Fused bicyclic aryl compounds for boron neutron capture therapy

Abstract

Disclosed are compounds, compositions, and methods useful for boron neutron capture therapy.

Description

Related applications

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 615,592, filed on December 28, 2023. Background Technology

[0002] Boron neutron capture therapy (BNCT) is a bimodal cancer therapy that requires the selective delivery of boron-containing molecules to cancer cells and an external beam of neutrons directed towards the cancer. Thermal neutrons pass through the interior of the cancer cells... 10 B-nuclear capture leads to nuclear fission, producing high-energy alpha particles and recoil. 7 Li nuclei. These high-energy particles damage tumor cells, leading to tumor cell death, while leaving surrounding healthy tissue unharmed. Novel boron delivery agents selectively distributed to tumor tissue, combined with tumor-directed external neutron beams, can be used in boron neutron capture therapy to treat various solid tumors.

[0003] Japan has approved the use of 4-boron-L-phenylalanine (BPA) in combination with an external neutron beam device for the treatment of recurrent unresectable head and neck cancer. While BPA has demonstrated therapeutic efficacy in boron neutron capture therapy, it has limitations. Its selectivity for tumor tissue is considered to be higher than its selectivity for healthy tissue, and its tumor uptake only meets the minimum requirements for successful boron neutron capture therapy. Agents that, compared to BPA, exhibit increased tumor cell uptake and an increased tumor:healthy tissue ratio may lead to enhanced anticancer efficacy. Summary of the Invention

[0004] One aspect of the present invention provides compounds, compositions, and methods that can be used in boron neutron capture therapy.

[0005] Therefore, this paper provides a compound having the structure of formula (I): (I), in A1 is selected from -O- and -NH-; A2 is selected from -C(R6)(R7)- and -C(O)-; A3 is selected from -O- and -N(R5)-; A4 is selected from single bonds and -C(R8)(R9)-; R1, R2, R3 and R4 are each independently selected from -H, halogen, hydroxyl, alkyl, alkoxy and -(CR'R'')C(H)(NH2)CO2H, provided that one and only one of R1, R2, R3 and R4 is -(CR'R'')C(H)(NH2)CO2H; R5 is selected from -H and alkyl groups; R' and R'' are each independently selected from -H, halogens, and alkyl groups; R6, R7, R8, and R9 are each independently selected from -H and alkyl groups; The compound is racemic, enriched with one enantiomer, or a single enantiomer; Or its pharmaceutically acceptable salt.

[0006] Another aspect of the present invention relates to a method for treating cancer, the method comprising: i) administering to a subject in need an effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I), wherein the compound accumulates in a plurality of cancer cells of 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 pertains. While similar or equivalent methods and materials described herein may be used to practice or test the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In case of conflict, this specification (including definitions) shall prevail. Furthermore, the materials, methods, and examples described are illustrative only and not intended to be limiting.

[0008] Other features, objectives, and advantages of the present invention will become apparent from the specific embodiments and claims. Detailed Implementation

[0009] definition For convenience, certain terms used in this specification, embodiments, and appended claims are collected herein before further description of the invention. These definitions should be read in light of the remainder of this disclosure and as understood by those skilled 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] To make the invention easier to understand, certain terms and phrases are defined below and throughout this specification.

[0011] In this article, the article “a / an” refers to one or more of the grammatical objects of the article (i.e., at least one). For example, “one element” means one element or more.

[0012] As used herein in this specification and claims, the phrase “and / or” should be understood to mean “any one or both” of the elements so connected, i.e., elements that are together in some cases and separate in others. Multiple elements listed using “and / or” should be interpreted in the same way, i.e., “one or more” of the elements so connected. Elements other than those explicitly identified by the “and / or” clause may optionally be present, whether related to or unrelated to those explicitly identified elements. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “comprising,” reference to “A and / or B” may in one embodiment mean only A (optionally including elements other than B); in another embodiment, only B (optionally including elements other than A); in yet another embodiment, both A and B (optionally including other elements); and so on.

[0013] As used herein in this specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when items in a list are separated, “or” or “and / or” should be interpreted as inclusive, that is, including not only the number of elements or at least one of them in the list, but also more than one, and optionally additional items not listed. Only terms explicitly specified to the contrary, such as “only one of…” or “exact one of…” or, when used in claims, “consisting of…” will refer to the number of elements or exactly one element in the list. In general, as used herein, when preceding exclusive terms such as “any one,” “one of…,” “only one of…” or “exact one of…”, the term “or” should only be interpreted as indicating an exclusive alternative (i.e., “one or the other but not both”). When used in claims, “consisting substantially of…” should have its ordinary meaning as used in the field of patent law.

[0014] As used herein in this specification and claims, the phrase “at least one” referring 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 element list, but not necessarily including at least one of each and every element expressly listed in the element list and does not exclude any combination of elements in the element list. This definition also allows for the optional presence of elements other than those expressly identified in the element list referred to by the phrase “at least one,” whether related to or unrelated to those expressly identified elements. 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”) may, in one embodiment, mean at least one, optionally including more than one A, with no B (and optionally including elements other than B); in another embodiment, mean at least one, optionally including more than one B, with no A (and optionally including elements other than A); in yet another embodiment, mean at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so on.

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

[0016] In the claims and the foregoing description, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” etc., should be understood as open-ended, that is, meaning including but not limited to. Only the transitional phrases “consisting of” and “substantially composed of” should each be closed or semi-closed transitional phrases, as set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0017] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. Furthermore, the polymers of the present invention may also be optically active. The present invention covers all such compounds, including their cis- and trans-isomers, as falling within the scope of the present invention. R -and S -Enantiomers, diastereomers Racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in this invention.

[0018] "Geometric isomer" refers to an isomer whose substituent atom orientation differs from that of a carbon-carbon double bond, cycloalkyl ring, or bridged bicyclic system. Atoms on each side of the carbon-carbon double bond (except H) can have an E (substituent on the opposite side of the carbon-carbon double bond) or Z (substituent on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" indicate the configuration relative to the core molecule. Some of the disclosed compounds may exist as "trans-restricted isomers" or as "trans-restricted isomers". Trans-restricted isomers are stereoisomers resulting from restricted rotation around a single bond, wherein the steric hindrance to rotation is sufficiently high to allow for the separation of conformational isomers. The compounds of this invention can be prepared as individual isomers through isomer-specific synthesis or by resolution from mixtures of isomers. Conventional resolution techniques include using optically active acids to form salts of the free base of each isomer in an isomer pair (followed by fractional crystallization and regeneration of the free base), using optically active amines to form salts of the acid form of each isomer in an isomer pair (followed by fractional crystallization and regeneration of the free acid), using optically pure acids, amines, or alcohols to form esters or amides of each isomer in an isomer pair (followed by chromatographic separation and removal of chiral auxiliaries), or using various well-known chromatographic methods to resolve mixtures of isomers of the starting material or the final product.

[0019] For example, if a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization using a chiral auxiliary agent, wherein the resulting diastereomeric mixture is isolated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in the case where the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed using a suitable optically active acid or base, followed by resolution of the resulting diastereomeric isomer by fractional crystallization or chromatographic means well known in the art, and subsequently the pure enantiomer is recovered.

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

[0021] When the disclosed compound is named or described by structure without indicating stereochemistry and the compound has at least one chiral center, it should be understood that the name or structure covers any enantiomer of the compound that does not contain the corresponding optical isomer, a compound or a racemic mixture of a mixture of enantiomers enriched relative to its corresponding optical isomer. When the disclosed compound is named or described by structure without indicating stereochemistry and has two or more chiral centers, it should be understood that the name or structure covers diastereomers that do not contain other diastereomers, a number of diastereomers that do not contain other diastereomer pairs, a mixture of diastereomers, a mixture of diastereomer pairs, a mixture of diastereomers in which one diastereomer is enriched relative to other diastereomers, or a mixture of diastereomers in which one or more diastereomers are enriched relative to other diastereomers. The invention encompasses all these forms.

[0022] The structures described in this article are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium, or by replacing carbon with... 13 C- or 14 C-enriched carbon can be replaced, or boron can be replaced with... 10 The compounds produced by β-enriched boron substitution are within the scope of this invention.

[0023] As used herein, the term "prodrug" encompasses compounds that are converted into therapeutically active agents under physiological conditions. A common method for preparing prodrugs involves hydrolyzing selected portions under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted via 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 medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, relating to the transport or transfer of a subject chemical from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense of being compatible with other components of the formulation, harmless to the patient, and substantially nonpyrogenic. Some examples of materials that can be used 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (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, and corn oil. (10) Soybean oil; (11) Glycols, such as propylene glycol; (12) Polyols; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Pyrogenic water; (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) Phosphate buffer solution; and (22) Other non-toxic and compatible substances used in pharmaceutical preparations. In some embodiments, the pharmaceutical compositions of the present invention are pyrogenic, i.e., do not induce a significant temperature rise when administered to a patient.

[0025] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of the compound. These salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound, in its free base form, alone with a suitable organic or inorganic acid, and then isolating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, gluconate, lactobionate, and laurylsulfonate, etc. (See, for example, Berge et al. (1977) "Pharmaceutical Salts") J. Pharm. Sci 66:1-19. In other cases, compounds used in the methods of this invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic base addition salt of the compound. These salts can also be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound, in its free acid form, with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or alone with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., above).

[0026] The term "pharmaceutically acceptable cocrystal" refers to a solid co-formation that does not form formal ionic interactions with small molecules.

[0027] The "therapeutic effective amount" (or "effective amount") of a compound used for treatment means the amount of a compound in a formulation which, when administered as part of a desired dosage regimen (to mammals, preferably humans), is used for clinically acceptable standards or cosmetic purposes, such as to alleviate symptoms, improve the condition, or slow the onset of a disease condition, based on the condition or disease to be treated, for a reasonable benefit / risk ratio applicable to any medical treatment.

[0028] The term "preventive or therapeutic" treatment is recognized in the art and includes the administration of one or more of the subject composition to a host. A treatment is preventive (i.e., it protects the host from developing an unwanted disease) if it is administered prior to the clinical manifestation of an unwanted disease (e.g., a disease or other unwanted state in the host animal), but is therapeutic (i.e., it aims to reduce, improve, or stabilize an existing unwanted disease or its side effects) if it is administered after the manifestation of an unwanted disease.

[0029] The terms "patient" or "subject" refer to a mammal that requires specific treatment. In some embodiments, the patient is a primate, canine, feline, or equine. In some embodiments, the patient is a human.

[0030] Aliphatic chains include the alkyl, alkenyl, and alkynyl categories as defined below. Straight-chain aliphatic chains are limited to the unbranched carbon chain portion. As used herein, the term "aliphatic group" refers to a straight-chain, branched, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl groups.

[0031] "Alkyl" refers to a fully saturated cyclic or acyclic branched or unbranched carbon chain moiety having a specified number of carbon atoms, or, if not specified, up to 30 carbon atoms. For example, alkyl groups with 1 to 8 carbon atoms refer to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties that are positional isomers of these moieties. Alkyl groups with 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, dodecyl, dodecyl, tridecyl, and tetradecyl. In some embodiments, straight-chain or branched alkyl groups have 30 or fewer carbon atoms in their main chain (e.g., for straight chains of C1-C). 30 For C3-C branch 30 ), and more preferably 20 or fewer. The alkyl groups may be substituted or unsubstituted.

[0032] As used herein, the term "heteroalkyl" refers to an alkyl moiety as defined above, which contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.

[0033] As used herein, the term “halogenated alkyl” refers to an alkyl group as defined above, which is substituted with at least one halogen.

[0034] As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined above, which is substituted with at least one hydroxyl group.

[0035] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms (e.g., 2 to 12 carbon atoms) and containing two connection points on its longest carbon chain that connect to the remainder of the compound. Non-limiting examples of alkylenes include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, etc. Alkylenes may be cyclic or acyclic branched or unbranched carbon chain moieties and may optionally be substituted with one or more substituents.

[0036] "Cycloalkyl" refers to a monocyclic, bicyclic, bridged, spirocyclic, or polycyclic saturated carbon ring, each having 3 to 12 carbon atoms. Preferred cycloalkyl groups have 3-10 carbon atoms in their ring structure, and more preferably 3-6 carbon atoms. Cycloalkyl groups may be substituted or unsubstituted.

[0037] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group as defined above that is substituted with at least one halogen.

[0038] "Cyclohexaalkyl" refers to a cycloalkyl moiety as defined above containing one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cyclohexaalkyl groups have 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably 4-6 carbon atoms and heteroatoms in their ring structure. Cyclohexaalkyl groups may be substituted or unsubstituted.

[0039] Unless the number of carbons is otherwise specified, as used herein, "lower alkyl" means an alkyl group as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, in its main chain structure, 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 alkyl groups. In some embodiments, substituents designated as alkyl groups herein are lower alkyl groups.

[0040] "Alkenyl" refers to a cyclic or acyclic branched or unbranched unsaturated carbon chain portion having a specified number of carbon atoms, or at most 26 carbon atoms if no limit is specified; and having one or more double bonds in the portion. Alkenyl groups with 6 to 26 carbon atoms are exemplified by the following: hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosene, dodecenyl, dodecenyl, tridecenyl, tetradecenyl, and dodecenyl, in their various isomers, wherein the unsaturated bonds may be located at any position in the portion and may have a (Z) or (E) configuration around the double bonds.

[0041] "Alkyne" refers to a hydrocarbon moiety that has the range of alkenyl groups but has one or more triple bonds in the moiety.

[0042] As used herein, the term "aryl" includes 3- to 12-membered monocyclic aromatic groups, substituted or unsubstituted, wherein each atom of the ring is a carbon (i.e., carbocyclic aryl) or one or more of the atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups comprise 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term "aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one of the rings is aromatic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, wherein the ring structure comprises 1 to 4 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl and heteroaryl groups can be monocyclic, bicyclic, or polycyclic.

[0043] As used herein, the terms “halogen,” “halide,” or “halogen” mean halogen and include (for example, but not limited to) fluorine, chlorine, bromine, iodine, etc., in both radioactive and non-radioactive forms. In a preferred embodiment, the halogen is selected from the group consisting of fluorine, chlorine, and bromine.

