BORON-CONTAINING SMALL MOLECULES

Abstract

This invention relates to, among other items, 6-substituted benzoxaborole compounds and their use for treating bacterial infections.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Pat. App. No. 61/260,384, filed Nov. 11, 2009, and U.S. Provisional Pat. App. No. 61/260,373, filed Nov. 11, 2009, each of which is incorporated by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

The global rise of bacteria and other microorganisms resistant to antibiotics and antimicrobials in general, poses a major threat. Deployment of massive quantities of antimicrobial agents into the ecosphere during the past 60 years has introduced a powerful selective pressure for the emergence and spread of antimicrobial-resistant pathogens. Thus, there is a need to discover new broad spectrum antimicrobials, such as antibiotics, useful in combating microorganisms, especially those with multidrug-resistance.

Boron-containing molecules, such as 1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborole (also sometimes known as 1-hydroxy-benzo[c][1,2]oxaborole or oxaboroles or cyclic boronic esters), useful as antimicrobials have been described previously, such as in U.S. patent application Ser. Nos. 12/142,692; 11/505,591 and 11/357,687. Generally speaking, a 1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborole has the following structure and substituent numbering system:

Surprisingly, it has now been discovered that certain classes of 1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaboroles which are substituted with at least two moieties on an aryl or heteroaryl sulfonamide moiety at the 6-position are surprisingly effective antibacterials. This, and other uses of these 1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaboroles are described herein.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a compound having a structure which is

wherein R⁵ is H or halogen; one of R^a2, R^a3, R^a5 and R^a6 is halogen or —NHC(O)OR³⁰ or alkyl substituted with —C(O)OR³⁰ or alkyl substituted with —S(O)₂R³⁰ or alkyl substituted with halogen or alkyl substituted with hydroxy or alkyl substituted with cyano or alkyl substituted with —NHC(O)OR³⁰ or alkyl substituted with unsubstituted oxazolyl or alkyl substituted with alkyl substituted oxazolyl or alkyl substituted with unsubstituted oxadiazolyl or alkyl substituted with alkyl substituted oxadiazolyl or alkyl substituted with —C(O)NHR³⁵, wherein R³⁰ is unsubstituted alkyl and R³⁵ is unsubstituted alkyl or unsubstituted cycloalkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰ and R¹¹ are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In a second aspect, the invention provides a combination comprising: a) a compound of the invention, or a pharmaceutically acceptable salt thereof; and b) a therapeutically active agent.

In a third aspect, the invention provides a pharmaceutical formulation comprising: a) a compound of the invention, or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.

In a fourth aspect, the invention provides a method of killing or inhibiting the growth of a bacteria, said method comprising: contacting said bacteria with an effective amount of a compound of the invention or a combination of the invention, or a pharmaceutically acceptable salt thereof, thereby killing or inhibiting the growth of the bacteria.

In a fifth aspect, the invention provides a method of treating a bacterial infection comprising: administering to an animal suffering from said infection an effective amount of a compound of the invention, or a pharmaceutically-acceptable salt thereof, thereby treating the bacterial infection.

In a sixth aspect, the invention provides a method of inhibiting the editing domain of a t-RNA synthetase, comprising: contacting the synthetase with an effective amount of a compound of the invention, or a pharmaceutically-acceptable salt thereof, thereby inhibiting the synthetase.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 displays biological data for exemplary compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions and Abbreviations

As used herein, the singular forms “a,” “an”, and “the” include plural references unless the context clearly dictates otherwise. For example, reference to “an active agent” includes a single active agent as well as two or more different active agents in combination. It is to be understood that present teaching is not limited to the specific dosage forms, carriers, or the like, disclosed herein and as such may vary.

The abbreviations used herein generally have their conventional meaning within the chemical and biological arts.

The following abbreviations have been used: Ac is acetyl; AcOH is acetic acid; ACTBr is cetyltrimethylammonium bromide; AIBN is azobisisobutyronitrile or 2,2 azobisisobutyronitrile; aq. is aqueous; Ar is aryl; B₂pin₂ is bis(pinacolato)diboron; Bn is, in general, benzyl [see Cbz for one example of an exception]; (BnS)₂ is benzyl disulfide; BnSH is benzyl thiol or benzyl mercaptan; BnBr is benzyl bromide; Boc is tert-butoxy carbonyl; Boc₂O is di-tert-butyl dicarbonate; Bz is, in general, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl or carboxybenzyl; Cs₂CO₃ is cesium carbonate; CSA is camphor sulfonic acid; CTAB is cetyltrimethylammonium bromide; Cy is cyclohexyl; DABCO is 1,4-diazabicyclo[2.2.2]octane; DCM is dichloromethane or methylene chloride; DHP is dihydropyran; DIAD is diisopropyl azodicarboxylate; DIEA or DIPEA is N,N-diisopropylethylamine; DMAP is 4-(dimethylamino)pyridine; DME is 1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO is dimethylsulfoxide; equiv or eq. is equivalent; EtOAc is ethyl acetate; EtOH is ethanol; Et₂O is diethyl ether; EDCI is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; ELS is evaporative light scattering; equiv or eq is equivalent; h is hours; HATU is O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; HOBt is N-hydroxybenzotriazole; HCl is hydrochloric acid; HPLC is high pressure liquid chromatography; ISCO Companion is automated flash chromatography equipment with fraction analysis by UV absorption available from Presearch; KOAc or AcOK is potassium acetate; K₂CO₃ is potassium carbonate; LiAlH₄ or LAH is lithium aluminum hydride; LDA is lithium diisopropylamide; LHMDS is lithium bis(trimethylsilyl) amide; KHMDS is potassium bis(trimethylsilyl) amide; LiOH is lithium hydroxide; m-CPBA is 3-chloroperoxybenzoic acid; MeCN or ACN is methyl cyanide or cyanomethane or ethanenitrile or acetonitrile which are all names for the same compound; MeOH is methanol; MgSO₄ is magnesium sulfate; mins or min is minutes; Mp or MP is melting point; NaCNBH₃ is sodium cyanoborohydride; NaOH is sodium hydroxide; Na₂SO₄ is sodium sulfate; NBS is N-bromosuccinimide; NH₄Cl is ammonium chloride; NIS is N-iodosuccinimide; N₂ is nitrogen; NMM is N-methylmorpholine; n-BuLi is n-butyllithium; overnight is O/N; PdCl₂(pddf) is 1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd/C is the catalyst known as palladium on carbon; Pd₂(dba)₃ is an organometallic catalyst known as tris(dibenzylideneacetone) dipalladium(0); Ra Ni or Raney Ni is Raney nickel; Ph is phenyl; PMB is p-methoxybenzyl; PrOH is 1-propanol; iPrOH is 2-propanol; POCl₃ is phosphorus chloride oxide; PTSA is para-toluene sulfonic acid; Pyr. or Pyr or Py as used herein means Pyridine; RT or rt or r.t. is room temperature; sat. is saturated; Si-amine or S₁—NH₂ is amino-functionalized silica, available from SiliCycle; Si-pyr is pyridyl-functionalized silica, available from SiliCycle; TEA or Et₃N is triethylamine; TFA is trifluoroacetic acid; Tf₂O is trifluoromethanesulfonic anhydride; THF is tetrahydrofuran; TFAA is trifluoroacetic anhydride; THP is tetrahydropyranyl; TMSI is trimethylsilyl iodide; H₂O is water; diNO₂PhSO₂Cl is dinitrophenyl sulfonyl chloride; 3-F-4-NO₂-PhSO₂Cl is 3-fluoro-4-nitrophenylsulfonyl chloride; 2-MeO-4-NO₂-PhSO₂Cl is 2-methoxy-4-nitrophenylsulfonyl chloride; and (EtO)₂POCH₂COOEt is a triethylester of phosphonoacetic acid known as triethyl phosphonoacetate.

“Compound of the invention,” as used herein refers to the compounds discussed herein, salts (e.g. pharmaceutically acceptable salts), prodrugs, solvates and hydrates of these compounds.

MIC, or minimum inhibitory concentration, is the point where the compound stops more than 50% of cell growth, preferably 60% of cell growth, preferably 70% of cell growth, preferably 80% of cell growth, preferably 90% of cell growth, relative to an untreated control.

The term “poly” as used herein means at least 2. For example, a polyvalent metal ion is a metal ion having a valency of at least 2.

“Moiety” refers to a radical of a molecule that is attached to the remainder of the molecule.

The symbol , whether utilized as a bond or displayed perpendicular to a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule.

The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C₁-C₁₀ means one to ten carbons). In some embodiments, the term “alkyl” means a straight or branched chain, or combinations thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by —CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

The term “alkenylene” by itself or as part of another substituent means a divalent radical derived from an alkene.

The term “cycloalkylene” by itself or as part of another substituent means a divalent radical derived from a cycloalkyl.

The term “heteroalkylene” by itself or as part of another substituent means a divalent radical derived from an heteroalkane.

The term “heterocycloalkylene” by itself or as part of another substituent means a divalent radical derived from an heteroalkane.

The term “arylene” by itself or as part of another substituent means a divalent radical derived from an aryl.

The term “heteroarylene” by itself or as part of another substituent means a divalent radical derived from heteroaryl.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom. In some embodiments, the term “heteroalkyl,” by itself or in combination with another term, means a stable straight or branched chain, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom. In an exemplary embodiment, the heteroatoms can be selected from the group consisting of B, O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) B, O, N and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃. Similarly, the term “heteroalkylene” by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C₁-C₄)alkyl” is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, substituent that can be a single ring or multiple rings (preferably from 1 to 3 rings), which are fused together or linked covalently. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to four heteroatoms. In an exemplary embodiment, the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 6-quinolyl, dioxaborolane, dioxaborinane and dioxaborepane. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes those radicals in which an aryl group is attached through the next moiety to the rest of the molecule. Thus, the term “arylalkyl” is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, 1-(3-nitrophenyl)ethyl and the like). A substituent such as benzyl or 1-(3-nitrophenyl)ethyl can also be represented by ‘substituted alkyl’ wherein the ethyl radical is substituted with a 3-nitrophenyl moiety. The term “aryloxy” is meant to include those radicals in which an aryl group is attached to an oxygen atom. The term “aryloxyalkyl” is meant to include those radicals in which an aryl group is attached to an oxygen atom which is then attached to an alkyl group (e.g., phenoxymethyl, 3-(1-naphthyloxy)propyl, and the like).

For brevity, the term “heteroaryl” when used in combination with other terms (e.g., heteroaryloxy, heteroarylthioxy, heteroarylalkyl) includes those radicals in which a heteroaryl group is attached through the next moiety to the rest of the molecule. Thus, the term “heteroarylalkyl” is meant to include those radicals in which a heteroaryl group is attached to an alkyl group (e.g., pyridylmethyl and the like). The term “heteroaryloxy” is meant to include those radicals in which a heteroaryl group is attached to an oxygen atom. The term “heteroaryloxyalkyl” is meant to include those radicals in which an aryl group is attached to an oxygen atom which is then attached to an alkyl group. (e.g., 2-pyridyloxymethyl and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and “heteroaryl”) are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generically referred to as “alkyl group substituents,” and they can be one or more of a variety of groups selected from, but not limited to: —R′, —OR′, ═O, =NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR′—C(NR′R″R′″)═NR″″, —NR″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR″SO₂R′, —CN, —NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a number ranging from zero to (2 m′+1), where m′ is the total number of carbon atoms in such radical. R′, R″, R′″, R″″ and R′″″ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″, R″″ and R′″″ groups when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R¹¹ is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are generically referred to as “aryl group substituents.” The substituents are selected from, for example: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR′″″—C(NR′R″R′″)═NR″″, —NR″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR″SO₂R′, —CN, —NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R″, R′″, R″″ and R′″″ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″, R″″ and R′″″ groups when more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T—C(O)—(CRR′)_q—U—, wherein T and U are independently —NR—, —O—, —CRR′— or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH₂)_r—B—, wherein A and B are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integer from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CRR′)_s—X—(CR″R′″)_d—, where s and d are independently integers from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substituents R, R′, R″ and R′″ are preferably independently selected from hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.

“Ring” as used herein, means a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. A ring includes fused ring moieties. The number of atoms in a ring is typically defined by the number of members in the ring. For example, a “5- to 7-membered ring” means there are 5 to 7 atoms in the encircling arrangement. Unless otherwise specified, the ring optionally includes a heteroatom. Thus, the term “5- to 7-membered ring” includes, for example phenyl, pyridinyl and piperidinyl. The term “5- to 7-membered heterocycloalkyl ring”, on the other hand, would include pyridinyl and piperidinyl, but not phenyl. The term “ring” further includes a ring system comprising more than one “ring”, wherein each “ring” is independently defined as above.

As used herein, the term “heteroatom” includes atoms other than carbon (C) and hydrogen (H). Examples include oxygen (O), nitrogen (N) sulfur (S), silicon (Si), germanium (Ge), aluminum (Al) and boron (B).

The symbol “R” is a general abbreviation that represents a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl groups.

By “effective” amount of a drug, formulation, or permeant is meant a sufficient amount of a active agent to provide the desired local or systemic effect. A “Topically effective,” “Cosmetically effective,” “pharmaceutically effective,” or “therapeutically effective” amount refers to the amount of drug needed to effect the desired therapeutic result.

The term “pharmaceutically acceptable salt” is meant to include a salt of a compound of the invention which is prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compounds in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

In addition to salt forms, the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment.

Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms.

Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the invention. The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are used to denote the absolute configuration of a stereocenter unless otherwise noted. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are included.

Compounds of the invention can exist in particular geometric or stereoisomeric forms. The invention contemplates all such compounds, including cis- and trans-isomers, (−)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention. Additional asymmetric carbon atoms can 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.

Optically active (R)- and (S)-isomers and d and/isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis, or by derivatization 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 an amino group, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. In addition, separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H or T), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.

The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable vehicle” refers to any formulation or carrier medium that provides the appropriate delivery of an effective amount of an active agent as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient. Representative carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, penetration enhancers, and the like. Their formulation is well known to those in the art of cosmetics and topical pharmaceuticals. Additional information concerning carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005) which is incorporated herein by reference.

The term “excipients” is conventionally known to mean carriers, diluents and/or vehicles used in formulating drug compositions effective for the desired use.

The term “microbial infection” or “infection by a microorganism” refers to any infection of a host tissue by an infectious agent including, but not limited to, bacteria or protozoa (see, e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991); Williams et al., J. of Medicinal Chem. 42:1481-1485 (1999), herein each incorporated by reference in their entirety).

“Biological medium,” as used herein refers to both in vitro and in vivo biological milieus. Exemplary in vitro “biological media” include, but are not limited to, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.

“Inhibiting” and “blocking,” are used interchangeably herein to refer to the partial or full blockade of enzyme. In an exemplary embodiment, the enzyme is an editing domain of a tRNA synthetase.

Boron is able to form dative bonds with oxygen, sulfur or nitrogen under some circumstances in this invention. Dative bonds are usually weaker than covalent bonds. In situations where a boron is covalently bonded to at least one oxygen, sulfur or nitrogen, and is at the same time datively bonded to an oxygen, sulfur or nitrogen, respectively, the dative bond and covalent bond between the boron and the two identical heteroatoms can interconvert or be in the form of a resonance hybrid. There is potential uncertainty surrounding the exact nature and extent of electron sharing in these situations. Generally, in boron compounds comprising both covalent and coordinate covalent (dative) bonds, the electrons in such bonds may be partially or fully delocalized.

Embodiments of the invention also encompass compounds that are poly- or multi-valent species, including, for example, species such as dimers, trimers, tetramers and higher homologs of the compounds of use in the invention or reactive analogues thereof.

“Salt counterion”, as used herein, refers to positively charged ions that associate with a compound of the invention when the boron is fully negatively or partially negatively charged. Examples of salt counterions include H⁺, H₃O⁺, ammonium, potassium, calcium, magnesium and sodium.

The compounds comprising a boron bonded to a carbon and three heteroatoms (such as three oxygens described in this section) can optionally contain a fully negatively charged boron or partially negatively charged boron, due to the nature of the dative bond between the boron and one of the oxygens. Due to the negative charge, a positively charged counterion may associate with this compound, thus forming a salt. Examples of positively charged counterions include H⁺, H₃O⁺, calcium, sodium, ammonium and potassium. The salts of these compounds are implicitly contained in descriptions of these compounds.

II. Introduction

The invention provides novel boron compounds and methods for the preparation of these molecules. The invention further provides methods of treating bacterial infections, killing or inhibiting the growth of bacteria in part or wholly through the use of the compounds described herein. In another aspect, the invention is a combination of a compound of the invention and an antibiotic. In another aspect, the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a compound of the invention. In another aspect, the invention is a pharmaceutical formulation comprising a compound of the invention, an antibiotic, and a pharmaceutically acceptable excipient.

III. a.) Compounds

In one aspect the invention provides a compound of the invention. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. In an exemplary embodiment, the salt of a compound described herein is a pharmaceutically acceptable salt. In an exemplary embodiment, the invention provides a compound described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the invention provides a compound described in a formula provided herein. In an exemplary embodiment, the invention provides a compound described herein.

In an exemplary embodiment, the compound has a structure which is

wherein R⁵ is H or halogen. In an exemplary embodiment, R⁵ is H. In an exemplary embodiment, R⁵ is halogen.

In an exemplary embodiment, the compound has a structure which is

In an exemplary embodiment, the compound has a structure which is

In an exemplary embodiment, the compound has a structure which is

wherein R⁵ is H or halogen, and R⁴⁰ is nitro or amino or cyano or halogen. In an exemplary embodiment, R⁵ is H and R⁴⁰ is nitro or amino or F or Cl or Br. In an exemplary embodiment, R⁵ is F and R⁴⁰ is nitro or amino or F or Cl or Br. In an exemplary embodiment, R⁵ is Cl and R⁴⁰ is nitro or amino or F or Cl or Br.

In an exemplary embodiment, the compound has a structure which is

wherein R⁵ is H or halogen, and R⁴⁰ is OR⁴¹, wherein OR⁴¹ is H or methyl or trifluoromethyl or ethyl or propyl or isopropyl or butyl or t-butyl or isobutyl. In an exemplary embodiment, R⁵ is H and R⁴⁰ is OR⁴¹, wherein OR⁴¹ is methyl or trifluoromethyl or ethyl or propyl or isopropyl. In an exemplary embodiment, R⁵ is F and R⁴⁰ is OR⁴¹, wherein OR⁴¹ is methyl or trifluoromethyl or ethyl or propyl or isopropyl. In an exemplary embodiment, R⁵ is H and R⁴⁰ is OH. In an exemplary embodiment, R⁵ is F and R⁴⁰ is OH.

In an exemplary embodiment, the compound has a structure which is

wherein R⁵ is H or halogen, and R⁴⁰ is CH₂NH₂ or (CH₂)₂NH₂, or (CH₂)₃NH₂.

In an exemplary embodiment, the compound has a structure which is

wherein R⁵ is H or halogen, and R⁴⁰ is C(O)NH₂ or NHC(O)R⁴², wherein R⁴² is methyl or ethyl or propyl or isopropyl. In an exemplary embodiment, R⁵ is H and R⁴⁰ is C(O)NH₂ or NHC(O)R⁴², wherein R⁴² is methyl or ethyl or propyl or isopropyl. In an exemplary embodiment, R⁵ is F and R⁴⁰ is C(O)NH₂ or NHC(O)R⁴², wherein R⁴² is methyl or ethyl or propyl or isopropyl.

In an exemplary embodiment, the compound has a structure which is

wherein R⁵ is H or halogen, and R⁴⁰ and R⁴¹ are each independently selected from the group consisting of F, Cl, and Br. In an exemplary embodiment, R⁵ is H and R⁴⁰ is F and R⁴¹ is F or Cl or Br. In an exemplary embodiment, R⁵ is F and R⁴⁰ is F and R⁴¹ is F or Cl or Br. In an exemplary embodiment, the compound has a structure which is

wherein R⁵, R⁴⁰ and R⁴¹ are as described herein.

In an exemplary embodiment, the compound has a structure which is

wherein R⁵ is H or halogen, and R⁴⁰ is amino or nitro or C(O)NH₂ or NHC(O)R⁴², wherein R⁴² is methyl or ethyl or propyl or isopropyl. In an exemplary embodiment, R⁵ is H and R⁴⁰ is C(O)NH₂ or NHC(O)R⁴², wherein R⁴² is methyl or ethyl or propyl or isopropyl. In an exemplary embodiment, R⁵ is F and R⁴⁰ is C(O)NH₂ or NHC(O)R⁴², wherein R⁴² is methyl or ethyl or propyl or isopropyl. In an exemplary embodiment, R⁵ is H and R⁴⁰ is amino. In an exemplary embodiment, R⁵ is F and R⁴⁰ is amino. In an exemplary embodiment, R⁵ is H and R⁴⁰ is nitro. In an exemplary embodiment, R⁵ is F and R⁴⁰ is nitro.

In an exemplary embodiment, the compound has a structure which is

wherein R⁵ is H or halogen, and R⁴⁰ is OR⁴¹, wherein OR⁴¹ is H or methyl or trifluoromethyl or ethyl or propyl or isopropyl or butyl or t-butyl or isobutyl. In an exemplary embodiment, R⁵ is H and R⁴⁰ is OR⁴¹, wherein OR⁴¹ is methyl or trifluoromethyl or ethyl or propyl or isopropyl. In an exemplary embodiment, R⁵ is F and R⁴⁰ is OR⁴¹, wherein OR⁴¹ is methyl or trifluoromethyl or ethyl or propyl or isopropyl. In an exemplary embodiment, R⁵ is H and R⁴⁰ is OH. In an exemplary embodiment, R⁵ is F and R⁴⁰ is OH.

In an exemplary embodiment, the compound has a structure which is

wherein R⁵ is H or halogen, and R⁴⁰ is amino. In an exemplary embodiment, R⁵ is H and R⁴⁰ is amino. In an exemplary embodiment, R⁵ is F and R⁴⁰ is amino. In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a4, R^a5 and R^a6 is halogen and the remaining members of R^a2, R^a3, R^a4, R^a5 and R^a6 are H, R¹⁰, R¹¹ and K are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a4, R^a5, R^a6, R⁵, R¹⁰, R¹¹ and R¹⁵ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a4, R^a5 and R^a6 is F or Cl or Br and the remaining members of R^a2, R^a3, R^a4, R^a5 and R^a6 are H, R are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a4, R^a5 and R^a6 is F or Cl or Br and the remaining members of R^a2, R^a3, R^a4, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is halogen, R¹⁰, R¹¹, and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is F, R^a6 is F or Cl or Br, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is F or Cl or Br, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is OR²⁰ and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R²⁰ is H or unsubstituted alkyl, and R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is OR²⁰ and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R²⁰ is H or unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is OR²⁰ and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R²⁰ is H or unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is OR²⁰, R²⁰ is H or unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is F, R^a6 is OR²⁰, R²⁰ is H or unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is OR²⁰, R²⁰ is H or unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is OR²⁰, R²⁰ is H or unsubstituted alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is OH. In an exemplary embodiment, R⁵ is H, R^a6 is OH. In an exemplary embodiment, R⁵ is F, R^a6 is OCH₃. In an exemplary embodiment, R⁵ is H, R^a6 is OCH₃. In an exemplary embodiment, R⁵ is F, R^a6 is OCH₂CH₃. In an exemplary embodiment, R⁵ is H, R^a6 is OCH₂CH₃. In an exemplary embodiment, R⁵ is F, R^a6 is OR²⁰, R²⁰ is unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is OR²⁰, R²⁰ is unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is OR²⁰, R²⁰ is unsubstituted C₄ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is OR²⁰, R²⁰ is unsubstituted C₄ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is OR²⁰, R²⁰ is unsubstituted C₅ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is OR²⁰, R²⁰ is unsubstituted C₅ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is OR²⁰, R²⁰ is unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is OR²⁰, R²⁰ is unsubstituted C₆ alkyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is cyano and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰ and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is cyano and the remaining members of R^a2R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is cyano and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is cyano, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is F, R^a6 is cyano, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is cyano, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is cyano. In an exemplary embodiment, R⁵ is F, R^a6 is cyano. In an exemplary embodiment, R⁵ is H, R^a6 is cyano.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is unsubstituted alkyl and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is unsubstituted alkyl. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₃. In an exemplary embodiment, R⁵ is H, R^a6 is CH₃. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₃. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₃. In an exemplary embodiment, R⁵ is F, R^a6 is unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is unsubstituted C₄ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is unsubstituted C₄ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is unsubstituted C₅ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is unsubstituted C₅ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is unsubstituted C₆ alkyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is unsubstituted alkenyl or unsubstituted alkynyl and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, and R^a6 are H, R¹⁰. R¹¹ and R¹⁵ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is unsubstituted alkenyl or unsubstituted alkynyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰ and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is unsubstituted alkenyl or unsubstituted alkynyl. In an exemplary embodiment, R⁵ is halogen, R^a6 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl. In an exemplary embodiment, R⁵ is F, R^a6 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl. In an exemplary embodiment, R⁵ is H, R^a6 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with cyano and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with cyano or ethyl substituted with cyano or C₃ alkyl substituted with cyano or C₄ alkyl substituted with cyano or C₅ alkyl substituted with cyano or C₆ alkyl substituted with cyano and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with cyano or ethyl substituted with cyano or C₃ alkyl substituted with cyano or C₄ alkyl substituted with cyano or C₅ alkyl substituted with cyano or C₆ alkyl substituted with cyano and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with cyano, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with cyano or ethyl substituted with cyano or C₃ alkyl substituted with cyano or C₄ alkyl substituted with cyano or C₅ alkyl substituted with cyano or C₆ alkyl substituted with cyano, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with cyano or ethyl substituted with cyano or C₃ alkyl substituted with cyano or C₄ alkyl substituted with cyano or C₅ alkyl substituted with cyano or C₆ alkyl substituted with cyano, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with cyano. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with cyano or ethyl substituted with cyano or C₃ alkyl substituted with cyano or C₄ alkyl substituted with cyano or C₅ alkyl substituted with cyano or C₆ alkyl substituted with cyano. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with cyano or ethyl substituted with cyano or C₃ alkyl substituted with cyano or C₄ alkyl substituted with cyano or C₅ alkyl substituted with cyano or C₆ alkyl substituted with cyano. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CN. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CN. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CN. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CN. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂CN. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂CN. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂CH₂CN. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂CH₂CN. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂CH₂CH₂CN. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂CH₂CH₂CN. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂CH₂CH₂CH₂CN. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂CH₂CH₂CH₂CN.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with hydroxy and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with hydroxy or ethyl substituted with hydroxy or C₃ alkyl substituted with hydroxy or C₄ alkyl substituted with hydroxy or C₅ alkyl substituted with hydroxy or C₆ alkyl substituted with hydroxy and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with hydroxy or ethyl substituted with hydroxy or C₃ alkyl substituted with hydroxy or C₄ alkyl substituted with hydroxy or C₅ alkyl substituted with hydroxy or C₆ alkyl substituted with hydroxy and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with hydroxy, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with hydroxy or ethyl substituted with hydroxy or C₃ alkyl substituted with hydroxy or C₄ alkyl substituted with hydroxy or C₅ alkyl substituted with hydroxy or C₆ alkyl substituted with hydroxy, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with hydroxy or ethyl substituted with hydroxy or C₃ alkyl substituted with hydroxy or C₄ alkyl substituted with hydroxy or C₅ alkyl substituted with hydroxy or C₆ alkyl substituted with hydroxy, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with hydroxy. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with hydroxy or ethyl substituted with hydroxy or C₃ alkyl substituted with hydroxy or C₄ alkyl substituted with hydroxy or C₅ alkyl substituted with hydroxy or C₆ alkyl substituted with hydroxy. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with hydroxy or ethyl substituted with hydroxy or C₃ alkyl substituted with hydroxy or C₄ alkyl substituted with hydroxy or C₅ alkyl substituted with hydroxy or C₆ alkyl substituted with hydroxy. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂OH. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂OH. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂OH. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂OH. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂OH. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂OH. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂CH₂OH. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂CH₂OH. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂CH₂CH₂OH. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂CH₂CH₂OH. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂CH₂CH₂CH₂OH. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂CH₂CH₂CH₂OH.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with OR³⁰, wherein R³⁰ is unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰ and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with OR³⁰ or ethyl substituted with OR³⁰ or C₃ alkyl substituted with OR³⁰ or C₄ alkyl substituted with OR³⁰ or C₅ alkyl substituted with OR³⁰ or C₆ alkyl substituted with OR³⁰, wherein R³⁰ is unsubstituted alkyl, and the remaining members of R^a2, R^a1, R^a5 and R^a6 are and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with OR³⁰ or ethyl substituted with OR³⁰ or C₃ alkyl substituted with OR³⁰ or C₄ alkyl substituted with OR³⁰ or C₅ alkyl substituted with OR³⁰ or C₆ alkyl substituted with OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with OR³⁰, wherein R³⁰ is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with OR³⁰ or ethyl substituted with OR³⁰ or C₃ alkyl substituted with OR³⁰ or C₄ alkyl substituted with OR³⁰ or C₅ alkyl substituted with OR³⁰ or C₆ alkyl substituted with OR³⁰, wherein R³⁰ is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with OR³⁰ or ethyl substituted with OR³⁰ or C₃ alkyl substituted with OR³⁰ or C₄ alkyl substituted with OR³⁰ or C₅ alkyl substituted with OR³⁰ or C₆ alkyl substituted with OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with OR³⁰, wherein R³⁰ is unsubstituted alkyl. In an exemplary embodiment, R⁵ is H or halogen, R^a2 is alkyl substituted with OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with NH₂ and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with NH₂ or ethyl substituted with NH₂ or C₃ alkyl substituted with NH₂ or C₄ alkyl substituted with NH₂ or C₅ alkyl substituted with NH₂ or C₆ alkyl substituted with NH₂ and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with NH₂ or ethyl substituted with NH₂ or C₃ alkyl substituted with NH₂ or C₄ alkyl substituted with NH₂ or C₅ alkyl substituted with NH₂ or C₆ alkyl substituted with NH₂ and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with NH₂, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with NH₂ or ethyl substituted with NH₂ or C₃ alkyl substituted with NH₂ or C₄ alkyl substituted with NH₂ or C₅ alkyl substituted with NH₂ or C₆ alkyl substituted with NH₂, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with NH₂ or ethyl substituted with NH₂ or C₃ alkyl substituted with NH₂ or C₄ alkyl substituted with NH₂ or C₅ alkyl substituted with NH₂ or C₆ alkyl substituted with NH₂, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with NH₂. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with NH₂ or ethyl substituted with NH₂ or C₃ alkyl substituted with NH₂ or C₄ alkyl substituted with NH₂ or C₅ alkyl substituted with NH₂ or C₆ alkyl substituted with NH₂. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with NH₂ or ethyl substituted with NH₂ or C₃ alkyl substituted with NH₂ or C₄ alkyl substituted with NH₂ or C₅ alkyl substituted with NH₂ or C₆ alkyl substituted with NH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂NH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂NH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂NH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂NH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂NH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂NH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂CH₂NH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂CH₂NH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂CH₂CH₂NH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂CH₂CH₂NH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂CH₂CH₂CH₂NH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂CH₂CH₂CH₂NH₂.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with R³¹, wherein R³¹ is halogen, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹, and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with R³¹ or ethyl substituted with R³¹ or C₃ alkyl substituted with R³¹ or C₄ alkyl substituted with R³¹ or C₅ alkyl substituted with R³¹ or C₆ alkyl substituted with R³¹, wherein R³¹ is halogen, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with R³¹ or ethyl substituted with R³¹ or C₃ alkyl substituted with R³¹ or C₄ alkyl substituted with R³¹ or C₅ alkyl substituted with R³¹ or C₆ alkyl substituted with R³¹, wherein R³¹ is F or Cl or Br, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with R³¹, wherein R³¹ is halogen, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with R³¹ or ethyl substituted with R³¹ or C₃ alkyl substituted with R³¹ or C₄ alkyl substituted with R³¹ or C₅ alkyl substituted with R³¹ or C₆ alkyl substituted with R³¹, wherein R³¹ is halogen, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with R³¹ or ethyl substituted with R³¹ or C₃ alkyl substituted with R³¹ or C₄ alkyl substituted with R³¹ or C₅ alkyl substituted with R³¹ or C₆ alkyl substituted with R³¹, wherein R³¹ is F or Cl or Br, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with two R³¹, wherein each R³¹ is independently selected from F or Cl or Br or I, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with three R³¹, wherein each R³¹ is independently selected from F or Cl or Br or I, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with one R³¹, wherein R³¹ is F or Cl or Br or I. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with two R³¹, wherein each R³¹ is independently selected from F or Cl or Br or I. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with three R³¹, wherein each R³¹ is independently selected from F or Cl or Br or I. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with R³¹, wherein R³¹ is F or Cl or Br. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂F. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂F. In an exemplary embodiment, R⁵ is H, R^a6 is CHF₂. In an exemplary embodiment, R⁵ is F, R^a6 is CHF₂. In an exemplary embodiment, R⁵ is H, R^a6 is CF₃. In an exemplary embodiment, R⁵ is F, R^a6 is CF₃. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is ethyl substituted with R³¹, wherein R³¹ is F or Cl or Br. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is ethyl substituted with two R³¹, wherein each R³¹ is independently selected from F or Cl or Br. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is ethyl substituted with three R³¹, wherein each R³¹ is independently selected from F or Cl or Br. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂F. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂F. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CHF₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CHF₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CF₃. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CF₃. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is C₃ alkyl substituted with R³¹, wherein R³¹ is F or Cl or Br. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is C₃ alkyl substituted with two R³¹, wherein each R³¹ is independently selected from F or Cl or Br. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is C₃ alkyl substituted with three R³¹, wherein each R³¹ is independently selected from F or Cl or Br. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂F. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂F. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CHF₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CHF₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CF₃. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CF₃.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a5 is alkyl substituted with one R³¹, wherein R³¹ is F or Cl or Br or I. In an exemplary embodiment, R⁵ is H or halogen, R^a5 is alkyl substituted with two R³¹, wherein each R³¹ is independently selected from F or Cl or Br or I. In an exemplary embodiment, R⁵ is H or halogen, R^a5 is alkyl substituted with three R³¹, wherein each R³¹ is independently selected from F or Cl or Br or I. In an exemplary embodiment, R⁵ is H or halogen, R^a5 is alkyl substituted with R³¹, wherein R³¹ is F or Cl or Br. In an exemplary embodiment, R⁵ is H, R^a5 is CH₂F. In an exemplary embodiment, R⁵ is F, R^a5 is CH₂F. In an exemplary embodiment, R⁵ is H, R^a5 is CHF₂. In an exemplary embodiment, R⁵ is F, R^a5 is CHF₂. In an exemplary embodiment, R⁵ is H, R^a5 is CF₃. In an exemplary embodiment, R⁵ is F, R^a5 is CF₃. In an exemplary embodiment, R⁵ is H or halogen, R^a5 is ethyl substituted with R³¹, wherein R³¹ is F or Cl or Br. In an exemplary embodiment, R⁵ is H or halogen, R^a5 is ethyl substituted with two R³¹, wherein each R³¹ is independently selected from F or Cl or Br. In an exemplary embodiment, R⁵ is H or halogen, R^a5 is ethyl substituted with three R³¹, wherein each R³¹ is independently selected from F or Cl or Br. In an exemplary embodiment, R⁵ is H, R^a5 is CH₂CH₂F. In an exemplary embodiment, R⁵ is F, R^a5 is CH₂CH₂F. In an exemplary embodiment, R⁵ is H, R^a5 is CH₂CHF₂. In an exemplary embodiment, R⁵ is F, R^a5 is CH₂CHF₂. In an exemplary embodiment, R⁵ is H, R^a5 is CH₂CF₃. In an exemplary embodiment, R⁵ is F, R^a5 is CH₂CF₃. In an exemplary embodiment, R⁵ is H or halogen, R^a5 is C₃ alkyl substituted with R³¹, wherein R³¹ is F or Cl or Br. In an exemplary embodiment, R⁵ is H or halogen, R^a5 is C₃ alkyl substituted with two R³¹, wherein each R³¹ is independently selected from F or Cl or Br. In an exemplary embodiment, R⁵ is H or halogen, R^a5 is C₃ alkyl substituted with three R³¹, wherein each R³¹ is independently selected from F or Cl or Br. In an exemplary embodiment, R⁵ is H, R^a5 is CH₂CH₂CH₂F. In an exemplary embodiment, R⁵ is F, R^a5 is CH₂CH₂CH₂F. In an exemplary embodiment, R⁵ is H, R^a5 is CH₂CH₂CHF₂. In an exemplary embodiment, R⁵ is F, R^a5 is CH₂CH₂CHF₂. In an exemplary embodiment, R⁵ is H, R^a5 is CH₂CH₂CF₃. In an exemplary embodiment, R⁵ is F, R^a5 is CH₂CH₂CF₃.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with —C(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —C(O)OR³⁰ or ethyl substituted with —C(O)OR³⁰ or C₃ alkyl substituted with —C(O)OR³⁰ or C₄ alkyl substituted with —C(O)OR³⁰ or C₅ alkyl substituted with —C(O)OR³⁰ or C₆ alkyl substituted with —C(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —C(O)OR³⁰ or ethyl substituted with —C(O)OR³⁰ or C₃ alkyl substituted with —C(O)OR³⁰ or C₄ alkyl substituted with —C(O)OR³⁰ or C₅ alkyl substituted with —C(O)OR³⁰ or C₆ alkyl substituted with —C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with —C(O)OR³⁰ or ethyl substituted with —C(O)OR³⁰ or C₃ alkyl substituted with —C(O)OR³⁰ or C₄ alkyl substituted with —C(O)OR³⁰ or C₅ alkyl substituted with —C(O)OR³⁰ or C₆ alkyl substituted with —C(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with —C(O)OR³⁰ or ethyl substituted with —C(O)OR³⁰ or C₃ alkyl substituted with —C(O)OR³⁰ or C₄ alkyl substituted with —C(O)OR³⁰ or C₅ alkyl substituted with —C(O)OR³⁰ or C₆ alkyl substituted with —C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)OCH(CH₃)₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)OCH(CH₃)₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)OCH(CH₃)₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)OCH(CH₃)₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)OCH(CH₃)₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)OCH(CH₃)₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)OC(CH₃)₃. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)OC(CH₃)₃. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)OC(CH₃)₃. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)OC(CH₃)₃. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)OC(CH₃)₃. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)OC(CH₃)₃.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)OH. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)OH. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)OH. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)OH. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)OH. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)OH. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)OH.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with —C(O)NHR³⁵, wherein R³⁵ is unsubstituted alkyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —C(O)NHR³⁵ or ethyl substituted with —C(O)NHR³⁵ or C₃ alkyl substituted with —C(O)NHR³⁵ or C₄ alkyl substituted with —C(O)NHR³⁵ or C₅ alkyl substituted with —C(O)NHR³⁵ or C₆ alkyl substituted with —C(O)NHR³⁵, wherein R³⁵ is unsubstituted alkyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —C(O)NHR³⁵ or ethyl substituted with —C(O)NHR³⁵ or C₃ alkyl substituted with —C(O)NHR³⁵ or C₄ alkyl substituted with —C(O)NHR³⁵, wherein R³⁵ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NHR³⁵, wherein R³⁵ is unsubstituted alkyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with —C(O)NHR³⁵ or ethyl substituted with —C(O)NHR³⁵ or C₃ alkyl substituted with —C(O)NHR³⁵ or C₄ alkyl substituted with —C(O)NHR³⁵ or C₅ alkyl substituted with —C(O)NHR³⁵ or C₆ alkyl substituted with —C(O)NHR³⁵, wherein R³⁵ is unsubstituted alkyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with —C(O)NHR³⁵ or ethyl substituted with —C(O)NHR³⁵ or C₃ alkyl substituted with —C(O)NHR³⁵ or C₄ alkyl substituted with —C(O)NHR³⁵ or C₅ alkyl substituted with —C(O)NHR³⁵ or C₆ alkyl substituted with —C(O)NHR³⁵, wherein R³⁵ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NHR³⁵, wherein R³⁵ is unsubstituted alkyl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NHR³⁵, wherein R³⁵ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)NHR³⁵, wherein R³⁵ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)NHR³⁵, wherein R³⁵ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)NHR³⁵, wherein R³⁵ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)NHR³⁵, wherein R³⁵ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)NHR³⁵, wherein R³⁵ is unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NHR³⁰, wherein R³⁰ is alkyl substituted with alkenyl or alkynyl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NHR³⁰, wherein R³⁰ is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)NHR³⁰, wherein R³⁰ is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)NHR³⁰, wherein R³⁰ is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NHR³⁰, wherein R³⁰ is benzyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)NHR³⁰, wherein R³⁰ is benzyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)NHR³⁰, wherein R³⁰ is benzyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)NH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)NH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)NH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)NH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)NH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)NH₂.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NHNH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)NHNH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)NHNH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)NHNH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)NHNH₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)NHNH₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)NHNH₂.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NHOR³⁰ wherein R³⁰ is unsubstituted alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)NHOR³⁰ wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)NHOR³⁰ wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)NHOR³⁰ wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)NHOR³⁰ wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂C(O)NHOR³⁰ wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂C(O)NHOR³⁰ wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —C(O)NR³³R³⁴, wherein R³³ and R³⁴, along with the nitrogen to which they are attached, form a 4 or 5 or 6 or 7 or 8 membered ring. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰ and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂C(O)NR³³R³⁴, wherein R³³ and R³⁴, along with the nitrogen to which they are attached, form a 4 or 5 or 6 or 7 or 8 membered ring. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂C(O)NR³³R³⁴, wherein R³³ and R³⁴, along with the nitrogen to which they are attached, form a 4 or 5 or 6 or 7 or 8 membered ring. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂C(O)NR³³R³⁴, wherein R³³ and R³⁴, along with the nitrogen to which they are attached, form a 4 or 5 or 6 or 7 or 8 membered ring. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂C(O)NR³³R³⁴, wherein R³³ and R³⁴, along with the nitrogen to which they are attached, form a 4 or 5 or 6 or 7 or 8 membered ring.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with —S(O)₂R³⁰, wherein R³⁰ is unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —S(O)₂R³⁰ or ethyl substituted with —S(O)₂R³⁰ or C₃ alkyl substituted with —S(O)₂R³⁰ or C₄ alkyl substituted with —S(O)₂R³⁰ or C₅alkyl substituted with —S(O)₂R³⁰ or C₆ alkyl substituted with —S(O)₂R³⁰, wherein R³⁰ is unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —S(O)₂R³⁰ or ethyl substituted with —S(O)₂R³⁰ or C₃ alkyl substituted with —S(O)₂R³⁰ or C₄ alkyl substituted with —S(O)₂R³⁰ or C₅ alkyl substituted with —S(O)₂R³⁰ or C₆ alkyl substituted with —S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —S(O)₂R³⁰, wherein R³⁰ is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with —S(O)₂R³⁰ or ethyl substituted with —S(O)₂R³⁰ or C₃ alkyl substituted with —S(O)₂R³⁰ or C₄ alkyl substituted with —S(O)₂R³⁰ or C₅ alkyl substituted with —S(O)₂R³⁰ or C₆ alkyl substituted with —S(O)₂R³⁰, wherein R³⁰ is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with —S(O)₂R³⁰ or ethyl substituted with —S(O)₂R³⁰ or C₃ alkyl substituted with —S(O)₂R³⁰ or C₄ alkyl substituted with —S(O)₂R³⁰ or C₅ alkyl substituted with —S(O)₂R³⁰ or C₆ alkyl substituted with —S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —S(O)₂R³⁰, wherein R³⁰ is unsubstituted alkyl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with —S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂S(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with —S(O)R³⁰, wherein R³⁰ is unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —S(O)R³⁰ or ethyl substituted with —S(O)R³⁰ or C₃ alkyl substituted with —S(O)R³⁰ or C₄ alkyl substituted with —S(O)R³⁰ or C₅ alkyl substituted with —S(O)R³⁰ or C₆ alkyl substituted with —S(O)R³⁰, wherein R³⁰ is unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —S(O)R³⁰ or ethyl substituted with —S(O)R³⁰ or C₃ alkyl substituted with —S(O)R³⁰ or C₄ alkyl substituted with —S(O)R³⁰ or C₅ alkyl substituted with —S(O)R³⁰ or C₆ alkyl substituted with —S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —S(O)R³⁰, wherein R³⁰ is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰ and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with —S(O)R³⁰ or ethyl substituted with —S(O)R³⁰ or C₃ alkyl substituted with —S(O)R³⁰ or C₄ alkyl substituted with —S(O)R³⁰ or C₅ alkyl substituted with —S(O)R³⁰ or C₆ alkyl substituted with —S(O)R³⁰, wherein R³⁰ is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with —S(O)R³⁰ or ethyl substituted with —S(O)R³⁰ or C₃ alkyl substituted with —S(O)R³⁰ or C₄ alkyl substituted with —S(O)R³⁰ or C₅ alkyl substituted with —S(O)R³⁰ or C₆ alkyl substituted with —S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —S(O)R³⁰, wherein R³⁰ is unsubstituted alkyl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with —S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂S(O)R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with —NHS(O)₂R³⁰, wherein R³⁰ is unsubstituted alkyl or unsubstituted C₃-C₈ cycloalkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —NHS(O)₂R³⁰ or ethyl substituted with —NHS(O)₂R³⁰ or C₃ alkyl substituted with —NHS(O)₂R³⁰ or C₄ alkyl substituted with —NHS(O)₂R³⁰ or C₅ alkyl substituted with —NHS(O)₂R³⁰ or C₆ alkyl substituted with —NHS(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl or unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —NHS(O)₂R³⁰ or ethyl substituted with —NHS(O)₂R³⁰ or C₃ alkyl substituted with —NHS(O)₂R³⁰ or C₄ alkyl substituted with —NHS(O)₂R³⁰ or C₅ alkyl substituted with —NHS(O)₂R³⁰ or C₆ alkyl substituted with —NHS(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl or unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl, and the remaining members of R^a2, R^a3, R^a5, and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —NHS(O)₂R³⁰, wherein R³⁰ is unsubstituted alkyl or unsubstituted C₃-C₈ cycloalkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with —NHS(O)₂R³⁰ or ethyl substituted with —NHS(O)₂R³⁰ or C₃ alkyl substituted with —NHS(O)₂R³⁰ or C₄ alkyl substituted with —NHS(O)₂R³⁰ or C₅ alkyl substituted with —NHS(O)₂R³⁰ or C₆ alkyl substituted with —NHS(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl or unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with —NHS(O)₂R³⁰ or ethyl substituted with —NHS(O)₂R³⁰ or C₃ alkyl substituted with —NHS(O)₂R³⁰ or C₄ alkyl substituted with —NHS(O)₂R³⁰ or C₅ alkyl substituted with —NHS(O)₂R³⁰ or C₆ alkyl substituted with —NHS(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl or unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —NHS(O)₂R³⁰, wherein R³⁰ is unsubstituted alkyl or unsubstituted C₃-C₈ cycloalkyl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with —NHS(O)₂R³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl or unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂NHS(O)₂R³⁰, wherein R³⁰ is unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂NHS(O)₂R³⁰, wherein R³⁰ is unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂NHS(O)₂R³⁰, wherein R³⁰ is unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂NHS(O)₂R³⁰, wherein R³⁰ is unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂NHS(O)₂R³⁰, wherein R³⁰ is unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂NHS(O)₂R³⁰, wherein R³⁰ is unsubstituted cyclopropyl or unsubstituted cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl or unsubstituted cycloheptyl or unsubstituted cyclooctyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with —NHC(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —NHC(O)OR³⁰ or ethyl substituted with —NHC(O)OR³⁰ or C₃ alkyl substituted with —NHC(O)OR³⁰ or C₄ alkyl substituted with —NHC(O)OR³⁰ or C₅ alkyl substituted with —NHC(O)OR³⁰ or C₆ alkyl substituted with —NHC(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with —NHC(O)OR³⁰ or ethyl substituted with —NHC(O)OR³⁰ or C₃ alkyl substituted with —NHC(O)OR³⁰ or C₄ alkyl substituted with —NHC(O)OR³⁰ or C₅ alkyl substituted with —NHC(O)OR³⁰ or C₆ alkyl substituted with —NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —NHC(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰ and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with —NHC(O)OR³⁰ or ethyl substituted with —NHC(O)OR³⁰ or C₃ alkyl substituted with —NHC(O)OR³⁰ or C₄ alkyl substituted with —NHC(O)OR³⁰ or C₅ alkyl substituted with —NHC(O)OR³⁰ or C₆ alkyl substituted with —NHC(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with —NHC(O)OR³⁰ or ethyl substituted with —NHC(O)OR³⁰ or C₃ alkyl substituted with —NHC(O)OR³⁰ or C₄ alkyl substituted with —NHC(O)OR³⁰ or C₅ alkyl substituted with —NHC(O)OR³⁰ or C₆ alkyl substituted with —NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —NHC(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is alkyl substituted with —NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂NHC(O)OCH(CH₃)₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂NHC(O)OCH(CH₃)₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂NHC(O)OCH₂CH(CH₃)₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂NHC(O)OCH₂CH(CH₃)₂. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂NHC(O)OCH(CH₂CH₃)₂. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂NHC(O)OCH(CH₂CH₃)₂.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with —NHC(O)OR³⁰, wherein R³⁰ is benzyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂NHC(O)OR³⁰, wherein R³⁰ is benzyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂NHC(O)OR³⁰, wherein R³⁰ is benzyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is benzyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is benzyl. In an exemplary embodiment, R⁵ is H, R^a6 is CH₂CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is benzyl. In an exemplary embodiment, R⁵ is F, R^a6 is CH₂CH₂CH₂NHC(O)OR³⁰, wherein R³⁰ is benzyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is alkyl substituted with R³², wherein R³² is unsubstituted oxazolyl or oxazolyl substituted with unsubstituted alkyl or unsubstituted oxadiazolyl or oxadiazolyl substituted with unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with R³² or ethyl substituted with R³² or C₃ alkyl substituted with R³² or C₄ alkyl substituted with R³² or C₅ alkyl substituted with R³² or C₆ alkyl substituted with R³², wherein R³² is unsubstituted oxazolyl or oxazolyl substituted with unsubstituted alkyl or unsubstituted oxadiazolyl or oxadiazolyl or substituted with unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is methyl substituted with R³² or ethyl substituted with R³² or C₃ alkyl substituted with R³² or C₄ alkyl substituted with R³² or C₅ alkyl substituted with R³² or C₆ alkyl substituted with R³², wherein R³² is unsubstituted oxazolyl or oxazolyl substituted with unsubstituted alkyl or unsubstituted oxadiazolyl or oxadiazolyl or substituted with unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with R³², wherein R³² is unsubstituted oxazolyl or oxazolyl substituted with unsubstituted alkyl or unsubstituted oxadiazolyl or oxadiazolyl or substituted with unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is methyl substituted with R³² or ethyl substituted with R³² or C₃ alkyl substituted with R³² or C₄ alkyl substituted with R³² or C₅ alkyl substituted with R³² or C₆ alkyl substituted with R³², wherein R³² is unsubstituted oxazolyl or oxazolyl substituted with unsubstituted alkyl or unsubstituted oxadiazolyl or oxadiazolyl or substituted with unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted with R³² or ethyl substituted with R³² or C₃ alkyl substituted with R³² or C₄ alkyl substituted with R³² or C₅ alkyl substituted with R³² or C₆ alkyl substituted with R³², wherein R³² is unsubstituted oxazolyl or oxazolyl substituted with unsubstituted alkyl or unsubstituted oxadiazolyl or oxadiazolyl or substituted with unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with R³², wherein R³² is unsubstituted oxazolyl or oxazolyl substituted with unsubstituted alkyl or unsubstituted oxadiazolyl or oxadiazolyl or substituted with unsubstituted alkyl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with unsubstituted oxazolyl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with unsubstituted oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-methyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-methyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-ethyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-ethyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₃ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₃ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₄ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₄ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₅ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₅ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₆ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₆ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with unsubstituted oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-methyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-methyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-ethyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-ethyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₃ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₃ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₄ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₄ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₅ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₅ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₆ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₆ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with unsubstituted oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-methyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-methyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-ethyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-ethyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₃ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₃ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₄ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₄ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₅ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₅ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₆ alkyl oxazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₆ alkyl oxazol-2-yl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is alkyl substituted with R³², wherein R³² is unsubstituted oxadiazolyl or oxadiazolyl or substituted with unsubstituted alkyl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with unsubstituted oxadiazolyl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with unsubstituted oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with unsubstituted 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with unsubstituted 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-methyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-methyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-methyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-methyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-methyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-methyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-ethyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-ethyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-ethyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-ethyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-ethyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-ethyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₃ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₃ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₃ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₃ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₃ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₃ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₄ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₄ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₄ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₄ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₄ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₄ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₅ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₅ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₅ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₅ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₅ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₅ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₆ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₆ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₆ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₆ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 4-unsubstituted C₆ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is methyl substituted with 5-unsubstituted C₆ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with unsubstituted oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with unsubstituted 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with unsubstituted 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-methyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-methyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-methyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-methyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-methyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-methyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-ethyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-ethyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-ethyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-ethyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-ethyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-ethyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-ethyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₃ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₃ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₃ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₃ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₃ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₃ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₄ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₄ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₄ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₄ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₄ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₄ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₅ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₅ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₅ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₅ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₅ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₅ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₆ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₆ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₆ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₆ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 4-unsubstituted C₆ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is ethyl substituted with 5-unsubstituted C₆ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with unsubstituted oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with unsubstituted 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with unsubstituted 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-methyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-methyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-methyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-methyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-methyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-methyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-ethyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-ethyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-ethyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-ethyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-ethyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-ethyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₃ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₃ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₃ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₃ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₃ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₃ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₄ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₄ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₄ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₄ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₄ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₄ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₅ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₅ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₅ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₅ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₅ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₅ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₆ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₆ alkyl oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₆ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₆ alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 4-unsubstituted C₆ alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R⁵ is H or F, R^a6 is C₃ alkyl substituted with 5-unsubstituted C₆ alkyl 1,3,4 oxadiazol-2-yl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is unsubstituted furan or unsubstituted oxadiazolyl or unsubstituted triazolyl or alkyl substituted oxadiazolyl or alkyl substituted triazolyl or pyridine or pyrimidine, and the remaining members of R^a2, R^a3, R^a5, and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is H, R^a6 is unsubstituted furan. In an exemplary embodiment, R⁵ is F, R^a6 is unsubstituted furan.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is unsubstituted furan or unsubstituted oxadiazolyl or unsubstituted triazolyl or alkyl substituted oxadiazolyl or alkyl substituted triazolyl or pyridine or pyrimidine, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰ and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is unsubstituted furan or unsubstituted oxadiazolyl or unsubstituted triazolyl or alkyl substituted oxadiazolyl or alkyl substituted triazolyl or pyridine or pyrimidine. In an exemplary embodiment, R⁵ is H, R^a6 is unsubstituted furan. In an exemplary embodiment, R⁵ is H, R^a6 is unsubstituted furan-2-yl. In an exemplary embodiment, R⁵ is F, R^a6 is unsubstituted furan. In an exemplary embodiment, R⁵ is F, R^a6 is unsubstituted furan-2-yl. In an exemplary embodiment, R⁵ is H, R^a6 is unsubstituted 1,2,4 oxadiazolyl. In an exemplary embodiment, R⁵ is H, R^a6 is unsubstituted 1,3,4 oxadiazolyl. In an exemplary embodiment, R⁵ is F, R^a6 is unsubstituted 1,2,4 oxadiazolyl. In an exemplary embodiment, R⁵ is F, R^a6 is unsubstituted 1,3,4 oxadiazolyl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted 1,2,4 oxadiazolyl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted 1,3,4 oxadiazolyl. In an exemplary embodiment, R⁵ is F, R^a6 is methyl substituted 1,2,4 oxadiazolyl. In an exemplary embodiment, R⁵ is F, R^a6 is methyl substituted 1,3,4 oxadiazolyl. In an exemplary embodiment, R⁵ is H, R^a6 is unsubstituted triazolyl. In an exemplary embodiment, R⁵ is F, R^a6 is unsubstituted triazolyl. In an exemplary embodiment, R⁵ is F, R^a6 is methyl triazolyl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted triazolyl. In an exemplary embodiment, R⁵ is H, R^a6 is methyl substituted triazolyl. In an exemplary embodiment, R⁵ is F, R^a6 is methyl substituted triazolyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, one of R^a2, R^a3, R^a5 and R^a6 is —NHC(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, one of R^a2, R^a3, R^a5 and R^a6 is —NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, one of R^a2, R^a3, R^a5 and R^a6 is —NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is —NHC(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a6, R⁵, R¹⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is halogen, R^a6 is —NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, R^a6 is —NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl, R¹⁰, R¹¹ and R¹⁵ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is —NHC(O)OR³⁰, wherein R³⁰ is unsubstituted alkyl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is —NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is —NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is —NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is —NHC(O)OR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is —NHC(O)OCH(CH₃)₂. In an exemplary embodiment, R⁵ is F, R^a6 is —NHC(O)OCH(CH₃)₂.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is —NHC(O)NHR³⁰, wherein R³⁰ is unsubstituted alkyl. In an exemplary embodiment, R⁵ is H or halogen, R^a6 is —NHC(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is H, R^a6 is —NHC(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is —NHC(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl. In an exemplary embodiment, R⁵ is F, R^a6 is —NHC(O)NHR³⁰, wherein R³⁰ is methyl or ethyl or unsubstituted C₃ alkyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a6 is —NHC(O)NH₂. In an exemplary embodiment, R⁵ is H, R^a6 is —NHC(O)NH₂. In an exemplary embodiment, R⁵ is F, R^a6 is —NHC(O)NH₂.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, two of R^a2, R^a3, R^a5 and R^a6 are each independently selected from the group consisting of methyl, ethyl, propyl and isopropyl, and the remaining members of R^a2, R^a3, R^a5, and R^a6 are H, R¹⁰, R¹¹ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁰, and R¹¹ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is F, two of R^a2, R^a3, R^a5 and R^a6 are methyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰ and R¹¹ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, two of R^a2, R^a3, R^a5 and R^a6 are methyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰ and R¹¹ are each a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, two of R^a2, R^a3, R^a5 and R^a6 are each independently selected from the group consisting of methyl, ethyl, propyl and isopropyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H. In an exemplary embodiment, R⁵ is F, two of R^a2, R^a3, R^a5 and R^a6 are methyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H. In an exemplary embodiment, R⁵ is H, two of R^a2, R^a3, R^a5 and R^a6 are methyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a2 and R^a6 are each independently selected from the group consisting of methyl, ethyl, propyl and isopropyl. In an exemplary embodiment, R⁵ is F, R^a2 and R^a6 are methyl. In an exemplary embodiment, R⁵ is H, R^a2 and R^a6 are methyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a3 and R^a6 are each independently selected from the group consisting of methyl, ethyl, propyl and isopropyl. In an exemplary embodiment, R⁵ is F, R^a1 and R^a6 are methyl. In an exemplary embodiment, R⁵ is H, R^a3 and R^a6 are methyl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, two of R^a2, R^a3, R^a5 and R^a6 are each independently selected from the group consisting of F, Cl, Br, methyl, ethyl, propyl and isopropyl, and the remaining members of R^a2, R^a3₅R^a5 and R^a6 are H, R¹⁵ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^a2, R^a3, R^a5, R^a6, R⁵, R¹⁵ are as described herein, and each hydrogen in said compound or a salt thereof can be replaced by deuterium. In an exemplary embodiment, R⁵ is F, two of R^a2, R^a3, R^a5 and R^a6 are methyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁵ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, two of R^a2, R^a3, R^a5 and R^a6 are methyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁵ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is F, two of R^a2, R^a3, R^a5 and R^a6 are chloro, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁵ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R⁵ is H, two of R^a2, R^a3, R^a5 and R^a6 are chloro, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁵ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, two of R^a2, R^a3, R^a5 and R^a6 are each independently selected from the group consisting of F, Cl, Br, methyl, ethyl, propyl and isopropyl, and the remaining members of R^a2, R^a3₅R^a5 and R^a6 are H. In an exemplary embodiment, R⁵ is F, two of R^a2, R^a3, R^a5 and R^a6 are methyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H. In an exemplary embodiment, R⁵ is H, two of R^a2, R^a3, R^a5 and R^a6 are methyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a2 and R^a6 are each independently selected from the group consisting of F, Cl, Br, methyl, ethyl, propyl and isopropyl. In an exemplary embodiment, R⁵ is F, R^a2 and R^a6 are methyl. In an exemplary embodiment, R⁵ is H, R^a2 and R^a6 are F.

