WO2011019616A1

WO2011019616A1 - Boron-containing small molecules as antiprotozoal agents

Info

Publication number: WO2011019616A1
Application number: PCT/US2010/044751
Authority: WO
Inventors: Matthew Orr; Matthew Jenks
Original assignee: Anacor Pharmaceuticals, Inc.
Priority date: 2009-08-14
Filing date: 2010-08-06
Publication date: 2011-02-17

Abstract

This invention provides, among other things, novel compounds useful for treating protozoal infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent. The compounds are of the following formula: wherein R¹ is a member selected from alkyl or aryl or heteroaryl, in which at least one substituent on said alkyl or said aryl or said heteroaryl is optionally substituted with a member selected from halogen, C₁or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, C₁ or C₂ or C₃or C₄ or C₅ or C₆ unsubstituted alkoxy, halosubstituted C₁ or C₂ or C₃or C₄ or C₅ or C₆ alkyl, halosubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆alkylthio, unsubstituted phenyl; and X is aryl or heteroaryl, in which one substituent on said aryl or said heteroaryl is a member selected from halogen, unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, halosubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, halosubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkylthio, unsubstituted phenyl or a salt thereof.

Description

BORON-CONTAINING SMALL MOLECULES AS ANTIPROTOZOAL

AGENTS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Pat. App. No. 61/234,229, filed August 14, 2009, which is incorporated by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

[0002] The global rise of protozoa resistant to 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 antiprotozoals, useful in combating microorganisms, especially those with multidrug-resistance.

[0003] Boron-containing molecules, such as oxaboroles, useful as antimicrobials have been described previously, such as in U.S. Pat. Pubs. US20060234981 and US20070155699. Generally speaking, an oxaborole has the following structure and substituent numbering system:

It has now been discovered that certain classes of oxaboroles which are surprisingly effective antiprotozoals. This, and other uses of these oxaboroles are described herein.

SUMMARY OF THE INVENTION

[0004] This invention provides, among other things, novel compounds useful for treating protozoa infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0005] Biological data for exemplary compounds of the invention is provided in FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

/. Definitions and Abbreviations

[0006] 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.

[0007] The abbreviations used herein generally have their conventional meaning within the chemical and biological arts.

[0008] 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

dicarbonate; Bz is, in general, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl or carboxybenzyl;

Cs₂Cθ3 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 NJSf- 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 Λ/-(3-dimethylaminopropyl)-Λ/"-ethylcarbodiimide hydrochloride; ELS is evaporative light scattering; equiv or eq is equivalent; h is hours; HATU is O-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOBt is JV-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(O); Ra Ni or Raney Ni is Raney nickel; Ph is phenyl; PMB is /?-methoxybenzyl; PrOH is 1-propanol; iPrOH is 2-propanol; POCI₃ is phosphorus chloride oxide; PTSA is /?αrα-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 Si-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.

[0009] "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. [0010] "Combination of the invention," as used herein refers to the compounds and antiprotozoals discussed herein as well as acids, bases, salt forms (such as

pharmaceutically acceptable salts), prodrugs, solvates and hydrates of these compounds and antiprotozoals. [0011] "Boron containing compounds", as used herein, refers to the compounds of the invention that contain boron as part of their chemical formula.

[0012] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents, which would result from writing the structure from right to left, e.g. , -CH₂O- is intended to also recite -OCH₂-.

[0013] 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.

[0014] "Moiety" refers to a radical of a molecule that is attached to the remainder of the molecule.

[0015] The symbol v/wvo _; 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.

[0016] 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. Ci-Cio 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-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers.

[0017] 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-, and further includes those groups described below as "heteroalkylene." 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. [0018] The term "alkenylene" by itself or as part of another substituent means a divalent radical derived from an alkene.

[0019] The term "cycloalkylene" by itself or as part of another substituent means a divalent radical derived from a cycloalkane.

[0020] The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from an heteroalkane.

[0021] The term "heterocycloalkylene" by itself or as part of another substituent means a divalent radical derived from an heterocycloalkane.

[0022] The term "arylene" by itself or as part of another substituent means a divalent radical derived from an aryl. [0023] The term "heteroarylene" by itself or as part of another substituent means a divalent radical derived from heteroaryl.

[0024] 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. [0025] 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(CHs)-CH₃, -CH₂-S-CH₂-CH₃, -CH₂-CH₂₅-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 -R⁵C(O)₂-.

[0026] 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.

[0027] 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(Ci-C₄)alkyl" is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. [0028] 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, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0029] For brevity, the term "aryl" when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g. , benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2- pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).

[0030] 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.

[0031] 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', =0, =NR', =N-0R', -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(0)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)₂NR⁵R", -NR"SO₂R', -CN, -NO₂, -N₃, -CH(Ph)₂, fiuoro(Ci-C₄)alkoxy, and fluoro(Ci-C₄)alkyl, in a number ranging from zero to (2m'+l), 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 'R" 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).

[0032] 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', =0, =NR', =N-0R', -NR'R", -SR', -halogen, -SiR'R"R'", -OC(O)R', -C(O)R', -CO₂R', -CONR'R", -0C(0)NR'R", -NR"C(O)R', -NR'-C(0)NR"R"', -NR"C(0)₂R',

-NR'""-C(NR'R"R'")=NR"", -NR""-C(NR'R")=NR'", -S(O)R', -S(O)₂R',

-S(O)₂NR⁹R", -NR"S0₂R', -CN, -NO₂, -N₃, -CH(Ph)₂, fiuoro(Ci-C₄)alkoxy, and fluoro(Ci-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.

[0033] 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(0)-(CRR')_q-U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is 0 or 1 or 2 or 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 1 or 2 or 3 or 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 selected from O or 1 or 2 or 3, and X is -0-, -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 Ci or C₂ or C3 or C₄ or C₅ or C₆ alkyl.

[0034] "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.

[0035] 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).

[0036] The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include triflate, chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like. [0037] 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.

[0038] By "effective" amount of a drug, formulation, or permeant is meant a sufficient amount of an active agent to provide the desired local or systemic effect. A "Topically effective," "pharmaceutically effective," or "therapeutically effective" amount refers to the amount of drug needed to effect the desired therapeutic result. [0039] "Topically effective" refers to a material that, when applied to the skin, nail, hair, claw or hoof produces a desired pharmacological result either locally at the place of application or systemically as a result of transdermal passage of an active ingredient in the material.

[0040] 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 (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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 olefmic 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.

[0045] 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.

[0046] Optically active (R)- and (5)-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).

[0047] 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), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). The compounds may also be labeled with stable isotopes such as deuterium. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.

[0048] 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.

[0049] "Pharmaceutically acceptable topical carrier" and equivalent terms refer to pharmaceutically acceptable carriers, as described herein above, suitable for topical application. An inactive liquid or cream vehicle capable of suspending or dissolving the active agent(s), and having the properties of being nontoxic and non-inflammatory when applied to the skin, nail, hair, claw or hoof is an example of a pharmaceutically- acceptable topical carrier. This term is specifically intended to encompass carrier materials approved for use in topical cosmetics as well.

[0050] The term "pharmaceutically acceptable additive" refers to preservatives, antioxidants, fragrances, emulsifϊers, dyes and excipients known or used in the field of drug formulation and that do not unduly interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient. Additives for topical formulations are well-known in the art, and may be added to the topical composition, as long as they are pharmaceutically acceptable and not deleterious to the epithelial cells or their function. Further, they should not cause deterioration in the stability of the composition. For example, inert fillers, anti- irritants, tackifiers, excipients, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactant, emollients, coloring agents, preservatives, buffering agents, other permeation enhancers, and other conventional components of topical or transdermal delivery formulations as are known in the art.

[0051] The terms "enhancement," "penetration enhancement" or "permeation enhancement" relate to an increase in the permeability of the skin, nail, hair, claw or hoof to a drug, so as to increase the rate at which the drug permeates through the skin, nail, hair, claw or hoof. The enhanced permeation effected through the use of such enhancers can be observed, for example, by measuring the rate of diffusion of the drug through animal skin, nail, hair, claw or hoof using a diffusion cell apparatus. A diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp. 161-162. The term "permeation enhancer" or "penetration enhancer" intends an agent or a mixture of agents, which, alone or in combination, act to increase the permeability of the skin, nail, hair or hoof to a drug.

[0052] The term "excipients" is conventionally known to mean carriers, diluents and/or vehicles used in formulating drug compositions effective for the desired use.

[0053] The term "topical administration" refers to the application of a

pharmaceutical agent to the external surface of the skin, nail, hair, claw or hoof, such that the agent crosses the external surface of the skin, nail, hair, claw or hoof and enters the underlying tissues. Topical administration includes application of the composition to intact skin, nail, hair, claw or hoof, or to a broken, raw or open wound of skin, nail, hair, claw or hoof. Topical administration of a pharmaceutical agent can result in a limited distribution of the agent to the skin and surrounding tissues or, when the agent is removed from the treatment area by the bloodstream, can result in systemic distribution of the agent. [0054] The term "transdermal delivery" refers to the diffusion of an agent across the barrier of the skin, nail, hair, claw or hoof resulting from topical administration or other application of a composition. The stratum corneum acts as a barrier and few pharmaceutical agents are able to penetrate intact skin. In contrast, the epidermis and dermis are permeable to many solutes and absorption of drugs therefore occurs more readily through skin, nail, hair, claw or hoof that is abraded or otherwise stripped of the stratum corneum to expose the epidermis. Transdermal delivery includes injection or other delivery through any portion of the skin, nail, hair, claw or hoof or mucous membrane and absorption or permeation through the remaining portion. Absorption through intact skin, nail, hair, claw or hoof can be enhanced by placing the active agent in an appropriate pharmaceutically acceptable vehicle before application to the skin, nail, hair, claw or hoof. Passive topical administration may consist of applying the active agent directly to the treatment site in combination with emollients or penetration enhancers. As used herein, transdermal delivery is intended to include delivery by permeation through or past the integument, i.e. skin, nail, hair, claw or hoof.

[0055] The terms "effective amount" or a "therapeutically effective amount" of a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to provide the desired effect. In the oral dosage forms of the present disclosure, an "effective amount" of one active of the combination is the amount of that active that is effective to provide the desired effect when used in combination with the other active of the combination. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0056] The phrases "active ingredient", "therapeutic agent", "active", or "active agent" mean a chemical entity which can be effective in treating a targeted disorder, disease or condition.