[0044] The term "heterocyclic group" or "heterocyclic group" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, and even more preferably a 5- to 10-membered ring, wherein the ring structure comprises 1 to 4 heteroatoms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclic groups include, for example, thiophene, thiathrone, furan, pyran, isobenzofuran, chromene, oxanthracene, phenoxthia, pyrrole, imidazole, pyrazole, isothiazol, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indazine, isoindole, indole, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxaline, quinazolin, cyclophosphine, cyclophosphine, cyclophosphine, pteridine, carbazole, caroline, phenanthridine, acridine, pyrimidine, phenanthroxaline, phenazine, phenpyrazine, phenthiazine, furazine, phenoxazine, pyrrole, oxacyclopentane, thiocyclopentane, oxazole, piperidine, piperazine, morpholine, lactone, lactam (such as azacyclobutanone and pyrrolidone), sulfonamide, sulfonyl lactone, etc. The heterocycle may be substituted at one or more positions with substituents as described above, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, mercapto, imino, amide, phosphate, phosphonate, phosphonite, carbonyl, carboxyl, silyl, aminosulfonyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, etc.

[0045] The term “substituted” refers to a portion of the main chain in which a substituent replaces a hydrogen atom on one or more carbons. It should be understood that “substitution” or “replaced by” includes substitution based on the permissible valence state of the substituted atom and the substituent and that the substitution results in a stable compound, for example, which does not spontaneously undergo transformation, such as by implicit conditions of rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is considered to include all permissible substituents of an organic compound. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Permissible substituents may be one or more and may be the same or different for the appropriate organic compound. For the purposes of this invention, for example, a nitrogen heteroatom may have a hydrogen substituent and / or any permissible substituent of the organic compound described herein, satisfying the valence state of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetates, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, phosphonites, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate groups, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moieties. In a preferred embodiment, the substituents on the substituted alkyl group are selected from C10. 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, carbonyl, cyano, or hydroxyl groups. In a more preferred embodiment, the substituent on the substituted alkyl group is selected from fluorine, carbonyl, cyano, or hydroxyl groups. Those skilled in the art will understand that the substituent itself can be substituted, if appropriate. Unless explicitly specified as “unsubstituted,” references to the chemical part herein should be understood to include substituted variants. For example, references to an “aryl” group or part implicitly include both substituted and unsubstituted variants.

[0046] As used herein, when each expression (e.g., alkyl, m, n, etc.) appears more than once in any structure, the definition of each expression is intended to be independent of its definition elsewhere in the same structure.

[0047] As used herein, "small molecule" refers to a small organic or inorganic molecule with a molecular weight of less than about 3,000 Daltons. Generally, small molecules used in this invention have a molecular weight of less than 3,000 Da. Small molecules may 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).

[0048] In some embodiments, "small molecule" refers to organic, inorganic, or organometallic compounds that typically have a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound with a size on the order of 1 nm. In some embodiments, the small molecule pharmaceuticals of the present invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.

[0049] "Effective amount" is an amount sufficient to achieve a beneficial or desired result. For example, a therapeutic amount is the amount required to achieve the desired therapeutic effect. This amount may be the same as or different from a preventive effective amount, which is the amount necessary to prevent the onset of disease or disease symptoms. An effective amount may be administered once or multiple times, applied topically, or in doses. The therapeutic effective amount of a composition depends on the composition chosen. The composition may be administered from once or more daily to once or more weekly; including every other day. Those skilled in the art will understand that certain factors can affect the dosage and duration required for effective treatment of a subject, including (but not limited to) the severity of the disease or condition, prior treatment, the subject's general health and / or age, and any other pre-existing conditions. Furthermore, treatment of a subject with a therapeutically effective amount of the composition described herein may comprise a single treatment or a series of treatments. A series of treatments may include a second or subsequent treatment several weeks to several months after the first or prior treatment.

[0050] The terms “reduce,” “reduced,” and “inhibit” are generally used herein to mean a reduction that is statistically significant relative to a reference level. However, to avoid ambiguity, “reduce,” “reduced,” or “inhibit” generally means a reduction of at least 10% compared to a reference level and may 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%, and at most include, for example, the complete absence of a given entity or parameter compared to a reference level, or any reduction between 10% and 99% compared to the absence of a given treatment.

[0051] The terms “increased / increase” or “enhancement” or “activation” are generally used herein to mean an increase of a statistically significant amount; to avoid any ambiguity, the terms “increased / increase” or “enhancement” or “activation” mean an increase of at least 10% compared to a reference level, for example, an increase of 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 at most and including 100% increase, or any increase between 10 and 100% compared to a reference level, or an increase of at least about 2, or at least about 3, or at least about 4, or at least about 5, or at least about 10 times compared to a reference level, or any increase between 2 and 10 times or greater.

[0052] As used in this article, the term “regulation” includes both upregulation and downregulation, such as enhancing or inhibiting a response.

[0053] As defined herein, a “radiopharmaceutical” is a pharmaceutical agent containing at least one radioactive isotope that emits radiation. Radiopharmaceuticals are routinely used in nuclear medicines for the diagnosis and / or treatment of various diseases. Radiolabeled pharmaceuticals (e.g., radiolabeled antibodies) contain a radioactive isotope (RI) that serves as a radiation source. As considered herein, the term “radioactive isotope” includes both metallic and nonmetallic radioactive isotopes. The choice of radioactive isotope is based on the medical application of the radiolabeled pharmaceutical agent. When the radioactive isotope is a metallic radioactive isotope, a chelating agent is typically used to bind the metallic radioactive isotope to the remainder of the molecule. When the radioactive isotope is a nonmetallic radioactive isotope, it is typically attached directly to or via a connector to the remainder of the molecule.

[0054] For the purposes of this invention, chemical elements are identified according to the periodic table, CAS version, Handbook of Chemistry and Physics, 67th edition, 1986-87 (inner cover).

[0055] Compounds of the present invention One aspect of the present invention relates to compounds of formula (I): (I), in A1 is selected from -O- and -NH-; A2 is selected from -C(R6)(R7)- and -C(O)-; A3 is selected from -O- and -N(R5)-; A4 is selected from single bonds and -C(R8)(R9)-; R1, R2, R3 and R4 are each independently selected from -H, halogen, hydroxyl, alkyl, alkoxy and -(CR'R'')C(H)(NH2)CO2H, provided that one and only one of R1, R2, R3 and R4 is -(CR'R'')C(H)(NH2)CO2H; R5 is selected from -H and alkyl groups; R' and R'' are each independently selected from -H, halogens, and alkyl groups; and R6, R7, R8, and R9 are each independently selected from -H and alkyl groups; The compound is racemic, enriched with one enantiomer, or a single enantiomer; In some embodiments, R1, R2, R3 and R4 are each independently selected from -H, halogen, hydroxyl and -(CH2)C(H)(NH2)CO2H, provided that one and only one of R1, R2, R3 and R4 is -(CH2)C(H)(NH2)CO2H.

[0056] In some embodiments, R1, R2, R3 and R4 are each independently selected from -H, halogen, and -(CH2)C(H)(NH2)CO2H, provided that one and only one of R1, R2, R3 and R4 is -(CH2)C(H)(NH2)CO2H.

[0057] In some implementations, the halogen is -F.

[0058] In some implementations, A1 is selected from -O-; A2 is -C(R6)(R7)-; A3 is selected from -O- and -N(R5)-; and A4 is a single bond.

[0059] In some embodiments, the compound has the following structure: .

[0060] In some embodiments, the compound has a structure selected from the following: , and ; Where * indicates ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

[0061] In some implementations, R1, R2, R3, and R4 are each -H.

[0062] In some embodiments, the compound has a structure selected from the following: , , and Or, or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the compound has a structure selected from the following: , and ; Where one of R' and R'' is -H and the other of R' and R'' is a halogen or alkyl group; * indicates having ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

[0064] In some implementations, R1, R2, R3, and R4 are each -H.

[0065] In some implementations, one of R' and R'' is -H and the other of R' and R'' is -F or -CH3.

[0066] In some embodiments, the compound has a structure selected from the following: , , and Or, or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the compound has a structure selected from the following: , and ; Where R2, R3, and R4 are not -H; *indicates that ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

[0068] In some implementations, R2, R3, and R4 are each halogens.

[0069] In some implementations, the halogen is -F.

[0070] In some embodiments, the compound has a structure selected from the following: , and , Where R1, R3, and R4 are not -H; *indicates that ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

[0071] In some implementations, R1, R3, and R4 are each halogens.

[0072] In some implementations, the halogen is -F.

[0073] In some embodiments, the compound has a structure selected from the following: , and ; Where R1, R2, and R4 are not -H; *indicates that ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

[0074] In some implementations, R1, R2, and R4 are each halogens.

[0075] In some implementations, the halogen is -F.

[0076] In some embodiments, the compound has a structure selected from the following: , and ; Where R1, R2, and R3 are not -H; *indicates that ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

[0077] In some implementations, R1, R2, and R3 are each halogens.

[0078] In some implementations, the halogen is -F.

[0079] In some embodiments, the compound has a structure selected from the following: , , , , , , , and , Or its pharmaceutically acceptable salt.

[0080] In some embodiments, the compound has the following structure: .

[0081] In some embodiments, the compound has a structure selected from the following: and ; Where * indicates ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

[0082] In some implementations, R1, R2, R3, and R4 are each -H.

[0083] In some embodiments, the compound has a structure selected from the following: , and , , and ; Where R1, R2, R3, and R4 are not -H; *indicates that ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

[0084] In some implementations, R1, R2, R3, and R4 are each halogens.

[0085] In some implementations, the halogen is -F.

[0086] In some implementations, R5 is -H.

[0087] In some implementations, R5 is -CH3.

[0088] In some embodiments, the compound has a structure selected from the following: , , and , Or its pharmaceutically acceptable salt.

[0089] In some implementations, A1 is -NH-; A2 is -C(R6)(R7)-; A3 is -O-; and A4 is a single bond.

[0090] In some embodiments, the compound has a structure selected from the following: ; Where * indicates ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

[0091] In some implementations, R1, R2, and R3 are each -H.

[0092] In some embodiments, the compound has the following structure: Or, or a pharmaceutically acceptable salt thereof.

[0093] In some implementations, A1 is -O-; A2 is -C(O)-; A3 is selected from -O- and -N(R5)-; and A4 is -C(R8)(R9)-.

[0094] In some embodiments, the compound has a structure selected from the following: , , and .

[0095] In some implementations, R1, R2, R3, and R4 are each -H.

[0096] In some implementations, R5 is -H.

[0097] In some implementations, R5 is -CH3.

[0098] In some embodiments, the compound has the following structure: Or, or a pharmaceutically acceptable salt thereof.

[0099] In some implementations, R' is -H.

[0100] In some implementations, R'' is selected from -H and halogens.

[0101] In some embodiments, R'' is selected from -H and alkyl groups.

[0102] In some implementations, R'' is a halogen.

[0103] In some embodiments, R'' is an alkyl group.

[0104] In some embodiments, the halogen is -F; and the alkyl group is -CH3.

[0105] In some embodiments, the absolute configuration of the chiral carbon represented by * is ( S In some embodiments, the absolute configuration of the chiral carbon represented by * is ( R ).

[0106] In some embodiments, the boron atom in the compound is 10 B.

[0107] In some embodiments, the compounds are selected from the following table:

[0108] In some embodiments, the compound is a transisomer. Additionally, unless otherwise specified, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium, or by replacing carbon with... 13 C- or 14 Compounds produced by C-enriched carbon substitution are within the scope of this invention. Such compounds can be used, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the invention. For example, in variable R... 1 In this case, (C1-C4)alkyl or -O-(C1-C4)alkyl may be partially or completely deuterated (e.g., -CH2CD3, -CD3 or -OCD3).

[0109] Include 11 B and 10 Compounds derived from the natural distribution of B are also within the scope of this invention.

[0110] 10 Compounds with increased concentration of B are also within the scope of this invention, for example, wherein 10 B exists at an abundance of >20%.

[0111] Any compound of the present invention can also be radiolabeled for use in the preparation of radiopharmaceuticals.

[0112] Treatment One aspect of the present invention provides compounds, compositions, and methods that can be used in boron neutron capture therapy.

[0113] Another aspect of the present invention relates to a method for treating cancer, the method comprising: i) administering an effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) to a subject in need, wherein the compound accumulates in multiple cancer cells of the subject; and ii) Irradiate the plurality of cancer cells with neutrons.

[0114] Another aspect of the present invention relates to a method for treating cancer, the method comprising: i) administering to a subject in need an effective amount of a compound of formula (IA) or a pharmaceutical composition comprising a compound of formula (IA), wherein the compound accumulates in multiple cancer cells of the subject; and ii) Irradiate the multiple cancer cells with neutrons.

[0115] Another aspect of the present invention relates to a method for treating cancer, the method comprising: i) administering to a subject in need an effective amount of a pharmaceutical composition of formula (IB) compound or inclusion (IB) compound, wherein the compound accumulates in multiple cancer cells of the subject; and ii) Irradiate the multiple cancer cells with neutrons.

[0116] Another aspect of the present invention relates to a method for treating cancer, the method comprising: i) administering to a subject in need an effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the compound accumulates in multiple cancer cells of the subject; and ii) Irradiate the multiple cancer cells with neutrons.

[0117] In some embodiments, the compound selectively or preferentially accumulates in the plurality of cancer cells relative to the non-cancer cells of the subject.

[0118] In some embodiments, the irradiation causes the compound to... 10 B atoms are converted into α-particles and lithium-7 ions.

[0119] In some embodiments, the compound or composition is administered intravenously.

[0120] In some embodiments, the compound is applied continuously during neutron irradiation.

[0121] In some embodiments, in step (i), the compound is administered for a first time period at a rate of about 100 mg / kg / h to about 500 mg / kg / h.

[0122] In some embodiments, in step (i), the compound is administered for a first time period at a rate of about 150 mg / kg / h to about 300 mg / kg / h.

[0123] In some embodiments, the first time period is from about 1 hour to about 3 hours. In some embodiments, the first time period is about 2 hours.

[0124] In some embodiments, in step (ii), the compound is administered for a second time period at a rate of about 50 mg / kg / h to about 150 mg / kg / h.

[0125] In some embodiments, in step (ii), the compound is administered for a second time period at a rate of about 100 mg / kg / h to about 200 mg / kg / h.

[0126] In some implementations, the second time period is from about 0.25 hours to about 1.25 hours.

[0127] In some implementations, the second time period is from about 0.5 hours to about 1 hour.

[0128] In some implementations, the cancer is a solid tumor.

[0129] In some implementations, the cancer is selected from head and neck cancer, glioblastoma, melanoma, sarcoma, breast cancer, meningioma, lung cancer, mesothelioma, hepatocellular carcinoma, and external Paget's disease.