In an exemplary embodiment, the compound, or a salt thereof, has a structure which is

wherein R⁵ is H or halogen, R^a3 and R^a5 are each independently selected from the group consisting of F or Cl. In an exemplary embodiment, R⁵ is F, R^a3 and R^a6 are F or Cl. In an exemplary embodiment, R⁵ is H, R^a3 and R^a6 are F or Cl.

In various embodiments of the invention, R¹⁰ and/or R¹¹ can be a prodrug moiety. Prodrugs of amines are known in the art. See Krise et al., “Prodrugs of Amines” in Prodrugs; Springer: 2007; Vol. V, Part III, 801-831. Examples of prodrugs for amines include, but are not limited to, N-acyl derivatives, carbamates, N-acyloxyalkyl derivatives, quaternary ammonium derivatives, N-oxides, N-Mannich bases, Schiff bases, enaminones, azo derivatives, oxazolidines, and 4-imidazolidinones. One of skill in the art will be able to select a suitable prodrug moiety.

In an exemplary embodiment, the prodrug moiety is an acyl derivative. In an exemplary embodiment, at least one of R¹⁰ and R¹¹ is

wherein R^p1 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^p1 is unsubstituted alkyl. In an exemplary embodiment, R^p1 is unsubstituted alkyl. In an exemplary embodiment, R^p1 is unsubstituted arylalkyl. In an exemplary embodiment, R^p1 is methyl. In another exemplary embodiment R^p1 is CF₃.

In an exemplary embodiment, the prodrug moiety is an ester. In an exemplary embodiment, at least one of R¹⁰ and R¹¹ is

wherein R^p2 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. In an exemplary embodiment, R^p2 is unsubstituted alkyl. In an exemplary embodiment, R^p2 is methyl. In another exemplary embodiment R^p2 is ethyl. In another exemplary embodiment R^p2 is n-propyl. In another exemplary embodiment R^p2 is isopropyl. In another exemplary embodiment R^p2 is iso-butyl. In another exemplary embodiment R^p2 is benzyl.

In an exemplary embodiment, the prodrug moiety is an ester. In an exemplary embodiment, at least one of R¹⁰ and R¹¹ is

wherein R^p3 and R^p4 are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the invention provides poly- or multi-valent species of the compounds of the invention, including a dimer or a trimer. Another exemplary embodiment of the invention provides an anhydride of the compounds of the invention. In another exemplary embodiment, the invention provides poly- or multi-valent species of the compounds of the invention. In an exemplary embodiment, the invention provides a dimer of the compounds described herein. In an exemplary embodiment, the invention provides a dimer of the compounds described herein.

In an exemplary embodiment, the invention provides a trimer of the compounds described herein. In an exemplary embodiment, the invention provides a trimer of the compounds described herein.

The compounds of the invention can form a hydrate with water, solvates with alcohols such as methanol, ethanol, propanol, and the like; adducts with amino compounds, such as ammonia, methylamine, ethylamine, and the like; adducts with acids, such as formic acid, acetic acid and the like; complexes with ethanolamine, quinoline, amino acids, and the like.

In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. In an exemplary embodiment, the salt is a pharmaceutically acceptable salt. In an exemplary embodiment, the invention provides a compound described herein, or a hydrate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a prodrug thereof. In an exemplary embodiment, the invention provides a salt of a compound described herein. In an exemplary embodiment, the invention provides a pharmaceutically acceptable salt of a compound described herein. In an exemplary embodiment, the invention provides a hydrate of a compound described herein. In an exemplary embodiment, the invention provides a solvate of a compound described herein. In an exemplary embodiment, the invention provides a prodrug of a compound described herein. In an exemplary embodiment, the invention provides a compound as described in FIG. 1, or a salt thereof. In an exemplary embodiment, the invention provides a compound as described in FIG. 1, or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment, alkyl is linear alkyl. In another exemplary embodiment, alkyl is branched alkyl.

In an exemplary embodiment, heteroalkyl is linear heteroalkyl. In another exemplary embodiment, heteroalkyl is branched heteroalkyl.

III. b) Combinations Comprising Additional Therapeutic Agents

The compounds of the invention may also be used in combination with additional therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of the invention together with at least one additional therapeutic agent, or a salt, prodrug, hydrate or solvate thereof. In an exemplary embodiment, the compound of the invention is a compound described herein, or a salt thereof. In an exemplary embodiment, the additional therapeutic agent is a compound of the invention. In an exemplary embodiment, the additional therapeutic agent includes a boron atom. In an exemplary embodiment, the additional therapeutic agent does not contain a boron atom. In an exemplary embodiment, the additional therapeutic agent is a compound described in section III a).

When a compound of the invention is used in combination with a second therapeutic agent active against the same disease state, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.

The individual components of such combinations may be administered either simultaneously or sequentially in a unit dosage form. The unit dosage form may be a single or multiple unit dosage forms. In an exemplary embodiment, the invention provides a combination in a single unit dosage form. An example of a single unit dosage form is a capsule wherein both the compound of the invention and the additional therapeutic agent are contained within the same capsule. In an exemplary embodiment, the invention provides a combination in a two unit dosage form. An example of a two unit dosage form is a first capsule which contains the compound of the invention and a second capsule which contains the additional therapeutic agent. Thus the term ‘single unit’ or ‘two unit’ or ‘multiple unit’ refers to the object which the animal (for example, a human) ingests, not to the interior components of the object. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

The combinations referred to herein may conveniently be presented for use in the form of a pharmaceutical formulation. Thus, an exemplary embodiment of the invention is a pharmaceutical formulation comprising a) a compound of the invention; b) an additional therapeutic agent and c) a pharmaceutically acceptable excipient. In an exemplary embodiment, the pharmaceutical formulation is a unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a single unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a single unit dosage form which includes a compound of the invention; an antibiotic and a pharmaceutically acceptable excipient. In an exemplary embodiment, the pharmaceutical formulation is a single unit dosage form which includes a compound of the invention; an antibiotic and at least one pharmaceutically acceptable excipient. In an exemplary embodiment, the pharmaceutical formulation is a two unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a two unit dosage form comprising a first unit dosage form and a second unit dosage form, wherein the first unit dosage form includes a) a compound of the invention and b) a first pharmaceutically acceptable excipient; and the second unit dosage form includes c) an additional therapeutic agent and d) a second pharmaceutically acceptable excipient. In an exemplary embodiment, the pharmaceutical formulation is a two unit dosage form comprising a first unit dosage form and a second unit dosage form, wherein the first unit dosage form includes a) a compound of the invention and b) a first pharmaceutically acceptable excipient; and the second unit dosage form includes c) an antibiotic and d) a second pharmaceutically acceptable excipient.

III. c) Preparation of Boron-Containing Compounds

Compounds of use in the invention can be prepared using commercially available starting materials, known intermediates, or by using the synthetic methods published in references described and incorporated by reference herein, such as U.S. patent application Ser. Nos. 12/142,692 and U.S. Pat. Pubs. US20060234981, US20070155699 and US20070293457.

The following general procedures were used as indicated in generating the examples and can be applied, using the knowledge of one of skill in the art, to other appropriate compounds to obtain additional analogues.

General Procedure 1: Sulfonylation of Amino 3H-benzo[c][1,2]oxaborol-1-ols

The sulfonyl chloride (1-1.2 equiv) and a base (either NMM, K₂CO₃, or pyridine 3-4 equiv) were added sequentially to a solution of the amine in MeCN (20 mL/g) at rt or cooled in an ice bath. After completion (typical duration O/N) the volatiles were removed in vacuo. H₂O was added to the residue and the mixture adjusted to ˜pH 6 with dilute HCl. The aqueous layer was then extracted with organic solvent (typically EtOAc), and the combined organic fractions dried (either Na₂SO₄ or MgSO₄), filtered, and concentrated in vacuo. The product was typically purified by either recrystallization from H₂O, trituration with CH₂Cl₂ or EtOAc, or flash chromatography.

General Procedure 2: Demethylation of substituted N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfonamide

Boron tribromide (3-5 equiv. 1M solution) was added slowly to an ice-cold solution of the methoxybenzenesulfonamide in DCM at 0° C. The reaction was allowed to stir at rt and monitored by TLC. The mixture was purified as: ice was added slowly and worked up with DCM, the organic layer was washed with brine, dried over Na₂SO₄ and dried in vacuo. Further purification was carried out by flash chromatography or preparative HPLC when required.

General Procedure 3: Deprotection of Substituted N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

The acetamide and 1:1 6N HCl: AcOH (5 equiv) were heated to 40° C. for 2 days. Purification involved removal of solvent, work up with EtOAc and 1N HCl, washed with brine, dry on Na₂SO₄ and removal of solvent. The product was recrystallized in EtOAc or purified by flash chromatography or preparative TLC when required.

General Procedure 4: Deprotection of Cbz Protected Amines/Reduction of Aromatic Nitro

A mixture of starting material, Pd/C (10% wet, 0.2 equiv) in methanol was placed under a hydrogen atmosphere at 50 psi. The reaction was monitored by LC/MS. The catalyst was filtered off through a pad of Celite® and the solvent was evaporated to give the amine. The product was purified by flash chromatography or preparative HPLC when required.

General Procedure 5: Formation of Substituted Sulfamoylcarbamate

A mixture of starting material, the chloroformate (5 equiv.) in THF was stirred at r.t. or heated to 60° C. if required. The reaction was monitored by LC/MS. The mixture was dried in vacuo. The crude product was carried on to next step or purified by flash chromatography or preparative HPLC when required.

General Procedure 6: Deprotection of 2,2,2-Trifluoroacetyl Protected Amines

The acetamide and NH₃ (7M in MeOH, 5 equiv) was heated to 80° C. for 2 hrs. The reaction was monitored by LC/MS. Purification: remove solvent. The product was recrystallized in EtOAc/MeOH or purified by flash chromatography or preparative HPLC when required.

General Procedure 15: Methylation of Substituted N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

MeI (1.5 equiv) was added dropwise to solution of the benzenesulfonamide and K₂CO₃ (3 equiv) in DMF. The reaction was allowed to stir at r.t. and monitored by TLC. The mixture was then worked up with EtOAc, H₂O, brine, dried over Na₂SO₄ and dried in vacuo. Further purification was carried out by flash chromatography when required.

General Procedure 16: Demethylation of Substituted N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfonamide

Boron tribromide (3-5 equiv. 1M solution) was added slowly to an ice-cold solution of the methoxybenzenesulfonamide in DCM at 0° C. The reaction was allowed to stir at rt and monitored by TLC. Purification: ice was added slowly and worked up with DCM, the organic layer was washed brine, dried over Na2SO4 and dried in vacuo.; Further purification was carried out by flash chromatography or preparative HPLC when required.

General Procedure 17: Deprotection of Substituted N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

General Procedure 17: the acetamide and 1:1 6N HCl: AcOH (5 equiv) was heated to 40° C. for 2 days. Purification: remove solvent, work up with EtOAc and 1N HCl, washed with brine, dry on Na₂SO₄, remove solvent. The product was recrystallized in EtOAc or purified by flash chromatography or preparative HPLC when required.

General Procedure 20: Deprotection of Substituted 2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

General Procedure 20: the acetamide and NH₃ (7M in MeOH, 5 equiv) was heated to 80° C. for 2 hrs. The reaction was monitored by LC/MS. Purification: remove solvent, The product was recrystallized in EtOAc/MeOH or purified by flash chromatography or preparative HPLC when required.

IV. Assays

Art-recognized techniques of genetics and molecular biology are of use to identify compounds that bind to and/or inhibit an enzyme, such as a tRNA synthetase. Moreover, these techniques are of use to distinguish whether a compound binds to and/or inhibits a particular domain of the enzyme. For example, for LeuRS, these techniques can distinguish whether a compound binds to and/or inhibits the synthetic domain, the editing domain, or both the editing and synthetic domains. LeuRS can be obtained from Genscript (Piscataway, N.J.) and also obtained from Prof. Susan Martinez (University of Illinois, Champaign, Ill.).

IV. a) LeuRS

In an exemplary assay, activity of a representative compound against the editing domain was confirmed. To identify the target of a novel boron-containing antibacterial compound, mutants in E. coli showing resistance to the compound were isolated. Characterization of mutants showed that they have an 32-256 fold increase in resistance to the compound over wildtype. The mutants were furthermore shown to be sensitive to various antibacterial agents with known modes of action, suggesting that the cellular target of the compound is distinct from the target of the other antibacterial agents. The leuS gene from the mutants was cloned onto a plasmid and their resistance was confirmed by MIC. The editing domain from these mutants were sequenced and the mutations were all located in the editing domain of this enzyme.

Assays to determine whether, and how effectively, a particular compound binds to and/or inhibits the editing domain of a selected tRNA synthetase are also set forth herein, and additional assays are readily available to those of skill in the art. Briefly, in an exemplary assay, an improperly charged tRNA and a tRNA synthetase that is capable of editing the improperly charged tRNA are combined. The resulting mixture is contacted with the putative inhibitor and the degree of editing inhibition is observed.

Another assay uses genetics to show that a drug works via the editing domain. In this assay, the compound is first tested against a strain of cells over-expressing copies of the tRNA synthetase gene. The compound's effect on the over-expressing strain is compared with a control strain to determine whether the compound is active against the synthetase. If the minimum inhibitory concentration (MIC) is 2-fold higher in the strain with extra copies of the synthetase gene than the MIC of the inhibitor against a wild type cell, a further genetic screen is conducted to determine whether the increased resistance is due to mutations in the editing domain. In this second screen, the control strain is challenged against a high concentration of the inhibitor. The colonies surviving the challenge are isolated and DNA from these cells is isolated. The editing domain is amplified using a proof-reading PCR enzyme and the appropriate primers. The PCR product can be purified using standard procedures. The sequence amplified mutant DNA is compared to wild-type. If the mutant DNA bears mutations in the editing domain, such results would suggest that the compound binds to the editing domain and affects the editing function of the molecule through this domain.

Generally, the compounds to be tested are present in the assays in ranges from about 1 pM to about 100 mM, preferably from about 1 pM to about 1 μM. Other compounds range from about 1 nM to about 100 nM, preferably from about 1 nM to about 1 μM.

The effects of the test compounds upon the function of the enzymes can also be measured by any suitable physiological change. When the functional consequences are determined using intact cells or animals, one can also measure a variety of effects such as transmitter release, hormone release, transcriptional changes to both known and uncharacterized genetic markers, changes in cell metabolism such as cell growth or pH changes, and changes in intracellular second messengers such as Ca²⁺, or cyclic nucleotides.

Utilizing the assays set forth herein and others readily available in the art, those of skill in the art will be able to readily and routinely determine other compounds and classes of compounds that operate to bind to and/or inhibit the editing domain of tRNA synthetases.

In another aspect, the invention provides a method for identifying a compound which binds to an editing domain of a tRNA synthetase comprising: a) contacting said editing domain with a test compound under conditions suitable for binding; and b) detecting binding of said test compound to said editing domain. In an exemplary embodiment, detecting binding of said compound comprises use of at least one detectable element, isotope, or chemical label attached to said compound. In an exemplary embodiment, the element, isotope or chemical label is detected by a fluorescent, luminescent, radioactive, or absorbance readout. In an exemplary embodiment, the contacting of said test compound with said editing domain also includes further contacting said test compound and said editing domain with a member selected from AMP and a molecule with a terminal adenosine. In an exemplary embodiment, the tRNA synthetase is derived from leucyl tRNA synthetase. In an exemplary embodiment, the tRNA synthetase is derived from a mutated tRNA synthetase, wherein said mutated tRNA synthetase comprises amino acid mutations in an editing domain. In another exemplary embodiment, wherein said editing domain of a tRNA synthetase comprises the amino acid sequence of a peptide sequence described herein.

In another aspect, the invention provides a method for identifying a compound which binds to an editing domain of a tRNA synthetase, said assay comprising: a) contacting said editing domain of a tRNA synthetase with said compound under conditions suitable for binding of said compound with said editing domain of a tRNA synthetase; b) comparing a biological activity of said editing domain of a tRNA synthetase contacting said compound to said biological activity when not contacting said compound; and c) identifying said compound as binding to said editing domain of a tRNA synthetase if said biological activity of said editing domain of a tRNA synthetase is reduced when contacting said compound. In an exemplary embodiment, the biological activity is hydrolysis of noncognate amino acid. In another exemplary embodiment, the hydrolysis of said noncognate amino acid is detected through the use of one or more labels. In another exemplary embodiment, the labels include a radiolabel, a fluorescent marker, an antibody, or a combination thereof. In another exemplary embodiment, said labels can be detected using spectroscopy. In another exemplary embodiment, said editing domain of a tRNA synthetase is derived from leucyl tRNA synthetase.

In another aspect, the invention provides a method of generating a tRNA molecule with a noncognate amino acid comprising: a) creating or isolating a mutated tRNA synthetase with altered amino acid editing domains; and b) contacting a tRNA molecule with said mutated tRNA synthetase and a noncognate amino acid. In another exemplary embodiment, the mutated tRNA synthetase contains one or more amino acid mutations in an editing domain. In another exemplary embodiment, the mutated tRNA synthetase is unable to bind with a compound of the invention. In another exemplary embodiment, the mutated tRNA synthetase is unable to bind with a compound described herein, or a pharmaceutically acceptable salt thereof. In another exemplary embodiment, the mutated tRNA synthetase is unable to bind with a compound according to a formula described herein, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a composition that comprises one or more tRNA molecules attached to noncognate amino acids, wherein said tRNA molecules are synthesized using one or more mutated tRNA synthetases isolated from a microorganism or a cell line derived from a microorganism. In an exemplary embodiment, the microorganism is a bacteria. In an exemplary embodiment, wherein said mutated tRNA synthetases contain amino acid mutations in their editing domains.

V. Amino Acid and Nucleotide Sequences Used in Assays

Amino acid and nucleotide sequences of use in the invention are published in references described and incorporated by reference herein, such as U.S. patent application Ser. Nos. 12/142,692 and U.S. Pat. Pubs. US20060234981, US20070155699 and US20070293457.

VI. Methods

In another aspect, the compounds of the invention can be utilized to inhibit an enzyme. In another aspect, the compounds of the invention and/or combinations of the invention exhibit potency against microorganisms, such as bacteria, and therefore have the potential to kill and/or inhibit the growth of microorganisms. In another aspect, the compounds of the invention and/or combinations of the invention exhibit potency against microorganisms, such as bacteria, and therefore have the potential to achieve therapeutic efficacy in the animals described herein.

VI. LeuRS—

In an exemplary embodiment, the compounds of the invention exhibit the ability of inhibiting the editing domain of tRNA synthetases, such as leucyl tRNA synthetase, of microorganisms, such as bacteria, and therefore have the potential to be used as editing domain inhibitors of microorganism tRNA synthetases.

According to another aspect of the invention, a method for binding to and/or inhibiting the editing domain of a tRNA synthetase is provided which comprises contacting a tRNA synthetase with a compound of the invention that inhibits the editing domain under conditions in which the tRNA synthetase interacts with its substrate to form an aminoacyl adenylate intermediate and, preferably, to form a charged tRNA. Such conditions are known to those skilled in the art. In an exemplary embodiment, the compound has a structure according to a formula described herein. In an exemplary embodiment, the compound is described herein, or a salt, hydrate or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. The tRNA synthetase is contacted with an amount of compound of the invention sufficient to result in a detectable amount of tRNA synthetase inhibition. This method can be performed on a tRNA synthetase that is contained within an organism or which is outside an organism. In an exemplary embodiment, the method is performed on a tRNA synthetase that is contained within a microorganism or a microbial cell that is in, or on the surface of, an animal. In an exemplary embodiment, the animal is a human. The method results in a decrease in the amount of charged tRNA produced by the tRNA synthetase that has an inhibited editing domain. In an exemplary embodiment, the inhibition takes place in a cell, such as a microorganism cell. In another exemplary embodiment, the microorganism cell is a bacteria. In another exemplary embodiment, the tRNA synthetase is leucyl tRNA synthetase.

In an exemplary embodiment, the invention provides a method of inhibiting conversion of a tRNA molecule into a charged tRNA molecule. The method involves contacting a tRNA synthetase with a compound of the invention effective to inhibit activity of an editing domain of said tRNA synthetase, under conditions sufficient to inhibit said activity, thereby inhibiting said conversion. In an exemplary embodiment, the compound of the invention is a compound described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the inhibition occurs within a cell, and the cell is a microorganism cell. In another exemplary embodiment, the microorganism cell is a bacteria. In another exemplary embodiment, the microorganism cell is a bacteria which is described herein. In another exemplary embodiment, the enzyme is a leucyl tRNA synthetase of a bacteria described herein. In another exemplary embodiment, the tRNA synthetase is leucyl tRNA synthetase. In another exemplary embodiment, the compound has a K_{D, synthesis} of greater than 100 μM against a synthetic domain of said tRNA synthetase.

In certain embodiments, the mechanism of action of a compound of the invention is to inhibit the conversion of a tRNA molecule into a charged tRNA molecule by binding to and/or inhibiting at least the editing domain of the synthetase. The compounds of use in this method may also inhibit or otherwise interact with the synthetic domain (e.g., the active site of the synthetic domain). In a presently preferred embodiment, the editing domain is inhibited selectively in the presence of the synthetic domain. In a preferred embodiment, the synthetic domain is essentially uninhibited, while the editing domain is inhibited at least 50%, preferably at least 60%, more preferably at least 70%, still more preferably, at least 80% and even still more preferably at least 90% of the activity of the tRNA synthetase. In another preferred embodiment, the synthetic domain is inhibited by at most 50%, preferably at most 30%, preferably at most 20%, 10%, preferably at most 8%, more preferably at most 5%, still more preferably, at most 3% and even still more preferably at most 1%. Inhibition of the editing domain produces a decrease in the amount of the properly charged tRNA which results in retardation or cessation of cell growth and division.

In another exemplary embodiment, the ratio of a minimum concentration of said compound inhibiting said editing domain to a minimum concentration of said compound inhibiting said synthetic domain of said tRNA synthetase, represented as K_{D, edit}/K_{D, synthesis}, is less than one. In another exemplary embodiment, the K_{D, edit}/K_{D, synthesis} of the compound is a member selected from less than 0.5, less than 0.1 and less than 0.05.

VI. a) Inhibiting Microorganism Growth or Killing Microorganisms

The compounds of the invention and/or combinations of the invention exhibit potency against microorganisms, such as bacteria, and therefore have the potential to treat, and/or prevent a microorganism infection, or kill and/or inhibit the growth of microorganisms.

In a further aspect, the invention provides a method of treating and/or preventing a microorganism infection, or a method of killing and/or inhibiting the growth of a microorganism, said method comprising: contacting said microorganism with an effective amount of a compound of the invention, thereby killing and/or inhibiting the growth of the microorganism. In a further aspect, the invention provides a method of treating and/or preventing a microorganism infection, or a method of killing and/or inhibiting the growth of a microorganism, said method comprising: contacting said microorganism with an effective amount of a combination of the invention, thereby killing and/or inhibiting the growth of the microorganism.

