WO2025144975A1

WO2025144975A1 - Fused bicyclic aryl compounds for boron neutron capture therapy

Info

Publication number: WO2025144975A1
Application number: PCT/US2024/062015
Authority: WO
Inventors: Andrew William STAMFORD; Zhiqiang Yang
Original assignee: Aviko Radiopharmaceuticals LLC
Current assignee: Aviko Radiopharmaceuticals LLC
Priority date: 2023-12-28
Filing date: 2024-12-27
Publication date: 2025-07-03
Anticipated expiration: 2026-06-28

Abstract

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

Description

FUSED BICYCLIC ARYL COMPOUNDS FOR BORON NEUTRON CAPTURE THERAPY

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Patent Application serial number 63/615,592, filed December 28, 2023.

BACKGROUND

Boron neutron capture therapy (BNCT) is a bimodal cancer therapy that requires a boron- containing molecule that selectively partitions into cancer cells and an external neutron beam directed to the cancer. Capture of thermal neutrons by the ¹⁰B nuclei inside the cancer cells results in nuclear fission to give high-energy alpha particles and recoiling ⁷Li nuclei. The high- energy particles damage the tumor cells resulting in tumor cell death while sparing surrounding healthy tissue. New boron delivery agents that selectively partition into tumor tissue in combination with an external neutron beam directed to the tumor may be useful in boron neutron capture therapy for the treatment of various solid tumors.

4-Borono-L-phenylalanine (BPA) is approved in Japan for use in combination with an external neutron beam device for the treatment of recurrent unresectable head & neck cancer. While BPA has demonstrated therapeutic utility in boron neutron capture therapy, it has limitations. Its selectivity for tumor tissue over healthy tissue and its tumor uptake are considered to meet only the minimal requirements for a successful boron neutron capture therapy agent. Agents that have improved uptake into tumor cells and have an improved tumor:healthy tissue ratio relative to BPA may result in improved anti-cancer efficacy.

SUMMARY

One aspect of the invention provides compounds, compositions, and methods useful for boron neutron capture therapy.

Accordingly, provided herein is a compound having the structure of Formula (I):

wherein

Ai is selected from -O- and -NH-;

A2 is selected from -C(Re)(R?)- and -C(O)-;

A3 is selected from -O- and -N(Rs)-;

A4 is selected from a single bond and -C(Rs)(R9)-;

Ri, R2, R3, and R4 are each independently selected from -H, halogen, hydroxy, alkyl, alkoxy, and -(CR'R")C(H)(NH2)CO2H, provided that one and only one of Ri, R2, R3, and R4 is - (CR'R")C(H)(NH₂)CO₂H;

R5 is selected from -H and alkyl;

R' and R" are each independently selected from -H, halogen, and alkyl;

Re, R7, Rs, and R9 are each independently selected from -H and alkyl; the compound is racemic, enriched in one enantiomer, or a single enantiomer; or a pharmaceutically acceptable salt thereof.

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

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

DETAILED DESCRIPTION

Definitions

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

In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification.

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

The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

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

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

“Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.” Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure.

When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a ¹³C- or ¹⁴C-enriched carbon, or of a boron with ¹⁰B-enriched boron, are within the scope of this invention.

The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non- pyrogenic. Some examples of materials which can serve 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; (5) malt; (6) gelatin; (7) talc;

(8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

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

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

The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule.

A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment.

The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

The term “patient” or “subject” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human.

An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group. “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Alkyl goups may be substituted or unsubstituted.

As used herein, the term “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.

As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one halogen.

As used herein, the term “hydroxyalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl.

As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene -(CH2CH2CH2)-, isopropylene - (CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

"Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted.

As used herein, the term “halocycloalkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen.

"Cycloheteroalkyl" refers to a cycloalkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure. Cycloheteroalkyl groups may be substituted or unsubstituted.

Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

“Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).

“Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety.

The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. 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, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.

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

The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from Ci-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

As used herein, “small molecules” refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da). The small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 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 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).

In some embodiments, a “small molecule” refers to an organic, inorganic, or organometallic compound typically having 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, small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.

An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments. A series of treatments may comprise a second or subsequent treatment weeks to months after a first or preceding treatment.

The terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by 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%, up to and including, for example, the complete absence of the given entity or parameter ascompared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment.

The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as 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 up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10- fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.

As used herein, the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response.

A “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and/or therapy of various diseases. The radiolabelled pharmaceutical agent, for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source. As contemplated herein, the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule.

For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

Compounds of the Invention

One aspect of the invention relates to a compound of Formula (I):

wherein

Ai is selected from -O- and -NH-; A 2 is selected from -C(Re)(R?)- and -C(O)-;

A3 is selected from -O- and -N(Rs)-;

A4 is selected from a single bond and -C(Rs)(R9)-;

Ri, R2, R3, and R4 are each independently selected from -H, halogen, hydroxy, alkyl, alkoxy, and -(CR'R")C(H)(NH2)CO2H, provided that one and only one of Ri, R2, R3, and R4 is -(CR'R")C(H)(NH₂)CO₂H;

R5 is selected from -H and alkyl;

R' and R" are each independently selected from -H, halogen, and alkyl; and

Re, R7, Rs, and R9 are each independently selected from -H and alkyl; the compound is racemic, enriched in one enantiomer, or a single enantiomer;

In certain embodiments, Ri, R2, R3, and R4 are each independently selected from -H, halogen, hydroxy, and -(CH2)C(H)(NH2)CO2H, provided that one and only one of Ri, R2, R3, and R4 is -(CH₂)C(H)(NH₂)CO₂H.

In certain embodiments, Ri, R2, R3, and R4 are each independently selected from -H, halogen, and -(CH2)C(H)(NH2)CO2H, provided that one and only one of Ri, R2, R3, and R is -(CH₂)C(H)(NH₂)CO₂H.

In certain embodiments, halogen is -F.

In certain embodiments, Ai is selected from -O-; A2 is -C(Re)(R?)-;

A3 is selected from -O- and -N(Rs)-; and A4 is a single bond.

In certain embodiments, the compound having the structure:

In certain embodiments, the compound having the structure selected from:

wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

In certain embodiments, Ri, R2, R3, and R4 are each -H.

In certain embodiments, the compound having the structure selected from:

_; or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound having the structure selected from:

wherein one of R' and R" is -H and the other of R' and R" is halogen or alkyl; * indicates a chiral carbon with an absolute configuration of (5) or (R): and the compound is not racemic.

In certain embodiments, Ri, R2, R3, and R4 are each -H. In certain embodiments, one of R' and R" is -H and the other of R' and R" is -F or -CH3.

In certain embodiments, the compound having the structure selected from:

In certain embodiments, the compound having the structure selected from:

wherein R2, R3, and R4 are not -H; * indicates a chiral carbon with an absolute configuration of (5) or (R); and the compound is not racemic.

In certain embodiments, R2, R3, and R4 are each halogen.

In certain embodiments, the halogen is -F.

In certain embodiments, the compound having the structure selected from:

wherein Ri, R3, and R4 are not -H; * indicates a chiral carbon with an absolute configuration of (5) or (R); and the compound is not racemic.

In certain embodiments, Ri, R3, and R4 are each halogen.

In certain embodiments, the halogen is -F.

In certain embodiments, the compound having the structure selected from:

wherein Ri, R2, and R4 are not -H; * indicates a chiral carbon with an absolute configuration of (5) or (R); and the compound is not racemic.

In certain embodiments, Ri, R2, and R4 are each halogen.

In certain embodiments, the halogen is -F.

In certain embodiments, the compound having the structure selected from:

wherein Ri, R2, and R3 are not -H; * indicates a chiral carbon with an absolute configuration of (5) or (R); and the compound is not racemic.

In certain embodiments, Ri, R2, and R3 are each halogen.

In certain embodiments, the halogen is -F.

In certain embodiments, the compound having the structure selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound having the structure:

In certain embodiments, the compound having the structure selected from:

wherein * indicates a chiral carbon with an absolute configuration of (S) or (R) and the compound is not racemic.

In certain embodiments, Ri, R2, R3, and R4 are each -H.

In certain embodiments, the compound having the structure selected from:

wherein Ri, R2, R3, and R are not -H; * indicates a chiral carbon with an absolute configuration of (5) or (R); and the compound is not racemic.

In certain embodiments, Ri, R2, R3, and R4 are each halogen.

In certain embodiments, the halogen is -F.

In certain embodiments, R5 is -H.

In certain embodiments, R5 is -CH3.

In certain embodiments, the compound having the structure selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, Ai is -NH-; A2 is -C(Re)(R?)-; A3 is -O-; and A4 is a single bond.

In certain embodiments, the compound having the structure selected from:

wherein * indicates a chiral carbon with an absolute configuration of (S) or (R): and the compound is not racemic.

In certain embodiments, Ri, R2, and R3 are each -H.

In certain embodiments, the compound having the structure:

In certain embodiments, Ai is -O-; A2 is -C(O)-; A3 is selected from -O- and -N(Rs) and A4 is -C(Rs)(R9)-.

In certain embodiments, the compound having the structure selected from:

In certain embodiments, Ri, R2, R3, and R4 are each -H.

In certain embodiments, R5 is -H.

In certain embodiments, R5 is -CH3.

In certain embodiments, the compound having the structure:

pharmaceutically acceptable salt thereof.

In certain embodiments, R' is -H.

In certain embodiments, R" is selected from -H and halogen.

In certain embodiments, R" is selected from -H and alkyl.

In certain embodiments, R" is halogen.

In certain embodiments, R" is alkyl.

In certain embodiments, the halogen is -F; and the alkyl is -CH3.

In certain embodiments, the absolute configuration of the chiral carbon denoted by * is (S). In certain embodiments, the absolute configuration of the chiral carbon denoted by * is (R).

In certain embodiments, the boron atom in the compound is ¹⁰B. In certain embodiments, the compound is selected from the following table:

In certain embodiments, the compounds are atropisomers. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. For example, in the case of variable R¹, the (Ci-C4)alkyl or the -O-(Ci- C4)alkyl can be partially or fully deuterated (e.g., -CH2CD3, -CD3, or -OCD3).

Also within the scope of the invention are compounds produced comprising the natural distribution of ⁿB and ¹⁰B.

