Small molecules for boron neutron capture therapy

Abstract

Compounds, compositions, and methods useful for boron neutron capture therapy are disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 397,626, filed August 12, 2022. [Background technology]

[0002] Boron neutron capture therapy (BNCT) is a bimodal cancer therapy that involves the use of boron-containing molecules to selectively divide cancer cells, and an external neutron beam that is directed at the cancer cells. 10 Capture of a thermal neutron by a B nucleus results in nuclear fission, producing high-energy alpha particles and recoil. 7 Li nuclei are generated. The high-energy particles damage tumor cells, resulting in tumor cell death while sparing surrounding healthy tissue. Novel boron delivery agents that selectively partition tumor tissue in combination with an external neutron beam directed at the tumor may be useful in boron neutron capture therapy to treat various solid tumors.

[0003] 4-Borono-L-phenylalanine (BPA) is approved in Japan for use in combination with an external neutron beam device for the treatment of recurrent, unresectable head and neck cancer. BPA has demonstrated therapeutic utility in boron neutron capture therapy, but its efficacy is limited. BPA's selectivity for tumor versus healthy tissue and tumor uptake appear to meet the minimum requirements for a successful boron neutron capture therapy agent. Agents with improved tumor cell uptake and improved tumor:healthy tissue ratios compared to BPA may offer improved anticancer efficacy. Summary of the Invention [Problem to be solved by the invention]

[0004] One aspect of the present invention provides compounds, compositions, and methods useful for boron neutron capture therapy. [Means for solving the problem]

[0005] Thus, there is provided herein a compound having the structure of formula (I): [ka] During the ceremony, Y1 is absent or -O-; Y2 is an optionally substituted -alkylene-; R1, R2, and R5 are each independently selected from -H and halo; R3 is selected from -H, halo, and -X1-X2; R4 is selected from -H, halo, and -X1-X2; X1 is -alkylene-; X2 is -C(H)(NH2)CO2H, The compound may be racemic, enriched in one enantiomer, or a single enantiomer, but shall contain exactly one occurrence of one -X1-X2, A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0006] Another aspect of the present invention relates to a method of treating cancer, comprising: i) administering a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I), to a subject in need thereof, wherein the compound accumulates in a plurality of cancer cells in the subject; and ii) irradiating the plurality of cancer cells with neutrons.

[0007] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0008] Other features, objects, and advantages of the invention will be apparent from the detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0009] definition For convenience, before further description of the present invention, certain terms employed in the specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and should be understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0010] In order to more readily understand the present invention, certain terms and phrases are defined below and throughout the specification.

[0011] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0012] The term "and / or," as used in the specification and claims, should be understood to refer to "either or both" of the elements so combined, i.e., elements that are conjunctive in some cases and disjunctive in other cases. Elements listed with "and / or" must be arranged in the same manner, i.e., "one or more" of the conjunctive elements. Other elements, whether related or unrelated to those elements specifically identified, may optionally be present in addition to the elements specifically identified in the "and / or" clause. Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising," a reference to "A and / or B" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); and so forth.

[0013] As used herein in the specification and claims, "or" shall be understood to have the same meaning as "and / or," as defined above. For example, when separating items in a list, "or" or "and / or" shall be construed as inclusive, i.e., including not only at least one, but also two or more of a number or list of elements, and optionally including additional items not listed. Only clearly indicated terms, such as "only one of," or "exactly one of," or, when used in the claims, "consisting of," shall mean the inclusion of exactly one element of a number or series of elements. Generally, as used herein, the term "or" shall only be construed as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." When used in the claims, "consisting essentially of" shall have its ordinary meaning as used in the field of patent law.

[0014] As used herein in the specification and claims, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one, optionally including two or more As, and no B (and optionally including elements other than B); in another embodiment to at least one, optionally including two or more Bs, and no A (and optionally including elements other than A); in yet another embodiment to at least one, optionally including two or more As, and at least one, optionally including two or more Bs (and optionally including other elements); and so forth.

[0015] It should also be understood that, unless expressly indicated otherwise, in any method claimed herein that includes more than one step or action, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited.

[0016] In the claims and the above specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, shall be understood to be open-ended, i.e., to mean including, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as defined in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0017] Certain compounds contained in the compositions of the present invention may exist in particular geometric forms or stereoisomers. In addition, the polymers of the present invention may also be optically active. The present invention contemplates that all such compounds are within the scope of the present invention, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0018] "Geometric isomer" refers to isomers that differ in the orientation of substituent atoms relative to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond can be in the E configuration (substituents on opposite sides of the carbon-carbon double bond) or the Z configuration (substituents on the same side). "R," "S," "S*," "R*," "E," "Z," "cis," and "trans" refer to structures relative to the core molecule. Certain disclosed compounds can exist in "atropisomeric" forms or as "atropisomers." Atropisomers are stereoisomers resulting from hindrance of rotation about a single bond, where the steric strain hindrance to rotation is sufficiently high to allow for separation of conformers. The compounds of the present invention can be prepared as individual isomers either by isomer-specific synthesis or by resolution from a mixture of isomers. Classical resolution techniques include using an optically active acid to form a salt of the free base of each isomer of the isomeric pair (followed by fractional crystallization and regeneration of the free base), using an optically active amine to form a salt of the acid form of each isomer of the isomeric pair (followed by fractional crystallization and regeneration of the free acid), using an optically pure acid, amine, or alcohol to form an ester or amide of each isomer of the isomer pair (followed by chromatographic separation and removal of the chiral auxiliary), or resolving the isomeric mixture of either the starting materials or the final product using a variety of well-known chromatographic methods.

[0019] For example, if a particular enantiomer of a compound of the present invention is desired, that enantiomer can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, separating the resulting mixture of diastereomers, and cleaving the auxiliary to obtain the desired pure enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by separation of the diastereomers so formed by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomers.

[0020] A mole fraction purity percentage is the mole ratio of an enantiomer (or diastereomer), or the ratio of moles of an enantiomer (or diastereomer) to moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction relative to other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction.

[0021] When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has at least one chiral center, the name or structure should be understood to encompass any enantiomer of the compound, free of the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has two or more chiral centers, the name or structure should be understood to encompass a diastereomer free of the other diastereomer, multiple diastereomers free of other diastereomeric pairs, a mixture of diastereomers, a mixture of diastereomeric pairs, a mixture of diastereomers enriched in one diastereomer relative to the other diastereomer(s), or a mixture of diastereomers enriched in one or more diastereomers relative to the other diastereomers. The present invention encompasses all of these forms.

[0022] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, hydrogen replaced with deuterium or tritium, or carbon replaced with 13 C or 14 C-enriched carbon or boron 10 Compounds produced by substitution with B-enriched boron are within the scope of the present invention.

[0023] The term "prodrug," as used herein, encompasses compounds that are converted into therapeutically active agents under physiological conditions. A common method for making a prodrug is to include selected moieties that hydrolyze under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity in the host animal.

[0024] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the subject chemical entity from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and Examples of suitable pharmaceutical compositions include soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances employed in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not cause a significant temperature increase when administered to a patient.

[0025] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of a compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfate. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19.)

[0026] In other cases, compounds useful in the methods of the present invention may contain one or more acidic functional groups, thereby enabling them to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compound(s). These salts can also be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in their free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, e.g., Berge et al., supra).

[0027] The term "pharmaceutically acceptable cocrystal" refers to a solid coformer that does not form formal ionic interactions with the small molecule.

[0028] A "therapeutically effective amount" (or "effective amount") of a compound, in terms of therapeutic use, means the quantity of the compound(s) that, when administered as part of a desired dosing regimen (to a mammal, preferably a human), reduces the symptoms, ameliorates the condition, or delays the onset of a disease or condition, e.g., in a preparation, at a reasonable benefit / risk ratio applicable to any medical treatment, or according to clinically acceptable standards for cosmetic purposes.

[0029] The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to a host of one or more of the subject compositions. A therapeutic agent is prophylactic (i.e., protects the host from the development of an undesired condition) when administered prior to the appearance of clinical symptoms of an undesired condition (e.g., a disease or other undesired condition in the host animal), whereas a therapeutic agent is therapeutic (i.e., aimed at reducing, ameliorating, or stabilizing an existing undesired condition or its side effects) when administered after the appearance of the undesired condition.

[0030] The term "patient" or "subject" refers to a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is human.

[0031] Aliphatic chains include the classes alkyl, alkenyl, and alkynyl, as defined below. Straight aliphatic chains are limited to unbranched carbon chain moieties. As used herein, the term "aliphatic group" refers to a straight, branched, or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups, such as alkyl, alkenyl, or alkynyl groups.

[0032] "Alkyl" refers to a fully saturated, cyclic or acyclic, branched or unbranched carbon chain moiety having the specified number of carbon atoms, or, if not specified, up to 30 carbon atoms. For example, alkyl having 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as moieties that are positional isomers of these moieties. Alkyl having 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, a straight-chain or branched-chain alkyl has up to 30, and more preferably up to 20, carbon atoms in its backbone (e.g., C1-C6 for a straight chain). 30 , C3-C for branched chains 30 The alkyl group may be substituted or unsubstituted.

[0033] As used herein, the term "heteroalkyl" means an alkyl moiety, as defined above, that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of a carbon atom.

[0034] As used herein, the term "haloalkyl" means an alkyl group, as defined above, substituted with at least one halogen.

[0035] As used herein, the term "hydroxyalkyl" means an alkyl group, as defined above, substituted with at least one hydroxyl.

[0036] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbons, e.g., 1 to 12 carbon atoms, that contains two points of attachment to the remainder of the compound on the longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH)-, ethylene-(CHCH)-, n-propylene-(CHCHCH)-, isopropylene-(CHCH(CH))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moieties, and can be optionally substituted with one or more substituents.

[0037] "Cycloalkyl" means a monocyclic, bicyclic, bridged, spirocyclic, or polycyclic saturated carbocyclic ring, each of which has from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3 to 10 carbon atoms in their ring structure, and more preferably have from 3 to 6 carbons in the ring structure. Cycloalkyl groups can be substituted or unsubstituted.

[0038] As used herein, the term "halocycloalkyl" means a cycloalkyl group, as defined above, that is substituted with at least one halogen.

[0039] "Cycloheteroalkyl" means a cycloalkyl moiety, as defined above, that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of a carbon atom. Preferred cycloheteroalkyls have from 4 to 8 carbon atoms and heteroatoms in the ring structure, and more preferably 4 to 6 carbon atoms and heteroatoms in the ring structure. Cycloheteroalkyl groups can be substituted or unsubstituted.

[0040] Unless the number of carbon atoms is otherwise specified, "lower alkyl," as used herein, refers to an alkyl group, as defined above, having 1 to 10 carbon atoms in its backbone structure, more preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent described herein as alkyl is a lower alkyl.

[0041] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having a specified number of carbon atoms, or up to 26 carbon atoms if no limit on the number of carbon atoms is specified, and having one or more double bonds within the moiety. Alkenyls having 6 to 26 carbon atoms are exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and tetracosenyl, and in various isomeric forms, the unsaturated bond(s) may be at any position within the moiety and may have either the (Z) or (E) configuration about the double bond(s).

[0042] "Alkynyl" refers to a hydrocarbyl moiety within the scope of alkenyl, but having one or more triple bonds within the moiety.

[0043] The term "aryl," as used herein, includes 3- to 12-membered substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or one or more atoms is a heteroatom (i.e., heteroaryl). Preferably, the aryl group includes a 5- to 12-membered ring, more preferably a 6- to 10-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is aromatic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, and more preferably 5- to 10-membered rings, in which the ring structure contains 1 to 4 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, etc. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0044] The terms "halo," "halide," or "halogen," as used herein, mean halogens, including, but not limited to, fluoro, chloro, bromo, iodo, and the like, in both radioactive and non-radioactive forms. In preferred embodiments, halo is selected from the group consisting of fluoro, chloro, and bromo.

[0045] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, and more preferably 5- to 10-membered rings, which include one to four heteroatoms in the ring structure. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathine, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with the substituents described above, such as, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF3, -CN, etc.

[0046] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more backbone carbons. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound (e.g., one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc.). As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfy the valence of the heteroatom. The substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. In a preferred embodiment, the substituent of the substituted alkyl is C 1-6 Alkyl, C 3-6 In a preferred embodiment, the substituent on the substituted alkyl is selected from fluoro, carbonyl, cyano, or hydroxyl. Those skilled in the art will understand that, where appropriate, the substituents themselves may be substituted. Unless specifically stated as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0047] As used herein, each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, means that it is independent of its definition elsewhere in the same structure.

[0048] As used herein, "small molecule" means a small organic or inorganic molecule having a molecular weight of less than about 3,000 Daltons. Generally, small molecules useful in the present invention have a molecular weight of less than 3,000 Daltons (Da). A small molecule can be, for example, at least about 100 Da to about 3,000 Da (e.g., about 100 to about 3,000 Da, about 100 to about 2,500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1,500, about 500 to about 1,000, about 300 to about 1,000 Da, or about 100 to about 250 Da).

[0049] In some embodiments, "small molecule" refers to an organic, inorganic, or organometallic compound, typically having a molecular weight of less than about 1000. In some embodiments, small molecules are organic compounds having sizes on the order of 1 nm. In some embodiments, small molecule drugs of the present invention include oligopeptides and other biomolecules having a molecular weight of less than about 1000.