In a further aspect, the invention provides a method of treating a bacterial infection comprising adminstering to an animal suffering from the infection an effective amount of a compound of the invention or a combination of the invention, or a pharmaceutically acceptable salt thereof, thereby treating the bacterial infection. In an exemplary embodiment, the invention provides a method of treating a bacterial infection comprising adminstering to an animal suffering from the infection an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an effective amount of an antibiotic, or a pharmaceutically acceptable salt thereof, thereby treating the bacterial infection.

In a further aspect, the invention provides a method of preventing a bacterial infection comprising adminstering to an animal a prophylactic amount of a compound of the invention or a combination of the invention, or a pharmaceutically acceptable salt thereof, thereby treating the bacterial infection. In an exemplary embodiment, the invention provides a method of preventing a bacterial infection comprising adminstering to an animal a prophylactic amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment, the microorganism is a bacteria. In an exemplary embodiment, the compound or combination is described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides a compound or combination described herein, or a salt, hydrate or solvate thereof. In an exemplary embodiment, the invention provides a compound or combination described herein, or a prodrug thereof. In an exemplary embodiment, the invention provides a compound or combination described herein, or a salt thereof. In another exemplary embodiment, the compound or combination of the invention is a compound or combination described herein, or a pharmaceutically acceptable salt thereof. In another exemplary embodiment, the compound or compound of the combination is described by a formula listed herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is part of a combination described herein. In an exemplary embodiment, the compound is part of a pharmaceutical formulation described herein. In another exemplary embodiment, the contacting occurs under conditions which permit entry of the compound into the organism. Such conditions are known to one skilled in the art and are described herein.

In another aspect, the microorganism is inside, or on the surface of an animal. In an exemplary embodiment, the animal is selected from the group consisting of human, cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey. In another exemplary embodiment, the animal is a human.

In an exemplary embodiment, the microorganism infection is treated and or prevented, or the microorganism is killed or its growth is inhibited, through oral administration of the compound of the invention and/or the combination of the invention. In an exemplary embodiment, the microorganism infection is treated and or prevented, or the microorganism is killed or its growth is inhibited through intravenous administration of the compound of the invention and/or the combination of the invention.

In an exemplary embodiment, the microorganism is a bacterium. In an exemplary embodiment, an infection is caused by and/or associated with a microorganism, particularly a bacterium. In an exemplary embodiment, the bacterium is a gram-positive bacteria. In another exemplary embodiment, the gram-positive bacterium is selected from the group consisting of Staphylococcus species, Streptococcus species, Bacillus species, Mycobacterium species, Corynebacterium species (Propionibacterium species), Clostridium species, Actinomyces species, Enterococcus species and Streptomyces species. In another exemplary embodiment, the gram-positive bacterium is selected from the group consisting of Propionibacterium acnes, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus haemolyticus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Bacillus anthracis, Mycobacterium avium-intracellulare, Mycobacterium tuberculosis, Acinetobacter baumanii, Corynebacterium diphtheria, Clostridium perfringens, Clostridium botulinum, Clostridium tetani, and Clostridium difficile. In another exemplary embodiment, the gram-positive bacterium is selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Clostridium difficile and Propionibacter acnes. In another exemplary embodiment, the bacterium is a gram-negative bacterium. In another exemplary embodiment, the gram-negative bacterium is selected from the group consisting of Acinetobacter species, Neisseria species, Pseudomonas species, Brucella species, Agrobacterium species, Bordetella species, Escherichia species, Shigelia species, Yersinia species, Salmonella species, Klebsiella species, Enterobacter species, Haemophilus species, Pasteurella species, Streptobacillus species, spirochetal species, Campylobacter species, Vibrio species, Helicobacter species, Bacteroides species, Citrobacter species, Proteus species, Providencia species, Serratia species, Stenotrophomonas species and Burkholderia species. In another exemplary embodiment, the gram-negative bacterium is selected from the group consisting of Acinetobacter species, Pseudomonas species, Escherichia species, Klebsiella species, Enterobacter species, Bacteroides species, Citrobacter species, Proteus species, Providencia species, Serratia species, Stenotrophomonas species and Burkholderia species. In another exemplary embodiment, the gram-negative bacterium is selected from the group consisting of Neisseria gonorrhoeae, Neisseria meningitidis, Pseudomonas aeruginosa, Legionella pneumophila, Escherichia coli, Yersinia pestis, Haemophilus influenzae, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Vibrio cholerae, Vibrio parahemolyticus, Trepomena pallidum, Actinomyces israelii, Rickettsia prowazekii, Rickettsia rickettsii, Chlamydia trachomatis, Chlamydia psittaci, Brucella abortus, Agrobacterium tumefaciens, Francisella tularensis, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii, Bacteroides fragilis, Citrobacter freundii, Proteus mirabilis, Providencia stuartii, Serratia marcescens, Stenotrophomonas maltophilia and Burkholderia cepacia. In another exemplary embodiment, the gram-negative bacterium is selected from the group consisting of Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii, Bacteroides fragilis, Citrobacter freundii, Proteus mirabilis, Providencia stuartii, Serratia marcescens, Stenotrophomonas maltophilia and Burkholderia cepacia. In another exemplary embodiment, the gram-negative bacterium is selected from the group consisting of Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens and Citrobacter freundii. In another exemplary embodiment, the gram-negative bacterium is a Providencia spp. In another exemplary embodiment, the gram-negative bacterium is an Enterobacter spp.

In another exemplary embodiment, the bacterium is a Pseudomonas species. In another exemplary embodiment, the bacterium is Pseudomonas aeruginosa. In another exemplary embodiment, the bacterium is selected from the group consisting of Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia and Burkholderia cepacia. In another exemplary embodiment, the bacterium is Acinetobacter baumannii. In another exemplary embodiment, the bacterium is Stenotrophomonas maltophilia. In another exemplary embodiment, the bacterium is Burkholderia cepacia. In another exemplary embodiment, the bacterium is Acinetobacter species. In another exemplary embodiment, the bacterium is Acinetobacter anitratus. In another exemplary embodiment, the bacterium is selected from the group consisting of Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii, E. coli, K. pneumoniae , P. mirabilis, Serratia marcescens, Citrobacter freundii and Providencia spp. In another exemplary embodiment, the bacterium is selected from the group consisting of Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii, E. coli, K. pneumoniae, P. mirabilis, Serratia marcescens, Citrobacter freundii, Providencia spp., S. aureus, S. pneumonia, S. pyogenes, E. faecalis, and E. faecium. In another exemplary embodiment, the bacterium is selected from the group consisting of Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, Burkholderia cepacia. In another exemplary embodiment, the bacterium is selected from the group consisting of S. aureus, S. pneumonia, S. pyogenes, E. faecalis, and E. faecium. In another exemplary embodiment, the bacterium is selected from the group consisting of Viridans group Strep. In another exemplary embodiment, the bacterium is selected from the group consisting of Strep. mitis, Strep. mutans, Strep. oxalis, Strep. sanguis, Strep. sobrinus and Strep. millari. In another exemplary embodiment, the bacterium is S. pneumonia. In another exemplary embodiment, the bacterium is H. influenzae. In another exemplary embodiment, the bacterium is S. aureus. In another exemplary embodiment, the bacterium is M. catarrhalis. In another exemplary embodiment, the bacterium is M. pneumoniae. In another exemplary embodiment, the bacterium is L. pneumoniae. In another exemplary embodiment, the bacterium is C. pneumoniae. In another exemplary embodiment, the bacterium is S. pyogenes. In another exemplary embodiment, the bacterium is an anaerobe. In another exemplary embodiment, the bacterium is an Alcaligenes species. In another exemplary embodiment, the bacterium is a B. cepacia. In another exemplary embodiment, the bacterium is selected from the group consisting of Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Serratia marcescens, and Citrobacter freundii. In another exemplary embodiment, the bacterium is resistant to methicillin. In another exemplary embodiment, the bacterium is methicillin-resistant staphylococcus aureus. In another exemplary embodiment, the bacterium is selected from the group consisting of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Mycobacterium catarrhalis, Mycobacterium pneumoniae, Legionella pneumophila and Chlamydia pneumoniae. In another exemplary embodiment, the bacterium is selected from the group consisting of Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Citrobacter freundii, Providencia stuartii, Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, Burkholderia cepacia, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, and Enterococcus faecium. In another exemplary embodiment, the bacterium is selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus pneumoniae.

In an exemplary embodiment, the microorganism is a bacterium, which is selected from the group consisting of acid-fast bacteria, including Mycobacterium species; bacilli, including Bacillus species, Corynebacterium species (also Propionibacterium) and Clostridium species; filamentous bacteria, including Actinomyces species and Streptomyces species; bacilli, such as Pseudomonas species, Brucella species, Agrobacterium species, Bordetella species, Escherichia species, Shigella species, Yersinia species, Salmonella species, Klebsiella species, Enterobacter species, Haemophilus species, Pasteurella species, and Streptobacillus species; spirochetal species, Campylobacter species, Vibrio species; and intracellular bacteria including Rickettsiae species and Chlamydia species.

VI. b) Microorganism Infection

The compounds of the invention and/or combinations of the invention exhibit potency against microorganisms, such as bacteria, and therefore have the potential to be used to treat and/or prevent a micororganism infection, such as a bacterial infection.

In a further aspect, the invention provides a method of treating a bacterial infection comprising adminstering to an animal suffering from the infection an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, thereby treating the bacterial infection. In an exemplary embodiment, the invention provides a method of treating a bacterial infection comprising adminstering to an animal suffering from the infection an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an effective amount of an antibiotic, or a pharmaceutically acceptable salt thereof, thereby treating the bacterial infection.

In a further aspect, the invention provides a method of preventing a bacterial infection comprising adminstering to an animal a prophylactic amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, thereby treating the bacterial infection. In an exemplary embodiment, the invention provides a method of preventing a bacterial infection comprising adminstering to an animal a prophylactic amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an effective amount of an antibiotic, or a pharmaceutically acceptable salt thereof, thereby treating the bacterial infection.

VI. c) Diseases

The compounds of the invention and/or combinations of the invention exhibit potency against microorganisms, such as bacteria, and therefore have the potential to achieve therapeutic efficacy in the animals described herein.

In another aspect, the invention provides a method of treating and/or preventing a disease. In an exemplary embodiment, the method includes administering to the animal a therapeutically effective amount of a compound of the invention, sufficient to treat and/or prevent the disease. In an exemplary embodiment, the method includes administering to the animal a therapeutically effective amount of a combination of the invention, sufficient to treat and/or prevent the disease. In an exemplary embodiment, the compound of the invention or the combination of the invention can be used in human or veterinary medical therapy, particularly in the treatment or prophylaxis of bacterial-associated disease. In an exemplary embodiment, the compound is described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides a compound described herein, or a prodrug thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. In another exemplary embodiment, the compound of the invention is a compound described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is a compound described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is according to a formula described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is part of a combination described herein. In an exemplary embodiment, the compound is part of a pharmaceutical formulation described herein. In another exemplary embodiment, the animal is selected from the group consisting of human, cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey. In another exemplary embodiment, the animal is a human. In another exemplary embodiment, the animal is selected from the group consisting of a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey. In another exemplary embodiment, the disease is a systemic disease. In another exemplary embodiment, the disease is a topical disease.

In an exemplary embodiment, the disease is treated through oral administration of a compound of the invention and/or a combination of the invention. In an exemplary embodiment, the disease is treated through intravenous administration of a compound of the invention and/or a combination of the invention.

Systemic Diseases

In another aspect, the invention provides a method of treating a systemic disease. The method involves contacting an animal with a compound of the invention and/or a combination of the invention.

In an exemplary embodiment, the disease is selected from the group consisting of candidiasis, aspergillosis, coccidioidomycosis, cryptococcosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, zygomycosis, phaeohyphomycosis and rhinosporidiosis.

In another exemplary embodiment, the disease is associated with infection by a Gram-positive bacteria. In an exemplary embodiment, the disease is associated with a Staphylococcus species. In another exemplary embodiment, the disease is selected from the group consisting of pneumonia, gastroenteritis, toxic shock syndrome, community acquired pneumonia (CAP), meningitis, septic arthritis, urinary tract infection, bacteremia, endocarditis, osteomylitis, skin and skin-structure infection. In an exemplary embodiment, the disease is associated with a Streptococcus species. In another exemplary embodiment, the disease is selected from the group consisting of strep throat, skin infections, necrotizing fasciitis, toxic shock syndrome, pneumonia, otitis media and sinusitis. In an exemplary embodiment, the disease is associated with an Actinomyces species. In another exemplary embodiment, the disease is actinomycosis. In an exemplary embodiment, the disease is associated with a Norcardia species. In another exemplary embodiment, the disease is pneumonia. In an exemplary embodiment, the disease is associated with a Corynebacterium species. In another exemplary embodiment, the disease is diptheria. In an exemplary embodiment, the disease is associated with a Listeria species. In another exemplary embodiment, the disease is meningitis. In an exemplary embodiment, the disease is associated with a Bacillus species. In another exemplary embodiment, the disease is anthrax or food poisoning. In an exemplary embodiment, the disease is associated with a Clostridium species. In another exemplary embodiment, the disease is selected from the group consisting of botulism, tetanus, gas gangrene and diarrhea. In an exemplary embodiment, the disease is associated with a Mycobacterium species. In another exemplary embodiment, the disease is tuberculosis or leprosy.

In another exemplary embodiment, the disease is associated with infection by a Gram-negative bacteria. In an exemplary embodiment, the disease is associated with a Neisseria species. In another exemplary embodiment, the disease is selected from the group consisting of meningitis, gonorrhea, otitis extema and folliculitis. In an exemplary embodiment, the disease is associated with an Escherichia species. In another exemplary embodiment, the disease is selected from the group consisting of diarrhea, urinary tract infections, meningitis, sepsis and HAP. In an exemplary embodiment, the disease is associated with a Shigella species. In another exemplary embodiment, the disease is selected from the group consisting of diarrhea, bacteremia, endocarditis, meningitis and gastroenteritis. In an exemplary embodiment, the disease is associated with a Salmonella species. In another exemplary embodiment, the disease is selected from the group consisting of typhoid fever, supsis, gastroenteritis, endocarditis, sinusitis and meningitis. In an exemplary embodiment, the disease is associated with a Yersinia species. In another exemplary embodiment, the disease is selected from the group consisting of typhoid fever, bubonic plague, enteric fever and gastroenteritis. In an exemplary embodiment, the disease is associated with a Klebsiella species. In another exemplary embodiment, the disease is sepsis or urinary tract infection. In an exemplary embodiment, the disease is associated with a Proteus species. In another exemplary embodiment, the disease is an urinary tract infection. In an exemplary embodiment, the disease is associated with an Enterobacter species. In another exemplary embodiment, the disease is a hospital-acquired infection. In an exemplary embodiment, the disease is associated with a Serratia species. In another exemplary embodiment, the disease is selected from the group consisting of a urinary tract infection, skin and skin-structure infection and pneumonia. In an exemplary embodiment, the disease is associated with a Vibrio species. In another exemplary embodiment, the disease is cholera or gastroenteritis. In an exemplary embodiment, the disease is associated with a Campylobacter species. In another exemplary embodiment, the disease is gastroenteritis. In an exemplary embodiment, the disease is associated with a Helicobacter species. In another exemplary embodiment, the disease is chronic gastritis. In an exemplary embodiment, the disease is associated with a Pseudomonas species. In another exemplary embodiment, the disease is selected from the group consisting of pneumonia, osteomylitis, burn-wound infections, sepsis, UTIs, endocarditis, otitis and corneal infections. In an exemplary embodiment, the disease is associated with a Bacteroides species. In another exemplary embodiment, the disease is periodontal disease or aspriation pneumonia. In an exemplary embodiment, the disease is associated with a Haemophilus species. In another exemplary embodiment, the disease is selected from the group consisting of meningitis, epiglottitis, septic arthritis, sepsis, chancroid and vaginitis. In an exemplary embodiment, the disease is associated with a Bordetella species. In another exemplary embodiment, the disease is Whooping cough. In an exemplary embodiment, the disease is associated with a Legionella species. In another exemplary embodiment, the disease is pneumonia or pontiac fever. In an exemplary embodiment, the disease is associated with a Francisella species. In another exemplary embodiment, the disease is tularemia. In an exemplary embodiment, the disease is associated with a Brucella species. In another exemplary embodiment, the disease is brucellosis. In an exemplary embodiment, the disease is associated with a Pasteurella species. In another exemplary embodiment, the disease is a skin infection. In an exemplary embodiment, the disease is associated with a Gardnerella species. In another exemplary embodiment, the disease is vaginitis. In an exemplary embodiment, the disease is associated with a Spirochetes species. In another exemplary embodiment, the disease is syphilis or Lyme disease. In an exemplary embodiment, the disease is associated with a Chlamydia species. In another exemplary embodiment, the disease is chlamydia. In an exemplary embodiment, the disease is associated with a Rickettsiae species. In another exemplary embodiment, the disease is Rocky Mountain spotted fever or typhus.

In an exemplary embodiment, the disease is associated with Mycoplasma pneumoniae. In another exemplary embodiment, the disease is tracheobronchitis or walking pneumonia. In an exemplary embodiment, the disease is associated with Ureaplasma urealyticum. In another exemplary embodiment, the disease is urethritis. In another exemplary embodiment, the disease is pyelonephritis. In another exemplary embodiment, the disease is an intra-abdominal infection. In another exemplary embodiment, the disease is febrile neutropenia. In another exemplary embodiment, the disease is a pelvic infection. In another exemplary embodiment, the disease is bacteraemia. In another exemplary embodiment, the disease is septicaemia.

In another exemplary embodiment, the disease is community acquired pneumonia (CAP). In another exemplary embodiment, the disease is sinusitis. In another exemplary embodiment, the disease is a urinary tract infection. In another exemplary embodiment, the disease is a skin and skin-structure infection. In another exemplary embodiment, the disease is pyelonephritis. In another exemplary embodiment, the disease is intra-abdominal infection. In another exemplary embodiment, the disease is an acute pelvic infection. In another exemplary embodiment, the disease is tonsillitis.

In another exemplary embodiment, the disease is chronic obstructive pulmonary disease. In an exemplary embodiment, the disease is an acute exacerbaton of chronic obstructive pulmonary disease. In an exemplary embodiment, the disease is chronic obstructive pulmonary disease. In an exemplary embodiment, the disease is pharyngitis. In an exemplary embodiment, the disease is tonsillitis. In an exemplary embodiment, the disease is Acute Exacerbation of Chronic Bronchitis (AECB). In an exemplary embodiment, the disease is cervicitis. In an exemplary embodiment, the disease is genital ulcer disease.

In an exemplary embodiment, for any of the methods described herein, the animal is selected from the group consisting of human, cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey. In another exemplary embodiment, for any of the methods described herein, the animal is selected from the group consisting of a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey. In another exemplary embodiment, for any of the methods described herein, the animal is a human.

In an exemplary embodiment, for any of the methods described herein, a compound of the invention, a combination of the invention, a compound described herein or a pharmaceutically acceptable salt thereof, or combination described herein, and/or a pharmaceutical formulation described herein can be used.

VII. Pharmaceutical Formulation

In another aspect, the invention provides a pharmaceutical formulation comprising: a) a compound of the invention; and b) a pharmaceutically acceptable excipient. In another aspect, the invention provides a pharmaceutical formulation comprising: a) a combination of the invention; and b) a pharmaceutically acceptable excipient. In an exemplary embodiment, the compound is according to a formula described herein. In an exemplary embodiment, the compound is according to an example described herein. In an exemplary embodiment, the compound of the invention in the pharmaceutical formulation is a compound described herein. In an exemplary embodiment, the compound of the invention in the pharmaceutical formulation is a pharmaceutically acceptable salt of a compound described herein.

In an exemplary embodiment, the compound of the invention is present in the pharmaceutical formulation in an amount of between about 0.0001% to about 60% (w/w). In an exemplary embodiment, the amount is between about 0.01% to about 10% (w/w). In an exemplary embodiment, the amount is between about 0.1% to about 10% (w/w). In an exemplary embodiment, the amount is between about 0.25% to about 6% (w/w). In an exemplary embodiment, the amount is between about 0.5% to about 5% (w/w). In an exemplary embodiment, the amount is between about 0.1% and about 1.0% (w/w). In an exemplary embodiment, the amount is between about 1.0% and about 2.0% (w/w). In an exemplary embodiment, the amount is between about 2.0% and about 3.0% (w/w). In an exemplary embodiment, the amount is between about 3.0% and about 4.0% (w/w). In an exemplary embodiment, the amount is between about 4.0% and about 5.0% (w/w).

The pharmaceutical formulations of the invention can take a variety of forms adapted to the chosen route of administration. Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutical formulations incorporating the compounds described herein. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable solvents that may be used to prepare solvates of the compounds of the invention, such as water, ethanol, propylene glycol, mineral oil, vegetable oil and dimethylsulfoxide (DMSO).

The pharmaceutical formulation of the invention may be administered orally, topically, intraperitoneally, parenterally, by inhalation or spray or rectally in unit dosage forms containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. It is further understood that the best method of administration may be a combination of methods. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In an exemplary embodiment, the pharmaceutical formulation is administered orally. In an exemplary embodiment, the pharmaceutical formulation is administered intravenously. In an exemplary embodiment, the pharmaceutical formulation is administered topically. In an exemplary embodiment, the pharmaceutical formulation is administered in a topically effective dose. In an exemplary embodiment, the pharmaceutical formulation is administered in a cosmetically effective dose. In an exemplary embodiment, the pharmaceutical formulation is administered in an orally effective dose.

The pharmaceutical formulations containing compounds of the invention are preferably in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical formulations, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents, which may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

Pharmaceutical formulations of the invention may also be in the form of oil-in-water emulsions and water-in-oil emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth; naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol; anhydrides, for example sorbitan monooleate; and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical formulations may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The composition of the invention may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Alternatively, the compositions can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

For administration to non-human animals, the composition containing the therapeutic compound may be added to the animal's feed or drinking water. Also, it will be convenient to formulate animal feed and drinking water products so that the animal takes in an appropriate quantity of the compound in its diet. It will further be convenient to present the compound in a composition as a premix for addition to the feed or drinking water. The composition can also added as a food or drink supplement for humans.

Dosage levels of the order of from about 5 mg to about 250 mg per kilogram of body weight per day and more preferably from about 25 mg to about 150 mg per kilogram of body weight per day, are useful in the treatment of the above-indicated conditions. The amount of active ingredient that may be combined with the carrier materials to produce a unit dosage form will vary depending upon the condition being treated and the particular mode of administration. Unit dosage forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

In an exemplary embodiment, the unit dosage form contains from about 1 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 1 mg to about 500 mg of an active ingredient. In an exemplary embodiment, the unit dosage form contains from about 100 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 200 mg to about 500 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 500 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 1 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 10 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 50 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 25 mg to about 75 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 40 mg to about 60 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 75 mg to about 200 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 1 mg to about 5 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 10 mg to about 25 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 50 mg to about 350 mg of a compound of the invention. In an exemplary embodiment, the unit dosage form contains from about 200 mg to about 400 mg of a compound of the invention.

In an exemplary embodiment, the daily dosage contains from about 1 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 1 mg to about 500 mg of an active ingredient. In an exemplary embodiment, the daily dosage contains from about 100 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 200 mg to about 500 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 500 mg to about 800 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 1 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 10 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 50 mg to about 100 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 75 mg to about 200 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 1 mg to about 5 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 10 mg to about 25 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 50 mg to about 350 mg of a compound of the invention. In an exemplary embodiment, the daily dosage contains from about 200 mg to about 400 mg of a compound of the invention.

Preferred compounds of the invention will have desirable pharmacological properties that include, but are not limited to, oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lives. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred.

The amount of the composition required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician.

VII. a) Testing

Preferred compounds for use in the pharmaceutical formulations described herein will have certain pharmacological properties. Such properties include, but are not limited to, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lives. Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova et al. (1996, J. Chromat. B677: 1-27).

Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD₅₀ and ED₅₀. Compounds that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage can vary within this range depending upon the unit dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See, e.g. Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1, p. 1).

VII. b) Administration

In general, the compounds prepared by the methods, and from the intermediates, described herein will be administered in a therapeutically or cosmetically effective amount by any of the accepted modes of administration for agents that serve similar utilities. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination, the severity of the particular disease undergoing therapy and the judgment of the prescribing physician. The drug can be administered from once or twice a day, or up to 3 or 4 times a day.

Usual patient dosages for systemic administration range from 0.1 to 1000 mg/day, preferably, 1-500 mg/day, more preferably 10-200 mg/day, even more preferably 100-200 mg/day. Stated in terms of patient body surface areas, usual dosages range from 50-91 mg/m²/day.

The amount of the compound in a pharmaceutical formulation can vary within the full range employed by those skilled in the art. Typically, the pharmaceutical formulation will contain, on a weight percent (wt %) basis, from about 0.01-10 wt % of the drug based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 0.1-3.0 wt %, more preferably, about 1.0 wt %.

Exemplary embodiments are summarized herein below.

In an exemplary embodiment, the invention is a compound having a structure which is a member selected from the group consisting of:

wherein R⁵ is H or halogen; each R^a2, R^a3, R^a4, R^a5 and R^a6 is independently selected from the group consisting of H, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, —C(O)NR¹⁰R¹¹, nitro, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each R¹⁰ and each R¹¹ is independently selected from the group consisting of H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; with the proviso that R¹⁰ and R¹¹, together with the atoms to which they are attached, are optionally combined to form a 5- to 7-membered substituted or unsubstituted heterocycloalkyl ring; with the proviso that when R⁵ is H, at least two members selected from the group consisting of R^a2, R^a3, R^a4, R^a5 and R^a6 are not H; with the proviso that when the structure is according to formula (I), and R⁵ is H, at least one member selected from the group consisting of R^a2, R^a3, R^a4, R^a5 and R^a6 is not a member selected from the group consisting of H, halogen, unsubstituted alkyl and halosubstituted alkyl; with the proviso that R^a2 and R^a3, together with the atoms to which they are attached, are optionally joined to form a 4 to 8 membered ring; with the proviso that R^a3 and R^a4, together with the atoms to which they are attached, are optionally joined to form a 4 to 8 membered ring; with the proviso that R^a4 and R^a5, together with the atoms to which they are attached, are optionally joined to form a 4 to 8 membered ring; with the proviso that R^a5 and R^a6, together with the atoms to which they are attached, are optionally joined to form a 4 to 8 membered ring; or a salt, hydrate or solvate thereof.

In an exemplary embodiment, according to any of the above paragraphs,

wherein R⁵ is H or halogen; one of R^a2, R^a3, R^a5 and R^a6 is halogen or —NHC(O)OR³⁰ or alkyl substituted with —C(O)OR³⁰ or alkyl substituted with —S(O)₂R³⁰ or alkyl substituted with halogen or alkyl substituted with hydroxy or alkyl substituted with cyano or alkyl substituted with —NHC(O)OR³⁰ or alkyl substituted with unsubstituted oxazolyl or alkyl substituted with alkyl substituted oxazolyl or alkyl substituted with unsubstituted oxadiazolyl or alkyl substituted with alkyl substituted oxadiazolyl or alkyl substituted with —C(O)NHR³⁵, wherein R³⁰ is unsubstituted alkyl and R³⁵ is unsubstituted alkyl or unsubstituted cycloalkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰ and R¹¹ are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, according to any of the above paragraphs, wherein R⁵ is H or halogen; one of R^a2, R^a3, R^a5 and R^a6 is halogen or —NHC(O)OR³⁰ or alkyl substituted with —C(O)OR³⁰ or alkyl substituted with —S(O)₂R³⁰ or alkyl substituted with halogen or alkyl substituted with hydroxy or alkyl substituted with cyano or alkyl substituted with —NHC(O)OR³⁰ or alkyl substituted with —C(O)NHR³⁵, wherein R³⁰ is unsubstituted alkyl and R³⁵ is unsubstituted alkyl or unsubstituted cycloalkyl, and the remaining members of R^a2, R^a3, R^a5 and R^a6 are H, R¹⁰ and R¹¹ are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, according to the above paragraph, the compound has a structure which is selected from the group consisting of

In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure which is selected from the group consisting of

In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure which is selected from the group consisting of

In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure which is selected from the group consisting of

In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure which is selected from the group consisting of

In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure which is selected from the group consisting of

In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure which is selected from the group consisting of

In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure which is selected from the group consisting of

In an exemplary embodiment, according to any of the above paragraphs, wherein R^a2 or R^a6 is selected from the group consisting of OR¹⁰, —NR¹⁰R¹¹, cyano, halogen, substituted or unsubstituted alkyl and substituted or unsubstituted heteroaryl, wherein each R¹⁰ and each R¹¹ is independently selected from the group consisting of H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, according to any of the above paragraphs, wherein R^a2 or R^a6 is selected from the group consisting of F, Cl, Br, I, OCH₃, OH, CH₃, CH₂CH₃, NHC(O)NH₂, NHC(O)NHR¹⁶, —NR¹⁰R¹¹, cyano, halogen, substituted or unsubstituted alkyl and substituted or unsubstituted heteroaryl, wherein R¹⁶ is selected from the group consisting of unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, according to any of the above paragraphs, wherein R^a2 or R^a6 is selected from the group consisting of cyano, F, Cl, Br, I, OCH₃, OH, CF₃, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂Br, CH₂CH₂OH, CH₂OH, CH₂NH₂, NH₂, NHC(O)NH₂, NHC(O)NHCH₃, NHC(O)NHCH₂CH₃, NHC(O)OCH₃, NHC(O)OCH₂CH₃, NHC(O)OCH(CH₃)₂, NHC(O)OCH₂CH(CH₃)₂, NHC(O)CH₂OH, NHC(O)CH₂NH₂, NHC(O)CH₂N(CH₃)₂, NHC(O)CF₃, NHC(O)CH₃, NHC(O)OCH₂CFH₂, NHC(O)OR³⁰, NHC(O)CH₂OR³¹, NHC(O)OCH₂R³¹, NHC(O)O(CH₂)₂OCH₃, NHC(O)R³², CH₂C(O)OH, CH₂C(O)OCH₃, CH₂C(O)OCH₂CH₃, CH₂C(O)NH₂, CH₂C(O)NHCH₃, CH₂C(O)NHCH₂CH₃, CH₂C(O)NH(CH₂)₂CH₃, CH₂C(O)NH(CH₂)₃CH₃, NHCH₂R³³, wherein R³⁰ is cyclohexyl, R³¹ is phenyl, R³² is pyridinyl, and R³³ is heteroaryl.

In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure which is

In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure which is

wherein R^a6 is F or Cl or Br.

In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure which is

wherein R^a6 is F or Cl or Br.

In an exemplary embodiment, according to any of the above paragraphs, R⁵ is H.

In an exemplary embodiment, according to any of the above paragraphs, R⁵ is F.

In an exemplary embodiment, according to any of the above paragraphs, R^a6 is Cl.

In an exemplary embodiment, the invention is a combination comprising a) a compound according to any of the above paragraphs, or a pharmaceutically acceptable salt thereof; and b) at least one therapeutic agent.

In an exemplary embodiment, the invention is a pharmaceutical formulation comprising a) a compound according to any of the above paragraphs or a combination according to any of the above paragraphs, or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.

In an exemplary embodiment, according to any of the above paragraphs, the formulation is a unit dosage form.

In an exemplary embodiment, according to any of the above paragraphs, the formulation is an oral unit dosage form or a topical unit dosage form.

In an exemplary embodiment, the invention is a method of killing or inhibiting the growth of a bacteria comprising: contacting said bacteria with an effective amount of a compound or a combination according to any of the above paragraphs, or a pharmaceutically acceptable salt thereof, thereby killing or inhibiting the growth of the bacteria.

In an exemplary embodiment, the invention is a method of treating a bacterial infection comprising: administering to an animal suffering from said infection an effective amount of a compound or a combination according to any of the above paragraphs, or a pharmaceutically acceptable salt thereof, thereby treating the bacterial infection.

In an exemplary embodiment, according to any of the above paragraphs, the animal is a human.

In an exemplary embodiment, the invention is a use of a compound or a combination according to any of the above paragraphs, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of bacterial infection.

In an exemplary embodiment, the invention is a method of inhibiting the editing domain of a t-RNA synthetase, comprising: contacting the synthetase with an effective amount of a compound described herein, or a pharmaceutically-acceptable salt thereof, thereby inhibiting the synthetase.

The invention is further illustrated by the Examples that follow. The Examples are not intended to define or limit the scope of the invention.

EXAMPLES

Proton NMR are recorded on Varian AS 300 spectrometer and chemical shifts are reported as δ (ppm) down field from tetramethylsilane. Mass spectra are determined on Micromass Quattro II.

Example 1

N-(5-Chloro-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfonamide

5-Chloro-6-nitro-3H-benzo[c][1,2]oxaborol-1-ol

To a solution of concentration HNO₃ (75 mL) at −60° C. was added 5-chloro-3H-benzo[c][1,2]oxaborol-1-ol (2.5 g, 14.84 mmol) portion-wise and the resulting solution stirred at −30° C. over a period of 3 h. The reaction was then poured into crushed ice and the precipitate that formed was filtered, washed with cold water and vacuum dried generating 2.62 g (82%) of the title compound as a tan color powder. ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ (ppm): 8.30 (s, 1H), 7.86 (s, 1H), 5.07 (s, 2H).

6-Amino-5-chloro-3H-benzo[c][1,2]oxaborol-1-ol; hydrochloride

To a solution of 5-chloro-6-nitro-3H-benzo[c][1,2]oxaborol-1-ol (2.5 g, 11.7 mmol) in 70 mL of methanol and 20 mL of 2M NH₃ in MeOH was added Raney Ni (1.0 g). The vessel was charged with a hydrogen atmosphere at 50 psi for 4 h. The reaction mixture was then filtered, washed with methanol and the combined filtrate evaporated in vacuo. To the residue was added diethyl ether (20 mL) and then evaporated to dryness twice affording. The material was then dissolved in minimum amount of THF and 4M HCl in dioxane was added. After 4 h at room temperature, the precipitate that formed was filtered, washed with diethyl ether and dried in vacuo generating 2.3 g (89%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ (ppm): 7.43 (s, 1H), 7.40 (s, 1H), 4.84 (s, 2H); MS (ESI) m/z=183 (M+1, positive).

N-(5-Chloro-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfonamide

To a solution of 6-amino-5-chloro-3H-benzo[c][1,2]oxaborol-1-ol; hydrochloride (0.30 g, 1.36 mmol) in 25 mL of anhydrous pyridine was added benzenesulfonyl chloride (0.175 ml, 1.36 mmol) and the resulting yellowish solution heated to 50° C. overnight under nitrogen atmosphere. Pyridine was removed in vacuo and the residue treated with 30 mL of 2N HCl. The resulting suspension was sonicated for 30 minutes and the fine precipitate that formed was filtered. The precipitate was re-crystallized from an EtOAc (20 mL) and MeOH (0.2 mL) mixture.

The resulting crystals were heated in water and the subsequent suspension was lyophilized producing 0.135 g (30%) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.97 (s, 1H), 9.36 (s, 1H), 7.68-7.65 (m, 3H), 7.63-7.59 (m, 1H), 7.54-7.50 (m, 2H), 7.44 (s, 1H), 4.90 (s, 2H); MS (ESI) m/z=322 (M−1, negative); HPLC purity: 97.78% (MaxPlot 200-400 nm), 98.53% (220 nm); Anal. Calcd for C₁₃H₁₁BClNO₄S: C, 48.26%; H, 3.43%; N, 4.33. Found: C, 47.98%; H, 3.48%; N, 4.45.

N-(5-Chloro-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-nitro-benzenesulfonamide

To a solution of 6-amino-5-chloro-3H-benzo[c][1,2]oxaborol-1-ol; hydrochloride (0.30 g, 1.36 mmol) in 20 mL of anhydrous pyridine was added 4-nitro-benzenesulfonyl chloride (0.302 g, 1.36 mmol) and the resulting reddish solution heated to 50° C. overnight under nitrogen atmosphere. Pyridine was removed in vacuo and the residue treated with 30 mL of 2N HCl. The solid that formed was filtered and washed with water and dried in vacuo. The material obtained was recrystallized twice from methanol. The crystals were then suspended in 20 mL of H₂O and sonicated for 4 h at 70° C. to form a fine white suspension which was lyophilized generating 0.107 g (21%) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.43 (s, 1H), 9.38 (s, 1H), 8.37 (d, J=8.8 Hz, 2H), 7.90 (d, J=9.2 Hz, 2H), 7.60 (s, 1H), 7.50 (s, 1H), 4.91 (s, 2H); MS (ESI) m/z=367 (M−1, negative); HPLC purity: 98.66% (MaxPlot 200-400 nm), 99.13% (220 nm).

4-Amino-N-(5-chloro-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfonamide; hydrochloride

To a solution of N-(5-chloro-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-nitro-benzenesulfonamide (0.402 g, 1.09 mmol) in methanol (100 ml) was added 5 mL of 2N NH₃ in MeOH and the resulting solution was added Raney Ni (0.1 g). The vessel was charged with hydrogen at 50 psi for 2 h. The reaction mixture was filtered, washed with methanol and the combined filtrate evaporated to dryness. Diethyl ether was added to the residue and evaporated twice to form a powdery material. This was dissolved in 5 mL of anhydrous THF and to it was added 10 mL of 1M HCl in ether solution. The precipitate that formed was sonicated for 1 h and filtered. Purification was accomplished by Preparative HPLC generating 15 mg (3%) of the title compound as a tan solid. ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ (ppm): 7.64 (brs, 1H), 7.41 (brs, 1H), 7.31-7.27 (m, 2H), 6.55-6.51 (m, 2H), 4.86 (s, 2H); MS (ESI) m/z=337 (M−1, negative); HPLC purity: 95.77% (MaxPlot 200-400 nm); 96.71% (220 nm).

N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and benzenesulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.15 (s, 1H), 9.25 (bs., 1H), 7.70 (m, 2H), 7.64 (m, 2H), 7.53 (m, 2H), 7.21 (d, J=7.6 Hz, 1H), 4.89 (s, 2H). MS (ESI): m/z=306.1 (M−H, negative).

3-Fluoro-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 3-fluoro benzenesulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.27 (s, 1H), 9.30 (s., 1H), 7.62 (m, 2H), 7.52 (m, 3H), 7.24 (d, J=10.4 Hz, 1H), 4.91 (s, 2H). MS (ESI): m/z=324.1 (M−H, negative).

2-Fluoro-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 2-fluoro benzenesulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.36 (s, 1H), 9.29 (s., 1H), 7.67 (m, 3H), 7.45 (t, J=8.4, 2.4 Hz, 1H), 7.31 (t, J=8 Hz, 1H), 7.23 (d, J=10 Hz, 1H), 4.91 (s, 2H). MS (ESI): m/z=324.1 (M−H, negative).

N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethoxy)benzenesulfonamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 2-trifluoromethoxy benzenesulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.27 (s, 1H), 9.29 (s., 1H), 7.81 (d, J=8 Hz, 1H), 7.77 (dm, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.56 (d, J=8 Hz, 1H), 7.49 (d, J=10 Hz, 1H), 7.23 (d, J=10.4 Hz, 1H), 4.91 (s, 2H). MS (ESI): m/z=390.1 (M−H, negative).

2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)benzamide

6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (0.33 g, 2 mmol), 2-cyanobenzene-1-sulfonyl chloride (0.52 g, 2.56 mmol), pyridine (1 mL), dichloromethane (5 mL), 0° C.-rt, O/N. Purification: remove solvent, work up with EtOAc and 3N HCl, washed with brine, dry on Na₂SO₄, remove solvent. The title compound was purified by preparative HPLC to give a white powder: yield 116 mg (17%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.25 (s, 1H), 9.71 (s, 1H), 9.47 (br. s., 1H), 9.09 (s, 1H), 7.94 (m, 2H), 7.67 (m, 1H), 7.55 (m, 3H), 5.04 (s, 2H). MS (ESI): m/z=351.0 (M+H, positive).

N-(4-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 4-acetamidobenzene-1-sulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.33 (s, 1H), 9.99 (s, 1H), 9.33 (s., 1H), 7.79 (d, J=8.4 Hz, 2H), 7.61 (m, 3H), 7.20 (d, J=10 Hz, 1H), 4.89 (s, 2H), 2.06 (s, 3H). MS (ESI): m/z=363.0 (M−H, negative).

N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-nitrobenzenesulfonamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 4-nitrobenzenesulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.53 (s, 1H), 9.33 (s., 1H), 8.40 (dd, J=6.8, 0.8 Hz, 2 H), 7.95 (dd, J=6.8, 2.0 Hz, 2H), 7.61 (d, J=7.6 Hz, 1H), 7.25 (d, J=10 Hz, 1H), 4.91 (s, 2H). MS (ESI): m/z=351.0 (M−H, negative).

N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-aminobenzenesulfonamide

N-(4-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide (0.2 g, 0.59 mmol), 6N HCl (3 mL), AcOH (3 mL) was heated to 40° C. for 2 days. Purification: remove solvent, work up with EtOAc and 1N HCl, washed with brine, dry on Na₂SO₄, remove solvent. The title compound was recrystallized in EtOAc to give a light-yellow solid as product: yield 53.1 mg (29%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.58 (s, 1H), 9.28 (s, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.32 (d, J=8 Hz, 2H), 7.18 (d, J=10 Hz, 1H), 6.52 (d, J=8.4 Hz, 2H), 5.95 (s, 2H), 4.89 (s, 2H); MS (ESI): m/z=321.0 (M−H, negative).