[0057] The phrase "pharmaceutically acceptable" means moieties or compounds that are, within the scope of medical judgment, suitable for use in humans without causing undesirable biological effects such as undue toxicity, irritation, allergic response, and the like, for example.

[0058] The phrase "oral dosage form" means any pharmaceutical composition administered to a subject via the oral cavity. Exemplary oral dosage forms include tablets, capsules, films, powders, sachets, granules, solutions, solids, suspensions or as more than one distinct unit (e.g., granules, tablets, and/or capsules containing different actives) packaged together for co-administration, and other formulations known in the art. An oral dosage form can be one, two, three, four, five or six units. When the oral dosage form has multiple units, all of the units are contained within a single package, (e.g. a bottle or other form of packaging such as a blister pack). When the oral dosage form is a single unit, it may or may not be in a single package. In a preferred embodiment, the oral dosage form is one, two or three units. In a particularly preferred embodiment, the oral dosage form is one unit.

[0059] The phrase "unit", as used herein, refers to the number of discrete objects to be administered which comprise the dosage form. In some embodiments, the dosage form includes a compound of the invention in one capsule. This is a single unit. In some embodiments, the dosage form includes a compound of the invention as part of a therapeutically effective dosage of a cream or ointment. This is also a single unit. In some embodiments, the dosage form includes a compound of the invention and another active ingredient contained within one capsule, or as part of a therapeutically effective dosage of a cream or ointment. This is a single unit, whether or not the interior of the capsule includes multiple discrete granules of the active ingredient. In some embodiments, the dosage form includes a compound of the invention in one capsule, and the active ingredient in a second capsule. This is a two unit dosage form, such as two capsules or tablets, and so such units are contained in a single package. Thus the term 'unit' refers to the object which is administered to the animal, not to the interior components of the object.

[0060] The term, "prodrug", as defined herein, is a derivative of a parent drug molecule that exerts its pharmacological effect only after chemical and/or enzymatic conversion to its active form in vivo. Prodrugs include those designed to circumvent problems associated with delivery of the parent drug. This may be due to poor physicochemical properties, such as poor chemical stability or low aqueous solubility, and may also be due to poor pharmacokinetic properties, such as poor bioavailability or poor half- life. Thus, certain advantages of prodrugs may include improved chemical stability, absorption, and/or PK properties of the parent carboxylic acids. Prodrugs may also be used to make drugs more "patient friendly," by minimizing the frequency (e.g., once daily) or route of dosing (e.g., oral), or to improve the taste or odor if given orally, or to minimize pain if given parenterally . [0061] In some embodiments, the prodrugs are chemically more stable than the active drug, thereby improving formulation and delivery of the parent drug, compared to the drug alone.

[0062] Prodrugs for carboxylic acid analogs of the invention may include a variety of esters. In an exemplary embodiment, the pharmaceutical compositions of the invention include a carboxylic acid ester. In an exemplary embodiment, the prodrug is suitable for treatment /prevention of those diseases and conditions that require the drug molecule to cross the blood brain barrier. In an exemplary embodiment, the prodrug enters the brain, where it is converted into the active form of the drug molecule. In one embodiment, a prodrug is used to enable an active drug molecule to reach the inside of the eye after topical application of the prodrug to the eye.

Additionally, a prodrug can be converted to its parent compound by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to its parent compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0063] "Antibiotic", as used herein, is a compound which can kill or inhibit the growth of bacteria. The term antibiotic is broad enough to encompass acids, bases, salt forms (such as pharmaceutically acceptable salts), prodrugs, solvates and hydrates of the antibiotic compound.

[0064] "Antiprotozoal" or "antiprotozoa", as used herein, is a compound which can kill or inhibit the growth of protozoa. The term antiprotozoal or antiprotozoa is broad enough to encompass acids, bases, salt forms (such as pharmaceutically acceptable salts), prodrugs, solvates and hydrates of the antiprotozoal or antiprotozoa compound.

[0065] The term "microbial infection" or "infection by a microorganism" refers to any infection of a host by an infectious agent including, but not limited to, viruses, bacteria, mycobacteria, fungus and parasites (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).

[0066] "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.

[0067] "Inhibiting" and "blocking," are used interchangeably herein to refer to the partial or full blockade of an enzyme, such as a beta-lactamase or a leucyl t-RNA synthetase.

[0068] Boron is able to form additional covalent or dative bonds with oxygen, sulfur or nitrogen under some circumstances in this invention.

[0069] 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 homo logs of the compounds of use in the invention or reactive analogues thereof. [0070] "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, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), and sodium.

[0071] 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 negative charge, a positively charged counterion may associate with this compound, thus forming a salt. Examples of positively charged counterions include H⁺, H₃O⁺, ammonium, potassium, calcium, magnesium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), and sodium. These salts of the compounds are implicitly contained in descriptions of these compounds.

//. Introduction

[0072] The invention provides novel boron compounds. The novel compounds, as well as pharmaceutical compositions containing such compounds or combinations of these compounds with at least one additional therapeutically effective agent, can be used for, among other things, treating protozoal infections.

///. The Compounds

III. a) Cyclic Boronic Esters

[0073] In one aspect, the invention provides a compound of the invention. In an exemplary embodiment, the invention is a compound described herein. In an exemplary embodiment, the invention is a compound according to a formula described herein.

[0074] In another aspect, the invention provides a compound having a structure according to the following formula:

wherein R¹ is alkyl or aryl or heteroaryl, optionally substituted with 1 or 2 or 3 substituents, and wherein said 1 or 2 or 3 substituents are each the same or different and are each selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkylthio, and unsubstituted phenyl. X is aryl or heteroaryl, optionally substituted with 1 or 2 substituents, in which said 1 or 2 substituents are each the same or different and are each selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy,

halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkylthio, and unsubstituted phenyl. R^3a is selected from the group consisting of H, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl and unsubstituted C₃ or C₄ or C₅ or C₆ cycloalkyl; R^3b is selected from the group consisting of H, unsubstituted C₃ or C₄ or C₅ or C₆ alkyl and unsubstituted C₃ or C₄ or C₅ or C₆ cycloalkyl; with the proviso that R^3a and R^3b, along with the atom to which they are attached, are optionally joined to form a 3 or 4 or 5 or 6 membered ring, or a salt thereof.

[0075] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein R¹, R^3a and R^3b are as

described herein, and R², R³, R⁴, R⁵ and R⁶ are members selected from the following table, or a salt thereof.

In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl. In an exemplary embodiment, for any of the entries in the above table, R^3a is H and R^3b is H. In an exemplary embodiment, for any of the entries in the above table, R^3a is CH3 and R^3b is CH3. In an exemplary embodiment, for any of the entries in the above table, R¹ is methyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is vinyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- chloro phenyl. In an exemplary

embodiment, for any of the entries in the above table, R¹ is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para- unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-methoxy phenyl or meta methoxy phenyl or ortho-methoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted at the para position with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with halogen and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or Ce unsubstituted alkoxy.

[0076] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein R¹, R^3a and R^3b are as d

escribed herein, and R², R³, R⁴, R⁵ and R⁶ are members selected from the following table, or a salt thereof.

wherein Y¹ is Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl. In an exemplary embodiment, for any of the entries in the above table, R^3a is H and R^3b is H. In an exemplary embodiment, for any of the entries in the above table, R^3a is CH3 and R^3b is CH₃. In an exemplary embodiment, for any of the entries in the above table, Y¹ is methyl. In an exemplary embodiment, for any of the entries in the above table, Y¹ is ethyl. In an exemplary embodiment, for any of the entries in the above table, Y¹ is unsubstituted C₃ alkyl. In an exemplary embodiment, for any of the entries in the above table, Y¹ is isopropyl. In an exemplary embodiment, for any of the entries in the above table, Y¹ is unsubstituted C₄ alkyl. In an exemplary embodiment, for any of the entries in the above table, Y¹ is t-butyl. In an exemplary embodiment, for any of the entries in the above table, Y¹ is unsubstituted C5 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y¹ is unsubstituted C₆ alkyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is

unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is methyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is vinyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho- unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-methoxy phenyl or meta methoxy phenyl or ortho-methoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C3 or C₄ or C5 or C₆

unsubstituted alkoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or Ce unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted at the para position with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with halogen and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or Ce unsubstituted alkoxy.

[0077] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein R¹, R^3a and R^3b are as d

wherein Y is unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R , 3a^a is H and R 3b is H. In an exemplary embodiment, for any of the entries in the above table, R^3a is CH3 and R^3b is CH3. In an exemplary embodiment, for any of the entries in the above table, Y² is unsubstituted Ci alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y² is unsubstituted C₂ alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y² is unsubstituted C3 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y² is n-propoxy. In an exemplary embodiment, for any of the entries in the above table, Y² is isopropoxy. In an exemplary embodiment, for any of the entries in the above table, Y² is unsubstituted C₄ alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y² is unsubstituted C₅ alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y² is unsubstituted C₆ alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is methyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is vinyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- chloro phenyl. In an exemplary

embodiment, for any of the entries in the above table, R¹ is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para- unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-methoxy phenyl or meta methoxy phenyl or ortho-methoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted at the para position with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with halogen and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy.

[0078] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein R¹, R^3a and R^3b are as described herein, and R², R³, R⁴, R⁵ and R⁶ are members selected from the following table, or a salt thereof.

wherein Y is halosubstituted alkyl. In an exemplary embodiment, for any of the entries in the above table, R , 3a^a is H and R , 3b is H. In an exemplary embodiment, for any of the entries in the above table, R^3a is CH₃ and R^3b is CH₃. In an exemplary embodiment, for any of the entries in the above table, Y³ is halosubstituted Ci alkyl. In an exemplary embodiment, for any of the entries in the above table, Y³ is halosubstituted C₂ alkyl. In an exemplary embodiment, for any of the entries in the above table, Y³ is halosubstituted C₃ alkyl. In an exemplary embodiment, for any of the entries in the above table, Y is halosubstituted C₄ alkyl. In an exemplary embodiment, for any of the entries in the above table, Y is halosubstituted Cs alkyl. In an exemplary embodiment, for any of the entries in the above table, Y is halosubstituted C₆ alkyl. In an exemplary embodiment, for any of the entries in the above table, Y³ is fluoro-substituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkyl. In an exemplary embodiment, for any of the entries in the above table, Y³ is alkyl substituted with one or two or three halogens. In an exemplary embodiment, for any of the entries in the above table, Y³ is trifluoro-substituted Ci or C₂ or C₃ or C₄ or Cs or Ce alkyl. In an exemplary embodiment, for any of the entries in the above table, Y is trifluoromethyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is methyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is vinyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- chloro phenyl. In an exemplary

embodiment, for any of the entries in the above table, R¹ is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para- unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-methoxy phenyl or meta methoxy phenyl or ortho-methoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted at the para position with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with halogen and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or Ce unsubstituted alkoxy.