[0050] An "effective amount" is an amount sufficient to achieve a beneficial or desired result. For example, a therapeutic amount is an amount that achieves a desired therapeutic effect. This amount can be the same as or different from a prophylactically effective amount, which is the amount necessary to prevent the onset of a disease or disease symptoms. An effective amount can be administered in one or more administrations, applications, or dosages. A therapeutically effective amount of a composition will vary depending on the composition selected. The composition can be administered once or more times daily to once or more times weekly (including once every other day). One of skill in the art will recognize that certain factors, including but not limited to, the severity of the disease or disorder, previous treatments, the subject's overall health and / or age, and other diseases present, can affect the dosage and timing required to effectively treat a subject. Furthermore, treatment of a subject with a therapeutically effective amount of a composition described herein can include a single treatment or a series of treatments. A series of treatments can include a second or subsequent treatment several weeks to months after the first or previous treatment.

[0051] The terms "reduce," "lower," "reduced," "reduce," "reduce," and "inhibit" are all generally used herein to refer to a statistically significant amount of reduction compared to a reference. However, for the avoidance of doubt, "reduce," "reduce," or "reduce," or "inhibit" typically refers to a reduction of at least 10% compared to a reference level, and can include, for example, a reduction of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, including any reduction between 10% and 99% compared to the complete absence of a given element or parameter compared to a reference level, or compared to the absence of a given treatment.

[0052] The terms "increased," "increase," or "improve," or "activate" are all used herein to generally mean an increase by a statistically significant amount, and for the avoidance of doubt, the terms "increased," "increase," or "improve," or "activate" mean an increase of at least 10% compared to a reference level, for example, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to and including a 100% increase compared to a reference level, or any increase between 10-100% compared to a reference level, or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold, or any increase between 2-fold and 10-fold or more compared to a reference level.

[0053] As used herein, the term "modulate" includes upregulation and downregulation, eg, enhancing or inhibiting a response.

[0054] As defined herein, a "radiopharmaceutical agent" refers to a pharmaceutical agent containing at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and / or treatment of various diseases. Radiolabeled pharmaceutical agents, such as radiolabeled antibodies, contain a radioisotope (RI) that functions as a radiation source. As contemplated herein, the term "radioisotope" includes metallic and non-metallic radioisotopes. The radioisotope is selected based on the medical use of the radiolabeled pharmaceutical agent. When the radioisotope is a metallic radioisotope, a chelating agent is typically used to bind the metallic radioisotope to the remainder of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically bound to the remainder of the molecule directly or via a linker.

[0055] For purposes of this invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, inside pages of Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0056] Compounds of the Invention One aspect of the present invention is a compound of formula (I): [ka] During the ceremony, Y1 is absent or -O-; Y2 is an optionally substituted -alkylene-; R1, R2, and R5 are each independently selected from -H and halo; R3 is selected from -H, halo, and -X1-X2; R4 is selected from -H, halo, and -X1-X2; X1 is -alkylene-; X2 is -C(H)(NH2)CO2H, The compound may be racemic, enriched in one enantiomer, or a single enantiomer, but shall contain exactly one occurrence of one -X1-X2, The present invention relates to a compound, or a pharmaceutically acceptable salt thereof.

[0057] In certain embodiments, the compound has the structure of formula (IA): [ka] wherein R4 is selected from -H and halo.

[0058] In certain embodiments, each of R1, R2, R4, and R5 is -H.

[0059] In certain embodiments, one of R1, R2, R4, and R5 is halo, and the remaining each of R1, R2, R4, and R5 is -H.

[0060] In certain embodiments, halo is —F.

[0061] In certain embodiments, the compound has a structure selected from the following: [ka] In the formula, * indicates a chiral carbon having an absolute configuration of (S) or (R), and the compound is not a racemic compound.

[0062] In certain embodiments, the absolute configuration of the chiral carbon is (S).

[0063] In certain embodiments, the absolute configuration of the chiral carbon is (R).

[0064] In certain embodiments, the compound has the structure of formula (IB): [ka] wherein R3 is selected from -H and halo.

[0065] In certain embodiments, each of R1, R2, R3, and R5 is -H.

[0066] In certain embodiments, one of R1, R2, R3, and R5 is halo, and the remaining ones of R1, R2, R3, and R5 are each hydrogen.

[0067] In certain embodiments, halo is —F.

[0068] In certain embodiments, the compound has a structure selected from the following: [ka] In the formula, * indicates a chiral carbon having an absolute configuration of (S) or (R), and the compound is not a racemic compound.

[0069] In certain embodiments, the absolute configuration of the chiral carbon is (S).

[0070] In certain embodiments, the absolute configuration of the chiral carbon is (R).

[0071] In certain embodiments, X1 is -(C1-C4)alkylene-.

[0072] In certain embodiments, X1 is -CH2-.

[0073] In certain embodiments, Y 1 is —O—.

[0074] In certain embodiments, Y2 is unsubstituted -(C1-C4)alkylene-.

[0075] In certain embodiments, Y2 is selected from -CH2- and -CH2CH2-.

[0076] In certain embodiments, Y2 is substituted -(C1-C4)alkylene-.

[0077] In certain embodiments, Y2 is substituted with halo, alkyl, heteroalkyl, cycloalkyl, or cycloheteroalkyl.

[0078] In certain embodiments, Y2 is selected from -C(Y3)(Y4)- and -C(Y3)(Y4)CH2-, where Y3 and Y4 are each independently selected from -H, halo, alkyl, and heteroalkyl, provided that at least one of Y3 and Y4 is not -H, or Y3 and Y4 together with the carbon to which they are attached form a cycloalkyl, cycloheteroalkyl, spirocycloalkyl, or spirocycloheteroalkyl.

[0079] In certain embodiments, Y3 and Y4 together with the carbon to which they are attached form a cyclopropyl.

[0080] In certain embodiments, Y1 is absent.

[0081] In certain embodiments, Y2 is unsubstituted -(C1-C4)alkylene-.

[0082] In certain embodiments, Y2 is selected from -CH2- and -CH2CH2-.

[0083] In certain embodiments, Y2 is substituted -(C1-C4)alkylene-.

[0084] In certain embodiments, Y2 is substituted with halo, alkyl, heteroalkyl, cycloalkyl, or cycloheteroalkyl.

[0085] In certain embodiments, Y2 is selected from -C(Y3)(Y4)- and -C(Y3)(Y4)CH2-, where Y3 and Y4 are each independently selected from -H, halo, alkyl, and heteroalkyl, provided that at least one of Y3 and Y4 is not -H, or Y3 and Y4 together with the carbon to which they are attached form a cycloalkyl, cycloheteroalkyl, spirocycloalkyl, or spirocycloheteroalkyl.

[0086] In certain embodiments, Y3 and Y4 together with the carbon to which they are attached form a cyclopropyl.

[0087] In certain embodiments, a compound having a structure selected from the following: [ka]

[0088] In certain embodiments, a compound having a structure selected from the following: [ka]

[0089] In certain embodiments, a compound having a structure selected from the following: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0090] In certain embodiments, a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0091] In certain embodiments, the boron atom in the compound is 10 It's B.

[0092] In certain embodiments, the compounds are atropisomers. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds produced by replacing the variable R with C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention. For example, 1 In the case of -C1-C4 alkyl, or -O-(C1-C4) alkyl, the alkyl group may be suitably deuterated (e.g., -CD3, -OCD3).

[0093] 11 B and 10 Compounds produced containing the natural distribution of B are also within the scope of the present invention.

[0094] 10B-enriched compounds, i.e., 10 Compounds in which B is present in an abundance greater than 20% are also within the scope of the present invention.

[0095] Any of the compounds of the present invention may also be radiolabeled for the preparation of radiopharmaceutical agents.

[0096] Treatment methods One aspect of the present invention provides compounds, compositions, and methods useful for boron neutron capture therapy.

[0097] Another aspect of the present disclosure relates to a method of treating cancer, the method comprising: i) administering a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I), to a subject in need thereof, wherein the compound accumulates in a plurality of cancer cells in the subject; ii) Irradiating multiple cancer cells with neutrons.

[0098] In certain embodiments, the compound selectively or preferentially accumulates in a plurality of cancer cells relative to non-cancerous cells in the subject.

[0099] In certain embodiments, the irradiating step comprises irradiating a compound 10 This results in the conversion of B atoms into alpha particles and lithium 7 ions.

[0100] In certain embodiments, the compound or composition is administered intravenously.

[0101] In certain embodiments, the compound is administered continuously during irradiation with neutrons.

[0102] In certain embodiments, in step (i), the compound is administered at about 100 mg / kg / h to about 500 mg / kg / h for a first period of time.

[0103] In certain embodiments, in step (i), the compound is administered at about 150 mg / kg / h to about 300 mg / kg / h for a first period of time.

[0104] In certain embodiments, the first period of time is from about 1 hour to about 3 hours, hi certain embodiments, the first period of time is about 2 hours.

[0105] In certain embodiments, in step (ii), the compound is administered at about 50 mg / kg / h to about 150 mg / kg / h for the second period of time.

[0106] In certain embodiments, in step (ii), the compound is administered at about 100 mg / kg / h to about 200 mg / kg / h for the second period of time.

[0107] In certain embodiments, the second period of time is from about 0.25 hours to about 1.25 hours.

[0108] In certain embodiments, the second period of time is from about 0.5 hours to about 1 hour.

[0109] In certain embodiments, the cancer is a solid tumor.

[0110] In certain embodiments, the cancer is selected from head and neck cancer, glioblastoma, melanoma, sarcoma, breast cancer, meningioma, lung cancer, mesothelioma, hepatocellular carcinoma, and extramammary Paget's disease.

[0111] In certain embodiments, the cancer is unresectable head and neck cancer.

[0112] In certain embodiments of any one of the disclosed methods, the compound of formula (I) is defined as follows: [ka] During the ceremony, Y1 is absent or -O-; Y2 is an optionally substituted -alkylene-; R1, R2, and R5 are each independently selected from -H and halo; R3 is selected from -H, halo, and -X1-X2; R4 is selected from -H, halo, and -X1-X2; X1 is -alkylene-; X2 is -C(H)(NH2)CO2H, The compound may be racemic, enriched in one enantiomer, or a single enantiomer, but Compounds which contain only one occurrence of one -X1-X2, or a pharmaceutically acceptable salt thereof.

[0113] Pharmaceutical Compositions, Routes of Administration, and Dosage In certain embodiments, the present invention is directed to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, a pharmaceutical composition comprises multiple compounds of the present invention and a pharmaceutically acceptable carrier.

[0114] In certain embodiments, the pharmaceutical compositions of the present invention further comprise at least one additional pharmaceutically active agent other than the compound of the present invention.

[0115] Pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0116] In certain embodiments, the pharmaceutical composition further comprises a saccharide.

[0117] In certain embodiments, the pharmaceutical composition further comprises a polyhydroxy acid.

[0118] In certain embodiments, the pharmaceutical composition further comprises a sugar alcohol.

[0119] As stated above, "effective amount" refers to any amount sufficient to achieve a desired biological effect. By combining the teachings provided herein and selecting from among various active compounds, and by weighing factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and method of administration, an effective prophylactic or therapeutic treatment regimen can be designed that is effective in treating a particular subject without causing substantial undesirable toxicity. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the particular compound of the present invention being administered, the size of the subject, or the severity of the disease or condition. Those of ordinary skill in the art can empirically determine the effective amount of a particular compound of the present invention and / or other therapeutic agent without necessitating undue experimentation. A maximum dosage, i.e., the highest safe dose according to some medical judgment, can be used. Multiple daily administrations may be contemplated to achieve an appropriate systemic dose of the compound. For example, an appropriate systemic dose can be determined by measuring a patient's peak or sustained plasma concentration of the drug. "Dose" and "administration" are used interchangeably herein.

[0120] In certain embodiments, intravenous administration of the compound may typically be from about 300 mg / kg / day to about 1000 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be from about 400 mg / kg / day to about 600 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be from about 450 mg / kg / day to about 500 mg / kg / day.

[0121] Dosage can be adjusted appropriately to achieve desired drug level locally or systemically depending on the mode of administration.For example, in intravenous administration, daily dosage is expected to be one to several orders of magnitude smaller.If subject's response is insufficient at this dosage, higher dosage (or effective high dosage by other more localized delivery route) can be adopted to the extent that patient's tolerance allows.In order to achieve appropriate internal concentration of compound, multiple administrations per day are contemplated.

[0122] For any compound described herein, the therapeutically effective amount can be first determined from animal models.The therapeutically effective amount can also be determined from human data for compounds tested in humans and for compounds known to exhibit similar pharmacological activity, such as other related active agents.Higher doses may be required for parenteral administration.The applied dose can be adjusted according to the relative bioavailability and efficacy of the administered compound.Adjusting the dose to achieve maximum efficacy based on the methods described above and other methods well known in the art is well within the capabilities of those skilled in the art.

[0123] The formulations of the present invention may be administered in pharmaceutically acceptable solutions, which may conventionally contain pharmaceutically acceptable concentrations of salts, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0124] When used in therapy, an effective amount of compound can be administered to a subject by any method that delivers the compound to the desired surface.The administration of pharmaceutical compositions can be carried out by any means known to those skilled in the art.Administration routes include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (e.g., into tumor or abscess), mucosal (e.g., topical to the eye), inhalation, and topical.

[0125] For intravenous and other parenteral administration routes, the compounds of the present invention can be formulated as lyophilized preparations, as lyophilized preparations of liposome intercalated or liposome-encapsulated active compounds, as lipid complexes in aqueous suspension, or as salt complexes. Lyophilized preparations are generally reconstituted with a suitable aqueous solution, such as sterile water or physiological saline, immediately prior to administration.

