phenylglycine tert-butyl ester (5.74 g, 19% yield) as a white solid. １ H-NMR (60MHz, CDCl ３ ) δ7.44-7.05 (m, 4H), 5.50 (m, 1H), 5.17 (m, 1H), 1.56 (s, 9H), 1.41 (s, 9H), 1.39 (s, 9H).

[0121] Dichloromethane (57 mL) and piperidine (13.5 mL) were added to N-Boc-4-tert-butyloxycarbonyloxy-L-phenylglycine tert-butyl ester (5.74 g, 13.6 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added to a 4% aqueous potassium hydrogen sulfate solution (200 mL) and extracted with diethyl ether (250 mL). The organic layer was washed with a 4% aqueous potassium hydrogen sulfate solution (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by recrystallization (ethyl acetate / hexane) to give N-Boc-4-hydroxy-L-phenylglycine tert-butyl ester (3.53 g, 80% yield) as a white powder. １ H-NMR (60MHz, CDCl ３ ) δ7.18 (d, J=8.5Hz, 2H), 6.66 (d, J=8.5Hz, 2H), 5.98 (brs, 1H), 5.60 (m, 1H), 5.06 (m, 1H), 1.43 (s, 9H), 1.38 (s, 9H).

[0122] To a solution of N-Boc-4-hydroxy-L-phenylglycine tert-butyl ester (4.2 g, 13 mmol), dichloromethane (60 mL), and pyridine (4.2 mL), a solution of trifluoromethanesulfonic anhydride (2.4 mL, 14.3 mmol) and dichloromethane (3 mL) was added dropwise over 7 minutes under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was added to an aqueous sodium bicarbonate solution (150 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography (ethyl acetate / hexane) to obtain N-Boc-4-trifluoromethylsulfonyloxy-L-phenylglycine tert-butyl ester (5.80 g, yield 98%) as a white solid. １ H-NMR (60MHz, CDCl ３ ) δ7.71-7.13 (m, 4H), 5.60 (m, 1H), 5.20 (m, 1H), 1.41 (s, 9H), 1.38 (s, 9H).

[0123] A mixture of N-Boc-4-trifluoromethylsulfonyloxy-L-phenylglycine tert-butyl ester (1.37 g, 3 mmol), molybdenum hexacarbonyl (0.40 g, 1.5 mmol), palladium acetate (0.07 g, 0.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.19 g, 0.3 mmol), 4-dimethylaminopyridine (0.73 g, 6.0 mmol), diisopropylethylamine (1.20 mL, 6.9 mmol), dioxane (3 mL), and water (1.5 mL) was stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was adjusted to pH 10 or higher with saturated aqueous sodium carbonate, added to water (100 mL), and washed with diethyl ether (100 mL). The aqueous layer was adjusted to pH 4 with 1 M hydrochloric acid under ice-cooling and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was recrystallized (ethyl acetate / hexane) to give N-Boc-4-hydroxycarbonyl-L-phenylglycine tert-butyl ester (0.83 g, yield 79%) as a pale brown powder. １H-NMR (60MHz, CDCl ３ ) δ8.10 (d, J=8.1Hz, 2H), 7.40 (d, J=8.1Hz, 2H), 5.73 (m, 1H), 5.25 (m, 1H), 1.42 (s, 9H), 1.38 (s, 9H).

[0124] Next, the compounds of the Examples were prepared using the intermediates of the Preparation Examples or compounds prepared in a similar manner.

[0125] (Example 1) Synthesis of 4-(4-borono-2-fluorobenzamido)-L-phenylalanine hydrochloride (Compound 75) A mixture of N-Boc-4-amino-L-phenylalanine tert-butyl ester (0.36 g, 0.9 mmol), 4-borono-2-fluorobenzoic acid (0.18 g, 0.99 mmol), HATU (0.41 g, 1.1 mmol), 4-dimethylaminopyridine (0.02 g, 0.2 mmol), diisopropylethylamine (0.19 mL, 1.1 mmol), and dimethylacetamide (3 mL) was stirred at room temperature for 6 hours. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give N-Boc-4-(4-borono-2-fluorobenzamido)-L-phenylalanine tert-butyl ester (0.42 g, 93% yield) as a white amorphous solid. １ H-NMR (60MHz, Acetone-d ６ ) δ9.34 (brs, 1H), 7.19-8.01 (m, 7H), 5.97 (d, J=8.4Hz, 1H), 4.00-4.33 (m, 1H), 2.98-3.09 (m, 2H), 1.44 (s, 9H), 1.37 (s, 9H). A 4M solution of hydrochloric acid in ethyl acetate (6 mL) was added to N-Boc-4-(4-borono-2-fluorobenzamido)-L-phenylalanine tert-butyl ester (0.41 g, 0.8 mmol), and the mixture was stirred at 50°C for 1.5 hours. Ethyl acetate (6 mL) was added to the reaction mixture, and the mixture was stirred under ice cooling, and the powder was collected by filtration. The obtained powder was dried under reduced pressure at 50°C to obtain 4-(4-borono-2-fluorobenzamido)-L-phenylalanine hydrochloride (0.29 g, yield 95%) as a white powder. １ H-NMR (60MHz, CD ３ OD) δ7.23-7.83 (7H, m), 4.16-4.37 (1H, m).

[0126] (Example 2) Synthesis of 4-(3-borono-6-trifluoromethoxybenzamido)-2-methoxy-L-phenylalanine hydrochloride (Compound 177) A mixture of N-Boc-4-amino-2-methoxy-L-phenylalanine tert-butyl ester (0.49 g, 1.2 mmol), 3-bromo-6-trifluoromethoxybenzoic acid (0.41 g, 1.44 mmol), HATU (0.59 g, 1.56 mmol), 4-dimethylaminopyridine (0.03 g, 0.24 mmol), diisopropylethylamine (0.27 mL, 1.56 mmol), and dimethylacetamide (3 mL) was stirred at room temperature overnight. The reaction mixture was added to water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give N-Boc-4-(3-bromo-6-trifluoromethoxybenzamido)-2-methoxy-L-phenylalanine tert-butyl ester (0.73 g, yield 96%) as a pale yellow solid. １ H-NMR (60MHz, CDCl ３ ) δ8.17 (d, J=2.4Hz, 2H), 7.87-7.52 (m, 2H), 7.26-6.76 (m, 3H), 5.06 (m, 1H ), 4.47 (m, 1H), 3.89 (s, 3H), 2.95 (d, J=6.5Hz), 1.40 (s, 9H), 1.39 (s, 9H).

[0127] A mixture of N-Boc-4-(3-bromo-6-trifluoromethoxybenzamido)-2-methoxy-L-phenylalanine tert-butyl ester (0.73 g, 1.15 mmol), bis(pinacolato)diboron (0.41 g, 1.61 mmol), potassium acetate (0.2 g, 2.0 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.08 g, 0.11 mmol), and DMSO (3 mL) was purged with nitrogen and then stirred for 8 hours at 110° C. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain crude N-Boc-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-trifluoromethoxybenzamido)-2-methoxy-L-phenylalanine tert-butyl ester.

[0128] Acetone (30 mL), water (15 mL), ammonium acetate (0.31 g, 4 mmol), and sodium periodate (0.86, 4 mmol) were added to the crude N-Boc-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-trifluoromethoxybenzamido)-2-methoxy-L-phenylalanine tert-butyl ester, and the mixture was stirred at room temperature overnight. The reaction solution was added to ethyl acetate, and insoluble matter was removed, followed by washing with water. The organic layer was washed with aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give N-Boc-4-(3-borono-6-trifluoromethoxybenzamido)-2-methoxy-L-phenylalanine tert-butyl ester (0.47 g, yield 68%) as a pale yellow amorphous product. １ H-NMR (60MHz, Acetone-d ６) δ9.50 (brs, 1H), 8.18-8.01 (m, 2H), 7.58-7.19 (m, 6H), 5.97 (d, J = 8.4Hz, 1H) , 4.33-4.03 (m, 1H), 3.88 (s, 3H), 3.04-2.97 (m, 2H), 1.40 (s, 9H), 1.37 (s, 9H).

[0129] A 4M solution of hydrochloric acid in ethyl acetate (4 mL) was added to N-Boc-4-(3-borono-6-trifluoromethoxybenzamido)-2-methoxy-L-phenylalanine tert-butyl ester (0.47 g, 0.79 mmol), and the mixture was stirred at 50°C for 2 hours. Ethyl acetate (3 mL) was added to the reaction mixture, and the mixture was stirred under ice cooling, and the powder was collected by filtration. The obtained powder was dried under reduced pressure at 50°C to give 4-(3-borono-6-trifluoromethoxybenzamido)-2-methoxy-L-phenylalanine hydrochloride (0.28 g, yield 74%) as a pale yellow powder. １ H-NMR (60MHz, CD ３ OD) δ7.69-8.14 (m, 2H), 7.17-7.61 (m, 4H), 4.04-4.34 (m, 1H), 3.90 (s, 3H).

[0130] Example 3 Synthesis of (S)-2-amino-3-(5-(3-boronobenzamido)pyridin-2-yl)propanoic acid hydrochloride (Compound 207) Under a nitrogen stream, zinc (2.58 g, 39.5 mmol) and N,N-dimethylformamide (8.8 mL) were mixed with trimethylsilyl chloride (167 μL, 1.32 mmol) and heated using a heat gun. After cooling, tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (2.94 g, 7.91 mmol) was added. After stirring at 40°C for 5 minutes, 6-bromopyridin-3-amine (1.14 g, 6.59 mmol), tris(dibenzylideneacetone)dipalladium(0) (151 mg, 0.165 mmol), and SPhos (135 mg, 0.330 mmol) were added. After stirring at 40°C for 8 hours, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give a crude product (1.61 g) containing tert-butyl (S)-3-(5-aminopyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate as an orange oil.