[0079] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein R¹, R^3a and R^3b are as d

wherein Y⁴ is halosubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R^3a is H and R^3b is H. In an exemplary embodiment, for any of the entries in the above table, R^3a is CH3 and R^3b is CH3. In an exemplary embodiment, for any of the entries in the above table, Y⁴ is halosubstituted Ci alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y⁴ is halosubstituted C₂ alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y⁴ is halosubstituted C3 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y⁴ is halosubstituted C₄ alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y⁴ is halosubstituted C5 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y⁴ is halosubstituted C₆ alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y⁴ is fluoro-substituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y⁴ is alkoxy substituted with one or two or three halogens. In an exemplary embodiment, for any of the entries in the above table, Y⁴ is trifluoro-substituted Ci or C₂ or C3 or C₄ or C5 or Ce alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y⁴ is trifluoromethoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is methyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is vinyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- chloro phenyl. In an exemplary

embodiment, for any of the entries in the above table, R¹ is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para- unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-methoxy phenyl or meta methoxy phenyl or ortho-methoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C₃ or C₄ or C5 or C₆ unsubstituted alkoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C5 or Ce unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or Ce unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted at the para position with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with halogen and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C₅ or Ce unsubstituted alkoxy. [0080] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein R¹, R^3a and R^3b are as d

wherein Y is halosubstituted alkylthio. In an exemplary embodiment, for any of the entries in the above table, R^3a is H and R^3b is H. In an exemplary embodiment, for any of the entries in the above table, R^3a is CH3 and R^3b is CH3. In an exemplary embodiment, for any of the entries in the above table, Y is halosubstituted C alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y⁵ is halosubstituted C₂ alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y⁵ is halosubstituted C3 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y⁵ is halosubstituted C₄ alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y⁵ is halosubstituted C5 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y⁵ is halosubstituted C₆ alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y⁵ is fluoro-substituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y⁵ is alkylthio substituted with one or two or three halogens. In an exemplary embodiment, for any of the entries in the above table, Y⁵ is trifluoro-substituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y⁵ is trifluoromethylthio. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or Ce alkyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is methyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is vinyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-chloro phenyl. In an exemplary

embodiment, for any of the entries in the above table, R¹ is meta- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para- unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is ortho-unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is meta- unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is para-methoxy phenyl or meta methoxy phenyl or ortho-methoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted at the para position with methoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy. In an exemplary embodiment, for any of the entries in the above table, R¹ is phenyl substituted with halogen and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkyl, Ci or C₂ or C3 or C₄ or C5 or C₆ unsubstituted alkoxy.

[0081] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein X, R^3a, and R^3b are as described herein, and R^la, R^lb, R^lc, R^ld and R^le are members selected from the following table, or a salt thereof.

In an exemplary embodiment, for any of the entries in the above table, R ₃a^a is H and

R > 3b is H. In an exemplary embodiment, for any of the entries in the above table, R ₃a^a is

CH₃ and R ₃'b^D is CH₃.

[0082] In an exemplary embodiment, the compound has a structure according to the following formula:

wherein R¹, R^3a, and R^3b are as described herein, and R², R³, R⁴, R⁵ and R⁶ are members selected from the following table, or a salt thereof.

In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, and Y² is as described herein and Y³ is as described herein. In an exemplary embodiment, for any of the entries in the above table, R^3a is H and R^3b is H. In an exemplary embodiment, for any of the entries in the above table, R^3a is CH3 and R^3b is CH3. In an exemplary embodiment, for any of the entries in the above table, R¹ is methyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is vinyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R¹ is substituted phenyl.

[0083] In an exemplary embodiment, the compound has a structure according to the following formula:

wherein X is as described herein, and R^la, R^lb, R^lc, R^ld and R^le are members selected from the following table, or a salt thereof.

wherein Y and Y are as described herein for all of the entries in the above table.

[0084] In an exemplary embodiment, the compound has a structure according to the following formula:

wherein for all of the entries in the above table each Y¹ is as described herein and are the same or different from other Y¹S.

[0085] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein one member selected from R², R³, R⁴, R⁵ and R⁶ is a member selected from halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkylthio, unsubstituted phenyl, and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H; and wherein one member selected from R^la, R^lb, R^lc, R^ld and R^le is a member selected from halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy and NR^lfR^lg, wherein R^lf is H or unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl and R^lg is H or

unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, and the remaining members of R^la, R^lb, R^lc, R^ld and R^le are H.

[0086] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein X is as described herein and one member selected from R^la, R^lb, R^lc, R^ld and R^le is NR^lfR^lg, wherein R^lf is H or unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl and R^lg is H or unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, and the remaining members of R^la, R^lb, R^lc, R^ld and R^le are H. In an exemplary embodiment, NR^lfR^lg is NH₂. In an exemplary embodiment, NR^lfR^lg is NHR^lg, wherein R^lg is unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, each R^lf andR^lg are the same or different and are each selected from unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, each R^lf andR^lg are the same or different and are each selected from unsubstituted Ci or C₂ or C3 alkyl. In an exemplary embodiment, NR^lfR^lg is N(CHs)₂. In an exemplary embodiment, NR^lfR^lg is N(CH₃)R^lg, wherein R^lg is unsubstituted Ci or C₂ or C₃ alkyl.

[0087] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein one member selected from R², R³, R⁴, R⁵ and R⁶ is a member selected from halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkylthio, unsubstituted phenyl, and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H; and wherein one member selected from R^la, R^lb, R^lc, R^ld and R^le is NR^lfR^lg, wherein R^lf is H or unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl and R^lg is H or unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, and the remaining members of R^la, R^lb, R^lc, R^ld and R^le are H.

[0088] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein one member selected

R is a member selected from halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkylthio, unsubstituted phenyl, and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H; and R^lc is a member selected from halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy and NR^lfR^lg, wherein R^lf is H or unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl and R^lg is H or unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. [0089] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein one member selected from R², R³, R⁴, R⁵ and R⁶ is a member selected from halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C3 or C₄ or C₅ or C₆ alkylthio, unsubstituted phenyl, and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H; and wherein one member selected from R^la, R^lb, R^lc, R^ld and R^le is a member selected from halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, and the remaining members of R^la, R^lb, R^lc, R^ld and R^le are H.

[0090] In an exemplary embodiment, the compound of the invention has a structure which is:

or or , wherein

R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹ is as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, R¹ is as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof.

[0091] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z⁵ is unsubstituted pyrimidinyl or unsubstituted pyrazinyl or unsubstituted pyridazinyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z⁵ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z⁵ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

or

wherein R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹ is as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, R¹ is as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof.

[0092] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z⁶ is halosubstituted pyridazinyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z⁶ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z⁶ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, Z⁶ is pyridazinyl, substituted with one halogen, and R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z⁶ is pyridazinyl, substituted with two halogens, and R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z⁶ is pyridazinyl, substituted with two chlorines, and R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

wherein each R¹⁴ is chlorine or fluorine, and R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, each R¹⁴ is chlorine, and R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0093] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein each R¹³ are the same or different and are each selected from H or -SH or - OH, wherein R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, R¹³ and R¹ and as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, each R¹³ are the same or different and are each selected from -SH or -OH, R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0094] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z is thiophenyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

[0095] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z¹ is unsubstituted alkylthiophenyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z¹ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z¹ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

wherein R¹⁵ is unsubstituted alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁵ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, R¹⁵ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, R¹⁵ is unsubstituted Ci alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁵ is unsubstituted C₂ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁵ is unsubstituted C3 alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁵ is unsubstituted C₄ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁵ is unsubstituted C₅ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁵ is unsubstituted C₆ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0096] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z² is unsubstituted benzothiophenyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z² and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z² and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof.

[0097] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z² is halosubstituted benzothiophenyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z² and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z² and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, Z² is benzothiophenyl substituted with chloro, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z² is

benzothiophenyl substituted with fluoro, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z² is benzothiophenyl substituted with one halogen, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z² is benzothiophenyl substituted with two halogens, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z² is

benzothiophenyl substituted with two fluorines, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z² is benzothiophenyl substituted with two chlorines, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z² is benzothiophenyl substituted with a fluorine and a chlorine, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, the compound of the invention is:

or wherein R¹⁶ is halogen, R¹⁷ is halogen, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁶, R¹⁷, and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, R¹⁶, R¹⁷, and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention is:

wherein each R¹⁶ and R¹⁷ are each the same or different and are each selected from halogen, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁶, R¹⁷, and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, R¹⁶, R¹⁷, and R¹ are as described herein, R^3a is CH3 and R^3b is CH3, or a salt thereof.

[0098] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted oxazo

are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

or wherein R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0099] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted alkyl oxazolyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

or wherein R¹⁸ is unsubstituted alkyl, R¹,

R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein R¹⁸ is unsubstituted alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁸ is Ci or C₂ or C₃ or C₄ or C5 or Ce alkyl, and R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0100] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted isoxazolyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

wherein R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0101] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted alkyl isoxazolyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

wherein R¹⁹ is unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein R¹⁹ is unsubstituted

as described herein, or a salt thereof. In an exemplary embodiment, R¹⁹ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, R¹⁹ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, R¹⁹ is unsubstituted Ci alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁹ is unsubstituted C₂ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁹ is unsubstituted C₃ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁹ is unsubstituted C₄ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁹ is unsubstituted C₅ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁹ is unsubstituted C₆ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0102] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted thiazolyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

wherein R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0103] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted alkyl

R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

or wherein R²⁰ is unsubstituted alkyl, R¹,

R^3a, R^3b are as ddeessccrriibbeedd hheerreeiinn,, oorr aa ssaalltt tthheerreeooff.. IInn an exemplary embodiment, the compound of the invention has a structure which is:

, wherein R²⁰ is unsubstituted alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R 20 is Ci or C₂ or C₃ or C₄ or Cs or C₆ alkyl, R . 1 , r R> 3a^a, r R> 3b are as described herein, or a salt thereof.