Also within the scope of the invention are compounds enriched in ¹⁰B, e.g., wherein the ¹⁰B is present in abundance of >20%. Any compound of the invention can also be radiolabed for the preparation of a radiopharmaceutical agent.

Methods of Treatment

Another aspect of the invention relates to a method of treating cancer, comprising: i) administering to a subject in need thereof 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 in the subject; and ii) irradiating the plurality of cancer cells with neutrons.

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

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

Another aspect of the invention relates to a method of treating cancer, comprising: i) administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the compound accumulates in a plurality of cancer cells in the subject; and ii) irradiating the plurality of cancer cells with neutrons.

In certain embodiments, the compound selectively or preferentially accumulates in the plurality of cancer cells relative to noncancerous cells in the subject.

In certain embodiments, the irradiation results in conversion of a ¹⁰B atom in the compound to an a-particle and a lithium-7 ion.

In certain embodiments, the compound or the composition is administered intravenously. In certain embodiments, the compound is continually administered during irradiation with neutrons.

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

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

In certain embodiments, the first period of time is about 1 hour to about 3 hours. In certain embodiments, the first period of time is about 2 hours.

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

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

In certain embodiments, the second period of time is about 0.25 hour to about 1.25 hours.

In certain embodiments, the second period of time is about 0.5 to about 1 hours.

In certain embodiments, the cancer is a solid tumor.

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

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

Pharmaceutical Compositions, Routes of Administration, and Dosing,

In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier.

In certain embodiments, a pharmaceutical composition of the invention further comprises at least one additional pharmaceutically active agent other than a compound of the invention.

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

In certain embodiments, the pharmaceutical composition further comprises a saccharide. In certain embodiments, the pharmaceutical composition further comprises a polyhydroxy acid.

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

As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and/or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein.

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

Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound. For any compound described herein the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well- known in the art is well within the capabilities of the ordinarily skilled artisan.

The formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical.

For intravenous and other parenteral routes of administration, a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.

It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention. EXAMPLES

The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

Abbreviations used in the instant specification, particularly the schemes and examples, are as follows in Table A:

Table A.

Example 1. Preparation of Compounds General Methods for Synthesis of the Compounds of the Invention

Scheme 1

Scheme 1 provides a general synthetic route to the fused dioxaborepinol or oxazaborepinol phenylalanine compounds disclosed herein. In Scheme 1 , Negishi cross-coupling of bromo phenol la and iodide lb gives 1c. Regioselective bromination with NBS affords Id. Subsequent alkylation of phenol hydroxyl group of Id with bromide le or If leads to the corresponding intermediate 1g or Ih respectively. Conversion of bromide to boronic acid li or Ij is achieved under Pd-mediated coupling with a diborane, followed by basic hydrolysis to afford the carboxylic acids Ik or 11. Under acidic condition, deprotection of the THP or Boc groups leads to cyclization with the neighboring boronic acid to give the dioxaborepinol or oxazaborepinol final products Im or In.

Preparation of Compound 1-S

Reagents and Conditions: (a) Zn, h, Pd2(dba)s, S-Phos, DMF, 50°C, overnight; (b)NBS, 'PnNH, DCM, rt, 3h; (c) K2CO3, DMF, rt, 2 h; (d) Pd(dppf)Cl₂, KO Ac, dioxane, rt, 2 h; (e) LiOH- H₂O,THF/H₂O , rt, 2 h;(f) 4 M HCl, dioxane, rt, 2h.

Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-hydroxyphenyl)propanoate (is-i).

To a stirred solution of Zn (6.05 g, 92.48 mmol, 4 equiv) in DMF (20 mL) was added I2 (0.59 g, 2.31 mmol, 0.1 equiv). The resulting mixture was stirred for 5 min at room temperature under nitrogen atmosphere. To a stirred solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3- iodopropanoate (15.22 g, 46.24 mmol, 2 equiv) in DMF (20 mL) was added I2 (0.81 g, 3.18 mmol, 0.1 equiv). The resulting mixture was stirred under nitrogen atmosphere at room temperature for 30 min. To the above mixture were added 2-bromophenol (4 g, 23.12 mmol, 1 equiv), Pd2(dba)s (2.12 g, 2.31 mmol, 0.1 equiv), S-Phos (1.42 g, 3.47 mmol, 0.15 equiv) in DMF (20mL). The resulting mixture was stirred under nitrogen atmosphere at 50 °C for overnight. The reaction was quenched with Water. The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (4 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 60% gradient in 10 min; detector, UV 254 nm] to afford the title product as a light brown solid (1.5 g, 21.97%). LCMS (ESI): mass calcd. for C15H21NO5, 295.1; m/z found, 196.0 [M+H-Boc]⁺ Preparation of methyl (2S)-3-(3-bromo-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino] propanoate (1S-2).

To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-hydroxyphenyl) propanoate (2.5 g, 8.47 mmol, 1 equiv) and bis(propan-2-yl)amine (0.09 g, 0.85 mmol, 0.1 equiv) in DCM (30 mL) was added NBS (1.51 g, 8.47 mmol, 1 equiv) in portions under nitrogen atmosphere at 0 °C. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 60% gradient in 10 min; detector, UV 254 nm] to afford the title product as a light yellow oil (1.5 g, 47.35%). LCMS (ESI): mass calcd. for Ci₅H₂oBrN0₅, 373.1; m/z found, 274.0 [M+H-Boc]⁺.

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

To a stirred solution of methyl (2S)-3-(3-bromo-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl) amino]propanoate (550 mg, 1.47 mmol, 1 equiv) and 2-(2-bromoethoxy)oxane (368.74 mg, 1.76 mmol, 1.2 equiv) in DMF (12 mL) was added K2CO3 (304.68 mg, 2.21 mmol, 1.5 equiv) . The resulting mixture was stirred under nitrogen atmosphere at room temperature for overnight. 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, filtrated was concentrated. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 90% gradient in 10 min; detector, UV 254 nm] to afford the title product as a light yellow oil (670 mg, 90.74%). LCMS (ESI): mass calcd. for C₂₂H3₂BrNO7,501.1; m/z found, 524.1 [M+Na]⁺.

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

To a stirred solution of methyl (2S)-3-(3-bromo-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (500 mg, 1.0 mmol, 1 equiv) and 2-(5,5- dimethyl-l,3,2-dioxaborinan-2-yl)-5,5-dimethyl-l,3,2-dioxaborinane (449.62 mg, 1.99 mmol, 2 equiv) in dioxane (15 mL) were added KO Ac (195.35 mg, 1.99 mmol, 2 equiv) and Pd(dppf)Cl₂ (72.82 mg, 0.10 mmol, 0.1 equiv). The resulting mixture was stirred under nitrogen atmosphere at 80 °C for overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 70% gradient in 10 min; detector, UV 254 nm] to afford the title product as a brown yellow oil (450 mg, 96.76%). LCMS (ESI): mass calcd. for C22H34BNO9,467.2; m/z found, 490.3 [M+Na]⁺.

Preparation of (2S)-3-(3-borono-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid (1S-5).

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 equiv) in THF (8 mL) and H2O (4 mL) was added lithiumol hydrate (71.83 mg, 1.71 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The mixture acidified to ‘pH 5’ with 2 M HC1 (aq.). 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, filtrated and concentrated. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm] to afford the title product as a light yellow oil (310 mg, 79.90%). LCMS (ESI): mass calcd. for C2iH32BNO9,453.2; m/z found, 452.2 [M-H]’.

Preparation of (S)-2-amino-3-(l-hydroxy-3,4-dihydro-lH-benzo[c][l,5,2]dioxaborepin-6- yl)propanoic acid (IS).

To a stirred solution of (2S)-3-(3-borono-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid (275 mg, 0.61 mmol, 1 equiv) in dioxane (0.2 mL) was added 4 M HCl(gas)in 1 ,4-dioxane (0.2 mL) under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified [by Prep-TLC (Column: Sunfire prep C18 column, 30*150 mm, 5pm; Mobile Phase A: Water(0.1 %FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 12% B in 10 min; Wave Length: 254nm/220nm; RTl(min): 7.63)] to afford the title product as a white solid (70 mg, 45.69%). LCMS (ESI): mass calcd. for C11H14BNO5, 251.1; m/z found, 252.1 [M+H]⁺. 'H NMR (400 MHz, Deuterium Oxide) 87.70 (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).

Preparation of Compound 1-R

Reagents and Conditions: (a) Zn, h, Pd2(dba)s, S-phos, DMF, 40 °C; (b) NBS, iPnNH, DCM, 0 °C; (c) K2CO3, DMF, r.t.; (d) Xphos Pd G2, X-Phos, KOAc, EtOH, 80 °C; (e) LiOH.H₂O, THF, H2O, r.t.; (f) 4MHCI in dioxane, dioxane, r.t.

Preparation of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-hydroxyphenyl) propanoate (LR-1).

A mixture of Zn (6.05 g, 92.48 mmol, 4 equiv) and I2 (0.58 g, 2.31 mmol, 0.1 equiv) in DMF (40 mL) was stirred under nitrogen atmosphere at room temperature for 5 min. To the above mixture was added a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (11.41 g, 34.68 mmol, 1.5 equiv) in DMF (15 mL) slowly, followed by the addition of I2 (0.58 g, 2.31 mmol, 0.1 equiv). The resulting mixture was stirred under nitrogen atmosphere at room temperature for 30 min. Then to the mixture was added a solution of 2-bromophenol (4 g, 23.12 mmol, 1 equiv) in DMF (10 mL), Pd2(dba)s (2.12 g, 2.31 mmol, 0.1 equiv) and S-phos (1.42 g, 3.47 mmol, 0.15 equiv). The reaction mixture was stirred under nitrogen atmosphere at 40 °C overnight. The reaction was quenched with water (20 mL). The mixture was filtered, the solid was 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 flash chromatography [with the following conditions: column, Cl 8; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 40% to 50% gradient in 5 min; detector, UV 220 nm] to give the title product as a brown yellow oil (4.35 g, 63.7%). LCMS (ESI): mass calcd. for C15H21NO5, 295.1; m/z found, 196.2 [M+H-Boc]⁺.