[0131] To the crude product (1.61 g) containing tert-butyl (S)-3-(5-aminopyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (947 mg, 3.82 mmol), 4-dimethylaminopyridine (93.3 mg, 0.764 mmol), and N,N-dimethylformamide (3.8 mL) were added N,N-diisopropylethylamine (592 mg, 4.58 mmol) and HATU (1.74 g, 4.58 mmol). After stirring at 40°C for 17 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate) gave a crude product (1.51 g) containing tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)pyridin-2-yl)propanoate as a yellow amorphous solid. To the crude product (1.51 g) containing tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)pyridin-2-yl)propanoate was added acetone / water (2 / 1, 27 mL), sodium periodate (2.28 g, 10.6 mmol), and ammonium acetate (817 mg, 10.6 mmol). After stirring for 18 hours, the mixture was filtered and concentrated under reduced pressure. After extraction with ethyl acetate, the organic phase was washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (S)-(3-((6-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)pyridin-3-yl)carbamoyl)phenyl)boronic acid (664 mg, 1.37 mmol, 21% in 3 steps) as a white solid. LC / MS [M+H] ＋ 486

[0132] A 4 M hydrochloric acid / ethyl acetate solution (1.4 mL, 5.60 mmol) was added to (S)-(3-((6-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)pyridin-3-yl)carbamoyl)phenyl)boronic acid (272 mg, 0.560 mmol). The mixture was stirred at 50° C. for 7 hours and then filtered. The resulting mixture was washed with ethyl acetate and dried under reduced pressure at 45° C. to obtain (S)-2-amino-3-(5-(3-boronobenzamido)pyridin-2-yl)propanoic acid hydrochloride (215 mg, 0.535 mmol, 95%) as a white solid. １ H-NMR (60MHz, D ２ O) δ9.23 (m, 1H), 8.60-7.46 (m, 6H), 4.31 (m, 1H), 3.65-3.54 (m, 2H).

[0133] (Example 4) 4-(4-borono-3-fluorophenyl)carbamoyl-3-fluoro-L-phenylalanine hydrochloride (Compound 28) A mixture of N-Boc-3-fluoro-4-hydroxycarbonyl-L-phenylalanine tert-butyl ester (0.31 g, 0.8 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.23 g, 0.96 mmol), HATU (0.40 g, 1.04 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), diisopropylethylamine (0.18 mL, 1.04 mmol), and dimethylacetamide (3 mL) was stirred overnight at 50° C. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain crude N-Boc-3-fluoro-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenyl)carbamoyl-L-phenylalanine tert-butyl ester.

[0134] Acetone (30 mL), water (15 mL), ammonium acetate (0.31 g, 4 mmol), and sodium periodate (0.86 g, 4 mmol) were added to the crude N-Boc-3-fluoro-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenyl)carbamoyl-L-phenylalanine tert-butyl ester, and the mixture was stirred at room temperature overnight. The reaction solution was added to ethyl acetate, and insoluble matter was removed, followed by washing with water. The organic layer was washed with aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was recrystallized (ethyl acetate / hexane) to give N-Boc-3-fluoro-4-(4-borono-3-fluorophenyl)carbamoyl-L-phenylalanine tert-butyl ester (0.23 g, yield 55%) as a pale brown powder. １ H-NMR (60MHz, Acetone-d ６ ) δ9.57 (brs, 1H), 7.07-7.99 (m, 6H), 6.11 (m, 1H), 4.27 (m, 1H), 3.30-3.00 (m, 2H), 1.46 (s, 9H), 1.39 (s, 9H). A 4M solution of hydrochloric acid in ethyl acetate (2.2 mL) was added to N-Boc-3-fluoro-4-(4-borono-3-fluorophenyl)carbamoyl-L-phenylalanine tert-butyl ester (0.47 g, 0.79 mmol), and the mixture was stirred at 50°C for 2 hours. Ethyl acetate (3 mL) was added to the reaction mixture, and the mixture was stirred under ice cooling, and the powder was collected by filtration. The obtained powder was dried under reduced pressure at 50°C to give 4-(4-borono-3-fluorophenyl)carbamoyl-3-fluoro-L-phenylalanine hydrochloride (0.16 g, yield 91%) as a pale brown powder. １ H-NMR (60MHz, CD ３ OD) δ8.00-7.17 (m, 6H), 4.36 (t, J=6.7Hz, 1H).

[0135] (Example 5) 4-(3-borono-6-fluorophenyl)carbamoyl-L-phenylalanine trifluoroacetate (Compound 15) A mixture of N-Boc-4-hydroxycarbonyl-L-phenylalanine tert-butyl ester (0.22 g, 0.6 mmol), 3-borono-6-fluoroaniline (0.11 g, 0.72 mmol), HATU (0.30 g, 0.78 mmol), 4-dimethylaminopyridine (0.015 g, 0.12 mmol), diisopropylethylamine (0.14 mL, 0.78 mmol), and dimethylacetamide (2 mL) was stirred overnight at 50° C. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to obtain N-Boc-4-(3-borono-6-fluorophenyl)carbamoyl-L-phenylalanine tert-butyl ester (0.27 g, yield 90%) as a white amorphous substance. １ H-NMR (60MHz, Acetone-d ６ ) δ9.15 (brs, 1H), 8.64-7.87 (m, 3H), 7.65-7.03 (m, 4H), 6.08 (d, J=8.4Hz, 1H), 4.13 (m, 1H), 3.05-3.20 (m, 2H), 1.44 (s, 9H), 1.38 (s, 9H).

[0136] Trifluoroacetic acid (2.1 mL) was added to N-Boc-4-(3-borono-6-fluorophenyl)carbamoyl-L-phenylalanine tert-butyl ester (0.27 g, 0.54 mmol), and the mixture was stirred at room temperature for 3 hours. Toluene (5 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was triturated with dichloromethane and THF, and the powder was collected by filtration. The obtained powder was dried at 50°C under reduced pressure to obtain the trifluoroacetate salt of 4-(3-borono-6-fluorophenyl)carbamoyl-L-phenylalanine (0.21 g, yield 85%) as a pale brown powder. １ H-NMR (60MHz, CD ３ OD) δ8.20-7.78 (m, 3H), 7.52-7.03 (m, 4H), 4.37-4.15 (m, 1H), 3.15-2.95 (m, 2H).

[0137] Example 6 Synthesis of (S)-2-amino-3-(4-((3-boronophenyl)carbamoyl)thiophen-2-yl)propanoic acid trifluoroacetate (Compound 53) To a mixture of 5-bromothiophene-3-carboxylic acid (508 mg, 2.45 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (537 mg, 2.45 mmol), 4-dimethylaminopyridine (59.9 mg, 0.490 mmol), and N,N-dimethylacetamide (2.5 mL), N,N-diisopropylethylamine (380 mg, 2.94 mmol) and HATU (1.12 g, 2.94 mmol) were added. The mixture was stirred at 40°C for 20 hours, and then purified by silica gel column chromatography (hexane / ethyl acetate) to give 5-bromo-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiophene-3-carboxamide (904 mg, 2.22 mmol, 90%) as a white solid. １ H-NMR (60MHz, CDCl ３ ) δ8.03-7.25 (m, 6H), 1.34 (s, 12H).

[0138] Under a nitrogen stream, trimethylsilyl chloride (28 μL, 0.222 mmol) and 1,2-dibromoethane (19 μL, 0.222 mmol) were added to zinc (218 mg, 3.33 mmol) and N,N-dimethylformamide (2.2 mL), and the mixture was heated using a heat gun. After cooling, tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (989 mg, 2.66 mmol) was added. After stirring for 10 minutes, 5-bromo-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiophene-3-carboxamide (904 mg, 2.22 mmol), tris(dibenzylideneacetone)dipalladium(0) (50.8 mg, 0.0555 mmol), and SPhos (45.6 mg, 0.111 mmol) were added. After stirring at 40°C for 17 hours, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give a crude product (287 mg) containing tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)thiophen-2-yl)propanoate as a brown oil.

[0139] Acetone / water (2 / 1, 5.0 mL), sodium periodate (536 mg, 2.51 mmol), and ammonium acetate (193 mg, 2.51 mmol) were added to the crude product (287 mg) containing tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)thiophen-2-yl)propanoate. After stirring for 17 hours, the mixture was filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate) gave (S)-(3-(5-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)thiophene-3-carboxamido)phenyl)boronic acid (168 mg, 0.343 mmol, 15% in 2 steps) as a white solid. １ H-NMR (60MHz, acetone-d ６): δ8.34-7.20 (m, 6H), 6.16 (m, 1H), 4.32 (m, 1H), 3.38-3.25 (m, 2H), 1.45 (s, 9H), 1.41 (s, 9H).

[0140] Trifluoroacetic acid (744 mg, 6.53 mmol) was added to (S)-(3-(5-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)thiophene-3-carboxamido)phenyl)boronic acid (160 mg, 0.326 mmol). After 17 hours, the mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure. The mixture was washed with dichloromethane and dried under reduced pressure at 45°C to obtain trifluoroacetate of (S)-2-amino-3-(4-((3-boronophenyl)carbamoyl)thiophen-2-yl)propanoic acid (146 mg, 0.326 mmol, 100%) as a pale yellow solid. １ H-NMR (60MHz, CD ３ OD): δ8.18-7.31 (m, 6H), 4.28 (m, 1H), 3.56-3.46 (m, 2H).

[0141] (Example 7) Synthesis of 4-(4-boronobenzoyl)-L-phenylalanine trifluoroacetate (Compound 56) To a solution of N-Boc-4-iodo-L-phenylalanine tert-butyl ester (1.0 g, 2.2 mmol) in THF (10 mL), a 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in THF (3.7 mL, 4.84 mmol) was added dropwise at −15° C. or below over 5 minutes, and the mixture was stirred at −20° C. for 1 hour. To the reaction solution, a solution of 4-bromo-N-methoxy-N-methylbenzamide (0.54 g, 2.2 mmol) in THF (5 mL) was added dropwise at −15° C. or below over 5 minutes, and the mixture was stirred from −20° C. to room temperature over 1 hour, and then further stirred at room temperature for 2 hours. To the reaction solution, saturated aqueous ammonium chloride (30 mL) was slowly added under ice-cooling, followed by addition of brine (150 mL) and extraction with ethyl acetate (150 mL). The organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give N-Boc-4-(4-bromobenzoyl)-L-phenylalanine tert-butyl ester (0.20 g, yield 18%) as a colorless oil. １ H-NMR (60MHz, CDCl ３ ) δ7.96-7.07 (m, 8H), 4.99 (m, 1H), 4.48 (m, 1H), 3.14 (d, J=6.0Hz, 2H), 1.46 (s, 9H), 1.43 (s, 9H).