2-Cyano-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 2-cyanobenzene-1-sulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.55 (s, 1H), 9.33 (s., 1H), 8.09 (dd, J=7.2, 1.6 Hz, 1H), 7.87 (m, 3H), 7.62 (d, J=8 Hz, 1H), 7.25 (d, J=10 Hz, 1H), 4.92 (s, 2H). MS (ESI): m/z=331.1 (M−H, negative).

2-(Aminomethyl)-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

2-cyano-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (0.16 g, 1 mmol), Raney Ni (2 equiv w/w), 2.0 M NH₃ in EtOH (5 mL), and absolute EtOH (20 mL/1 g) was shaken under an atmosphere of H₂ (40-50 psi) for 3 h at rt. Purification: The resultant mixture was filtered through a pad of Celite and washed with EtOH. The filtrate was concentrated in vacuo to give the free amine. The title compound was purified by preparative HPLC to give a white powder: yield 23 mg (13%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.40 (s, 1H), 9.33 (bs., 1H), 8.24 (b, 3H), 7.73 (m, 2H), 7.64 (d, J=7.6 Hz, 2H), 7.55 (dd, J=8, 1.2 Hz, 1H), 7.23 (d, J=10.4 Hz, 1H), 4.92 (s, 2H), 4.36 (d, J=5.2 Hz, 2H). MS (ESI): m/z=337.0 (M+H, positive).

2,6-Difluoro-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 2,6-fluoro benzenesulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.66 (s, 1H), 9.32 (s., 1H), 7.68 (m, 2H), 7.27 (m, 3H), 4.93 (s, 2H). MS (ESI): m/z=342.1 (M−H, negative).

N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and pyridine-2-sulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.28 (s, 1H), 9.28 (s., 1H), 8.73 (d, J=4.8 Hz, 1H), 8.04 (dt, J=7.6, 1.6 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.66 (m, 2H), 7.22 (d, J=10.4 Hz, 1H), 4.90 (s, 2H). MS (ESI): m/z=309.1 (M+H, positive).

5-Nitro-pyridine-2-sulfonic acid (1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide

5-Nitro-pyridine-2-sulfonyl chloride

To an ice-cold solution of 5-nitro-pyridine-2-thiol (1.27 g, 8.13 mmol) in 1N aqueous HCl (25 mL) and acetic acid (5 mL) was vigorously bubbled chlorine (gas) for 15 min, followed by nitrogen for 5 min. the solid was collected by filtration, washed with cold 1N aqueous HCl and water and dried in vacuo: yield 842 mg (47%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.60 (d, J=2.0 Hz, 1H), 8.84 (dd, J=8.6, 2.3 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H).

5-Nitro-pyridine-2-sulfonic acid (1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.2 g, 1.34 mmol), MeCN (4 mL), pyridine (0.22 mL, 2.69 mmol), and 5-nitro-pyridine-2-sulfonyl chloride (0.3 g, 1.34 mmol). Purification by filtration from water and wash with water and ethyl acetate generated 380 mg (84%) of the title compound as an orange solid. mp 211-213° C.; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.85 (s, 1H), 9.45 (d, J=2.2 Hz, 1H), 9.22 (s, 1H), 8.78 (dd, J=8.6, 2.5 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.52 (s, 1H), 7.34-7.15 (m, 2H), 4.88 (s, 2H); MS (ESI) m/z=334 (M−1, negative); HPLC purity: 93.99% (MaxPlot 200-400 nm), 93.92% (220 nm).

5-Amino-pyridine-2-sulfonic acid (1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide; hydrochloride

A mixture of 5-Nitro-pyridine-2-sulfonic acid (1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (1.51 g, 4.51 mmol)) and 10% Pd on carbon (1.51 g, 1:1 w/w substrate to catalyst) in THF (30 mL) and methanol (135 mL) was shaken under an atmosphere of H₂ (40 psi) in a Parr shaker. Once the reaction was complete (30 min), the mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue dissolved in acetonitrile—water, washed with ethyl ether and lyophilized to provide the title compound as a yellow solid: yield 827 mg (60%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.10 (s, 1H), 9.17 (br. s., 1H), 7.90 (d, J=2.5 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.47 (s, 1H), 7.27-7.13 (m, 2H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 6.17 (br. s., 2H), 4.86 (s, 2H); MS (ESI): m/z=304 (M−1, negative); HPLC purity: 95.56% (MaxPlot 200-400 nm), 95.55% (220 nm).

4-Amino-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

General Procedure 3: Starting Materials N-(2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-4-yl)acetamide, 6N HCl and AcOH. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.34 (s, 1H), 9.30 (bs, 1H), 8.03 (d, J=6 Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.24 (m, 2H), 7.04 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.6, 2.4 Hz, 1H), 6.82 (bs, 2H), 4.89 (s, 2H); MS (ESI): m/z=306.1 (M+H, positive).

6-Amino-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-3-sulfonamide

To a stirred solution of 6-aminopyridine-3-sulfonyl chloride (251 mg, 1.30 mmol) and 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (218 mg, 1.30 mmol) in 5 mL of ACN was added pyridine (210 uL, 2.6 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After quenched with water, the solvent was removed in vacuo. The residue was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na₂SO₄, and concentrated to give a yellow residue. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give 135 mg of the title compound as a white solid. MS calcd for (C₁₂H₁₁BFN₃O₄S): 323.1, MS found (ESI negative): (M−H)⁻=322.1. ¹H NMR (DMSO-d₆) δ (ppm): 9.80 (s, 1H), 9.20 (bs, 1H), 8.06 (s, 1H), 7.50 (d, 1H), 7.55 (d, 1H), 7.17 (d, 1H), 6.45 (d, 1H), 4.84 (s, 2H).

N-[6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methyl-pyridin-3-yl]-acetamide

2-Benzylsulfanyl-3-methyl-5-nitro-pyridine

To a solution of phenyl-methanethiol (4.12 mL, 31.87 mmol) in THF (25 mL) was added K₂CO₃ (5.20 g, 37.66 mmol) and the resulting suspension was heated at 60° C. for 30 min. A solution of 2-chloro-3-methyl-5-nitro-pyridine (5.00 g, 28.97 mmol) in THF (10 mL) was added dropwise and the mixture was heated to reflux. After ON, the mixture was cooled and the volatiles were removed in vacuo. The residue was treated with ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate and the combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Purification was accomplished by Biotage® (SP4, Silica gel 100 g SNAP™ column, eluting with 75%-100% DCM in hexanes) produced 5.83 g (77%) of the title compound as a pale yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.15 (d, J=2.0 Hz, 1H), 8.08 (s, 1H), 7.42 (d, J=7.4 Hz, 2H), 7.39-7.18 (m, 3H), 4.55 (s, 2H), 2.33 (s, 3H).

6-Benzylsulfanyl-5-methyl-pyridin-3-ylamine

To a solution of 2-benzylsulfanyl-3-methyl-5-nitro-pyridine (1.4 g, 5.38 mmol) in ethanol (20 mL) and water (5 mL) was added iron powder (3 g, 53.8 mmol) and concentrated HCl (0.25 mL). The mixture was heated to reflux for 2 h. After cooling to room temperature, the insoluble material was removed by filtration through Celite® and washed with 4:1 ethanol-water. The filtrate was concentrated in vacuo and the pH adjusted to −8 with 20% aqueous NaOH. The mixture was extracted with DCM (2×) and the combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo generating 1.26 g (quantitative) of the title compound that was used in the next step without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.89 (d, J=2.3 Hz, 1H), 7.43-7.13 (m, 7H), 6.76 (d, J=2.0 Hz, 1H), 4.38 (s, 2H), 2.15 (s, 3H); MS (ESI) m/z=231 (M+1, positive).

N-(6-Benzylsulfanyl-5-methyl-pyridin-3-yl)-acetamide

To a solution of 6-benzylsulfanyl-5-methyl-pyridin-3-ylamine (1.24 g, 5.38 mmol) in THF (10 mL) at 0° C. was added triethylamine (1.12 mL, 8.07 mmol). After 10 min, acetic anhydride (0.763 mL, 8.07 mmol) was added. The ice bath was removed. After overnight, slightly acidic water (dilute HCl) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo generating 1.02 g (70%) of the title compound that was used in the next step without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.31 (s, 1H), 7.77 (s, 1H), 7.40 (d, J=7.4 Hz, 2H), 7.35-7.17 (m, 3H), 7.08 (br. s., 1H), 4.45 (s, 2H), 2.23 (s, 3H), 2.19 (s, 3H).

5-Acetylamino-3-methyl-pyridine-2-sulfonyl chloride

Through a solution of N-(6-benzylsulfanyl-5-methyl-pyridin-3-yl)-acetamide (1.02 g, 3.75 mmol) in DCM (25 mL) and water (5 mL) cooled in an ice bath was vigorously bubbled chlorine for 15 min. After 15 min of additional stirring, nitrogen was bubbled through the reaction mixture for 30 min. The layers were separated and the organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo generating 1.142 g of the title compound as yellow oil that was used in the next step without further purification.

N-[6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methyl-pyridin-3-yl]-acetamide

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (558 mg, 3.75 mmol), pyridine (0.606 mL, 7.49 mmol), acetonitrile (10 mL) and 5-acetylamino-3-methyl-pyridine-2-sulfonyl chloride (3.75 mmol). The residue was repeatedly washed with DCM and after drying in vacuo 0.714 g (53% for 2 steps) of the title compound was isolated as a red powder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.43 (s, 1H), 10.42 (s, 1H), 9.19 (br. s., 1H), 8.56 (d, J=1.7 Hz, 1H), 8.01 (s, 1 H), 7.52 (s, 1H), 7.25 (s, 2H), 4.88 (s, 2H), 2.53 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z=362 (M+1, positive); HPLC purity: 97.65% (MaxPlot 200-400 nm), 97.61% (220 nm).

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-methylpyridine-2-sulfonamide

To a solution of N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methylpyridin-3-yl)acetamide (592 mg, 1.64 mmol) in 1,4-dioxane (30 mL) was added 6 M HCl (10 mL), and the mixture was stirred at 100° C. for 4 h. The pH was adjusted to 7 with aqueous NaOH, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with small amount of ethyl acetate to give 5-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-methylpyridine-2-sulfonamide (60 mg, 11%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 2.37 (s, 3H), 4.85 (s, 2H), 5.98 (br s, 2H), 6.71 (d, J=1.5 Hz, 1H), 7.20 (s, 2H), 7.45 (s, 1H), 7.66 (d, J=2.2 Hz, 1H), 9.15 (s, 1H), 10.1 (s, 1H).

5-Amino-3-methyl-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

General Procedure 1: 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (485 mg, 3 mmol), 3-methyl-5-(2,2,2-trifluoroacetamido)pyridine-2-sulfonyl chloride (302 mg, 1 mmol), pyridine (400 mg, 5 mmol), rt, 0.5 hour. Removed solvent, the crude was dissolved in MeOH (5 ml), treated with ammonia (2 ml, 7N in MeOH), heated at 100° C. for 2 hours in a sealed tube. After cooled down to rt, concentrated, the result solid was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). Title compound was obtained as white powder. MS calcd for (C₁₃H₁₃BN₃O₄FS): 337.13, MS found (ESI negative): (M−H)⁻=336.1. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.77 (s, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.64 (s, 1H), 7.18 (d, J=10.4 Hz, 1H), 6.74 (d, J=2 Hz, 1H), 4.87 (s, 2H), 2.33 (s, 3H).

5-Amino-3-ethyl-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

Tert-butyl pyridin-2-ylcarbamate

Into a 500-mL round-bottom flask were placed a solution of pyridin-2-amine (30 g, 319.15 mmol, 1.00 equiv) in tetrahydrofuran (200 mL) and (Boc)₂O (83.5 g, 383.03 mmol, 1.20 equiv). The resulting solution was heated to reflux overnight. The resulting mixture was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). This resulted in 15.5 g (24%) of tert-butyl pyridin-2-ylcarbamate as a white solid.

Tert-butyl 3-ethylpyridin-2-ylcarbamate

Into a 500-mL 3-necked round-bottom flask was placed a solution of tert-butyl pyridin-2-ylcarbamate (15.5 g, 79.90 mmol, 1.00 equiv) in tetrahydrofuran (200 mL). This was followed by the addition of n-BuLi (2.5M, 70.4 mL, 2.20 equiv) dropwise with stirring at −78° C. The reaction mixture was stirred 2 h at −78° C., then added iodoethane (18.72 g, 120.00 mmol, 1.50 equiv) dropwise with stirring at −78° C. The resulting solution was stirred overnight at room temperature, then quenched by the addition of 50 mL of NH₄Cl solution. The resulting mixture was extracted with 3×50 ml, of ethyl acetate. The organic layers were combined, washed with 1×30 mL of brine, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:10). This resulted in 6.5 g (35%) of tert-butyl 3-ethylpyridin-2-ylcarbamate as a light yellow solid.

3-Ethylpyridin-2-amine

Into a 50-mL round-bottom flask was placed a solution of tert-butyl 3-ethylpyridin-2-ylcarbamate (6 g, 27.03 mmol, 1.00 equiv) in DCM/CF₃COOH (30/10 mL) and stirred overnight at room temperature. The resulting solution was diluted with 10 mL of water, then adjusted to pH 9-10 with sodium hydroxide solution. The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, washed with 1×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). This resulted in 3 g (86%) of 3-ethylpyridin-2-amine as a yellow solid.

3-Ethyl-5-nitropyridin-2-amine

Into a 50-mL 3-necked round-bottom flask was placed a solution of 3-ethylpyridin-2-amine (1 g, 8.20 mmol, 1.00 equiv) in sulfuric acid (4.8 mL), then added a mixture of HNO₃ (0.7 ml) and sulfuric acid (0.7 ml) dropwise at 0-5° C. The resulting solution was stirred overnight at room temperature. LCMS showed the reaction was completed. The reaction mixture was used in the next step directly without further work up.

3-Ethyl-5-nitropyridin-2-ol

Into a 50-mL 3-necked round-bottom flask was placed a solution of 3-ethyl-5-nitropyridin-2-amine (˜800 mg, 4.79 mmol, 1.00 equiv) in sulfuric acid and HNO₃, then added HNO₃ (0.7 mL) dropwise at below 40° C. The resulting mixture was poured into 20 ml water and heated to 120° C. until no N₂ evolution. The reaction mixture was cooled with a water/ice bath. The isolated solid was collected by filtration and washed with 10 ml of water. This resulted in 0.7 g (83%) of 3-ethyl-5-nitropyridin-2-ol as a light yellow solid.

2-Chloro-3-ethyl-5-nitropyridine

A solution of 3-ethyl-5-nitropyridin-2-ol (500 mg, 2.98 mmol, 1.00 equiv) in POCl₃ (10 mL) was heated to reflux for 5 hr. The reaction mixture was cooled and concentrated under vacuum. The residue was diluted with 10 mL of water, then adjusted to pH 8-9 with sodium bicarbonate solution. The resulting solution was extracted with 2×20 mL of ether. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.5 g (86%) of 2-chloro-3-ethyl-5-nitropyridine as a yellow oil.

2-(Benzylthio)-3-ethyl-5-nitropyridine

Into a 50-mL round-bottom flask were placed a solution of phenylmethanethiol (370 mg, 2.98 mmol, 1.10 equiv) in tetrahydrofuran (50 mL) and potassium carbonate (482 mg, 3.49 mmol, 1.30 equiv), then added a solution of 2-chloro-3-ethyl-5-nitropyridine (500 mg, 2.69 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) dropwise with stirring. The resulting solution was heated to reflux overnight. The resulting mixture was cooled and concentrated under vacuum. The residue was diluted with 20 mL of water, then extracted with 4×20 mL of ethyl acetate. The organic layers were combined, washed with 1×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:100). This resulted in 0.65 g (84%) of 2-(benzylthio)-3-ethyl-5-nitropyridine as a yellow solid.

6-(Benzylthio)-5-ethylpyridin-3-amine

Into a 50-mL round-bottom flask were placed a solution of 2-(benzylthio)-3-ethyl-5-nitropyridine (650 mg, 2.37 mmol, 1.00 equiv) in ethanol/H₂O (10/2.5 mL), Fe (1.33 g, 23.75 mmol, 10.00 equiv) and HCl (0.125 mL). The resulting mixture was heated to reflux for 2 hr. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. This resulted in 0.53 g (87%) of 6-(benzylthio)-5-ethylpyridin-3-amine as a yellow oil.

N-(6-(Benzylthio)-5-ethylpyridin-3-yl)acetamide

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of 6-(benzylthio)-5-ethylpyridin-3-amine (530 mg, 2.17 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) and triethylamine (320 mg, 3.17 mmol, 1.50 equiv). This was followed by the addition of Ac₂O (320 mg, 3.14 mmol, 1.50 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature, then concentrated under vacuum. The residue was diluted with 5 mL of water, then extracted with 2×10 mL of ethyl acetate. The organic layers were combined, washed with 1×5 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). This resulted in 0.45 g (69%) of N-(6-(benzylthio)-5-ethylpyridin-3-yl)acetamide as a yellow solid.

5-Acetamido-3-ethylpyridine-2-sulfonyl chloride

Into a 50-mL 3-necked round-bottom flask was placed a solution of N-(6-(benzylthio)-5-ethylpyridin-3-yl)acetamide (450 mg, 1.57 mmol, 1.00 equiv) in DCM/H₂O (10/2 mL). The solution was cooled in an ice bath, then slowly bubbled Cl₂ into the reaction mixture for 15 min. The reaction mixture was stirred for additional 15 min. Nitrogen was then bubbled into the reaction mixture for 30 min to remove any excess Cl₂. The reaction mixture was diluted with DCM. The separated organic layer was dried over Na₂SO₄ and concentrated under vacuum. This resulted in 0.4 g (92%) of 5-acetamido-3-ethylpyridine-2-sulfonyl chloride as a yellow oil.

N-(5-ethyl-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)acetamide

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (200 mg, 1.34 mmol, 1.00 equiv) in CH₃CN (15 mL), potassium carbonate (575 mg, 4.17 mmol, 3.00 equiv) and 5-acetamido-3-ethylpyridine-2-sulfonyl chloride (400 mg, 1.53 mmol, 1.10 equiv). The resulting solution was stirred for 1 h at 0° C. The reaction was then quenched by the addition of 5 mL of water. The resulting mixture was concentrated under vacuum. The residue was diluted with 20 mL of water, then adjusted to pH 6 with 2N HCl. The resulting solution was extracted with 3×20 ml, of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (30:1). This resulted in 345 mg (65%) of N-(5-ethyl-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)acetamide as a yellow solid.

5-Amino-3-ethyl-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

Into a 100-mL round-bottom flask was placed a solution of N-(5-ethyl-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)acetamide (345 mg, 0.92 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) and HCl (10%, 20 mL). The resulting solution was stirred overnight at 60° C. The reaction mixture was cooled and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire C18, 19×150 mm, Sum; Mobile phase, water (with 0.05% TFA) and acetonitrile; Grident: 25% acetonitrile up to 45% in 6 min, then up to 100% in 0.1 min); Detector, UV 254 nm. This resulted in 139.8 mg (46%) of 5-amino-3-ethyl-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide as a white solid. LC-MS-(ES, m/z): 334 [M+H]⁺. H-NMR-(DMSO-d6, 300 MHz, ppm): 10.149 (1H, s), 7.179 (1H, s), 7.696-7.688 (1H, d, J=2.8), 7.501 (1H, s), 7.235 (2H, s), 6.37 (2H, s), 6.804-6.796 (1H, d, J=2.4), 6.012 (2H, s), 4.876 (2H, s), 2.879-2.805 (2H, m), 1.157-1.107 (3H, m).

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-isopropylpyridine-2-sulfonamide

Methyl 2-aminonicotinate

Into a 250-mL round-bottom flask was placed a solution of 2-aminonicotinic acid (15 g, 108.70 mmol, 1.00 equiv) in methanol (100 mL), then added thionyl chloride (38.5 g, 326.27 mmol, 3.00 equiv) dropwise at 0° C. The resulting solution was stirred overnight at 70° C. in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The residue was diluted with 30 mL of water, then adjusted to pH 7-8 with NaHCO₃ solution. The resulting solution was extracted with 3×40 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from ether. This resulted in 8 g (42%) of methyl 2-aminonicotinate as a white solid.

2-(2-Aminopyridin-3-yl)propan-2-ol

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 2-aminonicotinate (8 g, 52.63 mmol, 1.00 equiv) in tetrahydrofuran (100 mL). This was followed by the addition of methylmagnesium bromide (70 mL, 4.00 equiv) dropwise with stirring at −20° C. The resulting solution was stirred for 2.5 h at room temperature, then quenched by the addition of 60 mL of NH₄Cl solution. The resulting solution was extracted with 3×50 ml, of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 6.6 g (73%) of 2-(2-aminopyridin-3-yl)propan-2-ol as a white solid.

3-Isopropylpyridin-2-amine

A mixture of 2-(2-aminopyridin-3-yl)propan-2-ol (6 g, 39.47 mmol, 1.00 equiv), P (3.67 g, 118.39 mmol, 3.00 equiv) and HI (30 mL) was stirred overnight at 150° C. in an oil bath. The reaction mixture was cooled and filtered. The filtrate was washed with 3×10 mL of ether. The aqueous layer was adjusted to pH 6-7 with ammonia. The resulting solution was extracted with 3×10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3). This resulted in 4.6 g (77%) of 3-isopropylpyridin-2-amine as a white solid.

3-Isopropyl-5-nitropyridin-2-ol

Into a 100-mL round-bottom flask was placed a solution of 3-isopropylpyridin-2-amine (4.6 g, 33.82 mmol, 1.00 equiv) in sulfuric acid (22 mL). This was followed by the addition of mixture of sulfuric acid (3.2 mL) and HNO₃ (3.2 mL) dropwise with stirring at 5° C. The resulting solution was stirred overnight at 30° C. in an oil bath. A second batch of HNO₃ (3.2 mL) was added dropwise with stirring at below 40° C. The reaction mixture was then poured into 40 ml of water and heated to 120° C. The reaction mixture was cooled rapidly by placing in an ice-bath and by adding ice directly to the reaction mixture. The isolated solid was collected by filtration. This resulted in 3.1 g (46%) of 3-isopropyl-5-nitropyridin-2-ol as a yellow solid.

2-Chloro-3-isopropyl-5-nitropyridine

A solution of 3-isopropyl-5-nitropyridin-2-ol (100 mg, 0.55 mmol, 1.00 equiv) in POCl₃ (10 mL) was stirred for 4 h at 100° C. in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The residue was diluted with ice water and adjusted to pH 7 with sodium hydroxide solution. The resulting solution was extracted with 3×20 mL of ether. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 96 mg (79%) of 2-chloro-3-isopropyl-5-nitropyridine as a red oil.

2-(Benzylthio)-3-isopropyl-5-nitropyridine

Into a 50-mL round-bottom flask was placed a solution of phenylmethanethiol (70 mg, 0.56 mmol, 1.10 equiv) in tetrahydrofuran (10 mL), then added potassium carbonate (90 mg, 0.65 mmol, 1.30 equiv). The resulting mixture was stirred for 30 min at 60° C. in an oil bath. This was followed by the addition of a solution of 2-chloro-3-isopropyl-5-nitropyridine (100 mg, 0.50 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) dropwise with stirring. The resulting solution was stirred for an additional 3 h at 70° C. in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The residue was diluted with 10 mL of water, then extracted with 3×10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with PE/EtOAc (80:1). This resulted in 0.089 g (55%) of 2-(benzylthio)-3-isopropyl-5-nitropyridine as a yellow oil.

6-(Benzylthio)-5-isopropylpyridin-3-amine

A mixture of 2-(benzylthio)-3-isopropyl-5-nitropyridine (2.5 g, 8.68 mmol, 1.00 equiv), ethanol (50 mL), water (12 mL), Fe (4.86 g, 86.79 mmol, 10.00 equiv) and HCl (0.75 mL) was stirred for 2 h at 100° C. in an oil bath. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with EtOH/H₂O(4:1), then concentrated under vacuum. The residual solution was adjusted to pH 8 with sodium hydroxide solution (20%). The resulting solution was extracted with 2×40 mL of dichloromethane. The organic layers were combined, washed with 2×20 ml, of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.1 g (86%) of 6-(benzylthio)-5-isopropylpyridin-3-amine as a yellow oil.

N-(6-(Benzylthio)-5-isopropylpyridin-3-yl)acetamide

Into a 100-mL round-bottom flask was placed a solution of 6-(benzylthio)-5-isopropylpyridin-3-amine (2.1 g, 8.14 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) and triethylamine (1.23 g, 12.18 mmol, 1.50 equiv), then added acetic anhydride (1.24 g, 12.16 mmol, 1.50 equiv) at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 mL of HCl (4M). The resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, washed with 1×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.15 g (77%) of N-(6-(benzylthio)-5-isopropylpyridin-3-yl)acetamide as a yellow oil.

5-Acetamido-3-isopropylpyridine-2-sulfonyl chloride

Cl₂ gas was bubbled into a solution of N-(6-(benzylthio)-5-isopropylpyridin-3-yl)acetamide (2.1 g, 7.00 mmol, 1.00 equiv) in DCM (50 mL) and water (10 mL) for 15 min at 0° C. The resulting solution was stirred for 15 min at room temperature, then bubbled with N₂ for 30 min at 0° C. The resulting solution was extracted with 2×10 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from hexane. This resulted in 1.9 g (85%) of 5-acetamido-3-isopropylpyridine-2-sulfonyl chloride as a yellow solid.

N-{6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]-5-(propan-2-yl)pyridin-3-yl}acetamide

Into a 50-mL 3-necked round-bottom flask were placed a solution of 5-acetamido-3-isopropylpyridine-2-sulfonyl chloride (1 g, 3.62 mmol, 1.10 equiv) in MeCN (10 mL) and potassium carbonate (1.36 g, 9.86 mmol, 3.00 equiv). The resulting mixture was stirred for 10 min at 0° C., then added a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (490 mg, 3.29 mmol, 1.00 equiv) in MeCN (5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for an additional 30 min at room temperature, then concentrated under vacuum. The residue was diluted with 10 mL of water, then adjusted to pH 6 with HCl. The resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100:1). This resulted in 1.03 g (73%) of N-{6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]-5-(propan-2-yl)pyridin-3-yl}acetamide as a yellow solid.

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-isopropylpyridine-2-sulfonamide

A solution of N-{6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]-5-(propan-2-yl)pyridin-3-yl}acetamide (1 g, 2.57 mmol, 1.00 equiv) in tetrahydrofuran (50 mL) and HCl (50 mL, 10%) was stirred overnight at 60° C. in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The crude product (350 mg) was purified by prep-HPLC with the following conditions: Column, SunFire C18, Sum, 19×150 mm; Mobile phase, water (with 0.1% formic acid) and methanol; Gradient, 30% methanol up to 60% in 7 min, up to 100% in 2 min, down to 30% in 3 min; Detector, UV 220 & 254 nm. This resulted in 0.11 g (12%) of 5-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-isopropylpyridine-2-sulfonamide as a white solid. LC-MS (ES, m/z): 348 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6, ppm): 9.176 (1H, s), 10.145 (1H, s), 7.679 (1H, d, J=2.4 Hz), 7.515 (1H, s), 7.272 (2H, m), 6.948 (1H, d, J=2.4 Hz), 5.969 (2H, s), 4.879 (2H, s), 3.794 (1H, m), 1.135 (6H, d, J=6.9 Hz).

2-Chloro-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-nitrobenzenesulfonamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 2-chloro-4-nitrobenzene-1-sulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.73 (s, 1H), 9.28 (bs., 1H), 8.51 (d, J=2.4 Hz, 1H), 8.28 (dd, J=8.8, 2.0 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.27 (d, J=10 Hz, 1H), 4.92 (s, 2H). MS (ESI): m/z=385.0 (M−H, negative).

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluoromethyl)pyridine-2-sulfonamide

5-Nitro-3-(trifluoromethyl)pyridin-2-ol

Into a 500-mL 3-necked round-bottom flask was placed 3-(trifluoromethyl)pyridin-2-ol (10 g, 61.35 mmol, 1.00 equiv), then added sulfuric acid (98%) (40 mL) dropwise with stirring at 0° C. This was followed by the addition of HNO₃ (50 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 40° C. The reaction was quenched by the addition of 500 mL of water, then extracted with 3×200 mL of ether. The organic layers were combined, dried and concentrated under vacuum. This resulted in 6.5 g (51%) of 5-nitro-3-(trifluoromethyl)pyridin-2-ol as a white solid.

2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

Into a 250-mL round-bottom flask was placed a solution of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (5 g, 24.04 mmol, 1.00 equiv) in POCl₃ (270.5 g) and PCl₅ (14 g, 67.31 mmol, 2.80 equiv). The resulting solution was stirred for 2 h at 120° C. The reaction was then cooled and quenched by the addition of 800 mL of water/ice. The pH value of the solution was adjusted to 9 with sodium carbonate solution (60%). The resulting solution was extracted with 2×200 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 3.1 g (57%) of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine as a yellow solid.

2-(Benzylthio)-5-nitro-3-(trifluoromethyl)pyridine

Into a 100-mL 3-necked round-bottom flask was placed a solution of phenylmethanethiol (2 g, 16.13 mmol, 1.10 equiv) in tetrahydrofuran (50 mL), then added potassium carbonate (1.6 g, 11.59 mmol, 1.30 equiv). The resulting solution was stirred for 30 min at 60° C. This was followed by the addition of a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 8.85 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) dropwise with stirring at 60° C. The resulting solution was refluxed overnight. The reaction mixture was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). This resulted in 1.9 g (68%) of 2-(benzylthio)-5-nitro-3-(trifluoromethyl)pyridine as a yellow solid.

6-(Benzylthio)-5-(trifluoromethyl)pyridin-3-amine

Into a 250-mL round-bottom flask were placed a solution of 2-(benzylthio)-5-nitro-3-(trifluoromethyl)pyridine (2.1 g, 6.69 mmol, 1.00 equiv) in ethanol (50 mL), Fe (3.7 g, 66.07 mmol, 10.00 equiv) and acetic acid (5 mL). The resulting mixture was refluxed for 3 h. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100:1). This resulted in 1.8 g (95%) of 6-(benzylthio)-5-(trifluoromethyl)pyridin-3-amine as a yellow solid.

N-(6-(benzylthio)-5-(trifluoromethyl)pyridin-3-yl)-2,2,2-trifluoroacetamide

Into a 100-mL round-bottom flask was placed a solution of 6-(benzylthio)-5-(trifluoromethyl)pyridin-3-amine (1.8 g, 6.34 mmol, 1.00 equiv) in dichloromethane (50 mL), then added TEA (1.3 g, 12.87 mmol, 2.00 equiv). This was followed by the addition of (CF₃CO)₂O (2 g, 9.52 mmol, 1.50 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at room temperature, then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of dichloromethane. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). This resulted in 2.0 g (83%) of N-(6-(benzylthio)-5-(trifluoromethyl)pyridin-3-yl)-2,2,2-trifluoroacetamide as a white solid.

5-(2,2,2-Trifluoroacetamido)-3-(trifluoromethyl)pyridine-2-sulfonyl chloride

Into a 100-mL 3-necked round-bottom flask was placed a solution of N-(6-(benzylthio)-5-(trifluoromethyl)pyridin-3-yl)-2,2,2-trifluoroacetamide (700 mg, 1.84 mmol, 1.00 equiv) in dichloromethane (17.5 mL) and water (3.5 mL). Cl₂ gas was bubbled into the reaction mixture at 0° C. The resulting solution was stirred for 15 min at 0-5° C. The reaction mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 650 mg (crude) of 5-(2,2,2-trifluoroacetamido)-3-(trifluoromethyl)pyridine-2-sulfonyl chloride as a yellow solid.

2,2,2-Trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

Into a 100-mL 3-necked round-bottom flask were placed a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (250 mg, 1.68 mmol, 1.00 equiv) in CH₃CN (20 mL) and potassium carbonate (926 mg, 6.71 mmol, 4.00 equiv). This was followed by the addition of a solution of 5-(2,2,2-trifluoroacetamido)-3-(trifluoromethyl)pyridine-2-sulfonyl chloride (716 mg, 2.01 mmol, 1.20 equiv) in CH₃CN (10 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at room temperature, then concentrated under vacuum. The residue was diluted with 50 mL of water, then adjusted to pH 6 with HCl (1 mol/L). The resulting solution was extracted with 3×100 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (50:1). This resulted in 400 mg (crude) of 2,2,2-trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(trifluoromethyl)pyridin-3-yl)acetamide as a yellow solid.

5-Amino-N-(1-hydroxy-1,-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluoromethyl)pyridine-2-sulfonamide

Into a 100-mL round-bottom flask was placed a solution of 2,2,2-trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (300 mg, 0.64 mmol, 1.00 equiv) in tetrahydrofuran (50 mL), then added potassium carbonate (aq) (40 mL). The resulting mixture was stirred overnight at 40° C., then concentrated under vacuum. The residue was diluted with 50 mL of water, then adjusted to pH 7 with HCl (1 mol/L). The resulting solution was extracted with 3×100 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The collected fractions were combined and concentrated under vacuum. The crude product (400 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire C18, 19×150 mm, Sum; Mobile phase, water (with 0.1% TFA) and MeOH; Gradient: 40% MeOH up to 70% in 10 min). This resulted in 109.5 mg (46%) of 5-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluoromethyl)pyridine-2-sulfonamide as a yellow solid. The compound exhibited a melting point of 157-159° C. LC-MS-(ES, m/z): 374 [M+H]⁺. ¹H NMR-(300 MHz, DMSO-d6): 4.894 (2H, s), 6.598 (2H, s), 7.278-7.332 (3H, d, 16.2 Hz), 7.548 (1H, s), 8.022 (1H, s), 9.206 (1H, s), 10.432 (1H, s).

5-Amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide hydrochloride

2-Methoxynicotinonitrile

A solution of 2-chloronicotinonitrile (20 g, 144.93 mmol, 1.00 equiv) and MeONa (15.7 g, 290.74 mmol, 2.00 equiv) in methanol (300 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 500 mL of water, then extracted with 3×200 mL of dichloromethane. The organic layers were combined, dried and concentrated under vacuum. This resulted in 17 g (88%) of 2-methoxynicotinonitrile as a white solid.

2-Hydroxynicotinonitrile

A solution of 2-methoxynicotinonitrile (10 g, 74.63 mmol, 1.00 equiv) in HBr/AcOH (20 mL) was stirred for 30 min at 70° C. The reaction mixture was cooled and filtered. The filter cake was washed with 2×200 mL of ether. This resulted in 7.5 g (50%) of 2-hydroxynicotinonitrile hydrobromide as a yellow solid.

2-Hydroxy-5-nitronicotinonitrile

Into a 1000-mL 3-necked round-bottom flask was placed a solution of 2-hydroxynicotinonitrile hydrobromide (100 g, 500.00 mmol, 1.00 equiv) in acetic anhydride (250 mL). This was followed by the addition of a solution of fuming nitric acid (35 mL) in acetic anhydride (65 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at room temperature, then quenched by the addition of 500 mL of ether. The isolated solid was collected by filtration and washed with 3×50 mL of ether. This resulted in 39 g (47%) of 2-hydroxy-5-nitronicotinonitrile as a yellow solid.

2-Chloro-5-nitronicotinonitrile

Into a 1000-mL round-bottom flask were placed 2-hydroxy-5-nitronicotinonitrile (40 g, 242.42 mmol, 1.00 equiv), POCl₃ (845 g) and PCl₅ (141 g, 677.88 mmol, 2.80 equiv). The resulting solution was heated to reflux for 3 h. The reaction mixture was cooled and quenched by the addition of 2000 mL of water/ice.

The pH value of the solution was adjusted to 8 with potassium carbonate solution, then it was extracted with 3×200 mL of dichloromethane. The organic layers were combined, dried and concentrated under vacuum. This resulted in 40 g (90%) of 2-chloro-5-nitronicotinonitrile as a yellow solid.

2-(Benzylthio)-5-nitronicotinonitrile

Into a 1000-mL 4-necked round-bottom flask were placed a solution of 2-chloro-5-nitronicotinonitrile (40 g, 218.58 mmol, 1.00 equiv) in tetrahydrofuran (500 mL) and potassium carbonate (39.2 g, 284.06 mmol, 1.30 equiv). The resulting mixture was stirred for 30 min at 60° C., then added phenylmethanethiol (30 g, 241.94 mmol, 1.10 equiv) dropwise. The resulting solution was then heated to reflux overnight. The resulting mixture was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50-1:10). This resulted in 43 g (73%) of 2-(benzylthio)-5-nitronicotinonitrile as a yellow solid.

5-Amino-2-(benzylthio)nicotinonitrile

Into a 2000-mL 4-necked round-bottom flask were placed a solution of 2-(benzylthio)-5-nitronicotinonitrile (50 g, 184.50 mmol, 1.00 equiv) in ethanol (1000 mL) and Fe (103 g, 1.84 mol, 10.00 equiv). This was followed by the addition of AcOH (66.4 g, 1.11 mol, 6.00 equiv) dropwise with stirring. The resulting solution was heated to reflux for 5 h. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100:1). This resulted in 36 g (81%) of 5-amino-2-(benzylthio)nicotinonitrile as a yellow solid.

Methyl 6-(benzylthio)-5-cyanopyridin-3-ylcarbamate

Into a 500-mL round-bottom flask was placed a solution of 5-amino-2-(benzylthio)nicotinonitrile (24 g, 99.59 mmol, 1.00 equiv) in pyridine (250 mL). This was followed by the addition of methyl carbonochloridate (10.3 g, 109.57 mmol, 1.10 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at room temperature, then it was concentrated under vacuum. The residue was diluted with 200 ml, of water. The resulting solution was extracted with 3×100 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:5). This resulted in 25 g (84%) of methyl 6-(benzylthio)-5-cyanopyridin-3-ylcarbamate as a yellow solid.

Methyl 6-(chlorosulfonyl)-5-cyanopyridin-3-ylcarbamate

Chlorine gas was bubbled slowly into a solution of methyl 6-(benzylthio)-5-cyanopyridin-3-ylcarbamate (5 g, 16.72 mmol, 1.00 equiv) in dichloromethane (75 mL) and water (25 mL) at 0° C. for 5 minutes. The resulting solution was stirred for 15 min at 0° C. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 4.8 g (crude) of methyl 6-(chlorosulfonyl)-5-cyanopyridin-3-ylcarbamate as a yellow solid.

Methyl 5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

Into a 250-mL round-bottom flask were placed a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (2.98 g, 20.00 mmol, 1.00 equiv) in CH₃CN (50 mL) and potassium carbonate (11.1 g, 80.43 mmol, 4.00 equiv). This was followed by the addition of a solution of methyl 6-(chlorosulfonyl)-5-cyanopyridin-3-ylcarbamate (6.6 g, 23.91 mmol, 1.20 equiv) in CH₃CN (10 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at room temperature, then it was concentrated under vacuum. The residue was adjusted to pH 4-6 with HCl (10%), then extracted with 3×50 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100:1-50:1). This resulted in 5 g (64%) of the title compound as a yellow solid.

Methyl 5-(aminomethyl)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

A mixture of methyl 5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (3 g, 7.73 mmol, 1.00 equiv) and Raney Ni (6 g, 103.45 mmol, 13.38 equiv) in NH₃ solution (2M in methanol, 100 mL) was stirred for 3 h at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (20:1-5:1). This resulted in 1.8 g (59%) of the title compound as a yellow solid.

5-Amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

Into a 100-mL round-bottom flask was placed a solution of methyl 5-(aminomethyl)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (600 mg, 1.53 mmol, 1.00 equiv) in ethanol (10 mL), then added a solution of potassium hydroxide (171 mg, 3.05 mmol, 2.00 equiv) in water (10 mL). The resulting solution was stirred for 1 h at 90° C. The reaction mixture was cooled and adjusted to pH 7 with HCl (10%). The resulting mixture was concentrated under vacuum. This resulted in 500 mg (crude) of 5-amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide as a yellow solid.

Tert-butyl (5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)methylcarbamate

Into a 50-mL round-bottom flask was placed a solution of 5-amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide (300 mg, 0.90 mmol, 1.00 equiv) and Boc₂O (392 mg, 1.80 mmol, 2.00 equiv) in methanol (10 mL), then added a solution of potassium carbonate (211 mg, 1.53 mmol, 2.00 equiv) in water (20 mL). The resulting solution was stirred for 2 h at room temperature. Then it was adjusted to pH 7 with HCl (10%). The resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (20:1-5:1). This resulted in 301 mg (75%) of the title compound as a yellow solid.

5-Amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide hydrochloride

HCl gas was bubbled slowly into a solution of tert-butyl (5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)methylcarbamate (300 mg, 0.69 mmol, 1.00 equiv) in methanol (30 mL) for 30 min at room temperature. The resulting mixture was concentrated under vacuum. The residue was washed with 1×20 mL of ether. This resulted in 126 mg (47%) of the title compound as a yellow solid. LC-MS-(ES, m/z): 335 [M+H]⁺. ¹H-NMR-(300 MHz, DMSO-d6, ppm): 4.165-4.355 (m, 4H), 4.888 (s, 2H), 6.952-6.960 (d, J=2.4 Hz, 1H), 7.086 (s, 1H), 7.249-7.253 (d, J=1.2 Hz, 2H), 7.425 (s, 1H), 7.532 (s, 1H), 7.840-7.848 (d, J=2.4 Hz, 1H), 8.414 (s, 2H), 10.365 (s, 1H).