[0126] It will be understood by those skilled in the relevant art that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the invention contained herein, in view of the information known to those skilled in the art, and can be made without departing from the scope of the invention or any embodiment thereof. Having now described the invention in detail, the present invention will be more clearly understood by reference to the following examples. The examples are included herein for illustrative purposes only and are not intended to limit the invention. [Example]

[0127] The invention is described in more detail in the following examples, which do not limit the scope of the invention described in the claims.

[0128] Abbreviations used herein, particularly in the Schemes and Examples, are as set out in Table A below: JPEG2025526608000013.jpg232165JPEG2025526608000014.jpg57165

[0129] Example 1. Preparation of Compounds Scheme A. Synthesis of Compound (1) [ka] Reagents and conditions: (a) SOCl2, MeOH, 70 °C; (b) Boc2O, NaHCO3, dioxane, water, rt; (c) K2CO3, DMF, rt; (d) LiOH·H2O, THF, water, rt; (e) HCl, EA, rt;

[0130] Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propanoate (I-1.1) Step A. To a mixture of 3-hydroxy-L-phenylalanine (5 g, 27.6 mmol) in MeOH (100 mL) at 0 °C was added SOCl (6.57 g, 55 mmol, 2 equiv.) dropwise. The reaction mixture was heated at 70 °C for 4 h. The mixture was cooled to room temperature and concentrated in vacuo to give crude methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate as a gum, which was used directly in the next step.

[0131] Step B. To a mixture of methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate (1.37 g, 7.02 mmol, 1 equiv.) and NaHCO3 (1.47 g, 17.5 mmol, 2.5 equiv.) in dioxane (15 mL) / water (15 mL) at room temperature, di-tert-butyl dicarbonate (1.84 g, 8.4 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (1:2) to give methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propanoate as a colorless liquid (2.02 g, 99%). LCMS(ESI):C 15 H 21 Calculated mass for NO5, 295.1; observed m / z, 196.3 [M+H-Boc] + .

[0132] Preparation of (S)-3-(3-(boronomethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (I-1.2) Step C. To a mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propanoate (1 g, 3.39 mmol, 1 equiv.) and K2CO3 (0.94 g, 6.772 mmol, 2 equiv.) in DMF (10 mL) was added 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.96 g, 6.77 mmol, 2 equiv.). The reaction mixture was stirred at room temperature overnight and then diluted with brine (40 mL). The mixture was extracted with EtOAc (5 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product (1.8 g) was used directly in the next step without further purification. Note: 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was also used to improve yields.

[0133] Step D. To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methoxy]phenyl}propanoate (0.9 g, 2.07 mmol, 1 equiv.) in THF (10 mL) / water (5 mL), LiOH·HO (0.25 g, 6.01 mmol, 3 equiv.) was added at room temperature. The reaction mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc (3 × 10 mL). The resulting aqueous layer was acidified to pH 5 with 1 N HCl (aq.), and the resulting mixture was extracted again with EtOAc (5 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. This gave (S)-3-(3-(boronomethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid as a yellow oil (0.65 g, crude). LCMS (ESI): C 15 H 22 Calculated mass for BNO7, 339.1; observed m / z, 240.0 [M+H-Boc] + .

[0134] Preparation of (S)-2-amino-3-(3-(boronomethoxy)phenyl)propanoic acid; trifluoroacetate (I-1) To a stirred solution of (S)-3-(3-(boronomethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.65 g, crude) in 6 mL of EtOAc was added 4 M HCl in 3 mL of EtOAc at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: Column: Sunfire prep C18 column, 30*150 mm, 5 μm; Mobile phase A: water (0.05% TFA); Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 4% B to 11% B, 11% B in 7 min; Wavelength: 254 / 220 nm; RT (min): 4.95) to give (S)-2-amino-3-(3-(boronomethoxy)phenyl)propanoic acid; trifluoroacetic acid as a white solid (70 mg, 9.90%). LCMS(ESI):C 10 H 14 Calculated mass for BNO5: 239.1; observed m / z: 240.1 [M+H] + . 1 H NMR(400MHz, heavy water)δ 7.23(t,J=8.1Hz,1H),6.91-6.83(m,1H),6.83-6.73(m,2H),4.17-4.00(m,1 H),3.70(s,2H),3.19(dd,J=14.5,5.4Hz,1H),3.04(dd,J=14.5,7.9Hz,1H).

[0135] Scheme B. Synthesis of Compound (2) [ka] Reagents and conditions: (a) (trimethylsilyl)diazomethane (2 M in hexane), MeOH, toluene, 0° C.; (b) K2CO3, DMF, rt; (c) HCl (4 M in EtOAc), rt; (d) LiOH, THF, H2O, rt.

[0136] Preparation of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2-fluoro-4-hydroxyphenyl)propanoate (I-2.1) To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-4-hydroxyphenyl)propanoic acid (600 mg, 2.005 mmol, 1 equiv.) in toluene (20 mL) / MeOH (5 mL) was added (trimethylsilyl)diazomethane (2 M in hexanes) (2.406 mmol, 1.20 mL, 1.2 equiv.) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 h. The reaction was monitored by LCMS. The reaction was quenched at room temperature by the addition of AcOH (0.5 mL) and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.HO) in water, 55% to 65% gradient in 10 min; detector, UV 254 nm]. This gave methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-4-hydroxyphenyl)propanoate as a white solid (540 mg, 85.97%). LCMS (ESI): C 15 H 20 Calculated mass for FNO5: 313.13; measured m / z: 312.0 [MH] - .

[0137] Preparation of (S)-((4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-3-fluorophenoxy)methyl)methylboronate (I-2.2) To a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-4-hydroxyphenyl)propanoate (540 mg, 1.723 mmol, 1 equiv.) and K2CO3 (1190.95 mg, 8.615 mmol, 5 equiv.) in DMF (10 mL) at room temperature, 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2308.56 mg, 8.615 mmol, 5 equiv.) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (2 x 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.HO) in water, 50% to 60% gradient in 10 min; detector, UV 254 nm. This afforded (S)-((4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-3-fluorophenoxy)methyl)boronic acid as a white solid (590 mg, 92.18%). LCMS (ESI): C 16 H 23 Calculated mass for BFNO7, 371.16; observed m / z, 272.1 [M+H-Boc] + .

[0138] Preparation of 4-[(2S)-2-amino-3-methoxy-3-oxopropyl]-3-fluorophenoxymethylboronic acid (I-2.3) To a stirred mixture of methyl (S)-((4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-3-fluorophenoxy)methyl)boronate (100 mg, 0.221 mmol, 1 equiv.) in EtOAc (2.0 mL) at room temperature under a nitrogen atmosphere was added 4 M HCl in EtOAc (2.0 mL) dropwise. The resulting mixture was stirred at room temperature for 5 hours and then concentrated in vacuo. The residue was diluted with water and basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (2x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.HO) in water, 20% to 30% gradient over 8 min; detector, UV 254 nm. This afforded 4-[(2S)-2-amino-3-methoxy-3-oxopropyl]-3-fluorophenoxymethylboronic acid as a white solid (340 mg, 96.38%). LCMS (ESI): C 11 H 15 Calculated mass for BFNO5, 271.1; observed m / z, 272.2 [M+H] + .

[0139] Preparation of (S)-2-amino-3-(4-(boronomethoxy)-2-fluorophenyl)propanoic acid; trifluoroacetic acid (I-2) To a stirred mixture of 4-[(2S)-2-amino-3-methoxy-3-oxopropyl]-3-fluorophenoxymethylboronic acid (340 mg, 1.25 mmol, 1 equiv.) in THF (3 mL) / HO (1 mL) was added LiOH·HO (157.9 mg, 3.76 mmol, 3.00 equiv.) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 h. The reaction mixture was acidified to pH 6 with 1 N HCl (aq.) and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm]. The product was further purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 4% B to 10% B, 10% B in 7 min; Wavelength: 254 / 220 nm; RT1 (min): 5.92. This afforded (S)-2-amino-3-(4-(boronomethoxy)-2-fluorophenyl)propanoic acid; trifluoroacetic acid (110 mg, 22.50%) as a white solid. LCMS (ESI): C 10 H 13 Calculated mass for BFNO5: 257.1; observed m / z: 257.9 [M+H] + , 1 H NMR(400MHz, heavy water)δ 7.17(t,J=8.6Hz,1H),6.80-6.72(m,2H),4.06(dd,J=7.5,5.5Hz,1H),3.75(s,2H),3.24(dd,J=14.8,5.6Hz,1H),3.06(dd,J=14.8,7.6Hz,1H).

[0140] Scheme C. Synthesis of Compound (3) [ka] Reagents and conditions: (a) 1,2-dibromoethane, K2CO3, 18-crown-6, 80 °C; (b) CuCl, Xantphos, B2Pin2, tBuOK, DMF, 50 °C; (c) LiOH·H2O, MeOH, H2O, rt; (d) HCl, dioxane, rt; (e) NaIO4, HCl, THF, H2O, rt.

[0141] Preparation of (S)-methyl 3-(4-(2-bromoethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (I-3.1) To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (5 g, 16.930 mmol, 1 equiv.) in dibromoethane (20 mL) at room temperature, K2CO3 (16.00 g, 115.801 mmol, 6.84 equiv.) and 18-crown-6 (0.45 g, 1.693 mmol, 0.1 equiv.) were added. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 24 h. The mixture was cooled to room temperature and diluted with ethyl acetate (150 mL). The mixture was then washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give (S)-methyl 3-(4-(2-bromoethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as a white solid (5.6 g, 82.22%). LCMS (ESI): C 17 H 24 Calculated mass for BrNO2: 401.1; observed m / z: 302.0 [M-Boc+H] + .

[0142] Preparation of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy)phenyl)propanoate (I-3.2) To a stirred solution of (S)-methyl 3-[4-(2-bromoethoxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propanoate (5.6 g, 13.921 mmol, 1 equiv.) and bis(pinacolato)diboron (10.61 g, 41.762 mmol, 3 equiv.) in DMF (110 mL) at room temperature was added CuCl (413.44 mg, 4.177 mmol, 0.3 equiv.), Xantphos (2.41 g, 4.177 mmol, 0.3 equiv.), and potassium tert-butoxide (1 M in THF) (16.6 mL, 1.2 equiv.). The resulting mixture was purged with N for 1 min and then stirred at 50 °C under a nitrogen atmosphere for 3 h. The mixture was diluted with EA (80 mL) and washed with water (40 mL) and brine (40 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give methyl (S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy]phenyl}propanoate (2.8 g, 44.76%) as a colorless oil. LCMS (ESI): C 23 H 36 Calculated mass for BNO7: 449.3; observed m / z: 350.2 [M-Boc+H] + .

[0143] Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy)phenyl)propanoic acid (I-3.3) To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy]phenyl}propanoate (1.08 g, 2.403 mmol, 1 equiv.) in HO (20 mL) and MeOH (40 mL) at room temperature, LiOH·HO (302.6 mg, 7.21 mmol, 3 equiv.) was added portionwise. The resulting mixture was stirred at room temperature for 3 h. The mixture was then acidified to pH 4 with 1 N HCl (aq.), extracted with EA (3×30 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): C 22 H 34 Calculated mass for BNO7: 435.2; observed m / z: 336.2 [M-Boc+H] + .

[0144] Preparation of (S)-2-amino-3-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy)phenyl)propanoic acid (I-3.4) To a stirred solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy]phenyl}propanoic acid (920 mg, 2.11 mmol, 1 equiv.) in dioxane (9 mL) was added dropwise HCl (gas) solution (9 mL, 4 M in dioxane). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): C 17 H 26 Calculated mass for BNO5: 335.2; observed m / z: 336.2 [M+H] + .

[0145] Preparation of (2S)-2-amino-3-{4-[2-(dihydroxyboranyl)ethoxy]phenyl}propanoic acid (I-3) To a stirred solution of (2S)-2-amino-3-{4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy]phenyl}propanoic acid (800 mg, 2.39 mmol, 1 equiv.) in THF (20.00 mL) and HO (5.00 mL) at room temperature, sodium periodate (1.53 g, 7.161 mmol, 3 equiv.) was added portionwise. The resulting mixture was stirred at room temperature for 5 minutes, and then 2 N HCl (aq.) (1.00 mL, 2.005 mmol, 0.84 equiv.) was added. The reaction mixture was stirred at room temperature for an additional 2 hours. The mixture was then filtered, and the filter cake was washed with water (2 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by HP-flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 5% to 30% gradient in 20 min; detector, UV 220 nm. This afforded (2S)-2-amino-3-{4-[2-(dihydroxyboranyl)ethoxy]phenyl}propanoic acid as a white solid (150 mg, 24.12%). LCMS (ESI): C 11 H 16 Calculated mass for BNO5: 253.1; observed m / z: 254.1 [M+H] + ; 1 H NMR(400MHz, heavy water)δ 7.17(d,J=8.2Hz,2H),6.92(d,J=8.2Hz,2H),4.13(t,J=7.5Hz,2H),3.87(dd,J=7.6,5.3H z,1H),3.14(dd,J=14.6,5.2Hz,1H),2.99(dd,J=14.7,7.8Hz,1H),1.26(t,J=7.6Hz,2H).

[0146] Scheme D. Synthesis of Compound (4) [ka] Reagents and conditions: (a) K2CO3, DMF, rt; (b) HCl (4 M in EtOAc), EtOAc, rt.