Preparation of methyl (2R)-3-(3-bromo-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl) amino]propanoate (LR-2).

To a stirred solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-hydroxyphenyl) propanoate (4.35 g, 14.73 mmol, 1 equiv) and bis(propan-2-yl)amine (149.0 mg, 1.47 mmol, 0.1 equiv) in DCM (80 mL) under nitrogen atmosphere at 0 °C was added NBS (1.57 g, 8.84 mmol, 0.6 equiv) in portions. The resulting mixture was stirred under nitrogen atmosphere at room temperature overnight. Then the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8; mobile phase, MeCN in Water (0.1% FA), 50% to 60% gradient in 6 min; detector, UV 220 nm] to give the title product as a yellow oil (2.75 g, 49.9%). LCMS (ESI): mass calcd. for Ci₅H2oBrN0₅, 373.1; m/z found, 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)propanoate (1R-3).

To a stirred solution of methyl (2R)-3-(3-bromo-2-hydroxyphenyl)-2- [(tert-butoxycarbonyl) amino]propanoate (1.58 g, 4.22 mmol, 1 equiv) and 2-(2-bromoethoxy)oxane (1.06 g, 5.07 mmol, 1.2 equiv) in DMF (23 mL) was added K2CO3 (0.88 g, 6.33 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature overnight. The resulting mixture was filtered, the filter cake was washed with DMF (1 x 2 mL). The filtrate was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8; mobile phase, MeCN in Water (0.1% FA), 55% to 70% gradient in 5 min; detector, UV 220 nm] to give the title product as a light yellow oil (1.74 g, 82.03%). LCMS (ESI): mass calcd. for C22H₃₂BrNO7, 501.1; m/z found, 524.1 [M+Na]⁺. Preparation of (3-((R)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-(2- ((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid ( 1R-4).

To a stirred solution of methyl (2R)-3-(3-bromo-2-(2-((tetrahydro-2H-pyran-2-yl)oxy) ethoxy )phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (1.64 g, 3.26 mmol, 1 equiv) and tetrahydroxydiborane (877.94 mg, 9.79 mmol, 3 equiv) in EtOH (32 mL) were added KOAc (961.10 mg, 9.79 mmol, 3 equiv), XPhos Pd G2 (513.69 mg, 0.65 mmol, 0.2 equiv) and X-phos (155.62 mg, 0.33 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at 80 °C for 1 h. The mixture was allowed to cool down 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 flash chromatography [with the following conditions: column, Cl 8; mobile phase, MeCN in Water (0.1% FA), 40% to 55% gradient in 10 min; detector, UV 220 nm] to give the title product as a light yellow oil (860 mg, 56.38%). LCMS (ESI): mass calcd. for C22H34BNO9, 467.2; m/z found, 490.2 [M+Na]⁺

Preparation of (2R)-3-(3-borono-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid ( 1R-5).

To a stirred mixture of (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 equiv) inTHF (16 mL) / H2O (8 mL) was added LiOH.H2O (181.82 mg, 4.33 mmol, 2.5 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 1 h. The resulting mixture was extracted with EtOAc (3 x 50 mL) (keep aqueous layer). The aqueous layer was acidified to ‘pH 5’ with IN HC1 (aq.) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title product as a white oil (673 mg, 85.66%). LCMS (ESI): mass calcd. for C21H32BNO9, 453.2; m/z found, 452.1 [M-H]’.

Preparation of (R)-2-amino-3-(l-hydroxy-3,4-dihydro-lH-benzo[c][l,5,2]dioxaborepin-6- yl)propanoic acid hydrochloride ( 1R). To a stirred solution of (2R)-3-(3-borono-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid (623 mg, 1.37 mmol, 1 equiv) in dioxane (6 mL) was added 4M HC1 in dioxane (6 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by trituration with MTBE (40 mL). The precipitated solids were collected by filtration and washed with MTBE (3 x 5 mL) to give the title product as a white solid (218 mg, 55.17%). LCMS (ESI): mass calcd. for C11H14BNO5, 251.1; m/z found, 252.1 [M+Hf H NMR (400 MHz, Deuterium Oxide): 8 7.63 (dq, J = 6.2, 2.1 Hz, 1H), 7.25 (dq, J= 5.7, 1.8 Hz, 1H), 6.93 (tdd, 7 = 7.6, 3.4, 1.5 Hz, 1H), 4.22 (q, 7 = 6.7, 5.5 Hz, 3H), 4.09 (dd, 7 = 4.9, 2.7 Hz, 2H), 3.32 - 3.16 (m, 1H), 3.15 - 2.95 (m, 1H).

Preparation of Compound 2

Reagents and Conditions: (a) Zn, h, Pd2(dba)s, SPhos, DMF, 40°C; (b) i-PnNH, NBS, DCM, - 60°C; (c) K2CO3, DMF, r.t.; (d) B₂(OH)₄, Xphos-Pd-G2, Xphos, AcOK, EtOH, 80°C; (e) LiOH.IhO, H2O, THF, r.t.; (f) 4M HCl in dioxane, dioxane, r.t.

Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-6-hydroxyphenyl) propanoate (2-1).

A solution of Zn (12.32 g, 188.48 mmol, 4 equiv) in DMF (200 mL) was treated with I2 (1.20 g, 4.72 mmol, 0.1 equiv) under nitrogen atmosphere at room temperature for 5 min followed by the addition of methyl (27?)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (9.31 g, 28.27 mmol, 1.8 equiv) and I2 (1.20 g, 4.71 mmol, 0.1 equiv) at room temperature. The mixture was stirred under nitrogen atmosphere at room temperature for 30 min. To a stirred solution of 2-bromo-3- fluorophenol (9 g, 47.12 mmol, 1 equiv) and Pd2(dba)s (3.24 g, 3.53 mmol, 0.075 equiv) in DMF (200 mL) was added the above solution at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 40°C overnight. The reaction was quenched by the addition of Water (200 mL) at room temperature. The resulting mixture was filtered, and the solid was 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 flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 10% to 100% gradient in 10 min; detector, UV 254 nm] to afford the title product as a yellow oil (2 g, 13.55%). LCMS (ESI): mass calcd. for C15H20FNO5, 313.13; m/z found, 214.1 [M-Boc+H]⁺.

Preparation of methyl (2S)-3-(3-bromo-6-fluoro-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl) amino]propanoate (2-2).

To a stirred solution of methyl (25^,)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-6-hydroxyphenyl) propanoate (30 mg, 0.096 mmol, 1 equiv) and bis(propan-2-yl)amine (0.11 g, 1.05 mmol, 0.1 equiv) in DCM (50 mL) was added NBS (1.87 g, 10.53 mmol, 1 equiv) in portions at -60°C. The resulting mixture was stirred at -60°C for 2 h. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm] to afford the title product as a yellow oil (1.6 g, 38.73%). LCMS (ESI): mass calcd. for Ci5Hi₉BrFNO₅, 391.04, 393.04; m/z found, 292.05, 294.05 [M- Boc+H]⁺.

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

To a stirred solution of methyl (2S)-3-(3-bromo-6-fluoro-2-hydroxyphenyl)-2-[(tert- butoxycarbonyl)amino]propanoate (30 mg, 0.076 mmol, 1 equiv) and K2CO3 (1.69 g, 12.24 mmol, 3 equiv) in DMF (30 mL) was added 2-(2-bromoethoxy)oxane (1.71 g, 8.19 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. 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 flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 90% gradient in 10 min; detector, UV 254 nm] to afford the title product as a yellow oil (1.3 g, 61.24%). LCMS (ESI): mass calcd. for C22H3iBrFNO7,519.13; m/z found, 520.85 [M +H]⁺.

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).

To a stirred solution of methyl (2S)-3-(3-bromo-6-fluoro-2-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (800 mg, 1.54 mmol, 1 equiv) and AcOK (452.62 mg, 4.61 mmol, 3 equiv) in EtOH (2 mL) was added B2(OH)4 (275.64 mg, 3.07 mmol, 2 equiv), Xphos (73.29 mg, 0.15 mmol, 0.1 equiv) and Xphos-Pd-G2 (241.92 mg, 0.31 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 80°C for 1 h. The resulting mixture was filtered, and the solid was washed with EtOH (3 x 5 mL). The filtrate was concentrated under reduced pressure and purified by reversed- phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 90% gradient in 10 min; detector, UV 220 nm] to afford the title product as a yellow oil (300 mg, 40.21%). LCMS (ESI): mass calcd. for C22H33BFNO9, 485.22; m/z found, 508.15 [M +Na]⁺.

Preparation of (2S)-3-(3-borono-6-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (2-5).

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 equiv) in THF (2 mL) and H2O (1 mL) was added LiOH.H2O (24.21 mg, 0.58 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h and acidified to ‘pH 3’ with IM HC1. 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 in the next step directly without further purification. LCMS (ESI): mass calcd. for C21H31BFNO9, 471.21; m/z found, 272.15 [M-Boc+H]⁺. Preparation of (S)-2-amino-3-(7-fluoro-l-hydroxy-3,4-dihydro-lH-benzo[c][l,5,2] dioxaborepin-6-yl)propanoic acid (2).

To a stirred solution of (2S)-3-(3-borono-6-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (140 mg, 0.30 mmol, 1 equiv) in dioxane (2 mL) was added 4M HC1 in dioxane (1 mL, 4.00 mmol, 13.47 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The residue was purified by trituration with tert-Butyl methyl ether (3 mL). The precipitated solids were collected by filtration, and the solid was washed with tert-Butyl methyl ether (3 x 5 mL) to afford the title product as an off-white solid (27 mg, 33.28%). LCMS (ESI): mass calcd. for C11H13BFNO5, 269.09; m/z found, 270.05 [M+H]⁺. 'H NMR (400 MHz, Deuterium Oxide): 8 7.70 (m, 1H), 6.79 (m, 1H), 4.31 (q, J = 3.7 Hz, 2H), 4.17 - 4.07 (m, 3H), 3.25 (m, 1H), 3.16 (m, 1H).