Tert-butyl (5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)methylcarbamate

Into a 50-mL round-bottom flask was placed a solution of 5-amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide (300 mg, 0.90 mmol, 1.00 equiv) and Boc₂O (392 mg, 1.80 mmol, 2.00 equiv) in methanol (10 mL), then added a solution of potassium carbonate (211 mg, 1.53 mmol, 2.00 equiv) in water (20 mL). After stirred for 2 h at room temperature, the reaction mixture was adjusted to pH 7 with HCl (10%). The resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (20:1-5:1). This resulted in 301 mg (75%) of the title compound as a yellow solid. LC-MS-(ES, m/z): 435 [M+H]⁺. ¹H-NMR-(300 MHz, DMSO-d6, ppm): 1.418 (m, 9H), 4.405-4.427 (d, J=6.6 Hz, 2H), 4.877 (s, 1H), 6.205 (s, 2H), 6.838 (s, 1H), 7.237 (s, 3H), 7.499 (s, 1H), 7.703-7.711 (d, J=2.4 Hz, 1H), 9.185 (s, 1H), 10.220 (s, 1H).

5-Amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)nicotinic acid

Into a 50-mL round-bottom flask were placed a solution of methyl 2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)nicotinate (100 mg, 0.22 mmol, 1.00 equiv) in tetrahydrofuran/H₂O (1:1, 20 mL) and lithium hydroxide hydrate (91 mg, 2.17 mmol, 10.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting solution was washed with 20 mL of ethyl acetate. The aqueous layer was adjusted to pH 5-6 with HCl (4 mol/L). The resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from ethyl ether. This resulted in 30 mg (39.5%) of the title compound as a yellow solid. LC-MS-(ES, m/z): 350 [M+H]⁺. ¹H-NMR-(300 MHz, DMSO-d6, ppm): 13.38 (s, 1H), 10.15 (s, 1H), 9.17 (s, 1H), 7.88-7.87 (d, J=2.4 Hz, 1H), 7.48-7.47 (d, J=1.2 Hz, 1H), 7.28-7.20 (m, 2H), 6.94-6.93 (d, J=2.7 Hz, 1H), 6.32 (s, 2H), 4.87 (s, 2H).

5-Amino-N-ethyl-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)nicotinamide

2-Chloro-5-nitronicotinic acid

A solution of 2-hydroxy-5-nitrobenzoic acid (6.5 g, 35.52 mmol, 1.00 equiv) in phosphoryl trichloride (112.4 g, 739.47 mmol, 20.82 equiv) was stirred for 4 h at 120° C. in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The residue was diluted with 20 mL of THF, then added dropwise to 50 mL of water/ice. The resulting solution was adjusted to pH 4-5 with saturated NaHCO₃ solution, followed by extraction with 3×30 mL of tetrahydrofuran/Et₂O (1:2). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 4.5 g (63%) of 2-chloro-5-nitronicotinic acid as a yellow solid.

2-(Benzylthio)-5-nitronicotinic acid

Into a 500-mL round-bottom flask were placed a solution of phenylmethanethiol (3 g, 24.19 mmol, 1.08 equiv) in tetrahydrofuran (200 mL) and potassium carbonate (7 g, 50.72 mmol, 2.27 equiv). The resulting solution was stirred for 30 min at room temperature. This was followed by the addition of 2-chloro-5-nitrobenzoic acid (4.5 g, 22.39 mmol, 1.00 equiv) in several batches. The resulting solution was heated to reflux overnight in an oil bath. The reaction mixture was cooled and concentrated under vacuum. The residue was diluted with 100 mL of water and adjusted to pH 5-6 with HCl (4 mol/L). The resulting solution was extracted with 2×200 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 5.7 g (88%) of 2-(benzylthio)-5-nitrobenzoic acid as a yellow solid.

Methyl 2-(benzylthio)-5-nitronicotinate

Into a 250-mL round-bottom flask was placed a solution of 2-(benzylthio)-5-nitronicotinic acid (5.7 g, 19.66 mmol, 1.00 equiv) in methanol (100 mL), then added sulfuryl dichloride (28 g, 235.29 mmol, 11.97 equiv). The resulting solution was heated to reflux overnight in an oil bath. The reaction mixture was cooled to room temperature with an ice water bath. The isolated solid was collected by filtration. This resulted in 4 g (67%) of methyl 2-(benzylthio)-5-nitronicotinate as a yellow solid.

Methyl 5-amino-2-(benzylthio)nicotinate

Into a 250-mL round-bottom flask were placed a solution of methyl 2-(benzylthio)-5-nitronicotinate (4 g, 13.16 mmol, 1.00 equiv) in ethanol (100 mL) and iron (7.4 g, 132.14 mmol, 10.04 equiv), then added acetic acid (4.7 g, 78.33 mmol, 5.95 equiv). The resulting mixture was heated to reflux for 30 min in an oil bath. The reaction mixture was cooled and filtered. The filter cake was washed with 3×50 mL of methanol. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (2:1). The collected fractions were combined and concentrated under vacuum. This resulted in 4.6 g (crude) of methyl 5-amino-2-(benzylthio) nicotinate as a brown oil.

Methyl 2-(benzylthio)-5-(2,2,2-trifluoroacetamido)nicotinate

Into a 250-mL 3-necked round-bottom flask was placed a solution of methyl 5-amino-2-(benzylthio)nicotinate (3.6 g, 13.14 mmol, 1.00 equiv) in dichloromethane (60 mL) and TEA (2.6 g, 25.74 mmol, 1.96 equiv). This was followed by the addition of TFAA (4.1 g, 19.52 mmol, 1.49 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 2.5 h at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2×50 mL of dichloromethane. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:7). The collected fractions were combined and concentrated under vacuum. This resulted in 3.2 g (66%) of methyl 2-(benzylthio)-5-(2,2,2-trifluoroacetamido) nicotinate as a white solid.

Methyl 2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido)nicotinate

Chlorine gas was bubbled slowly into a solution of methyl 2-(benzylthio)-5-(2,2,2-trifluoroacetamido) nicotinate (3.2 g, 8.65 mmol, 1.00 equiv) in DCM/H₂O (2:1, 40 mL) for 15 min. Excess chlorine gas was removed by bubbling nitrogen gas through the reaction solution for 15 minutes. The resulting solution was extracted with 2×50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was directly used in the next step.

Methyl 2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)nicotinate

Into a 50-mL 3-necked round-bottom flask were placed a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (1 g, 6.71 mmol, 0.93 equiv) in acetonitrile (20 mL) and potassium carbonate (3.7 g, 26.81 mmol, 3.72 equiv). This was followed by the addition of a solution of methyl 2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido) nicotinate (2.5 g, 7.20 mmol, 1.00 equiv) in acetonitrile (5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature, then it was concentrated under vacuum. The residue was diluted with 50 mL of H₂O, then it was adjusted to pH 5-6 with HCl (4 mol/L). The resulting solution was extracted with 2×100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3). The collected fractions were combined and concentrated under vacuum. This resulted in 2.3 g (70%) of the title compound as a yellow solid.

5-Amino-N-ethyl-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)nicotinamide

Into a 100-mL round-bottom flask was placed a solution of methyl 2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)nicotinate (500 mg, 1.09 mmol, 1.00 equiv) in ethanol (40 mL), then added a solution of ethanamine in H₂O (70% wt, 2 mL). The resulting solution was heated to reflux for 30 min in an oil bath. The reaction progress was monitored by LC-MS. Once reaction was completed, the reaction mixture was cooled and concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C₁₈, Sum, 19×150 mm; Mobile phase, water (with 0.1% formic acid) and CH₃CN; Gradient, 25% CH₃CN up to 35% in 4 min, up to 100% in 1.5 min; Detector, UV 220 & 254 nm. This resulted in 0.12 g (29%) of the title compound as a light yellow solid. LC-MS-(ES, m/z): 377 [M+H]⁺. ¹H-NMR-(300 MHz, DMSO-d6, ppm): 9.75 (s, 1H), 9.17 (s, 1H), 8.37-8.33 (t, J=5.4 Hz, 1H), 7.83-7.82 (d, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.31-7.21 (m, 2H), 6.83-6.82 (d, J=1.8 Hz, 1H), 6.27 (s, 2H), 4.88 (s, 2H), 3.28-3.19 (m, 2H), 2.52-2.51 (t, J=1.8 Hz, 3H).

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-4H-1,2,4-triazol-3-yl)pyridine-2-sulfonamide

N-(6-(Benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide

Into a 250-mL round-bottom flask was placed a solution of 5-amino-2-(benzylthio)nicotinonitrile (3.5 g, 14.52 mmol, 1.00 equiv) in dichloromethane (50 mL) and TEA (3 g, 29.70 mmol, 2.05 equiv). This was followed by the addition of trifluoroacetic anhydride (4.8 g, 22.86 mmol, 1.57 equiv) dropwise with stirring at 0° C. After stirred for 1 h at room temperature, the resulting mixture was diluted with 20 ml, of water. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). This resulted in 4 g (82%) of N-(6-(benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide as a yellow solid.

3-Cyano-5-(2,2,2-trifluoroacetamido)pyridine-2-sulfonyl chloride

Chlorine gas was bubbled into a solution of N-(6-(benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide (4 g, 11.87 mmol, 1.00 equiv) in dichloromethane (100 mL) and water (20 mL) for 15 min. Then nitrogen is bubbled through the reaction mixture for 30 min. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 4 g of 3-cyano-5-(2,2,2-trifluoroacetamido) pyridine-2-sulfonyl chloride as light red oil.

N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)-2,2,2-trifluoroacetamide

Into a 250-mL 3-necked round-bottom flask were placed a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (1.5 g, 10.07 mmol, 0.88 equiv) in acetonitrile (50 mL) and potassium carbonate (6.5 g, 47.10 mmol, 4.11 equiv). This was followed by the addition of a solution of 3-cyano-5-(2,2,2-trifluoroacetamido) pyridine-2-sulfonyl chloride (4 g, 11.46 mmol, 1.00 equiv, 90%) in acetonitrile (40 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at room temperature, then it was diluted with 30 mL of water. The resulting solution was extracted with 3×50 ml, of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:51:1). This resulted in 2.6 g (51%) of the title compound as a yellow solid.

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-4H-1,2,4-triazol-3-yl)pyridine-2-sulfonamide

Into a 100-mL round-bottom flask were placed a solution of N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)-2,2,2-trifluoroacetamide (500 mg, 1.12 mmol, 1.00 equiv, 95%) in ethanol (50 mL), acetohydrazide (870 mg, 11.76 mmol, 10.54 equiv) and EtONa (240 mg, 3.53 mmol, 3.17 equiv). The resulting solution was heated to reflux for 3 days. The reaction progress was monitored by LC-MS. Once the reaction was completed, the resulting mixture was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100:1). This resulted in 127.2 mg (29%) of 5-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-4H-1,2,4-triazol-3-yl)pyridine-2-sulfonamide as a light yellow solid. LC-MS (ES, m/z): 387 [M+H]⁺. ¹H-NMR—(300 MHz, DMSO-d6, ppm): 14.053 (s, 1H), 10.355 (s, 1H), 9.188 (s, 1H), 7.816 (s, 1H), 7.518 (s, 1H), 7.282-7.261 (d, 3H), 6.274 (s, 2H), 4.893 (s, 2H).

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-2-sulfonamide

2-Chloro-5-nitronicotinic acid

Into a 250-mL round-bottom flask was placed 2-hydroxy-5-nitrobenzoic acid (15 g, 81.97 mmol, 1.00 equiv), then added phosphoryl trichloride (90.9 g, 598.03 mmol, 7.30 equiv). The resulting solution was heated to reflux for 4 h in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The residue was diluted with 20 mL of tetrahydrofuran, then quenched by the addition of 50 mL of water/ice. The pH value of the solution was adjusted to 4-5 with saturated NaHCO₃ solution. The resulting solution was extracted with 3×30 mL of tetrahydrofuran/Et₂O (1:2). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 8.6 g (52%) of 2-chloro-5-nitrobenzoic acid as a yellow solid.

2-(Benzylthio)-5-nitronicotinic acid

Into a 500-mL round-bottom flask was placed a solution of phenylmethanethiol (7 g, 56.45 mmol, 1.33 equiv) in tetrahydrofuran (200 mL), then added potassium carbonate (13.5 g, 97.83 mmol, 2.31 equiv). The reaction mixture was stirred for 30 min at room temperature. This was followed by the addition of 2-chloro-5-nitrobenzoic acid (8.6 g, 42.36 mmol, 1.00 equiv) in several batches. The resulting solution was heated to reflux overnight in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The residue was diluted with 100 mL of water and was adjusted to pH 5-6 with HCl (4 mol/L). The resulting solution was extracted with 2×200 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 10 g (81%) of 2-(benzylthio)-5-nitrobenzoic acid as a brown solid.

2-(2-(Benzylthio)-5-nitropyridin-3-yl)-5-methyl-1,3,4-oxadiazole

Into a 250-mL round-bottom flask were placed 2-(benzylthio)-5-nitronicotinic acid (8 g, 27.59 mmol, 1.00 equiv), acetohydrazide (10.2 g, 137.84 mmol, 5.00 equiv) and phosphoryl trichloride (85.2 mL). The resulting solution was heated to reflux for 2 h in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The residue was diluted with 50 mL of tetrahydrofuran, then quenched by the addition of 150 mL of water/ice. The pH value of the solution was adjusted to 9-10 with saturated NaHCO₃ solution. The resulting solution was extracted with 2×100 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:6). The collected fractions were combined and concentrated under vacuum. This resulted in 4 g (44%) of 2-(2-(benzylthio)-5-nitropyridin-3-yl)-5-methyl-1,3,4-oxadiazole as a yellow solid.

6-(Benzylthio)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-amine

Into a 500-mL round-bottom flask were placed a solution of 2-(2-(benzylthio)-5-nitropyridin-3-yl)-5-methyl-1,3,4-oxadiazole (4 g, 12.20 mmol, 1.00 equiv) in ethanol (150 mL) and iron (6.8 g, 121.43 mmol, 9.96 equiv). This was followed by the addition of a solution of acetic acid (4.4 g, 73.33 mmol, 6.01 equiv) in ethanol (50 mL) dropwise while the reaction mixture was heated to reflux. The resulting solution was refluxed for 30 min in an oil bath, then it was cooled. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (1:10). The collected fractions were combined and concentrated under vacuum. This resulted in 1.6 g (44%) of 6-(benzylthio)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-amine as a brown solid.

5-Amino-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-2-sulfonyl chloride

Into a 50-mL 3-necked round-bottom flask was placed a solution of 6-(benzylthio)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-amine (850 mg, 2.85 mmol, 1.00 equiv) in DCM/H₂O (2:1, 30 mL). This was followed by the addition of dichloromethane saturated with chlorine gas (15 mL) dropwise with stirring at 0° C. After stirred for 30 minutes at 0° C. in a water/ice bath, the reaction mixture was diluted with DCM. The separated organic layer was dried and concentrated under vacuum. The crude solid was directly used in the next step.

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-2-sulfonamide

Into a 50-mL 3-necked round-bottom flask were placed a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (350 mg, 2.35 mmol, 0.98 equiv) in acetonitrile (20 mL) and potassium carbonate (1.2 g, 8.70 mmol, 3.62 equiv). This was followed by the addition of a solution of 5-amino-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-2-sulfonyl chloride (660 mg, 2.40 mmol, 1.00 equiv, crude) in acetonitrile (5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LC-MS. The resulting mixture was concentrated under vacuum. The residue was diluted with 50 mL of H₂O, then adjusted to pH 5-6 with HCl (4 mol/L). The resulting solution was extracted with 2×100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C₁₈, Sum, 19×100 mm; Mobile phase, water (with 0.1% formic acid) and CH₃CN; Gradient, 20% CH₃CN up to 40% in 6 min; Detector, UV 254 nm. This resulted in 120 mg (13%) of 5-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-2-sulfonamide as a light-yellow solid. LC-MS-(ES, m/z): 388 [M+H]⁺. ¹H-NMR-(300 MHz, DMSO-d6, ppm): 10.29 (s, 1H), 9.19 (s, 1H), 8.06-8.05 (d, J=2.4 Hz, 1H), 7.46 (s, 1H), 7.26-7.17 (m, 2H), 7.10-7.09 (d, J=2.7 Hz, 1H), 6.53 (s, 2H), 4.89 (s, 2H), 3.55 (s, 3H).

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-2-sulfonamide

2,2,2-Trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(N-hydroxycarbamimidoyl)pyridin-3-yl)acetamide

Into a 100-mL round-bottom flask were placed a solution of N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)-2,2,2-trifluoroacetamide (2 g, 4.46 mmol, 1.00 equiv, 95%) in methanol (50 mL), NH₂OH.HCl (1 g, 14.49 mmol, 3.25 equiv) and TEA (2 g, 19.80 mmol, 4.44 equiv). The resulting solution was stirred for 3 h at room temperature, then it was concentrated under vacuum. The residue was dissolved in 50 mL of EtOAc. The resulting mixture was washed with 1×20 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.1 g (92%) of the title compound as a yellow solid.

2,2,2-Trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)acetamide

Into a 50-mL round-bottom flask was placed a solution of 2,2,2-trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(N-hydroxycarbamimidoyl)pyridin-3-yl)acetamide (2.1 g, 4.12 mmol, 1.00 equiv, 90%) in AcOH (30 mL) and acetic anhydride (1 g, 9.80 mmol, 2.38 equiv). The resulting solution was stirred for 4 h at 100° C. The resulting mixture was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100:1). This resulted in 0.8 g (36%) of the title compound as a yellow solid.

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-2-sulfonamide

Into a 100-mL round-bottom flask were placed a solution of 2,2,2-trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)acetamide (400 mg, 0.75 mmol, 1.00 equiv, 90%) in methanol/H₂O (50:1, 50 mL) and potassium carbonate (200 mg, 1.45 mmol, 1.94 equiv). The resulting solution was stirred for 4 days at room temperature. The reaction progress was monitored by LC-MS. Once reaction was completed, the reaction mixture was adjusted to pH 7 with AcOH. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions: Column, Atlantis T3, Sum, 19×150 mm; Mobile phase, water (with 0.05% TFA) and CH₃CN; Gradient, 20% CH₃CN up to 23% in 3 min, hold at 23% for 9 min, up to 100% in 0.1 min, hold at 100% for 1.9 min; Detector, UV 220 nm. This resulted in 70.2 mg (24%) of the title compound as a white solid. LC-MS-(ES, m/z): 388 [M+H]⁺. ¹H-NMR— (300 MHz, DMSO-d6, ppm): 10.109 (s, 1H), 9.115 (s, 1H), 8.011 (s, 1H), 7.470 (s, 1H), 7.229 (s, 2H), 7.006 (s, 1H), 6.441 (s, 2H), 4.887 (s, 2H), 2.693 (s, 3H).

5-Amino-3-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

2-(Benzylthio)-3-chloro-5-nitropyridine

Into a 250-mL round-bottom flask was placed a solution of phenylmethanethiol (7.1 g, 57.26 mmol, 1.10 equiv) in tetrahydrofuran (40 mL) and potassium carbonate (9.34 g, 67.68 mmol, 1.30 equiv). The resulting solution was stirred for 30 min at 60° C. in an oil bath. This was followed by the addition of a solution of 2,3-dichloro-5-nitropyridine (10 g, 52.08 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) dropwise with stirring. The resulting solution was refluxed for an additional 4 h. The reaction mixture was then cooled and quenched by the addition of 30 mL of water. The resulting solution was extracted with 50 mL of ethyl acetate. The organic layers were combined, washed with brine, dried and concentrated under vacuum. This resulted in 14.6 g (95%) of 2-(benzylthio)-3-chloro-5-nitropyridine as a brown solid.

6-(Benzylthio)-5-chloropyridin-3-amine

Into a 250-mL round-bottom flask were placed a solution of 2-(benzylthio)-3-chloro-5-nitropyridine (7 g, 25.00 mmol, 1.00 equiv) in ethanol (140 mL) and water (35 mL), Fe (14 g, 250.00 mmol, 10.00 equiv) and HCl (3.5 mL). The resulting mixture was heated to reflux for 2 h in an oil bath. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residue was diluted with water and adjusted to pH 8 with sodium hydroxide solution (20%). The resulting solution was extracted with 3×50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 6 g (92%) of 6-(benzylthio)-5-chloropyridin-3-amine as red oil.

N-(6-(benzylthio)-5-chloropyridin-3-yl)acetamide

To a 100-mL round-bottom flask was added a solution of 6-(benzylthio)-5-chloropyridin-3-amine (6 g, 24.00 mmol, 1.00 equiv) in tetrahydrofuran (60 mL) and triethylamine (3.6 g, 35.64 mmol, 1.50 equiv). The resulting solution was stirred for 10 min. Then acetic anhydride (3.7 g, 36.27 mmol, 1.50 equiv) was added. The resulting solution was stirred for 7 h at room temperature. The reaction was then quenched by the addition of 5 mL of HCl (2M). The resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). This resulted in 5.7 g (77%) of N-(6-(benzylthio)-5-chloropyridin-3-yl)acetamide as a yellow solid.

5-Acetamido-3-chloropyridine-2-sulfonyl chloride

A 250-mL 3-necked round-bottom flask was added a solution of N-(6-(benzylthio)-5-chloropyridin-3-yl)acetamide (2 g, 6.85 mmol, 1.00 equiv) in DCM (50 mL) and water (10 mL). The resulting solution was vigorously bubbled with Cl₂ gas for 15 min at 0° C. The resulting solution was extracted with 2×30 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.63 g (86%) of 5-acetamido-3-chloropyridine-2-sulfonyl chloride as a yellow solid.

N-{5-chloro-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyridin-3-yl}acetamide

Into a 50-mL round-bottom flask were placed a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (200 mg, 1.34 mmol, 1.00 equiv) in CH₃CN (10 mL), 5-acetamido-3-chloropyridine-2-sulfonyl chloride (400 mg, 1.49 mmol, 1.10 equiv) and potassium carbonate (648 mg, 4.70 mmol, 3.50 equiv). The resulting solution was stirred for 1 min at room temperature, then quenched by the addition of 10 mL of water. The pH value of the solution was adjusted to 6 with HCl. The resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 500 mg (98%) of N-{5-chloro-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyridin-3-yl}acetamide as a yellow solid.

5-Amino-3-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

Into a 50-mL round-bottom flask was placed a solution of N-{5-chloro-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyridin-3-yl}acetamide (500 mg, 1.31 mmol, 1.00 equiv) in tetrahydrofuran (25 mL) and HCl (10%, 25 mL). The resulting solution was heated to reflux overnight. The resulting mixture was cooled and concentrated under vacuum. The crude product (500 mg) was purified by prep-HPLC with the following conditions: Column, SunFire C18, 19×150 mm, Sum; Mobile phase, water (with 0.05% TFA) and methanol; Gradient: 30% methanol up to 50% in 6 min, up to 100% in 1 min, down to 30% in 1 min; Detector, UV 254 nm and 220 nm. This resulted in 102 mg (23%) of 5-amino-3-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide as a white solid. LC-MS-(ES, m/z): 340 [M+H]⁺. ¹H-NMR-(300 MHz, CD₃OD, ppm): 7.78 (1H, d, J=2.4 Hz), 7.43 (1H, s), 7.30 (2H, m), 7.02 (1H, d, J=2.4 Hz), 4.99 (2H, s).

5-Amino-3-bromo-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

2-(Benzylthio)-3-bromo-5-nitropyridine

Into a 250-mL round-bottom flask were placed a solution of phenylmethanethiol (2.89 g, 23.31 mmol, 1.10 equiv) in tetrahydrofuran (40 mL) and potassium carbonate (3.8 g, 27.54 mmol, 1.30 equiv). The resulting mixture was stirred for 30 min at 60° C., then added a solution of 3-bromo-2-chloro-5-nitropyridine (5 g, 21.19 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) dropwise with stirring. The resulting solution was refluxed overnight, then cooled and quenched by the addition of 30 mL of water. The resulting solution was extracted with 50 mL of ethyl acetate. The organic layers were combined, washed with brine, dried and concentrated under vacuum. This resulted in 6 g (83%) of 2-(benzylthio)-3-bromo-5-nitropyridine as a yellow solid.

6-(Benzylthio)-5-bromopyridin-3-amine

Into a 250-mL round-bottom flask were placed a solution of 2-(benzylthio)-3-bromo-5-nitropyridine (6 g, 18.52 mmol, 1.00 equiv) in ethanol (120 mL) and water (30 mL), Fe (10.3 g, 183.93 mmol, 10.00 equiv) and HCl (2.5 mL, 1.00 equiv). The resulting mixture was heated to reflux for 2 h in an oil bath. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum to remove most of EtOH. The residual solution was adjusted to pH 8 with sodium hydroxide solution (20%). The resulting solution was extracted with 3×50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 4.2 g (74%) of 6-(benzylthio)-5-bromopyridin-3-amine as a red oil.

N-(6-(Benzylthio)-5-bromopyridin-3-yl)acetamide

To a 100-mL round-bottom flask was added a solution of 6-(benzylthio)-5-bromopyridin-3-amine (4.2 g, 14.29 mmol, 1.00 equiv) in tetrahydrofuran (42 mL) and triethylamine (2.15 g, 21.29 mmol, 1.50 equiv), then added acetic anhydride (2.17 g, 21.27 mmol, 1.50 equiv) at 0° C. The resulting solution was stirred for 7 h at room temperature, then quenched by the addition of 5 mL of HCl (2M). The resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). This resulted in 4.1 g (81%) of N-(6-(benzylthio)-5-bromopyridin-3-yl)acetamide as a yellow solid.

5-Acetamido-3-bromopyridine-2-sulfonyl chloride

Cl₂ gas was bubbled into a solution of N-(6-(benzylthio)-5-bromopyridin-3-yl)acetamide (1.5 g, 4.46 mmol, 1.00 equiv) in DCM 37.5 mL) and water (7.5 mL) for 15 min at 0° C. The resulting solution was extracted with 2×30 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.5 g(crude) of 5-acetamido-3-bromopyridine-2-sulfonyl chloride as a yellow solid.

N-{5-bromo-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyridin-3-yl}acetamide

Into a 50-mL round-bottom flask was placed a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (200 mg, 1.34 mmol, 1.00 equiv) in CH₃CN (20 mL), 5-acetamido-3-bromopyridine-2-sulfonyl chloride (460 mg, 1.47 mmol, 1.10 equiv) and potassium carbonate (648 mg, 4.70 mmol, 3.50 equiv). The resulting solution was stirred for 30 min at room temperature, then quenched by the addition of 10 mL of water. The pH value of the solution was adjusted to 6 with HCl. The resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 500 mg (crude) of N-{5-bromo-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyridin-3-yl}acetamide as a red oil.

5-Amino-3-bromo-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

A solution of N-{5-bromo-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyridin-3-yl}acetamide (500 mg, 1.18 mmol, 1.00 equiv) in tetrahydrofuran (25 mL) and HCl (10%, 25 mL) was heated to reflux overnight in an oil bath. The resulting solution was cooled and extracted with 3×25 mL of ethyl acetate. The organic layers were combined, dried over anhydrous calcium chloride and concentrated under vacuum. The crude product (350 mg) was purified by prep-HPLC with the following conditions: Column, SunFire C18, 19×150 mm, 5 um; Mobile phase, water (with 0.1% formic acid) and methanol; Gradient, 30% methanol up to 80% in 8 min; Detector, UV 254 nm. This resulted in 200 mg (43%) of 5-amino-3-bromo-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide as a light yellow solid. LC-MS (ES, m/z): 386 [M+H]⁺. ¹H-NMR (DMSO-d6, 300 MHz, ppm): 10.31 (1H, s), 9.21 (1H, s), 7.81 (1H, d, J=2.1 Hz), 7.51 (1H, s), 7.22 (3H, m), 6.37 (2H, s), 4.88 (2H, s).

6-Amino-4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-3-sulfonamide

N-(5-(benzylthio)-4-fluoropyridin-2-yl)acetamide

Into a 50-mL round-bottom flask was placed a solution of N-(5-(benzylthio)-4-chloropyridin-2-yl)acetamide (2.8 g, 9.59 mmol, 1.00 equiv) in DMSO (10 mL), KF (4 g, 68.97 mmol, 7.19 equiv) and Me₄NCl (50 mg). The resulting solution was stirred for 4 days at 130° C. in an oil bath. The reaction mixture was then cooled and quenched by the addition of 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/hexane (1/15˜1/5). This resulted in 0.3 g (crude) of N-(5-(benzylthio)-4-fluoropyridin-2-yl)acetamide as a white solid.

6-Acetamido-4-fluoropyridine-3-sulfonyl chloride

Chlorine gas was bubbled slowly into a solution of N-(5-(benzylthio)-4-fluoropyridin-2-yl)acetamide (160 mg, 0.58 mmol, 1.00 equiv) in dichloromethane (5 mL) and water (1 mL) cooled at 0° C. in an ice bath for 10 min. The reaction mixture was then bubbled with nitrogen for 30 min. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 2×10 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 100 mg (crude) of 6-acetamido-4-fluoropyridine-3-sulfonyl chloride as a yellow solid.

N-(4-fluoro-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-2-yl)acetamide

Into a 50-mL 3-necked round-bottom flask was placed a solution of 6-acetamido-4-fluoropyridine-3-sulfonyl chloride (100 mg, 0.40 mmol, 1.00 equiv) in CH₃CN (10 mL), then added 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (86 mg, 0.58 mmol, 1.00 equiv) and potassium carbonate (320 mg, 2.32 mmol, 4.00 equiv). The resulting mixture was stirred for 1 h at 0° C. in an ice/salt bath. The pH value of the solution was adjusted to 6 with HCl (10%), followed by extraction with 3×10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with DCM/MeOH (1:20). This resulted in 0.05 g (32%) of N-(4-fluoro-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-2-yl)acetamide as a white solid.

6-Amino-4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-3-sulfonamide

A solution of N-(4-fluoro-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-2-yl)acetamide (200 mg, 0.55 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) and HCl (5 mL, 35%) was stirred for 1.5 h at 60° C. in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions: Column, SunFire Prep C18, 5 um, 19×100 mm; Mobile phase, water (with 0.1% formic acid) and CH₃CN; Gradient, CH₃CN starting from 20% and increasing to 28% in 6 min, then to 100% in 1 min, decreasing to 20% in 1 min; Detector, UV 220 nm. This resulted in 43.8 mg (25%) of 6-amino-4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-3-sulfonamide as a white solid. LC-MS-(ES, m/z): 324 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6, ppm): 4.886 (2H, s), 6.158-6.201 (1H, d, J=12.9 Hz), 7.15-7.21 (3H, m), 7.26-7.30 (1H, m), 7.492-7.498 (1H, d, J=1.8 Hz), 8.188-8.225 (1H, d, J=11.1 Hz), 9.237 (1H, s), 10.306 (1H, s).

6-Amino-4-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-3-sulfonamide

4-Chloro-5-iodopyridin-2-amine

Into a 100-mL round-bottom flask were placed a solution of 4-chloropyridin-2-amine (5.9 g, 46.09 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL) and NIS (13.35 g, 59.33 mmol, 1.30 equiv). The resulting solution was stirred overnight at room temperature, then quenched by the addition of 10 mL of Na₂S₂O₃ solution. The resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from ether/hexane in the ratio of 1:1. This resulted in 11 g (crude) of 4-chloro-5-iodopyridin-2-amine as a yellow solid.

5-(Benzylthio)-4-chloropyridin-2-amine

Sodium (480 mg, 20.87 mmol, 1.50 equiv) was added to methanol (20 mL) in portions. The resulting solution was stirred for 1 hr at reflux. Then added Cu (360 mg, 5.62 mmol, 0.30 equiv), phenylmethanethiol (2.81 g, 22.66 mmol, 1.20 equiv) and 4-chloro-5-iodopyridin-2-amine (4.8 g, 18.90 mmol, 1.00 equiv). The resulting mixture was heated to reflux for an additional 6 h. The reaction mixture was then cooled and quenched by the addition of H₂O. The resulting solution was extracted with 3×30 ml of ethyl acetate. The organic layers combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc:PE (1/10). This resulted in 5 g (crude) of 5-(benzylthio)-4-chloropyridin-2-amine as a yellow solid.

N-(5-(benzylthio)-4-chloropyridin-2-yl)acetamide

Into a 100-mL 3-necked round-bottom flask was placed a solution of 5-(benzylthio)-4-chloropyridin-2-amine (4.5 g, 18.00 mmol, 1.00 equiv) in acetic anhydride (9.6 g) and triethylamine (9.59 g, 94.95 mmol, 5.00 equiv). The resulting solution was stirred for 3 h at 60° C. in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/20). This resulted in 2 g (crude) of N-(5-(benzylthio)-4-chloropyridin-2-yl)acetamide as a white solid.

6-Acetamido-4-chloropyridine-3-sulfonyl chloride

Chlorine gas was bubbled slowly into a solution of N-(5-(benzylthio)-4-chloropyridin-2-yl)acetamide (1.07 g, 3.65 mmol, 1.00 equiv) in dichloromethane (25 mL) and water (5 mL) for 10 min at 0° C. in an ice/salt bath. The reaction mixture was then bubbled with nitrogen gas for 20 min and stirred for 10 min at 0° C. in an ice/salt bath. The resulting solution was diluted with water, followed by extraction with 2×50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was used in the next step directly without further purification.

N-(4-chloro-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-2-yl)acetamide

Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (546 mg, 3.66 mmol, 1.00 equiv), a solution of potassium carbonate (2.02 g, 14.64 mmol, 4.00 equiv) in CH₃CN (20 mL) at 0° C. This was followed by the addition of 6-acetamido-4-chloropyridine-3-sulfonyl chloride (1 g, 3.72 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at room temperature, then quenched by the addition of water. The pH value of the solution was adjusted to 6 with HCl (1M), then extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (1:20). This resulted in 500 mg (28%) of the title compound as a white solid.

6-Amino-4-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-3-sulfonamide

A solution of N-(4-chloro-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-2-yl)acetamide (300 mg, 0.79 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) and HCl (10 mL, 10%) was heated to reflux for 3 h in an oil bath. The resulting mixture was cooled and concentrated under vacuum to remove THF. The residual mixture was cooled with an ice bath. The isolated solid was collected by filtration. This resulted in 0.2 g (73%) of 6-amino-4-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-3-sulfonamide as a white solid. LC-MS-(ES, m/z): 340[M+H]⁺. ¹H NMR-(400 MHz, DMSO-d6, ppm): 4.77 (2H, s), 6.63 (1H, s), 7.20-7.29 (2H, m), 7.50 (1H, s), 8.38 (1H, s), 10.36 (1H, s).

5-Amino-3-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

2-Nitro-1,3-dioxopropan-2-ide

Into a 250-mL 3-necked round-bottom flask was placed a solution of NaNO₂ (10.2 g, 147.83 mmol, 3.78 equiv) in water (10 mL). This was followed by the addition of a solution of (E)-2,3-dibromo-4-oxobut-2-enoic acid (10 g, 39.06 mmol, 1.00 equiv) in ethanol (10 mL) dropwise with stirring at 54° C. over 18 min. The resulting solution was stirred for 30 min at 54° C. The reaction mixture was cooled to 5° C. and filtered. The filter cake was washed with 60 mL of ethanol. The filtrate was concentrated under vacuum. This resulted in 5 g (crude) of 2-nitro-1,3-dioxopropan-2-ide as a yellow solid.

2-Hydroxy-5-nitronicotinonitrile

Into a 500-mL 3-neck-round-bottom flask was placed a solution of 2-nitro-1,3-dioxopropan-2-ide (31.4 g, 225.90 mmol, 1.00 equiv) in water (400 mL). This was followed by the addition of 2-cyanoacetamide (16.4 g, 195.24 mmol, 0.91 equiv) at 20° C. To this was added N,N,N-triethylbenzenaminium hydroxide (7 g, 35.90 mmol, 0.16 equiv) at 20° C. The resulting solution was stirred for 30 min at 30° C. The reaction mixture was cooled to 0° C. with an ice/salt bath. The isolated solid was collected by filtration and purified by re-crystallization from H₂O (20 mL). This resulted in 4 g (10%) of 2-hydroxy-5-nitronicotinonitrile as a yellow solid.

2-Chloro-5-nitronicotinonitrile

A solution of 2-hydroxy-5-nitronicotinonitrile (10 g, 60.61 mmol, 1.00 equiv) in POCl₃ (122.6 g) and PCl₅ (35 g, 168.27 mmol, 2.80 equiv) was stirred for 2 h at 120° C. The reaction mixture was cooled and quenched by the addition of 800 mL of water/ice. The pH value of the solution was adjusted to >7 with sodium carbonate solution (60%). The resulting solution was extracted with 2×200 mL of dichloromethane. The organic layers were combined, dried and concentrated under vacuum. This resulted in 10.1 g (91%) of 2-chloro-5-nitronicotinonitrile as a yellow solid.

2-(Benzylthio)-5-nitronicotinonitrile

Into a 100-mL 3-necked round-bottom flask was placed a solution of phenylmethanethiol (1.4 g, 11.29 mmol, 1.10 equiv) in tetrahydrofuran (40 mL), then added potassium carbonate (1.9 g, 13.77 mmol, 1.30 equiv). The resulting mixture was stirred for 30 min at 60° C. This was followed by the addition of a solution of 2-chloro-5-nitronicotinonitrile (1.9 g, 10.38 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) dropwise with stirring at 60° C. The resulting solution was refluxed overnight. The resulting mixture was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50). This resulted in 1.9 g (61%) of 2-(benzylthio)-5-nitronicotinonitrile as a yellow solid.

5-Amino-2-(benzylthio)nicotinonitrile

A mixture of 2-(benzylthio)-5-nitronicotinonitrile (3.9 g, 14.39 mmol, 1.00 equiv), ethanol (100 mL), Fe (8.1 g, 144.64 mmol, 10.00 equiv) and acetic acid (10 mL) was refluxed for 3 h. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100:1). This resulted in 3.4 g (98%) of 5-amino-2-(benzylthio)nicotinonitrile as a yellow solid.

N-(6-(benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide

Into a 100-mL round-bottom flask was placed a solution of 5-amino-2-(benzylthio)nicotinonitrile (3.4 g, 14.11 mmol, 1.00 equiv) in dichloromethane (50 mL) and TEA (2.8 g, 27.72 mmol, 2.00 equiv). This was followed by the addition of (CF₃C0)₂O (4.4 g, 20.95 mmol, 1.50 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 15 min at 0-5° C., then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of dichloromethane. The organic layers were combined, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). This resulted in 3.5 g (74%) of N-(6-(benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide as a white solid.

3-Cyano-5-(2,2,2-trifluoroacetamido) pyridine-2-sulfonyl chloride

Cl₂ (gas) was bubbled into a solution of N-(6-(benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide (3.37 g, 10.00 mmol, 1.00 equiv) in dichloromethane (75 mL) and water (15 mL) at 0° C. in 15 min. The resulting solution was stirred for 15 min at room temperature, then dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 3.0 g (96%) of 3-cyano-5-(2,2,2-trifluoroacetamido) pyridine-2-sulfonyl chloride as a yellow oil.

N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)-2,2,2-trifluoroacetamide

Into a 100-mL round-bottom flask were placed a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (200 mg, 1.34 mmol, 1.00 equiv) in CH₃CN (50 mL) and potassium carbonate (741 mg, 5.37 mmol, 4.00 equiv). This was followed by the addition of a solution of 3-cyano-5-(2,2,2-trifluoroacetamido) pyridine-2-sulfonyl chloride (504 mg, 1.61 mmol, 1.20 equiv) in CH₃CN (10 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at room temperature, then concentrated under vacuum. The residue was diluted with 50 mL of water, then adjusted to pH 6 with HCl (1 mol/L). The resulting solution was extracted with 3×100 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100:1-50:1). This resulted in 300 mg (crude) of N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)-2,2,2-trifluoroacetamide as a yellow solid.

5-Amino-3-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

Into a 250-mL round-bottom flask was placed a solution of N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-yl)-2,2,2-trifluoroacetamide (300 mg, 0.70 mmol, 1.00 equiv) in methanol (50 mL), then added potassium carbonate solution (50 mL). The resulting solution was stirred for 18 h at room temperature, then concentrated under vacuum. The residue was diluted with 50 mL of water. The pH value of the solution was adjusted to 7 with HCl (1 mol/L). The resulting solution was extracted with 2×100 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was washed with 1×10 mL of methanol and dried. This resulted in 104 mg (43%) of 5-amino-3-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide as a yellow solid. The compound exhibited a melting point of 234-237° C. LC-MS (ES, m/z): 331 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6): 4.898 (2H, s), 6.639 (2H, s), 7.236-7.287 (2H, m), 7.485-7.489 (1H, d, J=1.2 Hz), 8.085-8.092 (1H, d, J=2.1 Hz), 9.201 (1H, s), 10.484 (1H, s).

6-Amino-4-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-3-sulfonamide

2-(4-Methoxybenzylamino)isonicotinonitrile

Into a 500-mL round-bottom flask were placed a solution of 2-chloroisonicotinonitrile (11.0 g, 79.71 mmol, 1.00 equiv) in pyridine (250 mL), (4-methoxyphenyl)methanamine (12.4 g, 90.51 mmol, 1.14 equiv) and sodium bicarbonate (15.0 g, 178.57 mmol, 2.20 equiv). The resulting mixture was heated to reflux overnight in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The crude product was purified by re-crystallization from EtOAc. This resulted in 7.5 g (crude) of 2-(4-methoxybenzylamino)isonicotinonitrile as a yellow solid.

2-Aminoisonicotinonitrile

A solution of 2-(4-methoxybenzylamino)isonicotinonitrile (3.59 g, 15.08 mmol, 1.00 equiv) in trifluoroacetic acid (40 mL) was stirred for 3 h at 60° C. The resulting mixture was cooled and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 9-10 with potassium carbonate solution. The resulting solution was extracted with ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/4). This resulted in 1.8 g (crude) of 2-aminoisonicotinonitrile as a yellow solid.