[0147] Preparation of tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methoxy]phenyl}propanoate (I-4.1) To a stirred mixture of tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (1 g, 2.964 mmol, 1 equiv.) and K2CO3 (0.82 g, 5.928 mmol, 2 equiv.) in DMF (10 mL) at room temperature, 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.31 g, 5.928 mmol, 2 equiv.) was added. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water and then extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (3 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methoxy]phenyl}propanoate as a pale yellow oil (1.34 g, crude). LCMS (ESI): C 25 H 40 Calculated mass for BNO7: 477.4; observed m / z: 378 [M+H-Boc] + .

[0148] Preparation of 2-amino-3-{4-[(dihydroxyboranyl)methoxy]phenyl}propanoic acid (I-4) To a stirred mixture of tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methoxy]phenyl}propanoate (670 mg, 1.40 mmol, 1 equiv.) in EtOAc (5 mL) at room temperature was added dropwise HCl (g) solution (10 mL, 4 M in EtOAc). The resulting mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration and washed with ethyl ether (3 x 5 mL). The crude product (358 mg) was purified by preparative HPLC under the following conditions (Column: Atlantis Prep T3 OBD Column, 19*150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 2% B to 6% B, 6% B in 6 min; Wavelength: 254 / 220 nm; RT1 (min): 4.57) to give 2-amino-3-{4-[(dihydroxyboranyl)methoxy]phenyl}propanoic acid as a white solid (49.1 mg, 14.61%).

[0149] LCMS(ESI):C 10 H 14 Calculated mass for BNO5: 239.0; observed m / z: 240.0 [M+H] + . 1 H NMR(400MHz, heavy water)δ 7.17(d,J=8.7Hz,2H),6.93(d,J=8.6Hz,2H),3.87(dd,J=7.8,5.1Hz,1H),3.75(s,2H),3.15(dd,J=14.7,5.2Hz,1H),2.99(dd,J=14.7,7.8Hz,1H).

[0150] Scheme E. Synthesis of Compound (5) [ka] Reagents and conditions: (a) Pd(OAc)2, S-Phos, K3PO4, dioxane, H2O, 90 °C; (b) EtOH, EDCI, DMAP, DCM, rt; (c) BH3-THF, H2O, rt; (d) LiOH, MeOH, H2O, rt; (e) TFA, DCM, rt.

[0151] Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(3-vinylphenyl)propanoic acid (I-5.1) To a stirred mixture of (2S)-3-(3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (2 g, 5.81 mmol, 1 equiv.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.34 g, 8.72 mmol, 1.5 equiv.) in dioxane (50 mL) and HO (5 mL) at room temperature, KPO (4.93 g, 23.2 mmol, 4 equiv.), S-phos (0.48 g, 1.162 mmol, 0.2 equiv.), and Pd(OAc) (0.13 g, 0.581 mmol, 0.1 equiv.) were added. The reaction mixture was purged with N for 1 minute and then stirred at 90 °C under a nitrogen atmosphere for 8 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-ethenylphenyl)propanoic acid (2.1 g, crude) as a brown oil. LCMS (ESI): 16 H 21 Calculated mass for NO4: 291.1; observed m / z: 192 [M-Boc+H] + .

[0152] Preparation of (S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(3-vinylphenyl)propanoate (I-5.2) To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-ethenylphenyl)propanoic acid (2.2 g, 7.551 mmol, 1 equiv.), EtOH (3.48 g, 75.510 mmol, 10 equiv.), and DMAP (0.09 g, 0.755 mmol, 0.1 equiv.) in DCM (60 mL) was added EDCI (1.59 g, 8.306 mmol, 1.1 equiv.) at room temperature. The reaction mixture was stirred at 25° C. for 8 hours and then concentrated under reduced pressure. The residue was purified by reverse flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 10% to 80% gradient in 10 min; detector, UV 254 / 220 nm] to give ethyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-ethenylphenyl)propanoate as a pale yellow solid (1.5 g, 62.19%). LCMS (ESI): C 18 H 25 Calculated mass for NO4: 319.2; observed m / z: 220.1 [M-Boc+H] + .

[0153] Preparation of (S)-(3-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)phenethyl)boronic acid (I-5.3) To a stirred mixture of ethyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-ethenylphenyl)propanoate (800 mg, 2.505 mmol, 1 equiv.) in THF (10 mL) at 0° C. was added dropwise borane solution (1 M in THF, 5 mL, 5.01 mmol, 2 equiv.). The reaction mixture was stirred at 25° C. for 2 hours and then quenched by the addition of water at 0° C. The mixture was stirred at 25° C. for an additional 2 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 10% to 50% gradient in 10 min; detector, UV 254 / 220 nm] to give 2-{3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]phenyl}ethylboronic acid as a pale yellow oil (600 mg, 65.59%). LCMS (ESI): C 18 H 28 Calculated mass for BNO6: 365.2; observed m / z: 266.2 [M-Boc+H] + .

[0154] Preparation of (S)-3-(3-(2-boronoethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (I-5.4) To a stirred mixture of 2-{3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]phenyl}ethylboronic acid (600 mg, 1.64 mmol, 1 equiv.) in MeOH (6 mL) and HO (6 mL) was added LiOH·HO (344.70 mg, 8.215 mmol, 5 equiv.). The mixture was stirred at 25 °C for 2 h and then acidified to pH 4 with 2 N HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 10% to 50% gradient in 10 min; detector, UV 254 / 220 nm] to give (S)-3-(3-(2-boronoethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid as an off-white solid (580 mg, crude). LCMS (ESI): C 16 H 24 Calculated mass for BNO6: 337.2; observed m / z: 238.1 [M-Boc+H] + .

[0155] Preparation of (S)-2-amino-3-(3-(2-boronoethyl)phenyl)propanoic acid (I-5) To a stirred mixture of (S)-3-(3-(2-boronoethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (480 mg, 1.42 mmol, 1 equiv.) in DCM (10 mL) at room temperature was added TFA (1 mL) dropwise. The mixture was stirred at 25° C. for 2 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*150 mm, 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: MeOH-HPLC; Flow rate: 25 mL / min; Gradient: 9% B to 10% B, 10% B in 6 min; Wavelength: 220 nm; RT1 (min): 4.11) to give (2S)-2-amino-3-{3-[2-(dihydroxyboranyl)ethyl]phenyl}propanoic acid as an off-white solid (83.3 mg, 24.19%). LCMS (ESI): C 11 H 16Calculated mass for BNO4: 237.1; observed m / z: 238.0 [M+H] + ; 1 H NMR (400 MHz, methanol-d₄) δ 7.24 (t, J = 7.5 Hz, 1H), 7.20-7.03 (m, 3H), 4.00-3.84 (m, 1H), 3.31-3.21 (m, 1H), 3.01 (dd, J = 14.5, 8.3 Hz, 1H), 2.67 (t, J = 8.1 Hz, 2H), 1.11 (t, J = 8.2 Hz, 2H).

[0156] Scheme F. Synthesis of Compound (6) [ka] Reagents and conditions: (a) 1,2-dibromoethane, K2CO3, 18-crown-6, 80 °C; (b) CuCl, Xantphos, B2Pin2, t BuOK, DMF, 50 °C; (c) LiOH·H2O, THF, H2O, rt; (d) NaIO4, HCl, THF, H2O, rt; (e) HCl, EA, rt.

[0157] Preparation of methyl (2S)-3-(4-(2-bromoethoxy)-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (I-6.1) To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-4-hydroxyphenyl)propanoate (I-2.1, 1.03 g, 3.28 mmol, 1 equiv.) in 1,2-dibromoethane (27.2 mL) at room temperature, K2CO3 (3.12 g, 22.62 mmol, 6.9 equiv.) and 18-crown-6 (86.6 mg, 0.327 mmol, 0.1 equiv.) were added. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 24 h. The reaction was cooled to room temperature and diluted with ethyl acetate (80 mL). The mixture was then washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give methyl (2S)-3-[4-(2-bromoethoxy)-2-fluorophenyl]-2-[(tert-butoxycarbonyl)amino]propanoate as a pale yellow oil (1.17 g, 85.20%). LCMS (ESI): C 17 H 23 Calculated mass for BrFNO5: 419.1; observed m / z: 320 [M-Boc+H] + .

[0158] Preparation of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{2-fluoro-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy]phenyl}propanoic acid (I-6.2) A mixture of CuCl (82.9 mg, 0.837 mmol, 0.3 equiv.) and Xantphos (484.62 mg, 0.837 mmol, 0.3 equiv.) in DMF (22 mL) was stirred under a nitrogen atmosphere at room temperature for 0.5 h. Next, methyl (2S)-3-[4-(2-bromoethoxy)-2-fluorophenyl]-2-[(tert-butoxycarbonyl)amino]propanoate (1.17 g, 2.79 mmol, 1 equiv.), bis(pinacolato)diboron (2.13 g, 8.372 mmol, 3 equiv.), and potassium tert-butoxide (1 M in THF) (3.3 mL, 3.3 mmol, 1.2 equiv.) were added. The resulting mixture was purged with N2 for 1 min and then stirred under a nitrogen atmosphere at 50 °C for 3 h. The reaction was quenched by the addition of water (80 mL), and the mixture was extracted with EA (3 x 60 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography, eluting with PE / EA (4:1) to give methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{2-fluoro-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy]phenyl}propanoate as a pale yellow oil (587 mg, 44.96%). LCMS (ESI): C 23 H 35 Calculated mass for BFNO7: 467.3; observed m / z: 368.2 [M-Boc+H] + .

[0159] Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(2-fluoro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy)phenyl)propanoic acid (I-6.3) To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{2-fluoro-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy]phenyl}propanoate (587 mg, 1.25 mmol, 1 equiv.) in HO (15 mL) and THF (30 mL) at room temperature was added LiOH·HO (105.3 mg, 2.51 mmol, 2.00 equiv.) portionwise. The resulting mixture was stirred at room temperature for 3 h. The mixture was acidified to "ph" 4 with 1 M HCl (aq.) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI): C 22 H 33 Calculated mass for BFNO7: 453.2; observed m / z: 354 [M-Boc+H] + .

[0160] Preparation of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(dihydroxyboranyl)ethoxy]-2-fluorophenyl}propanoic acid (I-6.4) To a stirred solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{2-fluoro-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy]phenyl}propanoic acid (560 mg, 1.235 mmol, 1 equiv.) in THF (9.0 mL) and HO (2.3 mL) at room temperature, sodium periodate (792.46 mg, 3.705 mmol, 3.0 equiv.) was added portionwise. The resulting mixture was stirred at room temperature for 5 minutes. Then, 2N HCl (aq.) (0.49 mL, 0.988 mmol, 0.8 equiv.) was added to the above solution. The reaction was stirred at room temperature for an additional 2 hours. The mixture was filtered, and the filter cake was washed with water (2×5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 80% FA gradient in 15 min; detector, UV 220 nm. This afforded (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(dihydroxyboranyl)ethoxy]-2-fluorophenyl}propanoic acid as a pale yellow solid (280 mg, 61.08%). LCMS (ESI): C 16 H 23 Calculated mass for BFNO7: 371.2; observed m / z: 272.1 [M-Boc+H] + .

[0161] Preparation of (2S)-2-amino-3-{4-[2-(dihydroxyboranyl)ethoxy]-2-fluorophenyl}propanoic acid (I-6) To a stirred solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(dihydroxyboranyl)ethoxy]-2-fluorophenyl}propanoic acid (280 mg, 0.755 mmol, 1 equiv.) in EA (5 mL) at room temperature was added hydrogen chloride (5 mL, 20.000 mmol, 4 M in EA) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18, 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 26% B, 26% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 5.23) to give (2S)-2-amino-3-{4-[2-(dihydroxyboranyl)ethoxy]-2-fluorophenyl}propanoic acid as a white solid (65 mg, 31.76%). LCMS (ESI): C 11 H 15 Calculated mass for BFNO5, 271.1; observed m / z, 272.1 [M+H] + ; 1 H NMR(400MHz, heavy water)δ 7.13(t,J=8.6Hz,1H),6.75-6.64(m,2H),4.08(t,J=7.6Hz,2H),3.86(dd,J=7.5,5.6Hz ,1H),3.18(dd,J=14.8,5.4Hz,1H),2.97(dd,J=14.8,7.8Hz,1H),1.24(t,J=7.5Hz,2H).

[0162] Scheme G. Synthesis of compound (7) [ka] Reagents and conditions: (a) Pd(OAc)2, SPhos, K3PO4, dioxane / H2O, 95°C; (b) EtOH, EDCI, DMAP, DCM, rt; (c) BH3-THF, THF, rt; (d) LiOH, HO, EtOH, rt; (e) TFA, DCM, rt.

[0163] Preparation of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-ethenylphenyl)propanoic acid (I-7.1) To a stirred mixture of (2S)-3-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (5 g, 14.526 mmol, 1 equiv.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.36 g, 21.789 mmol, 1.5 equiv.) in 1,4-dioxane (100 mL) and HO (10 mL) at room temperature, KPO (12.33 g, 58.104 mmol, 4 equiv.), SPhos (1192.71 mg, 2.905 mmol, 0.2 equiv.), and Pd(OAc) (0.33 g, 1.453 mmol, 0.1 equiv.) were added. The resulting mixture was purged with N for 1 min and then stirred overnight at 95 °C under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The resulting aqueous layer was acidified to pH 5 with 2N HCl (aq.) and extracted again with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 10% to 80% gradient in 15 min; detector, UV 254 / 220 nm]. This afforded (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-ethenylphenyl)propanoic acid as a brown oil (5.12 g, crude). LCMS (ESI): C 16 H 21 Calculated mass for NO4: 291.1; measured m / z: 290.0 [MH] - .