[0104] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted pyrazolyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ and as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ and as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

wherein R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0105] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted alkyl pyrrolyl or unsubstituted phenyl pyrrolyl or unsubstituted phenyl (unsubstituted alkyl) pyrrolyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is CH3 and R^3b is CH3, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein each R are the same or different and are each selected from unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl or phenyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

e same or different and are each selected from unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl or phenyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure which is:

wherein R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, each R²¹ is unsubstituted Ci alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²¹ is unsubstituted C₂ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²¹ is unsubstituted C₃ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²¹ is unsubstituted C₄ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²¹ is unsubstituted C5 alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²¹ is unsubstituted C₆ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²¹ is unsubstituted phenyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein R²¹ is as described herein, R¹, R , R^3b are as described herein, or a salt thereof.

[0106] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted furanyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound is:

wherein R . 1 , r R> 3a^a, r R> 3b are as described herein, or a salt thereof.

[0107] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted alkylfuranyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound of the invention is :

wherein Y⁷ is unsubstituted

as described herein, or a salt thereof. In an exemplary embodiment, Y⁷ is unsubstituted Ci alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Y⁷ is unsubstituted C₂ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Y⁷ is unsubstituted C3 alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Y⁷ is unsubstituted C₄ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Y⁷ is unsubstituted C5 alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Y⁷ is unsubstituted C₆ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0108] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted pyrrole, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound is:

wherein R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0109] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z³ is unsubstituted alkyl pyrrole, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z³ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, the compound is:

or wherein R²² is unsubstituted alkyl, R¹,

R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, the compound is:

or wherein R²² is unsubstituted alkyl, R¹,

R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²² is unsubstituted Ci alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²² is unsubstituted C₂ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²² is unsubstituted C₃ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²² is unsubstituted C₄ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²² is unsubstituted C₅ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R²² is unsubstituted C₆ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. [0110] In an exemplary embodiment, the compound of the invention has a structure which is:

wherein R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹ is as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, R¹ is as described herein, R^3a is CH3 and R^3b is CH3, or a salt thereof.

[0111] In an exemplary embodiment, the compound of the invention has a structure which is:

[0112] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z⁹ is unsubstituted alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z⁹ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z⁹ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, Z⁹ is unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z⁹ is methyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z⁹ is

unsubstituted C₄ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z⁹ is n-butyl or sec-butyl or isobutyl or tert-butyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z⁹ is tert- butyl, R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0113] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein R¹⁵ is unsubstituted alkyl, R¹⁶ is H or phenyl substituted alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹, R¹⁵, R , 1¹6 are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, R¹, R¹⁵, R¹⁶ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, R¹⁵ is unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁵ is unsubstituted C₃ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁶ is benzyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, R¹⁶ is H, R¹, R^3a, R^3b are as described herein, or a salt thereof.

[0114] In an exemplary embodiment, the compound of the invention has a structure according to the following formula:

wherein Z¹⁰ is hydroxy-substituted alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. In an exemplary embodiment, Z¹⁰ and R¹ are as described herein, R^3a is H and R^3b is H, or a salt thereof. In an exemplary embodiment, Z¹⁰ and R¹ are as described herein, R^3a is CH₃ and R^3b is CH₃, or a salt thereof. In an exemplary embodiment, Z¹⁰ is hydroxysubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, R¹, R^3a, R^3b are as described herein, or a salt thereof. [0115] In an exemplary embodiment, the cytotoxicity on murine L929 IC50 of a compound of the invention is a member selected from about 1 μM to 20 μM.

[0116] In an exemplary embodiment, the in vitro metabolism T 1/2 (Mouse/human liver microsomes) of a compound of the invention is a member selected from about 300 minutes to 400 minutes. In an exemplary embodiment, the in vitro metabolism T 1/2 (Mouse/human liver microsomes) of a compound of the invention is a member selected from about 340 minutes to 360 minutes.

[0117] In an exemplary embodiment, the in vitro metabolism T 1/2 (Mouse S9) of a compound of the invention is a member selected from about 100 minutes to 300 minutes.

[0118] In an exemplary embodiment, a compound of the invention essentially does not inhibit a cytochrome P450 enzyme. In an exemplary embodiment, a compound of the invention does not inhibit a cytochrome P450 enzyme. In an exemplary embodiment, the cytochrome P450 enzyme is a member selected from CP1A2, 2C9, 2D6 and 3A4. In an exemplary embodiment, the cytochrome P450 enzyme is

CYP2C19.

[0119] In an exemplary embodiment, a compound of the invention is essentially not a substrate for the P-gp transporter. In an exemplary embodiment, a compound of the invention is not a substrate for the P-gp transporter. [0120] 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.

[0121] In an exemplary embodiment, alkyl is linear alkyl. In another exemplary embodiment, alkyl is branched alkyl.

[0122] In an exemplary embodiment, heteroalkyl is linear heteroalkyl. In another exemplary embodiment, heteroalkyl is branched heteroalkyl.

HLb) Combinations comprising additional therapeutic agents

[0123] 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 described herein or a pharmaceutically acceptable salt thereof together with at least one additional therapeutic agent. 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.

[0124] 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. In an exemplary embodiment, the additional therapeutic agent is berenil. In an exemplary

embodiment, the additional therapeutic agent is diminazene. In an exemplary embodiment, the additional therapeutic agent is an antiprotozoa. In an exemplary embodiment, the additional therapeutic agent is selected from the group consisting of benznidazole, buparvaquone, carbarsone, clioquinol, disulfϊram, eflornithine, emetine, etofamide, furazolidone, meglumine antimoniate, melarsoprol, metronidazole, miltefosine, nifurtimox, nimorazole, nitazoxanide, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, secnidazole and tinidazole. In an exemplary

embodiment, the additional therapeutic agent is pentamidine. In an exemplary embodiment, the additional therapeutic agent is suramin. In an exemplary

embodiment, the additional therapeutic agent is eflornithine. In an exemplary embodiment, the additional therapeutic agent is melarsoprol. In an exemplary embodiment, the additional therapeutic agent is nifurtimox. In an exemplary embodiment, the additional therapeutic agent contains a 5-nitrofuran moiety. In an exemplary embodiment, the additional therapeutic agent contains a 5-nitroimidazolyl moiety. In an exemplary embodiment, the additional therapeutic agent is

fexinidazole. In an exemplary embodiment, the additional therapeutic agent is an antiparasitic. In an exemplary embodiment, the additional therapeutic agent is selected from the group consisting of amitraz, avermectin, carbadox,

diethylcarbamazine, dimetridazole, diminazene, ivermectin, macrofilaricide, malathion, mitaban, organophosphate, oxamniquine, permethrin, praziquantel, pyrantel pamoate, selamectin, sodium stibogluconate and thiabendazole. In an exemplary embodiment, the additional therapeutic agent is selected from the group consisting of antimony, meglumine antimoniate, sodium stibogluconate,

amphotericin, miltefosine and paromomycin.

[0125] The compounds of the invention, or pharmaceutical formulations thereof may also be used in combination with other therapeutic agents, for example immune therapies [e.g. interferon, such as interferon alfa-2a (ROFERONd)-A; Hoffmann-La Roche), interferon alpha-2b (INTRONd)-A; Schering-Plough), interferon alfacon-1 (INFERGEN®; Intermune), peginterferon alpha-2b (PEGINTRON™; Schering- Plough) or peginterferon alpha-2a (PEGASYSd); Hoffmann-La Roche)], therapeutic vaccines, antifibrotic agents, anti-inflammatory agents [such as corticosteroids or NSAIDs], bronchodilators [such as beta-2 adrenergic agonists and xanthines (e.g. theophylline)], mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion [e.g. ICAM antagonists], anti-oxidants [e.g. N-acetylcysteine], cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial. The

compositions according to the invention may also be used in combination with gene replacement therapy. [0126] 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 patient 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. [0127] 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 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.

[0128] It is to be understood that the invention covers all combinations of aspects and/or embodiments, as well as suitable, convenient and preferred groups described herein.

HLc) Preparation of Boron-Containing Compounds

[0129] Compounds of use in the invention can be prepared using commercially available starting materials, known intermediates, or by using the synthetic methods described herein, or published in references described and incorporated by reference herein, such as PCT Pub. No. WO2008157726 and U.S. Pat. Pubs. US20060234981, US20070155699 and US20070293457. [0130] In one embodiment, the compound of the invention can be synthesized according to the following scheme:

wherein Y is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, unsubstituted cycloalkyl, halosubstituted alkyl and unsubstituted alkyl, wherein the acid chloride is added to a mixture of 6- aminobenzo[c][l,2]oxaborol-l(3H)-ol and an agent such as Et₃N in an appropriate solvent and is stirred for an appropriate period of time at an appropriate temperature to form the product. [0131] In one embodiment, the compound of the invention can be synthesized according to the following scheme:

wherein Y is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, unsubstituted cycloalkyl, halosubstituted alkyl and unsubstituted alkyl, wherein the mixture includes a carboxylic acid comprising molecule, a solvent such as DMF, and agents such as HATU and DIEA. The mixture can then be contacted with 5-amino-2-hydroxymethylphenylboronic acid

hydrochloride, and stirred for an appropriate amount of time and temperature to form the product. [0132] The compound of the invention can then be synthesized according to the following procedure:

wherein B is commercially available from, for example, Sigma-Aldrich (St. Louis, MO, USA). A and B can be contacted under Grignard addition conditions stirred for an appropriate period of time at an appropriate temperature to form the product C.