2-Amino-5-iodoisonicotinonitrile

Into a 100-mL round-bottom flask was placed a solution of 2-aminoisonicotinonitrile (1.8 g, 15.13 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL), then added NIS (4.42 g, 19.64 mmol, 1.30 equiv). The resulting solution was stirred overnight at room temperature, then quenched by the addition of 30 mL of Na₂S₂O₃ solution. The resulting solution was extracted with 3×15 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/10). This resulted in 2.6 g (70%) of 2-amino-5-iodoisonicotinonitrile as a yellow solid.

2-Amino-5-(benzylthio)isonicotinonitrile

Sodium (101 mg, 4.39 mmol, 1.20 equiv) was added to methanol (15 mL) and stirred for 20 min at room temperature. Then added Cu (80 mg, 1.25 mmol, 0.30 equiv), phenylmethanethiol (610 mg, 4.92 mmol, 1.20 equiv) and 2-amino-5-iodoisonicotinonitrile (1.0 g, 4.08 mmol, 1.00 equiv). The resulting solution was heated to reflux for an additional 6 h. The reaction mixture was cooled with a water bath, then diluted with 100 ml of water. The resulting solution was extracted with 3×50 ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EA:PE (1:10). This resulted in 0.2 g (20%) of 2-amino-5-(benzylthio)isonicotinonitrile as a yellow solid.

N-(5-(benzylthio)-4-cyanopyridin-2-yl)acetamide

A solution of 2-amino-5-(benzylthio)isonicotinonitrile (2 g, 8.30 mmol, 1.00 equiv) in acetic anhydride (4 g) and triethylamine (4 g, 39.60 mmol, 5.00 equiv) was stirred for 5 h at 60° C. in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). This resulted in 2.2 g (94%) of N-(5-(benzylthio)-4-cyanopyridin-2-yl)acetamide as a light yellow solid.

4-Acetamido-6-cyanopyridine-3-sulfonyl chloride

Chlorine gas was bubbled slowly into a solution of N-(5-(benzylthio)-2-cyanopyridin-4-yl)acetamide (665 mg, 2.35 mmol, 1.00 equiv) in dichloromethane (15 mL) and water (5 mL) cooled at 0° C. in a water/ice bath for 10 min. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.6 g (crude) of 4-acetamido-6-cyanopyridine-3-sulfonyl chloride as a yellow solid.

N-(4-cyano-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-2-yl)acetamide

Into a 50-mL 3-necked round-bottom flask was placed a solution of 4-acetamido-6-cyanopyridine-3-sulfonyl chloride (600 mg, 1.00 equiv, crude) in CH₃CN (10 mL), then added 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (305 mg, 2.05 mmol, 1.00 equiv) and potassium carbonate (276 mg, 2.00 mmol, 4.00 equiv). The resulting mixture was stirred for 1 h at 0° C. in a water/ice bath. The pH value of the solution was adjusted to 6 with HCl (10%), then it was extracted with 3×10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.2 g (crude) of N-(4-cyano-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-2-yl)acetamide as a white solid.

6-Amino-4-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-3-sulfonamide

A solution of N-(4-cyano-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-2-yl)acetamide (500 mg, 1.34 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) and HCl (10%, 10 mL) was stirred for 3 h at 60° C. in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The crude product (0.4 g) was purified by preparative-HPLC with the following conditions: Column, SunFire Prep C18, Sum, 19×150 mm; Mobile phase, water (with 0.05% TFA) and CH₃CN; Gradient, MeCN starting at 25%, increasing to 34% in 6 min, then to 100% in 1.5 min; Detector, uv 220&254 nm. This resulted in 0.2 g (45%) of 6-amino-4-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-3-sulfonamide as a white solid. LC-MS-(ES, m/z): 331 [M+H]⁺. ¹H-NMR-(300 MHz, DMSO-d6, ppm): 4.901 (2H, s), 6.825 (1H, s), 7.181-7.321 (2H, m), 7.479 (1H, s), 8.406 (1H, s), 9.250 (1H, s), 10.414 (1H, s).

Benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)sulfamoyl)pyridin-3-ylcarbamate

2-Hydroxy-5-nitronicotinic acid

Into a 2000-mL 4-necked round-bottom flask was placed a solution of 2-hydroxynicotinic acid (98 g, 705.04 mmol, 1.00 equiv) in sulfuric acid (280 mL). This was followed by the addition of HNO₃ (70 mL) dropwise with stirring. The resulting solution was stirred for 5 h at 50° C. The reaction was then cooled and quenched by the addition of 2000 mL of water/ice. The solid was collected by filtration and dried in an oven under reduced pressure. This resulted in 100 g (69%) of 2-hydroxy-5-nitronicotinic acid as a yellow solid.

2-Chloro-5-nitronicotinic acid

A solution of 2-hydroxy-5-nitronicotinic acid (100 g, 543.48 mmol, 1.00 equiv) in POCl₃ (250 mL) was heated to reflux for 3 hr. The resulting mixture was cooled and concentrated under vacuum. The residue was then quenched by the addition of 2000 mL of water/ice. The resulting solution was extracted with 4×300 mL of ethyl acetate and 2×300 mL of THF/Et₂O (1:1). The organic layers were combined, washed with 1×1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 115 g (crude) of 2-chloro-5-nitronicotinic acid as a yellow solid.

2-(Benzylthio)-5-nitronicotinic acid

Into a 3000-mL 4-necked round-bottom flask was placed a solution of phenylmethanethiol (77.65 g, 626.21 mmol, 1.00 equiv) in tetrahydrofuran (1800 mL), then added potassium carbonate (180.69 g, 1.31 mol, 2.30 equiv). The resulting mixture was heated to reflux for 1 hr. This was followed by the addition of a solution of 2-chloro-5-nitronicotinic acid (115 g, 569.31 mmol, 1.00 equiv) in tetrahydrofuran (400 mL) in portions. The resulting solution was refluxed for an additional 5 h. The reaction mixture was then cooled and quenched by the addition of 1000 mL of water. The pH value of the solution was adjusted to 3-4 with HCl (12 mol/L). The resulting solution was extracted with 3×1500 mL of ethyl acetate. The organic layers were combined, washed with 1×1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was washed with 3×500 mL of petroleum ether and dried. This resulted in 130 g (72%) of 2-(benzylthio)-5-nitronicotinic acid as a yellow solid.

Tert-butyl 2-(benzylthio)-5-nitropyridin-3-ylcarbamate

Into a 3000-mL 4-necked round-bottom flask were placed a solution of 2-(benzylthio)-5-nitronicotinic acid (130 g, 448.28 mmol, 1.00 equiv) in tert-butanol (1500 mL), triethylamine (58.86 g, 582.77 mmol, 1.30 equiv) and DPPA (147.9 g, 537.82 mmol, 1.20 equiv). The resulting solution was heated to reflux overnight. The reaction mixture was cooled and concentrated under vacuum. The residue diluted with 2000 ml, of water, then adjusted to pH 8 with sodium carbonate. The resulting solution was diluted with 2000 ml of H₂O and 500 ml of EtOAc. The isolated solid was collected by filtration and dried. This resulted in 148 g (82%) of tert-butyl 2-(benzylthio)-5-nitropyridin-3-ylcarbamate as a yellow solid.

Tert-butyl 5-amino-2-(benzylthio)pyridin-3-ylcarbamate

Into a 3000-mL 4-necked round-bottom flask were placed a solution of tert-butyl 2-(benzylthio)-5-nitropyridin-3-ylcarbamate (125 g, 346.26 mmol, 1.00 equiv) in methanol (1500 mL) and H₂O (150 mL), Fe (116.3 g, 2.08 mol, 6.00 equiv) and NH₄Cl (110.1 g, 2.08 mol, 6.00 equiv). The resulting mixture was heated to reflux overnight. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The solid was collected by filtration, washed 2 times with 500 ml of water and dried in an oven under reduced pressure. This resulted in 120 g (crude) of tert-butyl 5-amino-2-(benzylthio)pyridin-3-ylcarbamate as a yellow solid.

Tert-butyl 5-(benzylcarbamoyl-amino-2-(benzylthio)pyridin-3-ylcarbamate

Into a 3000-mL 4-necked round-bottom flask was placed a solution of tert-butyl 5-amino-2-(benzylthio)pyridin-3-ylcarbamate (120 g, 362.54 mmol, 1.00 equiv) in tetrahydrofuran/H₂O (1:1, 2 L), then added sodium carbonate (57.6 g, 538.3 mmol, 1.30 equiv). This was followed by the addition of Cbz-Cl (74 g, 435.29 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 500 mL of NH₄Cl solution. The resulting solution was extracted with 3×500 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:10). This resulted in 102 g (58%) of the title compound as a yellow solid.

Benzyl 5-(tert-butyl carbamoylamino)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)sulfamoyl)pyridin-3-ylcarbamate

Into a 500-mL round-bottom flask was placed a solution of tert-butyl 5-(benzylcarbamoyl-amino-2-(benzylthio)pyridin-3-ylcarbamate (10 g, 21.51 mmol, 1.00 equiv) in acetic acid (150 mL) and water (70 mL), then added NCS (11.4 g, 85.71 mmol, 3.99 equiv). After stirred for 30 min at room temperature, the reaction mixture was extracted with 2×200 mL of ethyl acetate. The organic layers were combined, washed with 1×200 mL of water. The organic layer was diluted with 200 ml of water, then added potassium carbonate solution till pH 8 was reached. The separated organic layer was washed with 1×100 mL of brine, dried over sodium sulfate and concentrated under vacuum. This resulted in 9 g (76%) of benzyl 5-(tert-butyl carbamoylamino)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)sulfamoyl)pyridin-3-ylcarbamate as a yellow oil. The product was used in the next step directly.

Benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)sulfamoyl)pyridin-3-ylcarbamate

A solution of benzyl 5-(tert-butyl carbamoylamino)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)sulfamoyl)pyridin-3-ylcarbamate (74 g, 126.90 mmol, 1.00 equiv, 95%) in DCM/CF₃COOH (400/100 mL) was stirred for 5 h at room temperature. The reaction was quenched by the addition of 500 mL of water. The pH value of the solution was adjusted to 8-9 with potassium carbonate solution. The solid was collected by filtration. The filtrate was extracted with 500 mL of dichloromethane. The filter cake and aqueous layer were combined. The resulting solution was adjusted to pH 4-5 with HCl (6N), then extracted with 2×200 mL of ethyl acetate. All the organic layers were combined, washed with 100 mL of brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with DCM:MeOH (100:1-50:1). This resulted in 44.36 g (79%) of the title compound as a light yellow solid. The compound exhibited a melting point of 174-176° C. LC-MS (ES, m/z): 455 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6, ppm): 10.30 (s, 1H), 10.12 (s, 1H), 9.20 (s, 1H), 7.80 (s, 1H), 7.73-7.80 (m, 7H), 7.19-7.26 (m, 2H), 6.19 (s, 2H), 5.16-5.19 (d, J=9 Hz, 2H), 4.88 (s, 2H).

3,5-Diamino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)pyridine-2-sulfonamide

A mixture of Palladium carbon (0.2 g) and benzyl N-5-amino-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyridin-3-ylcarbamate (900 mg, 1.98 mmol, 1.00 equiv) in methanol (20 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20/1). The crude product (500 mg) was purified by prep-HPLC with the following conditions: Column, SunFire C18, Sum, 19×100 mm; Mobile phase: water and acetonitrile; Gradient: 10% acetonitrile up to 50% in 7 min; Detector, UV 254 nm. This resulted in 75.7 mg (12%) of 3,5-diamino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)pyridine-2-sulfonamide as a white solid. LC-MS-(ES, m/z): 321 [M+H]⁺. ¹H-NMR-(300 MHz, DMSO-d6, ppm): 9.17 (1H, s), 7.46 (1H, s), 7.19-7.20 (3H, d, J=3 Hz), 6.11-6.12 (1H, d, J=3 Hz), 5.80-5.82 (4H, d, J=6 Hz), 4.87 (2H, s).

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(ureidomethyl)pyridine-2-sulfonamide

Methyl 6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(ureidomethyl)pyridin-3-ylcarbamate

Into a 100-mL round-bottom flask was placed a solution of methyl 5-(aminomethyl)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (1 g, 2.55 mmol, 1.00 equiv) in AcOH (20 mL), then added a solution of KOCN (200 mg, 2.47 mmol, 1.10 equiv) in H₂O (20 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with DCM:MeOH (100:1-20:1). This resulted in 400 mg (36%) of the title compound as a yellow solid.

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(ureidomethyl)pyridine-2-sulfonamide

Into a 100-mL round-bottom flask was placed a solution of methyl 6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(ureidomethyl)pyridin-3-ylcarbamate (300 mg, 0.69 mmol, 1.00 equiv) in ethanol (10 mL), then added a solution of potassium hydroxide (77 mg, 1.38 mmol, 2.00 equiv) in water (10 mL). The resulting solution was stirred for 1 h at 90° C. The reaction mixture was cooled and adjusted to pH 7 with HCl (10%). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-3:1). The crude product (400 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C₁₈, 19×150 mm, Sum; Mobile phase, water (with 0.05% TFA) and CH₃CN; Gradient, 10% CH₃CN up to 28% in 6 min, up to 100% in 1.5 min, down to 10% in 1.5 min; Detector, UV 254 nm. This resulted in 167.9 mg (64%) of the title compound as a white solid. LC-MS (ES, m/z): 378 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6, ppm): 4.426-4.446 (d, J=6 Hz, 2H), 4.878 (s, 2H), 5.720 (s, 2H), 6.163 (s, 2H), 6.376-6.417 (t, 1H), 6.905-6.913 (d, J=2.4 Hz, 1H), 7.237-7.241 (d, J=1.2 Hz, 2H), 7.515 (s, 1H), 7.700-7.708 (d, J=2.4 Hz, 1H), 9.235 (s, 1H), 10.219 (s, 1H).

5-Amino-3-(3-ethylureido)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

Benzyl 5-(3-ethylureido)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

Into a 30-mL sealed tube were placed a solution of Benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (500 mg, 1.10 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) and isocyanatoethane (800 mg, 11.27 mmol, 10.00 equiv). The resulting solution was stirred overnight at 70° C. The reaction was then cooled and quenched by the addition of 3 mL of methanol. The resulting mixture was concentrated under vacuum. This resulted in 0.5 g (52%) of crude benzyl 5-(3-ethylureido)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate as light yellow oil which was used in the next step directly without further purification.

5-Amino-3-(3-ethylureido)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

A mixture of benzyl 5-(3-ethylureido)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (500 mg, 0.57 mmol, 1.00 equiv, 60%) and Pd/C (500 mg, 41.67 mmol, 72.92 equiv) in methanol (20 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, Sum, 19×100 mm; Mobile phase, water (with 0.1% formic acid) and CH₃CN; This resulted in 33.4 mg (15%) of the title compound as a white solid (m.p. 195-197° C.). LC-MS (ES, m/z): 392 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆, ppm): 10.28 (s, 1H), 9.14 (s, 1H), 8.41 (s, 1H), 7.75-7.76 (d, 1H, J=4 Hz), 7.48 (s, 2H), 7.37 (s, 1H), 7.24 (s, 2H), 6.08 (s, 2H), 4.88 (s, 2H), 3.04-3.09 (m, 2H), 1.04-1.07 (m, 3H).

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(methylsulfonamido)pyridine-2-sulfonamide

Benzyl 5-amino-6-(benzylthio)pyridin-3-ylcarbamate

A solution of tert-butyl 5-(benzyloxycarbonylamino)-2-(benzylthio)pyridin-3-ylcarbamate (4.65 g, 10.00 mmol, 1.00 equiv) in DCM (40 mL) and TFA (10 mL) was stirred overnight at room temperature. The reaction was quenched by the addition of 10 mL of water and then adjusted to pH 8-9 with sodium hydroxide solution. The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10-1:5). This resulted in 3.5 g (96%) of benzyl 5-amino-6-(benzylthio)pyridin-3-ylcarbamate as a yellow solid.

Benzyl 6-(benzylthio)-5-(methylsulfonamido)pyridin-3-ylcarbamate

Into a 50-mL round-bottom flask was placed a solution of benzyl 5-amino-6-(benzylthio)pyridin-3-ylcarbamate (1.5 g, 4.11 mmol, 1.00 equiv) in pyridine (10 mL). This was followed by the addition of methanesulfonyl chloride (560 mg, 4.91 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. Then it was concentrated under vacuum. The residue was diluted with 30 mL of EtOAc and washed with 1×20 mL of 1N HCl and 1×10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.2 g (66%) of benzyl 6-(benzylthio)-5-(methylsulfonamido)pyridin-3-ylcarbamate as a yellow solid.

2-Hydroxy-5-nitronicotinonitrile

Chlorine gas was bubbled slowly into a solution of benzyl 6-(benzylthio)-5-(methylsulfonamido)pyridin-3-ylcarbamate (660 mg, 1.49 mmol, 1.00 equiv) in DCM (10 mL) and water (2 mL) for 5 min at 0-5° C. The resulting solution was stirred for 30 min at 0-5° C., then it was diluted with water (10 mL) and DCM (20 mL). The separated organic layer was dried over sodium sulfate and concentrated under vacuum. This resulted in 600 mg (48%) of benzyl 6-(chlorosulfonyl)-5-(methylsulfonamido)pyridin-3-ylcarbamate as a yellow solid.

2-Chloro-5-nitronicotinonitrile

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (213.4 mg, 1.43 mmol, 1.00 equiv) in CH₃CN (15 mL) and potassium carbonate (592.8 mg, 4.30 mmol, 3.00 equiv). This was followed by the addition of a solution of benzyl 6-(chlorosulfonyl)-5-(methylsulfonamido)pyridin-3-ylcarbamate (600 mg, 0.86 mmol, 1.00 equiv, 60%) in CH₃CN (5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at room temperature, then quenched by the addition of 10 mL of water. The resulting mixture was concentrated under vacuum. The residual solution was adjusted to pH 4 with 6N HCl, then extracted with 3×20 ml, of ethyl acetate. The organic layers were combined, washed with 2×10 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100:1-50:1). This resulted in 640 mg (76%) of benzyl 6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(methylsulfonamido)pyridin-3-ylcarbamate as a yellow solid.

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(methylsulfonamido)pyridine-2-sulfonamide

A mixture of benzyl 6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(methylsulfonamido)pyridin-3-ylcarbamate (840 mg, 1.58 mmol, 1.00 equiv) and Palladium carbon (1 g, 83.33 mmol, 52.78 equiv) in methanol (20 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 5 um, 19×100 mm; Mobile phase, water (with 0.1% formic acid) and CH₃CN; Gradient, 20% CH₃CN up to 40% in 6 min, up to 100% in 1 min, down to 20% in 1 min; Detector, UV 220 & 254 nm. This resulted in 200.3 mg (32%) of the title compound as a white solid (m.p. 209-210° C.). LC-MS-(ES, m/z): 399 [M+H]⁺. ¹H-NMR— (300 MHz, DMSO-d6, ppm): 10.46 (s, 1H), 9.23 (s, 1H), 8.88 (s, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 7.18-7.29 (m, 2H), 7.03-7.04 (d, 1H, J=3 Hz), 6.43 (s, 2H), 4.89 (s, 2H), 3.03 (s, 3H).

5-Amino-3-(5-aminopyridin-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

Benzyl 6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(5-nitropyridin-2-ylamino)pyridin-3-ylcarbamate

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (500 mg, 1.02 mmol, 1.00 equiv, 93%) in 1,4-dioxane (20 mL), 2-chloro-5-nitropyridine (210 mg, 1.33 mmol, 1.20 equiv), Pd₂(dba)₃ (20 mg, 0.02 mmol, 0.02 equiv), Xantphos (40 mg, 0.07 mmol, 0.06 equiv) and potassium carbonate (215 mg, 1.56 mmol, 1.40 equiv). The resulting mixture was stirred for 3 h at 80° C. in an oil bath. The resulting mixture was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1). This resulted in 520 mg (71%) of the title compound as a yellow solid.

5-Amino-3-(5-aminopyridin-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

A mixture of benzyl 6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(5-nitropyridin-2-ylamino)pyridin-3-ylcarbamate (520 mg, 0.72 mmol, 1.00 equiv, 80%) and Palladium carbon (10%, 500 mg) in methanol (50 mL) was stirred for 12 h at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product (362 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 5 um, 19×150 mm; Mobile phase: water and CH₃CN; Gradient, 15% CH₃CN up to 30% in 8 min, up to 100% in 2 min; Detector, UV 220 & 254 nm. This resulted in 103.6 mg (35%) of the title compound as a brown solid. LC-MS (ES, m/z): 413 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6, ppm): 10.24 (1H, s), 9.18 (1H, s), 8.21 (1H, s), 7.66 (1H, d, J=2.7 Hz), 7.51 (1H, s), 7.41 (2H, d, J=2.1 Hz), 7.36 (2H, d, J=2.1 Hz), 6.99 (1H, m), 5.98 (2H, s), 5.05 (2H, m), 4.84 (2H, s).

5-Amino-3-(5-cyanopyridin-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

Benzyl 5-(5-cyanopyridin-2-ylamino)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

Into a 50-mL 3-necked round-bottom flask were placed a solution of benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (400 mg, 0.88 mmol, 1.00 equiv) in dioxane (25 mL), 6-chloronicotinonitrile (146 mg, 1.06 mmol, 1.20 equiv), potassium carbonate (170 mg, 1.23 mmol, 1.40 equiv), Pd₂(dba)₃ (16 mg, 0.02 mmol, 0.02 equiv) and Xantphos (30 mg, 0.05 mmol, 0.06 equiv). The resulting solution was stirred for 1 h at 90° C., then it was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate. This resulted in 450 mg (87%) of the title compound as an orange solid.

5-Amino-3-(5-cyanopyridin-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

A mixture of benzyl 5-(5-cyanopyridin-2-ylamino)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (450 mg, 0.81 mmol, 1.00 equiv) and Pd(OH)₂/C (450 mg, 2.25 mmol, 1.00 equiv) in ethanol/EtOAc(10/10 mL) was stirred for 4.5 h at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, Sum, 19×150 mm; Mobile phase, water (with 0.05% TFA) and CH₃CN; Gradient, 22% CH₃CN up to 42% in 6 min, up to 100% in 1 min; Detector, UV 220 & 254 nm. This resulted in 160 mg (47%) of the title compound as a white solid. LC-MS (ES, m/z): 423 [M+H]⁺. ¹H-NMR (DMSO-d6, 300 MHz, ppm): 10.23 (s, 1H), 9.14 (s, 1H), 8.95 (s, 1H), 8.50 (J=2.1 Hz, d, 1H), 7.94 (J=2.4, 8.7 Hz, dd, 1H), 7.63 (J=2.4 Hz, d, 1H), 7.54 (J=2.1 Hz, d, 1H), 7.44 (s, 1H), 7.14 (d, 2H), 6.90 (J=8.7 Hz, d, 1H), 6.23 (s, 2H), 4.78 (s, 2H).

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(pyrazin-2-ylamino)pyridine-2-sulfonamide

Benzyl 6-(N-(1-hydroxy-1,3-dihydrobenzok[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(pyrazin-2-ylamino)pyridin-3-ylcarbamate

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of benzyl-N-5-amino-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyridin-3-ylcarbamate (1000 mg, 2.05 mmol, 1.00 equiv, 93%) in 1,4-dioxane (20 mL), 2-chloropyrazine (301 mg, 2.65 mmol, 1.20 equiv), Pd₂(dba)₃ (40 mg, 0.04 mmol, 0.02 equiv), Xantphos (80 mg, 0.14 mmol, 0.06 equiv) and potassium carbonate (425 mg, 3.08 mmol, 1.40 equiv). The resulting solution was stirred for 6 h at 80° C. in an oil bath. Then it was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1). This resulted in 600 mg (44%) of the title compound as a yellow solid.

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(pyrazin-2-ylamino)pyridine-2-sulfonamide

A mixture of benzyl 6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(pyrazin-2-ylamino)pyridin-3-ylcarbamate (600 mg, 0.90 mmol, 1.00 equiv, 80%) and Palladium carbon (500 mg) in methanol (30 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions: Column, Atlantis T3, Sum, 19×150 mm; Mobile phase, water (with 0.05% TFA) and CH₃CN; Gradient, 20% CH₃CN up to 30% in 8 min; Detector, UV 254 nm. This resulted in 39.6 g (11%) of the title compound as a yellow solid. LC-MS-(ES, m/z): 399 [M+H]⁺. ¹H-NMR-(300 MHz, DMSO-d6, ppm): 10.26 (1H, s), 9.13 (1H, m), 8.77 (1H, s), 8.23 (1H, s), 8.11 (1H, s), 8.04 (1H, J=2.7 Hz, d), 7.73 (1H, J=2.4 Hz, d), 7.56 (1H, J=2.1 Hz, d), 7.46 (1H, s), 7.17 (2H, s), 6.21 (2H, m), 4.78 (2H, s).

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(pyrimidin-2-ylamino)pyridine-2-sulfonamide

Benzyl 6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(pyrimidin-2-ylamino)pyridin-3-ylcarbamate

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of benzyl-N-5-amino-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyi]pyridin-3-ylcarbamate (800 mg, 1.64 mmol, 1.00 equiv, 93%) in 1,4-dioxane (30 mL), 2-bromopyrimidine (336 mg, 2.11 mmol, 1.20 equiv), Pd₂(dba)₃ (40 mg, 0.04 mmol, 0.02 equiv), Xantphos (80 mg, 0.14 mmol, 0.06 equiv) and sodium 2-methylpropan-2-olate (338 mg, 3.52 mmol, 2.00 equiv). The resulting mixture was stirred for 6 h at 110° C. in an oil bath, then it was cooled and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1). This resulted in 500 mg (46%) of the title compound as a yellow solid.

5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(pyrimidin-2-ylamino)pyridine-2-sulfonamide

A mixture of benzyl 6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(pyrimidin-2-ylamino)pyridin-3-ylcarbamate (500 mg, 0.75 mmol, 1.00 equiv, 80%) and palladium on carbon (500 mg) in methanol (50 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with methanol/DCM (1/10). This resulted in 80.9 mg (27%) of the title compound as a light yellow solid. LC-MS-(ES, m/z): 399 [M+H]⁺. ¹H-NMR-(300 MHz, DMSO-d6, ppm): 10.36 (1H, s), 9.37 (1H, s), 9.18 (1H, s), 8.52 (2H, J=5.1 Hz, d), 8.11 (1H, J=2.4 Hz, d), 7.56 (1H, J=2.4 Hz, d), 7.50 (1H, s), 7.20 (2H, J=1.5 Hz, d), 6.99 (1H, m), 6.25 (2H, s), 4.82 (2H, s).

Methyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

Methyl chloroformate (1.23 g, 13 mmol) was added to the solution of benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (820 mg, 1.8 mmol) in THF (12 ml) at rt. Stirring was kept for 2 days. Removed solvent, diluted with EtOAc (100 ml), washed with water (20 ml×2) and brine (20 ml×2), dried over Na₂SO₄. Concentrated to give off white solid. The mixture of the crude and Pd/C (500 mg, 10 wt %) in MeOH (20 ml), was degassed with Nitrogene, then placed under hydrogen atmosphere at 50 psi for 4 hours. The catalyst was filtered with a pad of Celite, washed with MeOH (100 ml), the solution was then concentrated. The crude was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as white powder. MS calcd for (C₁₄H₁₅BN₄O₆S): 378.169, MS found (ESI negative): (M−H)⁻=377.0. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.35 (s, 1H), 9.19 (s, 1H), 8.95 (s, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 7.14 (dd, J=8.4 Hz, 1H), 6.32 (bs, 2H), 4.86 (s, 2H), 3.64 (s, 3H).

Ethyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

Ethyl chloroformate (570 mg, 3.5 mmol) was added to the solution of benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (227 mg, 0.5 mmol) in THF (8 ml) at rt. Stirring was kept for 2 days. Removed solvent, diluted with EtOAc (100 ml), washed with water (20 ml×2) and brine (20 ml×2), dried over Na₂SO₄. Concentrated to give off white solid. The mixture of the crude and Pd/C (100 mg, 10 wt %) in MeOH (20 ml), was degassed with Nitrogene, then placed under hydrogen atmosphere at 50 psi for 4 hours. The catalyst was filtered with a pad of Celite, washed with MeOH (100 ml), the solution was then concentrated. The crude was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as white powder, yield 91 mg. MS calcd for (C₁₅H₁₇BN₄O₆S): 392.195, MS found (ESI negative): (M−H)⁻=391.0. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.35 (s, 1H), 8.90 (s, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.46 (d, J=2 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 7.14 (dd, J=8 Hz, 1H), 4.83 (s, 2H).

2-Fluoroethyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

General Procedure 4 and 5: Starting material—benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate and 2-fluoroethyl carbonochloridate. Preparative HPLC was applied for the purification and give the title compound as white powder yield 108 mg. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.40 (s, 1H), 9.19 (bs, 1H), 9.05 (s, 1H), 7.61 (m, 2H), 7.47 (d, J=1.6 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.18 (dd, J=8.0, 2 Hz, 1H), 6.38 (bs, 2H), 4.87 (s, 2H), 4.71 (t, J=4 Hz, 2H), 4.59 (t, J=4 Hz, 2H), 4.36 (t, J=4 Hz, 2H), 4.29 (t, J=4 Hz, 2H); MS (ESI) m/z=409.1 (M−H, negative).

2-Hydroxyethyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

2-Benzyloxyethyl chloroformate (2.7 ml, 15 mmol) was added to the solution of benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (910 mg, 2 mmol) in THF (20 ml) at rt. Stirring was kept for 2 days. Removed solvent, diluted with EtOAc (200 ml), washed with water (20 ml×2) and brine (20 ml×2), dried over Na₂SO₄. Concentrated to give off white solid. The mixture of the crude and Pd/C (500 mg, 10 wt %) in MeOH (20 ml), was degassed with nitrogen, then placed under hydrogen atmosphere at 50 psi for 4 hours. The catalyst was filtered with a pad of Celite, washed with MeOH (100 ml), the solution was then concentrated. The crude was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). MS calcd for (C₁₅H₁₇BN₄O₇S): 408.09, MS found (ESI negative): (M−H)⁻=407.1. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.39 (s, 1H), 8.96 (s, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.16 (dd, J=8.4 Hz, 1H), 4.86 (s, 2H), 4.06 (t, J=4.8 Hz, 2H), 3.58 (t, J=4.8 Hz, 2H).

2-(Benzyloxy)ethyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

2-Benzyloxyethyl chloroformate (2.7 ml, 15 mmol) was added to the solution of benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (910 mg, 2 mmol) in THF (20 ml) at rt. Stirring was kept for 2 days. Removed solvent, diluted with EtOAc (200 ml), washed with water (20 ml×2) and brine (20 ml×2), dried over Na₂SO₄. Concentrated to give off white solid. The mixture of the crude and Pd/C (500 mg, 10 wt %) in MeOH (20 ml), was degassed with Nitrogen, then placed under hydrogen atmosphere at 50 psi for 4 hours. The catalyst was filtered with a pad of Celite, washed with MeOH (100 ml), the solution was then concentrated. The crude was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). MS calcd for (C₂₂H₂₃BN₄O₇S): 498.14, MS found (ESI negative): (M−H)⁻=497.1. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.39 (s, 1H), 9.00 (s, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.35-7.25 (m, 5H), 7.22 (d, J=8.4 Hz, 1H), 7.16 (dd, J=8.4 Hz, 1H), 4.84 (s, 2H), 4.51 (s, 2H), 4.22 (t, J=6 Hz, 2H), 3.64 (t, J=4.8 Hz, 2H).

Propyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

Allyl chloroformate (5 ml, 48 mmol) was added to the solution of benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (910 mg, 2 mmol) in THF (50 ml) at rt. Stirring was kept for 2 days. Removed solvent, diluted with EtOAc (300 ml), washed with water (40 ml×2) and brine (40 ml×2), dried over Na₂SO₄. Concentrated to give off white solid. The mixture of the crude (1.62 g, 3 mmol) and Pd/C (900 mg, 10 wt %) in MeOH (30 ml), was degassed with Nitrogen, then placed under hydrogen atmosphere at 50 psi for 4 hours. The catalyst was filtered with a pad of Celite, washed with MeOH (100 ml), the solution was then concentrated. The crude was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). MS calcd for (C₁₆H₁₉BN₄O₆S): 406.11, MS found (ESI negative): (M−H)⁻=405.1. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.34 (s, 1H), 9.17 (s, 1H), 8.92 (s, 1H), 7.62 (d, J=2 Hz, 1H), 7.57 (d, J=2 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.15 (dd, J=8 Hz, 1H), 6.30 (s, 2H), 4.86 (s, 2H), 4.00 (t, J=6.4 Hz, 2H), 1.61 (m, 2H), 0.88 (t, J=7.2 Hz, 3H).

Isobutyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate-

General Procedure 4 and 5: Starting Material compound benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate and isobutyl carbonochloridate. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.36 (s, 1H), 9.20 (bs, 1H), 8.96 (s, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.47 (d, J=2.4 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 7.16 (dd, J=8.0, 2 Hz, 1H), 4.87 (s, 2H), 3.86 (d, J=6.8 Hz, 2H), 1.91 (m, 1H), 0.89 (d, J=6.8 Hz, 6H); MS (ESI) m/z=419.1 (M−H, negative).

Hexyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

Hexyl chloroformate (2.45 ml, 15 mmol) was added to the solution of benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (910 mg, 2 mmol) in THF (20 ml) at rt. Stirring was kept for 2 days. Removed solvent, diluted with EtOAc (100 ml), washed with water (20 ml×2) and brine (20 ml×2), dried over Na₂SO₄. Concentrated to give off white solid. The mixture of the crude and Pd/C (100 mg, 10 wt %) in MeOH (20 ml), was degassed with nitrogen, then placed under hydrogen atmosphere at 50 psi for 4 hours. The catalyst was filtered with a pad of Celite, washed with MeOH (100 ml), the solution was then concentrated. The crude was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as white powder. MS calcd for (C₁₉H₂₅BN₄O₆S): 448.16, MS found (ESI negative): (M−H)⁻=447.1. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.30 (s, 1H), 9.11 (br, 1H), 8.86 (s, 1H), 7.57 (d, J=2 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.40 (s, 1H), 7.18 (d, J=8 Hz, 1H), 7.08 (dd, J=8 Hz, 1H), 6.26 (br, 2H), 4.81 (s, 2H), 3.98 (t, J=6.8 Hz, 2H), 1.53 (m, J=6.4 Hz, 2H), 1.22 (s, 6H), 0.81 (t, J=6.8 Hz, 3H).

Cyclopentyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

General Procedure 4 and 5: Starting Materials. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.35 (s, 1H), 9.20 (bs, 1H), 8.84 (s, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.47 (s, 1H), 7.24 (d, J=8 Hz, 1H), 7.15 (dd, J=8, 2 Hz, 1H), 6.32 (bs, 2H), 5.03 (m, 1H), 4.88 (s, 2H), 1.84 (m, 2H), 1.65 (m, 4H), 1.57 (m, 2H); S (ESI) m/z=431.1 (M−H, negative).

Cyclohexyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

Cyclohexyl chloroformate (2.44 g, 15 mmol) was added to the solution of benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (910 mg, 2 mmol) in THF (12 ml) at rt. Stirring was kept for 2 days. Removed solvent, diluted with EtOAc (200 ml), washed with water (20 ml×2) and brine (20 ml×2), dried over Na₂SO₄. Concentrated to give off white solid. The mixture of the crude and Pd/C (500 mg, 10 wt %) in MeOH (20 ml), was degassed with Nitrogene, then placed under hydrogen atmosphere at 50 psi for 4 hours. The catalyst was filtered with a pad of Celite, washed with MeOH (100 ml), the solution was then concentrated. The crude was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as light yellow powder. MS calcd for (C₁₉H₂₃BN₄O₆S): 446.28, MS found (ESI negative): (M−H)⁻=445.1 ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.35 (s, 1H), 9.18 (bs, 1H), 8.73 (s, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.57 (d, J=2 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 7.14 (dd, J=8.4 Hz, 1H), 6.30 (bs, 2H), 4.86 (s, 2H), 3.65 (s, 2H), 1.90-1.20 (m, 9H).

Phenyl 5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate

Phenyl chloroformate (1.8 ml, 14 mmol) was added to the solution of benzyl 5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (910 mg, 2 mmol) in THF (20 ml) at rt. Stirring was kept for 2 days. Removed solvent, diluted with EtOAc (100 ml), washed with water (20 ml×2) and brine (20 ml×2), dried over Na₂SO₄. Concentrated and got off white solid. The crude was treated with HBr (in acetic acid, 5 ml), stirred at r.t. for 4 hours, concentrated. The residue was dissolved in DMSO then purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as off white powder, yield 240 mg. MS calcd for (C₁₉H₁₇BN₄O₆S): 440.10, MS found (ESI positive): (M+H)⁺=441.0. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.41 (s, 1H), 9.35 (s, 1H), 9.21 (s, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.50 (s, 1H), 7.42 (t, J=8 Hz, 2H), 7.26 (m, 3H), 7.19 (d, J=7.6 Hz, 2H), 6.36 (s, 2H), 4.87 (s, 2H).

N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy benzenesulfonamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 4-methoxybenzenesulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.97 (s, 1H), 9.32 (s., 1H), 7.64 (m, 3H), 7.21 (d, J=10 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 4.89 (s, 2H), 3.80 (s, 3H). MS (ESI): m/z=336.0 (M−H, negative).

N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-hydroxybenzenesulfonamide

N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfonamide (0.2 g, 0.59 mmol), DCM (5 mL), was added boron tribromide 1M solution in DCM (1.7 ml, 1.78 mmol) at 0° C. overnight. Purification: ice was added and worked up with EtOAc; preparative HPLC was applied for the purification and give product as white powder yield 5 mg (1%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.41 (s, 1H), 9.81 (s, 1H)), 9.29 (s, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.51 (d, J=8 Hz, 2H), 7.20 (d, J=10 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 4.89 (s, 2H); MS (ESI): m/z=322.0 (M−H, negative).

5-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sulfonamide

2-Benzylsulfanyl-5-methoxy-pyridine

To a solution of 2-bromo-5-methoxy-pyridine (2.0 g, 10.6 mmol) in THF (20 mL) at −78° C. was added n-BuLi (1.6 M in hexane, 6.65 mL, 10.64 mmol). After 20 min, dibenzyldisulfide (3.15 g, 12.7 mmol) was added and the mixture was stirred for 1 h in an ice bath and 1 h at ambient temperature. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Partial purification was accomplished by flash silica gel column chromatography (Biotage®, 15-40% ethyl acetate in hexanes gradient) resulting in 1.086 g of the title compound that was used without further purification in the next step.

5-Methoxy-pyridine-2-sulfonyl chloride

Through a solution of 2-benzylsulfanyl-5-methoxy-pyridine (1.086 g) in DCM (25 mL) and water (5 mL) at 0° C. was bubbled chlorine for 15 min. The mixture was stirred for 15 min before bubbling nitrogen for 15 min. The organic layer was separated, dried over Na₂SO₄, filtered and concentrated in vacuo providing the 1.039 g (47% over 2 steps) of the title compound that was directly used in the next step without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.43 (d, J=2.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.66 (dd, J=9.0, 2.7 Hz, 1H), 4.00 (s, 3H).

5-Methoxy-pyridine-2-sulfonic acid (1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.400, 2.68 mmol), pyridine (0.434 mL, 5.37 mmol), acetonitrile (10 mL), and 5-methoxy-pyridine-2-sulfonyl chloride (1.039 g, 2.68 mmol). Purification was accomplished by Biotage® silica gel chromatography (50 g SNAP™ column, eluting with 2-25% MeOH in DCM gradient) followed by lyophilizing from an acetonitrile-water mixture produced 0.691 g (80%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.39 (s, 1H), 9.20 (s, 1H), 8.37 (d, J=2.7 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.58-7.47 (m, 2H), 7.36 (d, J=4.7 Hz, 1H), 7.31-7.16 (m, 1H), 4.87 (s, 2H), 3.87 (s, 3H).

5-Hydroxy-pyridine-2-sulfonic acid (1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide

To a solution of 5-methoxy-pyridine-2-sulfonic acid (1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (0.690 g, 2.16 mmol) in DCM (35 mL) at 0° C. was added BBr₃ (1 M in DCM, 8.62 mL, 8.62 mmol). After 3 h, the ice bath was removed and after an additional 3 h at room temperature more BBr₃ (1 M in DCM, 2.16 mL, 2.16 mmol) was added. After overnight, the mixture was poured into crushed ice. After the ice melted the solid was collected by filtration, washed with water and dried in vacuo generating 291 mg of crude material. The organic layer of the filtrate was separated and dried in vacuo producing another 321 mg of crude material. The two fractions (291 mg and 321 mg) were combined, dissolved in 10% MeOH in EtOAc and dried in vacuo producing 585 mg of crude material. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.94 (s, 1H). 10.28 (s, 1H), 9.83 (s, 1H), 9.20 (bs, 1H), 8.16 (d, J=2.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.24 (m, 3H), 4.86 (s, 2H); MS (ESI) m/z=305.0 (M−H, negative).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-3-methyl-benzenesulfonamide

To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.25 g, 1.34 mmol) in anhydrous pyridine (30 mL) at 5° C. was added 4-methoxy-3-methyl-benzenesulfonyl chloride (0.29 g, 1.34 mmol). After overnight at room temperature, the volatiles were removed in vacuo. The residue was treated with H₂O (80 mL) and sonicated for 4 h. The fine precipitate that formed was filtered, washed with water and dried in vacuo generating 0.22 g (48%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.06 (brs, 1H), 9.21 (s, 1H), 7.56-7.53 (m, 2H), 7.48 (d, J=1.6 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.17 (dd, J=8.2, 1.8 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H), 4.87 (s, 2H), 3.81 (s, 3H), 2.13 (s, 3H); MS (ESI) m/z=332 (M−1, negative); HPLC purity: 97.58% (MaxPlot 200-400 nm), 97.89% (220 nm).