[0164] Preparation of ethyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-ethenylphenyl)propanoate (I-7.2) To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-ethenylphenyl)propanoic acid (5.12 g, 17.574 mmol, 1 equiv.) and DMAP (0.21 g, 1.757 mmol, 0.1 equiv.) in EtOH (50 mL) and DCM (100 mL) at room temperature, EDCI (3.71 g, 19.331 mmol, 1.1 equiv.) was added portionwise. The resulting mixture was stirred at room temperature for 8 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 30% to 100% FA gradient in 15 min; detector, UV 254 / 220 nm]. This gave ethyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-ethenylphenyl)propanoate as a brown oil (2.86 g, 50.95%). LCMS (ESI): C 18 H 25 Calculated mass for NO4, 319.1; observed m / z, 220.0 [M-Boc+H] + .

[0165] Preparation of 2-{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]phenyl}ethylboronic acid (I-7.3) To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-ethenylphenyl)ethyl propanoate (2.86 g, 8.95 mmol, 1 equiv.) in THF (40 mL) at 0 °C under a nitrogen atmosphere, BH3-THF (17.91 mL, 17.908 mmol, 2 equiv., 1 M in THF) was added dropwise. The resulting mixture was stirred at room temperature for 2 h and then quenched by adding water at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h and then concentrated under reduced pressure. The resulting mixture was extracted with CHCl2 (3 × 60 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous NaSO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 2-{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]phenyl}ethylboronic acid as a light brown oil (3.37 g, crude). LCMS (ESI): C 18 H 28 Calculated mass for BNO6: 365.2; observed m / z: 266.1 [M-Boc+H] + .

[0166] Preparation of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(dihydroxyboranyl)ethyl]phenyl}propanoic acid (I-7.4) To a stirred mixture of 2-{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]phenyl}ethylboronic acid (3.85 g, 10.541 mmol, 1 equiv.) in EtOH (60 mL) and HO (6 mL) at room temperature, LiOH·HO (2.21 g, 52.705 mmol, 5 equiv.) was added portionwise. The resulting mixture was stirred at room temperature for 2 h and then diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The resulting aqueous layer was acidified to pH 4–5 with 2 N HCl (aq.). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(dihydroxyboranyl)ethyl]phenyl}propanoic acid as a light brown oil (3.37 g, 94.81%). LCMS (ESI): C 16 H 24 Calculated mass for BNO6: 337.1; observed m / z: 238.1 [M-Boc+H] + .

[0167] Preparation of (2S)-2-amino-3-{4-[2-(dihydroxyboranyl)ethyl]phenyl}propanoic acid (I-7) To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(dihydroxyboranyl)ethyl]phenyl}propanoic acid (900 mg, 2.669 mmol, 1 equiv.) in DCM (18 mL) at room temperature was added TFA (4.00 mL) dropwise. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 6% B, 6% B in 6 min; wavelength: 254 / 220 nm; RT1 (min): 4.77) to give (2S)-2-amino-3-{4-[2-(dihydroxyboranyl)ethyl]phenyl}propanoic acid as a white solid (62.5 mg, 9.88%). LCMS (ESI): C 11 H 16 Calculated mass for BNO4, 237.1; observed m / z, 237.9 [M+H] + ; 1 H NMR(400MHz, methanol-d4)δ 7.26-7.14(m,4H),3.75(dd,J=8.8,4.2Hz,1H),3.30-3.22(m,1H),2.96(dd,J=14.6,8.9Hz,1H),2.65(t,J=8.1Hz,2H),1.09(t,J=8.1Hz,2H).

[0168] Scheme H. Synthesis of Compounds (8) and (9) [ka] Reagents and conditions: (a) SOCl2, EtOH, 60°C; (b) Boc2O, Na2CO3, EtOH, rt; (c) Pd(OAc)2, S-phos, K3PO4, dioxane, HO, 90°C; (d) BH3-THF, HO, rt, followed by chiral resolution; (e) LiOH, MeOH, HO, rt; (f) LiOH, MeOH, HO, rt; (g) TFA, DCM, rt; (h) TFA, DCM, rt.

[0169] Preparation of ethyl 3-(4-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (I-8.1) Step A. To a stirred mixture of 2-amino-3-(4-bromo-2-fluorophenyl)propanoic acid (2 g, 7.631 mmol, 1 equiv.) in ethyl alcohol (30 mL) was added thionyl chloride (4.54 g, 38.155 mmol, 5 equiv.) dropwise at room temperature. The mixture was stirred at 60° C. for 8 hours and then concentrated under reduced pressure. The residue was basified with saturated NaCO (aq.) to pH 8 and then extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 2-amino-3-(4-bromo-2-fluorophenyl)propanoate as a pale yellow solid (2.5 g, crude), which was used directly in the next step.

[0170] Step B. To a stirred mixture of ethyl 2-amino-3-(4-bromo-2-fluorophenyl)propanoate (2.1 g, 7.24 mmol, 1 equiv.) and Na2CO3 (3.07 g, 28.95 mmol, 4 equiv.) in EtOH (50 mL) at room temperature, di-tert-butyl dicarbonate (3.16 g, 14.48 mmol, 2 equiv.) was added. The reaction mixture was stirred at 25 °C for 8 h and then concentrated under reduced pressure. The residue was diluted with water and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 3-(4-bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate as a pale yellow solid (4.6 g, crude). LCMS (ESI): C 16 H 21 Calculated mass for BrFNO4, 389.1; observed m / z, 290.0 [M-Boc+H] + .

[0171] Preparation of ethyl 2-((tert-butoxycarbonyl)amino)-3-(2-fluoro-4-vinylphenyl)propanoate (I-8.2) To a stirred mixture of ethyl 3-(4-bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (4.2 g, 10.762 mmol, 1 equiv.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.49 g, 16.143 mmol, 1.5 equiv.) in dioxane (80 mL) and HO (8 mL) at room temperature, KPO (9.14 g, 43.048 mmol, 4 equiv.), S-Phos (0.88 g, 2.152 mmol, 0.2 equiv.), and Pd(OAc) (0.24 g, 1.076 mmol, 0.1 equiv.) were added. The reaction mixture was purged with N for 1 minute and then stirred at 90 °C under a nitrogen atmosphere for 8 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give ethyl 2-[(tert-butoxycarbonyl)amino]-3-(4-ethenyl-2-fluorophenyl)propanoate as a pale yellow solid (2.1 g, 57.83%). LCMS (ESI): C 18 H 24 Calculated mass for FNO4: 337.2; observed m / z: 238.2 [M-Boc+H] + .

[0172] Preparation of 2-{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]-3-fluorophenyl}ethylboronic acid (I-8.3) and 2-{4-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]-3-fluorophenyl}ethylboronic acid (I-8.3') To a stirred mixture of ethyl 2-[(tert-butoxycarbonyl)amino]-3-(4-ethenyl-2-fluorophenyl)propanoate (2 g, 5.928 mmol, 1 equiv.) in THF (40 mL) at 0° C. was added dropwise borane solution (1 M in THF, 5.9 mL, 11.86 mmol, 2 equiv.). The mixture was stirred at 25° C. for 2 hours and then quenched by the addition of water at 0° C. The mixture was stirred at 25° C. for an additional 2 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC [the following conditions (Column: Sunfire prep C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: MeOH--preparative; Flow rate: 60 mL / min; Gradient: 55% B to 70% B, 70% B in 11 min; Wavelength: 254 / 220 nm; RT1 (min): 9.48)] to give 2-(4-{2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl}-3-fluorophenyl)ethyl-boronic acid (560 mg, 24.65%) as a colorless oil.

[0173] The product (560 mg) was then separated by preparative SFC under the following conditions (Column: CHIRALCEL AY-H, 2*25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: EtOH—HPLC; Flow rate: 40 mL / min; Gradient: Isocratic 10% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 2.87; RT2 (min): 3.77; Sample solvent: MeOH—preparative; Injection volume: 0.2 mL) to give 2-{4-[(2S*)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-methyl-2-propanol}-4-yl]propanol. 2-{4-[(2R*)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]-3-fluorophenyl}ethylboronic acid (I-8.3, 132 mg, 23.57%, ee > 99%, first isomer by HPLC) was obtained as an off-white solid, and 2-{4-[(2R*)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]-3-fluorophenyl}ethylboronic acid (I-8.3', 135 mg, 24.11%, ee > 97%, second isomer by HPLC) was obtained as an off-white solid. LCMS (ESI): C 18 H 27Calculated mass for BFNO6: 383.2; observed m / z: 284.0 [M-Boc+H] + .

[0174] Preparation of (S*)-3-(4-(2-boronoethyl)-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (I-8.4) To a stirred mixture of 2-{4-[(2S*)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]-3-fluorophenyl}ethylboronic acid (130 mg, 0.339 mmol, 1 equiv.) in MeOH (2 mL) and HO (2 mL) at room temperature, LiOH·HO (71.12 mg, 1.695 mmol, 5 equiv.) was added. The mixture was stirred at 25 °C for 2 h and then acidified to pH 4 with 2 N HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, ACN (0.1% FA) in water, 10% to 60% gradient in 10 min; detector, UV 254 / 220 nm] to give (2S*)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(dihydroxyboranyl)ethyl]-2-fluorophenyl}propanoic acid (100 mg, crude) as an off-white solid. LCMS (ESI): C 16 H 23 Calculated mass for BFNO6: 355.2; observed m / z: 255.95 [M-Boc+H] + .

[0175] Preparation of (R*)-3-(4-(2-boronoethyl)-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (I-8.4') To a stirred mixture of 2-{4-[(2R*)-2-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]-3-fluorophenyl}ethylboronic acid (130 mg, 0.339 mmol, 1 equiv.) in MeOH (2 mL) and HO (2 mL) at room temperature was added LiOH·HO (71.12 mg, 1.695 mmol, 5 equiv.). The mixture was stirred at 25 °C for 2 h and then acidified to pH 4 with 2 N HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 60% gradient in 10 min; detector, UV 254 / 220 nm] to give (2R*)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(dihydroxyboranyl)ethyl]-2-fluorophenyl}propanoic acid as an off-white solid (100 mg, crude). LCMS (ESI): C 16 H 23 Calculated mass for BFNO6: 355.2; observed m / z: 256.0 [M-Boc+H] + .

[0176] Preparation of (S*)-2-amino-3-(4-(2-boronoethyl)-2-fluorophenyl)propanoic acid (I-8) To a stirred mixture of (2S*)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(dihydroxyboranyl)ethyl]-2-fluorophenyl}propanoic acid (100 mg, 0.282 mmol, 1 equiv.) in DCM (3 mL) was added TFA (0.5 mL) dropwise at room temperature. The mixture was stirred at 25° C. for 2 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: MeOH-HPLC; Flow rate: 25 mL / min; Gradient: 5% B to 17% B, 17% B in 6 min; Wavelength: 220 nm; RT1 (min): 4.72) to give (2S*)-2-amino-3-{4-[2-(dihydroxyboranyl)ethyl]-2-fluorophenyl}propanoic acid; trifluoroacetic acid (56.9 mg, 54.76%) as an off-white solid. LCMS (ESI): C 11 H 15 Calculated mass for BFNO4, 255.2; observed m / z, 255.9 [M+H] + ; 1 H NMR(400MHz, methanol-d4)δ 7.22(t,J=7.8Hz,1H),7.07-6.87(m,2H),4.07-3.87(m,1H),3.41-3.32(m,1H ),3.05(dd,J=14.6,7.9Hz,1H),2.67(t,J=8.1Hz,2H),1.10(t,J=8.2Hz,2H).

[0177] Preparation of (R*)-2-amino-3-(4-(2-boronoethyl)-2-fluorophenyl)propanoic acid (I-9) To a stirred mixture of (2R*)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(dihydroxyboranyl)ethyl]-2-fluorophenyl}propanoic acid (110 mg, 0.310 mmol, 1 equiv.) in DCM (3 mL) was added TFA (0.5 mL) dropwise at room temperature. The mixture was stirred at 25° C. for 2 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: MeOH-HPLC; Flow rate: 25 mL / min; Gradient: 5% B to 20% B, 20% B in 7 min; Wavelength: 220 nm; RT1 (min): 4.85) to give (2R*)-2-amino-3-{4-[2-(dihydroxyboranyl)ethyl]-2-fluorophenyl}propanoic acid; trifluoroacetic acid as an off-white solid (38.3 mg, 33.18%). LCMS (ESI): C 11 H 15 Calculated mass for BFNO4, 255.2; observed m / z, 256.15 [M+H] + ; 1 H NMR(400MHz, methanol-d4)δ 7.23(t,J=7.8Hz,1H),7.06-6.87(m,2H),3.91-3.71(m,1H),3.41-3.32(m,1H ),2.99(dd,J=14.5,8.5Hz,1H),2.67(t,J=8.0Hz,2H),1.10(t,J=8.0Hz,2H).

[0178] Scheme I. Synthesis of compound (10) [ka] Reagents and conditions: (a) SOCl2, MeOH, 50 °C; (b) Boc2O, TEA, DCM, THF; (c) K2CO3, DMF, 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; (d) HCl in EA, EA; (e) LiOH HO, THF, HO.