[0133] Compounds described herein can be converted into hydrates and solvates by methods similar to those described herein. IV. Methods of Inhibiting Microorganism Growth or Killing Microorganisms

[0134] The compounds of the invention exhibit potency against microorganisms, such as protozoa, and therefore have the potential to kill and/or inhibit the growth of microorganisms . [0135] In a further aspect, the invention provides 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 an exemplary embodiment, the microorganism is a protozoa. In an exemplary embodiment, the microorganism is a kinetoplastid. In another exemplary embodiment, the protozoa is a Trypanosoma. In an exemplary embodiment, the Trypanosoma is a member selected from T. avium, T boissoni, T brucei, T carassii, T cruzi, T congolense, T equinum, T equiperdum, T evansi, T hosei, T levisi, T melophagium, T parroti, T percae, T rangeli, T rotatorium, T rugosae, T sergenti, T simiae, T sinipercae, T suis, T theileri, T triglae and T. vivax. In another exemplary embodiment, the protozoa is a Trypanosoma brucei. In another exemplary embodiment, the protozoa is a member selected from Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. In another exemplary embodiment, the protozoa is a member selected from Trypanosoma brucei rhodesiense and

Trypanosoma brucei gambiense. In another exemplary embodiment, the protozoa is Trypanosoma cruzi. In another exemplary embodiment, the protozoa is a member of the genus Leishmania. In another exemplary embodiment, the protozoa is a member of Leishmania Viannia. In an exemplary embodiment, the protozoa is a member selected from L. donovani, L. infantum, L. chagasi; L. mexicana, L. amazonensis, L. venezuelensis, L. tropica, L. major, L. aethiopica, L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) peruviana. In an exemplary embodiment, the protozoa is L. donovani. In an exemplary embodiment, the protozoa is L.

infantum. 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 salt, hydrate or 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 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 another exemplary embodiment, the compound is described by a formula listed herein, or a pharmaceutically acceptable salt thereof. 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 specific conditions are set forth in the Examples appended hereto.

[0136] In another aspect, the microorganism is inside, or on the surface of an animal. In an exemplary embodiment, the animal is a member selected from 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. [0137] In an exemplary embodiment, the microorganism is killed or its growth is inhibited through oral administration of the compound of the invention. In an exemplary embodiment, the microorganism is killed or its growth is inhibited through intravenous administration of the compound of the invention. In an exemplary embodiment, the microorganism is killed or its growth is inhibited through topical administration of the compound of the invention. In an exemplary embodiment, the microorganism is killed or its growth is inhibited through intraperitoneal

administration of the compound of the invention. In an exemplary embodiment, the compound is administered in a topically effective amount. In an exemplary embodiment, the compound is administered in a cosmetically effective amount. In an exemplary embodiment, the pharmaceutical formulation is administered in an orally effective amount.

V. Methods of Treating and/or Preventing Disease

[0138] The compounds of the invention exhibit potency against microorganisms, such as protozoa, and therefore have the potential to achieve therapeutic efficacy in the animals described herein.

[0139] In another aspect, the invention provides a method of treating and/or preventing a disease. The method includes administering to the animal a therapeutically effective amount of the compound of the invention, sufficient to treat and/or prevent the disease. In an exemplary embodiment, the compound of the invention can be used in human or veterinary medical therapy, particularly in the treatment or prophylaxis of protozoa-associated disease. In an exemplary

embodiment, the compound of the invention can be used in human or veterinary medical therapy, particularly in the treatment or prophylaxis of kinetoplastid- associated disease. In an exemplary embodiment, the disease is associated with a Trypanosoma. In an exemplary embodiment, the Trypanosoma is a member selected from T. avium, T. boissoni, T. brucei, T. carassii, T. cruzi, T. congolense, T equinum, T equiperdum, T evansi, T hosei, T levisi, T melophagium, T parroti, T. percae, T rangeli, T rotatorium, T rugosae, T sergenti, T simiae, T sinipercae, T suis, T theileri, T triglae and T. vivax. In an exemplary embodiment, the disease is associated with a Trypanosoma brucei. In an exemplary embodiment, the disease is associated with a member selected from Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. In an exemplary

embodiment, the disease is associated with Trypanosoma brucei rhodesiense. In an exemplary embodiment, the disease is associated with Trypanosoma brucei gambiense. In an exemplary embodiment, the disease is associated with

Trypanosoma cruzi. In an exemplary embodiment, the disease is a trypanosomiasis. In an exemplary embodiment, the disease is a human trypanosomiasis. In an exemplary embodiment, the disease is an animal trypanosomiasis. In an exemplary embodiment, the disease is a member selected from nagana, surra, mal de caderas, murrina de caderas, dourine, cachexial fevers, Gambian horse sickness, baleri, kaodzera, tahaga, galziekte or galzietzke and peste-boba. In an exemplary

embodiment, the disease is a member selected from Chagas disease (or Human American trypanosomiasis), nagana, surra, Covering sickness (or dourine) and sleeping sickness (or African sleeping sickness or Human African trypanosomiasis). In an exemplary embodiment, the disease is Chagas disease. In an exemplary embodiment, the disease is sleeping sickness (or African sleeping sickness). In an exemplary embodiment, the disease is acute phase sleeping sickness. In an exemplary embodiment, the disease is chronic phase sleeping sickness. In an exemplary embodiment, the disease is an acute phase of a trypanosomiasis. In an exemplary embodiment, the disease is a chronic phase of a trypanosomiasis. In an exemplary embodiment, the disease is the non-CNS form of a trypanosomiasis. In an exemplary embodiment, the disease is the CNS form of a trypanosomiasis. In an exemplary embodiment, the disease is the non-CNS form of sleeping sickness. In an exemplary embodiment, the disease is the CNS form of sleeping sickness. In an exemplary embodiment, the disease is early stage Human African trypanosomiasis. In an exemplary embodiment, the disease is late stage Human African trypanosomiasis. In another exemplary embodiment, the disease is associated with a member of the genus Leishmania. In another exemplary embodiment, the disease is associated with a member of Leishmania Viannia. In an exemplary embodiment, the disease is associated with a member selected from L. donovani, L. infantum, L. chagasi; L. mexicana, L. amazonensis, L. venezuelensis, L. tropica, L. major, L. aethiopica, L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) peruviana. In an exemplary embodiment, the disease is associated with L. donovani. In an exemplary embodiment, the disease is associated with L. infantum. In an exemplary

embodiment, the disease is leishmaniasis. In an exemplary embodiment, the disease is visceral leishmaniasis. In an exemplary embodiment, the disease is cutaneous leishmaniasis. In an exemplary embodiment, the disease is diffuse cutaneous leishmaniasis and/or mucocutaneous leishmaniasis. 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 salt, hydrate or 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 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 another exemplary embodiment, the compound is described by a formula listed herein, or a pharmaceutically acceptable salt thereof. 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 specific conditions are set forth in the Examples appended hereto.

[0140] In another exemplary embodiment, the animal is a member selected from 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 a mouse. In another exemplary embodiment, the animal is a member selected from a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey. In another exemplary embodiment, the animal is a human.

[0141] In an exemplary embodiment, the disease is treated through oral

administration of the compound of the invention. In an exemplary embodiment, the disease is treated through intravenous administration of the compound of the invention. In an exemplary embodiment, the disease is treated through topical administration of the compound of the invention. In an exemplary embodiment, the disease is treated through intraperitoneal administration of the compound of the invention. In an exemplary embodiment, the compound is administered in a topically effective amount. In an exemplary embodiment, the compound is administered in a cosmetically effective amount. In an exemplary embodiment, the pharmaceutical formulation is administered in an orally effective amount.

[0142] In an exemplary embodiment, the disease is associated with an infection by a microorganism described herein. In an exemplary embodiment, the disease is associated with an infection by a protozoa described herein. VI. Pharmaceutical Formulations

[0143] In another aspect, the invention is a pharmaceutical formulation which includes: (a) a pharmaceutically acceptable excipient; and (b) a compound of the invention. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound according to a formula described herein. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, hydrate or solvate thereof, or a combination thereof. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, hydrate or solvate thereof. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a salt of a compound described herein. In an exemplary embodiment, the salt is a pharmaceutically acceptable salt. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a prodrug of a compound described herein. In another aspect, the pharmaceutical formulation includes: (a) a

pharmaceutically acceptable excipient; and (b) a compound described herein. 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.

[0144] 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).

[0145] 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 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. [0146] 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. [0147] 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. [0148] 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. [0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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. [0157] 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.

[0158] 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.

[0159] 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. [0160] 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. [0161] 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. [0162] 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. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of laboratory animals that receive the compound intravenously.

[0163] Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al. (Journal of

Chromatography B (1996) volume 677, pages 1-27).

[0164] Compound half- life is inversely proportional to the frequency of dosage of a compound. In vitro half- lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).

[0165] 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. VI. a) Testins

[0166] 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). Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half- lives of compounds may be predicted from assays of microsomal half- life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).

[0167] 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). VI. b) Administration

[0168] For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays, as disclosed herein. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the EC50 (effective dose for 50% increase) as determined in cell culture, i.e., the concentration of the test compound which achieves a half-maximal inhibition of protozoa cell growth. Such information can be used to more accurately determine useful doses in humans.

[0169] 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.

[0170] Dosage amount and interval can be adjusted individually to provide plasma levels of the active moiety that are sufficient to maintain protozoa cell growth inhibitory effects. 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.

[0171] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the 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%.

[0172] Exemplary embodiments are summarized herein below. [0173] In an exemplary embodiment, the invention provides a compound having a structure according to the following formula:

wherein R¹ is alkyl or aryl or heteroaryl, in which at least one substituent on said alkyl or said aryl or said heteroaryl is optionally substituted with a member selected from the group consisting of halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkylthio, and unsubstituted phenyl; and X is aryl or heteroaryl, in which one substituent on said aryl or said heteroaryl is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or Ce alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkylthio, and unsubstituted phenyl, or a salt thereof. [0174] In an exemplary embodiment, according to the above paragraph, the compound has a structure according to the following formula:

wherein X is phenyl or heteroaryl, in which one substituent on said phenyl or said heteroaryl is selected from the group consisting of F, Cl, -CH₃, -CH₂CHs, CH(CHs)₂, C(CHs)₃, CF₃, -OCH₃, -OCH₂CH₃, -OCF₃, and -SCH₃. [0175] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R², R³, R⁴, R⁵ and R⁶ are the same or different and are each selected from the group consisting of H, halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C3 or C₄ or C₅ or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkylthio, and unsubstituted phenyl with the proviso that R², R³, R⁴, R⁵ and R⁶ cannot all be H. [0176] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R², R³, R⁴, R⁵ and R⁶ are the same or different and are each selected from the group consisting of H, F, Cl, -CH₃, -CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CF₃, -OCH₃, - OCH₂CH₃, -OCF₃, and -SCH₃ with the proviso that R², R³, R⁴, R⁵ and R⁶ cannot all be H.