Preparation of Compound 3

Reagents and Conditions: (a) Zn, h, Pd2(dba)s, SPhos, DMF, 40°C; (b) i-PnNH, NBS, DCM, 0°C; (c) K2CO3, DMF, r.t.; (d) B₂(OH)₄, Xphos-Pd-G2, Xphos, AcOK, EtOH, 80°C; (e) LiOH.IhO, H2O, THF, r.t.; (f) 4M HCl in dioxane, dioxane, r.t.

Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-fluoro-2-hydroxyphenyl) propanoate (3-1).

A mixture of Zn (6.85 g, 104.71 mmol, 4 equiv) and I2 (0.66 g, 2.62 mmol, 0.1 equiv) in DMF (50 mL) was stirred under nitrogen atmosphere at room temperature for 5 min. To the above mixture were added methyl (27?)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (15.51 g, 47.12 mmol, 1.8 equiv) and I2 (0.66 g, 2.62 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. To the above mixture were added 2-bromo-4-fluorophenol (5 g, 26.18 mmol, 1 equiv), Pd2(dba)s (1.80 g, 1.96 mmol, 0.075 equiv) and S-Phos (1.61 g, 3.93 mmol, 0.15 equiv) at room temperature. The resulting mixture was stirred at 40 °C overnight. The reaction was quenched with Water at room temperature. The resulting mixture was filtered, the solid was 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 flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 10% to 100% gradient in 10 min; detector, UV 254 nm] to afford the title product as a brown oil (1.21 g, 14.75%). LCMS (ESI): mass calcd. for C15H20FNO5, 313.13; m/z found, 214.0 [M-Boc+H]⁺.

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

To a stirred mixture of methyl (25^,)-2-[(tert-butoxycarbonyl)amino]-3-(5-fluoro-2- hydroxyphenyl)propanoate (100 mg, 0.32 mmol, 1 equiv) and diisopropylamine (35.85 mg, 0.35 mmol, 0.1 equiv) in DCM (20 mL) was added NBS (0.63 g, 3.54 mmol, 1 equiv) in portions under nitrogen atmosphere at 0 °C. The resulting mixture was stirred under nitrogen atmosphere at 0°C for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 0% to 100% gradient in 10 min; detector, UV 254 nm] to afford the title product as a brown oil (600 mg, 43.18%). LCMS (ESI): mass calcd. for Ci5Hi₉BrFNO₅, 391.04, 393.04; m/z found, 292.05, 294.05 [M-Boc+H]⁺.

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

To a stirred mixture of methyl (2S)-3-(3-bromo-5-fluoro-2-hydroxyphenyl)-2-[(tert- butoxycarbonyl)amino]propanoate (570 mg, 1.45 mmol, 1 equiv) and K2CO3 (602.54 mg, 4.36 mmol, 3 equiv) in DMF (5 mL) was added 2-(2-bromoethoxy)oxane (607.70 mg, 2.91 mmol, 2 equiv) under nitrogen atmosphere at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature overnight. The resulting mixture was diluted with water (5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 10% to 90% gradient in 10 min; detector, UV 220 nm] to afford the title product as a brown oil (600 mg, 79.34%). LCMS (ESI): mass calcd. for C2₂H₃iBrFNO7,519.13, 521.13; m/z found, 517.85, 519.85 [M-H]’.

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).

To a stirred mixture of methyl (2S)-3-(3-bromo-5-fhioro-2-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (50 mg, 0.096 mmol, 1 equiv) and B₂(OH)4 (279.08 mg, 3.11 mmol, 3 equiv) in EtOH (10 mL) were added XPhos Pd G2(7.56 mg, 0.010 mmol, 0.1 equiv), Xphos (49.47 mg, 0.104 mmol, 0.1 equiv) and AcOK (305.52 mg, 3.11 mmol, 3 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 80 °C for 2 h. The mixture was allowed to cool down 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 flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 220 nm] to afford the title product as an off-white solid (360 mg, 71.49%). LCMS (ESI): mass calcd. for C₂₂H33BFNO9, 485.22; m/z found, 508.15 [M +Na]⁺.

Preparation of (2S)-3-(3-borono-5-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (3-5).

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 equiv) in THF (2 mL) and H₂O (1 mL) was added LiOH.H₂O (62.25 mg, 1.48 mmol, 2 equiv) under nitrogen atmosphere at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2h. 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 IM HC1. 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 afford the title product as an off-white solid (210 mg, 60.07%). LCMS (ESI): mass calcd. for C21H31BFNO9, 471.21; m/z found, 272.15 [M-Boc+H]⁺.

Preparation of (S)-2-amino-3-(8-fluoro-l-hydroxy-3,4-dihydro-lH-benzo[c][l,5,2] dioxaborepin-6-yl)propanoic acid (3).

A mixture of (2S)-3-(3-borono-5-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid (160 mg, 0.41 mmol, 1 equiv) and 4M HCl(gas) in 1,4-dioxane (0.5 mL) in dioxane (0.5 mL) was stirred under nitrogen atmosphere at room temperature for Ih. The product was precipitated by the addition of 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 afford the title product as a brown solid (61.7 mg, 47.16%). LCMS (ESI): mass calcd. for C11H13BFNO5, 269.09; m/z found, 270.05 [M+H]⁺. 'H NMR (400 MHz, Deuterium Oxide): 87.34 (dd, J = 9.4, 3.3 Hz, IH), 7.07 (dd, J = 8.4, 3.3 Hz, IH), 4.24 (dd, 7= 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, IH), 3.09 (dd, 7 = 14.3, 7.2 Hz, IH).

Preparation of Compound 4

Reagents and Conditions :(a)Zn, h, Pd2(dba)s, S-Phos, DMF, 40" C; (b)NBS, 'PnNH, DCM, r.t.; (C)K₂CO₃, DMF, r.t.; (d) B₂(OH)₄, X-phos Pd G2, X-phos, KOAc, EtOH, 80°C; (e)LiOH-H₂O, THF/H2O, r.t.; (f)HCl, dioxane, r.t. Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (4-1).

To a stirred mixture of Zn (6.05 g, 92.5 mmol, 4 equiv) and I2 (0.55 g, 2.3 mmol, 0.1 equiv) in dry DMF (15 mL) was added methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (11.4 g, 34.7 mmol, 1.5 equiv) in dry DMF(15 mL) dropwise under nitrogen atmosphere at room temperature. Into a reaction mixture were added I2 (0.55 g, 2.3 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 30 min. Into a reaction mixture were added 4-bromophenol (4 g, 23.1 mmol, 1 equiv), Pd2(dba)s (1.59 g, 1.73 mmol, 0.075 equiv) and S-Phos (1.42 g, 3.47 mmol, 0.15 equiv) in dry DMF (15 mL) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 40°C for overnight. The resulting mixture was diluted with brine (50 mL). The precipitated solids were collected by filtration and washed 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 (1x10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 20% to 60% gradient in 10 min; detector, UV 220 nm] to afford the title product as a white solid (5.5 g, 80.55%). LCMS (ESI): mass calcd. for Ci₅H2iNO₅,295.14; m/z found, 294.20 [M-H]’.

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

A solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (3 g, 10.2 mmol, 1 equiv) in DCM (50 mL) was followed by the addition of NBS (1.27 g, 7.1 mmol, 0.7 equiv) in portions at 0°C. The resulting mixture was stirred at room temperature for 5h. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow solid (0.8 g, 21.04%). LCMS (ESI): mass calcd. for CisFLoBrNCL, 373.05; m/z found, 272.00 [M-H]’. Preparation of methyl (2S)-3-(3-bromo-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (4-3).

A solution of methyl (2S)-3-(3-bromo-4-hydroxyphenyl)-2-[(tert-butoxycarbonyl) amino]propanoate (1.4 g, 3.74 mmol, 1 equiv), K2CO3 (1.55 g, 11.2 mmol, 3 equiv) and 2-(2- bromoethoxy)oxane (1.56 g, 7.48 mmol, 2 equiv) in DMF (15 mL) was stirred at room temperature for 5h. 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 flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 30% to 90% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow oil(1.6 g, 85.13%). LCMS (ESI): mass calcd. for C22H32BrNO?,501.14; m/z found, 519.10 [M+NH4]⁺.

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).

A mixture of methyl (2S)-3-(3-bromo-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoate (1.5 g, 2.99 mmol, 1 equiv), B2(OH)4 (0.80 g, 8.96 mmol, 3 equiv), X-Phos Pd G2 (0.47 g, 0.60 mmol, 0.2 equiv), X-Phos (0.14 g, 0.30 mmol, 0.1 equiv) and AcOK (0.88 g, 8.96 mmol, 3 equiv) in EtOH (15 mL) was stirred under nitrogen atmosphere at 80°C for Ih. The resulting mixture was filtered, and the solid was washed with MeOH (5 x 10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 70% gradient in 10 min; detector, UV 220 nm] to afford the title product as a yellow oil(0.9 g, 64.50%). LCMS (ESI): mass calcd. for C22H34BNO9, 467.23; m/z found, 490.10 [M+Na]⁺.

Preparation of (2S)-3-(3-borono-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid (4-5).

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 equiv) and lithiumol hydrate (0.24 g, 5.78 mmol, 3 equiv) in H2O (5 mL) and THF (10 mL) was stirred under nitrogen atmosphere at room temperature for Ih. The resulting mixture was diluted with H2O (15 mL). The aqueous layer was extracted with EtOAc (3x10 mL) and was acidified to ‘pH 6’ with HC1 (aq.). 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, filtrated and concentrated under reduced pressure to afford the title product as a white solid (0.7 g, 80.18%). LCMS (ESI): mass calcd. for C2iH₃2BNO₉,453.22; m/z found, 252.15 [M-Boc-OTHP]⁺.

Preparation of (S)-2-amino-3-(l-hydroxy-3,4-dihydro-lH-benzo[c][l,5,2]dioxaborepin-8- yl)propanoic acid (4).

A solution of (2S)-3-(3-borono-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid (200 mg, 0.44 mmol, 1 equiv) in 4M HCl(gas)in 1,4- dioxane (2 mL) andl,4-dioxane (2 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with MTBE (10 mL). The precipitated solids were collected by filtration and washed with MTBE (3 x 5 mL) to afford the title product as an off-white solid (55 mg, 43.36%). LCMS (ESI): mass calcd. for C11H14BNO5, 251.10; m/z found, 252.05 [M+H]⁺ . 'H NMR (400 MHz, Deuterium Oxide): 8 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, 7 = 14.7, 5.6 Hz, 1H), 3.11 (dd, J = 14.7, 7.6 Hz, 1H).