[0179] Preparation of methyl (2S)-2-amino-3-(3-fluoro-4-hydroxyphenyl)propanoate (I-10.1) To a stirred mixture of 3-fluorotyrosine (1 g, 5.021 mmol, 1 equiv.) in methanol (20 mL) at 0 °C under a nitrogen atmosphere, thionyl chloride (3.58 g, 30.126 mmol, 6 equiv.) was added dropwise. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 4 h and then concentrated. The residue was basified with saturated NaHCO (aq.) to a pH of 8. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH H O) in water, 30% to 40% gradient in 8 min; detector, UV 254 / 220 nm]. This afforded methyl (2S)-2-amino-3-(3-fluoro-4-hydroxyphenyl)propanoate as a white solid (920 mg, 85.95%). LCMS (ESI): C 10 H 12 Calculated mass for FNO3: 213.1; observed m / z: 214.3 [M+H] + .

[0180] Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-4-hydroxyphenyl)propanoate (I-10.2) To a stirred mixture of methyl (2S)-2-amino-3-(3-fluoro-4-hydroxyphenyl)propanoate (860 mg, 4.034 mmol, 1 equiv.) and TEA (612.26 mg, 6.051 mmol, 1.5 equiv.) in DCM / THF (10 mL / 10 mL) at room temperature under a nitrogen atmosphere, di-tert-butyl dicarbonate (1056.40 mg, 4.841 mmol, 1.2 equiv.) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column; mobile phase: MeCN (0.1% NH₃·H₂O) in water, 30% to 50% gradient over 8 min; UV 254 / 220 nm). This gave methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-4-hydroxyphenyl)propanoate as a white solid (924 mg, 73.11%). LCMS (ESI): C 15 H 20 Calculated mass for FNO5: 313.1; observed m / z: 314.2 [M+H] + .

[0181] Preparation of 4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid (I-10.3) To a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-4-hydroxyphenyl)propanoate (924 mg, 2.949 mmol, 1 equiv.) and KCO (2.04 g, 14.745 mmol, 5 equiv.) in DMF (18 mL) at room temperature under a nitrogen atmosphere, 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.95 g, 14.744 mmol, 5.00 equiv.) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was directly purified by reverse-phase flash chromatography [following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 30% to 50% FA gradient in 8 min; detector, UV 254 / 220 nm]. This gave 4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid as a white solid (630 mg, 57.56%). LCMS (ESI): C 16 H 23 Calculated mass for BFNO7, 371.2; observed m / z, 272.1 [M+H-Boc] + .

[0182] Preparation of 4-[(2S)-2-amino-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid (I-10.4) To a stirred mixture of 4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid (900 mg, 2.43 mmol, 1 equiv.) in 10 mL of EtOAc at room temperature under a nitrogen atmosphere, hydrogen chloride (5 mL, 4 M in EtOAc) was added dropwise. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), 15% to 40% gradient in 7 minutes; detector: UV 254 / 220 nm]. This afforded 4-[(2S)-2-amino-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid (550 mg, 83.68%) as a white solid. LCMS (ESI): C 11 H 15 Calculated mass for BFNO5, 271.1; observed m / z, 272.3 [M+H] + .

[0183] Preparation of (2S)-2-amino-3-{4-[(dihydroxyboranyl)methoxy]-3-fluorophenyl}propanoic acid (I-10) To a stirred mixture of 4-[(2S)-2-amino-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid (550 mg, 2.029 mmol, 1 equiv.) in THF / HO (8 mL / 8 mL) at room temperature under a nitrogen atmosphere, LiOH·HO (255.43 mg, 6.087 mmol, 3 equiv.) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h and then acidified to pH 6 with 2 N HCl (aq.). The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, MeCN (0.1% FA) in water, 0% to 5% FA gradient over 8 min, UV 254 / 220 nm). The product was further purified by preparative HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19*150 mm, 5 μm; Mobile Phase A: Water (0.1% TFA), Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: 8% B to 22% B, 22% B in 7 min; Wavelength: 254 / 220 nm; RT1 (min): 5.04. This afforded (2S)-2-amino-3-{4-[(dihydroxyboranyl)methoxy]-3-fluorophenyl}propanoic acid; trifluoroacetic acid as a white solid (68 mg, 13.04%). LCMS (ESI): C 10 H 13 Calculated mass for BFNO5: 257.1; observed m / z: 258.1 [M+H] + . 1 H NMR (400MHz, heavy water) δ 7.12-6.96(m,3H),3.95(dd,J=7.7,5.3Hz,1H),3.85(s,2H),3.17(dd,J=14.7,5.3Hz,1H),3.03(dd,J=14.7,7.7Hz,1H).

[0184] Scheme J. Synthesis of compound (11) [ka] Reagents and conditions: (a) SOCl2, MeOH, 50 °C; (b) Boc2O, DCM, TEA; (c) K2CO3, DMF, 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; (d) HCl in EA, EA; (e) LiOH HO, THF, HO.

[0185] Preparation of methyl (2S)-2-amino-3-(4-fluoro-3-hydroxyphenyl)propanoate (I-11.1) To a stirred mixture of (2S)-2-amino-3-(4-fluoro-3-hydroxyphenyl)propanoic acid hydrochloride (900 mg, 3.819 mmol, 1 equiv.) in methanol (18 mL) at 0°C under a nitrogen atmosphere, thionyl chloride (5 mL) was added. The resulting mixture was stirred overnight at 50°C under a nitrogen atmosphere and then concentrated in vacuo. The residue was basified to pH 8 with saturated Na2CO3 (aq.). The mixture was purified by reverse-phase flash chromatography [following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 30% to 40% gradient in 10 min; detector, UV 254 / 220 nm]. This afforded methyl (2S)-2-amino-3-(4-fluoro-3-hydroxyphenyl)propanoate as a white solid (680 mg, 83.50%). LCMS (ESI): C 10 H 12 Calculated mass for FNO3: 213.1; observed m / z: 214.1 [M+H] + .

[0186] Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-fluoro-3-hydroxyphenyl)propanoate (I-11.2) To a stirred mixture of methyl (2S)-2-amino-3-(4-fluoro-3-hydroxyphenyl)propanoate (800 mg, 3.752 mmol, 1 equiv.) and TEA (759.39 mg, 7.504 mmol, 2 equiv.) in DCM (16 mL) at room temperature under a nitrogen atmosphere, di-tert-butyl dicarbonate (982.70 mg, 4.502 mmol, 1.2 equiv.) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column; mobile phase: MeCN (0.1% NH₃·H₂O) in water, 50% to 60% gradient in 7 min; detector: UV 254 / 220 nm). This gave methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-fluoro-3-hydroxyphenyl)propanoate as a white solid (297 mg, 25.26%). LCMS (ESI): C 15 H 20 Calculated mass for FNO5: 313.1; measured m / z: 312.2 [MH] - .

[0187] Preparation of 5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-fluoro-phenoxymethylboronic acid (I-11.3) To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-fluoro-3-hydroxyphenyl)methylpropanoate (488 mg, 1.557 mmol, 1 equiv.) and KCO (1.08 g, 7.785 mmol, 5 equiv.) in DMF (9 mL) at room temperature under a nitrogen atmosphere, 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.09 g, 7.785 mmol, 5 equiv.) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was directly purified by reverse-phase flash chromatography [following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 30% to 55% FA gradient in 8 min; detector, UV 254 / 220 nm]. This gave 5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid as a white solid (434 mg, 75.07%). LCMS (ESI): C 16 H 23 Calculated mass for BFNO7, 371.2; observed m / z, 272.3 [M+H-Boc] + .

[0188] Preparation of 5-[(2S)-2-amino-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid (I-11.4) To a stirred mixture of 5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid (290 mg, 0.781 mmol, 1 equiv.) in EtOAc (3 mL) at room temperature under a nitrogen atmosphere, HCl (1 mL, 4N in EtOAc) was added dropwise. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0% to 5% FA gradient in 10 min; detector, UV 254 / 220 nm]. This afforded 5-[(2S)-2-amino-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid as a white solid (167 mg, 78.86%). LCMS (ESI): C 11 H 15 Calculated mass for BFNO5, 271.1; observed m / z, 272.2 [M+H] + .

[0189] Preparation of (2S)-2-amino-3-{3-[(dihydroxyboranyl)methoxy]-4-fluorophenyl}propanoic acid (I-11) To a stirred mixture of 5-[(2S)-2-amino-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid (317 mg, 1.170 mmol, 1 equiv.) in THF / HO (6 mL / 3 mL) at room temperature under a nitrogen atmosphere, LiOH·HO (147.22 mg, 3.510 mmol, 3 equiv.) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h and then acidified to pH 6 with 2 N HCl (aq.). The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0% to 5% FA gradient in 8 min; detector, UV 254 / 220 nm]. The product was further purified by preparative HPLC under the following conditions: Column: YMC-Actus Triart C18, 30*150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 20% B, 20% B in 7 min; Wavelength: 254 / 220 nm; RT1 (min): 3.58. This gave (2S)-2-amino-3-{3-[(dihydroxyboranyl)methoxy]-4-fluorophenyl}propanoic acid as a white solid (60 mg, 19.04%). LCMS (ESI): C 10 H 13 Calculated mass for BFNO5, 257.1; observed m / z, 258.2 [M+H] + . 1 H NMR(400MHz, heavy water)δ 7.07(dd,J=11.5,8.3Hz,1H),6.98(d,J=8.3Hz,1H),6.82-6.75(m,1H),3.93-3.8 7(m,1H),3.82(s,2H),3.17(dd,J=14.6,5.2Hz,1H),3.02(dd,J=14.6,7.9Hz,1H).

[0190] Scheme K. Synthesis of compound (12) [ka] Reagents and conditions: (a) SOCl2, MeOH, 50 °C; (b) Boc2O, NaHCO3, dioxane, H2O; (c) K2CO3, DMF, 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; (d) LiOH H2O, THF, H2O; (e) HCl in EA, EA.

[0191] Preparation of methyl (2S)-2-amino-3-(2-fluoro-3-hydroxyphenyl)propanoate (I-12.1) To a stirred mixture of (2S)-2-amino-3-(2-fluoro-3-hydroxyphenyl)propanoic acid (800 mg, 4.016 mmol, 1 equiv.) in methanol (16 mL) at 0 °C under a nitrogen atmosphere, thionyl chloride (8 mL) was added dropwise. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 4 h. The resulting mixture was concentrated. The residue was basified to pH 8 with saturated NaHCO (aq.). The residue was purified by reverse-phase flash chromatography [following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH H O) in water, 10% to 20% gradient in 8 min; detector, UV 254 / 220 nm]. This afforded methyl (2S)-2-amino-3-(2-fluoro-3-hydroxyphenyl)propanoate as a white solid (790 mg, 92.25%). LCMS (ESI): C 10 H 12 Calculated mass for FNO3: 213.1; observed m / z: 214.3 [M+H] + .

[0192] Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-3-hydroxyphenyl)propanoate (I-12.2) To a stirred mixture of methyl (2S)-2-amino-3-(2-fluoro-3-hydroxyphenyl)propanoate (2.72 g, 12.8 mmol, 1 equiv.) and NaHCO3 (2.68 g, 31.9 mmol, 2.5 equiv.) in dioxane / HO (27 mL / 27 mL) at room temperature under a nitrogen atmosphere, di-tert-butyl dicarbonate (4.18 g, 19.1 mmol, 1.5 equiv.) was added portionwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 h. The resulting mixture was filtered, and the filter pad was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3·HO) in water, 30% to 50% gradient in 8 min; detector, UV 254 / 220 nm]. This gave methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-3-hydroxyphenyl)propanoate as a white solid (1.914 g, 47.88%). LCMS (ESI): C 15 H 20 Calculated mass for FNO5: 313.1; measured m / z: 312.2 [MH] - .

[0193] Preparation of 3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid (I-12.3) To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-3-hydroxyphenyl)methylpropanoate (286 mg, 0.913 mmol, 1 equiv.) and KCO (630.76 mg, 4.565 mmol, 5 equiv.) in DMF (5 mL) at room temperature under a nitrogen atmosphere, 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 4.565 mmol, 5 equiv.) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was directly purified by reverse-phase flash chromatography [following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 30% to 45% FA gradient in 8 min; detector, UV 254 / 220 nm]. This gave 3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid as a white solid (210 mg, 61.98%). LCMS (ESI): C 16 H 23 Calculated mass for BFNO7, 371.2; observed m / z, 272.1 [M+H-Boc] + .

[0194] Preparation of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[(dihydroxyboranyl)methoxy]-2-fluorophenyl}propanoic acid (I-12.4) To a stirred mixture of 3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-fluorophenoxymethylboronic acid (302 mg, 0.814 mmol, 1 equiv.) in THF / HO (6 mL / 3 mL) was added LiOH·HO (58.46 mg, 2.442 mmol, 3 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h and then acidified to pH 6 with 1 N HCl (aq.). The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography [following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 20% to 35% gradient in 8 min; detector, UV 254 / 220 nm]. This gave (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[(dihydroxyboranyl)methoxy]-2-fluorophenyl}propanoic acid as a white solid (210 mg, 72.27%). LCMS (ESI): C 15 H 21 Calculated mass for BFNO7: 357.1; observed m / z: 356.3 [MH] - .