[0142] A mixture of N-Boc-4-(4-borominobenzoyl)-L-phenylalanine tert-butyl ester (0.20 g, 0.4 mmol), bis(pinacolato)diboron (0.12 g, 0.48 mmol), potassium acetate (0.06 g, 0.6 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.014 g, 0.02 mmol), and DMSO (2 mL) was purged with nitrogen and then stirred for 8 hours at 100° C. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give N-Boc-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-L-phenylalanine tert-butyl ester (0.20 g, yield 91%) as a light brown amorphous substance. １ H-NMR (60MHz, CDCl ３ ) δ7.99-7.65 (m, 6H), 7.35-7.26 (m, 2H), 5.03 (m, 1H), 4.50 (m, 1H), 3.13 (d, J = 6.1Hz, 2H), 1.46-1.37 (m, 20H).

[0143] Acetone (8 mL), water (4 mL), ammonium acetate (0.11 g, 1.4 mmol), and sodium periodate (0.31 g, 1.4 mmol) were added to N-Boc-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-L-phenylalanine tert-butyl ester (0.20 g, 0.36 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was added to water (150 mL), and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain N-Boc-4-(4-boronobenzoyl)-L-phenylalanine tert-butyl ester (0.14 g, yield 84%) as a colorless amorphous substance.

[0144] Trifluoroacetic acid (0.92 mL) was added to N-Boc-4-(4-boronobenzoyl)-L-phenylalanine tert-butyl ester (0.14 g, 0.3 mmol), and the mixture was stirred at room temperature for 3 hours. Toluene (4 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was triturated with dichloromethane and THF, and the powder was collected by filtration. The obtained powder was dried at 50°C under reduced pressure to obtain the trifluoroacetate salt of 4-(4-boronobenzoyl)-L-phenylalanine (0.06 g, yield 47%) as a pale brown powder. １ H-NMR (60MHz, DMSO-d ６ +D ２ O) δ8.00-6.85 (m, 8H), 4.13 (m, 1H), 3.27-3.17 (m, 2H).

[0145] (Example 8) Synthesis of 4-(4-borono-α-hydroxybenzyl)-L-phenylalanine trifluoroacetate (Compound 59) To a solution of N-Boc-4-iodo-L-phenylalanine tert-butyl ester (1.0 g, 2.2 mmol) in THF (10 mL), a 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in THF (3.7 mL, 4.84 mmol) was added dropwise at −15° C. or below over 5 minutes, and the mixture was stirred at −20° C. for 1 hour. To the reaction solution, a solution of 4-bromobenzaldehyde (0.50 g, 2.64 mmol) in THF (4 mL) was added dropwise at −15° C. or below over 5 minutes, and the mixture was stirred from −20° C. to room temperature over 1 hour. A saturated aqueous solution of ammonium chloride (30 mL) was slowly added to the reaction solution under ice-cooling, and then the mixture was added to brine (150 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give N-Boc-4-(4-bromo-α-hydroxybenzyl)-L-phenylalanine tert-butyl ester (0.66 g, yield 59%) as a white amorphous product. １ H-NMR (60MHz, CDCl ３) δ6.79-7.53 (m, 8H), 5.77 (brs, 1H), 4.93 (M, 1H), 4.37 (m, 1H), 3.01 (d, J=6.1Hz, 2H), 1.40 (s, 9H), 1.37 (s, 9H).

[0146] A mixture of N-Boc-4-(4-bromo-α-hydroxybenzyl)-L-phenylalanine tert-butyl ester (0.66 g, 1.3 mmol), bis(pinacolato)diboron (0.40 g, 1.56 mmol), potassium acetate (0.19 g, 1.95 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(III) (0.05 g, 0.065 mmol), and DMSO (5 mL) was purged with nitrogen and then stirred for 8 hours at 95° C. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give N-Boc-4-(α-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-L-phenylalanine tert-butyl ester (0.55 g, yield 76%) as a white amorphous substance. １ H-NMR (60MHz, CDCl ３ ) δ7.80-7.03 (m, 8H), 5.81 (brs, 1H), 4.95 (d, J = 8.3Hz, 1H), 4.40 (m, 1H), 3.01 (d, J = 6.0Hz, 2H), 1.40-1.23 (m, 30H).

[0147] Acetone (20 mL), water (10 mL), ammonium acetate (0.23 g, 3 mmol) and sodium periodate (0.64 g, 3 mmol) were added to N-Boc-4-(α-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-L-phenylalanine tert-butyl ester (0.55 g, 1 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was added to water (150 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give N-Boc-4-(4-borono-α-hydroxybenzyl N-Boc-4-(4-borono-α-hydroxybenzyl)-L-phenylalanine tert-butyl ester (0.47 g, 99% yield) was obtained as a colorless amorphous substance. Trifluoroacetic acid (2.3 mL) was added to N-Boc-4-(4-borono-α-hydroxybenzyl)-L-phenylalanine tert-butyl ester (0.47 g, 1 mmol), and the mixture was stirred at room temperature for 3 hours. Toluene (5 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was triturated with acetone, and the powder was collected by filtration. The obtained powder was dried at 50°C under reduced pressure to obtain 4-(4-borono-α-hydroxybenzyl)-L-phenylalanine trifluoroacetate (0.13 g, 30% yield) as a pale brown powder. １ H-NMR (60MHz, D ２ O) δ8.00-6.80 (m, 8H), 4.29 (brs, 1H), 3.31 (brs, 2H).

[0148] (Example 9) Synthesis of 4-(4-boronophenyl)ureido-L-phenylalanine trifluoroacetate (Compound 217) Diphenylphosphoryl azide (0.19 mL, 0.88 mmol) was added to a mixture of N-Boc-4-hydroxycarbonyl-L-phenylalanine tert-butyl ester (0.29 g, 0.8 mmol), triethylamine (0.17 mL, 1.2 mmol), and 1,2-dimethoxyethane (4 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was then stirred at 80°C for 2 hours. 4-Bromoaniline (0.15 g, 0.88 mmol) was added to the reaction mixture, and the mixture was then stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate / hexane) to give N-Boc-4-(4-bromophenyl)ureido-L-phenylalanine tert-butyl ester (0.27 g, 90% yield) as a light brown solid. １ H-NMR (60MHz, CDCl ３ ) δ7.61-6.95 (m, 8H), 5.00 (m, 1H), 4.30 (m, 1H), 2.94 (d, J = 8.1Hz, 2H, 1.47 (s, 9H), 1.42 (s, 9H).

[0149] A mixture of N-Boc-4-(4-bromophenyl)ureido-L-phenylalanine tert-butyl ester (0.30 g, 0.6 mmol), bis(pinacolato)diboron (0.18 g, 0.72 mmol), potassium acetate (0.09 g, 0.9 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.02 g, 0.03 mmol), and DMSO (3 mL) was purged with nitrogen and then stirred for 8 hours at 100° C. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give N-Boc-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido-L-phenylalanine tert-butyl ester (0.29 g, yield 83%) as a light brown amorphous product. Acetone (10 mL), water (5 mL), ammonium acetate (0.19 g, 2.5 mmol), and sodium periodate (0.53 g, 2.5 mmol) were added to N-Boc-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido-L-phenylalanine tert-butyl ester (0.29 g, 0.5 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was added to water (150 mL), and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / hexane) to obtain N-Boc-4-(4-boronophenyl)ureido-L-phenylalanine tert-butyl ester (0.04 g, yield 16%) as a light brown amorphous product. １ H-NMR (60MHz, Acetone-d ６ ) δ8.38-7.09 (m, 8H), 5.94 (d, 8.2Hz, 1H), 4.25 (m, 1H), 3.04-2.93 (m, 2H), 1.43 (s, 9H), 1.39 (s, 9H).

[0150] Trifluoroacetic acid (1 mL) was added to N-Boc-4-(4-boronophenyl)ureido-L-phenylalanine tert-butyl ester (0.04 g, 0.08 mmol), and the mixture was stirred at room temperature for 3 hours. Toluene (3 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was triturated with dichloromethane and THF, and the powder was collected by filtration. The obtained powder was dried at 50°C under reduced pressure to give 4-(4-boronophenyl)ureido-L-phenylalanine trifluoroacetic acid (0.028 g, yield 77%) as a pale brown powder. １ H-NMR (60MHz, DMSO-d ６ +D ２ O) δ7.80-7.10 (m, 8H), 4.18 (m, 1H), 3.27-3.17 (m, 2H).

[0151] (Example 10) Synthesis of 4-(4-boronophenyl)sulfonamido-L-phenylalanine trifluoroacetate (Compound 71) Dichloromethane (2.0 mL), pyridine (174 mg, 2.20 mmol), and 4-bromobenzenesulfonyl chloride (281 mg, 1.10 mmol) were added to ethyl (S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (308.4 mg, 1.00 mmol). After stirring for 22 hours, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give a crude product (597 mg) containing ethyl (S)-3-(4-((4-bromophenyl)sulfonamido)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as a colorless amorphous substance. Under a nitrogen atmosphere, bis(pinacolato)diboron (305 mg, 1.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (40.8 mg, 0.05 mmol), potassium acetate (196 mg, 2.00 mmol), and dimethyl sulfoxide (2.0 mL) were added to the crude product (597 mg) containing ethyl (S)-3-(4-((4-bromophenyl)sulfonamido)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate. After stirring at 100°C for 8 hours, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give a crude product (520 mg) containing ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonamido)phenyl)propanoate as a yellow oil.

[0152] Acetone / water (2 / 1, 10 mL), sodium periodate (856 mg, 4.00 mmol), and ammonium acetate (308 mg, 4.00 mmol) were added to the crude product (520 mg) containing ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonamido)phenyl)propanoate. After stirring for 17 hours, the mixture was filtered and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (hexane / ethyl acetate) to obtain (S)-(4-(N-(4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)phenyl)sulfamoyl)phenyl)boronic acid (249 mg, 0.506 mmol, 51% in 3 steps) as a white solid. １ H-NMR (60MHz, acetone-d ６ ) δ7.97 (d, J=8.4Hz, 2H), 7.74 (d, J=8.4Hz, 2H), 7.14 (s, 4H), 4.36-3.90 (m, 4H), 1.34 (s, 9H), 1.14 (t, J=7.2Hz, 3H).