[0130] In some implementations, the cancer is unresectable head and neck cancer.

[0131] Pharmaceutical composition, route of administration and administration In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention and pharmaceutically acceptable carriers.

[0132] In some embodiments, the pharmaceutical composition of the present invention further comprises at least one additional pharmaceutically active agent in addition to the compound of the present invention.

[0133] The 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 pharmaceutical active agents.

[0134] In some embodiments, the pharmaceutical composition further comprises sugars.

[0135] In some embodiments, the pharmaceutical composition further comprises a polyhydroxy acid.

[0136] In some embodiments, the pharmaceutical composition further comprises sugar alcohols.

[0137] As specified above, “effective amount” means any amount sufficient to achieve the desired biological effect. Combined with the teachings provided herein, effective prophylactic or therapeutic treatment regimens can be planned that do not cause substantial undesirable toxicity but are still effective in treating a particular subject by selecting various active compounds and weighting factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and administration mode. The effective amount for any particular application may vary depending on factors such as the disease or ailment being treated, the specific compound of the invention being administered, the subject’s body type, or the severity of the disease or ailment. Those skilled in the art can determine the effective amount of a specific compound and / or other therapeutic agent of the invention empirically without excessive experimentation. A maximum dose may be used, i.e., the highest safe dose based on some medical judgment. Multiple daily doses may be considered to achieve appropriate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by measuring the patient’s peak drug levels or sustained plasma drug levels. In this document, “dose” and “dosage” are used interchangeably.

[0138] In some embodiments, intravenous administration of the compound is typically from about 300 mg / kg / day to about 1000 mg / kg / day. In one embodiment, intravenous administration of the compound is typically from about 400 mg / kg / day to about 600 mg / kg / day. In one embodiment, intravenous administration of the compound is typically from about 450 mg / kg / day to about 500 mg / kg / day.

[0139] The dosage may be adjusted as needed to achieve the desired drug level, locally or systemically, depending on the administration method. For example, intravenous administration may be expected to be one to several orders of magnitude lower daily. In cases where the response in the subject is insufficient at such dosages, even higher doses (or higher doses via different, more localized delivery routes) may be used, to the extent permitted by patient tolerance. Multiple daily doses may be considered to achieve appropriate systemic levels of the compound.

[0140] For any of the compounds described herein, the therapeutically effective dose can be initially determined based on animal models. The therapeutically effective dose can also be determined based on human data from compounds already tested in humans and compounds known to exhibit similar pharmacological activity (e.g., other relevant active agents). Higher doses may be required for parenteral administration. The dosage can be adjusted based on the relative bioavailability and potency of the compound being administered. Adjusting the dosage to achieve maximum efficacy based on the methods described above and other methods well known in the art is entirely within the capabilities of those skilled in the art.

[0141] The formulations of the present invention can be administered as pharmaceutically acceptable solutions, which may conventionally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0142] For use in therapy, an effective amount of a compound can be administered to a subject by any mode of delivery to the desired surface. Administration of the pharmaceutical composition can be achieved by any method known to a skilled technician. Routes of administration include (but are not limited to) intravenous, intramuscular, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (e.g., to a tumor or abscess), transmucosal (e.g., locally to the eye), inhalation, and topical.

[0143] For intravenous and other parenteral administration routes, the compounds of the present invention can be formulated into lyophilized formulations, lyophilized formulations of active compounds with liposome insertion or encapsulation, lipid complexes, or salt complexes contained in an aqueous suspension. Lyophilized formulations are typically reconstituted in a suitable aqueous solution (e.g., in sterile water or saline) shortly before administration.

[0144] Those skilled in the art will understand that, based on the description of the invention contained herein and in view of information known to those skilled in the art, other suitable modifications and adaptations to the compositions and methods described herein will be apparent and can be made without departing from the scope of the invention or any embodiments thereof. The invention is now described in detail, and will be more clearly understood by reference to the following examples, which are included for illustrative purposes only and are not intended to limit the invention.

[0145] Example The invention is further described in the following embodiments, which do not limit the scope of the invention as described in the claims.

[0146] The abbreviations used in this specification, particularly in the schemes and embodiments, are listed in Table A below: Table A.

[0147] Example 1. Preparation of Compounds General methods for synthesizing the compounds of the present invention Option 1 Scheme 1 provides a general synthetic route for the fused dioxaborane-heptanol or oxazaborane-heptanol phenylalanine compounds disclosed herein. In Scheme 1, bromophenol 1a is cross-coupled with the root of iodide 1b via Negishi to obtain 1c. Regioselective bromination with NBS yields 1d. Subsequent alkylation of the phenolic hydroxyl group of 1d with bromide 1e or 1f yields the corresponding intermediates 1g or 1h, respectively. The conversion of bromide to borate 1i or 1j is achieved via Pd-mediated coupling with diborane, followed by alkaline hydrolysis to give carboxylic acid 1k or 1l. Under acidic conditions, deprotection of the THP or Boc group leads to cyclization with the adjacent borate to give the final product 1m or 1n of dioxaborane-heptanol or oxazaborane-heptanol.

[0148] Preparation of compound 1- S Reagents and conditions: (a) Zn, I 2 Pd 2 (dba) 3 (a) S-Phos, DMF, 50°C, overnight; (b) NBS, i Pr 2 NH, DCM, rt, 3h; (c) K 2 CO 3 , DMF, rt, 2 h; (d) Pd(dppf)Cl 2 KOAc, dioxane, rt, 2 h; (e) LiOH-H 2 O， THF / H 2 O, rt, 2 h; (f) 4 M HCl, dioxane, rt, 2 h.

[0149] Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-hydroxyphenyl)propionate (1 S -1).

[0150] Add I2 (0.59 g, 2.31 mmol, 0.1 equivalent) to a stirred solution of Zn (6.05 g, 92.48 mmol, 4 equivalents) in DMF (20 mL). Stir the resulting mixture at room temperature under a nitrogen atmosphere for 5 minutes. Add I2 (0.81 g, 3.18 mmol, 0.1 equivalent) to a stirred solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropionate methyl ester (15.22 g, 46.24 mmol, 2 equivalents) in DMF (20 mL). Stir the resulting mixture at room temperature under a nitrogen atmosphere for 30 minutes. Add 20 mL of DMF containing 2-bromophenol (4 g, 23.12 mmol, 1 equivalent), Pd2(dba)3 (2.12 g, 2.31 mmol, 0.1 equivalent), and S-Phos (1.42 g, 3.47 mmol, 0.15 equivalent) to the above mixture. Stir the resulting mixture overnight at 50 °C under a nitrogen atmosphere. Quench the reaction with water. Extract the resulting mixture with EtOAc (2 x 30 mL). Wash the combined organic layers with water (4 x 30 mL), dry to anhydrous Na2SO4, filter, and concentrate. Purify the residue by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 60% gradient over 10 min; detector, UV 254 nm] to give the title product (1.5 g, 21.97%) as a light brown solid. LCMS (ESI): C 15 H 21 The calculated mass of NO5 is 295.1; the measured m / z value is 196.0 [M+H-Boc]. + .

[0151] Preparation of methyl (2S)-3-(3-bromo-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (1 S -2).

[0152] Under a nitrogen atmosphere at 0 °C, NBS (1.51 g, 8.47 mmol, 1 equivalent) was added in multiple portions to a stirred solution containing (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-hydroxyphenyl)propionate (2.5 g, 8.47 mmol, 1 equivalent) and bis(propyl-2-yl)amine (0.09 g, 0.85 mmol, 0.1 equivalent) in DCM (30 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 60% gradient over 10 min; detector, UV 254 nm] to give the title product (1.5 g, 47.35%) as a pale yellow oil. LCMS (ESI): C 15 H 20 Calculated mass of BrNO5: 373.1; Measured m / z: 274.0 [M+H-Boc] + .

[0153] Preparation of methyl (2S)-3-(3-bromo-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (1 S -3).

[0154] K₂CO₃ (304.68 mg, 2.21 mmol, 1.5 equivalent) was added to a stirred solution containing methyl (2S)-3-(3-bromo-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (550 mg, 1.47 mmol, 1 equivalent) and 2-(2-bromoethoxy)oxane (368.74 mg, 1.76 mmol, 1.2 equivalent) in DMF (12 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (5 x 20 mL), dried over anhydrous Na₂SO₄, and the filtrate was concentrated. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 90% gradient over 10 minutes; detector, UV 254 nm] to give the title product (670 mg, 90.74%) as a pale yellow oil. LCMS (ESI): C 22 H 32 Calculated mass of BrNO7: 501.1; Measured m / z: 524.1 [M+Na] + .

[0155] Preparation of (3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (1 S -4).

[0156] KOAc (195.35 mg, 1.99 mmol, 2 equivalents) and Pd(dppf)Cl2 (72.82 mg, 0.10 mmol, 0.1 equivalents) were added to a stirred solution containing (2S)-3-(3-bromo-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (500 mg, 1.0 mmol, 1 equivalent) and 2-(5,5-dimethyl-1,3,2-dioxaborhexane-2-yl)-5,5-dimethyl-1,3,2-dioxaborhexane (449.62 mg, 1.99 mmol, 2 equivalents). The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 70% gradient over 10 min; detector, UV 254 nm] to give the title product (450 mg, 96.76%) as a brownish-yellow oil. LCMS (ESI): C 22 H 34 Calculated mass of BNO9: 467.2; Measured m / z: 490.3 [M+Na] + .

[0157] Preparation of (2S)-3-(3-dihydroxyboryl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (1 S -5).

[0158] At room temperature and under a nitrogen atmosphere, lithium hydroxide monohydrate (71.83 mg, 1.71 mmol, 2 equivalents) was added to a stirred solution of (3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (400 mg, 0.86 mmol, 1 equivalent) in THF (8 mL) and H₂O (4 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was acidified to pH 5 with 2 M HCl (aqueous solution). The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 50% gradient over 10 min; detector, UV 254 nm] to give the title product (310 mg, 79.90%) as a pale yellow oil. LCMS (ESI): C 21 H 32 Calculated mass of BNO9: 453.2; Measured m / z: 452.2 [MH] - .

[0159] Preparation of (S)-2-amino-3-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborheptan-6-yl)propionic acid (1 S ).

[0160] Under a nitrogen atmosphere, 1,4-dioxane (0.2 mL) containing 4 M HCl (gas) was added to a stirred solution of (2S)-3-(3-dihydroxyboryl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (275 mg, 0.61 mmol, 1 equivalent) in dioxane (0.2 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was then concentrated under reduced pressure. The residue was purified [by preparative TLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 12% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.63)] to give the title product (70 mg, 45.69%) as a white solid. LCMS (ESI): C 11 H 14Calculated mass of BNO5: 251.1; Measured m / z: 252.1 [M+H] + . 1 H NMR (400 MHz, deuterium oxide) δ 7.70 (d, J = 7.6 Hz, 1H), 7.38 -7.23 (m, 1H), 7.02 (t, J = 7.5 Hz, 1H), 5.39 (s, 1H), 4.32 (s, 2H), 4.16 (s,2H), 3.95 (dd, J = 8.2, 5.0 Hz, 1H), 3.30 (dd, J = 14.3, 5.0 Hz, 1H), 3.00 (dd, J = 14.3, 8.1 Hz, 1H), 2.01 (s, 1H), 1.37 - 0.86 (m, 1H).

[0161] Preparation of compound 1- R Reagents and conditions: (a) Zn, I 2 Pd 2 (dba) 3 , S-phos, DMF, 40℃; (b) NBS, iPr 2 NH, DCM, 0℃; (c) K 2 CO 3 , DMF, rt; (d) Xphos Pd G2, X-Phos, KOAc, EtOH, 80℃; (e) LiOH.H 2 O, THF, H 2 O， rt; (f) Dioxane containing 4M HCl, dioxane, rt Preparation of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-hydroxyphenyl)propionate (1 R -1).

[0162] A mixture of Zn (6.05 g, 92.48 mmol, 4 equivalents) and I2 (0.58 g, 2.31 mmol, 0.1 equivalents) in DMF (40 mL) was stirred at room temperature for 5 minutes under a nitrogen atmosphere. A solution of (2S)-2-[(tert-Butoxycarbonyl)amino]-3-iodopropionate (11.41 g, 34.68 mmol, 1.5 equivalents) in DMF (15 mL) was slowly added to the mixture, followed by the addition of I2 (0.58 g, 2.31 mmol, 0.1 equivalents). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. Then, a solution of 2-bromophenol (4 g, 23.12 mmol, 1 equivalent) in DMF (10 mL), Pd2(dba)3 (2.12 g, 2.31 mmol, 0.1 equivalent), and S-phos (1.42 g, 3.47 mmol, 0.15 equivalent) were added to the mixture. The reaction mixture was stirred overnight at 40 °C under a nitrogen atmosphere. The reaction was quenched with water (20 mL). The mixture was filtered, and the solids were washed with EtOAc (2 x 10 mL). The filtrate was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 40% to 50% gradient over 5 minutes; detector, UV 220 nm] to give the title product (4.35 g, 63.7%) as a brownish-yellow oil. LCMS (ESI): C 15 H 21 The calculated mass of NO5 is 295.1; the measured m / z value is 196.2 [M+H-Boc]. + .

[0163] Preparation of methyl (2R)-3-(3-bromo-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (1 R -2).

[0164] Under a nitrogen atmosphere at 0 °C, NBS (1.57 g, 8.84 mmol, 0.6 equivalent) was added in multiples to a stirred solution containing methyl (2R)-2-[(tert-butyloxycarbonyl)amino]-3-(2-hydroxyphenyl)propionate (4.35 g, 14.73 mmol, 1 equivalent) and bis(propyl-2-yl)amine (149.0 mg, 1.47 mmol, 0.1 equivalent) in DCM (80 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18; mobile phase, MeCN / water (0.1% FA), 50% to 60% gradient over 6 min; detector, UV 220 nm] to give the title product (2.75 g, 49.9%) as a yellow oil. LCMS (ESI): C 15 H 20 Calculated mass of BrNO5: 373.1; Measured m / z: 274.1 [M+H-Boc] + Preparation of methyl (2R)-3-(3-bromo-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (1 R -3).