[0195] Preparation of (2S)-2-amino-3-{3-[(dihydroxyboranyl)methoxy]-2-fluorophenyl}propanoic acid; trifluoroacetic acid (I-12) To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[(dihydroxyboranyl)methoxy]-2-fluorophenyl}propanoic acid (210 mg, 0.588 mmol, 1 equiv.) in 2 mL of EtOAc at room temperature under a nitrogen atmosphere, HCl (2 mL, 4 M in EtOAc) was added. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 h and then concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: Column: XBridge Prep Amide OBD Column, 19*150 mm, 5 μm; Mobile Phase A: water (0.05% TFA); Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: 95% B to 83% B in 2 min, 83% B to 60% B in 10 min, 60% B; Wavelength: 220 nm; RT (min): 7.79. This gave (2S)-2-amino-3-{3-[(dihydroxyboranyl)methoxy]-2-fluorophenyl}propanoic acid; trifluoroacetic acid as a white solid (55 mg, 36.39%). LCMS (ESI): C 10 H 13 Calculated mass for BFNO5: 257.1; observed m / z: 258.1 [M+H] + . 1 H NMR(400MHz, heavy water)δ 7.10-6.98(m,2H),6.85-6.75(m,1H),4.06(dd,J=7.6,5.8Hz,1H),3.81(s,2H),3.29(dd,J=14.5,5.7Hz,1H),3.10(dd,J=14.7,7.7Hz,1H).

[0196] Scheme L. Synthesis of compound (13) [ka] Reagents and conditions: (a) SOCl2, MeOH, 50 °C; (b) Boc2O, NaHCO3, dioxane, HO, rt; (c) 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, K2CO3, DMF, rt; (d) LiOH·HO, THF, HO, rt; (e) HCl in EtOAc (4 M), EtOAc, rt.

[0197] Preparation of (S)-2-amino-3-(3-fluoro-5-hydroxyphenyl)propanoate (I-13.1) To a stirred mixture of (2S)-2-amino-3-(3-fluoro-5-hydroxyphenyl)propanoic acid (1 g, 5.02 mmol, 1 equiv.) in MeOH (20 mL) at 0° C. under a nitrogen atmosphere was added SOCl (10 mL) dropwise. The resulting mixture was stirred overnight at 50° C. under a nitrogen atmosphere and then concentrated in vacuo. The residue was basified to pH 8 with saturated NaHCO (aq.). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×80 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI): C 10 H 12 Calculated mass for FNO3: 213.1; observed m / z: 214.3 [M+H] + .

[0198] Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-5-hydroxyphenyl)propanoate (I-13.2) To a stirred mixture of (S)-methyl 2-amino-3-(3-fluoro-5-hydroxyphenyl)propanoate (1.5 g, 7.035 mmol, 1 equiv.) and NaHCO3 (0.89 g, 10.553 mmol, 1.5 equiv.) in dioxane / HO (15 mL / 15 mL) at room temperature under a nitrogen atmosphere, Boc2O (1.54 g, 7.035 mmol, 1 equiv.) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours and then diluted with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 50% to 80% gradient in 15 min; detector, UV 254 / 220 nm. This afforded methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-5-hydroxyphenyl)propanoate as a white solid (750 mg, 34.02%). LCMS (ESI): C 15 H 20 Calculated mass for FNO5: 313.1; measured m / z: 312.2 [MH] - .

[0199] Preparation of 3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-5-fluoro-phenoxymethylboronic acid (I-13.3) To a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-5-hydroxyphenyl)propanoate (630 mg, 2.01 mmol, 1 equiv.) and KCO (1.39 g, 10.1 mmol, 5 equiv.) in DMF (8 mL) at room temperature under a nitrogen atmosphere, 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.69 g, 10.055 mmol, 5 equiv.) was added. The resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 55% to 60% gradient in 10 min; detector, UV 254 / 220 nm. This afforded 3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-5-fluorophenoxymethylboronic acid as a white solid (520 mg, 69.68%). LCMS (ESI): C 16 H 23 Calculated mass for BFNO7, 371.2; observed m / z, 272.1 [M+H-Boc] + .

[0200] Preparation of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[(dihydroxyboranyl)methoxy]-5-fluorophenyl}propanoic acid (I-13.4) To a stirred mixture of 3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-5-fluorophenoxymethylboronic acid (888 mg, 2.392 mmol, 1 equiv.) in THF / HO (16 mL / 8 mL) at room temperature under a nitrogen atmosphere, LiOH·HO (301.16 mg, 7.177 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h and then neutralized to pH 7 with 2 N HCl. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 35% to 45% FA gradient in 10 min; detector, UV 254 / 220 nm]. This gave (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[(dihydroxyboranyl)methoxy]-5-fluorophenyl}propanoic acid as a white solid (630 mg, 73.73%). LCMS (ESI): C 15 H 21 Calculated mass for BFNO7: 357.1; observed m / z: 356.1 [MH] - .

[0201] Preparation of (2S)-2-amino-3-{3-[(dihydroxyboranyl)methoxy]-5-fluorophenyl}propanoic acid (I-13) To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[(dihydroxyboranyl)methoxy]-5-fluorophenyl}propanoic acid (210 mg, 0.588 mmol, 1 equiv.) in EtOAc (2 mL) at room temperature under a nitrogen atmosphere, HCl (1 mL, 4N in EtOAc) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours and then concentrated in vacuo. The residue was neutralized to pH 7 with NaOH (aq.). The mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 3% to 5% FA gradient in 8 minutes; detector, UV 254 / 220 nm. The product was further purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 50 mL / min; Gradient: 2% B to 18% B, 18% B in 8 min; Wavelength: 254 / 220 nm; RT1 (min): 7.28. This gave (2S)-2-amino-3-{3-[(dihydroxyboranyl)methoxy]-5-fluorophenyl}propanoic acid as a white solid (105 mg, 69.48%). LCMS (ESI): C 10 H 13 Calculated mass for BFNO5, 257.1; observed m / z, 258.2 [M+H] + . 1 H NMR(400MHz, heavy water)δ 6.69-6.61(m,2H),6.59(d,J=9.2Hz,1H),3.91(dd,J=7.9,5.2Hz,1H),3.72(s,2H),3.16(dd,J=14.5,5.3Hz,1H),3.00(dd,J=14.5,8.0Hz,1H).

[0202] Scheme M. Synthesis of compound 14 [ka] aReagents and conditions: (a) CataCXium A Pd G3, Cs2CO3, dioxane / H2O, 100 °C; (b) LiOH·H2O, THF, water, rt; (c) HCl, dioxane, rt.

[0203] Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]phenyl}propanoate (I-14.1) To a stirred mixture of methyl (2S)-3-(3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (731.06 mg, 2.041 mmol, 1.20 equiv) and 4,4,5,5-tetramethyl-2-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-1,3,2-dioxaborolane (500 mg, 1.701 mmol, 1.00 equiv) in dioxane (16 mL) / HO (1.6 mL) was added CataCXium A Pd G3 (123.85 mg, 0.170 mmol, 0.1 equiv) and CsCO3 (1662.29 mg, 5.103 mmol, 3 equiv). The resulting mixture was purged with nitrogen for 1 minute and then stirred at 100°C under a nitrogen atmosphere for 5 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 60% to 80% gradient in 15 minutes; detector, UV 220 nm]. This afforded methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]phenyl}propanoate as a pale yellow oil (240 mg, 31.69%). LCMS (ESI): C 24 H 36 Calculated mass for BNO6: 445.3; observed m / z: 446.3 [M+H] + .

[0204] Preparation of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[1-(dihydroxyboranyl)cyclopropyl]phenyl}propanoic acid (I-14.2) To a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]phenyl}propanoate (240 mg, 0.539 mmol, 1 equiv.) in HO (2.5 mL) / THF (2.5 mL), LiOH·HO (67.84 mg, 1.617 mmol, 3 equiv.) was added. The resulting mixture was stirred at room temperature for 3 h. The mixture was acidified to pH 7 with 2 M HCl (aq.) and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography [following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 40% to 60% FA gradient in 10 min; detector, UV 220 nm]. This gave (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[1-(dihydroxyboranyl)cyclopropyl]phenyl}propanoic acid as a colorless oil (120 mg, 63.77%). LCMS (ESI): C 17 H 24 Calculated mass for BNO6: 349.2; observed m / z: 250.1 [M-Boc+H] +

[0205] Preparation of (2S)-2-amino-3-{3-[1-(dihydroxyboranyl)cyclopropyl]phenyl}propanoic acid (I-14) To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{3-[1-(dihydroxyboranyl)cyclopropyl]phenyl}propanoic acid (150 mg, 0.430 mmol, 1 equiv.) in dioxane (2.0 mL) was added dropwise a solution of HCl (0.7 mL) in 1,4-dioxane (4 mL). The resulting mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: Column: XBridge Prep Phenyl OBD Column, 19*150 mm, 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: MeOH-HPLC; Flow rate: 25 mL / min; Gradient: 17% B to 42% B, 42% B in 7 min; Wavelength: 220 nm; RT1 (min): 5.11) to give (2S)-2-amino-3-{3-[2-(dihydroxyboranyl)cyclopropyl]phenyl}propanoic acid as a white solid (27 mg, 25.24%). LCMS (ESI): C 12 H 16 Calculated mass for BNO4, 249.1; observed m / z, 250.2 [M+H] + . 1 H NMR(400MHz, heavy water)δ 7.27-7.18(m,2H),7.16(s,1H),7.04(d,J=7.0Hz,1H),3.89(dd,J=8.0,5.2Hz,1H),3.17(d d,J=14.5,5.2Hz,1H),2.98(dd,J=14.5,8.3Hz,1H),1.05-0.97(m,2H),0.87-0.80(m,2H).

[0206] Scheme N. Synthesis of compound (15) [ka] Reagents and conditions: (a) CataCXium A Pd G3, Cs2CO3, dioxane / H2O, 100 °C; (b) LiOH·H2O, THF, water, rt; (c) HCl, dioxane, rt.

[0207] Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]phenyl}propanoate (I-15.1) To a stirred mixture of methyl (2S)-3-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (292.42 mg, 0.816 mmol, 1.2 equiv) and 4,4,5,5-tetramethyl-2-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-1,3,2-dioxaborolane (200 mg, 0.680 mmol, 1.00 equiv) in dioxane (6 mL) / HO (0.6 mL) was added CataCXiumA Pd G (74.31 mg, 0.102 mmol, 0.15 equiv) and CsCO (54.57 mg, 0.168 mmol, 3 equiv). The resulting mixture was purged with nitrogen for 1 minute and then stirred at 80°C under a nitrogen atmosphere for 5 hours. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 60% to 80% gradient in 20 minutes; detector, UV 220 nm]. This afforded methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]phenyl}propanoate as a pale yellow oil (110 mg, 36.31%). LCMS (ESI): C 24 H 36 Calculated mass for BNO6: 445.3; observed m / z: 468.2 [M+Na] + .

[0208] Preparation of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[1-(dihydroxyboranyl)cyclopropyl]phenyl}propanoic acid (I-15.2) To a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]phenyl}propanoate (100 mg, 0.225 mmol, 1 equiv.) in HO (1.0 mL) / THF (1.0 mL), LiOH·HO (28.26 mg, 0.675 mmol, 3 equiv.) was added. The resulting mixture was stirred at room temperature for 3 h. The mixture was acidified to pH 7 with 2 M HCl (aq.) and then concentrated in vacuo. The residue was purified by reverse-phase flash chromatography [following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 40% to 60% gradient in 15 min; detector, UV 220 nm]. This gave (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[1-(dihydroxyboranyl)cyclopropyl]phenyl}propanoic acid as a colorless oil (70 mg, 89.28%). LCMS (ESI): C 17 H 24 Calculated mass for BNO6: 349.2; observed m / z: 250.1 [M-Boc+H] + .

[0209] Preparation of (2S)-2-amino-3-{4-[1-(dihydroxyboranyl)cyclopropyl]phenyl}propanoic acid (I-15) To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[1-(dihydroxyboranyl)cyclopropyl]phenyl}propanoic acid (70 mg, 0.200 mmol, 1 equiv.) in dioxane (1.2 mL) was added dropwise a 4 M solution of HCl (0.40 mL) in 1,4-dioxane. The resulting mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 7% B to 19% B, 19% B in 7 min; Wavelength: 220nm; RT1 (min): 6.78) to give (2S)-2-amino-3-{4-[1-(dihydroxyboranyl)cyclopropyl]phenyl}propanoic acid as a white solid (31mg, 62.09%). LCMS (ESI): C 12 H 16 Calculated mass for BNO4, 249.1; observed m / z, 250.1 [M+H] + . 1 H NMR(400MHz, heavy water)δ 7.24(d,J=7.9Hz,2H),7.12(d,J=7.9Hz,2H),3.91-3.81(m,1H),3.14(dd,J=14.5 ,5.3Hz,1H),2.99(dd,J=14.5,7.8Hz,1H),1.05-0.92(m,2H),0.88-0.74(m,2H).

[0210] Scheme O. Synthesis of compound (16) [ka] Reagents and conditions: (a) Zn, I2, Pd2(dba)3, S-Phos, DMF, 45 °C; (b) K2CO3, DMF, rt; (c) LiOH·H2O, THF, H2O, rt; (d) HCl, dioxane, rt.