[0153] To a solution of (S)-(4-(N-(4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)phenyl)sulfamoyl)phenyl)boronic acid (249 mg, 0.506 mmol) in tetrahydrofuran (1.0 mL) was added 1 M aqueous sodium hydroxide solution (2.5 mL, 2.5 mmol) at 0° C. After stirring for 1 hour, citric acid was added to adjust the pH to 3. After extraction with ethyl acetate, the organic phase was washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product (223 mg) containing (S)-3-(4-((4-boronophenyl)sulfonamido)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid as a white solid. Trifluoroacetic acid (1.15 g, 10.1 mmol) was added to the crude product (223 mg) containing (S)-3-(4-((4-boronophenyl)sulfonamido)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid. After 3 days, the mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure. The mixture was washed with dichloromethane and dried under reduced pressure at 45°C to obtain the TFA salt of 4-(4-boronophenyl)sulfonamido-L-phenylalanine (194 mg, 0.406 mmol, 80%) as a brown solid. １ H-NMR (60MHz, D ２ O) δ7.95-7.57 (m, 4H), 7.28-6.84 (m, 4H), 4.24 (m, 1H), 3.25-2.94 (m, 2H).

[0154] (Example 11) Synthesis of 3-(3'-borono-[1,1'-biphenyl]-3-yl)-L-phenylalanine trifluoroacetate (Compound 224) To (S)-2-((tert-butoxycarbonyl)amino)-3-(3-iodophenyl)propanoic acid (780 mg, 1.9 mmol), (3-bromophenyl)boronic acid (440 mg, 2.19 mmol), potassium carbonate (1.10 g, 7.96 mmol), tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.0995 mmol), and toluene / ethanol / water (8 / 1 / 1, 20 mL) were added. The mixture was stirred under reflux for 8 hours. Citric acid was added to adjust the pH to 3, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude product (820 mg) containing (S)-3-(3'-bromo-[1,1'-biphenyl]-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid as a brown oil.

[0155] Dichloromethane (10 mL), ethanol (367 mg, 7.96 mmol), 4-dimethylaminopyridine (267 mg, 2.19 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (420 mg, 2.19 mmol) were added to the crude product (820 mg) containing (S)-3-(3'-bromo-[1,1'-biphenyl]-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid. After stirring for 17 hours, the mixture was concentrated under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate) gave ethyl (S)-3-(3'-bromo-[1,1'-biphenyl]-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (499 mg, 1.11 mmol, 56% in 2 steps) as a pale yellow oil. １ H-NMR (60MHz, CDCl ３ ) δ7.71-7.26 (m, 8H), 5.10-3.95 (m, 4H), 3.19-3.10 (m, 2H), 1.41-1.11 (m, 12H).

[0156] To ethyl (S)-3-(3'-bromo-[1,1'-biphenyl]-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate, bis(pinacolato)diboron (338 mg, 1.33 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (45.2 mg, 0.0555 mmol), potassium acetate (218 mg, 2.22 mmol), and dimethyl sulfoxide (2.2 mL) were added. After stirring at 100°C for 8 hours, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give a crude product (459 mg) containing ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)propanoate as a colorless oil.

[0157] Acetone / water (2 / 1, 9.3 mL), sodium periodate (792 mg, 3.70 mmol), and ammonium acetate (285 mg, 3.70 mmol) were added to the crude product (459 mg) containing ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)propanoate. After stirring for 19 hours, the mixture was filtered and concentrated under reduced pressure. After extraction with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate) gave (S)-(3'-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)-[1,1'-biphenyl]-3yl)boronic acid (331 mg, 0.801 mmol, 72% in 3 steps) as a colorless oil. １ H-NMR (60MHz, acetone-d ６ ) δ8.19-7.29 (m, 8H), 4.50-3.88 (m, 4H), 3.20-3.06 (m, 2H), 1.33-1.08 (m, 12H).

[0158] To a solution of (S)-(3'-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)-[1,1'-biphenyl]-3yl)boronic acid (331 mg, 0.801 mmol) in tetrahydrofuran (1.6 mL) was added 1 M aqueous sodium hydroxide solution (3.2 mL, 3.2 mmol) at 0°C. After stirring for 2 hours, citric acid was added to adjust the pH to 3. After extraction with ethyl acetate, the organic phase was washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product (317 mg) containing (S)-3-(3'-borono-[1,1'-biphenyl]-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid as a colorless amorphous solid. Trifluoroacetic acid (1.83 g, 16.0 mmol) was added to the crude product (317 mg) containing (S)-3-(3'-borono-[1,1'-biphenyl]-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid. After 23 hours, the mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure. The resulting mixture was washed with dichloromethane and dried under reduced pressure at 45°C to obtain the TFA salt of 3-(3'-borono-[1,1'-biphenyl]-3-yl)-L-phenylalanine (287 mg, 0.719 mmol, 90% in 2 steps) as a white solid. １ H-NMR (60MHz, D ２ O) δ7.82-7.26 (m, 8H), 4.24 (m, 1H), 3.25-3.12 (m, 2H).

[0159] (Example 12) Synthesis of 4-(4-boronobenzyl)oxy)-L-phenylalanine trifluoroacetate (Compound 61) To N-Boc-L-tyrosine ethyl ester (309.4 mg, 1.00 mmol) were added 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (312 mg, 1.05 mmol), acetonitrile (2.0 mL), and cesium carbonate (358 mg, 1.10 mmol). After stirring for 22 hours, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Purification was performed by silica gel column chromatography (hexane / ethyl acetate) to obtain a crude product (492 mg) containing ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)propanoate as a colorless oil. Acetone / water (2 / 1, 9.4 mL), sodium periodate (801 mg, 3.74 mmol), and ammonium acetate (288 mg, 3.74 mmol) were added to the crude product (492 mg) containing ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)propanoate. After stirring for 2 days, the mixture was filtered and concentrated under reduced pressure. After extraction with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate) gave (S)-(4-((4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)phenoxy)methyl)phenyl)boronic acid (388 mg, 0.875 mmol, 88% in 2 steps) as a colorless amorphous substance. １ H-NMR (60MHz, CDCl ３ ) δ8.25 (d, J=7.2Hz, 2H), 7.56 (d, J=7.2Hz, 2H), 7.16-6.81 (m, 4H), 5.15-4 .65 (m, 4H), 4.17 (q, J=7.2Hz, 2H), 3.07-2.97 (m, 2H), 1.55-1.12 (m, 12H).

[0160] Tetrahydrofuran (1.8 mL) was added to (S)-(4-((4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)phenoxy)methyl)phenyl)boronic acid (388 mg, 0.875 mmol), and 1 M aqueous sodium hydroxide solution (2.6 mL, 2.6 mmol) was added at 0°C. After stirring for 45 minutes, citric acid was added to adjust the pH to 3. After extraction with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude product (465 mg) containing (S)-3-(4-((4-boronobenzyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid as a colorless amorphous substance. Trifluoroacetic acid (2.00 g, 17.5 mmol) was added to the crude product containing (S)-3-(4-((4-boronobenzyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid. After 2 days, the mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure. The mixture was washed with dichloromethane and dried under reduced pressure at 45°C to obtain 4-(4-boronobenzyl)oxy)-L-phenylalanine (423 mg, quant.) as a pale yellow solid. １ H-NMR (60MHz, D ２ O): δ7.89-6.69 (m, 8H), 5.38 (m, 2H), 4.09 (m, 1H), 3.15-2.82 (m, 2H).

[0161] (Example 13) 4-((-boronophenyl)ethynyl)-L-phenylalanine trifluoroacetate (Compound 219) Copper iodide (19.0 mg, 0.100 mmol) was added to tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)propanoate (447 mg, 1.00 mmol), (3-ethynylphenyl)boronic acid (146 mg, 1.00 mmol), bis(triphenylphosphine)palladium(II) dichloride (140 mg, 0.200 mmol), N,N-diisopropylethylamine (388 mg, 3.00 mmol), and acetonitrile (2.0 mL). The mixture was stirred at 60°C for 2 hours and then concentrated under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate) gave a crude product (130 mg) containing (S)-(3-((4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)ethynyl)phenyl)boronic acid as a brown oil. Trifluoroacetic acid (637 mg, 5.59 mmol) was added to the crude product (130 mg) containing (S)-(3-((4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)ethynyl)phenyl)boronic acid. After 17 hours, the mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure. The solid was washed with dichloromethane and dried under reduced pressure at 45° C. to obtain 4-((-boronophenyl)ethynyl)-L-phenylalanine trifluoroacetate (96.9 mg, 0.229 mmol, 23% in 2 steps) as a brown solid. １ H-NMR (60MHz, CD ３ OD): δ7.61-7.28 (m, 8H), 4.28 (m, 1H), 3.36-3.25 (m, 2H).

[0162] Example 14 Synthesis of (S)-2-amino-5-(3-boronophenyl)pent-4-ynoic acid hydrochloride (Compound 226) Copper iodide (24.9 mg, 0.131 mmol) was added to (S)-(3-(5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopent-1-yn-1-yl)phenyl)boronic acid (354 mg, 1.31 mmol), (3-ethynylphenyl)boronic acid (326 mg, 1.31 mmol), bis(triphenylphosphine)palladium(II) dichloride (184 mg, 0.262 mmol), N,N-diisopropylethylamine (508 mg, 3.93 mmol), and acetonitrile (2.6 mL). The mixture was stirred for 10 minutes and then concentrated under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate) gave (S)-(3-(5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopent-1-yn-1-yl)phenyl)boronic acid (229 mg, 0.588 mmol, 45%) as a brown amorphous substance. １ H-NMR (60MHz, acetone-d ６ ) δ8.21-7.22 (m, 4H), 4.31 (m, 1H), 2.96-2.86 (m, 2H), 1.49 (s, 9H), 1.42 (s, 9H).

[0163] A 4 M hydrochloric acid / ethyl acetate solution (1.5 mL, 5.83 mmol) was added to (S)-(3-(5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopent-1-yn-1-yl)phenyl)boronic acid (227 mg, 0.583 mmol). The mixture was stirred at 50°C for 2 hours and then filtered. The resulting mixture was washed with ethyl acetate and dried under reduced pressure at 45°C to obtain (S)-2-amino-5-(3-boronophenyl)pent-4-ynoic acid hydrochloride (120 mg, 0.445 mmol, 76%) as a pale yellow solid. １ H-NMR (60MHz, CD ３ OD): δ7.73-7.41 (m, 4H), 4.20 (m, 1H), 3.36-3.10 (m, 2H).