[0177] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein one member selected from R², R³, R⁴, R⁵ and R⁶ is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkylthio, unsubstituted phenyl, and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H. [0178] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein one member selected from R², R³, R⁴, R⁵ and R⁶ is selected from the group consisting of F, Cl, -CH₃, -CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CF₃, -OCH₃, -OCH₂CH₃, - OCF₃ and -SCH₃ and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

[0179] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is halogen or unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl or halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

[0180] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is selected from the group consisting of F, Cl, Br, I, CH₃, CF₃ and OCH₃; and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

[0181] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is F or Cl or CH₃ or CF₃; and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H. [0182] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein two members selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ are the same or different and are each selected from F or Cl or Br or I; and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

[0183] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is F or Cl or Br or I; one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is halogen or unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl or halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl; and the remaining members of R², R³, R⁴, R⁵, and R⁶ are H. [0184] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from the group consisting of R², R³, R⁴, R⁵, and R⁶ is halogen; one member selected from the group consisting of R², R³, R⁴, R⁵, and R⁶ is F or Cl or Br or I or CH₃ or CF₃ or OCH₃; and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

[0185] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is F; one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is halogen or unsubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkyl or halosubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkyl; and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

[0186] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is F; and one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is Cl or CH₃ or CF₃; and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

[0187] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R² is a member selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkylthio, and unsubstituted phenyl. [0188] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R² is a member selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, and halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. [0189] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R² is a member selected from the group consisting of F, Cl, CH₃ and CF₃.

[0190] In an exemplary embodiment, according to any of the above paragraphs, the

compound is

[0191] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R is a member selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkylthio, and unsubstituted phenyl.

[0192] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R is a member selected from the group consisting of halogen, unsubstituted

Ci or C₂ or C₃ or C₄ or Cs or C₆ alkyl, and halosubstituted Ci or C₂ or C₃ or C₄ or Cs or Ce alkyl. [0193] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R³ is selected from the group consisting of F, Cl, CH₃, and CF₃.

[0194] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R³ is selected from the group consisting of F, Cl, CH₃, and CF₃. [0195] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R⁴ is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkylthio, and unsubstituted phenyl.

[0196] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R⁴ is selected from the group consisting of halogen, unsubstituted Ci or C₂ or

C3 or C₄ or C5 or C₆ alkyl, and halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl.

[0197] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R⁴ is selected from the group consisting of F, Cl, CH₃, and CF₃.

[0198] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R⁴ is halogen; and R² is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or Ce alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkyl,

halosubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkylthio, and unsubstituted phenyl. [0199] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R⁴ is halogen; and R² is selected from the group consisting of F, Cl, -CH₃, - CH₂CH₃, CH(CHs)₂, C(CH₃)₃, CF₃, -OCH₃, -OCH₂CH₃, -OCF₃ and -SCH₃.

[0200] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

whereinR⁴ is halogen; and R³ is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or Ce alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkyl,

halosubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkylthio, and unsubstituted phenyl.

[0201] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R⁴ is F or Cl or Br or I; and R^J is selected from the group consisting of F, Cl, -CH₃, -CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CF₃, -OCH₃, -OCH₂CH₃, -OCF₃ and -SCH₃.

[0202] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R² is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkylthio, and unsubstituted phenyl. [0203] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R is selected from the group consisting of F, Cl, -CH₃, -CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CF₃, -OCH₃, -OCH₂CH₃, -OCF₃, and -SCH₃.

[0204] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkylthio, and unsubstituted phenyl.

[0205] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

[0206] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R² is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkylthio, and unsubstituted phenyl [0207] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R² is selected from the group consisting of F, Cl, -CH₃, -CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CF₃, -OCH₃, -OCH₂CH₃, -OCF₃, and -SCH₃.

[0208] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or Cs or C₆ alkylthio, and unsubstituted phenyl.

[0209] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

[0210] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R⁴ is halogen; and R² is selected from the group consisting of Cl, CH₃ and CF₃. [0211] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R⁴ is halogen; and R² is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, and halosubstituted Ci or C₂ or C₃ or C₄ or C ₅ or C₆ alkyl.

[0212] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R⁴ is halogen and R² is halogen.

[0213] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R⁴ is F; and R² is selected from the group consisting of Cl, CH₃ and CF₃.

[0214] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

[0215] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R⁴ is halogen. [0216] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R² is halogen. [0217] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

[0218] In an exemplary embodiment, according to any of the above paragraphs, wherein the halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl is

trifluorosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl.

[0219] In an exemplary embodiment, according to any of the above paragraphs, wherein the halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy is

trifluorosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy.

[0220] In an exemplary embodiment, the invention provides a compound having a structure according to the following formula:

wherein X¹ is selected from the group consisting of substituted and unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or Cs or C9 or C 10 alkyl, in which at least one substituent on said alkyl is optionally substituted with a member selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkylthio, and unsubstituted phenyl, or a salt thereof. [0221] In an exemplary embodiment, according to the above paragraph, having a structure according to the following formula:

wherein X¹ is Ci or C₂ or C3 or C₄ or C5 or C₆ or C₇ or Cs or C9 or C₁₀ alkyl, optionally substituted with a member selected from the group consisting of halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl,

halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkylthio, and unsubstituted phenyl on the carbon adjacent to the carbonyl carbon.

[0222] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein n is 1 or 2 or 3 or 4

or 5 or 6, at least one member selected from R , R , R , R⁵ and R⁶ is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkylthio, and unsubstituted phenyl, and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

[0223] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein n is 1 or 2 or 3 or 4 or 5 or 6; and one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is selected from the group consisting of F, Cl, - CH₃, -CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CF₃, -OCH₃, -OCH₂CH₃, -OCF₃ and -SCH₃ and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H. [0224] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is halogen; one member selected from the group consisting of R², R³, R⁴, R⁵ and R⁶ is halogen or unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl or halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl; and the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

[0225] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein R⁴ is halogen; and R² is a member selected from the group consisting of halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, and halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl.

[0226] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein n is 1 or n is 2. [0227] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R¹ is unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl.

[0228] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R¹ is methyl. [0229] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R¹ is vinyl.

[0230] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R¹ is unsubstituted phenyl.

[0231] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R¹ is phenyl, substituted with a member selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, and unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkylthio.

[0232] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:

wherein one member selected

and R^le is selected from the group consisting of halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkylthio, and unsubstituted phenyl, and the remaining members of R^la, R^lb, R^lc, R^ld and R^le are H.

[0233] In an exemplary embodiment, according to any of the above paragraphs, the compound has one substituent on said phenyl which is selected from the group consisting of Cl, -CH₃ and -OCH₃. [0234] In an exemplary embodiment, according to any of the above paragraphs, the compound having a structure according to the following formula:

wherein two members selected from R^la, R^lb, R^lc, R^ld and R^le are the same or different and are each selected from the group consisting of halogen, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkylthio, and unsubstituted phenyl, and the remaining members of R^la, R^lb, R^lc, R^ld and R^le are H. [0235] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure in which said two members selected from R^la, R^lb, R^lc, R^ld and R^le are the same or different and are each selected from the group consisting of Cl, -CH₃ and -OCH₃.

[0236] In an exemplary embodiment, according to any of the above paragraphs, the compound having a structure according to the following formula:

wherein three members selecte

R^ld and R^le are the same or different and are each selected from unsubstituted Ci or C₂ or C₃ or C₄ or C5 or C₆ alkyl, and the remaining members of R^la, R^lb, R^lc, R^ld and R^le are H.

[0237] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein R¹ is unsubstituted heteroaryl.

[0238] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure wherein the unsubstituted heteroaryl is thiophenyl.

[0239] In an exemplary embodiment, the invention provides a combination comprising the compound according to any of the above paragraphs, together with at least one other therapeutically active agent.

[0240] In an exemplary embodiment, the invention provides a pharmaceutical formulation comprising: a) the compound according to any of the above paragraphs, or a salt thereof; and b) a pharmaceutically acceptable excipient.

[0241] In an exemplary embodiment, according to any of the above paragraphs, the pharmaceutical formulation is a unit dosage form.

[0242] In an exemplary embodiment, according to any of the above paragraphs, the salt of the compound according to any of the above paragraphs is a

pharmaceutically acceptable salt.

[0243] In an exemplary embodiment, the invention provides a method of killing and/or preventing the growth of a protozoa, comprising: contacting the protozoa with an effective amount of the compound of the invention, thereby killing and/or preventing the growth of the protozoa. [0244] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure described herein.

[0245] In an exemplary embodiment, according to any of the above paragraphs, the protozoa is a member of the trypanosome genus. [0246] In an exemplary embodiment, according to any of the above paragraphs, the protozoa is a member of the Leishmania genus.

[0247] In an exemplary embodiment, according to any of the above paragraphs, the protozoa is Trypanosoma brucei.

[0248] In an exemplary embodiment, according to any of the above paragraphs, the Trypanosoma brucei is a member selected from Trypanosoma brucei brucei, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense.

[0249] In an exemplary embodiment, according to any of the above paragraphs, the protozoa is a member selected from Leishmania donovani, Leishmania infantum, Leishmania chagasi, Leishmania mexicana, Leishmania amazonensis, Leishmania venezuelensis, Leishmania tropica, Leishmania major, Leishmania aethiopica.

[0250] In an exemplary embodiment, according to any of the above paragraphs, the protozoa is Leishmania donovani.

[0251] In an exemplary embodiment, the invention provides a method of treating and/or preventing a disease in an animal, comprising: administering to the animal a therapeutically effective amount of the compound of the invention, thereby treating and/or preventing the disease.

[0252] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure described herein.

[0253] In an exemplary embodiment, according to any of the above paragraphs, the disease is African sleeping sickness.

[0254] In an exemplary embodiment, according to any of the above paragraphs, the disease is leishmaniasis. [0255] In an exemplary embodiment, according to any of the above paragraphs, the leishmaniasis is a member selected from visceral leishmaniasis, cutaneous leishmaniasis, diffuse cutaneous leishmaniasis and mucocutaneous leishmaniasis.

[0256] In an exemplary embodiment, according to any of the above paragraphs, the leishmaniasis is visceral leishmaniasis.

[0257] In an exemplary embodiment, according to any of the above paragraphs, the leishmaniasis is cutaneous leishmaniasis.