4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-methyl-benzenesulfonamide

To a suspension of N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-3-methyl-benzenesulfonamide (0.80 g, 2.40 mmol) in 100 mL of anhydrous DCM at 5° C. was added 1N solution of BBr₃ in DCM (3 mL). The resulting solution stirred at room temperature overnight. The precipitate that formed was filtered, washed with DCM and briefly dried before suspending in water. The gummy material formed was extracted into EtOAc, and the organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo. This was further purified through preparative HPLC affording 0.030 g (3% yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.33 (brs, 1H), 9.98 (brs, 1H), 9.21 (s, 1H), 7.47 (d, J=2.5 Hz, 2H), 7.5 (d, J=1.9 Hz, 2H), 7.36 (dd, J=8.6, 2.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.14 (dd, J=8.2, 1.8 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 4.85 (s, 2H), 2.07 (s, 3H); MS (ESI) m/z=318 (M−1, negative); HPLC purity: 99.91% (MaxPlot 200-400 nm), 99.83% (220 nm).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-methyl-benzenesulfonamide

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (721 mg, 3.62 mmol), pyridine (10 mL), and 4-methoxy-2-methyl-benzenesulfonyl chloride (800 mg, 3.62 mmol). Purification: Column chromatography using 50-70% EtOAc in hexane. Product was isolated as a light-yellow solid: yield 900 mg (75%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.19 (s, 1H), 9.18 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.24-7.19 (m, 1H), 7.15 (d, J=2.0 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.83 (d, J=9.0 Hz, 1H), 4.84 (s, 2H), 3.74 (s, 3H), 2.53 (s, 3H); MS (ESI) m/z=332 (M−1, negative); HPLC purity: 96.93% (MaxPlot 200-400 nm), 97.02% (220 nm).

4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-methyl-benzenesulfonamide

To a solution of N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-methyl-benzenesulfonamide (400 mg, 1.20 mmol) in DCM (10 mL) was added BBr₃ (1M in DCM, 3.60 mL, 3.6 mmol). After overnight at rt, water was added and the CH₂Cl₂ layer was separated, dried over MgSO₄, filtered and concentrated in vacuo. Purification was accomplished by preparative HPLC generating 140 mg (36%) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.25 (s, 1H), 10.11 (s, 1H), 9.18 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.43 (s, 1H), 7.20-7.25 (m, 1H), 7.11-7.17 (m, 1H), 6.57-6.70 (m, 2H), 4.86 (s, 2H), 2.48 (s, 3H); MS (ESI) m/z=318 (M−1, negative); HPLC purity: 99.12% (MaxPlot 200-400 nm), 99.49% (220 nm).

N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-methylbenzenesulfonamide

General Procedure 1: Starting Materials 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 4-methoxy-2-methylbenzene-1-sulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.95 (s, 1H), 9.30 (s., 1H), 7.67 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.19 (d, J=10.4 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 6.80 (dd, J=8.8, 2.8 Hz, 1H), 4.89 (s, 2H), 3.78 (s, 3H), 2.57 (s, 2H). MS (ESI): m/z=350.0 (M−H, negative).

N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-hydroxy-2-methylbenzenesulfonamide

Boron tribromide (3.4 mL, 3.4 mmol, 1M solution) was added drop-wise slowly to an ice-cold solution of the N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-methylbenzenesulfonamide (0.4 g, 1.13 mmol) in DCM at 0° C. The reaction was allowed to stir at r.t. and monitored by LC/MS. Purification: ice was added slowly to the mixture and worked up with DCM, the organic layer was washed with brine, dried over Na₂SO₄ and dried in vacuo. Further purification was carried out by preparative HPLC to give title product N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-hydroxy-2-methylbenzene sulfonamide (35 mg, yield: 9.2%) ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.26 (bs, 1H), 9.83 (s, 1H), 9.30 (bs, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.19 (d, J=10.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.58 (dd, J=8.8, 2.4 Hz, 1H), 4.89 (s, 2H), 2.50 (s, 3H); MS (ESI) m/z=336.1 (M−H, negative).

2-Hydroxy-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-benzoic acid

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (200 mg, 1.3 mmol), 5-(chlorosulfonyl)salicylic acid (378 mg, 1.6 mmol), pyridine (0.4 mL, 5.2 mmol), DMSO (2 mL), and MeCN (10 mL) at rt O/N. 1 M HCl (5 mL) was added and the mixture was concentrated in vacuo at 40° C. The remaining DMSO solution was purified by RP-Biotage (10-100% MeOH/0.1% aq TFA). The major fraction was concentrated in vacuo at 40° C. and then lyophilized to give the title compound as a white solid: yield; 95 mg (21%). ¹H NMR (400 MHz, DMSO-d₆+HCl) δ (ppm): 10.24 (s, 1H), 8.08-8.07 (m, 1H), 7.76-7.73 (m, 1H), 7.44-7.43 (m, 1H), 7.23-7.21 (m, 1H), 7.14-7.12 (m, 1H), 7.05-7.03 (m, 1H), 4.83 (s, 2H); MS (ESI) m/z=348 (M−1, negative); HPLC purity: 98.77% (MaxPlot 200-400 nm), 98.61% (220 nm).

[2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-phenyl]-acetic acid ethyl ester

(2-Chlorosulfonyl-5-methoxy-phenyl)-acetic acid ethyl ester

Ethyl 3-methoxyphenyl acetate (3.0 mL, 15 mmol) was added dropwise to chlorosulfonic acid (10 mL, 0.15 mol) at 0° C. The mixture was allowed to warm to rt and stirred for 3 h. The mixture was then diluted with H₂O and the precipitate was isolated by filtration to give the title compound as a white solid: yield; 2.4 g (52%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.64-7.62 (m, 1H), 6.76-6.73 (m, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.99 (s, 2H), 3.71 (s, 3H), 1.14 (t, J=7.3 Hz, 3H), 4.88 (s, 2H).

[2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-phenyl]-acetic acid ethyl ester

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (750 mg, 5.0 mmol), (2-chlorosulfonyl-5-methoxy-phenyl)-acetic acid ethyl ester (1.77 g, 6.0 mmol), pyridine (1.5 mL, 20 mmol), DMSO (5.0 mL), and MeCN (20 mL) at rt O/N. The mixture was concentrated in vacuo at 40° C. and the remaining DMSO soln was purified by RP-Biotage (10-100% MeOH/0.1% aq TFA). The major fraction was concentrated in vacuo, then lyophilized from MeCN/H₂O to give the title compound as a pale yellow solid: yield; 643 mg (32%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.19 (s, 1H), 9.21 (s, 1H), 7.76-7.74 (m, 1H), 7.44-7.43 (m, 1H), 7.25-7.23 (m, 1H), 7.13-7.10 (m, 1H), 6.96-6.92 (m, 2H), 4.87 (s, 2H), 4.05 (q, J=7.3 Hz, 2H), 4.02 (s, 2H), 4.05 (t, J=7.3 Hz, 3H); MS (ESI) m/z=404 (M−1, negative); HPLC purity: 93.84% (MaxPlot 200-400 nm), 94.60% (220 nm).

[2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-phenyl]-acetic acid

A mixture of [2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-phenyl]-acetic acid ethyl ester (590 mg, 1.5 mmol), LiOH (105 mg, 4.4 mmol), H₂O (10 mL), and MeOH (30 mL) was stirred at rt O/N. 1 M HCl (5 mL) was added and the mixture was concentrated in vacuo at 40° C. The residue was purified by RP-Biotage (10-100% MeOH/0.1% aq TFA). The major fraction was concentrated in vacuo at 40° C. and then lyophilized to give the title compound as a white solid: yield; 239 mg (42%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.28 (bs, 1H), 10.13 (s, 1H), 9.19 (s, 1H), 7.73-7.71 (m, 1H), 7.43-7.42 (m, 1H), 7.23-7.21 (m, 1H), 7.12-7.11 (m, 1H), 6.93-6.89 (m, 2H), 4.85 (s, 2H), 3.93 (s, 2H), 3.75 (s, 3H); MS (ESI) m/z=378 (M+H, positive); HPLC purity: 98.23% (MaxPlot 200-400 nm), 97.92% (220 nm).

[5-Hydroxy-2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-phenyl]-acetic acid

1 M BBr₃ (4.5 mL, 4.5 mmol) was added to a solution of [2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-phenyl]-acetic acid (170 mg, 0.45 mmol) in CH₂Cl₂ (10 mL) at rt resulting in the formation of a fine suspension. After stirring at rt O/N the mixture was concentrated in vacuo at 40° C. The residue was purified by RP-Biotage (10-100% MeOH/0.1% aq TFA). The major fraction was concentrated in vacuo at 40° C. and then lyophilized to give the title compound as a white solid: yield; 32 mg (20%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.34 (s, 1H), 10.07 (s, 1H), 9.20 (s, 1H), 7.65-7.62 (m, 1H), 7.43-7.42 (m, 1H), 7.24-7.22 (m, 1H), 7.13-7.10 (m, 1H), 6.73-6.68 (m, 2H), 4.87 (s, 2H), 3.89 (s, 2H); MS (ESI) m/z=364 (M+H, positive); HPLC purity: 94.07% (MaxPlot 200-400 nm), 92.99% (220 nm).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-hydroxymethyl-4-methoxy-benzenesulfonamide

4-Methoxy-2-methyl-benzenesulfonic acid

1-Methoxy-3-methyl-benzene (10.0 g, 81.85 mmol) was added to H₂SO₄ (conc.) (15 mL) and stirred for 1 h at rt. The reaction mixture was then poured into cooled brine solution (200 mL). After 30 min, the white solid that precipitated was filtered and dried to afford the title compound (15.6 g, 94%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.62 (d, J=9.2 Hz, 1H), 6.69-6.58 (m, 2H), 3.71 (s, 3H), 2.41 (s, 3H).

5-Methoxy-2-sulfo-benzoic acid

To a solution of 4-methoxy-2-methyl-benzenesulfonic acid (15.6 g, 77.13 mmol) in KOH (100 mL, 1.5 M) was heated to 80° C. and KMnO₄ (50.0 g, 316.39 mmol) was added in portions at the same temperature. After 1 h, the reaction was cooled and the black solid was removed by filtration through Celite. The filtrate was concentrated to half of the volume under reduced pressure and acidified with conc. HCl to pH 1 and cooled in an ice bath. The white precipitate that formed was collected by filtration and after drying generated 4.86 g (27%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.77 (d, J=9.2 Hz, 1H), 7.26 (d, J=3.1 Hz, 1 H), 7.09 (dd, J=9.2, 3.1 Hz, 1H), 3.81 (s, 3H).

5-Methoxy-1,1-dioxo-1H-1λ6-benzo[c][1,2]oxathiol-3-one

A suspension of 5-methoxy-2-sulfo-benzoic acid (4.86 g, 20.92 mmol) in benzene (50 mL) containing SOCl₂ (2.98 g, 25.11 mmol) was stirred O/N at 80° C. Half of the solvent was removed under reduced pressure. After cooling in an ice-water bath, the solid precipitate was filtered and dried generating 4.30 g (96%) of the title compound. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.88 (d, J=9.0 Hz, 1 H), 7.54-7.43 (m, 2H), 3.99 (s, 3H).

5-Methoxy-2-sulfo-benzoic acid methyl ester

A solution of 5-methoxy-1,1-dioxo-1H-1λ⁶-benzo[c][1,2]oxathiol-3-one (4.30 g, 20.07 mmol) in MeOH (20 mL) was stirred at 50° C. for 2 h. The reaction mixture was then concentrated under reduced pressure to give a thick liquid that on standing partially crystallized. Yield 4.20 g, 85%. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.62 (d, J=9.2 Hz, 1H), 6.96 (dd, J=9.2, 3.4 Hz, 1H), 6.77 (d, J=2.2 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H).

2-Chlorosulfonyl-5-methoxy-benzoic acid methyl ester

A mixture of 5-methoxy-2-sulfo-benzoic acid methyl ester (4.20 g, 17.05 mmol) and PCl₅ (4.26 g, 20.46 mmol) was heated at 100° C. for 3 h. The volatile component (POCl₃) was removed under reduced pressure, and the residue was dissolved in Et₂O. The ethereal solution was washed several times with ice-water and dried over MgSO₄. Filtration and evaporation of the solvent afforded the target compound (3.60 g, 80%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.62 (d, J=9.4 Hz, 1H), 6.96 (dd, J=9.4, 3.1 Hz, 1H), 6.76 (d, J=2.8 Hz, 1H), 3.77 (s, 3H), 3.69 (s, 3H).

2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-benzoic acid methyl ester

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (2.02 g, 13.60 mmol), pyridine (15 mL), and 2-chloro-sulfonyl-5-methoxy-benzoic acid methyl ester (3.60 g, 13.60 mmol). Purification: Column chromatography using 50-70% EtOAc in hexane. Product was isolated as a light-yellow solid: yield 2.8 g (55%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.91 (s, 1H), 9.22 (s, 1H), 7.74 (d, J=9.4 Hz, 1H), 7.48 (d, J=2.2 Hz, 1H), 7.31-7.24 (m, 1H), 7.22-7.11 (m, 3H), 4.89 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H), MS (ESI) m/z=376 (M−1, negative).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-hydroxymethyl-4-methoxy-benzenesulfonamide

To a solution in 2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-benzoic acid methyl ester (1.0 g, 2.65 mmol) and MeOH (0.42 mL, 10.6 mmol) in THF (20 mL) at 0° C. was added LiBH₄ (2.65 mL, 2M in THF). The reaction mixture was stirred for 3 h at rt. Slowly HCl (1M, 20 mL) was added. After 30 min. the THF was removed in vacuo. Water and ethyl acetate were added and the organic layer was separated, dried over MgSO₄, filtered and concentrated in vacuo generating 800 mg (86%) of the title compound as a white solid. mp.>280° C. (decomp.); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.18 (s, 1H), 9.21 (s, 1H), 7.76 (d, J=9.2 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.25-7.23 (m, 2H), 7.14 (dd, J=8.6, 2.2 Hz, 1H), 6.88 (dd, J=9.2, 3 Hz, 1H), 5.59-5.33 (m, 1H), 4.86 (s, 4H), 3.79 (s, 3H); MS (ESI) m/z=348 (M−1, negative); HPLC purity: 94.19% (MaxPlot 200-400 nm), 94.30% (220 nm).

2-Aminomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfonamide

2-Bromomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfonamide

To a solution of N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-hydroxymethyl-4-methoxy-benzenesulfonamide (300 mg, 0.86 mmol) in DCM (5 mL) was added BBr₃ (1M in DCM, 2 mL, 2.0 mmol) and stirred overnight at rt. The reaction mixture was quenched with H₂O and organic materials were extracted with CH₂Cl₂ and dried over MgSO₄. Filtration and evaporation of the solvent afforded the title compound (200 mg, 58%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.62 (s, 1H), 10.33 (s, 1H), 9.26 (br. s., 1H), 7.76 (d, J=8.6 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 7.03 (d, J=2.7 Hz, 1H), 6.84 (dd, J=8.6, 2.3 Hz, 1H), 4.98 (s, 2H), 4.93 (s, 2H); MS (ESI) m/z=396 and 398 (M−1, negative).

2-Azidomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1, 2]oxaborol-6-yl)-benzenesulfonamide

To a solution of 2-bromomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c]-[1,2]oxaborol-6-yl)-benzenesulfonamide (80 mg, 0.20 mmol) in DMF (3.0 mL) was added NaN₃ (39 mg, 0.60 mmol) and stirred for 3 h at rt. The reaction mixture was quenched with H₂O and organic materials were extracted with EtOAc and washed with water, brine and dried over MgSO₄. Filtration and evaporation of the solvent afforded the title compound (60 mg, 83%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.57 (s, 1H), 10.16 (s, 1H), 9.21 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.44 (s, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 6.92 (d, J=2.3 Hz, 1H), 6.82-6.72 (m, 1H), 4.87 (s, 2H), 4.75 (s, 2H); MS (ESI) m/z=360 (M−1, negative).

2-Aminomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfonamide

To a solution of 2-azidomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]-oxaborol-6-yl)-benzenesulfonamide (60 mg, 0.17 mmol) in MeOH (15 mL) was added Pd/C (60 mg, 10% wet). The reaction mixture was placed under a hydrogen atmosphere at 30 psi for 1.5 h at rt. The solid catalyst was removed by filtration through Celite. After evaporation of the solvent, the crude compound was purified by preparative HPLC generating 10 mg (18%) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.24 (s, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.10 (dd, J=8.2, 2.0 Hz, 1H), 6.96 (d, J=2.3 Hz, 1H), 6.68 (dd, J=8.6, 2.3 Hz, 1H), 4.86 (s, 2H), 4.09 (s, 2H); MS (ESI) m/z=335 (M+1, positive); HPLC purity: 94.52% (MaxPlot 200-400 nm), 94.91% (220 nm).

N-Butyl-2-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

Ethyl 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetate

To a stirred solution of ethyl 2-(2-(chlorosulfonyl)-5-methoxyphenyl)acetate (9.54 g, 32.6 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (4.86 g, 32.6 mmol) in 400 mL of ACN was added NaHCO₃ (8.22 g, 97.8 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered through a pad of silica gel and washed with ACN. The filtrate was concentrated to give 11.6 g of the title compound as a yellow solid. MS calcd. for (C₁₈H₂₀BNO₇S): 405.1, MS found (ESI negative): (M−H)⁻=404.1

2-(2-(N-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetic acid

To a stirred solution of ethyl 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetate (11.6 g, 28.6 mmol) in 400 mL of MeOH and water (3:1, v/v) was added LiOH (2.1 g, 85.9 mmol) in portion. The reaction mixture was stirred at room temperature for 16 hours. More LiOH (1.0 g, 41.8 mmol) was added, and the reaction mixture was stirred for additional 4 hours. After MeOH was removed in vacuo, the residue was dissolved in water and acidified with 6N HCl. The mixture was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na₂SO₄, and concentrated to give 8.1 g of the title compound as an off-white solid. MS calcd for (C₁₆H₁₆BNO₇S): 377.1, MS found (ESI negative): (M−H)⁻=376.0.

N-Butyl-2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetamide

To a stirred solution of 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetic acid (1.0 g, 2.65 mmol) and n-butylamine (317 uL, 3.18 mmol) in 20 mL of DMF was added HATU (1.51 g, 3.98 mmol) and DIEA (1.85 mL, 10.6 mmol). The reaction mixture was stirred at room temperature for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na₂SO₄ and concentrated to give a yellow residue. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give 0.38 g of the title compound as a white solid. MS calcd for (C₂₀H₂₅BN₂O₆S): 432.2, MS found (ESI negative): (M−H)⁻=431.1. ¹H NMR (DMSO-d₆) δ (ppm): 10.09 (s, 1H), 9.20 (bs, 1H), 8.08 (t, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.43 (s, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.95 (s, 1H), 6.87 (d, J=8.8 Hz, 1H), 4.86 (s, 2H), 3.91 (s, 2H), 3.75 (s, 3H), 3.08 (q, 2H), 1.39 (m, 2H), 1.28 (m, 2H), 0.85 (t, 3H).

N-Butyl-2-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

To a stirred solution of N-butyl-2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetamide (202 mg, 0.467 mmol) in 10 mL of CH₂Cl₂ at 0° C. was added BBr₃ (1.0 M solution in CH₂Cl₂, 1.4 mL, 1.4 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After quenched with water, the solvent was removed in vacuo. The residue was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na₂SO₄, and concentrated to give an off-white residue. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give 89.4 mg of the title compound as a white solid. MS calcd for (C₁₉H₂₃BN₂O₆S): 418.1, MS found (ESI negative): (M−H)⁻=417.1. ¹H NMR (DMSO-d₆) δ (ppm): 10.33 (bs, 1H), 10.04 (s, 1H), 9.20 (bs, 1H), 8.05 (t, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.77 (s, 1H), 6.64 (d, J=8.8 Hz, 1H), 4.86 (s, 2H), 3.84 (s, 2H), 3.08 (q, 2H), 1.40 (m, 2H), 1.29 (m, 2H), 0.85 (t, 3H).

N-Ethyl-2-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

N-Ethyl-2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetamide

To a stirred solution of 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetic acid (1.02 g, 2.71 mmol) and ethylamine (2.0 M solution in THF, 5.41 mL, 10.82 mmol) in 20 mL of DMF was added HATU (1.54 g, 4.06 mmol). The reaction mixture was stirred at room temperature for 2 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na₂SO₄ and concentrated to give a yellow residue. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give 0.39 g of the title compound as a white solid. MS calcd for (C₁₈H₂₁BN₂O₆S): 404.1, MS found (ESI negative): (M−H)⁻=403.1.

N-Ethyl-2-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

To a stirred solution of N-ethyl-2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetamide (272 mg, 0.673 mmol) in 10 mL of CH₂Cl₂ at ° C. was added BBr₃ (1.0 M solution in CH₂Cl₂, 2.0 mL, 2.0 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After quenched with water, the solvent was removed in vacuo. The residue was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na₂SO₄, and concentrated to give an off-white residue. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give 155 mg of the title compound as a white solid. MS calcd for (C₁₇H₁₉BN₂O₆S): 390.1, MS found (ESI negative): (M−H)⁻=389.1. ¹H NMR (DMSO-d₆) δ (ppm): 10.34 (s, 1H), 10.04 (s, 1H), 9.20 (bs, 1H), 8.07 (t, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.76 (s, 1H), 6.64 (d, J=8.8 Hz, 1H), 4.86 (s, 2H), 3.83 (s, 2H), 3.11 (q, 2H), 1.03 (t, 3H).

Ethyl 2-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetate

To a solution of ethyl 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetate (208 mg, 0.513 mmol) in 10 mL of CH₂Cl₂ at 0° C. was added BBr₃ (1.0 M solution in CH₂Cl₂, 1.54 mL, 1.54 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After quenched with water, the solvent was removed in vacuo. The residue was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na₂SO₄, and concentrated to give an off-white residue. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give 7 mg of the title compound as a white solid. MS calcd for (C₁₇H₁₈BNO₇S): 391.1, MS found (ESI negative): (M−H)⁻=390.1. ¹H NMR (DMSO-d₆) δ (ppm): 10.35 (s, 1H), 10.06 (s, 1H), 9.20 (bs, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.71 (s, 1H), 6.69 (d, 1H), 4.85 (s, 2H), 4.02 (q, 2H), 3.95 (s, 2H), 1.14 (t, 3H).

4-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydroxyethyl)benzenesulfonamide and

2-(2-bromoethyl)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl) benzenesulfonamide

N-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydroxyethyl)-4-methoxy benzenesulfonamide

To a solution of 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetic acid (524 mg, 1.39 mmol) in 20 mL of THF was added borane (1.0 M solution in THF, 5.6 mL, 5.6 mmol). After quenched with water, the solvent was removed in vacuo. The residue was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na₂SO₄, and concentrated to give a white solid. MS calcd for (C₁₆H₁₈BNO₆S): 363.1, MS found (ESI negative): (M−H)⁻=362.1.

4-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydroxyethyl)benzenesulfonamide and 2-(2-bromoethyl)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1, 2]oxaborol-6-yl)benzenesulfonamide

To a solution of N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydroxyethyl)-4-methoxybenzenesulfonamide (105 mg, 0.289 mmol) in 2 mL of CH₂Cl₂ at ° C. was added BBr₃ (1.0 M solution in CH₂Cl₂, 1.16 mL, 1.16 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After quenched with water, the solvent was removed in vacuo. The residue was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na₂SO₄, and concentrated to give a yellow residue. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give 24 mg of 4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydroxyethyl)benzenesulfonamide and as a white solid and 17 mg of 2-(2-bromoethyl)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide as a white solid.

Analytical data for 4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydroxyethyl)benzenesulfonamide

MS calcd for (C₁₅H₁₆BNO₆S): 349.1, MS found (ESI negative): (M−H)⁻=348.0. ¹H NMR (DMSO-d₆) δ (ppm): 10.25 (s, 1H), 10.13 (s, 1H), 9.19 (bs, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 6.65 (d, J=8.8 Hz, 1H), 4.86 (s, 2H), 3.62 (t, 2H), 3.07 (t, 2H).

Analytical data for 2-(2-bromoethyl)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

MS calcd for (C₁₅H₁₅BBrNO₅S): 411.0, MS found (ESI negative): (M−H)⁻=410.0. ¹H NMR (DMSO-d₆) δ (ppm): 10.39 (s, 1H), 10.24 (s, 1H), 9.20 (bs, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 6.69 (d, J=8.8 Hz, 1H), 4.84 (s, 2H), 3.64 (t, 2H), 3.39 (t, 2H).

2-Hydroxy-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-benzoic acid methyl ester

5-Chlorosulfonyl-2-hydroxy-benzoic acid methyl ester

2-Hydroxy-benzoic acid methyl ester (5.0 g, 32.8 mmol) was added drop-wise to chlorosulfonic acid (32.8 g, 0.32 mol) at 0° C. The mixture was allowed to warm to rt, Then heated at 40° C. for 30 min. The mixture was cooled to rt, then poured into crushed ice and the precipitate was isolated by filtration to providing 5.2 g (63%) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.00 (d, J=2.2 Hz, 1H), 7.68 (dd, J=8.5, 2.2 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 3.86 (s, 3H).

2-Hydroxy-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-benzoicacid methyl ester

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (1.18 g, 7.9 mmol), acetonitrile (40 mL), 5-chlorosulfonyl-2-hydroxy-benzoic acid methyl ester (2.0 g, 7.9 mmol), pyridine (3.15 g, 39.8 mmol). This generated 1.5 g (53%) of the title compound as a pale yellow solid. A portion (200 mg) of this material was purified further by reverse-phase preparative HPLC (gradient of water (0.1% formic acid) and methanol) providing 0.10 g of the title compound as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 11.02 (s, 1H), 10.17 (s, 1H), 9.22 (s, 1H), 8.12 (d, J=2.3 Hz, 1H), 7.76 (dd, J=8.6, 2.3 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.17 (dd, J=8.2, 2.3 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 4.88 (s, 2H), 3.86 (s, 3H); MS (ESI) m/z=364 (M+1, positive); HPLC purity: 99.39% (MaxPlot 200-400 nm), 99.33% (220 nm).

4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-hydroxymethyl-benzenesulfonamide

Acetic acid 5-hydroxy-2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-benzyl ester

A mixture of 2-bromomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxa-borol-6-yl)-benzenesulfonamide (200 mg, 0.5 mmol) and NaOAc (123 mg, 1.50 mmol) in glacial AcOH (5 mL) was heated at 110° C. (bath temp) for 4 h. The mixture was concentrated in vacuo and the residue was treated with H₂O and ethyl acetate. The layers were separated and the organic layer was washed with H₂O, brine, dried MgSO₄, filtered and concentrated in vacuo. Purification was accomplished by flash chromatography (70% EtOAc/hexane) providing 130 mg (69%) of the title compound. This material was used directly in the next step without further purification.

4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-hydroxymethyl-benzenesulfonamide

To a solution of acetic acid 5-hydroxy-2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-benzyl ester (130 mg, 0.34 mmol) in THF (3.0 mL) was added HCl (5 ml, 10%), and the reaction mixture was heated at 60° C. for 3 h. After removal of the solvent, purification was accomplished by two preparative HPLC (gradient of 10-50% and 15-47% respectively of acetonitrile in 0.1% aqueous AcOH) affording 29 mg of impure title compound. MS (ESI) m/z=334 (M−1, negative); HPLC purity 72.22% (MaxPlot).

4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-hydroxymethyl-benzenesulfonamide

To a suspension of lithium aluminum hydride (80 mg, 2.0 mmol) in THF (10 mL) at −10° C. was added solution of 2-hydroxy-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-ylsulfamoyl)-benzoic acid methyl ester (0.50 g, 1.3 mmol) in THF (10 mL). The reaction mixture was allowed to warm to rt. After 3 h, the reaction mixture was cooled in an ice bath and saturated aq. NH₄Cl solution (5 mL) was added. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic layer was separated, washed with water, brine and dried over Na₂SO₄, decanted and concentrated under reduced pressure. Purification was accomplished by preparative HPLC generating 44 mg (9%) of the title compound as an off-white solid. MS (ESI): m/z=334 (M−1, negative); HPLC purity: 84.44% (MaxPlot 200-400 nm), 82.7% (220 nm).

4-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-methoxy-benzenesulfonamide

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.968 g, 4.31 mmol), MeCN (20 mL), pyridine (1.05 mL, 12.9 mmol), and 4-fluoro-3-methoxy-benzenesulfonyl chloride (0.674 g, 4.53 mmol). After addition of water and dilute HCl (2 N) the mixture was concentrated in vacuo to removed MeCN. A small quantity of acetone was added and the resulting aqueous suspension was heated to remove the acetone. After cooling to room temperature, the solid was collected and washed with water. The title compound (1.31 g, 86%) was obtained as a light red solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.25 (s, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.48 (dd, J=7.9, 2.2 Hz, 1H), 7.38 (dd, J=11.1, 8.6 Hz, 1H), 7.31-7.27 (m, 2H), 7.18 (dd, J=8.2, 1.9 Hz, 1H), 4.89 (s, 2H), 3.84 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ (ppm): −128.56-−128.62 (m, 1F); MS (ESI) m/z=336 (M−1, negative); HPLC purity: 91.37% (MaxPlot 200-400 nm), 91.38% (220 nm); Anal. Calcd for C₁₄H₁₃BFNO₅S.0.25 H₂O: C, 49.22%; H, 3.98%; N, 4.10%. Found: C, 49.32%; H, 4.44%; N, 3.89%.

4-Fluoro-3-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfonamide

To a suspension of 4-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-methoxy-benzenesulfonamide (0.812 g, 2.40 mmol) in DCM (60 mL) was added BBr₃ (1M in DCM, 40 mL, 40 mmol) and the suspension was heated to reflux overnight. After consumption of 4-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-methoxy-benzenesulfonamide, the reaction was cooled to ambient temperature and added to methanol chilled in an ice bath. The solution was concentrated in vacuo and the residue was treated with water and heated. The hot solution was decanted and then cooled and lyophilized. Purification was accomplished by preparative reverse phase HPLC (acetonitrile/water (with 0.1% acetic acid) gradient) producing 0.089 g (11%) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.62 (brs, 1H), 10.21 (s, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.37-7.27 (m, 3H), 7.19-7.14 (m, 2H), 4.90 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ (ppm): −129.81-−129.87 (m, 1F); MS (ESI) m/z=322 (M−1, negative); HPLC purity: 93.03% (MaxPlot 200-400 nm), 92.92% (220 nm); Anal. Calcd for C₁₃H₁₁BFNO₅S.0.6 H₂O: C, 46.76%; H, 3.68%; N, 4.19%. Found: C, 46.55%; H, 3.59%; N, 4.46%.

3-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-benzenesulfonamide

To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.25 g, 1.34 mmol) in anhydrous pyridine (30 mL) at 5° C. was added 3-fluoro-4-methoxy-benzenesulfonyl chloride (0.30 g, 1.34 mmol) and the resulting orange solution stirred to room temperature overnight. The reaction was briefly warmed to 40° C. for 1 h and then evaporated to dryness in vacuo. The residue was treated with H₂O (80 mL) and sonicated for 6 h at 60° C. The resulting fine precipitate was filtered, washed with water and dried in vacuo generating 0.28 g (62%) of the title compound as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.20 (brs, 1H), 9.23 (s, 1H), 7.55-7.48 (m, 3H), 7.31-7.27 (m, 2H), 7.17 (dd, J=8.0, 2.0 Hz, 1H), 4.88 (s, 2H), 3.87 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ (ppm): −133.34 (t, J=9.8 Hz, 1F); MS (ESI) m/z=336 (M−1, negative); HPLC purity: 98.28% (MaxPlot 200-400 nm), 98.29% (220 nm).

3-Fluoro-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfonamide

To a suspension of 3-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-benzenesulfonamide (1.0 g, 2.96 mmol) in 100 mL of anhydrous DCM at 5° C. was added 1N solution of BBr₃ in DCM (3 mL). The resulting solution stirred at room temperature overnight. The precipitate that formed was filtered, washed with DCM and briefly dried before suspending in water. The gummy material formed was extracted into EtOAc, and the organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo. This was further purified through preparative HPLC affording 0.186 g (19% yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.96 (brs, 1H), 10.10 (s, 1H), 7.49-7.45 (m, 2H), 7.36 (dd, J=8.8, 1.6 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.16 (dd, J=8.4, 1.8 Hz, 1H), 7.02 (t, J=8.6 Hz, 1H), 4.88 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ (ppm): −134.62 (t, J=10.2 Hz, 1F); MS (ESI) m/z=322 (M−1, negative); HPLC purity: 95.05% (MaxPlot 200-400 nm), 95.58% (220 nm).

2-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-benzenesulfonamide

2-Fluoro-4-methoxy-benzenesulfonyl chloride and 4-Fluoro-2-methoxy-benzenesulfonyl chloride

To a solution of 1-fluoro-3-methoxy-benzene (5.0 mL, 43.76 mmol) in DCM (20 mL) cooled to 0° C., was added slowly chlorosulfonic acid (14.44 mL, 218.8 mmol). The ice bath was then removed. After 1 h, the mixture was poured into ice and the organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo. The 2.94 g obtained was a 1:1 mixture of 2-fluoro-4-methoxy-benzenesulfonyl chloride and 4-fluoro-2-methoxy-benzenesulfonyl chloride and was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.70 (t, J=7.8 Hz, 1H), 7.57 (t, J=8.6 Hz, 1H), 6.86 (dd, J=11.7, 2.3 Hz, 1H), 6.74-6.64 (m, 3H), 3.77 (s, 3H), 3.76 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ (ppm): −109.37-−109.42 (m, 1F), −110.35-−110.42 (m, 1F).

2-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-benzenesulfonamide

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (2.05 g, 13.7 mmol), MeCN (20 mL), pyridine (1.05 mL, 12.9 mmol), and 1:1 mixture of 2-fluoro-4-methoxy-benzenesulfonyl chloride and 4-fluoro-2-methoxy-benzenesulfonyl chloride (2.94 g, 13.1 mmol). Purification was accomplished by Biotage® silica gel column chromatography (340 g SNAP™ cartridge with the sample loaded as a DCM solution to the sample and air dried, mobile phase was gradient of ethyl acetate (0.5% AcOH) and hexanes) followed by dissolving the residue in acetonitrile, adding water, removal of the acetonitrile in vacuo and lyophilization. Mixed regioisomer fractions (1.50 g total) were obtained in addition to the 0.78 g (5%, 2 steps) of the title compound that was obtained as a light orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.36 (s, 1H), 9.23 (s, 1H), 7.67 (t, J=8.8 Hz, 1H), 7.46 (s, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.17 (dd, J=8.2, 1.6 Hz, 1H), 6.97 (dd, J=12.1, 2.3 Hz, 1H), 6.84 (dd, J=8.6, 2.3 Hz, 1H), 4.85 (s, 2H), 3.77 (s, 3H) [10 mol % acetic acid also present by ¹HNMR]; ¹⁹F NMR (376 MHz, DMSO-d₆) δ (ppm): −107.6 (dd, J=11.5, 9.2 Hz, 1F); MS (ESI) m/z=336 (M−1, negative); HPLC purity: 96.86% (MaxPlot 200-400 nm), 96.51% (220 nm); Anal. Calcd for C₁₄H₁₃BFNO₅S.0.1C₂H₄O₂+0.25 H₂O: C, 49.06%; H, 4.03%; N, 4.03%. Found: C, 48.99%; H, 3.89%; N, 4.18%.

2-Fluoro-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfonamide

To a suspension of 2-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-benzenesulfonamide (0.640 g, 1.90 mmol) in DCM (10 mL) cooled in an ice bath was added BBr₃ (1M in DCM, 5.7 mL, 5.7 mmol). After 3 h, 5 h and 6 h additional BBr₃ (1M in DCM, 1.9 mL three times for a combined total of 11.4 mL, 11.4 mmol). After 12 h, the suspension was poured into ice and stirred vigorously overnight. The solid was collected by filtration. To this was added water and enough acetonitrile to dissolve most of the sample. The remaining dark solid was filtered off and the acetonitrile was removed in vacuo. The resulting aqueous suspension was heated and sonicated briefly. After cooling to ambient temperature the solid was collected by vacuum filtration and was washed with a small amount of water and air dried. This generated 0.395 g (64%) of the title compound as an off-white solid. mp 239-241° C. (dec); ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.89 (br.s, 1H), 10.31 (s, 1H), 9.21 (s, 1H), 7.59 (t, J=8.8 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.19 (dd, J=8.2, 2.0 Hz, 1H), 6.68-6.63 (m, 2H), 4.87 (s, 2H) [4 mol % acetonitrile was present by ¹HNMR]; ¹⁹F NMR (376 MHz, DMSO-d₆) δ (ppm): −108.31 (t, J=10.3 Hz, 1F); MS (ESI) m/z=322 (M−1, negative); HPLC purity: 93.25% (MaxPlot 200-400 nm), 93.31% (220 nm); Anal. Calcd for C₁₃H₁₁BFNO₅S.0.04C₂H₃N+0.2H₂O: C, 47.85%; H, 3.54%; N, 4.44%. Found: C, 47.84%; H, 3.51%; N, 4.61%.

2-Chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfonamide

Neat 1-chloro-3-methoxybenzene (3.65 mL, 30 mmol) was put on an ice-water bath. Chlorosulfonic acid was added drop-wise via dropping funnel at 0° C., during which the mixture solidified. Let stir at 0° C. around ten minutes, and transferred to a beaker of ice water. The mixture was stirred until all the ice melted, and the product was extracted using ethyl ether. The organic later was washed two more times with water, then washed with brine, dried over sodium sulfate, and filtered. The solvent was removed under slightly reduced pressure to give 2-chloro-4-methoxybenzene-1-sulfonyl chloride (1.7 g, 24% yield).

Triethylamine (1.4 mL, 70.5 mmol) was added to a solution of 2-chloro-4-methoxybenzene-1-sulfonyl chloride (1.70 g, 7.05 mmol), 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (0.745 g, 5 mmol) in N,N-dimethylformamide (14 mL). The solution was stirred at room temperature for thirty minutes and was then neutralized to pH 6 using 1 N hydrochloric acid. The solution was the extracted using ethyl acetate and water. The organic layer was washed four times with water, then washed with brine, dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica column using Combiflash to give 2-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzene sulfonamide (0.828 g, 33% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 3.30 (s, 3 H), 4.84 (s, 2H), 6.99 (dd, J=2.6 Hz, J=9.0 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.19 (d, J=1.9 Hz, 1H), 7.22 (s, 1H), 7.46 (d, J=1.5 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 9.19 (s, 1H), 10.39 (s, 1H).

2-Chloro-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

A solution of 2-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfonamide (0.728 g, 2.06 mmol) in dry dichloromethane (10 mL) was cooled to −78° C. with acetone-dry ice bath. 1 M tribromoborane in dichloromethane (6.2 mL) was added drop-wise. The reaction was stirred in the acetone-dry ice bath and allowed to warm to room temperature overnight. The solution was then put on an ice-water bath and was quenched with ice chips. The solvent was removed under reduced pressure. The residue was extracted using ethyl acetate and water. The aqueous layer was extracted with ethyl acetate six times. The organic layers were dried over sodium sulfate and combined. The solvent was removed under reduced pressure. The residue was purified by silica column using Combiflash to give 2-chloro-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (0.098 g, 14% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 4.84 (s, 2H), 6.77 (dd, J=2.3 Hz, J=8.6 Hz, 1H), 6.88 (d, J=2.3 Hz, 1H), 7.23-7.16 (m, 2H), 7.44 (d, J=1.5 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 9.18 (s, 1H), 10.29 (s, 1H), 10.83 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,4-dimethoxy-benzenesulfonamide

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (300 mg, 2.0 mmol), 2,4-dimethoxybenzenesulfonyl chloride (570 mg, 2.4 mmol), Si-pyridine (4.2 g, 6.0 mmol), and MeCN (20 mL) at rt O/N. Si-amine (1.0 g, 1.8 mmol) was added and the mixture stirred at rt for 2 h. The mixture was filtered, H₂O was added to the filtrate, and the resulting soln was concentrated in vacuo at 40° C. until precipitation was observed. The suspension was decanted and the remaining soln left to stand at rt resulting in the formation of a precipitate. The precipitate was isolated by filtration to give the title compound as a yellow solid: yield; 552 mg (78%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.82 (s, 1H), 9.19 (s, 1H), 7.64-7.62 (m, 1H), 7.46-7.45 (m, 1H), 7.22-7.16 (m, 2H), 6.63-6.62 (m, 1H), 6.56-6.53 (m, 1H), 4.85 (s, 2H), 3.87 (s, 3H), 3.78 (s, 3H); MS (ESI) m/z=348 (M−1, negative); HPLC purity: 91.94% (MaxPlot 200-400 nm), 90.96% (220 nm).