Preparation of Compound 5

Reagents and Conditions :(a)Zn, h, Pd2(dba)s, S-Phos, DMF, 40" C; (b)NBS, 'PnNH, DCM, r.t.; (C)K₂CO₃, DMF, r.t.; (d) B₂(OH)₄, X-phos Pd G2, X-phos, KOAc, EtOH, 80°C; (e)TBD, MeCN/IhO, r.t.; (f)4 M HCl, dioxane, r.t.

Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-4-hydroxyphenyl) propanoate (5-1).

A mixture of Zn (6.85 g, 104.7 mmol, 4 equiv) and I2 (0.66 g, 2.62 mmol, 0.1 equiv) in DMF (20 mL) was stirred under nitrogen atmosphere at room temperature for 5 min. To the above mixture was added a solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (17.23 g, 52.4 mmol, 2 equiv) and I2 (0.66 g, 2.62 mmol, 0.1 equiv) in DMF (10 mL) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for additional 30 min. To the above mixture was added a solution of 4-bromo-3-fluorophenol (5 g, 26.2 mmol, 1 equiv), Pd2(dba)s (2.40 g, 2.62 mmol, 0.1 equiv) and S-Phos (1.61 g, 3.93 mmol, 0.15 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 40 °C for overnight. 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 (lx 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluted with PE / EA (1:1)] to afford the title product as a brown oil (5.6 g, 68.27%). LCMS (ESI): mass calcd. for C15H20FNO5, 313.13; m/z found, 312.00 [M-H]’.

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

To a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-4- hydroxyphenyl)propanoate (5.3 g, 16.9 mmol, 1 equiv) in was added NBS (2.11 g, 11.8 mmol, 0.7 equiv) in portions at 0°C. The resulting mixture was stirred under nitrogen atmosphere at 0°C for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow solid (1.26 g, 18.99%). ’H NMR (400 MHz, Methanol- d₄ . 87.31 (d, 7 = 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).

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

To a stirred solution of methyl (2S)-3-(5-bromo-2-fluoro-4-hydroxyphenyl)-2-[(tert- butoxycarbonyl)amino]propanoate (1.15 g, 2.93 mmol, 1 equiv) and 2-(2-bromoethoxy)oxane (0.74 g, 3.52 mmol, 1.2 equiv) in DMF (23.00 mL) was added K2CO3 (0.61 g, 4.4 mmol, 1.5 equiv). The resulting mixture was stirred under nitrogen atmosphere at room temperature for overnight. 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 flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1 % FA), 10% to 90% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow oil (1.25 g, 81.92%). LCMS (ESI): mass calcd. for C22H3iBrFNO7,519.13; m/z found, 542.00 [M+Na]⁺.

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).

To a stirred mixture of methyl (2S)-3-(5-bromo-2-fluoro-4-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (1.15 g, 2.21 mmol, 1 equiv), B2(OH)4 (594 mg, 6.63 mmol, 3 equiv) and AcOK (650 mg, 6.63 mmol, 3 equiv) in EtOH (30.00 mL) were added X-Phos Pd G2 (348 mg, 0.44 mmol, 0.2 equiv) and X-Phos (105 mg, 0.22 mmol, 0.1 equiv) under nitrogen atmosphere at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 80 °C for 1 h. The resulting mixture was filtered, and the solid was washed with MeOH (5 x 10 mL). The combined filtrate was 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 flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 70% gradient in 10 min; detector, UV 220 nm] to afford the title product as a yellow oil(0.7 g, 65.27%). LCMS (ESI): mass calcd. for C22H33BFNO9,485.22; m/z found, 508.15 [M+Na]⁺.

Preparation of (2S)-3-(5-borono-2-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (5-5).

A mixture 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 (680 mg, 1.4 mmol, 1 equiv) and TBD (585 mg, 4.2 mmol, 3 equiv) in MeCN (7 mL) and H2O (0.7 mL) was stirred at room temperature for 2h. 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 HC1 (aq.). 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, filtrated and concentrated under reduced pressure. The residue was purified by re versed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 50% gradient in 10 min; detector, UV 220 nm] to afford the title product as a white solid (360 mg, 54.52%). LCMS (ESI): mass calcd. for C2iH3iBFNO₉,471.21; m/z found, 270.15 [M-Boc-OTHP]⁺.

Preparation of (S)-2-amino-3-(7-fluoro-l-hydroxy-3,4-dihydro-lH-benzo[c][l,5,2] dioxaborepin-8-yl)propanoic acid (5).

A solution of (2S)-3-(5-borono-2-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid (180 mg, 0.38 mmol, 1 equiv) and 4M HCl(gas)in 1 ,4-dioxane ( 1 mL) in 1 ,4-dioxane ( 1 mL) was stirred at room temperature for 2h. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions [Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 12 % B in 10 min; Wave Length: 254nm/220nm; RTl(min): 5.676] to afford the title product as a white solid(59 mg, 57.42%).LCMS (ESI): mass calcd. for C11H13BFNO5, 269.09; m/z found, 270.05 [M+H]⁺. 'H NMR (400 MHz, Deuterium Oxide): 87.39 (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). Preparation of Compound 6

Reagents and Conditions :(a)Zn, h, Pd2(dba)₃, S-Phos, DMF, 4(PC; (b)NBS, 'PnNH, DCM, r.t.; (C)K₂CO₃, DMF, r.t.; (d) B₂(OH)₄, X-phos Pd G2, X-phos, KOAc, EtOH, 8( C; (e)TBD, MeCN/H₂O, r.t.; f) 4M HCl, dioxane, r.t.

Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-4-hydroxyphenyl) propanoate (6-1).

To a stirred mixture of Zn (4.11 g, 62.8 mmol, 4 equiv) and I2 (0.40 g, 1.55 mmol, 0.1 equiv) in dry DMF (15 mL) was added methyl methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3- iodopropanoate (7.75 g, 23.6 mmol, 1.5 equiv) in dry DMF(15ml) dropwise under nitrogen atmosphere at room temperature. Into a reaction mixture were added I2 (0.40 g, 1.55 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 30 min. Into a reaction mixture were added 4-bromo-2-fluorophenol (3 g, 15.7 mmol, 1 equiv), Pd2(dba)s (0.72 g, 0.78 mmol, 0.05 equiv) and SPhos (0.64 g, 1.57 mmol, 0.1 equiv) in DMF(15 mL) at room temperature. The resulting mixture was stirred for overnight at 40°C under nitrogen atmosphere. The resulting mixture was filtered, and the solid was 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 flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 30% to 80% gradient in 10 min; detector, UV 254 nm] to afford the title product as a light yellow liquid (4.6 g, 93.47%). LCMS (ESI): mass calcd. for C15H20FNO5, 313.13; m/z found, 312.10 [M-H]’.

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

A solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-4-hydroxyphenyl) propanoate (4.6 g, 14.7 mmol, 1 equiv) and bis(propan-2-yl)amine (0.15 g, 1.47 mmol, 0.1 equiv) in DCM (40 mL) followed by the addition of NBS (2.61 g, 14.7 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 30% to 80% gradient in 10 min; detector, UV 220 nm] to afford the title product as a brown solid (4.5 g, 78.15%). LCMS (ESI): mass calcd. for CisHigBrFNOs, 391.04; m/z found, 390.10 [M-H]’.

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

A solution of methyl (2S)-3-(3-bromo-5-fluoro-4-hydroxyphenyl)-2-[(tert-butoxycarbonyl) amino]propanoate (2.5 g, 6.37 mmol, 1 equiv), 2-(2-bromoethoxy)oxane (2.67 g, 12.7 mmol, 2 equiv) and K2CO3 (2.64 g, 19.1 mmol, 3 equiv) in DMF (30 mL) was stirred at room temperature for 3h.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 flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 40% to 90% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow liquid (3.1 g, 93.46%). LCMS (ESI): mass calcd. for C22H3iBrFNO7,519.13; m/z found, 518.05 [M-H]’.

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). A mixture of methyl (2S)-3-(3-bromo-5-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (1.5 g, 2.88 mmol, 1 equiv), B2(OH)4 (0.78 g, 8.65 mmol, 3 equiv), X-Phos Pd G2 (0.45 g, 0.58 mmol, 0.2 equiv), X-Phos (0.14 g, 0.29 mmol, 0.1 equiv) andAcOK (0.85 g, 8.646 mmol, 3 equiv) in EtOH (15.00 mL) was stirred under nitrogen atmosphere for Ih at 80°C. The resulting mixture was filtered, and the solid was washed with EtOAc (3 x 10 mL). The combined filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (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 flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 70% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow oil (0.7 g, 50.04%). LCMS (ESI): mass calcd. for C22H33BFNO9, 485.22; m/z found, 508.15 [M+Na]⁺.

Preparation of (2S)-3-(3-borono-5-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (6-5).

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 equiv) and lithiumol hydrate (0.16 g, 3.71 mmol, 3 equiv) in THF (6 mL) and H2O (3 mL) was stirred for 2h at room temperature. The resulting mixture was diluted with H2O (15 mL). The aqueous layer was extracted with EtOAc (3x10 mL) and was acidified to ‘pH 6’ with HC1 (aq.).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, filtrated and concentrated under reduced pressure. The residue was purified by re versed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 50% gradient in 20 min; detector, UV 220 nm] to afford the title product as a white solid (180 mg, 30.89%). LCMS (ESI): mass calcd. for C21H₃IBFNO₉,471.21; m/z found, 270.15 [M-Boc-OTHP]⁺.

Preparation of (S)-2-amino-3-(6-fluoro-l-hydroxy-3,4-dihydro-lH-benzo[c] [1,5,2] dioxaborepin-8-yl)propanoic acid (6). A solution of (2S)-3-(3-borono-5-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid (180 mg, 0.38 mmol, 1 equiv) and 4M HCl(gas)in 1,4-dioxane (1.80 mL) in 1,4-dioxane (1.8 mL) was stirred under nitrogen atmosphere for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions [Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: MeOH; Flow rate: 60 rnL/min; Gradient: 2% B to 12 % B in 10 min; Wave Length: 254nm/220nm; RTl(min): 7.267] to afford (the title product as a white solid(52 mg, 50.61%). LCMS (ESI): mass calcd. for C11H13BFNO5, 269.09; m/z found, 270.05 [M+H]⁺. 'H NMR (400 MHz, Methanol-^): 8 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 = 6.4 Hz, 1H), 3.28- 3.05 (m, 2H).