[0258] In an exemplary embodiment, according to any of the above paragraphs, the animal is a human. [0259] In an exemplary embodiment, according to any of the above paragraphs, the invention is a use of a compound of the invention or a combination of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of protozoal infection.

[0260] 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

[0261] The following Examples illustrate the synthesis of representative compounds used in the invention and the following Reference Examples illustrate the synthesis of intermediates in their preparation. These examples are not intended, nor are they to be construed, as limiting the scope of the invention. It will be clear that the invention may be practiced otherwise than as particularly described herein.

Numerous modifications and variations of the invention are possible in view of the teachings herein and, therefore, are within the scope of the invention.

[0262] All temperatures are given in degrees Centigrade. Room temperature means 20 to 25⁰C. Reagents were purchased from commercial sources or prepared following standard literature procedures. Unless otherwise noted, reactions were carried out under a positive pressure of nitrogen. Reaction vessels were sealed with either rubber septa or Teflon screw caps. Nitrogen was introduced through Tygon tubing, fitted with a large bore syringe needle. Concentration under vacuum refers to the removal of solvent on a Bϋchi Rotary Evaporator. [0263] Analytical HPLC was performed using a Supelco discovery C₁₈ 15 cm x 4.6 mm / 5 μm column coupled with an Agilent 1050 series VWD UV detector at 210 nm. Conditions: Solvent A: H₂O/1% acetonitrile/0.1% HCO₂H; Solvent B:

methanol. [0264] Proton magnetic resonance (¹H NMR) spectra were recorded on a Varian INOVA NMR spectrometer [400 MHz (¹H) or 500 MHz (¹H)]. AU spectra were determined in the solvents indicated. Although chemical shifts are reported in ppm downfield of tetramethylsilane, they are referenced to the residual proton peak of the respective solvent peak for ¹H NMR. Interproton coupling constants are reported in Hertz (Hz).

[0265] LCMS spectra were obtained using a ThermoFinnigan AQA MS ESI instrument utilizing a Phenomenex Aqua 5 micron C₁₈ 125 A 50 x 4.60 mm column. The spray setting for the MS probe was at 350 μL/min with a cone voltage at 25 mV and a probe temperature at 450 ⁰C. The spectra were recorded using ELS and UV (254 nm) detection. Alternatively, LCMS spectra were obtained using an Agilent 1200SL HPLC equipped with a 6130 mass spectrometer operating with electrospray ionization.

[0266] Silica gel chromatography was carried out on either a Teledyne ISCO CombiFlash Companion or Companion Rf Flash Chromatography System with a variable flow rate from 5-100 mL/min. The columns used were Teledyne ISCO RediSep Disposable Flash Columns (4, 12, 40, 80, or 120 g prepacked silica gel), which were run with a maximum capacity of 1 g crude sample per 1O g silica gel. Samples were preloaded on Celite in Analogix Sample Loading Cartridges with frits (I/in, I/out). The eluent was 0-100% EtOAc in heptane or 0-10% MeOH in CH₂Cl₂ as a linear gradient over the length of the run (14-20 minutes). Peaks were detected by variable wavelength UV absorption (200-360 nm). The resulting fractions were analyzed, combined as appropriate, and evaporated under reduced pressure to provide purified material.

[0267] HPLC purification was performed using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C₁₈ column, Dyonex Chromeleon operating system coupled with a Varian Prostar 320 UV-vis detector (254 nm) and a Sedex55 ELS detector. Conditions: Solvent A: H₂O/1% acetonitrile/0.1% HCO₂H; Solvent B: MeOH. The appropriate solvent gradient for purification was determined based on the results of analytical HPLC experiments. The resulting fractions were analyzed, combined as appropriate, and evaporated under reduced pressure to provide purified material. [0268] The following experimental sections illustrate procedures for the preparation of intermediates and methods for the preparation of products according to this invention. It should be evident to those skilled in the art that appropriate substitution of both the materials and methods disclosed herein will produce the examples illustrated below and those encompassed by the scope of the invention. [0269] All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of N₂.

[0270] Compounds are named using the AutoNom 2000 add-on for MDL ISIS™ Draw 2.5 SP2 or their catalogue name if commercially available. [0271] Starting materials used were either available from commercial sources or prepared according to literature procedures and had experimental data in accordance with those reported. 6-aminobenzo[c][l,2]oxaborol-l(3H)-ol (C50), for example, can be synthesized according to the methods described in U.S. Pat. Pubs. US20060234981 and US20070155699. EXAMPLE 1

1 N-d-Phenyl-U-dihydro-benzotcimioxaborol-ό-vD-benzamide

[0272] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with phenyl magnesium bromide replacing p-tolyl magnesium bromide and N-(I -hydroxy- l,3-dihydro-lH-benzo[b]borol-6-yl)-benzamide replacing JV-(I -hydroxy- 1, 3- dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 314 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 5.35 (s, 2 H) 7.45 - 7.60 (m, 6 H) 7.97 (d, J=7.4 Hz, 3 H) 8.05 (d, J=6.6 Hz, 2 H) 8.51 (s, 1 H) 10.31 (s, 1 H). 2 4-Methyl-N-(l-phenyl-l,3-dihvdro-benzotcltl,21oxaborol-6-yl)-benzamide

[0273] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with phenyl magnesium bromide replacing p-to\y\ magnesium bromide and N-(I -hydroxy- l,3-dihydro-lH-benzo[b]borol-6-yl)-/?-tolyl amide replacing N-( 1 -hydroxy- 1,3 - dihydrobenzo [c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 328 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 2.40 (s, 3 H) 5.39 (s, 2 H) 7.36 (d, J=8.0 Hz, 2 H) 7.48 - 7.61 (m, 4 H) 7.93 (d, J=8.1 Hz, 2 H) 8.02 (dd, J=8.3, 1.8 Hz, 1 H) 8.09 (d, J=6.5 Hz, 2 H) 8.55 (d, J=1.4 Hz, 1 H) 10.26 (s, 1 H).

3 4-Ethyl-N-(l-phenyl-l,3-dihvdro-benzofcJfl,2Joxaborol-6-yl)-benzamide

[0274] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with phenyl magnesium bromide replacing /?-tolyl magnesium bromide and N-(I -hydroxy- l,3-dihydro-lH-benzo[b]borol-6-yl)-4-ethyl benzamide replacing N-( 1 -hydroxy- 1,3 - dihydrobenzo [c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 342 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.13 - 1.27 (m, 3 H) 2.67 (q, J=7.7 Hz, 2 H) 5.35 (s, 2 H) 7.35 (d, J=8.2 Hz, 2 H) 7.43 - 7.58 (m, 4 H) 7.91 (d, J=8.2 Hz, 2 H) 7.97 (dd, J=8.2, 1.6 Hz, 1 H) 8.06 (s, 2 H) 8.51 (s, 1 H) 10.23 (s, 1 H).

4 4-Methoxy-N-(l-phenyl-l,3-dihvdro-benzofcJfl,2Joxaborol-6-yl)-benzamide

[0275] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with phenyl magnesium bromide replacing p-tolyl magnesium bromide and N-(I -hydroxy- l,3-dihydro-lH-benzo[b]borol-6-yl)-4-methoxy benzamide replacing JV-(I -hydroxy- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 344 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 3.85 (s, 3 H) 5.39 (s, 2 H) 7.08 (d, J=8.8 Hz, 2 H) 7.48 - 7.62 (m, 4 H) 7.96 - 8.05 (m, 3 H) 8.10 (s, 2 H) 8.54 (s, 1 H) 10.19 (s, I H).

5 2-Chloro-N-(l-phenyl-l,3-dihvdro-benzofcIfl,2Ioxaborol-6-yl)-benzatnide

[0276] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with phenyl magnesium bromide replacing p-to IyI magnesium bromide and TV-(I -hydroxy- l,3-dihydro-lH-benzo[b]borol-6-yl)-2- chloro benzamide replacing TV-(I -hydroxy- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 348 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 5.39 (s, 2 H) 7.44 - 7.60 (m, 7 H) 7.61 - 7.66 (m, 1 H) 7.88 - 7.93 (m, 1 H) 8.05 (d, J=6.5 Hz, 2 H) 8.52 (s, 1 H) 10.59 (s, 1 H).

6 4-Chlow-N-(l-phenyl-l,3-dihvdw-benzofcJfl,2Joxaborol-6-yl)-benzamide

[0277] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with phenyl magnesium bromide replacing p-to IyI magnesium bromide and /V-(l-hydroxy- l,3-dihydro-lH-benzo[b]borol-6-yl)-4-chloro benzamide replacing N-( 1 -hydroxy- 1,3- dihydrobenzo [c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 348; ¹H NMR (400 MHz, DMSO-J₆) δ ppm 5.39 (s, 2 H) 7.49 - 7.60 (m, 4 H) 7.63 (d, J=8.5 Hz, 2 H) 7.99 (dd, J=S.2, 1.5 Hz, 1 H) 8.03 (s, 2 H) 8.08 (d, J=6.6 Hz, 2 H) 8.52 (s, 1 H) 10.41 (s, 1 H). N-(l-Phenyl-l,3-dihvdrobenzofclfl,21oxaborol-6-yl)-2- trifluoromethylbenzamide

[0278] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with phenyl magnesium bromide replacing p-to IyI magnesium bromide. Data: LCMS (m/z) : 382 (M+H); ¹H NMR (400 MHz, DMSO-J6) δ ppm 5.39 (s, 2 H) 7.43 - 7.63 (m, 4 H) 7.66 - 7.92 (m, 5 H) 8.05 (dd, J=8.0, 1.6 Hz, 2 H) 8.46 (d, J=I.8 Hz, 1 H) 10.64 (s, 1 H). 8 4-Fluoro-N-(l-phenyl-2,3-dihydro-lH-benzofb]borol-6-yl)-2- trifluoromethyl-benzamide

[0279] A mixture of 6-amino- 1 -hydroxy- 1 ,2-benzoxaborolane hydrochloride (5 g, 26.9 mmol) and 4-fluoro-2-(trifluoromethyl)benzoyl chloride in Et₃N (11.2 mL, 80.7 mmol) and DCM (200 mL) was allowed to stir overnight at room temperature. To the reaction was added aqueous hydrochloric acid (100 mL, 1 M), and the mixture was stirred for 1 hour. The resulting precipitate was collected by filtration, washed with additional DCM, and dried under vacuum to yield El as an off-white solid. Data for El: LCMS m/e: 340 (M+H); ¹U NMR (400 MHz, DMSO- d6) δ ppm 4.96 (s, 2 H) 7.39 (d, J=8.4 Hz, 1 H) 7.61 - 7.73 (m, 2 H) 7.75 - 7.87 (m, 2 H) 8.13 (dd, J=I.8, 0.4 Hz, 1 H) 9.25 (s, 1 H) 10.59 (s, 1 H). Amount obtained, 5.2 g (57 % yield).