[0164] (Example 15) Synthesis of 3-(3-boronobenzamido)-L-homophenylalanine trifluoroacetate (Compound 194) Under a nitrogen stream, zinc (255 mg, 3.89 mmol) and N,N-dimethylformamide (2.6 mL) were mixed with trimethylsilyl chloride (33 μL, 0.260 mmol) and 1,2-dibromoethane (23 μL, 0.260 mmol), and the mixture was heated using a heat gun. After cooling, tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-iodopropanoate (1.00 g, 2.60 mmol) was added. After stirring at 40°C for 5 minutes, 3-iodoaniline (569 mg, 2.60 mmol), tris(dibenzylideneacetone)dipalladium(0) (59.5 mg, 0.0650 mmol), and SPhos (53.4 mg, 0.130 mmol) were added. After stirring at 40°C for 20 hours, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl (S)-4-(3-aminophenyl)-2-((tert-butoxycarbonyl)amino)butanoate (400 mg, 1.14 mmol, 44%) as a yellow oil. １ H-NMR (60MHz, CDCl ３ ) δ7.16-6.55 (m, 4H), 5.06 (m, 1H), 4.32 (m, 1H), 2.69-1.91 (m, 4H), 1.54 (s, 18H).

[0165] N,N-Diisopropylethylamine (89.3 mg, 0.691 mmol) and HATU (263 mg, 0.691 mmol) were added to tert-butyl (S)-4-(3-aminophenyl)-2-((tert-butoxycarbonyl)amino)butanoate (202 mg, 0.576 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (143 mg, 0.576 mmol), 4-dimethylaminopyridine (14.1 mg, 0.115 mmol), and N,N-dimethylacetamide (1.2 mL). After stirring at 40°C for 4 hours, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give a crude product (288 mg) containing tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)phenyl)butanoate as a pale yellow oil.

[0166] To the crude product (288 mg) containing tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)phenyl)butanoate were added acetone / water (2 / 1, 5.0 mL), sodium periodate (637 mg, 2.97 mmol), and ammonium acetate (229 mg, 2.97 mmol). After stirring for 19 hours, the mixture was filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate) gave (S)-(3-((3-(4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)phenyl)carbonyl)phenyl)boronic acid (187 mg, 0.375 mmol, 65% in 2 steps) as a colorless amorphous substance. １ H-NMR (60MHz, acetone-d ６ ) δ8.43-6.93 (m, 8H), 6.24 (m, 1H), 4.06 (m, 1H), 2.63 (m, 2H), 1.98-1.96 (m, 2H), 1.49 (s, 9H), 1.47 (s, 9H).

[0167] Trifluoroacetic acid (855 mg, 7.50 mmol) was added to (S)-(3-((3-(4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)phenyl)carbonyl)phenyl)boronic acid (187 mg, 0.375 mmol). After 17 hours, the mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure. The mixture was washed with dichloromethane and dried under reduced pressure at 45°C to obtain the trifluoroacetate salt of 3-(3-boronobenzamido)-L-homophenylalanine (138 mg, 0.303 mmol, 81%) as a yellow solid. １ H-NMR (60MHz, acetone-d ６ +D ２ O) δ8.22-6.95 (m, 8H), 3.92 (m, 1H), 2.89-2.60 (m, 2H), 2.31-1.93 (m, 2H).

[0168] Example 16 Synthesis of (3-(3-boronophenyl)carbamoyl)-L-homophenylalanine trifluoroacetate (Compound 47) To a mixture of 3-iodobenzoic acid (459 mg, 1.85 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (405 mg, 1.85 mmol), 4-dimethylaminopyridine (45.2 mg, 0.370 mmol), and N,N-dimethylacetamide (1.9 mL), N,N-diisopropylethylamine (287 mg, 2.22 mmol) and HATU (844 mg, 2.22 mmol) were added. After stirring at 40°C for 22 hours, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give 3-iodo-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (687 mg, 1.53 mmol, 83%) as a white solid. １ H-NMR (60MHz, CDCl ３ ) δ8.22-7.09 (m, 8H), 1.35 (s, 12H).

[0169] Trimethylsilyl chloride (19 μL, 0.153 mmol) and 1,2-dibromoethane (13 μL, 0.153 mmol) were added to zinc (150 mg, 2.30 mmol) and N,N-dimethylformamide (1.5 mL) under a nitrogen stream, and the mixture was heated using a heat gun. After cooling, tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-iodobutanoate (648 mg, 1.68 mmol) was added. After stirring at 40°C for 5 minutes, 3-iodo-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (687 mg, 1.53 mmol), tris(dibenzylideneacetone)dipalladium(0) (35.0 mg, 0.0383 mmol), and SPhos (31.4 mg, 0.0765 mmol) were added. After stirring at 40°C for 17 hours, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give a crude product (562 mg) containing tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)phenyl)butanoate as a brown amorphous solid.

[0170] To the crude product (562 mg) containing tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)phenyl)butanoate were added acetone / water (2 / 1, 9.7 mL), sodium periodate (1.04 g, 4.84 mmol), and ammonium acetate (373 mg, 4.84 mmol). After stirring for 22 hours, the mixture was filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate) gave (S)-(3-(3-(4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)benzamido)phenyl)boronic acid (409 mg, 0.821 mmol, 54% in 2 steps) as a colorless amorphous substance. １ H-NMR (60MHz, acetone-d ６) δ8.15-7.18 (m, 8H), 6.28 (m, 1H), 4.07 (m, 1H), 2.97-2.72 (m, 2H), 2.23-1.89 (m, 2H), 1.46 (s, 9H), 1.43 (s, 9H).

[0171] Trifluoroacetic acid (1.79 g, 15.7 mmol) was added to (S)-(3-(3-(4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)benzamido)phenyl)boronic acid (391 mg, 0.785 mmol). After 21 hours, the mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure. The mixture was washed with dichloromethane and dried under reduced pressure at 45°C to obtain the trifluoroacetate salt of (3-(3-boronophenyl)carbamoyl)-L-homophenylalanine (343 mg, 0.752 mmol, 96%) as a white solid. １ H-NMR (60MHz, CD ３ OD): δ7.93-7.16 (m, 8H), 4.02 (m, 1H), 2.94-2.78 (m, 2H), 2.41-2.01 (m, 2H).

[0172] (Example 17) 4-(3-(borono- １０ B) Synthesis of (phenyl)carbamoyl)-L-phenylalanine hydrochloride (Compound 11) To benzophenone (10.0 g, 54.9 mmol) were added p-toluenesulfonic acid monohydrate (522 mg, 2.75 mmol), toluene / methanol (1 / 3, 55 mL), and trimethyl orthoformate (8.74 g, 82.4 mmol). The mixture was stirred under reflux for 6 hours and then concentrated under reduced pressure. 3-Bromoaniline (9.44 g, 54.9 mmol) and toluene (55 mL) were added. The mixture was stirred under reflux for 10 hours and then concentrated under reduced pressure. Purification was performed by silica gel column chromatography (hexane / ethyl acetate) to obtain N-(3-bromophenyl)-1,1-diphenylmethanimine (12.8 g, 38.0 mmol, 70%) as a yellow solid. １ H-NMR (60MHz, CD ３ OD) δ7.83-6.51 (m, 14H).

[0173] Tetrahydrofuran (17 mL) was added to N-(3-bromophenyl)-1,1-diphenylmethanimine (2.88 g, 8.57 mmol), and n-butyllithium (2.8 M hexane solution, 4.3 mL, 12 mmol) was added at −78° C. After stirring for 20 minutes, １０ Tributyl borate (3.5 mL, 12.9 mmol) was added. After stirring for 45 minutes, 1 M aqueous sulfuric acid solution was added to adjust the pH to 1. Aqueous sodium hydroxide solution was added dropwise to the aqueous phase to adjust the pH to 7.2, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The organic phase was washed with dichloromethane and dried under reduced pressure at 45°C to obtain (3-aminophenyl)- １０ Boronic acid B (447 mg, 3.28 mmol, 38%) was obtained as a white solid. LC / MS [M+H] ＋ 137.

[0174] (3-aminophenyl)- １０ To boronic acid B (136 mg, 1.00 mmol) were added (S)-4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)benzoic acid (365 mg, 1.00 mmol), 4-dimethylaminopyridine (24.4 mg, 0.200 mmol), and N,N-dimethylacetamide (1.0 mL). N,N-Diisopropylethylamine (155 mg, 1.20 mmol) and HATU (456 mg, 1.20 mmol) were added. After stirring at 40°C for 21 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (S)-(3-(4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)benzamido)phenyl)- １０ Boronic acid B (269 mg, 0.556 mmol, 56%) was obtained as a pale yellow solid. １ H-NMR (60MHz, acetone-d6) δ8.17-7.17 (m, 8H), 6.09 (m, 1H), 4.33 (m, 1H), 3.19-2.74 (m, 2H), 1.43 (s, 9H), 1.38 (s, 9H).

[0175] (S)-(3-(4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)benzamido)phenyl)- １０ To the boronic acid B (265 mg, 0.548 mmol) was added a 4 M hydrochloric acid / ethyl acetate solution (1.4 mL, 5.48 mmol). After stirring at 50°C for 2 hours, the mixture was filtered. The 4-(3-(borono- １０ B) Phenyl)carbamoyl)-L-phenylalanine hydrochloride (177 mg, 0.487 mmol, 89%) was obtained as a white solid. LC / MS [M+H] ＋ 328.

[0176] (Example 18) 4-(3-(borono- １０ B) Synthesis of benzamido-L-phenylalanine hydrochloride (Compound 74) Tetrahydrofuran (10 mL) was added to 3-iodobenzoic acid (2.48 g, 10.0 mmol), and isopropylmagnesium chloride lithium chloride complex (1.3 M tetrahydrofuran solution, 23 mL, 30 mmol) was added dropwise at −30° C. After stirring for 30 minutes, １０ Tributyl borate (4.0 mL, 15 mmol) was added dropwise to the reaction mixture. Aqueous citric acid solution was added dropwise to adjust the pH to 3. After extraction with ethyl acetate, the organic phase was washed with saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The mixture was purified by recrystallization (hexane / tetrahydrofuran) to give 3-(borono- １０ B) Benzoic acid (621 mg, 3.76 mmol, 38%) was obtained as a pale yellow solid. LC / MS [M-H] － 164.