[0165] At room temperature, K₂CO₃ (0.88 g, 6.33 mmol, 1.5 equivalent) was added to a stirred solution containing methyl (2R)-3-(3-bromo-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (1.58 g, 4.22 mmol, 1 equivalent) and 2-(2-bromoethoxy)oxane (1.06 g, 5.07 mmol, 1.2 equivalent) in DMF (23 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (1 x 2 mL). The filtrate was purified by reversed-phase rapid chromatography [using the following conditions: column, C18; mobile phase, MeCN / water (0.1% FA), 55% to 70% gradient over 5 min; detector, UV 220 nm] to give the title product (1.74 g, 82.03%) as a pale yellow oil. LCMS (ESI): C 22 H 32 Calculated mass of BrNO7: 501.1; Measured m / z: 524.1 [M+Na] + .

[0166] Preparation of (3-((R)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (1 R -4).

[0167] At room temperature, under a nitrogen atmosphere, KOAc (961.10 mg, 9.79 mmol, 3 equivalents), XPhos Pd G2 (513.69 mg, 0.65 mmol, 0.2 equivalents), and X-phos (155.62 mg, 0.33 mmol, 0.1 equivalents) were added to a stirred solution containing (2R)-3-(3-bromo-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (1.64 g, 3.26 mmol, 1 equivalent) and tetrahydroxydiborane (877.94 mg, 9.79 mmol, 3 equivalents) in EtOH (32 mL). The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The mixture was cooled to room temperature and filtered. The filter cake was washed with EtOH (1 x 2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18; mobile phase, MeCN / water (0.1% FA), 40% to 55% gradient over 10 minutes; detector, UV 220 nm] to give the title product (860 mg, 56.38%) as a pale yellow oil. LCMS (ESI): C 22 H 34 Calculated mass of BNO9: 467.2; Measured m / z: 490.2 [M+Na] + Preparation of (2R)-3-(3-dihydroxyboryl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (1 R -5).

[0168] At room temperature and under a nitrogen atmosphere, LiOH·H2O (181.82 mg, 4.33 mmol, 2.5 equivalents) was added to a stirred mixture containing (3-((R)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (810 mg, 1.73 mmol, 1 equivalent) in THF (16 mL) / H2O (8 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was extracted with EtOAc (3 x 50 mL) (retaining the aqueous layer). The aqueous layer was acidified to 'pH 5' with 1N HCl (aqueous solution) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title product (673 mg, 85.66%) as a white oil. LCMS (ESI): calculated mass of C21H32BNO9, 453.2; measured m / z, 452.1 [MH] - .

[0169] Preparation of (R)-2-amino-3-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborheptan-6-yl)propionate (1 R ).

[0170] At room temperature, dioxane (6 mL) containing 4 M HCl was added to a stirred solution of (2R)-3-(3-dihydroxyboryl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (623 mg, 1.37 mmol, 1 equivalent) in dioxane (6 mL). The resulting mixture was stirred at room temperature for 1 hour. The residue was purified by wet milling with MTBE (40 mL). The precipitate was collected by filtration and washed with MTBE (3 x 5 mL) to give the title product (218 mg, 55.17%) as a white solid. LCMS (ESI): C 11 H 14 Calculated mass of BNO5: 251.1; Measured m / z: 252.1 [M+H] + . 1 ¹H NMR (400 MHz, deuterium oxide): δ 7.63 (dq, J = 6.2, 2.1 Hz, 1H), 7.25 (dq, J = 5.7, 1.8 Hz, 1H), 6.93 (tdd,J = 7.6, 3.4, 1.5 Hz, 1H), 4.22 (q, J =6.7, 5.5 Hz, 3H), 4.09 (dd, J = 4.9, 2.7 Hz, 2H), 3.32 - 3.16 (m, 1H), 3.15 -2.95 (m, 1H).

[0171] Preparation of compound 2 Reagents and conditions: (a) Zn, I 2 Pd 2 (dba) 3 , Sphos, DMF, 40℃; (b) i-Pr 2 NH, NBS, DCM, -60 ℃;(c) K 2 CO 3 DMF, rt; (d) B 2 (OH) 4 , Xphos-Pd-G2, Xphos, AcOK, EtOH, 80℃; (e) LiOH.H 2 O, H 2 O, THF, rt; (f) Dioxane containing 4M HCl, dioxane, rt Preparation (2) S Methyl 2-[(tert-Butoxycarbonyl)amino]-3-(2-fluoro-6-hydroxyphenyl)propionate (2-1).

[0172] Under a nitrogen atmosphere, at room temperature, a solution of Zn (12.32 g, 188.48 mmol, 4 equivalents) in DMF (200 mL) was treated with I2 (1.20 g, 4.72 mmol, 0.1 equivalents) for 5 minutes, followed by the addition of (2... RMethyl 2-[(tert-Butoxycarbonyl)amino]-3-iodopropionate (9.31 g, 28.27 mmol, 1.8 equivalents) and I2 (1.20 g, 4.71 mmol, 0.1 equivalents). The mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The above solution was added to a stirred solution of 2-bromo-3-fluorophenol (9 g, 47.12 mmol, 1 equivalent) and Pd2(dba)3 (3.24 g, 3.53 mmol, 0.075 equivalents) in DMF (200 mL) at room temperature. The resulting mixture was stirred overnight at 40 °C under a nitrogen atmosphere. The reaction was quenched by adding water (200 mL) at room temperature. The resulting mixture was filtered, and the solids were washed with EtOAc (3 x 100 mL). The filtrate was concentrated under reduced pressure and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with water (3 x 300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH₄HCO₃), 10% to 100% gradient over 10 min; detector, UV 254 nm] to give the title product (2 g, 13.55%) as a yellow oil. LCMS (ESI): C 15 H 20 Calculated mass of FNO5: 313.13; Measured m / z: 214.1 [M-Boc+H] + .

[0173] Preparation (2) S Methyl 3-(3-bromo-6-fluoro-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (2-2).

[0174] At -60°C, (2) was added to DCM (50 mL) S Methyl 2-[(tert-Butoxycarbonyl)amino]-3-(2-fluoro-6-hydroxyphenyl)propionate (30 mg, 0.096 mmol, 1 equivalent) and bis(propyl-2-yl)amine (0.11 g, 1.05 mmol, 0.1 equivalent) were added in multiples of NBS (1.87 g, 10.53 mmol, 1 equivalent) in a stirred solution. The resulting mixture was stirred at -60 °C for 2 h. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 100% gradient over 10 min; detector, UV 254 nm] to give the title product (1.6 g, 38.73%) as a yellow oil. LCMS (ESI): C15 H 19 Calculated mass values ​​of BrFNO5: 391.04, 393.04; Measured m / z values: 292.05, 294.05 [M-Boc+H] + .

[0175] Preparation of methyl (2S)-3-(3-bromo-6-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (2-3).

[0176] At room temperature, add (2) to DMF (30 mL) S Methyl 3-(3-bromo-6-fluoro-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (30 mg, 0.076 mmol, 1 equivalent) and K₂CO₃ (1.69 g, 12.24 mmol, 3 equivalents) were mixed with 2-(2-bromoethoxy)oxane (1.71 g, 8.19 mmol, 2 equivalents). The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 90% gradient over 10 min; detector, UV 254 nm] to give the title product (1.3 g, 61.24%) as a yellow oil. LCMS (ESI): C 22 H 31 Calculated mass of BrFNO7: 519.13; Measured m / z: 520.85 [M +H] + .

[0177] Preparation of (3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-4-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (2-4).

[0178] At room temperature, B2(OH)4 (275.64 mg, 3.07 mmol, 2 equivalents), Xphos (73.29 mg, 0.15 mmol, 0.1 equivalents), and Xphos-Pd-G2 (241.92 mg, 0.31 mmol, 0.2 equivalents) were added to a stirred solution containing methyl (2S)-3-(3-bromo-6-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (800 mg, 1.54 mmol, 1 equivalent) and AcOK (452.62 mg, 4.61 mmol, 3 equivalents) in EtOH (2 mL). The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was filtered, and the solids were washed with EtOH (3 x 5 mL). The filtrate was concentrated under reduced pressure and purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 90% gradient over 10 minutes; detector, UV 220 nm] to give the title product (300 mg, 40.21%) as a yellow oil. LCMS (ESI): C 22 H 33 Calculated mass of BFNO9: 485.22; Measured m / z: 508.15 [M + Na] + .

[0179] Preparation of (2S)-3-(3-dihydroxyboryl-6-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (2-5).

[0180] At room temperature, LiOH·H2O (24.21 mg, 0.58 mmol, 2 equivalents) was added to a stirred solution of (3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-4-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (140 mg, 0.29 mmol, 1 equivalent) in THF (2 mL) and H2O (1 mL). The resulting mixture was stirred at room temperature for 2 hours and acidified to pH 3 with 1 M HCl. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI): C 21 H 31Calculated mass of BFNO9: 471.21; Measured m / z: 272.15 [M-Boc+H] + .

[0181] Preparation of (S)-2-amino-3-(7-fluoro-1-hydroxy-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborheptan-6-yl)propionic acid (2).

[0182] At room temperature, dioxane (1 mL, 4.00 mmol, 13.47 equivalents) containing 4M HCl was added to a stirred solution of (2S)-3-(3-dihydroxyboron-6-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (140 mg, 0.30 mmol, 1 equivalent) in dioxane (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The residue was purified by wet milling with tert-butyl methyl ether (3 mL). The precipitated solid was collected by filtration and washed with tert-butyl methyl ether (3 x 5 mL) to give the title product (27 mg, 33.28%) as a grayish-white solid. LCMS (ESI): C 11 H 13 Calculated mass of BFNO5: 269.09; Measured m / z: 270.05 [M+H] + . 1 ¹H NMR (400 MHz, deuterium oxide): δ 7.70 (m, ¹H), 6.79 (m, ¹H), 4.31 (q, δ ) J = 3.7 Hz, 2H), 4.17 - 4.07 (m, 3H), 3.25 (m, 1H), 3.16 (m, 1H).

[0183] Preparation of compound 3 Reagents and conditions: (a) Zn, I 2 Pd 2 (dba) 3 , Sphos, DMF, 40℃; (b) i-Pr 2 NH, NBS, DCM, 0℃; (c) K 2 CO 3 DMF, rt; (d) B 2 (OH) 4 , Xphos-Pd-G2, Xphos, AcOK, EtOH, 80℃; (e) LiOH.H 2 O，H 2 O, THF, rt; (f) Dioxane containing 4M HCl, dioxane, rt Preparation (2) S Methyl 2-[(tert-Butoxycarbonyl)amino]-3-(5-fluoro-2-hydroxyphenyl)propionate (3-1).

[0184] Under a nitrogen atmosphere, at room temperature, a mixture of Zn (6.85 g, 104.71 mmol, 4 equivalents) and I2 (0.66 g, 2.62 mmol, 0.1 equivalents) in DMF (50 mL) was stirred for 5 minutes. At room temperature, (2... R Methyl 2-[(tert-Butoxycarbonyl)amino]-3-iodopropionate (15.51 g, 47.12 mmol, 1.8 equivalents) and I2 (0.66 g, 2.62 mmol, 0.1 equivalents). The resulting mixture was stirred at room temperature for 0.5 hours. At room temperature, 2-bromo-4-fluorophenol (5 g, 26.18 mmol, 1 equivalent), Pd2(dba)3 (1.80 g, 1.96 mmol, 0.075 equivalents) and S-Phos (1.61 g, 3.93 mmol, 0.15 equivalents) were added to the mixture. The resulting mixture was stirred overnight at 40 °C. The reaction was quenched with water at room temperature. The resulting mixture was filtered, and the solids were washed with DMF (3 x 20 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH₄HCO₃), 10% to 100% gradient over 10 min; detector, UV 254 nm] to give the title product (1.21 g, 14.75%) as a brown oil. LCMS (ESI): C 15 H 20 Calculated mass of FNO5: 313.13; Measured m / z: 214.0 [M-Boc+H] + .

[0185] Preparation (2) S Methyl 3-(3-bromo-5-fluoro-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (3-2).

[0186] Under a nitrogen atmosphere at 0°C, (2) was added to DCM (20 mL) containing (2) SMethyl 2-[(tert-Butoxycarbonyl)amino]-3-(5-fluoro-2-hydroxyphenyl)propionate (100 mg, 0.32 mmol, 1 equivalent) and diisopropylamine (35.85 mg, 0.35 mmol, 0.1 equivalent) were added in multiples of NBS (0.63 g, 3.54 mmol, 1 equivalent) to a stirred mixture. The resulting mixture was stirred at 0 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 0% to 100% gradient over 10 min; detector, UV 254 nm] to give the title product (600 mg, 43.18%) as a brown oil. LCMS (ESI): C 15 H 19 Calculated mass values ​​of BrFNO5: 391.04, 393.04; Measured m / z values: 292.05, 294.05 [M-Boc+H] + .

[0187] Preparation of methyl (2S)-3-(3-bromo-5-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (3-3).

[0188] Under a nitrogen atmosphere at room temperature, (2) was added to a container of DMF (5 mL) containing (2) S Methyl 3-(3-bromo-5-fluoro-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (570 mg, 1.45 mmol, 1 equivalent) and K2CO3 (602.54 mg, 4.36 mmol, 3 equivalents) were mixed with 2-(2-bromoethoxy)oxane (607.70 mg, 2.91 mmol, 2 equivalents). The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 90% gradient over 10 min; detector, UV 220 nm] to give the title product (600 mg, 79.34%) as a brown oil. LCMS (ESI): C 22 H 31 Calculated mass values ​​for BrFNO7: 519.13, 521.13; Measured m / z values: 517.85, 519.85 [MH] - .

[0189] Preparation of (3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-5-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (3-4).

[0190] At room temperature, XPhos Pd G2 (7.56 mg, 0.010 mmol, 0.1 equivalent), Xphos (49.47 mg, 0.104 mmol, 0.1 equivalent), and AcOK (305.52 mg, 3.11 mmol, 3 equivalent) were added to a stirred mixture containing (2S)-3-(3-bromo-5-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (50 mg, 0.096 mmol, 1 equivalent) and B2(OH)4 (279.08 mg, 3.11 mmol, 3 equivalent) in EtOH (10 mL). The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature. The resulting mixture was filtered, and the solid was washed with MeOH (30 mL) (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 0% to 100% gradient over 10 min; detector, UV 220 nm] to give the title product (360 mg, 71.49%) as a grayish-white solid. LCMS (ESI): C 22 H 33 Calculated mass of BFNO9: 485.22; Measured m / z: 508.15 [M + Na] + .

[0191] Preparation of (2S)-3-(3-dihydroxyboryl-5-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (3-5).