2,4-Dihydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfonamide

1 M BBr₃ in CH₂Cl₂ (5.0 mL, 5.0 mmol) was added to a soln of N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,4-dimethoxy-benzenesulfonamide (500 mg, 1.4 mmol) in CH₂Cl₂ (15 mL) and stirred at rt O/N. H₂O was added and mixture was concentrated in vacuo at 50° C. The residue was purified by prep HPLC (20-90% MeCN/0.1% aq HCO₂H) to give the title compound as a white solid: yield; 41 mg (9%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.46-7.44 (m, 2H), 7.18 (s, 2H), 6.29-6.28 (m, 1H), 6.22-6.19 (m, 1H), 4.85 (s, 2H); MS (ESI) m/z=320 (M−1, negative); HPLC purity: 97.63% (MaxPlot 200-400 nm), 97.59% (220 nm).

N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3,4-dimethoxybenzenesulfonamide

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol, MeCN, pyridine, and 3,4-dimethoxy-benzenesulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.25 (s, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.48 (dd, J=7.9, 2.2 Hz, 1H), 7.38 (dd, J=11.1, 8.6 Hz, 1H), 7.31-7.27 (m, 2H), 7.18 (dd, J=8.2, 1.9 Hz, 1H), 4.89 (s, 2H), 3.84 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ (ppm): −128.56-−128.62 (m, 1F); MS (ESI) m/z=336 (M−1, negative); HPLC purity: 91.37% (MaxPlot 200-400 nm), 91.38% (220 nm); Anal. Calcd for C₁₄H₁₃BFNO₅S.0.25 H₂O: C, 49.22%; H, 3.98%; N, 4.10%. Found: C, 49.32%; H, 4.44%; N, 3.89%.

N-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-nitrobenzenesulfonamide

To a solution of 4-methoxy-2-nitrobenzenesulfonyl chloride (8.72 g, 34.6 mmol), 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (5.00 g, 33.6 mmol), and triethylamine (5.6 mL, 40.3 mL) in DMF 70 mL was stirred at room temperature for 1 h. The mixture was poured into ethyl acetate and water. The organic layer was washed with water twice and brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from dichloromethane to give N-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-nitrobenzenesulfonamide (7.23 g, 59%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 3.84 (s, 3H), 4.88 (s, 2H), 7.21 (dd, J=8.3, 2.0 Hz, 1H), 7.25-7.32 (m, 2H), 7.49 (d, J=1.6 Hz, 1H), 7.53 (d, J=2.5 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 9.22 (s, 1H), 10.4 (s, 1H).

4-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitrobenzenesulfonamide

To a solution of N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-nitrobenzenesulfonamide (1.00 g, 2.74 mmol) in dichloromethane (150 mL) was added boron tribromide (1 M in dichloromethane, 8.2 mL) at −78° C., and the mixture was stirred for 6 days at room temperature. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column (19:1 dichloromethane/methanol) to give 4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitrobenzenesulfonamide (290 mg, 30%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 4.88 (s, 2H), 7.03 (dd, J=8.8, 2.3 Hz, 1H), 7.16-7.22 (m, 2H), 7.29 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 9.21 (s, 1H), 10.3 (s, 1H), 11.4 (s, 1H).

2-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfonamide

A mixture of N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-nitrobenzenesulfonamide (6.00 g, 16.5 mmol) and 10% palladium on charcoal (1.50 g) in methanol (400 mL) was stirred under hydrogen atmosphere with a balloon at room temperature for 4 h. The atmosphere was replaced with nitrogen, and the mixture was filtered through a Celite pad. The solution was removed under reduced pressure, and the residue was purified by silica gel column (2:8 hexane/ethyl acetate) to give 2-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfonamide (5.09 g, 92%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 3.65 (s, 3H), 4.85 (s, 2H), 5.96 (br s, 2H), 6.10 (dd, J=8.8, 2.3 Hz, 1H), 6.21 (d, J=2.3 Hz, 1H), 7.13 (dd, J=8.2, 1.9 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.43 (s, 1H), 9.18 (s, 1H), 10.0 (s, 1H).

2-Amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

To a solution of 2,2,2-trifluoro-N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide (2.00 g, 4.81 mmol) in methanol (40 mL) was added 3 M NaOH (10 mL), and the mixture was stirred at room temperature for overnight. The pH was adjusted to 7 with 6 M HCl and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column (8:1 chloroform/methanol) followed by water-toluene co-boiling to give 2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (1.10 g, 71%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 4.85 (s, 2H), 5.83 (br s, 2H), 5.93 (dd, J=8.8, 2.5 Hz, 1H), 6.05 (d, J=2.4 Hz, 1H), 7.11 (dd, J=8.4, 2.2 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.41 (d, J=1.6 Hz, 1H), 9.16 (s, 1H), 9.80 (br s, 1H), 9.92 (br s, 1H).

2,2,2-Trifluoro-N-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetamide

To a solution of 2-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfonamide (2.01 g, 6.00 mmol) in DMF (15 mL) was added trifluoroacetic anhydride (1.2 mL, 8.8 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was poured into ethyl acetate and water. The organic layer was washed with water twice and brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column (3:7 hexane/ethyl acetate) to give 2,2,2-trifluoro-N-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetamide (1.40 g, 54%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 3.80 (s, 3H), 4.88 (s, 2H), 6.98 (dd, J=9.0, 2.6 Hz, 1H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 7.42 (s, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.66 (d, J=9.0 Hz, 1H), 9.20 (s, 1H), 10.2 (s, 1H), 10.6 (s, 1H).

2,2,2-Trifluoro-1-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

To a solution of 2,2,2-trifluoro-N-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenyl)acetamide (960 mg, 2.23 mmol) in dichloromethane (150 mL) was added boron tribromide (1 M in dichloromethane, 6.0 mL) at −78° C., and the mixture was stirred for 2 days at room temperature. Water was added and the precipitates formed were collected by filtration to give 2,2,2-trifluoro-N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide (155 mg, 17%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 4.87 (s, 2H), 6.72 (dd, J=8.8, 2.6 Hz, 1H), 7.05 (dd. J=8.2, 2.1 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 9.19 (s, 1H), 10.1 (s, 1H), 10.5 (s, 1H), 10.8 (s, 1H).

N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-hydroxyacetamide

N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-chloroacetamide

A solution of chloro-acetyl chloride (1.65 g, 7.3 mmol) in DCM was added to a solution of 2-amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (3 g, 7.3 mmol) in DCM and Py (1.734, 21.9 mmol) at r.t, and stirred overnight. Then the mixture was washed with brine, dried and concentrated to give product N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-chloroacetamide (2.4 g, 67%).

2-(5-(Benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1, 2]oxaborol-6-yl)sulfamoyl)phenylamino)-2-oxoethyl acetate

A solution of compound N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-chloroacetamide (200 mg, 0.41 mmol) and AcOK (66.5 mg, 0.82 mmol) in DMF (5 mL) was stirred at 50° C. overnight, then cooled to r.t. The mixture was poured in water and extracted with DCM, dried and concentrated to give product 2-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylamino)-2-oxoethyl acetate (200 mg, crude).

N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-hydroxyacetamide

A solution of 2-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylamino)-2-oxoethyl acetate (200 mg, crude) in CH₃OH and aq. NH₄OH (v/v=1:1) was stirred at r.t overnight, then the mixture was concentrated and extracted with DCM, dried and purified by Prep-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H₂O; B-MeCN+0.025% TFA] B %: 25%-55%, 25 min) to give the title compound (93 mg). ¹H NMR: DMSO-d6 400 MHz δ 10.42 (1H, s), 10.23 (1H, s), 9.21 (1H, s), 8.10-8.09 (1H, m), 7.63-706 (1H, m), 7.41-7.35 (5H, m), 7.28-7.26 (1H, m), 7.18-7.16 (1H, m), 6.06-6.03 (1H, m), 5.09 (1H, s), 4.88 (1H, s), 3.95-3.95 (2H, m), 4.72-4.71 (2H, m). ESI-MS m/z 367 (M−H, negative); HPLC purity: 97.52% (MaxPlot 190-370 nm), 98.83% (220 nm), 99.65% (254 nm).

2-Hydroxy-N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

A solution of 2-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylamino)-2-oxoethyl acetate (500 mg, 1 mmol) was dissolved in CH₃OH and NH₄OH, then the mixture and Pd/C was stirred under H₂ (50 Psi) overnight. The mixture was filtrated and the filtrate was concentrated, extracted with DCM. The organics was dried and purified by Prep-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H₂O; B-MeCN+0.025% TFA] B %: 10%-40%, 25 min) to give the title compound (130 mg, 35%). ¹H NMR: DMSO-d6 400 MHz δ 10.45 (1H, s), 10.35 (1H, s), 10.07 (1H, s), 9.17 (1H, s), 7.89-7.88 (1H, m), 7.51-7.49 (1H, m), 7.39-7.38 (1H, m), 7.26-7.24 (1H, m), 7.16-7.13 (1H, m), 6.52-6.49 (1H, m), 6.00-5.97 (1H, m), 4.87 (2H, s), 3.94-3.92 (2H, m). ESI-MS m/z 401 (M+Na, positive); HPLC purity: 94.17% (MaxPlot 190-370 nm), 99.76% (220 nm), 100% (254 nm).

2-Amino-N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

A solution of compound N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-chloroacetamide (500 mg, crude) was dissolved in CH₃OH and NH₄OH, then the mixture was stirred at 50° C. for 2 hrs. The mixture was adjusted to pH=4, extracted with DCM, dried and purified by Prep-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H₂O; B-MeCN+0.025% TFA] B %: 15%-45%, 25 min) to give the title compound (110 mg). ¹H NMR: DMSO-d6 400 MHz δ 10.65 (1H, s), 9.74 (1H, s), 9.2 (1H, s), 8.28 (1H, s), 7.68-7.52 (1H, m), 7.38-7.33 (5H, m), 7.21-7.19 (2H, m), 6.91-6.88 (2H, m), 5.07 (1H, s), 4.84 (1H, s), 4.01 (1H, s). ESI-MS m/z 468 (M+1, positive); HPLC purity: 99.08% (MaxPlot 190-370 nm), 98.8% (220 nm), 99.02% (254 nm).

2-Amino-N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

A solution of 2-amino-N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide (500 mg, crude) was dissolved in CH₃OH, then the mixture and Pd/C was stirred under H₂ (50 Psi) overnight. The mixture was filtrated and the filtrate was concentrated, dissolved in DCM, washed with brine. The organics was dried and purified by Prep-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H₂O; B-MeCN+0.025% TFA]B %: 5%-35%, 25 min) to give the title compound (100 mg, 35%). ¹H NMR: DMSO-d6 400 MHz δ9.21 (1H, s), 7.56-7.54 (1H, m), 7.51-7.50 (1H, m), 7.37-7.36 (1H, m), 7.23-7.21 (1H, m), 7.18-7.17 (1H, m), 6.61-6.58 (1H, m), 4.86 (2H, m), 3.98 (2H, s), 3.94-3.92 (2H, m). ESI-MS m/z 378 (M+1, positive); HPLC purity: 94.57% (MaxPlot 190-370 nm), 94.11% (220 nm), 94.8% (254 nm).

N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

A solution of N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-chloroacetamide (500 mg, 1.07 mmol), dimethylamine hydrochloride (870 mg, 10.7 mmol) and NMM (1.09 g, 10.7 mmol) was dissolved in CH₃OH. The mixture was stirred at 50° C. overnight. The mixture was adjusted to pH=4, then concentrated and extracted with DCM. The organics was dried, concentrated and purified by Prep-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H₂O; B-MeCN+0.025% TFA] B %: 13%-55%, 25 min) to give the title compound (300 mg, 56.8%). ¹HNMR: DMSO 400 MHz δ 10.3 (1H, s), 9.9 (1H, s), 9.21 (1H, s), 7.72-7.47 (1H, m), 7.46-7.36 (7H, m), 7.26-7.24 (1H, m), 7.14-7.11 (1H, m), 7.00-6.97 (1H, m), 5.11 (2H, s), 4.87 (2H, s), 4.23 (2H, s), 2.85 (2H, s). ESI-MS m/z 496 (M+H, positive); HPLC purity: 96.44% (MaxPlot 190-370 nm), 99.9% (220 nm), 99.84% (254 nm).

2-(Dimethylamino)-N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

A mixture of N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide (130 mg, 0.263 mmol), Pd/C (0.2 g) in CH₃OH was stirred under H₂ (50 Psi) for 1 hr. Then the mixture was filtrated and the filtrate was concentrated and purified by Prep-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H₂O; B-MeCN+0.025% TFA]B %: 3%-43%, 25 min) to give the title compound (100 mg, 94%). ¹HNMR: DMSO-d₆ 400 MHz δ 10.65 (1H, s), 10.55 (1H, s), 9.98-9.87 (2H, m), 7.57-7.54 (1H, m), 7.50-7.48 (1H, m), 7.27-7.23 (2H, m), 7.18-7.15 (1H, m), 4.86 (2H, s), 4.30 (2H, s), 2.80 (6H, s). ESI-MS m/z 406 (M+H, positive); HPLC purity: 95.79% (MaxPlot 190-370 nm), 97.98% (220 nm), 97.83% (254 nm).

N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-phenoxyacetamide

A solution of 2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (0.250 g, 0.781 mmol) and 2-phenoxyacetyl chloride (108 μL, 0.781 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature for two and a half hours. 2-phenoxyacetyl chloride (32 μL, 0.234 mmol) was again added to the solution, which was then stirred at room temperature for one hour. The solution was extracted using ethyl acetate and water. The organic layer was washed three times with water, then washed with brine, dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica column using dichloromethane and methanol using 2.5% methanol to 5% methanol to 10% methanol. The fractions were collected and the solvent was removed under reduced pressure. Water and toluene were added and were co-evaporated under reduced pressure to give N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-phenoxyacetamide (0.196 g, 55% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 4.457 (s, 2H), 4.85 (s, 2H), 6.54 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.06-6.70 (m, 3H), 7.12 (s, 2H), 7.33-7.37 (m, 3H), 7.51 (d, J=8.8 Hz, 1H), 9.15 (s, 1H), 10.13 (br s, 1H), 10.34 (br s, 1 H), 10.51 (br s, 1H).

N-(5-Hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide

This compound was made from 2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide and acetic anhydride in a similar way to N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-phenoxyacetamide. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 2.04 (s, 3H), 4.87 (s, 2H), 6.49 (dd, J=8.8, 2.5 Hz, 1H), 7.09 (dd, J=8.2, 2.1 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 9.05 (s, 1H), 9.20 (s, 1H), 10.2 (s, 1H), 10.4 (s, 1H).

N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)nicotinamide

This compound was made from 2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide and nicotynoyl chloride in a similar way to N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-phenoxyacetamide. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 4.73 (s, 2H), 6.56 (dd, J=2.5 Hz, J=8.9 Hz, 1H), 6.99 (dd, J=2.0 Hz, J=8.1 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 7.34 (d, J=1.7 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.56 (m, 1H), 7.77 (d, J=2.3 Hz, 1H), 8.09 (m, 1H), 8.75 (dd, J=1.5 Hz, J=4.8 Hz, 1H), 8.91 (d, J=1.9 Hz, 1H), 9.97 (s, 1H), 10.09 (s, 1H), 10.40-10.64 (br s, 1 H).

Ethyl 2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenylcarbamate

This compound was made from 2-amino-4-methoxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide and ethyl chloroformate in a similar way to N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-phenoxyacetamide. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 1.21 (t, J=7.1 Hz, 3H), 3.75 (s, 3H), 4.07 (q, J=7.1 Hz, 2H), 4.87 (s, 2H), 6.70 (dd, J=9.0, 2.6 Hz, 1H), 7.08 (dd, J=8.2, 2.1 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.64 (d, J=2.5 Hz, 1H), 8.65 (s, 1H), 9.22 (s, 1H), 10.3 (s, 1H).

3-(Ethoxycarbonylamino)-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl pivalate

To a solution of ethyl 5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylcarbamate (197 mg, 0.503 mmol) in pyridine (3 mL) was added pivaloyl chloride (0.195 mL, 0.830 mmol), and the mixture was stirred at room temperature for 24 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column (55:45 hexane/ethyl acetate) followed by trituration with isopropyl ether-hexane to give 3-(ethoxycarbonylamino)-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl pivalate (75 mg, 31%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 1.26 (s, 9H), 4.88 (s, 2H), 6.93 (dd, J=8.7, 2.3 Hz, 1H), 7.08 (dd, J=8.0, 2.0 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.48 (d, J=1.7 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 8.69 (s, 1H), 9.23 (s, 1H), 10.5 (s, 1H).

Ethyl 5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylcarbamate

A solution of ethyl chloroformate (0.47 g, 4.35 mmol) in DCM was added to the solution of 2-amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzene sulfonamide (0.6 g, 1.46 mmol) in DCM and Py (1.5 g, 19 mmol) at r.t, and stirred overnight. Then the mixture was washed with brine, dried and concentrated, purified by pre-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H₂O; B-MeCN+0.025% TFA] B %: 40%-65%, 25 min) to give the title compound (120 mg g, 17%). ¹HNMR: DMSO-d6 400 MHz δ 10.35 (1H, s), 9.30 (1H, s), 8.67 (1H, s), 7.74-7.73 (1H, m), 7.63-7.61 (1H, m), 7.47-7.43 (1H, m), 7.43-7.38 (5H, m), 7.29-7.27 (1H, m), 7.10-7.08 (1H, s), 6.82-6.79 (1H, m), 5.1 (2H, s), 4.89 (1H, s), 4.11-4.05 (2H, m). ESI-MS m/z 481 (M−H, negative); HPLC purity: 95.79% (MaxPlot 190-370 nm), 97.98% (220 nm), 97.83% (254 nm).

Ethyl 5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylcarbamate

A solution of 2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (0.250 g, 0.781 mmol) and ethyl chloroformate (0.38 mL, 4.0 mmol) in N,N-dimethylformamide (3 mL) was stirred overnight at rt. The solution was extracted using ethyl acetate and water. The organic layer was washed three times with water, then washed with brine, dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica column (4:6 hexane/ethyl acetate) followed by recrystallization from ethyl acetate/hexane to give the desired product (144 mg, 47% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 1.21 (t, J=7.0 Hz, 3H), 4.05 (q, J=7.0 Hz, 2H), 4.87 (s, 2H), 6.46 (dd, J=8.8, 2.4 Hz, 1H), 7.61 (dd, J=8.2, 1.9 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 8.60 (s, 1H), 9.21 (s, 1H), 10.2 (s, 1H), 10.5 (s, 1H).

Isobutyl 5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylcarbamate

This compound was made from 2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide and isobutyl chloroformate in a similar way to N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-phenoxyacetamide. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 0.89 (d, J=6.7 Hz, 6H), 1.88 (sept, J=6.7 Hz, 1H), 3.81 (d, J=6.6 Hz, 2H), 4.87 (s, 2H), 6.47 (dd, J=2.2 Hz, J=8.9 Hz, 1H), 7.07 (dd, J=1.9 Hz, J=8.0 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.42 (d, J=1.4 Hz, 1H), 7.48-7.53 (m, 2H), 8.65 (br s, 1H), 9.20 (s, 1H), 10.21 (br s, 1H), 10.47 (br s, 1H).

Benzyl 2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-methoxyphenylcarbamate

This compound was made from 2-amino-4-methoxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide and benzyl chloroformate in a similar way to N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-phenoxyacetamide. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 3.75 (s, 3H), 4.86 (s, 2H), 5.13 (s, 2H), 6.71 (dd, J=9.2, 2.5 Hz, 1H), 7.10 (dd, J=8.1, 2.0 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.32-7.45 (m, 6H), 7.59 (d, J=9.0 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 8.81 (s, 1H), 9.21 (s, 1H), 10.4 (s, 1H).

Benzyl 5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylcarbamate

This compound was made from 2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide and benzyl chloroformate in a similar way to N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-phenoxyacetamide. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 4.86 (s, 2H), 5.11 (s, 2H), 6.47 (dd, J=8.8, 2.1 Hz, 1H), 7.09 (dd, J=8.2, 1.7 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.32-7.46 (m, 6H), 7.48 (d, J=8.8 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 8.76 (s, 1H), 9.21 (s, 1H), 10.3 (s, 1H), 10.5 (s, 1H).

2-Methoxyethyl 5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylcarbamate

This compound was made from 2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide and 2-methoxyethyl chloroformate in a similar way to N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2-phenoxyacetamide. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 3.54 (t, J=4.5 Hz, 2H), 4.15 (t, J=4.5 Hz, 2H), 4.87 (s, 2H), 6.46 (dd, J=8.8, 2.3 Hz, 1H), 7.09 (dd, J=8.0, 1.9 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 8.69 (s, 1H), 9.21 (s, 1H), 10.1 (s, 1H), 10.5 (s, 1H).

4-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(pyridin-3-ylmethylamino)benzenesulfonamide

N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-(pyridin-3-ylmethylamino)benzenesulfonamide

A mixture of nicotinaldehyde (0.5 g, 5.2 mmol), 2-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfonamide (0.5 g, 1.22 mmol) and catalytic amount of TiCl₄ (1M in DCM) in a solution of DCM (12 mL) was stirred at r.t. for 2 hrs, then followed by and Na(AcO)₃BH (2.12 g, 10 mmol). The mixture was quenched with water then worked up with EtOAc, H₂O, brine, dried over Na₂SO₄ and dried in vacuo. Further purification by flash chromatography give product N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-(pyridin-3-ylmethylamino) benzenesulfonamide (200 mg, 33.5%).

4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(pyridin-3-ylmethylamino)benzenesulfonamide

General Procedure 16: Starting Materials compound N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-(pyridin-3-ylmethylamino) benzenesulfonamide and boron tribromide 1M solution in DCM. ¹H NMR (400 MHz, DMSO-d₆) (ppm): 10.14 (s, 1H), 9.98 (s, 1H), 9.20 (bs, 1H), 8.62 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 7.84 (d, J=6.8 Hz, 1H), 7.46 (m, 3H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (dd, J=8.0, 2 Hz, 1H), 6.54 (t, J=5.6 Hz, 1H), 6.02 (dd, J=8.4, 2 Hz, 1H); 5.89 (d, J=2.0 Hz, 1H), 4.87 (s, 2H), 4.48 (d, J=6 Hz, 2H); MS (ESI) m/z=410.0 (M−H, negative).

2-((1H-imidazol-2-yl)methylamino)-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide dihydrochloride

A mixture of 1H-Imidazole-2-carbaldehyde (0.5 g, 5.2 mmol), 2-amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzene sulfonamide (0.5 g, 1.22 mmol) and Na(AcO)₃BH (2.12 g, 10 mmol) in a solution of CH₃OH/TFA (1:5, 12 mL) was stirred at 50° C. for 2 hrs. The mixture was quenched with water and purified by pre-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H₂O; B-MeCN+0.025% TFA] B %: 15%-45%, 25 min) to give the title compound (200 mg, 33.5%). ¹HNMR: DMSO 400 MHz δ 10.04 (1H, s), 9.19 (1H, s), δ 7.65-7.56 (2H, s), 7.48-7.43 (2H, s), 7.33-7.39 (4H, m), 7.22-7.20 (2H, m), 6.64-6.60 (1H, m), 6.37-6.30 (1H, m), 6.27-6.26 (2H, m), 4.99 (1H, s), 4.85 (1H, s), 4.72-4.71 (1H, m). ESI-MS m/z 491 (M+H, positive); HPLC purity: 98.41% (MaxPlot 190-370 nm), 97.64% (220 nm), 98% (254 nm).

2-((1H-imidazol-2-yl)methylamino)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide dihydrochloride

2-Amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

A mixture 4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitro benzenesulfonamide (3.0 g, 6.8 mmol), Pd/C (0.5 g) in CH₃OH was stirred under H₂ (50 psi) for 2 hrs. Then the mixture was filtrated and the filtrate was concentrated to give the crude product 2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (2.0 g, 91%). ¹HNMR: DMSO DMSO-d6 400 MHz δ 9.79 (1H, s), 9.16 (1H, s), 7.41-7.40 (1H, m), 7.30-7.27 (1H, m), 7.21-7.19 (1H, m), 7.12-7.09 (1H, m), 6.04-6.04 (1H, m), 5.19-5.91 (1H, m), 5.86-5.83 (2H, m), 4.84 (2H, s), 4.07-4.06 (2H, s).

2-((1H-imidazol-2-yl)methylamino)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide dihydrochloride

A mixture of 1H-Imidazole-2-carbaldehyde (1.08 g, 10.5 mmol), 2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (1.2 g, crude) and Na(AcO)₃BH (3.97 g, 20 mmol) was stirred at 50° C. in CH₃OH/TFA (1:5, 12 M1) for 2 hrs. The mixture was quenched with water and purified by pre-HPLC(column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H₂O; B-MeCN+0.025% TFA] B %: 5%-35%, 25 min) to give the title compound (350 mg). ¹H NMR: DMSO-d6 400 MHz δ 10.3 (1H, s), 10.23 (1H, s), 9.3 (1H, s), 7.66-7.60 (1H, s), 7.50 (1H, m), 7.40-7.30 (1H, m), 6.67-6.64 (1H, m), 6.12-6.09 (1H, m), 6.06-5.99 (1H, m), 4.90 (1H, s), 4.75-4.66 (2H, m), 4.72-4.71 (2H, m). ESI-MS m/z 401 (M+H, positive); HPLC purity: 94.9% (MaxPlot 190-370 nm), 95.06% (220 nm), 96.71% (254 nm).

Benzyl 4-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl) sulfamoyl)phenylamino)piperidine-1-carboxylate

4-(Benzyloxy)-2-nitroaniline

To a solution of 4-amino-3-nitrophenol (50 g, 0.325 mol) and t-BuOK (36 g, 0.32 mol) in DMF (1 L) was slowly added BnBr (55 g, 0.32 mol) at 0-5° C. Then the mixture was warmed slowly, and stirred at r.t overnight. The mixture was poured into sat. NH₄Cl, the suspension was filtrated, and the filtrated cake was dissloved in DCM, and dried and concentrated to give 4-(benzyloxy)-2-nitroaniline (40 g, 50.5%).

4-(Benzyloxy)-2-nitrobenzene-1-sulfonyl chloride

4-Benzyloxy-2-nitroaniline (30 g, 123 mmol) was dissolved in TFA (400 mL) and concentrated HCl (40 mL). After cooling to 0° C., NaNO₂ (10.6 g, 154 mmol) in H₂O was added dropwise over 30 min. Once the addition was complete the reaction was stirred for an additional 5 min. The resulting solution was poured into AcOH (400 mL), H₂SO₃ (400 mL), and CuCl₂ (8.26 g, 60 mmol) containing a catalytic amount of CuCl (ca. 0.5 g) at 0° C. After stirring 35 min at room temperature, the solid material was filtered off and washed with water. This provided 4-benzyloxy-2-nitrobenzenesulfonyl chloride (14.8 g, 40%).

4-(Benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitro benzenesulfonamide

To a stirred solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (13.8 g, 0.049 mol, 0.5 eq) in acetonitrile (300 mL) and NMM (14.8 g, 0.147 mol, 3 eq) was added a solution of 4-(benzyloxy)-2-nitrobenzene-1-sulfonyl chloride (30 g, 0.097 mol) in anhydrous acetonitrile (150 mL) at 0-5° C. Then the mixture was stirred at r.t overnight, the mixture was concentrated and dissolved in DCM and washed with brine, dried and concentrated, purified by column chromatography to give product 4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitrobenzenesulfonamide (31 g, 80%).

2-Amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1, 2]oxaborol-6-yl)benzenesulfonamide

A mixture 4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitro benzenesulfonamide (2.2 g, 5 mmol), Raney Ni (0.5 g) in CH₃OH and NH₄OH was stirred under H₂ (30 Psi) for 2 hrs. Then the mixture was filtrated and the filtrate was dried and concentrated to give crude product of 2-amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (1.6 g crude). ¹HNMR: DMSO DMSO-d6 400 MHz M0.03 (1H, s), 9.19 (1H, s), δ 7.43-7.39 (1H, m), 7.36-7.30 (6H, m), 7.23-7.20 (1H, m), 7.14-7.12 (1H, m), 6.29 (1H, s), 6.19-6.17 (1H, m), 5.96 (2H, s), 4.97 (2H, s), 4.85 (2H, s).

Benzyl 4-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylamino)piperidine-1-carboxylate

A mixture of 2-amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (0.5 g, 1.22 mmol) and Na(AcO)₃BH (2.10 g, 10 mol) was stirred at 50° C. in CH₃OH/TFA (1:5) for 2 hrs. The mixture was quenched with water and purified by Prep-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H₂O; B-MeCN+0.025% TFA] B %: 45%-70%, 25 min) to give the title compound (100 mg, 13.5%). ¹HNMR: DMSO-d6 400 MHz δ 10.23 (1H, s), 7.62-7.59 (1H, s), 7.33-7.31 (1H, m), 7.21-7.19 (1H, m), 6.38-6.35 (2H, s), 5.79-5.77 (1H, m), 5.20-5.18 (4H, m), 4.96-4.92 (2H, m), 4.00-3.96 (2H, m), 3.68-3.68 (1H, m), 3.09-3.08 (2H, m), 1.88-1.86 (2H, m). ESI-MS m/z 628 (M+H, positive); HPLC purity: 94.34% (MaxPlot 190-370 nm), 94.74% (220 nm), 96.7% (254 nm).

4-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(piperidin-4-ylamino)benzenesulfonamide dihydrochloride

A mixture of benzyl 4-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylamino)piperidine-1-carboxylate (0.4 g, crude), Pd/C (0.5 g) in CH₃OH was stirred under H₂ (50 Psi) for 1 hr. Then the mixture was filtrated and the filtrate was concentrated to give the crude product and purified by Prep-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H₂O; B-MeCN+0.025% TFA] B %: 2%-32%, 25 min) to give the title compound (100 mg). ¹H NMR: DMSO-d6 400 MHz δ 10.25 (1H, s), δ 10.08 (1H, s), δ 9.20 (1H, s), 8.92 (1H, s), 7.421-7.39 (2H, m), 7.23-7.21 (1H, m), 7.12-7.10 (1H, m), 6.14-6.13 (1H, m), 6.06-6.03 (1H, m), 5.67-5.65 (1H, m), 4.86 (1H, s), 3.58-3.56 (1H, m), 3.27-3.24 (2H, m), 3.02-2.95 (2H, m), 1.99-1.97 (2H, m), 1.68-1.60 (2H, m). ESI-MS m/z 404 (M+H, positive); HPLC purity: 86.77% (MaxPlot 190-370 nm), 98.57% (220 nm), 99.19% (254 nm).

2-(Benzo[d]oxazol-2-ylamino)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

A mixture of 2-amino-4-methoxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (1.00 g, 3.00 mmol) and 2-chlorobenzoxazole (0.453 mL, 4.00 mmol) in DMF (10 mL) was stirred at 120° C. for 3 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column (45:55 hexane/ethyl acetate) to give 2-(benzo[d]oxazol-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzene sulfonamide (276 mg, 20%).

To a solution of 2-(benzo[d]oxazol-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfonamide (272 mg, 0.537 mmol) in dichloromethane (20 mL) was added boron tribromide (1 M in dichloromethane, 1.6 mL) at −78° C., and the mixture was stirred for overnight allowing to warm to room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column (35:65 hexane/ethyl acetate) and preparative TLC (35:65 hexane/ethyl acetate) followed by trituration with isopropyl ether-hexane to give 2-(benzo[d]oxazol-2-ylamino)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (20 mg, 8.5%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 4.61 (s, 2H), 6.5-8.0 (m, 10H), 9.16 (s, 2H), 10.3 (s, 1H), 10.6 (s, 1H).

3,5-Dichloro-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide

General Procedure 1: 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (150 mg, 1 mmol), 3,5-dichloro-4-hydroxybenzenesulfonyl chloride (260 mg, 1 mmol), DIPEA (650 mg, 5 mmol), rt, 2 hours. Purification: prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as off white powder, yield 156 mg. MS calcd for (C₁₃H₁₀BNO₅SCl₂): 374.004, MS found (ESI negative): (M−H)⁻=372.0. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 11.41, (bs, 1H), 10.22 (s, 1H), 9.22 (bs, 1H), 7.62 (s, 2H), 7.47 (d, J=2 Hz, 1H), 7.3 (d, J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 4.88 (s, 2H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-2,6-dimethyl-benzenesulfonamide

General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.500 g, 3.36 mmol), MeCN (10 mL), pyridine (0.544 mL, 6.71 mmol), and 4-methoxy-2,6-dimethyl-benzenesulfonyl chloride (0.788 g, 3.36 mmol, generated according to procedures in US2008/249128). This produced 1.16 g (99% yield) of material that was used in the next step without further purification. A small sample (50 mg) was filtered through a short silica gel column (5% MeOH in DCM as the mobile phase). The solid obtained was dissolved in a minimum of acetonitrile, water (acidified with dilute HCl) was added and the mixture was lyophilized generating 39 mg (77%) of the title compound as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.02 (s, 1H), 9.22 (s, 1H), 7.40 (d, J=1.3 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.10 (dd, J=8.3, 1.9 Hz, 1H), 6.72 (s, 2H), 4.87 (s, 2H), 3.74 (s, 3H), 2.54 (s, 6H); MS (ESI) m/z=348 (M+1, positive); HPLC purity: 97.27% (MaxPlot 200-400 nm), 97.12% (220 nm).

4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,6-dimethyl-benzenesulfonamide

To a suspension of N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-2,6-dimethyl-benzenesulfonamide (0.640 g, 1.90 mmol) in DCM (10 mL) cooled in an −78° C. bath was added BBr₃ (1M in DCM, 2.16 mL, 2.16 mmol). After 4 h, the −78° C. bath was removed. After 8 h, the solution was cooled to −20° C. and more BBr₃ (1M in DCM, 0.72 mL, 0.72 mmol) was added. After overnight at ambient temperature, the reaction was cooled in an ice bath and water was added. After stirring over the weekend, ethyl acetate was added and the organic layer was separated and washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Purification was accomplished by Biotage® silica gel chromatography (25 g SNAP™ column, eluting with 2-20% MeOH in DCM), followed by lyophilization from MeCN/water, reverse-phase preparative HPLC (MeCN/0.1% aqueous AcOH gradient) and lyophilization generating 80 mg (2%) of the title compound as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.95 (br.s, 1H), 9.19 (s, 1H), 7.39 (br.s, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.09 (dd, J=8.2, 2.3 Hz, 1H), 6.49 (s, 2H), 4.87 (s, 2H), 2.48 (s, 6H); MS (ESI) m/z=334 (M+1, positive); HPLC purity: 98.97% (MaxPlot 200-400 nm), 99.28% (220 nm).

4-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2,5-dimethylbenzenesulfonamide

N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1, 2]oxaborol-6-yl)sulfamoyl)-2,5-dimethylphenyl)acetamide

General Procedure 1: 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (300 mg, 2 mmol), 4-acetylamino-2,5-dimethylbenzenesulfonyl chloride (500 mg, 1.9 mmol), sodium bicarbonate (504 mg, 6 mmol), rt, 3 hours. Purification: prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as light yellow solid. MS calcd for (C₁₇H₁₉BN₂O₅5): 374.22, MS found (ESI negative): (M−H)⁻=373.1. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.25 (s, 1H), 9.29 (s, 1H), 9.18 (s, 1H), 7.69 (s, 1H), 7.54 (s, 1H), 7.45 (d, J=2 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 4.85 (s, 2H), 2.16 (s, 3H), 2.04 (s, 3H).

4-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2,5-dimethylbenzenesulfonamide

N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-2,5-dimethylphenyl)acetamide (530 mg, 1.4 mmol) was mixed with acetic acid (20 ml), HCl (6N, 2 ml), heated at 100° C. for 3 hours. Removed solvent, and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as white powder, yield 280 mg. MS calcd for (C₁₅H₁₇BN₂O₄S): 332.18, MS found (ESI negative): (M−H)⁻=331.1. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.89 (s, 1H), 7.45 (s, 1H), 7.41 (d, J=1.6 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 4.83 (s, 2H).

4-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2,6-dimethylbenzenesulfonamide

N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3,5-dimethylphenyl)acetamide

General Procedure 1: Starting Materials 6-amino-3H-benzo[c][1,2]oxaborol-1-ol and 4-acetamido-2,6-dimethylbenzene-1-sulfonyl chloride. ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 10.06 (s, 1H), 10.04 (s, 1H), 9.21 (bs, 1H), 7.39 (s, 1H), 7.34 (s, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.09 (dd, J=8, 1.6 Hz, 1H), 4.87 (s, 2H), 2.50 (s, 6H), 2.01 (s, 3H); MS (ESI) m/z=373.1 (M−H, negative).

4-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2,6-dimethylbenzenesulfonamide

The N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3,5-dimethylphenyl)acetamide (0.40 g, 1.07 mmol) was added to 1:1 6N HCl: AcOH (10 mL) and heated to 40° C. for 2 days. The reaction was monitored by LC/MS. Purification: The reaction was concentrated under vacuum, worked up with EtOAc and 1N HCl, washed with brine, dry over Na₂SO₄, and evaporated in vacuo. The product was recrystallized in EtOAc to give title product 4-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2,6-dimethylbenzenesulfonamide 195 mg. (yield: 55%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.74 (s, 1H), 9.20 (bs, 1H), 7.38 (d, J=1.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.09 (dd, J=8.4, 2 Hz, 1H), 6.21 (s, 2H), 5.14 (bs, 2H), 4.87 (s, 2H), 2.41 (s, 6H); MS (ESI) m/z=331.1 (M−H, negative).

Example 2

LeuRS1050 Testing

Experiments were performed in 96-well microtiter plates, using 80 μL reaction mixtures containing 50 mM HEPES-KOH (pH 8.0), 30 mM MgCl₂ and 30 mM KCl, 13 μM [¹⁴C]leucine (306 mCi/mmol, Perkin-Elmer), 15 uM total E. coli tRNA (Roche, Switzerland), 0.02% (w/v) BSA, 1 mM DTT, 0.2 μM LeuRs and 4 mM ATP at 30° C. Reactions were started by the addition of 4 mM ATP. After 7 minutes, reactions were quenched and tRNA was precipitated by the addition of 50 μL of 10% (w/v) TCA and transferred to 96-well nitrocellulose membrane filter plates (Millipore Multiscreen HTS, MSHAN4B50). Each well was then washed three times with 100 μL of 5% TCA. Filter plates were then dried under a heat lamp and the precipitated [¹⁴C]leucine tRNA^Leu were quantified by liquid scintillation counting using a Wallac MicroBeta Trilux model 1450 liquid scintillation counter (PerkinElmer, Waltham Mass.).

To determine the inhibitor concentration which reduces enzyme activity by 50% (IC₅₀), increasing concentrations of inhibitor were incubated with LeuRS enzyme, tRNA and leucine for 20 minutes. Reactions were initiated by the addition of 4 mM ATP and stopped after 7 minutes then precipitated and counted to quantify radioactivity.

Biochemical testing results for exemplary compounds of the invention are provided in FIG. 1. Units for enzyme activity are μM.

Example 3

Antibacterial MIC Testing

All MIC testing of bacteria followed the Clinical and Laboratory Standards Institute (CLSI) guidelines for antimicrobial testing of aerobic bacteria (Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Seventh Edition) (M07-A7) and anaerobic bacteria (Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard—Seventh Edition) (M11-A7).

Antibacterial MIC testing results for exemplary compounds of the invention are provided in FIG. 1. Units for MIC are μg/mL.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A compound, or a salt thereof, having a structure which is

wherein R5 is H or halogen; one of Ra2, Ra3, Ra5 and Ra6 is halogen or —NHC(O)OR30 or alkyl substituted with —C(O)OR30 or alkyl substituted with —S(O)2R30 or alkyl substituted with halogen or alkyl substituted with hydroxy or alkyl substituted with cyano or alkyl substituted with —NHC(O)OR30 or alkyl substituted with unsubstituted oxazolyl or alkyl substituted with alkyl substituted oxazolyl or alkyl substituted with unsubstituted oxadiazolyl or alkyl substituted with alkyl substituted oxadiazolyl or alkyl substituted with —C(O)NHR35, wherein R30 is unsubstituted alkyl and R35 is unsubstituted alkyl or unsubstituted cycloalkyl,

and the remaining members of Ra2, Ra3, Ra5 and Ra6 are H, R10 and R11 are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

2. The compound of claim 1, having a structure which is

3. The compound of claim 1, having a structure which is wherein Ra6 is F or Cl or Br.

4. The compound of claim 1, having a structure which is wherein Ra6 is F or Cl or Br.

5. A combination comprising:

a) a compound of claim 1, or a pharmaceutically acceptable salt thereof; and

b) a therapeutically active agent.

6. A pharmaceutical formulation comprising:

a) a compound of claim 1 or a combination of claim 5, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically acceptable excipient.

7. The pharmaceutical formulation of claim 6, wherein said formulation is a unit dosage form.

8. The pharmaceutical formulation of claim 6, wherein said formulation is a member selected from an oral unit dosage form and a topical unit dosage form.

9. A method of killing or inhibiting the growth of a bacteria, said method comprising:

contacting said bacteria with an effective amount of a compound of claim 1 or a combination of claim 5, or a pharmaceutically acceptable salt thereof, thereby killing or inhibiting the growth of the bacteria.

10. A method of treating a bacterial infection comprising: administering to an animal suffering from said infection an effective amount of a compound of claim 1, or a pharmaceutically-acceptable salt thereof, thereby treating the bacterial infection.

11. The method of claim 10, wherein said animal is a human.

12. A method of inhibiting the editing domain of a t-RNA synthetase, comprising: contacting the synthetase with an effective amount of a compound of claim 1, or a pharmaceutically-acceptable salt thereof, thereby inhibiting the synthetase.

13. The method of claim 12, wherein the synthetase is a leucyl t-RNA synthetase.

14. The use of a compound of claim 1 or a combination of claim 6 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of bacterial infection.