[0177] 3-(Borono- １０B) To benzoic acid (165 mg, 1.00 mmol) were added tert-butyl (S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (336 mg, 1.00 mmol), 4-dimethylaminopyridine (24.4 mg, 0.200 mmol), and N,N-dimethylacetamide (2.0 mL). N,N-Diisopropylethylamine (155 mg, 1.20 mmol) and HATU (456 mg, 1.20 mmol) were added. After stirring at 40°C for 17 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (S)-(3-((4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)carbamoyl)phenyl) １０ Boronic acid B (90.0 mg, 0.186 mmol, 19%) was obtained as a pale yellow solid. １ H-NMR (60MHz, acetone-d ６ ) δ8.42-7.32 (m, 8H), 4.25 (m, 1H), 3.11-2.75 (m, 2H), 1.43 (s, 9H), 1.39 (s, 9H).

[0178] (S)-(3-((4-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)carbamoyl)phenyl) １０ To the boronic acid B (90.0 mg, 0.186 mmol) was added a 4 M hydrochloric acid / ethyl acetate solution (0.5 mL, 1.9 mmol). After stirring at 50°C for 2 hours, the mixture was filtered. The mixture was washed with ethyl acetate and dried under reduced pressure at 45°C to give 4-(3-(borono- １０ B) Benzamido)-L-phenylalanine hydrochloride (59.2 mg, 0.163 mmol, 87%) was obtained as a pale yellow solid. LC / MS [M+H] ＋ 328.

[0179] Example 19 １８F-labeled amino acid derivatives were prepared according to the method described in reference 1 (Jay S. Wright, Liam S. Schanninghausen, Sean Preshlock, Allen F. Brooks, Melanie S. Sanford, and Peter J. H. Scott. Sequential Ir / Cu-Mediated Method for the Meta-Selective C—H Radiofluorination of (Hetero)Arenes. Journal of the American Chemical Society 2021 143 (18), 6915-6921) can be synthesized by the following manufacturing route.

[0180] (Example 20) １３１ I-labeled amino acid derivatives were prepared according to the method described in reference 2 (Shigeki Watanabe, Mohammad Anwar-Ul Azim, Ichiro Nishinaka, Ichiro Sasaki, Yasuhiro Ohshima, Keiichi Yamada and Noriko S. Ishioka. A convenient and reproducible method for the synthesis of astatinated 4-[211At]astato-L-phenylalanine via electrophilic desilylation. Org. Biomol. Chem. , 2019, 17, 165-171) or Reference 3 (Patent No. 7232527) can be synthesized by the following manufacturing route.

[0181] (Example 21) ２１１ The At-labeled amino acid derivatives can be synthesized by the following production route with reference to Reference 2 or Reference 3.

[0182] Example 22 ９９ｍThe Tc-labeled amino acid derivative can be synthesized by the following production route with reference to Reference 3 (Fan-Lin Kong, Mohammad S. Ali, Yinhan Zhang, Chang-Sok Oh, Dong-Fang Yu, Mithu Chanda, and David J. Yang Synthesis and Evaluation of Amino Acid-Based Radiotracer 99mTc-N4-AMT for Breast Cancer Imaging J Biomed Biotechnol. 2011; 2011: 276907.).

[0183] Example 23 １１１ In-labeled amino acid derivatives were prepared as described in Reference 4 (Nobuhiro Oshima, Hiromichi Akizawa, Songji Zhao, Yan Zhao, Ken-ichi Nishijima, Yoji Kitamura, Yasushi Arano, Yuji Kuge, Kazue Ohkura. Design, synthesis, and biological evaluation of negatively charged In-DTPA-octreotide derivatives. Bioorganic & Medicinal Chemistry). (2014), 22(4), 1377-1382.) It can be synthesized using the following manufacturing route.

[0184] (Example 24) １７７Lu-labeled amino acid derivatives were prepared as described in reference 5 (Hsiou-Ting Kuo, Helen Merkens, Zhengxing Zhang, Carlos F. Uribe, Joseph Lau, Chengcheng Zhang, Nadine Colpo, Kuo-Shyan Lin, and Francois Benard. Enhancing Treatment Efficacy of 177Lu-PSMA-617 with the Conjugation of an Albumin-Binding Motif: Preclinical Dosimetry and It can be synthesized by the following manufacturing route with reference to Endoradiotherapy Studies Molecular Pharmaceutics 2018 15 (11), 5183-5191).

[0185] The compounds obtained, including those prepared by similar syntheses, are shown in the table below.

[0186] (Example 25) Synthesis of 4-(2-(4-iodoanilino)-2-oxoethoxy)-L-phenylalanine hydrochloride (SPD-757B) A mixture of N-Boc-4-hydroxy-L-phenylalanine tert-butyl ester (6.75 g, 20 mmol), methyl bromoacetate (3.37 g, 22 mmol), potassium carbonate (5.53 g, 40 mmol), and dimethylacetamide (60 mL) was stirred at 50°C for 3 hours. The reaction mixture was added to water (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give N-Boc-4-(methoxycarbonylmethoxy)-L-phenylalanine tert-butyl ester (8.18 g, 100% yield) as a colorless oil. 1H-NMR (60 MHz, CDCl3) δ 7.26-6.78 (m, 4H), 5.00 (m, 1H), 4.64 (s, 2H), 4.45 (m, 1H), 2.98 (d, J= 6.0 Hz), 1.41 (s, 18H).

[0187] To a solution of N-Boc-4-(methoxycarbonylmethoxy)-L-phenylalanine tert-butyl ester (4.09 g, 10 mmol), THF (30 mL), and methanol (30 mL) was added 1M aqueous sodium hydroxide solution (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with aqueous citric acid, then added to water (200 mL), and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N-Boc-4-(hydroxycarbonylmethoxy)-L-phenylalanine tert-butyl ester (3.9 g, 99% yield) as a white solid. 1H-NMR (60 MHz, CDCl3) δ 7.19-6.75 (m, 4H), 5.00 (m, 1H), 4.61 (s, 2H), 4.47 (m, 1H), 2.99 (d, J= 5.9 Hz), 1.42 (s, 9H), 1.40 (s, 9H). A mixture of N-Boc-4-(hydroxycarbonylmethoxy)-L-phenylalanine tert-butyl ester (0.28 g, 0.7 mmol), 4-iodoaniline (0.18 g, 0.84 mmol), HATU (0.37 g, 0.98 mmol), diisopropylethylamine (0.24 mL, 1.4 mmol), and dimethylacetamide (3 mL) was stirred at room temperature overnight. The reaction mixture was added to water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give N-Boc-4-(2-(4-iodoanilino)-2-oxoethoxy)-L-phenylalanine tert-butyl ester (0.73 g, yield 96%) as a light brown solid. 1H-NMR (60 MHz, CDCl3) δ 8.22 (brs, 1H), 7.84-7.29 (m, 4H), 7.24-6.81 (m, 4H), 4.92 (m, 1H), 4.57 (s, 2H), 4.44 (m, 1H), 3.01 (d, J= 5.9 Hz), 1.42 (s, 9H), 1.41 (s, 9H).

[0188] A 4M solution of hydrochloric acid in ethyl acetate (2.8 mL) was added to N-Boc-4-(2-(4-iodoanilino)-2-oxoethoxy)-L-phenylalanine tert-butyl ester (0.33 g, 0.55 mmol), and the mixture was stirred at 50°C for 2 hours. Ethyl acetate (3 mL) was added to the reaction mixture, and the mixture was stirred under ice cooling, and the powder was collected by filtration. The obtained powder was dried under reduced pressure at 50°C to give 4-(2-(4-iodoanilino)-2-oxoethoxy)-L-phenylalanine hydrochloride (0.25 g, yield 95%) as a white powder. 1H-NMR (60 MHz, CD3OD) δ 7.75-7.37 (m, 4H), 7.33-6.95 (m, 4H), 4.13 (t, J= 7.0 Hz), 3.13 (d, J= 5.9 Hz).

[0189] The compounds obtained, including those prepared by similar syntheses, are shown in the table below.

[0190] [Uptake Test 1] (1) Preparation of HEK293 Cell Lines Highly Expressing Human LAT1 and LAT2 HEK293 cells stably expressing high levels of human LAT1 and LAT2 were prepared according to the method described in the paper by Khunweeraphong, N. et al. (Journal of Pharmacology Science, 2012, vol. 119, pp. 368-380). Shuttle vector DNA (LAT1: EX-H4509-M02, LAT2: EX-U0514-M02, GeneCopoeia) was constructed containing ampicillin and neomycin resistance markers and the full-length cDNA of human LAT1 or LAT2 inserted under the CMV (cytomegalovirus) promoter. This vector is transfected into HEK293 cells using Lipofectamine® 2000 (Invitrogen) according to the manufacturer's instructions. Cell clones stably expressing the transgene are then selected by limiting dilution in the presence of 0.9 mg / mL Geneticin®, and cell clones showing increased L-boronophenylalanine (L-BPA) uptake by approximately 2- to 5-fold compared to HEK293 cells prior to transfection are obtained. These cells are then passaged and used to evaluate the selective uptake of LAT1 and LAT2.

[0191] Evaluation of LAT1 and LAT2 Selective Uptake Cellular uptake was evaluated using the same method as in the paper by Khunweeraphong, N et al. (Journal of Pharmacology Science, 2012, vol. 119, pp. 368-380). Evaluation was performed using the cells obtained in (1). However, no radioisotopes were used, and a substrate concentration of 0.1 mM was used, with 2 mM BCH (2-amino-2-norbornanecarboxylic acid) as an LAT1 and LAT2 inhibitor. After the reaction, the cells were recovered with 0.05% Tween 20, and the concentration of the boronophenylalanine amide derivative in the resulting cell solution was determined. Quantification of intracellular boronophenylalanine amide derivatives is performed according to the method described in Hattori, Y. et al.'s paper (Sensors 2017, 17, 2436), using 2-(2-hydroxyphenyl)pyridine (boron sensor 5) as a boron sensor. When evaluating cellular uptake, taking into account inter-experimental variability, the results are evaluated as a relative value (LAT1 selectivity) to the uptake of L-BPA, a control performed on the same day. LAT1 selectivity = (quantitative uptake value of compound in LAT1 cells / quantitative uptake value of control LBPA in LAT1 cells) / (quantitative uptake value of compound in LAT2 cells / quantitative uptake value of control LBPA in LAT2 cells).