[0192] Under a nitrogen atmosphere at room temperature, LiOH·H2O (62.25 mg, 1.48 mmol, 2 equivalents) was added to a stirred solution of (3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-5-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (360 mg, 0.74 mmol, 1 equivalent) in THF (2 mL) and H2O (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was diluted with H2O (10 mL). The resulting mixture was washed with EtOAc (3 x 5 mL). The aqueous phase was acidified to pH 4 with 1 M HCl. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title product (210 mg, 60.07%) as a grayish-white solid. LCMS (ESI): C 21 H 31 Calculated mass of BFNO9: 471.21; Measured m / z: 272.15 [M-Boc+H] + .

[0193] preparation( S )-2-amino-3-(8-fluoro-1-hydroxy-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborheptan-6-yl)propionic acid (3).

[0194] Under a nitrogen atmosphere at room temperature, a mixture of (2S)-3-(3-dihydroxyboron-5-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (160 mg, 0.41 mmol, 1 equivalent) in dioxane (0.5 mL) and 1,4-dioxane containing 4 M HCl (gas) was stirred for 1 hour. The product was precipitated by adding tert-butyl methyl ether (20 mL). The mixture was filtered, and the solid was washed with tert-butyl methyl ether (3 x 5 mL) to give the title product (61.7 mg, 47.16%) as a brown solid. LCMS (ESI): C 11 H 13 Calculated mass of BFNO5: 269.09; Measured m / z: 270.05 [M+H] + . 1 ¹H NMR (400 MHz, deuterium oxide): δ 7.34 (dd, J =9.4, 3.3 Hz, 1H), 7.07 (dd,J = 8.4, 3.3 Hz, 1H), 4.24 (dd, J = 7.7, 5.3 Hz, 3H), 4.12 (dd, J = 4.7, 2.5 Hz, 2H), 3.27 (dd, J = 14.3, 6.0 Hz, 1H), 3.09 (dd, J =14.3, 7.2 Hz, 1H).

[0195] Preparation of compound 4 Reagents and conditions: (a) Zn, I 2 Pd 2 (dba) 3 , S-Phos, DMF, 40℃; (b) NBS, i Pr 2 NH, DCM, rt; (c)K 2 CO 3 DMF, rt; (d) B 2 (OH) 4 , X-phos Pd G2, X-phos, KOAc, EtOH, 80℃; (e) LiOH-H 2 O， THF / H 2 O, rt; (f)HCl, dioxane, rt Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionate (4-1).

[0196] Under a nitrogen atmosphere at room temperature, methyl (2R)-2-[(tert-butyloxycarbonyl)amino]-3-iodopropionate (11.4 g, 34.7 mmol, 1.5 equivalents) in DMF (15 mL) was added dropwise to a stirred mixture containing Zn (6.05 g, 92.5 mmol, 4 equivalents) and I2 (0.55 g, 2.3 mmol, 0.1 equivalents) in DMF (15 mL). I2 (0.55 g, 2.3 mmol, 0.1 equivalents) was then added to the reaction mixture at room temperature. The resulting mixture was stirred for 30 minutes under a nitrogen atmosphere at room temperature. At room temperature, 4-bromophenol (4 g, 23.1 mmol, 1 equivalent), Pd2(dba)3 (1.59 g, 1.73 mmol, 0.075 equivalent), and S-Phos (1.42 g, 3.47 mmol, 0.15 equivalent) in anhydrous DMF (15 mL) were added to the reaction mixture. The resulting mixture was stirred overnight at 40 °C under a nitrogen atmosphere. The resulting mixture was diluted with brine (50 mL). The precipitate was collected by filtration and diluted with EtOAc (3 x 20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 20% to 60% gradient over 10 min; detector, UV 220 nm] to give the title product (5.5 g, 80.55%) as a white solid. LCMS (ESI): C 15 H 21 Calculated mass of NO5: 295.14; Measured m / z: 294.20 [MH] - .

[0197] Preparation of methyl (2S)-3-(3-bromo-4-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (4-2).

[0198] At 0 °C, NBS (1.27 g, 7.1 mmol, 0.7 equivalent) was added in multiple portions to a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionate (3 g, 10.2 mmol, 1 equivalent) contained in DCM (50 mL). The resulting mixture was stirred at room temperature for 5 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 50% gradient over 10 min; detector, UV 220 nm] to give the title product (0.8 g, 21.04%) as a pale yellow solid. LCMS (ESI): C 15 H 20 Calculated mass of BrNO5: 373.05; Measured m / z: 272.00 [MH] - .

[0199] Preparation of methyl (2S)-3-(3-bromo-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (4-3).

[0200] A solution containing methyl (2S)-3-(3-bromo-4-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (1.4 g, 3.74 mmol, 1 equivalent), K₂CO₃ (1.55 g, 11.2 mmol, 3 equivalents), and 2-(2-bromoethoxy)oxane (1.56 g, 7.48 mmol, 2 equivalents) in DMF (15 mL) was stirred at room temperature for 5 hours. The resulting mixture was diluted with brine (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 30% to 90% gradient over 10 min; detector, UV 220 nm] to give the title product (1.6 g, 85.13%) as a pale yellow oil. LCMS (ESI): C 22 H 32 Calculated mass of BrNO7: 501.14; Measured m / z: 519.10 [M+NH4] + .

[0201] Preparation of (5-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (4-4).

[0202] Under a nitrogen atmosphere and at 80 °C, a mixture containing methyl (2S)-3-(3-bromo-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (1.5 g, 2.99 mmol, 1 equivalent), B2(OH)4 (0.80 g, 8.96 mmol, 3 equivalent), X-Phos Pd G2 (0.47 g, 0.60 mmol, 0.2 equivalent), X-Phos (0.14 g, 0.30 mmol, 0.1 equivalent), and AcOK (0.88 g, 8.96 mmol, 3 equivalent) in EtOH (15 mL) was stirred for 1 hour. The resulting mixture was filtered, and the solids were washed with MeOH (5 x 10 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 30% to 70% gradient over 10 min; detector, UV 220 nm] to give the title product (0.9 g, 64.50%) as a yellow oil. LCMS (ESI): C 22 H 34 Calculated mass of BNO9: 467.23; Measured m / z: 490.10 [M+Na] + .

[0203] Preparation of (2S)-3-(3-dihydroxyboryl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (4-5).

[0204] Under a nitrogen atmosphere, at room temperature, a mixture of (5-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (0.9 g, 1.93 mmol, 1 equivalent) and lithium hydroxide monohydrate (0.24 g, 5.78 mmol, 3 equivalents) in H2O (5 mL) and THF (10 mL) was stirred for 1 hour. The resulting mixture was diluted with H2O (15 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL) and acidified to pH 6 with HCl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title product (0.7 g, 80.18%) as a white solid. LCMS (ESI): C 21 H 32 Calculated mass of BNO9: 453.22; Measured m / z: 252.15 [M-Boc-OTHP] + .

[0205] Preparation of (S)-2-amino-3-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborheptan-8-yl)propionic acid (4).

[0206] A solution containing (2S)-3-(3-dihydroxyboryl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (200 mg, 0.44 mmol, 1 equivalent) in 1,4-dioxane (2 mL) and 1,4-dioxane (2 mL) in 4 M HCl (gas) was stirred at room temperature for 2 hours. The resulting mixture was diluted with MTBE (10 mL). The precipitated solid was collected by filtration and washed with MTBE (3 x 5 mL) to give the title product (55 mg, 43.36%) as a grayish-white solid. LCMS (ESI): C 11 H 14 Calculated mass of BNO5: 251.10; Measured m / z: 252.05 [M+H] + . 1 ¹H NMR (400 MHz, deuterium oxide): δ 7.46 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 8.5, 2.5 Hz, 1H), 6.98 (d, J= 8.5 Hz, 1H), 4.24 - 4.18 (m, 1H), 4.16 - 4.11 (m, 2H), 3.94 -3.86 (m, 2H), 3.22 (dd, J = 14.7, 5.6 Hz, 1H), 3.11 (dd, J = 14.7, 7.6 Hz, 1H).

[0207] Preparation of compound 5 Reagents and conditions: (a) Zn, I 2 Pd 2 (dba) 3 , S-Phos, DMF, 40℃; (b) NBS, i Pr 2 NH, DCM, rt; (c)K 2 CO 3 DMF, rt; (d) B 2 (OH) 4 , X-phos Pd G2, X-phos, KOAc, EtOH, 80℃; (e) TBD, MeCN / H 2 O, rt; (f)4 M HCl, dioxane, rt Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-4-hydroxyphenyl)propionate (5-1).

[0208] Under a nitrogen atmosphere, at room temperature, a mixture of Zn (6.85 g, 104.7 mmol, 4 equivalents) and I2 (0.66 g, 2.62 mmol, 0.1 equivalents) in DMF (20 mL) was stirred for 5 minutes. At room temperature, a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropionate methyl ester (17.23 g, 52.4 mmol, 2 equivalents) and I2 (0.66 g, 2.62 mmol, 0.1 equivalents) in DMF (10 mL) was added to the mixture. The resulting mixture was then stirred for another 30 minutes under a nitrogen atmosphere at room temperature. At room temperature, a solution of 4-bromo-3-fluorophenol (5 g, 26.2 mmol, 1 equivalent), Pd2(dba)3 (2.40 g, 2.62 mmol, 0.1 equivalent), and S-Phos (1.61 g, 3.93 mmol, 0.15 equivalent) was added to the above mixture. The resulting mixture was stirred overnight at 40 °C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluting with PE / EA (1:1)] to give the title product (5.6 g, 68.27%) as a brown oil. LCMS (ESI): C 15 H 20 Calculated mass of FNO5: 313.13; Measured m / z: 312.00 [MH] - .

[0209] Preparation of methyl (2S)-3-(5-bromo-2-fluoro-4-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (5-2).

[0210] At 0 °C, NBS (2.11 g, 11.8 mmol, 0.7 equivalent) was added in multiples to a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-4-hydroxyphenyl)propionate (5.3 g, 16.9 mmol, 1 equivalent). The resulting mixture was stirred at 0 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 0% to 50% gradient over 10 min; detector, UV 220 nm] to give the title product (1.26 g, 18.99%) as a pale yellow solid. 1 HNMR (400 MHz, methanol-) d 4): δ 7.31 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 11.2 Hz, 1H), 4.35 - 4.23 (m, 1H), 3.71 (s, 3H), 3.17 - 3.03 (m, 1H), 2.85 - 2.70 (m, 1H), 1.38 (s, 9H).

[0211] Preparation of methyl (2S)-3-(5-bromo-2-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (5-3).

[0212] K₂CO₃ (0.61 g, 4.4 mmol, 1.5 equivalent) was added to a stirred solution of (2S)-3-(5-bromo-2-fluoro-4-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (1.15 g, 2.93 mmol, 1 equivalent) and 2-(2-bromoethoxy)oxane (0.74 g, 3.52 mmol, 1.2 equivalent). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (150 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 90% gradient over 10 minutes; detector, UV 220 nm] to give the title product (1.25 g, 81.92%) as a pale yellow oil. LCMS (ESI): C 22 H 31 Calculated mass of BrFNO7: 519.13; Measured m / z: 542.00 [M+Na] + .

[0213] Preparation of (5-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-4-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (5-4).

[0214] Under a nitrogen atmosphere, at room temperature, X-Phos Pd G2 (348 mg, 0.44 mmol, 0.2 equivalent) and X-Phos (105 mg, 0.22 mmol, 0.1 equivalent) were added to a stirred mixture of (2S)-3-(5-bromo-2-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (1.15 g, 2.21 mmol, 1 equivalent), B2(OH)4 (594 mg, 6.63 mmol, 3 equivalent), and AcOK (650 mg, 6.63 mmol, 3 equivalent) in EtOH (30.00 mL). The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was filtered, and the solids were washed with MeOH (5 x 10 mL). The combined filtrates were concentrated under reduced pressure. The residue was dissolved in water (50 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 30% to 70% gradient over 10 min; detector, UV 220 nm] to give the title product (0.7 g, 65.27%) as a yellow oil. LCMS (ESI): C 22 H 33 Calculated mass of BFNO9: 485.22; Measured m / z: 508.15 [M+Na] + .

[0215] Preparation of (2S)-3-(5-dihydroxyboryl-2-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (5-5).

[0216] A mixture containing (5-((S)-2-((tert-butyloxycarbonyl)amino)-3-methoxy-3-oxopropyl)-4-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (680 mg, 1.4 mmol, 1 equivalent) and TBD (585 mg, 4.2 mmol, 3 equivalent) in MeCN (7 mL) and H2O (0.7 mL) was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL) and acidified to pH 6 with HCl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 30% to 50% gradient over 10 min; detector, UV 220 nm] to give the title product (360 mg, 54.52%) as a white solid. LCMS (ESI): C 21 H 31 Calculated mass of BFNO9: 471.21; Measured m / z: 270.15 [M-Boc-OTHP] + .

[0217] Preparation of (S)-2-amino-3-(7-fluoro-1-hydroxy-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborheptan-8-yl)propionic acid (5).

[0218] A solution of (2S)-3-(5-dihydroxyboryl-2-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (180 mg, 0.38 mmol, 1 equivalent) in 1,4-dioxane (1 mL) and 1,4-dioxane (1 mL) containing 4 M HCl (gas) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions: [Column: XBridge Prep Phenyl OBD column 19*250mm, 5m; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 12% B over 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 5.676], yielding the title product (59 mg, 57.42%) as a white solid. LCMS (ESI): C 11 H 13Calculated mass of BFNO5: 269.09; Measured m / z: 270.05 [M+H] + . 1 HNMR (400 MHz, deuterium oxide): δ 7.39 (d, J = 9.4 Hz, 1H), 6.73 (d, J = 12.2 Hz, 1H), 4.17- 3.98 (m, 2H), 3.93 - 3.73 (m, 3H), 3.15 (dd, J = 14.7, 5.5 Hz, 1H), 2.96 (dd, J = 14.7, 7.7 Hz, 1H).

[0219] Preparation of compound 6 Reagents and conditions: (a) Zn, I 2 Pd 2 (dba) 3 , S-Phos, DMF, 40℃; (b) NBS, i Pr 2 NH, DCM, rt; (c)K 2 CO 3 DMF, rt; (d) B 2 (OH) 4 , X-phos Pd G2, X-phos, KOAc, EtOH, 80℃; (e) TBD, MeCN / H 2 O, rt; (f) 4M HCl, dioxane, rt Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-4-hydroxyphenyl)propionate (6-1).