Preparation of Compound 7

Reagents and Conditions: (a) SOCI2, MeOH, 50 °C; (b) NaHCOs, dioxane, water, r.t.; (c) NBS, ^l Pr₂NH, DCM, r.t.; (d) K2CO3, DMF, r.t.; (e) B₂(OH)₄, X-phos Pd G2, X-phos, KOAc, EtOH, 80" C; (f) TBD, MeCN/H₂O, r.t.; (g) 4MHCI, dioxane, r.t.

Preparation of methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate (7-1).

To a stirred solution of meta-tyrosine (7 g, 38.6 mmol, 1 equiv) in MeOH (70 mL) was added SOCI2 (9.19 g, 77.3 mmol, 2 equiv) dropwise at 0°C. The resulting mixture was stirred at 50°C for 4 h. The resulting mixture was concentrated under vacuum to afford the title product as a light brown solid(7.5 g, crude). LCMS (ESI): mass calcd. for C10H13NO5, 195.09; m/z found, 196.15 [M+H]⁺. Preparation of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propanoate (7-2).

To a stirred mixture of methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate (7.55 g, 38.7 mmol, 1 equiv) and NaHCCh (8.12 g, 96.7 mmol, 2.5 equiv) in dioxane (70 mL) and H2O (70 mL) was added BOC2O (10.13 g, 46.4mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for overnight. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluted with PE / EA (5: 1)] to afford the title product as a light yellow solid(11.2 g, 98.06%). LCMS (ESI): mass calcd. for C15H21NO5, 295.14; m/z found, 294.25 [M+H]⁺.

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

To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl) propanoate (11 g, 37.2 mmol, 1 equiv) and ' P^NH (0.38 g, 3.72 mmol, 0.1 equiv) in DCM (220 mL) was added NBS (3.98 g, 22.3 mmol, 0.6 equiv) in portions at -50°C. The resulting mixture was stirred at room temperature for overnight. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1 % FA), 10% to 50% gradient in 30 min; detector, UV 220 nm] to afford the title product as a white solid (2.5 g, 17.94%). LCMS (ESI): mass calcd. for C15H20BrNO5, 373.05; m/z found, 372.0 [M-H]’. 'H NMR (400 MHz, DMSO-tfc): 8 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).

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

A solution of methyl (2S)-3-(4-bromo-3-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino] propanoate (2.4 g, 6.41 mmol, 1 equiv) K2CO3 (2.66 g, 19.2 mmol, 3 equiv) and 2-(2- bromoethoxy)oxane (2.68 g, 12.8 mmol, 2 equiv) in DMF (15 mL) was stirred at room temperature for overnight. 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 re versed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 50% to 80% gradient in 10 min; detector, UV 220 nm to afford the title product as a light yellow oil (2 g, 62.07%). LCMS (ESI): mass calcd. for C22H₃₂BrNO7,501.14; m/z found, 524.15 [M+Na]⁺.

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).

A mixture of methyl (2S)-3-(4-bromo-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoate (1.9 g, 3.8 mmol, 1 equiv), B₂(OH)4 (1.02 g, 11.3 mmol, 3 equiv), X-Phos (0.18 g, 0.38 mmol, 0.1 equiv), X-Phos Pd G2 (0.60 g, 0.76 mmol, 0.2 equiv) and AcOK (1.11 g, 11.3 mmol, 3 equiv) in EtOH (20 mL) was stirred under nitrogen atmosphere at 80°C for Ih. The resulting mixture was filtered, and the solid was washed with MeOH (3 x 10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 60% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow oil (1.1 g, 62.24%). LCMS (ESI): mass calcd. for C22H34BNO9, 467.23; m/z found, 490.20 [M+Na]⁺.

Preparation of (2S)-3-(4-borono-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid (7-6).

A solutione of (4-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-(2- ((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)boronic acid (1 g, 2.14 mmol, 1 equiv) and TBD (596 mg, 4.28 mmol, 2 equiv) in MeCN (10 mL) and H₂O (1 mL) was stirred under nitrogen atmosphere at room temperature for Ih. The resulting mixture was diluted with EtOAc (30 mL) and was extracted with IM NaOH (3 x 10 mL). The aqueous layer was acidified to ‘pH 5’ with 1 M HC1 (aq.), and was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO4, filtrated and concentrated under reduced pressure to afford the title product as a white solid (0.6 g, 61.86%). LCMS (ESI): mass calcd. for C2iH₃2BNO₉,453.22; m/z found, 252.00 [M-Boc-OTHP]⁺. Preparation of (S)-2-amino-3-(l-hydroxy-3,4-dihydro-lH-benzo[c][l,5,2]dioxaborepin-7- yl)propanoic acid (7).

A solution of (2S)-3-(4-borono-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid (400 mg, 0.88 mmol, 1 equiv) and 4 M HC1 in 1,4-dioxane (3 mL) in dioxane (3 mL) was stirred for 2h at room temperature. The precipitated solids were collected by filtration and washed with MTBE (3 x 5 mL) to afford the title product as a white solid (174 mg, 68.59%). LCMS (ESI): mass calcd. for C11H14BNO5, 251.10; m/z found, 252.10 [M+H]⁺ . 'H NMR (400 MHz, Deuterium Oxide) 8 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).

Preparation of Compound 8

Reagents and Conditions: (a) Zn, F, Pd2(dba)s, SPhos, DMF, 40°C; (b) i-P^NH, TEA, DCM, - 60°C; (c) K2CO3, DMF, r.t.; (d) B₂(OH)₄, Xphos-Pd-G2, Xphos, AcOK, EtOH, 80°C; (e) LiOH'FEO, FEO, THF, r.t.; (f) HCl in dioxane, dioxane, r.t.

Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-3-hydroxyphenyl) propanoate (8-1).

A solution of Zn (5.48 g, 83.772 mmol, 4 equiv) in DMF (60 mL) was treated with I2 (0.53 g, 2.094 mmol, 0.1 equiv) for 5 min at room temperature under nitrogen atmosphere followed by the addition of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (9305.41 mg, 28.273 mmol, 1.8 equiv) and I2 (0.53 g, 2.094 mmol, 0.1 equiv) at room temperature. The mixture was stirred under nitrogen atmosphere at room temperature for 30 min. To a stirred solution of 2- bromo-3-fluorophenol (9 g, 47.121 mmol, 1 equiv) and Pd2(dba)s (1.44 g, 1.571 mmol, 0.075 equiv) in DMF (60 mL) was added the above solution at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 40°C overnight. The reaction was quenched by the addition of Water (200 mL) at room temperature. The resulting mixture was filtered, 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 flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm] to afford the title product as a yellow oil (3 g, 45.72%). LCMS (ESI): mass calcd. for C15H20FNO5, 313.13; m/z found, 214.1 [M-Boc+H]⁺.

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

To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-3- hydroxyphenyl)propanoate (3 g, 9.575 mmol, 1 equiv) and bis(propan-2-yl)amine (0.10 g, 0.958 mmol, 0.1 equiv) in DCM (60 mL) was added NBS (1.36 g, 7.660 mmol, 0.8 equiv) in portions at -50°C. 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 flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm] to afford the title product as a yellow oil (1.8 g, 47.93%). LCMS (ESI): mass calcd. for Ci5Hi₉BrFNO₅, 391.04, 393.04; m/z found, 292.05, 294.05 [M-Boc+H]⁺.

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

To a stirred solution of methyl (2S)-3-(4-bromo-2-fluoro-3-hydroxyphenyl)-2-[(tert- butoxycarbonyl)amino]propanoate (1.8 g, 4.589 mmol, 1 equiv) and K2CO3 (1.90 g, 13.767 mmol, 3 equiv) in DMF (20 mL) were added 2-(2-bromoethoxy)oxane (1.92 g, 9.178 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x lOOmL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1 % FA), 10% to 50% gradient in 10 min; detector, UV 254 nm] to afford the title product as a yellow oil (1.2 g, 50.25%). LCMS (ESI): mass calcd. for C22H₃iBrFNO7, 519.13; m/z found, 520.85 [M+H]⁺.

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).

To a stirred solution of methyl (2S)-3-(4-bromo-2-fluoro-3-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (500 mg, 0.961 mmol, 1 equiv) and tetrahydroxydiborane (258.41 mg, 2.883 mmol, 3 equiv) in EtOH (5 mL) was added KOAc (282.89 mg, 2.883 mmol, 3 equiv), X-phos (45.80 mg, 0.096 mmol, 0.1 equiv) and 2nd X-phos Pd G2 (151.20 mg, 0.192 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 70°C for 1 h. 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 flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm] to the title product as a yellow oil (120 mg, 25.73%). LCMS (ESI): mass calcd. for C22H33BFNO9, 485.22; m/z found, 508.15 [M+Na]⁺.

Preparation of (2S)-3-(4-borono-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (8-5).

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 equiv) in THF (1.5 mL) and H2O (0.5 mL) was added lithiumol hydrate (25.94 mg, 0.618 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 3 with IM HC1 (aq.). 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 in the next step directly without further purification. LCMS (ESI): mass calcd. for C21H31BFNO9, 471.21; m/z found, 272.15 [M-Boc+H]⁺.

Preparation of (S)-2-amino-3-(6-fluoro-l-hydroxy-3,4-dihydro-lH-benzo[c] [1,5,2] dioxaborepin-7-yl)propanoic acid (8).

To a stirred solution of (2S)-3-(4-borono-2-fluoro-3-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (200 mg, 0.424 mmol, 1 equiv) in dioxane (4 mL) was added 4 M HC1 in dioxane (1.43 mL, 5.711 mmol, 13.47 equiv,) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure and purified by Prep-HPLC [with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5pm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 10 % B in 10 min; Wave Length: 254nm/220nm; RTl(min): 5.062)] to afford the title product as a white solid (54 mg, 46.54%). LCMS (ESI): mass calcd. for C11H13BFNO5, 269.09; m/z found, 270.05 [M+H]⁺. 1H NMR (400 MHz, Deuterium Oxide): 87.37 (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).