[0192] The results for the uptake of major compounds are shown in the table below. In the table, uptake A: 1.6 times or more higher than BPA (higher than BPA), B: 1.2 to less than 1.6 times higher than BPA (slightly higher than BPA), C: 0.8 to less than 1.2 times higher than BPA (similar to BPA), D: 0.4 to less than 0.8 times higher than BPA (slightly lower than BPA), E: less than 0.4 times higher than BPA (meaning lower than BPA).

[0193]

[0194] [Uptake Test 2] (1) Test to Evaluate Uptake into Tumor Cells (Biological Evaluation 2) 1.5 x 106 human tongue cancer cells (SAS cells), human glioma cells (A172 cells), or human breast cancer cells (MCF-7) were seeded onto a 100 mm dish and pre-cultured at 37°C in a 5% CO2 atmosphere for 24 hours. The culture medium was removed by suction, and a culture medium containing 1 mM of each drug of the Examples or Reference Examples was added, followed by exposure culture at 37°C in a 5% CO2 atmosphere for 3 hours. After removing the culture medium by suction, the cells were washed once with PBS and then trypsinized to recover the cells. The recovered cells were counted, packed by centrifugation, and then diluted with HClO ４ (60%, 0.3 mL) and H ２ O ２ (31%, 0.6 mL) was added and heated at 75°C overnight to prepare an ashing solution. The ashing solution was filled up to 5 mL with pure water and then filtered through a 5C filter paper. The boron concentration in the solution was measured using an Agilent 710 ICP-OES to determine the amount of boron (μg) per 10 cells. Cellular uptake was evaluated as a relative value to the uptake of L-BPA from the reference example, which was performed on the same day, taking into account inter-experimental variability.

[0195] The results of the uptake test are shown in the table below, where 4-borono-L-phenylalanine (L-BPA), which has been used in clinical studies of BNCT, was used as a control.

[0196] As a result, it was found that many of the amino acid derivatives of the present invention were taken up into cells at the same or higher concentration than BPA when treated at the same concentration.

[0197] The results for the uptake of major compounds are shown in the table below. In the table, uptake A: 1.6 times or more higher than BPA (higher than BPA), B: 1.2 to less than 1.6 times higher than BPA (slightly higher than BPA), C: 0.8 to less than 1.2 times higher than BPA (similar to BPA), D: 0.4 to less than 0.8 times higher than BPA (slightly lower than BPA), E: less than 0.4 times higher than BPA (meaning lower than BPA).

[0198]

[0199] As is clear from the table, the compounds of the examples were shown to have excellent uptake ability into tumor cells.

[0200] [Cell proliferation inhibition test] 0.5 × 10 CT26 cells derived from mouse colon cancer were ４ The cells were adjusted to 1000 cells / mL and seeded into a 96-well plate at 1,000 cells / well. The cells were incubated in RPMI 1640 medium supplemented with 10% fetal bovine serum at 5% CO ２ The cells are cultured at 37°C for 24 hours after the start of culture, and the medium is replaced with a medium containing the compound of the example to examine the effect of the compound on cell proliferation. The compound is used at concentrations of 0.01, 0.03, 0.1, 0.3, 1, 3, 10, or 30 μM. As a control, the cells are cultured in a medium without the compound. 72 hours after the start of compound treatment, the cell number is evaluated using a CCK-8 assay (Cell Counting Kit-8, Dojindo Co., Ltd.), and the compound concentration (IC) that gives 50% growth inhibition compared to the control is determined. ５０ value) can be calculated.

[0201] Inhibition of cell proliferation is observed depending on the compound concentration. The compound concentration that gives 50% inhibition of proliferation compared to the control (IC ５０ The compounds of the Examples exhibit a strong cell proliferation inhibitory effect even at low concentrations.

[0202] [Metabolic Stability Test] Using commercially available pooled human liver microsomes, the target compound was reacted for a set period of time. The residual fraction was calculated by comparing the reacted and unreacted samples to assess the extent of hepatic metabolism. Human liver microsomes were reacted in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL in the presence of 1 mmol / L NADPH at 37°C for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction mixture was added to 100 μL of a 1 / 1 (v / v) methanol / acetonitrile solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The test compound in the supernatant was quantified by LC / MS / MS, and the remaining amount of test compound after the reaction was calculated based on the amount of compound at 0 minutes of reaction (100%).

[0203] [Pharmacokinetics study in rats] Materials and methods (1) Animals used: SD rats were used. (2) Breeding conditions: SD rats were allowed free access to solid feed and sterilized tap water. (3) Dosage and grouping: Intravenous administration 50 mg / kg (n=2-3, intravenous administration was administered at a predetermined dose. (Dosage may vary depending on the compound) (4) Preparation of administration solution: For intravenous administration, the compound was solubilized and administered. (5) Administration method: For intravenous administration, the compound was administered via the tail vein using a syringe with an injection needle attached. (6) Evaluation items: Blood was collected over time, and the plasma concentration of the compound of the present invention was measured using LC / MS / MS. (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) was calculated for the progression of the plasma concentration of the compound of the present invention using the nonlinear least squares program WinNonlin (registered trademark). (Results)

[0204] As a result, it was confirmed that the blood concentration of the compounds of the examples was maintained for a certain period of time after administration, and then they were rapidly excreted from the body.

[0205] [Uptake Inhibition Test] (1) Preparation of HEK293 Cell Lines Highly Expressing Human LAT1 and LAT2 HEK293 cells stably expressing high levels of human LAT1 and LAT2 were prepared according to the method described in the paper by Khunweeraphong, N. et al. (Journal of Pharmacology Science, 2012, vol. 119, pp. 368-380). Shuttle vector DNA (LAT1: EX-H4509-M02, LAT2: EX-U0514-M02, GeneCopoeia) was constructed containing ampicillin and neomycin resistance markers and the full-length cDNA of human LAT1 or LAT2 inserted under the CMV (cytomegalovirus) promoter. This vector is transfected into HEK293 cells using Lipofectamine® 2000 (Invitrogen) according to the manufacturer's instructions. Cell clones stably expressing the transgene are then selected by limiting dilution in the presence of 0.9 mg / mL Geneticin®, and cell clones showing increased L-boronophenylalanine (L-BPA) uptake by approximately 2- to 5-fold compared to HEK293 cells prior to transfection are obtained. These cells are then passaged and used to evaluate the selective uptake of LAT1 and LAT2.

[0206] Evaluation of LAT1 and LAT2 Selective Uptake Cellular uptake was evaluated by the method described in the paper by Wiriyasermkul P. et al. (Journal of Nuclear Medicine, 2012, vol. 53, pp. 1253-1261), in which competitive inhibition of uptake between each substrate and L-BPA was performed and the L-BPA uptake inhibition rate was calculated. However, the above-mentioned human LAT1 and LAT2 highly expressing HEK293 cell line was used. １４L-BPA was used instead of C-leucine, with both L-BPA and substrate concentrations at 0.1 mM and an uptake time of 3 minutes. L-BPA was quantified in the cell sap obtained by recovering the cells after the reaction with 0.05% Tween 20 according to the method described in Hattori et al.'s paper (Sensors 2017, 17, 2436) using 2-(2-hydroxyphenyl)pyridine (Boron Sensor 5) as a boron sensor. The results of the inhibition of BPA uptake by major compounds are shown in the table below. In the table, Inhibition A: 80-100% inhibition of BPA uptake; B: 60% to less than 80% inhibition of BPA uptake; C: 40% to less than 60% inhibition of BPA uptake; D: 20% to less than 40% inhibition of BPA uptake; E: Less than 20% inhibition of BPA uptake.

[0207]