[0211] Preparation of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propanoate (I-16.1) A mixture of Zn (3.4 g, 52.02 mmol, 3 equiv.) and I2 (0.22 g, 1.73 mmol, 0.1 equiv.) in DMF (30 mL) was stirred at room temperature under a nitrogen atmosphere for 5 min. To the above mixture, methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (6.85 g, 20.81 mmol, 1.2 equiv.) in DMF (30 mL) was slowly added, followed by I2 (0.22 g, 1.73 mmol, 0.1 equiv.). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. To the mixture was then added a suspension of 3-bromophenol (3 g, 17.34 mmol, 1 equiv.), S-Phos (0.71 g, 1.73 mmol, 0.1 equiv.), and Pd2(dba)3 (0.79 g, 0.86 mmol, 0.05 equiv.) in DMF (10 mL). The reaction was stirred overnight at 45 °C under a nitrogen atmosphere. The reaction was quenched with water (20 mL), diluted with EA (80 mL), and filtered through Celite. The filtrate was washed with brine (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 40% to 60% in 20 min; detector, UV 254 nm] to give the title product as a yellow oil (2.7 g, 52.7%). LCMS(ESI):C 15 H 21 Calculated mass for NO5: 295.1; observed m / z: 296.1 [M+H] + .

[0212] Preparation of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-{3-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methoxy]phenyl}propanoate (I-16.2) To a stirred mixture of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propanoate (2.7 g, 9.14 mmol, 1 equiv.) and K2CO3 (1.9 g, 13.71 mmol, 1.5 equiv.) in DMF (20 mL) was slowly added 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.9 g, 10.97 mmol, 1.2 equiv.). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 40% gradient in 60 min; detector, UV 254 nm] to give the title product as a brown oil (675 mg, 17.0%). LCMS (ESI): C 24 H 35 Calculated mass for BFNO6: 435.2; observed m / z: 434.2 [MH] - .

[0213] Preparation of (2R)-2-[(tert-butoxycarbonyl)amino]-3-{3-[(dihydroxyboranyl)methoxy]phenyl}propanoic acid (I-16.3) To a stirred mixture of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-{3-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methoxy]phenyl}propanoate (391 mg, 0.90 mmol, 1 equiv.) in THF (8 mL) / HO (4 mL) was added LiOH·HO (75.6 mg, 1.80 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 3 h. The mixture was then acidified to pH 5 with 2 N HCl (aq.) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 10% to 50% in 30 min; detector, UV 220 nm] to give the title product as a pale yellow solid (215 mg, 70.6%). LCMS(ESI):C 15 H 22 Calculated mass for BNO7: 339.2; measured m / z: 337.8 [MH] - .

[0214] Preparation of (2R)-2-amino-3-{3-[(dihydroxyboranyl)methoxy]phenyl}propanoic acid (16) To a stirred solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-{3-[(dihydroxyboranyl)methoxy]phenyl}propanoic acid (200 mg, 0.59 mmol, 1 equiv.) in dioxane (2 mL), HCl (2 mL, 4 mol / L in dioxane) was slowly added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC [conditions: Column: XBridge Prep Amide OBD Column, 19*150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 95% B to 83% B in 10 min; Wavelength: 254 nm / 220 nm; RT (min): 8.32] to give the title product as a white solid (57.3 mg, 40.5%). LCMS(ESI):C10 H 14 Calculated mass for BNO5, 239.10; observed m / z, 240.10 [M+H] + ; 1 H NMR(400MHz, heavy water)δ 7.33-7.21(m,1H),6.93-6.86(m,1H),6.86-6.79(m,2H),4.29-4.16(m,1H),3.80-3.64(m,2H),3.32-3.16(m,1H),3.16-3.01(m,1H).

[0215] Example 2. Cellular uptake assay cell culture 1.1 How to unzip 1.1.1 15 mL of cell culture medium was placed in a T225 flask. 1.1.2 The flask was placed in a humidified 37°C, 5% CO2 incubator for 15 minutes to allow the medium to equilibrate to the appropriate pH and temperature. 1.1.3 The vial was removed from the liquid nitrogen and rapidly thawed in a 37°C water bath with gentle agitation for 1-2 minutes, then decontaminated by wiping with 70% ethanol before being opened in a Class II biological safety cabinet. 1.1.4 The contents of the vial were transferred dropwise into 10 mL of cell culture medium in a sterile 15 mL conical tube. 1.1.5 The cells were centrifuged at 1,300 rpm for 5 minutes. 1.1.6 The supernatant was aspirated, the cells were resuspended and transferred to a T225 flask containing cell culture medium.

[0216] 1.2 Propagation Methods 1.2.1 The culture medium was changed every 2–3 days. 1.2.2 Keep the flask in a humidified 37°C, 5% CO2 incubator.

[0217] Assay procedure 2.1 Cell seeding The cells were harvested and diluted in culture medium to the indicated concentrations. Then, the cells were cultured in T25 flasks, with one T25 flask used for one sample.

[0218] 2.2 Test Compound Formulation 2.2.1 L-boronophenylalanine (L-BPA, 4-boron-L-phenylalanine, purity: 95%, chemical formula: CHBNO, MW: 209.01, CAS: 76410-58-7) and fructose were dissolved in PBS at a molar ratio of 1:5, and then 1.27M of 1N NaOH was added. The mixture was stirred until L-BPA was completely dissolved, and the pH was titrated to 7.2-7.4 with 1N HCl. 2.2.2 For test compounds other than BPA, stock solutions of each compound were prepared in DMSO or fructose formulations at a concentration of 20 mM (to achieve a final DMSO%=0.5% in the cell assay medium).

[0219] 2.3 Compound Treatment 2.3.1 Cells were seeded overnight (12-18 hours) to allow adequate cell attachment. 2.3.2 Stock solutions of each compound were added to each T25 flask to give a final concentration of 100 uM (0.1 mM) for each compound. 2.3.3 The flasks were placed in an incubator at 37°C and 5% CO2 for 1 hour, 4 hours, and 24 hours. 2.3.4 After 1 hour, 4 hours, and 24 hours of treatment, cells were harvested using 0.25% trypsin with 0.53 mM EDTA. 2.3.5 Centrifuge at 1,300 rpm for 5 minutes and collect the cell pellet.

[0220] result The compounds disclosed herein were selectively taken up by representative human cancer cell lines SAS (head and neck cancer), U87-MG (glioblastoma), and B6 (melanoma) compared to a representative normal human cell line (NIH-3T3). Compounds 1-3, 10-11, and 13-15 showed increased uptake in cancer cells compared to BPA, in addition to showing preferential partitioning into cancer cells compared to normal cells.

[0221] [Table 1]

[0222]

Table 2

[0223]

Table 3

[0224]

Table 4

[0225]

Table 5

[0226]

Table 6

[0227]

Table 7

[0228]

Table 8

[0229]

Table 9

[0230]

Table 10

[0231]

Table 11

[0232] [Table 12]

[0233] [Table 13]

[0234] Incorporation by Reference All U.S. applications and published U.S. and PCT patent applications cited herein are hereby incorporated by reference.

[0235] equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A compound of formula (I) 【Chemical 1】 During the ceremony, Y １ is absent or is —O—, Y ２ is an optionally substituted -alkylene-; R １ , R ２ , and R ５ are each independently selected from —H and halo; R ３ is -H, halo, and -X １ -X ２ is selected from R ４ is -H, halo, and -X １ -X ２ is selected from X １ is -alkylene-, X ２ is -C(H)(NH ２ ) CO ２ H, The compound may be racemic, enantiomerically enriched, or a single enantiomer, One -X １ -X ２ shall contain only one occurrence of The compound or a pharmaceutically acceptable salt thereof.

2. Having the structure of formula (IA): 【Chemistry 2】 In the formula, R ４ The compound of claim 1 , wherein is selected from —H and halo.

3. R １ , R ２ , R ４ , and R ５ The compound of claim 1 or 2, wherein each of is —H.

4. R １ , R ２ , R ４ , and R ５ One of the groups is a halo, and R １ , R ２ , R ４ , and R ５ The compound of any one of claims 1 to 3, wherein each of the remainder is -H.

5. The compound of claim 4, wherein halo is -F.

6. having a structure selected from: 【Chemistry 3】 6. The compound of any one of claims 1 to 5, wherein * indicates a chiral carbon having an absolute configuration of (S) or (R), and wherein the compound is not racemic.

7. 7. The compound of claim 6, wherein the absolute configuration of the chiral carbon is (S).

8. having the structure of formula (IB): 【Chemistry 4】 In the formula, R ３ The compound of claim 1 , wherein is selected from —H and halo.

9. R １ , R ２ , R ３ , and R ５ 9. The compound of claim 8, wherein each of is —H.

10. R １ , R ２ , R ３ , and R ５ One of the groups is a halo, and R １ , R ２ , R ３ , and R ５ 10. The compound of claim 8 or 9, wherein each remainder is hydrogen.

11. The compound of claim 10, wherein halo is -F.

12. having a structure selected from: 【Chemistry 5】 12. The compound of any one of claims 8 to 11, wherein * indicates a chiral carbon having an absolute configuration of (S) or (R), and wherein the compound is not racemic.

13. 13. The compound of claim 12, wherein the absolute configuration of the chiral carbon is (S).

14. X １ But -(C １ ~C ４ 14. The compound according to any one of claims 1 to 13, wherein:

15. X １ But -CH ２ The compound of claim 14, wherein

16. Y １ The compound according to any one of claims 1 to 15, wherein is -O-.

17. Y １ The compound according to any one of claims 1 to 15, wherein is absent.

18. Y ２ is unsubstituted -(C １ ~C ４ ) alkylene-.

19. Y ２ But -CH ２ - and -CH ２ CH ２ The compound of claim 18, wherein the compound is selected from:

20. Y ２ is substituted -(C １ ~C ４ ) alkylene-.

21. Y ２ But -C(Y ３ ) (Y ４ )- and -C(Y ３ ) (Y ４ ) CH ２ - is selected from, Y ３ and Y ４ are each independently selected from —H, halo, alkyl, and heteroalkyl; ３ and Y ４ at least one of which is not —H; or Y ３ and Y ４ 21. The compound of claim 20, wherein, together with the carbon to which they are attached, form a cycloalkyl, cycloheteroalkyl, spirocycloalkyl, or spirocycloheteroalkyl.

22. Y ３ and Y ４ 22. The compound of claim 21, wherein together with the carbon to which they are attached form a cyclopropyl.

23. Y ２ is unsubstituted -(C １ ~C ４ ) alkylene-.

24. Y ２ But -CH ２ - and -CH ２ CH ２ 24. The compound of claim 23, wherein the compound is selected from:

25. Y ２ is substituted -(C １ ~C ４ ) alkylene-.

26. Y ２ But -C(Y ３ ) (Y ４ )- and -C(Y ３ ) (Y ４ ) CH ２ - is selected from, Y ３ and Y ４ are each independently selected from —H, halo, alkyl, and heteroalkyl; ３ and Y ４ at least one of which is not —H; or Y ３ and Y ４ 26. The compound of claim 25, wherein, together with the carbon to which they are attached, form a cycloalkyl, cycloheteroalkyl, spirocycloalkyl, or spirocycloheteroalkyl.

27. Y ３ and Y ４ 27. The compound of claim 26, wherein together with the carbon to which they are attached form a cyclopropyl.

28. The compound of claim 1 having a structure selected from the following: 【Chemistry 6】 or a pharmaceutically acceptable salt thereof.

29. structure 【Chemistry 7】 2. The compound of claim 1, having the formula:

30. The boron atom in the compound １０ The compound according to any one of claims 1 to 29, wherein B is

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30 and a pharmaceutically acceptable excipient.

32. 32. The pharmaceutical composition of claim 31, further comprising a saccharide.

33. 33. The pharmaceutical composition of claim 31 or 32, further comprising a polyhydroxy acid.

34. The pharmaceutical composition according to any one of claims 31 to 33, further comprising a sugar alcohol.

35. 1. A method of treating cancer, comprising: i) administering a compound according to any one of claims 1 to 30 or a composition according to any one of claims 31 to 34 to a subject in need of cancer treatment, wherein the compound accumulates in a plurality of cancer cells in the subject; ii) irradiating the plurality of cancer cells with neutrons.

36. 36. The method of claim 35, wherein the compound selectively or preferentially accumulates in the plurality of cancer cells relative to non-cancerous cells in the subject.

37. The irradiating step causes the compound １０ 37. The method of claim 35 or 36, resulting in the conversion of B atoms into alpha particles and lithium 7 ions.

38. The method of any one of claims 35 to 37, wherein the compound or composition is administered intravenously.

39. 39. The method of any one of claims 35 to 38, wherein the compound is administered continuously during neutron irradiation.

40. 40. The method of any one of claims 35 to 39, wherein in step (i), the compound is administered at about 100 mg / kg / h to about 500 mg / kg / h for a first period of time.

41. 40. The method of any one of claims 35 to 39, wherein in step (i), the compound is administered at about 150 mg / kg / h to about 300 mg / kg / h for a first period of time.

42. 42. The method of claim 40 or 41, wherein the first period of time is from about 1 hour to about 3 hours.

43. 43. The method of any one of claims 35 to 42, wherein in step (ii), the compound is administered at about 50 mg / kg / h to about 150 mg / kg / h for the second period of time.

44. 43. The method of any one of claims 35 to 42, wherein in step (ii), the compound is administered at about 100 mg / kg / h to about 200 mg / kg / h for the second period of time.

45. 45. The method of claim 43 or 44, wherein the second period of time is from about 0.25 hours to about 1.25 hours.

46. The method of any one of claims 35 to 45, wherein the cancer is a solid tumor.

47. 47. The method of any one of claims 35 to 46, wherein the cancer is selected from head and neck cancer, glioblastoma, melanoma, sarcoma, breast cancer, meningioma, lung cancer, mesothelioma, hepatocellular carcinoma, and extramammary Paget's disease.

48. The method of any one of claims 35 to 47, wherein the cancer is unresectable head and neck cancer.

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