Preparation of Compound 9

Reagents and Conditions: (a) Zn, h, Pd2(dba)s, S-phos, DMF, 40 °C; (b) NBS, Diisopropylamine, DCM, -50 °C; (c) K2CO3, DMF, r.t.; (d) B2(OH)4, EtOH, X-phos, Xphos Pd G2, 70 °C.; (e) LiOH H2O, THF, H2O, r.t.; (f) 1,4-dioxane, 4M HCl in dioxane, r.t. Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-5-hydroxyphenyl) propanoate (9-1).

A mixture of Zn (6.85 g, 104.712 mmol, 4 equiv) and I2 (0.66 g, 2.618 mmol, 0.1 equiv) in DMF (30 mL) was stirred under nitrogen atmosphere at room temperature for 5 min. To the above mixture was added a solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (12.92 g, 39.267 mmol, 1.5 equiv) in DMF (20 mL) and I2 (0.66 g, 2.618 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred for additional 30 min at room temperature under nitrogen atmosphere. To the above mixture was added a solution of 3-bromo- 4-fluorophenol (5 g, 26.178 mmol, 1 equiv), Pd2(dba)s (2.40 g, 2.618 mmol, 0.1 equiv) and S-Phos (1.61 g, 3.927 mmol, 0.15 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 40 °C overnight. After cooling down 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 [eluted with PE / EA (2: 1)] to afford the title product as a brown oil (6.5 g, 79.25%). LCMS (ESI): mass calcd. for C15H20FNO5, 313.13; m/z found, 214.05 [M-Boc+H]⁺.

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

To a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-fluoro-5- hydroxyphenyl)propanoate (6 g, 19.149 mmol, 1 equiv) in DCM (60 mL) was added NBS (2.04 g, 11.489 mmol, 0.6 equiv) in portions at -50 °C. The resulting mixture was stirred at -50 °C for 2 h. The resulting mixture was concentrated under vacuum and purified by reversed-phase flash chromatography with the following conditions [column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 45% gradient in 10 min; detector, UV 220 nm] to afford the title product as a yellow oil (1.1 g, 14.65%). LCMS (ESI): mass calcd. for CisHigBrFNOs, 391.04; m/z found, 390.00 [M-H]’.

Preparation of methyl (2S)-3-(4-bromo-2-fluoro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy) ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (9-3). A mixture of methyl (2S)-3-(4-bromo-2-fluoro-5-hydroxyphenyl)-2-[(tert-butoxycarbonyl)amino] propanoate (1.1 g, 2.805 mmol, 1 equiv), K2CO3 (1.16 g, 8.415 mmol, 3 equiv) and 2-(2- bromoethoxy)oxane (1.17 g, 5.610 mmol, 2 equiv) in DMF (15 mL) was stirred under nitrogen atmosphere at room temperature 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 [eluted with PE / EA (2:1)] to afford the title product as a yellow oil (810 mg, 55.50%). LCMS (ESI): mass calcd. for C22H₃iBrFNO7, 519.13; m/z found, 542.00 [M+Na]⁺.

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).

A mixture of methyl (2S)-3-(4-bromo-2-fluoro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (760 mg, 1.460 mmol, 1 equiv), tetrahydroxydiborane (392.78 mg, 4.380 mmol, 3 equiv), Xphos (69.62 mg, 0.146 mmol, 0.1 equiv) and 2nd Xphos Pd G2 (229.82 mg, 0.292 mmol, 0.2 equiv) in EtOH (10 mL) was stirred under nitrogen atmosphere at 70 °C for 1 h. After cooling down to room temperature, the resulting mixture was filtered, 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 flash chromatography with the following conditions [column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow solid (230 mg, 32.45%). LCMS (ESI): mass calcd. for C22H33BFNO9, 485.22; m/z found, 508.25 [M+Na]⁺.

Preparation of (2S)-3-(4-borono-2-fluoro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (9-5).

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 equiv) and lithiumol hydrate (51.88 mg, 1.236 mmol, 3 equiv) in THF (2 mL) and H2O (2 mL) was stirred under nitrogen atmosphere at room temperature for 2 h. The mixture was acidified to ‘pH 6’ with IM HC1 (aq.) 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 afford the title product as a yellow oil (260 mg, crude). LCMS (ESI): mass calcd. for C21H31BFNO9, 471.21; m/z found, 470.20 [M-H]’.

Preparation of (S)-2-amino-3-(8-fluoro-l-hydroxy-3,4-dihydro-lH-benzo[c] [1,5,2] dioxaborepin-7-yl)propanoic acid (9).

To a stirred mixture of (2S)-3-(4-borono-2-fluoro-5-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (210 mg, 0.446 mmol, 1 equiv) in dioxane (2 mL, 23.608 mmol) was added 4M HC1 in 1,4-dioxane (2 mL, 65.826 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The precipitated solids were collected by filtration and washed with MTBE (1 x 10 mL) to afford the title product as a white solid (84.8 mg, 61.67%). LCMS (ESI): mass calcd. for C11H13BFNO5, 269.09; m/z found, 270.05 [M+H]⁺. 'H NMR (400 MHz, Deuterium Oxide): 87.29 (d, J = 10.1 Hz, 1H), 6.89 (d, J = 5.7 Hz, 1H), 4.21 (dd, 7= 7.3, 5.9 Hz, 1H), 4.17 - 4.08 (m, 2H), 3.94 - 3.83 (m, 2H), 3.30 (dd, 7 = 14.5, 5.9 Hz, 1H), 3.15 (dd, 7= 14.5, 7.3 Hz, 1H).

Preparation of Compound 10

Reagents and Conditions :(a)Zn, h, Pd2(dba)₃, S-Phos, DMF, 50°C, overnight; (b)NBS, 'PnNH, DCM, rt, 3h; (c)K₂CO₃, DMF, rt, 2 h; (d) Pd(dppf)Cl₂, KO Ac, dioxane, rt, 2 h; (e)LiOH.H₂O, THF/H2O , rt, 2 h;(f) 4 M HCl in dioxane, dioxane, rt, 2h. Preparation of methyl (2S)-3-(3-bromo-2-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)-2- [(tert-butoxycarbonyl)amino]propanoate (10-1).

To a stirred solution of methyl (2S)-3-(3-bromo-2-hydroxyphenyl)-2-[(tert-butoxycarbonyl) amino]propanoate (800 mg, 2.14 mmol, 1 equiv) and tert-butyl N-(2-bromoethyl)carbamate (574.87 mg, 2.57 mmol, 1.2 equiv) in DMF (15 mL) was added K2CO3 (443.16 mg, 3.21 mmol, 1.5 equiv). The resulting mixture was stirred under nitrogen atmosphere at room temperature for overnight. 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, filtrated and concentrated. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 10 min; detector, UV 254 nm] to afford the title product as a light brown oil (900 mg, 81.37%). LCMS (ESI): mass calcd. for C22H33BrN2O?,516.2; m/z found, 539.0[M+Na]⁺-

Preparation of 3- [ ( 2S) -2- [(tert-butoxycarbonyl)amino] -3-methoxy-3-oxopropy 1] -2- {2- [(tert- butoxycarbonyl)amino]ethoxy}phenylboronic acid (10-2).

To a stirred solution of methyl (2S)-3-(3-bromo-2-{2-[(tert-butoxycarbonyl) amino]ethoxy}phenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (50 mg, 0.10 mmol, 1 equiv) and 2-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-5,5-dimethyl-l,3,2-dioxaborinane (436.57 mg, 1.93 mmol, 2 equiv) in dioxane (15 mL) were added Pd(dppf)C12 (70.71 mg, 0.10 mmol, 0.1 equiv) and KO Ac (189.68 mg, 1.93 mmol, 2 equiv). The resulting mixture was stirred under nitrogen atmosphere at 80 °C for overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 70% gradient in 10 min; detector, UV 254 nm] to afford the title product as a brown yellow oil (340 mg, 72.95%). LCMS (ESI): mass calcd. for C22H35BN2O9, 482.2; m/z found, 505.2 [M+Na]⁺.

Preparation of (S)-3-(3-borono-2-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid (10-3).

To a stirred solution of 3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2-{2- [(tert-butoxycarbonyl)amino]ethoxy}phenylboronic acid (300 mg, 0.62 mmol, 1 equiv) in THF (6 mL) and H2O (3 mL) was added lithiumol hydrate (52.20 mg, 1.24 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The mixture was acidified to ‘pH 5’ with 2 M HC1 (aq.). 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, filtrated and concentrated. The residue was purified by re versed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 40% gradient in 10 min; detector, UV 254 nm] to afford the title product as a light yellow oil (280 mg, 96.13%). LCMS (ESI): mass calcd. for C21H33BN2O9, 468.2; m/z found, 467.2 [M-H]’.

Preparation of (S)-2-amino-3-(l-hydroxy-l,2,3,4-tetrahydrobenzo[f][l,4,5]oxazaborepin-6- yl)propanoic acid (10).

To a stirred solution of (S)-3-(3-borono-2-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid (280 mg, 0.598 mmol, 1 equiv) in dioxane (2 mL) was added 4M HC1 (2 mL, in dioxane) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC [with the following conditions (Column: XB ridge Prep Amide OBD Column, 19*150 mm, 5pm; Mobile Phase A: Water(0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 90%B to 73%B in 8 min; Wave Length: 254/220 nm; RTl(min): 7.87; Number Of Runs: 5)] to afford the itle product as a white solid (90 mg, 39.40%). LCMS (ESI): mass calcd. for C17H23BFNO6, 367.16; m/z found, 268.0 [M+H-Boc]⁺. 'H NMR (300 MHz, Deuterium Oxide): 8 7.44 (dt, 7 = 7.4, 1.7 Hz, 1H), 7.29 (dd, 7 = 7.5, 1.8 Hz, 1H), 7.12 (td, 7= 7.5, 1.2 Hz, 1H), 4.23 - 3.98 (m, 3H), 3.48 - 3.20 (m, 3H), 3.04 (dd, 7 = 14.4, 7.5 Hz, 1H).