Claims

1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: wherein in formula (I), ring A represents a 5- to 7-membered aromatic carbocyclic ring or a 5- to 7-membered aromatic heterocyclic ring; １ are independently halogen, hydroxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyloxy, C2-6 alkynyloxy, carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted C1-6 alkoxycarbonyl, substituted or unsubstituted C2-6 alkenyloxycarbonyl, substituted or unsubstituted C2-6 alkynyloxycarbonyl, substituted or unsubstituted C1-6 alkylcarbonyl, COOR １０ (R １０ is H or C1-6 alkyl, C1-6 alkylamino, or di(C1-6 alkyl)amino), a 3- to 8-membered non-aromatic heterocycle, morpholinocarbonyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C3-8 cycloalkynyl, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C2-6 alkenylthio, substituted or unsubstituted C1-6 alkynylthio, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfonyl, sulfo, substituted or unsubstituted -X- represents a group independently selected from the group consisting of substituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted borono, substituted or unsubstituted sulfanyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted non-aromatic heterocycle, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocycle-oxy, substituted or unsubstituted aromatic carbocycle-oxy, and substituted or unsubstituted aromatic heterocycle-oxy; １１ R １２ ) n-, -(CR １１ R １２ )nO(CR １３ R １４ )n'-, -(CR １１ R １２ ) nCO(CR １３ R １４ )n'-, -(CR １１ R １２ )nOCO(CR １３ R １４ ) n'-, -(CH ２ ) nS(CH ２ ) n'-, -(CH ２ ) nN(R １５ ) (CH ２ )n'-, -(CR １１ R １２ ) nCON(R １５ ) (CR １３ R １４ )n'-, -(CR １１ R １２ ) nN(R １５ ) CO(CR １３ R １４ )n'-, -(CR １１ R １２ ) nSO ２ N (R １５ ) (CR １３ R １４ )n'-, -(CR １１ R １２ ) nN(R １５ ) SO ２ (CR １３ R １４ )n'-, -(CR １１ R １２ ) n-, -(CR １１ R １２ ) nN(R １５ ) CON (R １６） (CR １３ R １４ )n'-, -C(R １５ )=CH(R １６ )- or -CC-, where n and n' each independently represent an integer of 0 to 3, and where R １１ , R １２ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R １３ and R １４ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R １５ , R １６ each independently represents hydrogen or substituted or unsubstituted alkyl; -Y- optionally represents (R ５ ) represents any one of structures selected from the group consisting of a 5- to 7-membered aromatic carbocyclic group, a 5- to 7-membered aromatic heterocyclic group, and an 8- to 16-membered polycyclic group, each of which may be substituted with s′, an alkynyl, or a simple bond; R ５ is halogen, hydroxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyloxy, C2-6 alkynyloxy, carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted C1-6 alkoxycarbonyl, substituted or unsubstituted C2-6 alkenyloxycarbonyl, substituted or unsubstituted C2-6 alkynyloxycarbonyl, substituted or unsubstituted C1-6 alkylcarbonyl, COOR １０ (R １０ represents H or C1-6 alkyl, C1-6 alkylamino, or di(C1-6 alkyl)amino), a 3- to 8-membered non-aromatic heterocycle, morpholinocarbonyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C3-8 cycloalkynyl, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C2-6 alkenylthio, substituted or unsubstituted C1-6 alkynylthio, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfonyl, sulfo , substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted borono, substituted or unsubstituted sulfanyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted non-aromatic heterocycle, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocycle-oxy, substituted or unsubstituted aromatic carbocycle-oxy, substituted or unsubstituted aromatic heterocycle-oxy, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F) and astatine ( ２１１ At); s and s' are integers of 0 to 3; -Z- represents a group independently selected from the group consisting of -(CR １７ R １８ )m-, where R １７ and R １８ are each independently hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or taken together to form a carbonyl, and m is an integer of 0 to 3; R ２ represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino; -W- is independently -(CR １９ R ２０ ) n-, -(CR １９ R ２０ )nO(CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nCO(CR ２１ R ２２ )n'-, -(CR １９ R ２０ )nOCO(CR ２１ R ２２ ) n'-, -(CH ２ ) nS(CH ２ ) n'-, -(CH ２ ) nN(R ２３ ) (CH ２ )n'-, -(CR １９ R ２０ ) nCON(R ２３ ) (CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nN(R ２３ ) CO(CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nSO ２ N (R ２３ ) (CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) nN(R ２３ ) SO ２ (CR ２１ R ２２ )n'-, -(CR １９ R ２０ ) n-, -(CR １９ R ２０ ) nN(R １５ ) CON (R ２４ ) (CR ２１ R ２２ )n'-, -C(R ２３ )=CH(R ２４ )-, R-CC-, or a simple bond, where n and n' each independently represent an integer of 0 to 3, and where R １９ , R ２０ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R ２１ and R ２２ each independently represents hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, or together form a carbonyl; R ２３ , R ２４ each independently represents hydrogen or substituted or unsubstituted alkyl; R ３ are independently -BR ３０ R ４０ , oxaborole, a radioisotope, or a group containing a radioisotope; ３０ R ４０ is -B(NR ３００ ) ２ , or -B(OR ３００ ) ２ or a group having a chain structure represented by the formula: ３０ R ４０ represents a group having a cyclic structure, where R ３００ represents a linear or branched C1-C10 alkyl group, and the radioisotope is technetium ( ９９ｍ Tc), indium ( １１１ In), iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), carbon ( １１ C), Gallium ( ６８ Ga), yttrium ( ９０ Y), Rin ( ３２ P), radium ( ２２３ Ra), lutetium ( １７７ Lu), or astatine ( ２１１ At), and m' represents an integer of 0 to 2.

2. The ring A represents a 5- to 7-membered aromatic carbocyclic ring or a 5- to 7-membered aromatic heterocyclic ring; R １ are independently halogen, hydroxy, cyano, nitro, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkoxylC1-6 alkoxylC1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyloxy, carbamoyl, C1-6 alkylaminocarbonyl, di(C1-6 alkyl)aminocarbonyl, COOR １０ (R １０ represents H or C1-6 alkyl, C1-6 alkylamino, or di(C1-6 alkyl)amino), a 3- to 8-membered non-aromatic heterocycle optionally substituted with halogen, morpholinocarbonyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8 cycloalkynyl, C3-8 cycloalkylamino, a 3- to 8-membered non-aromatic heterocycle-substituted amino, C1-6 haloalkylsulfanyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 alkylthio, C2-6 alkenylthio, C1-6 alkynylthiosulfinyl, C1-6 alkylsulfinyl, sulfonyl, C1-6 alkylsulf R represents a group independently selected from the group consisting of phenyl, aminosulfonyl, sulfo, sulfamoyl, borono, sulfanyl, sulfinyl, aromatic heterocycle optionally substituted with halogen, C1-6 haloalkyl, C1-6 alkyl; aromatic carbocycle, cycloalkyloxy, cycloalkenyloxy, non-aromatic heterocycle-oxy optionally substituted with halogen, C1-6 haloalkyl, C1-6 alkyl; aromatic carbocycle-oxy optionally substituted with halogen, C1-6 haloalkyl, C1-6 alkyl; and aromatic heterocycle-oxy optionally substituted with halogen, C1-6 haloalkyl, C1-6 alkyl; R ５ is halogen, hydroxy, cyano, nitro, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkoxylC1-6 alkoxylC1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyloxy, carbamoyl, C1-6 alkylaminocarbonyl, di(C1-6 alkyl)aminocarbonyl, aminocarbonyl, C1-6 alkoxycarbonyl, C2-6 alkenyloxycarbonyl, C2-6 alkynyloxycarbonyl, C1-6 alkylcarbonyl, COOR １０ (R １０ is H or C1-6 alkyl, C1-6 alkylamino, or di(C1-6 alkyl)amino), morpholinocarbonyl, C3-8 cycloalkylC3-8 cycloalkenyl, C3-8 cycloalkynyl, C3-8 cycloalkylamino, 3-8 membered non-aromatic heterocycle-substituted amino, C1-6 haloalkylsulfanyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 alkylthio, C2-6 alkenylthio, C1-6 alkynylthio, sulfinyl, C1-6 alkylsulfinyl, sulfonyl, C1-6 alkylsulfonyl, aminosulfonyl, sulfo, sulfamoyl, carbamoyl, sulfanyl, sulfinyl, non-aromatic heterocycle, aromatic heterocycle, aromatic carbocycle, cycloalkyloxy, cycloalkenyloxy, non-aromatic heterocycle-oxy, aromatic carbocycle-oxy, aromatic heterocycle-oxy, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F) and astatine ( ２１１ 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each of the groups represented by the formula (I) represents a group independently selected from the group consisting of: ##STR1## and ##STR2##; s and s' are integers of 0 to 3.

3. The A ring represents benzene, thiophene, or pyridine, and R １ independently represent halogen, borono, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkyloxy, C1-6 alkyl-substituted phenyloxy, C1-6 alkyl-substituted pyridyloxy, C1-6 haloalkyl-substituted phenyloxy, C1-6 haloalkyl-substituted pyridyloxy, halogen-substituted phenyloxy, or halogen-substituted pyridyloxy, s represents an integer of 0 to 2, and -X- is -(CH ２ ) n-, -(CH ２ )nN(H)CO(CH ２ ) n'-, -(CH ２ )nN(CH ３ )CO(CH ２ ) n'-, -(CH ２ )nCO(CH ２ ) n'-, -(CH ２ )nOCO(CH ２ ) n'-, -(CH ２ )nO(CH ２ )n'-, -(CH(OH))n-, -CH ２ -CH(NH ２ ))-CONH- or -CC-, wherein n and n' each independently represent an integer of 0 to 2, and Y is optionally selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkyloxy, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), or astatine ( ２１１ -Z- represents benzene, naphthalene, thiophene, pyridine, alkynyl, or pyrazine, each of which may be independently substituted with one or two of -(CH ２ ) m-, where m is an integer of 0 to 3; R ２ represents hydrogen or 1-6 alkyl; ２ ) n-, -(CH ２ )nN(H)CO(CH ２ ) n'-, -(CH ２ )nN(CH ３ )CO(CH ２ ) n'-, -(CH ２ )nCO(CH ２ ) n'-, -(CH ２ )nOCO(CH ２ ) n'-, -(CH ２ )nO(CH ２ )n'-, -(CH(OH))n-, -CH ２ -CH(NH ２ )) represents -CONH- or -CC-, where n and n' each independently represent an integer of 0 to 2, and R ３ Is -BR ３０ R ４０ and -B(NR ３００ ) ２ , or -B(OR ３００ ) ２ or a group having a chain structure represented by the formula: ３０ R ４０ represents a group having a cyclic structure, where R ３００ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein represents a linear or branched C1-C10 alkyl group.

4. The -W- is -(CH ２ ) n-, -(CH ２ )nN(H)CO(CH ２ ) n'-, -(CH ２ )nN(CH ３ )CO(CH ２ ) n'-, -(CH ２ )nCO(CH ２ ) n'-, -(CH ２ )nOCO(CH ２ ) n'-, -(CH ２ )nO(CH ２ )n'-, -(CH(OH))n-, -CH ２ -CH(NH ２ )) represents -CONH- or -CC-, where n and n' each independently represent an integer of 0 to 2; R ３ is a radioisotope or a group containing a radioisotope, and the radioisotope is technetium ( ９９ｍ Tc), indium ( １１１ In), iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), carbon ( １１ C), Gallium ( ６８ Ga), yttrium ( ９０ Y), Rin ( ３２ P), radium ( ２２３ Ra), lutetium ( １７７ Lu), or astatine ( ２１１ 2. The compound of claim 1, wherein:

5. Any of the following compounds or pharmaceutically acceptable salts thereof: or Here, the compounds represented by the above two chemical formulas have in common: R １ represents a halogen, a C1-6 alkoxyl group, or a C1-6 alkyl group; s represents 0 or 1; R ３ is B(OH) ２ , oxaborole, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), astatine ( ２１１ At) or together with atom B, R ３０ R ４０ represents a group having a cyclic structure, and the cyclic structure forms a benzoxaborole together with an adjacent benzene ring; R ５ is a halogen, iodine ( １２３ I, １２５ I, １３１ I), fluorine ( １８ F), astatine ( ２１１ At), a C1-6 alkoxy group, or a C1-6 alkyl group; and s' represents 0 or 1.

6. A pharmaceutical composition for therapeutic use comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. A drug for BNCT comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. A cancer diagnostic agent comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. A theranostic agent comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

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