[0220] Under a nitrogen atmosphere and at room temperature, methyl (2R)-2-[(tert-Butoxycarbonyl)amino]-3-iodopropionate (7.75 g, 23.6 mmol, 1.5 equivalents) containing Zn (4.11 g, 62.8 mmol, 4 equivalents) and I2 (0.40 g, 1.55 mmol, 0.1 equivalents) in anhydrous DMF (15 mL) was added dropwise. I2 (0.40 g, 1.55 mmol, 0.1 equivalents) was then added to the reaction mixture at room temperature. The resulting mixture was stirred for 30 minutes under a nitrogen atmosphere at room temperature. At room temperature, 4-bromo-2-fluorophenol (3 g, 15.7 mmol, 1 equivalent), Pd2(dba)3 (0.72 g, 0.78 mmol, 0.05 equivalent), and SPhos (0.64 g, 1.57 mmol, 0.1 equivalent) contained in DMF (15 mL) were added to the reaction mixture. The resulting mixture was stirred overnight at 40 °C under a nitrogen atmosphere. The resulting mixture was filtered, and the solids were washed with EtOAc (5 x 10 mL). The resulting mixture was diluted with water (60 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 30% to 80% gradient over 10 min; detector, UV 254 nm] to give the title product (4.6 g, 93.47%) as a pale yellow liquid. LCMS (ESI): C 15 H 20 Calculated mass of FNO5: 313.13; Measured m / z: 312.10 [MH] - .

[0221] Preparation of methyl (2S)-3-(3-bromo-5-fluoro-4-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (6-2).

[0222] At room temperature, NBS (2.61 g, 14.7 mmol, 1 equivalent) was added to a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-4-hydroxyphenyl)propionate (4.6 g, 14.7 mmol, 1 equivalent) and bis(propyl-2-yl)amine (0.15 g, 1.47 mmol, 0.1 equivalent) in DCM (40 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 30% to 80% gradient over 10 min; detector, UV 220 nm] to give the title product (4.5 g, 78.15%) as a brown solid. LCMS (ESI): C 15 H 19 Calculated mass of BrFNO5: 391.04; Measured m / z: 390.10 [MH] - .

[0223] Preparation of methyl (2S)-3-(3-bromo-5-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (6-3).

[0224] A solution containing methyl (2S)-3-(3-bromo-5-fluoro-4-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (2.5 g, 6.37 mmol, 1 equivalent), 2-(2-bromoethoxy)oxane (2.67 g, 12.7 mmol, 2 equivalents), and K₂CO₃ (2.64 g, 19.1 mmol, 3 equivalents) in DMF (30 mL) was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 40% to 90% gradient over 10 min; detector, UV 220 nm] to give the title product (3.1 g, 93.46%) as a pale yellow liquid. LCMS (ESI): C 22 H 31 Calculated mass of BrFNO7: 519.13; Measured m / z: 518.05 [MH] - .

[0225] Preparation of (5-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (6-4).

[0226] Under a nitrogen atmosphere and at 80 °C, a mixture containing methyl (2S)-3-(3-bromo-5-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (1.5 g, 2.88 mmol, 1 equivalent), B2(OH)4 (0.78 g, 8.65 mmol, 3 equivalent), X-Phos Pd G2 (0.45 g, 0.58 mmol, 0.2 equivalent), X-Phos (0.14 g, 0.29 mmol, 0.1 equivalent), and AcOK (0.85 g, 8.646 mmol, 3 equivalent) in EtOH (15.00 mL) was stirred for 1 hour. The resulting mixture was filtered, and the solids were washed with EtOAc (3 x 10 mL). The combined filtrates were concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 30% to 70% gradient over 10 min; detector, UV 220 nm] to give the title product (0.7 g, 50.04%) as a pale yellow oil. LCMS (ESI): C 22 H 33 Calculated mass of BFNO9: 485.22; Measured m / z: 508.15 [M+Na] + .

[0227] Preparation of (2S)-3-(3-dihydroxyboryl-5-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (6-5).

[0228] A solution of (5-((S)-2-((tert-Butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (0.6 g, 1.24 mmol, 1 equivalent) and lithium hydroxide monohydrate (0.16 g, 3.71 mmol, 3 equivalents) in THF (6 mL) and H₂O (3 mL) was stirred at room temperature for 2 hours. The resulting mixture was diluted with H₂O (15 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL) and acidified to pH 6 with HCl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 30% to 50% gradient over 20 minutes; detector, UV 220 nm] to give the title product (180 mg, 30.89%) as a white solid. LCMS (ESI): C 21 H 31 Calculated mass of BFNO9: 471.21; Measured m / z: 270.15 [M-Boc-OTHP] + .

[0229] Preparation of (S)-2-amino-3-(6-fluoro-1-hydroxy-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborheptan-8-yl)propionic acid (6).

[0230] Under a nitrogen atmosphere, at room temperature, a solution containing (2S)-3-(3-dihydroxyboron-5-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (180 mg, 0.38 mmol, 1 equivalent) in 1,4-dioxane (1.80 mL) and 4M HCl (gas) was stirred for 2 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions: [Column: XBridge PrepPhenyl OBD column 19*250 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: MeOH; Flow rate: 60 mL / min; Gradient: 2% B to 12% B over 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.267], yielding the title product (52 mg, 50.61%) as a white solid. LCMS (ESI): C 11 H13 Calculated mass of BFNO5: 269.09; Measured m / z: 270.05 [M+H] + . 1 H NMR (400 MHz, methanol-) d 4 ): δ 7.68 -7.53 (m, 1H), 7.19 (dd, J =11.7, 2.3 Hz, 1H), 4.42 - 4.34 (m, 2H), 4.34 - 4.26 (m, 2H), 4.23 (t, J = 6.4Hz, 1H), 3.28- 3.05 (m, 2H).

[0231] Preparation of compound 7 Reagents and conditions: (a) SOCl 2 (a) MeOH, 50℃; (b) NaHCO3 3 Dioxane, water, rt; (c) NBS, i- Pr 2 NH, DCM, rt; (d) K 2 CO 3 , DMF, rt; (e) B 2 (OH) 4 , X-phos Pd G2, X-phos, KOAc, EtOH, 80 ℃; (f) TBD, MeCN / H 2 O, rt; (g) 4M HCl, dioxane, rt Preparation of methyl (2S)-2-amino-3-(3-hydroxyphenyl)propionate (7-1).

[0232] SOCl2 (9.19 g, 77.3 mmol, 2 equivalents) was added dropwise to a stirred solution of m-tyrosine (7 g, 38.6 mmol, 1 equivalent) in MeOH (70 mL) at 0 °C. The resulting mixture was stirred at 50 °C for 4 hours. The mixture was concentrated under vacuum to give the title product (7.5 g, crude product) as a light brown solid. LCMS (ESI): C 10 H 13 Calculated mass of NO5: 195.09; Measured m / z: 196.15 [M+H] + .

[0233] Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propionate (7-2).

[0234] At room temperature, Boc2O (10.13 g, 46.4 mmol, 1.2 equivalent) was added dropwise to a stirred mixture containing methyl (2S)-2-amino-3-(3-hydroxyphenyl)propionate (7.55 g, 38.7 mmol, 1 equivalent) and NaHCO3 (8.12 g, 96.7 mmol, 2.5 equivalent) in dioxane (70 mL) and H2O (70 mL). The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluting with PE / EA (5:1)] to give the title product (11.2 g, 98.06%) as a pale yellow solid. LCMS (ESI): C 15 H 21 Calculated mass of NO5: 295.14; Measured m / z: 294.25 [M+H] + .

[0235] Preparation of methyl (2S)-3-(4-bromo-3-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (7-3).

[0236] At -50°C, methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propionate (11 g, 37.2 mmol, 1 equivalent) and [other components] contained in DCM (220 mL) were subjected to [treatment / treatment]. i- NBS (3.98 g, 22.3 mmol, 0.6 equivalent) was added in multiple portions to a stirred solution of Pr₂NH (0.38 g, 3.72 mmol, 0.1 equivalent). The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 50% gradient over 30 min; detector, UV 220 nm] to give the title product (2.5 g, 17.94%) as a white solid. LCMS (ESI): calculated mass of C₁₅H₂₀BrNO₅, 373.05; m / z determined, 372.0 [MH] - . 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.18 (bs, 1H), 7.35 (d, J =8.1 Hz, 1H), 7.27 (d, J= 8.1 Hz, 1H), 6.80 (s, 1H), 6.66 - 6.55 (m, 1H), 4.33- 3.92 (m, 1H), 3.62 (s, 3H), 3.00 -2.63 (m, 2H), 1.33 (s, 9H).

[0237] Preparation of methyl (2S)-3-(4-bromo-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (7-4).

[0238] A solution containing methyl (2S)-3-(4-bromo-3-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (2.4 g, 6.41 mmol, 1 equivalent), K₂CO₃ (2.66 g, 19.2 mmol, 3 equivalents), and 2-(2-bromoethoxy)oxane (2.68 g, 12.8 mmol, 2 equivalents) in DMF (15 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 50% to 80% gradient over 10 minutes; detector, UV 220 nm, to give the title product (2 g, 62.07%) as a pale yellow oil. LCMS (ESI): C 22 H 32 Calculated mass of BrNO7: 501.14; Measured m / z: 524.15 [M+Na] + .

[0239] Preparation of (4-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (7-5).

[0240] Under a nitrogen atmosphere and at 80 °C, a mixture containing methyl (2S)-3-(4-bromo-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (1.9 g, 3.8 mmol, 1 equivalent), B2(OH)4 (1.02 g, 11.3 mmol, 3 equivalent), X-Phos (0.18 g, 0.38 mmol, 0.1 equivalent), X-PhosPd G2 (0.60 g, 0.76 mmol, 0.2 equivalent), and AcOK (1.11 g, 11.3 mmol, 3 equivalent) in EtOH (20 mL) was stirred for 1 hour. The resulting mixture was filtered, and the solids were washed with MeOH (3 x 10 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 30% to 60% gradient over 10 min; detector, UV 220 nm] to give the title product (1.1 g, 62.24%) as a pale yellow oil. LCMS (ESI): C 22 H 34 Calculated mass of BNO9: 467.23; Measured m / z: 490.20 [M+Na] + .

[0241] Preparation of (2S)-3-(4-dihydroxyboryl-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (7-6).

[0242] Under a nitrogen atmosphere, at room temperature, a solution containing (4-((S)-2-((tert-butyloxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (1 g, 2.14 mmol, 1 equivalent) and TBD (596 mg, 4.28 mmol, 2 equivalents) in MeCN (10 mL) and H₂O (1 mL) was stirred for 1 hour. The resulting mixture was diluted with EtOAc (30 mL) and extracted with 1M NaOH (3 x 10 mL). The aqueous layer was acidified to pH 5 with 1 M HCl (aqueous solution) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title product (0.6 g, 61.86%) as a white solid. LCMS (ESI): C 21 H 32Calculated mass of BNO9: 453.22; Measured m / z: 252.00 [M-Boc-OTHP] + .

[0243] Preparation of (S)-2-amino-3-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborheptan-7-yl)propionic acid (7).

[0244] A solution of (2S)-3-(4-dihydroxyboryl-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (400 mg, 0.88 mmol, 1 equivalent) in dioxane (3 mL) and 1,4-dioxane (3 mL) containing 4 M HCl was stirred at room temperature for 2 hours. The precipitate was collected by filtration and washed with MTBE (3 x 5 mL) to give the title product (174 mg, 68.59%) as a white solid. LCMS (ESI): C 11 H 14 Calculated mass of BNO5: 251.10; Measured m / z: 252.10 [M+H] + . 1 ¹H NMR (400 MHz, deuterium oxide) δ 7.56 (d, J = 7.5 Hz,1H), 6.94 - 6.88 (m, 1H), 6.87 (s, 1H), 4.28 - 4.20 (m, 1H), 4.17 - 4.10 (m,2H), 3.94 - 3.88 (m, 2H), 3.25 (dd, J = 14.5, 5.6 Hz, 1H), 3.13 (dd, J = 14.5, 7.6 Hz, 1H).

[0245] Preparation of compound 8 Reagents and conditions: (a) Zn, I 2 Pd 2 (dba) 3 , Sphos, DMF, 40℃; (b) i-Pr 2 NH, TEA, DCM, -60 ℃;(c) K 2 CO 3 DMF, rt; (d) B 2 (OH) 4 , Xphos-Pd-G2, Xphos, AcOK, EtOH, 80℃; (e) LiOH• H 2 O, H 2 O, THF, rt; (f) dioxane containing HCl, dioxane, rt Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-3-hydroxyphenyl)propionate (8-1).

[0246] At room temperature and under a nitrogen atmosphere, a solution of Zn (5.48 g, 83.772 mmol, 4 equivalents) in DMF (60 mL) was treated with I2 (0.53 g, 2.094 mmol, 0.1 equivalents) for 5 minutes, followed by the addition of methyl (2R)-2-[(tert-Butoxycarbonyl)amino]-3-iodopropionate (9305.41 mg, 28.273 mmol, 1.8 equivalents) and I2 (0.53 g, 2.094 mmol, 0.1 equivalents) at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The above solution was then added to a stirred solution of 2-bromo-3-fluorophenol (9 g, 47.121 mmol, 1 equivalent) and Pd2(dba)3 (1.44 g, 1.571 mmol, 0.075 equivalents) in DMF (60 mL) at room temperature. The resulting mixture was stirred overnight at 40 °C under a nitrogen atmosphere. The reaction was quenched by adding water (200 mL) at room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x 100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with water (3 x 300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 50% gradient over 10 min; detector, UV 254 nm] to give the title product (3 g, 45.72%) as a yellow oil. LCMS (ESI): C 15 H 20 Calculated mass of FNO5: 313.13; Measured m / z: 214.1 [M-Boc+H] + .

[0247] Preparation of methyl (2S)-3-(4-bromo-2-fluoro-3-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (8-2).

[0248] At -50 °C, NBS (1.36 g, 7.660 mmol, 0.8 equivalent) was added in multiple portions to a stirred solution containing methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-3-hydroxyphenyl)propionate (3 g, 9.575 mmol, 1 equivalent) and bis(propyl-2-yl)amine (0.10 g, 0.958 mmol, 0.1 equivalent) in DCM (60 mL). The resulting mixture was stirred at -50 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 50% gradient over 10 min; detector, UV 254 nm] to give the title product (1.8 g, 47.93%) as a yellow oil. LCMS (ESI): C 15 H 19 Calculated mass values ​​of BrFNO5: 391.04, 393.04; Measured m / z values: 292.05, 294.05 [M-Boc+H] + .

[0249] Preparation of methyl (2S)-3-(4-bromo-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (8-3).