Preparation of Compound 11

Reagents and Conditions: (a) K2CO3, DMF, rt, overnight (b) LiOH.HzO, THF, H2O, rt, 2h; (c) 4 MHCl, dioxane, rt, 2h.

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

To a stirred solution of methyl (2S)-3-[2-(bromomethyl)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-2-[(tert-butoxycarbonyl)amino]propanoate (1 g, 2.01 mmol, 1 equiv) and K2CO3 (0.55 g, 4.01 mmol, 2 equiv) in DMF (15 mL) was added methyl 2- (methylamino)acetate hydrochloride (0.34 g, 2.41 mmol, 1.2 equiv). The resulting mixture was stirred under nitrogen atmosphere at room temperature for overnight. 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, filtrated and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 10% to 40% gradient in 10 min; detector, UV 254 nm] to to give the title product as a white solid (320 mg, 36.38%). LCMS (ESI): mass calcd. C20H31BN2O8, 438.2; m/z found, 439.2[M+H]⁺.

Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(l-hydroxy-5-methyl-3-oxo-3,4,5,6- tetrahydro-lH-benzo[c][l,6,2]oxazaborocin-7-yl)propanoic acid (11-2).

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, 0.68mmol, 1 equiv) in THF (3 mL) and H2O (3 mL) was added LiOH.ILO (114.89 mg, 2.74 mmol, 4 equiv). The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The mixture was acidified to ‘pH 5’ with 2M HC1 (aq.). 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, filtrated and concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 40% gradient in 10 min; detector, UV 254 nm] to give the title product as a white solid (160 mg, 59.60%). LCMS (ESI): mass calcd. C18H25BN2O7, 392.18; m/z found, 391.1[M-H] . Preparation of (S)-2-amino-3-(l-hydroxy-5-methyl-3-oxo-3,4,5,6-tetrahydro-lH-benzo [c][l,6,2]oxazaborocin-7-yl)propanoic acid (11).

To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(l-hydroxy-5-methyl-3-oxo- 3,4,5,6-tetrahydro-lH-benzo[c][l,6,2]oxazaborocin-7-yl)propanoic acid (150 mg, 0.38 mmol, 1 equiv) in dioxane (1.5 mL, 17.71 mmol, 46.30 equiv) was added 4M HCl(gas)in 1,4-dioxane (1.5 mL) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2h. The resulting mixture was concentrated under reduced pressure to give the title product as a light yellow solid (100 mg, 85.04%). LCMS (ESI): mass calcd. for C13H17BN2O5, 292.12; m/z found, 294.2[M+H]⁺. ’H NMR (400 MHz, Deuterium Oxide): 8 7.44 (d, J = 7.2 Hz, 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).

Example 2. Cell Uptake Assays

Cell Culture

1.1 Thawing Method

1.1.1 15 mL of cell culture medium was placed into a T225 flask.

1.1.2 The flask was placed in a humidified 37°C, 5% CO2 incubator for 15 minutes to allow medium to equilibrate to the proper pH and temperature.

1.1.3 The vial was removed from liquid nitrogen and thawed rapidly by placing at 37 °C in a water bath with gentle agitation for 1-2 minutes and then decontaminated by wiping with 70% ethanol before opening in a Class II biological safety cabinet.

1.1.4 The vial contents were transferred dropwise into 10 mL of cell culture medium in a sterile 15 mL conical tube.

1.1.5 The cells were centrifuged at 1,300 rpm for 5 minutes.

1.1.6 The supernatant was aspirated and re-suspended the cells and transferred the cells into T225 flask containing cell culture medium.

1.2 Propagation Method

1.2.1 Culture medium were renewed every 2-3 days.

1.2.2 Keep the flask in a humidified 37°C, 5% CO2 incubator Assay Procedures

2.1 Cell Seeding

Cells were harvested and diluted in culture medium to the designated concentration. Then the cells were cultured in T25 flasks, one T25 flask for one sample.

2.2 Formulation of test compounds

2.2.1 L-Boronophenylalanine (L-BPA, 4-boron-L-phenylalanine, Purity: 95%, Chemical formula: C9H12BNO4, MW: 209.01, CAS: 76410-58-7) and fructose were dissolved in PBS at a molar ratio of 1:5, and then a 1.27 M ratio of 1 N NaOH is added. The mixture was stirred until L-BPA is completely dissolved, and the pH value was titrated to 7.2-7.4 with 1 N HC1.

2.2.2 For test compounds other than BPA, stock solutions were prepared of each compound in DMSO or fructose formulation at a concentration of 20 mM (such that final % DMSO in the cellular assay medium= 0.5%)

2.3 Compound treatment

2.3.1 The cells were seeded overnight (12-18 hours) to allow the cells to adhere well.

2.3.2 The stock solution of each compound was added to each T25 flask such that the final concentration for each compound is 100 uM (0.1 mM).

2.3.3 The flasks were placed in a 37°C, 5% CO2 incubator for 1 hour, 4 hours and 24 hours.

2.3.4 After treatment for 1 hour, 4 hour, and 24 hours, the cells were collected by using 0.25% Trypsin with 0.53 mM EDTA.

2.3.5 Centrifuged at 1,300 rpm for 5 min to collect cell pellets.

Results

The compounds disclosed herein were selectively taken up by the representative cancer cell lines SAS (human head & neck cancer), B16F10 (mouse melanoma), and U87-MG (human glioblastoma) relative to a representative normal human cell line (NIH-3T3). Cell Uptake of Compound 1-S with L-BPA as comparator:

1-5 L-BPA

Cell Uptake of Compound 1-R with L-BPA as comparator:

1-7? L-BPA

Cell Uptake of Compound 2 with L-BPA as comparator:

2 L-BPA

Cell Uptake of Compound 3 with L-BPA as comparator:

3 L-BPA

Cell Uptake of Compound 4 with L-BPA as comparator:

4 L-BPA

Cell Uptake of Compound 5 with L-BPA as comparator:

5 L-BPA

Cell Uptake of Compound 6 with L-BPA as comparator:

6 L-BPA

Cell Uptake of Compound 7 with L-BPA as comparator:

7 L-BPA

Cell Uptake of Compound 8 with L-BPA as comparator:

8 L-BPA

Cell Uptake of Compound 9 with L-BPA as comparator:

9 L-BPA

Cell Uptake of Compound 10 with L-BPA as comparator:

10 L-BPA

Cell Uptake of Compound 11 with L-BPA as comparator:

11 L-BPA

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. and PCT patent application publications cited herein are hereby incorporated by reference.

EQUIVALENTS

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

Claims

We claim:

1. A compound of Formula (I):

wherein

Ai is selected from -O- and -NH-;

A2 is selected from -C(Re)(R?)- and -C(O)-;

A3 is selected from -O- and -N(Rs)-;

A4 is selected from a single bond and -C(Rs)(R9)-;

R5 is selected from -H and alkyl;

R' and R" are each independently selected from -H, halogen, and alkyl;

Re, R7, Rs, and R9 are each independently selected from -H and alkyl; and the compound is racemic, enriched in one enantiomer, or a single enantiomer; or a pharmaceutically acceptable salt thereof.

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

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

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

5. The compound of any one of claims 1-4, wherein

Ai is selected from -O-;

A₂ is -C(R₆)(R₇)-; A3 is selected from -O- and -N(Rs)-; and

A4 is a single bond.

6. The compound of claim 5 having the structure:

7. The compound of claim 6 having the structure selected from:

wherein * indicates a chiral carbon with an absolute configuration of (S) or (7?); and the compound is not racemic.

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

9. The compound of claim 8 having the structure selected from:

10. The compound of claim 6 having the structure selected from:

11. The compound of claim 10, wherein Ri, 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 of any one of claims 10-12 having the structure selected from:

14. The compound of claim 6 having the structure selected from:

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

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

17. The compound of claim 6 having the structure selected from:

18. The compound of claim 17, wherein Ri, R3, and R4 are each halogen.

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

20. The compound of claim 6 having the structure selected from:

21. The compound of claim 20, wherein Ri, R2, and R4 are each halogen.

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

23. The compound of claim 6 having the structure selected from:

24. The compound of claim 23 wherein Ri, R2, and R3 are each halogen.

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

26. The compound of any one of claims 17-25 having the structure selected from:

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 5 having the structure:

28. The compound of claim 27 having the structure selected from:

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

30. The compound of claim 28 having the structure selected from:

wherein Ri, R2, R3, and R4 are not -H; * indicates a chiral carbon with an absolute configuration of (5) or (R): and the compound is not racemic.

31. The compound of claim 30, wherein Ri, R2, R3, and R4 are each halogen.

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

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

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

35. The compound of any one of claims 27-34 having the structure selected from:

or a pharmaceutically acceptable salt thereof.

36. The compound of any one of claims 1-4, wherein

Ai is -NH-;

A₂ is -C(R₆)(R₇)-;

A3 is -O-; and

A4 is a single bond.

37. The compound of claim 36 having the structure selected from:

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

39. The compound of ckaim 37 or 38 having the structure:

40. The compound of any one of claims 1-4, wherein

Ai is -O-;

A₂ is -C(O)-;

A3 is selected from -O- and -N(Rs)-; and

A₄ is -C(R₈)(R₉)-.

41. The compound of claim 40 having the structure selected from:

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

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

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

45. The compound of claim 37 or 38 having the structure:

, or a pharmaceutically acceptable salt thereof.

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

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

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

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

50. The compound of any one of claims 1-6, 10, 36, 40, or 46, wherein R" is alkyl.

51. The compound of any one of claims 47-50, wherein the halogen is -F; and the alkyl 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 wherein the absolute configuration of the chiral carbon is (R).

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

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

56. The pharmaceutical composition of claim 55, further comprising a saccharide.

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

58. The pharmaceutical composition of any one of claims 55-57, further comprising a polyhydroxy acid.

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

60. The pharmaceutical composition of any one of claims 55-59, further comprising a sugar alcohol.

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

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

64. The method of claim 62 or 63, wherein the irradiation results in conversion of a ¹⁰B atom in the compound to an a -particle and a lithium -7 ion.

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

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

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

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