[0250] At room temperature, 2-(2-bromoethoxy)oxane (1.92 g, 9.178 mmol, 2 equivalents) was added to a stirred solution containing methyl (2S)-3-(4-bromo-2-fluoro-3-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (1.8 g, 4.589 mmol, 1 equivalent) and K₂CO₃ (1.90 g, 13.767 mmol, 3 equivalents) in DMF (20 mL). The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 50% gradient over 10 min; detector, UV 254 nm] to give the title product (1.2 g, 50.25%) as a yellow oil. LCMS (ESI): C 22 H 31 Calculated mass of BrFNO7: 519.13; Measured m / z: 520.85 [M+H] + .

[0251] Preparation of (4-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (8-4).

[0252] At room temperature, KOAc (282.89 mg, 2.883 mmol, 3 equivalents), X-phos (45.80 mg, 0.096 mmol, 0.1 equivalents), and 2nd X-phos Pd G2 (151.20 mg, 0.192 mmol, 0.2 equivalents) were added to a stirred solution containing methyl (2S)-3-(4-bromo-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (500 mg, 0.961 mmol, 1 equivalent) and tetrahydroxydiborane (258.41 mg, 2.883 mmol, 3 equivalents) in EtOH (5 mL). The resulting mixture was stirred at 70 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOH (5 mL) (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 50% gradient over 10 min; detector, UV 254 nm] to give the title product (120 mg, 25.73%) as a yellow oil. LCMS (ESI): C 22 H 33 Calculated mass of BFNO9: 485.22; Measured m / z: 508.15 [M+Na] + .

[0253] Preparation of (2S)-3-(4-dihydroxyboryl-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (8-5).

[0254] At room temperature, lithium hydroxide monohydrate (25.94 mg, 0.618 mmol, 3 equivalents) was added to a stirred solution of (4-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (100 mg, 0.206 mmol, 1 equivalent) in THF (1.5 mL) and H₂O (0.5 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 3 with 1M HCl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with H₂O (3 x 5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI): C 21 H 31 Calculated mass of BFNO9: 471.21; Measured m / z: 272.15 [M-Boc+H] + .

[0255] Preparation of (S)-2-amino-3-(6-fluoro-1-hydroxy-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborheptan-7-yl)propionic acid (8).

[0256] At room temperature, dioxane (1.43 mL, 5.711 mmol, 13.47 equivalents) containing 4 M HCl was added to a stirred solution of (2S)-3-(4-dihydroxyboryl-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (200 mg, 0.424 mmol, 1 equivalent) in dioxane (4 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC [using the following conditions (column: XBridge Prep Phenyl OBD column 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 10% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 5.062)] to give the title product (54 mg, 46.54%) as a white solid. LCMS (ESI): C 11 H 13 Calculated mass of BFNO5: 269.09; Measured m / z: 270.05 [M+H] +¹H NMR (400 MHz, deuterium oxide): δ 7.37 (dd, J = 7.8, 1.4 Hz, 1H), 6.91 (td, J = 7.9, 6.3 Hz, 1H), 4.32 - 4.26 (m, 2H), 4.04 (d, J =4.4 Hz, 2H), 3.92 (dd, J = 7.8, 5.6 Hz, 1H), 3.26 (dd, J = 14.4, 5.7, 1.5 Hz,1H), 3.07 (m, 1H).

[0257] Preparation of compound 9 Reagents and conditions: (a) Zn, I 2 Pd 2 (dba) 3 (a) S-phos, DMF, 40℃; (b) NBS, diisopropylamine, DCM, - 50℃; (c) K 2 CO 3 DMF, rt; (d) B 2 (OH) 4 , EtOH, X-phos, Xphos Pd G2, 70℃; (e) LiOH . H 2 O， THF, H 2 O, rt; (f) 1,4-dioxane, dioxane containing 4M HCl, rt Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-5-hydroxyphenyl)propionate (9-1).

[0258] Under a nitrogen atmosphere, at room temperature, a mixture of Zn (6.85 g, 104.712 mmol, 4 equivalents) and I2 (0.66 g, 2.618 mmol, 0.1 equivalents) in DMF (30 mL) was stirred for 5 minutes. At room temperature, a solution of (2R)-2-[(tert-Butoxycarbonyl)amino]-3-iodopropionate methyl ester (12.92 g, 39.267 mmol, 1.5 equivalents) and I2 (0.66 g, 2.618 mmol, 0.1 equivalents) in DMF (20 mL) was added to the mixture. The resulting mixture was then stirred for another 30 minutes at room temperature under a nitrogen atmosphere. At room temperature, a solution of 3-bromo-4-fluorophenol (5 g, 26.178 mmol, 1 equivalent), Pd2(dba)3 (2.40 g, 2.618 mmol, 0.1 equivalent), and S-Phos (1.61 g, 3.927 mmol, 0.15 equivalent) was added to the above mixture. The resulting mixture was stirred overnight at 40 °C under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluting with PE / EA (2:1)] to give the title product (6.5 g, 79.25%) as a brown oil. LCMS (ESI): C 15 H 20 Calculated mass of FNO5: 313.13; Measured m / z: 214.05 [M-Boc+H] + .

[0259] Preparation of methyl (2S)-3-(4-bromo-2-fluoro-5-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (9-2).

[0260] At -50°C, NBS (2.04 g, 11.489 mmol, 0.6 equivalent) was added in multiples to a stirred mixture containing methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-5-hydroxyphenyl)propionate (6 g, 19.149 mmol, 1 equivalent) in DCM (60 mL). The resulting mixture was stirred at -50°C for 2 hours. The resulting mixture was concentrated under vacuum and purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 5% to 45% gradient over 10 min; detector, UV 220 nm] to give the title product (1.1 g, 14.65%) as a yellow oil. LCMS (ESI): C 15 H19 Calculated mass of BrFNO5: 391.04; Measured m / z: 390.00 [MH] - .

[0261] Preparation of methyl (2S)-3-(4-bromo-2-fluoro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (9-3).

[0262] Under a nitrogen atmosphere, at room temperature, a mixture containing methyl (2S)-3-(4-bromo-2-fluoro-5-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (1.1 g, 2.805 mmol, 1 equivalent), K₂CO₃ (1.16 g, 8.415 mmol, 3 equivalents), and 2-(2-bromoethoxy)oxane (1.17 g, 5.610 mmol, 2 equivalents) in DMF (15 mL) was stirred overnight. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluting with PE / EA (2:1)] to give the title product (810 mg, 55.50%) as a yellow oil. LCMS (ESI): C 22 H 31 Calculated mass of BrFNO7: 519.13; Measured m / z: 542.00 [M+Na] + .

[0263] Preparation of (4-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-5-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (9-4).

[0264] Under a nitrogen atmosphere, at 70 °C, a mixture containing methyl (2S)-3-(4-bromo-2-fluoro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (760 mg, 1.460 mmol, 1 equivalent), tetrahydroxydiborane (392.78 mg, 4.380 mmol, 3 equivalents), Xphos (69.62 mg, 0.146 mmol, 0.1 equivalents), and 2nd Xphos Pd G2 (229.82 mg, 0.292 mmol, 0.2 equivalents) in EtOH (10 mL) was stirred for 1 hour. After cooling to room temperature, the resulting mixture was filtered, and the filter cake was washed with EtOAc (1 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions [column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 0% to 50% gradient over 10 min; detector, UV 220 nm] to give the title product (230 mg, 32.45%) as a pale yellow solid. LCMS (ESI): C 22 H 33 Calculated mass of BFNO9: 485.22; Measured m / z: 508.25 [M+Na] + .

[0265] Preparation of (2S)-3-(4-dihydroxyboryl-2-fluoro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (9-5).

[0266] Under a nitrogen atmosphere at room temperature, a mixture of (4-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-5-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (200 mg, 0.412 mmol, 1 equivalent) and lithium hydroxide monohydrate (51.88 mg, 1.236 mmol, 3 equivalents) in THF (2 mL) and H₂O (2 mL) was stirred for 2 hours. The mixture was acidified to pH 6 with 1 M HCl (aqueous solution) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title product (260 mg, crude product) as a yellow oil. LCMS (ESI): C 21 H 31 Calculated mass of BFNO9: 471.21 m / z; Measured m / z: 470.20 [MH] -.

[0267] Preparation of (S)-2-amino-3-(8-fluoro-1-hydroxy-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborheptan-7-yl)propionic acid (9).

[0268] At room temperature, 1,4-dioxane (2 mL, 65.826 mmol) containing 4M HCl was added dropwise to a stirred mixture containing (2S)-3-(4-dihydroxyboryl-2-fluoro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (210 mg, 0.446 mmol, 1 equivalent) in dioxane (2 mL, 23.608 mmol). The resulting mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and washed with MTBE (1 x 10 mL) to give the title product (84.8 mg, 61.67%) as a white solid. LCMS (ESI): C 11 H 13 Calculated mass of BFNO5: 269.09; Measured m / z: 270.05 [M+H] + . 1 ¹H NMR (400 MHz, deuterium oxide): δ 7.29 (d, J = 10.1 Hz, 1H), 6.89 (d, J = 5.7 Hz, 1H), 4.21 (dd, J = 7.3, 5.9 Hz, 1H), 4.17 - 4.08 (m,2H), 3.94 - 3.83 (m, 2H), 3.30 (dd, J = 14.5, 5.9 Hz, 1H), 3.15 (dd, J = 14.5, 7.3 Hz, 1H).

[0269] Preparation of compound 10 Reagents and conditions: (a) Zn, I 2 Pd 2 (dba) 3 (a) S-Phos, DMF, 50°C, overnight; (b) NBS, i Pr 2 NH, DCM, rt, 3h; (c)K 2 CO 3 , DMF, rt, 2 h; (d) Pd(dppf)Cl2 KOAc, dioxane, rt, 2 h; (e)LiOH.H 2 O, THF / H 2 O, rt, 2 h; (f) Dioxane containing 4 M HCl, dioxane, rt, 2 h.

[0270] Preparation of methyl (2S)-3-(3-bromo-2-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)-2-[(tert-butoxycarbonyl)amino]propionate (10-1).

[0271] K₂CO₃ (443.16 mg, 3.21 mmol, 1 equivalent) was added to a stirred solution of (2S)-3-(3-bromo-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propionate (800 mg, 2.14 mmol, 1 equivalent) and N-(2-bromoethyl)carbamate tert-butyl (574.87 mg, 2.57 mmol, 1.2 equivalent) in DMF (15 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 80% gradient over 10 min; detector, UV 254 nm] to give the title product (900 mg, 81.37%) as a light brown oil. LCMS (ESI): C 22 H 33 Calculated mass of BrN₂O₇: 516.2; Measured m / z: 539.0 [M+Na] + .

[0272] Preparation of 3-[(2S)-2-[(tert-Butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-{2-[(tert-Butoxycarbonyl)amino]ethoxy}phenylboronic acid (10-2).

[0273] Pd(dppf)Cl2 (70.71 mg, 0.10 mmol, 0.1 equivalent) and KOAc (189.68 mg, 1.93 mmol, 2 equivalent) were added to a stirred solution containing (2S)-3-(3-bromo-2-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)-2-[(tert-butoxycarbonyl)amino]propionate (50 mg, 0.10 mmol, 1 equivalent) and 2-(5,5-dimethyl-1,3,2-dioxaborhexane-2-yl)-5,5-dimethyl-1,3,2-dioxaborhexane (436.57 mg, 1.93 mmol, 2 equivalent) in dioxane (15 mL). The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 70% gradient over 10 min; detector, UV 254 nm] to give the title product (340 mg, 72.95%) as a brownish-yellow oil. LCMS (ESI): C 22 H 35 Calculated mass of BN₂O₉: 482.2; Measured m / z: 505.2 [M+Na] + .

[0274] Preparation of (S)-3-(3-dihydroxyboryl-2-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (10-3).

[0275] At room temperature and under a nitrogen atmosphere, lithium hydroxide monohydrate (52.20 mg, 1.24 mmol, 2 equivalents) was added to a stirred solution of 3-[(2S)-2-[(tert-butyloxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-{2-[(tert-butyloxycarbonyl)amino]ethoxy}phenylboronic acid (300 mg, 0.62 mmol, 1 equivalent) in THF (6 mL) and H₂O (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was acidified to pH 5 with 2M HCl (aqueous solution). The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 40% gradient over 10 min; detector, UV 254 nm] to give the title product (280 mg, 96.13%) as a pale yellow oil. LCMS (ESI): C21 H 33 Calculated mass of BN2O9: 468.2; Measured m / z: 467.2 [MH] - .

[0276] Preparation of (S)-2-amino-3-(1-hydroxy-1,2,3,4-tetrahydrobenzo[f][1,4,5]oxazaboronheptan-6-yl)propionic acid (10).

[0277] At room temperature and under a nitrogen atmosphere, 4M HCl (2 mL, contained in dioxane) was added to a stirred solution of (S)-3-(3-dihydroxyboryl-2-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (280 mg, 0.598 mmol, 1 equivalent) in dioxane (2 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC [using 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: 60 mL / min; gradient: 93% B to 73% B over 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.87; number of runs: 5)] to obtain the title product (90 mg, 39.40%) as a white solid. LCMS (ESI): C 17 H 23 Calculated mass of BFNO6: 367.16; Measured m / z: 268.0 [M+H-Boc] + . 1 ¹H NMR (300 MHz, deuterium oxide): δ 7.44 (dt, J = 7.4, 1.7 Hz, 1H), 7.29 (dd, J = 7.5, 1.8 Hz, 1H), 7.12 (td, J = 7.5, 1.2Hz, 1H), 4.23 - 3.98 (m, 3H), 3.48 - 3.20 (m, 3H), 3.04 (dd, J = 14.4, 7.5 Hz, 1H).

[0278] Preparation of compound 11 Reagents and conditions: (a) K 2 CO3 DMF, rt, overnight (b) LiOH.H 2 O, THF, H 2 O, rt, 2 h; (c) 4 M HCl, dioxane, rt, 2 h.

[0279] Preparation of 3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-{[(2-methoxy-2-oxoethyl)(methyl)amino]methyl}phenylboronic acid (11-1).

[0280] 2-(methylamino)acetic acid methyl hydrochloride (0.34 g, 2.41 mmol, 1.2 equivalents) was added to a stirred solution containing (2S)-3-[2-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenyl]-2-[(tert-butoxycarbonyl)amino]propionate (1 g, 2.01 mmol, 1 equivalent) and K₂CO₃ (0.55 g, 4.01 mmol, 2 equivalents). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (5 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 40% gradient over 10 min; detector, UV 254 nm] to give the title product (320 mg, 36.38%) as a white solid. LCMS (ESI): C 20 H 31 Calculated mass of BN₂O₈: 438.2; Measured m / z: 439.2 [M+H] + .

[0281] Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-5-methyl-3-oxo-3,4,5,6-tetrahydro-1H-benzo[c][1,6,2]oxazaborone-octane-7-yl)propionic acid (11-2).

[0282] LiOH·H2O (114.89 mg, 2.74 mmol, 4 equivalents) was added to a stirred solution of (S)-(3-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-(((2-methoxy-2-oxoethyl)(methyl)amino)methyl)phenyl)boronic acid (300 mg, 0.68 mmol, 1 equivalent) in THF (3 mL) and H2O (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was acidified to pH 5 with 2M HCl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography [using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 40% gradient over 10 min; detector, UV 254 nm] to give the title product (160 mg, 59.60%) as a white solid. LCMS (ESI): C 18 H 25 Calculated mass of BN2O7: 392.18; Measured m / z: 391.1 [MH] - .

[0283] Preparation of (S)-2-amino-3-(1-hydroxy-5-methyl-3-oxo-3,4,5,6-tetrahydro-1H-benzo[c][1,6,2]oxazaborone-octane-7-yl)propionic acid (11).

[0284] At room temperature, 1,4-dioxane (1.5 mL) containing (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-5-methyl-3-oxo-3,4,5,6-tetrahydro-1H-benzo[c][1,6,2]oxazaborone-octane-7-yl)propionic acid (150 mg, 0.38 mmol, 1 equivalent) in dioxane (1.5 mL, 17.71 mmol, 46.30 equivalent) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure to give the title product (100 mg, 85.04%) as a pale yellow solid. LCMS (ESI): C 13 H 17 Calculated mass of BN2O5: 292.12; Measured m / z: 294.2 [M+H] + . 1 ¹H NMR (400 MHz, deuterium oxide): δ 7.44 (d, J= 7.2Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 4.39 (s, 2H), 4.04(s, 1H), 3.87 (d, J = 2.3 Hz, 2H), 3.38 - 3.13 (m, 1H), 3.05 (s, 1H), 2.73 (s, 3H).

[0285] Example 2. Cellular uptake assay Cell culture 1.1 Thawing method 1.1.1 Place 15 mL of cell culture medium in a T225 flask.

[0286] 1.1.2 Place the flask in a humidified 37°C, 5% CO2 incubator for 15 minutes to allow the culture medium to equilibrate to the appropriate pH and temperature.

[0287] 1.1.3 Remove the vial from the liquid nitrogen and thaw it quickly by placing it in a 37°C water bath and gently stirring for 1-2 minutes. Then remove any contamination by wiping with 70% ethanol before opening it in a Class II biosafety cabinet.

[0288] 1.1.4 Transfer the contents of the vial dropwise to 10 mL of cell culture medium in a sterile 15 mL conical tube.

[0289] 1.1.5 Centrifuge the cells at 1,300 rpm for 5 minutes.

[0290] 1.1.6 Aspirate the supernatant and resuspend the cells and transfer them to a T225 flask containing cell culture medium.

[0291] 1.2 Reproduction methods 1.2.1 Change the culture medium every 2-3 days.

[0292] 1.2.2 Keep the flask in a humidified incubator at 37°C and 5% CO2. Measurement Procedure 2.1 Cell Seeding Harvest the cells and dilute them to the specified concentration in culture medium. Then culture the cells in T25 flasks, one sample per T25 flask.

[0293] 2.2 Formulation of the test compound 2.2.1 L-Dihydroxyboronylphenylalanine (L-BPA, 4-boron-L-phenylalanine, purity: 95%, chemical formula: C9H) 12 BNO4 (MW: 209.01, CAS: 76410-58-7) and fructose were dissolved in PBS at a molar ratio of 1:5, and then 1N NaOH at a ratio of 1.27 M was added. The mixture was stirred until L-BPA was completely dissolved, and the pH was titrated with 1N HCl to 7.2-7.4.

[0294] 2.2.2 For the test compounds other than BPA, stock solutions of each compound were prepared in DMSO or fructose formulation at a concentration of 20 mM (so that the final DMSO% in the cell assay medium was 0.5%).

[0295] 2.3 Compound Treatment 2.3.1 Seed cells overnight (12-18 hours) to allow cells to adhere to the wells.

[0296] 2.3.2 Add the stock solution of each compound to each T25 flask to achieve a final concentration of 100 μM (0.1 mM) for each compound.

[0297] 2.3.3 Place the flask in a 37°C, 5% CO2 incubator for 1 hour, 4 hours and 24 hours.

[0298] 2.3.4 Cells were collected after 1 hour, 4 hours and 24 hours of treatment using 0.25% trypsin with 0.53 mM EDTA.

[0299] 2.3.5 Centrifuge at 1,300 rpm for 5 minutes to collect cell pellets.

[0300] result The compounds disclosed in this paper are selectively taken up by representative cancer cell lines SAS (human head and neck cancer), B16F10 (mouse melanoma), and U87-MG (human glioblastoma) relative to representative normal human cell lines (NIH-3T3).

[0301] Cellular uptake of compound 1-S, using L-BPA as a comparison: Cellular uptake of compound 1-R, using L-BPA as a comparison: Cellular uptake of compound 2, using L-BPA as a comparison: Cellular uptake of compound 3, using L-BPA as a comparison: Cellular uptake of compound 4, using L-BPA as a comparison: Cellular uptake of compound 5, using L-BPA as a comparison: Cellular uptake of compound 6, using L-BPA as a comparison: Cellular uptake of compound 7, using L-BPA as a comparison: Cellular uptake of compound 8, using L-BPA as a comparison: Cellular uptake of compound 9, using L-BPA as a comparison: Cellular uptake of compound 10, using L-BPA as a comparison: Cellular uptake of compound 11, using L-BPA as a comparative: By incorporating references All U.S. patents and U.S. and PCT patent applications cited in this document are hereby incorporated by reference.

[0302] equivalent Those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments of the invention described herein using only conventional experiments. Such equivalents are intended to be covered by the following claims.

Claims

1. A compound of formula (I): (I)， in A1 is selected from -O- and -NH-; A2 is selected from -C(R6)(R7)- and -C(O)-; A3 is selected from -O- and -N(R5)-; A4 is selected from single bonds and -C(R8)(R9)-; R1, R2, R3 and R4 are each independently selected from -H, halogen, hydroxyl, alkyl, alkoxy and -(CR'R'')C(H)(NH2)CO2H, provided that one and only one of R1, R2, R3 and R4 is -(CR'R'')C(H)(NH2)CO2H; R5 is selected from -H and alkyl groups; R' and R'' are each independently selected from -H, halogens, and alkyl groups; R6, R7, R8, and R9 are each independently selected from -H and alkyl groups; and The compound is racemic, enriched with one enantiomer, or a single enantiomer; Or its pharmaceutically acceptable salt.

2. The compound of claim 1, wherein R1, R2, R3 and R4 are each independently selected from -H, halogen, hydroxyl and -(CH2)C(H)(NH2)CO2H, provided that one and only one of R1, R2, R3 and R4 is -(CH2)C(H)(NH2)CO2H.

3. The compound of claim 2, wherein R1, R2, R3 and R4 are each independently selected from -H, halogen and -(CH2)C(H)(NH2)CO2H, provided that one and only one of R1, R2, R3 and R4 is -(CH2)C(H)(NH2)CO2H.

4. The compound according to any one of claims 1-3, wherein the halogen is -F.

5. The compound according to any one of claims 1-4, wherein A1 is selected from -O-; A2 is -C(R6)(R7)-; A3 is selected from -O- and -N(R5)-; and A4 is a single bond.

6. The compound of claim 5, wherein the compound has the following structure: 。 7. The compound of claim 6, wherein the compound has a structure selected from the following: , , and ; Where * indicates ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

8. The compound of claim 7, wherein R1, R2, R3 and R4 are each -H.

9. The compound of claim 8, wherein the compound has a structure selected from the following: , , and Or, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 6, wherein the compound has a structure selected from the group consisting of: , , and ; Where one of R' and R'' is -H and the other of R' and R'' is a halogen or alkyl group; * indicates having ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

11. The compound of claim 10, wherein R1, R2, R3 and R4 are each -H.

12. The compound of claim 10 or 11, wherein one of R' and R'' is -H and the other of R' and R'' is -F or -CH3.

13. The compound according to any one of claims 10-12, wherein the compound has a structure selected from the group consisting of: , , and Or, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 6, wherein the compound has a structure selected from the group consisting of: , and ; Where R2, R3, and R4 are not -H; *indicates that ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

15. The compound of claim 14, wherein R2, R3 and R4 are each halogens.

16. The compound of claim 15, wherein the halogen is -F.

17. The compound of claim 6, wherein the compound has a structure selected from the group consisting of: , and , Where R1, R3, and R4 are not -H; *indicates that ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

18. The compound of claim 17, wherein R1, R3 and R4 are each halogens.

19. The compound of claim 18, wherein the halogen is -F.

20. The compound of claim 6, wherein the compound has a structure selected from the group consisting of: , and ; Where R1, R2, and R4 are not -H; *indicates that ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

21. The compound of claim 20, wherein R1, R2 and R4 are each halogens.

22. The compound of claim 21, wherein the halogen is -F.

23. The compound of claim 6, wherein the compound has a structure selected from the group consisting of: , and ; Where R1, R2, and R3 are not -H; *indicates that ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

24. The compound of claim 23, wherein R1, R2 and R3 are each halogens.

25. The compound of claim 24, wherein the halogen is -F.

26. The compound according to any one of claims 17-25, wherein the compound has a structure selected from the group consisting of: , , , , , , , and , Or its pharmaceutically acceptable salt.

27. The compound of claim 5, wherein the compound has the following structure: 。 28. The compound of claim 27, wherein the compound has a structure selected from the group consisting of: and ; Where * indicates ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

29. The compound of claim 28, wherein R1, R2, R3 and R4 are each -H.

30. The compound of claim 28, wherein the compound has a structure selected from the group consisting of: , and , , and ; Where R1, R2, R3, and R4 are not -H; *indicates that ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

31. The compound of claim 30, wherein R1, R2, R3 and R4 are each halogens.

32. The compound of claim 31, wherein the halogen is -F.

33. The compound according to any one of claims 27-32, wherein R5 is -H.

34. The compound according to any one of claims 27-32, wherein R5 is -CH3.

35. The compound according to any one of claims 27-34, wherein the compound has a structure selected from the group consisting of: , , and , Or its pharmaceutically acceptable salt.

36. The compound according to any one of claims 1-4, wherein A1 is -NH-; A2 is -C(R6)(R7)-; A3 is -O-; and A4 is a single bond.

37. The compound of claim 36, wherein the compound has a structure selected from: ； Where * indicates ( S )or( R The compound is a chiral carbon with an absolute configuration; and the compound is not racemic.

38. The compound of claim 37, wherein R1, R2 and R3 are each -H.

39. The compound of claim 37 or 38, wherein the compound has the following structure: Or, or a pharmaceutically acceptable salt thereof.

40. The compound according to any one of claims 1-4, wherein A1 is -O-; A2 is -C(O)-; A3 is selected from -O- and -N(R5)-; and A4 is -C(R8)(R9)-.

41. The compound of claim 40, wherein the compound has a structure selected from the group consisting of: , , and .

42. The compound of claim 41, wherein R1, R2, R3 and R4 are each -H.

43. The compound according to any one of claims 40-42, wherein R5 is -H.

44. The compound according to any one of claims 40-42, wherein R5 is -CH3.

45. The compound of claim 37 or 38, wherein the compound has the following structure: Or, or a pharmaceutically acceptable salt thereof.

46. ​​The compound according to any one of claims 1-6, 10, 36 or 40, wherein R' is -H.

47. The compound according to any one of claims 1-6, 10, 36, 40 or 46, wherein R'' is selected from -H and halogens.

48. The compound according to any one of claims 1-6, 10, 36, 40 or 46, wherein R'' is selected from -H and alkyl groups.

49. The compound according to any one of claims 1-6, 10, 36, 40 or 46, wherein R'' is a halogen.

50. The compound according to any one of claims 1-6, 10, 36, 40 or 46, wherein R'' is an alkyl group.

51. The compound of any one of claims 47-50, wherein the halogen is -F; and the alkyl group is -CH3.

52. The compound of any one of claims 7, 10, 14, 17, 20, 23, 28, 30, 37, and 41, wherein the absolute configuration of the chiral carbon is ( S ).

53. The compound of any one of claims 7, 10, 14, 17, 20, 23, 28, 30, 37, and 41, wherein the absolute configuration of the chiral carbon is ( R ).

54. The compound according to any one of claims 1-53, wherein the boron atom in the compound is 10 B.

55. A pharmaceutical composition comprising the compound of any one of claims 1-54; and a pharmaceutically acceptable excipient.

56. The pharmaceutical composition of claim 55, wherein the pharmaceutical composition further comprises carbohydrates.

57. The pharmaceutical composition of claim 56, wherein the sugar is fructose.

58. The pharmaceutical composition according to any one of claims 55-57, wherein the pharmaceutical composition further comprises a polyhydroxy acid.

59. The pharmaceutical composition of claim 58, wherein the polyhydroxy acid is lactobionic acid.

60. The pharmaceutical composition according to any one of claims 55-59, wherein the pharmaceutical composition further comprises sugar alcohol.

61. The pharmaceutical composition of claim 60, wherein the sugar alcohol is sorbitol or mannitol.

62. A method for treating cancer, the method comprising: i) administering to a subject in need an effective amount of the compound of any one of claims 1-54 or the composition of any one of claims 55-61, wherein the compound accumulates in multiple cancer cells of the subject; and ii) Irradiate the plurality of cancer cells with neutrons.

63. The method of claim 62, wherein the compound selectively or preferentially accumulates in the plurality of cancer cells relative to non-cancer cells in the subject.

64. The method of claim 62 or 63, wherein the irradiation causes [the compound to contain irradiated substances]. 10 B atoms are converted into α-particles and lithium-7 ions.

65. The method of any one of claims 62-64, wherein the compound or the composition is administered intravenously.

66. The method of any one of claims 62-65, wherein the cancer is a solid tumor.

67. The method of any one of claims 62-65, wherein the cancer is selected from head and neck cancer, glioblastoma, melanoma, and sarcoma.

68. The method of any one of claims 62-65, wherein the cancer is an unresectable head and neck cancer.

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