[0280] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with phenyl magnesium bromide replacing p-to IyI magnesium bromide and 4-fluoro-iV-(l- hydroxy-2,3-dihydro-lH-benzo[b]borol-6-yl)-2-trifluoromethylbenzamide replacing Λ/-(l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data : LCMS m/e: 400 (M+H); ¹H NMR (400 MHz, DMSO- dβ) δ ppm 5.38 (s, 2 H) 7.45 - 7.62 (m, 4 H) 7.70 (td, J=SA, 2.6 Hz, 1 H) 7.83 (ddd, J=I 8.7, 8.8, 2.3 Hz, 3 H) 8.04 (dd, J=7.8, 1.6 Hz, 2 H) 8.43 (d, J=2.0 Hz, 1 H) 10.66 (s, 1 H).

9 N-(3,3-Dimethyl-l-phenyl-2,3-dihvdro-lH-benzotblborol-6-yl)-4-fluoro-2- trifluoromethylbenzatnide

HNO₃

[0281] To a suspension of 2-bromophenylboronic acid (75.Og, 373.4 mmol) in toluene (525 niL) was added JV-butyldiethanolamine (64.ImL, 392.1 mmol, 1.05 equiv.) via a syringe. The mixture was heated at 50 ⁰C for two hours. After cooling to room temperature, the toluene was evaporated under reduced pressure and the remaining clear colorless oil was treated with heptanes (500 mL). The heptanes mixture was then sonicated for 5 min and the resulting suspension was allowed to stand at room temperature overnight. The solid that precipitated was collected by filtration, washed with heptanes, and dried in a vacuum oven overnight to yield 2-(2'- bromophenyl)-6-butyl[l,3,6,2]dioxazaborocan as a white solid. Data: ¹H NMR (400 MHz, CHLOROFORM-^) δ ppm 0.86 (t, J=7.4 Hz, 3 H) 1.14 - 1.25 (m, 2 H) 1.51 - 1.62 (m, 2 H) 2.61 - 2.70 (m, 2 H) 3.01 - 3.11 (m, 2 H) 3.26 - 3.37 (m, 2 H) 4.09 - 4.26 (m, 4 H) 7.10 (td, J=7.6, 2.0 Hz, 1 H) 7.24 (td, J=7.3, 1.1 Hz, 1 H) 7.51 (d, J=7.9 Hz, 1 H) 7.81 (dd, J=IA, 1.9 Hz, 1 H). Amount obtained, 123.7 g (98.6% yield).

[0282] To a solution of 2-(2'-bromophenyl)-6-butyl[l,3,6,2]dioxazaborocan (30.0g, 89.2 mmol) in THF (740 mL) at -78 ⁰C was added /?-BuLi (42.8 mL, 2.5M in hexane, 107.0 mmol, 1.2 equiv.) dropwise via a syringe over a period of 10 min while maintaining reaction temperature at -78 ⁰C. After the addition the reaction solution was stirred for 20 min at -78 ⁰C before acetone (7.5 mL, 124.8 mmol, 1.4 equiv.) was added dropwise via a syringe over a period of 10 min while maintaining the reaction temperature at -78 ⁰C. The resulting mixture was allowed to stir for 20 min at -78 ⁰C then warm to room temperature gradually. Once the reaction vessel reached room temperature, 6N HCl solution (150 mL) was added and the mixture was stirred for an additional 30 min. The mixture was extracted with EtOAc (3X). The EtOAc extracts were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The light yellow oil was then subjected to flash chromatography (Isco Companion, 8Og SiO₂ cartridge, solid loaded SiO₂, neat heptanes to 20:80 EtOAc gradient at 60 ml/min for 90 min). 3,3-Dimethyl-3H-benzo[c][l,2]oxaborol-l-ol was recovered as clear colorless oil. ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.44 (s, 6 H) 7.31 (d, J=Ll Hz, 1 H) 7.38 - 7.47 (m, 2 H) 7.66 (d, J=7.2 Hz, 1 H) 8.99 (s, 1 H). Amount obtained: 9.4O g (65.2 % yield).

[0283] To 60 mL fuming HNO₃ at -45 ⁰C was slowly added a solution of 3,3- dimethyl-3H-benzo[c][l,2]oxaborol-l-ol (9.4 g, 58.0 mmol) in 11.9 mL nitrobenzene via a syringe while maintaining the reaction temperature between -40 to -45 ⁰C. Once the addition was complete the resulting solution was allowed to stir at -45 ° C for an additional 45 min before poured into crushed ice. The ice mixture was allowed to melt and the aqueous solution was extracted with DCM (3X). The combined DCM extracts were dried over Na₂SO₄ then evaporated. The crude oil remaining was mixed with one liter 1 : 1 DCM/heptanes. The volume of the solution was reduced under reduced pressure by half and the resulting solution was allowed to stand overnight in a -20 ⁰C freezer. The precipitate formed was filtered out, washed with heptanes and vacuum dried to give 3,3-dimethyl-6-nitro-3H-benzo[c][1.2]oxaborol-l-ol as a white solid. ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.46 (s, 6 H) 7.69 (d, J=8.4 Hz, 1 H) 8.28 (dd, J=8.4, 2.3 Hz, 1 H) 8.48 (d, J=2.2 Hz, 1 H) 9.41 (br. s., 1 H). Amount obtained: 7.31 g (60.4 % yield).

[0284] To a solution of 3,3-dimethyl-6-nitro-3H-benzo[c][l .2]oxaborol-l-ol (6.98 g, 33.3 mol) in THF ( 277 mL) was added 6N HC1( 16.6 mL, 100.2 mmol, 3.0 equiv.). The vessel was vacuum/N₂ purged three times and 5% Pd/C (3.5 g) was added. The mixture was again vacuum/N₂ purged three times then vacuum purged again. H₂ was then introduced from a balloon and the reaction was allowed to stir at room

temperature over night. The reaction solution was filtered through a short pad of celite and the filtrate was evaporated to yield 6-amino-3, 3 -dimethyl -3H- benzo[c][l,2]oxaborol-l-ol HCl salt as a dark brown foamy solid. ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.36 (s, 6 H) 4.94 (s, 2 H) 6.66 (dd, J=8.1, 2.2 Hz, 1 H) 6.79 (d, J=2.0 Hz, 1 H) 7.01 (d, J=8.1 Hz, 1 H) 8.72 (s, 1 H). Amount obtained: 8.29 g (100% yield).

[0285] To a solution of 6-amino-3, 3 -dimethyl -3H-benzo[c][l,2]oxaborol-l-ol HCl salt (8.29 g, 33.3 mmol) in DCM (170 mL) was added Et₃N (11.6 mL, 83.2 mmol, 2.5 equiv.). The mixture was cooled to 0 ⁰C and 2-trifluoromethyl-4- fluorobenzoyl chloride (6.1 mL, 39.9 mmol, 1.2 equiv.) was added slowly via a syringe. The resulting solution was allowed to warm to room temperature gradually and stir for 2 hours. The reaction solution was diluted with DCM, washed with IN HCl, H₂O, brine and then dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to give an off- white solid. The solid was recrystallized from DCM/heptanes to give 4-fluoro-N-(l-hydroxy-3,3-dimethyl-l,3-dihydro- benzo[c][l,2]oxaborol-6-yl-2-trifluoromethyl benzamide as a white solid. LCMS (M/Z) : 368 (M+H); ¹H NMR (DMSO-d₆) δ: 10.58 (s, IH), 9.11 (s, IH), 8.02 (d, J = 1.7 Hz, IH), 7.75 - 7.83 (m, 2H), 7.60 - 7.71 (m, 2H), 7.38 (d, J = 8.2 Hz, IH), 1.44 (s, 6H). Amount obtained: 11.7 g (96% yield).

[0286] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with phenyl magnesium bromide replacing p-to IyI magnesium bromide and 4-fluoro-iV-(l- hydroxy-3,3-dimethyl-2,3-dihydro-lH-benzo[b]borol-6-yl)-2-trifluoromethyl benzamide replacing N-(I -hydroxy-1 ,3-dihydrobenzo[c] [ 1 ,2]oxaborol-6-yl)-2- trifiuoromethylbenzamide. Data: LCMS m/e: 428 (M+H); ¹H NMR (400 MHz, DMSO-J6) δ ppm 1.59 (s, 6 H) 7.46 - 7.62 (m, 4 H) 7.71 (td, J=8.5, 2.7 Hz,l H) 7.77 - 7.90 (m, 3 H) 8.00 - 8.09 (m, 2 H) 8.39 (d, J=2.0 Hz, 1 H) 10.66 (s, 1 H). 10 N-fl-p-Tolyl-lJ-dihydro-benzofcIflJIoxaborol-ό-vD-benzatnide

[0287] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with N- ( 1 -hydroxy- 1 ,3 -dihydro- 1 H-benzo [b]borol-6-yl)-benzamide replacing N-(I -hydroxy- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 328 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 2.40 (s, 3 H) 5.39 (s, 2 H) 7.36 (d, J=I .1 Hz, 2 H) 7.49 -7.65 (m, 4 H) 7.96 - 8.08 (m, 6 H) 8.57 (s, 1 H) 10.36 (s, I H).

11 ^Methyl-N-d-p-tolyl-U-dihydro-benzofcUUloxaborol-ό-vD-benzamide

[0288] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with TV- (l-hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-/?-tolyl amide replacing TV-(I- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 342 (M+H); ¹U NMR (400 MHz, DMSO-J₆) δ ppm 2.40 (d, J=3.0 Hz, 6 H) 5.39 (s, 2 H) 7.36 (d, J=6.5 Hz, 4 H) 7.57 (d, J=8.3 Hz, 1 H) 7.93 (d, J=8.1 Hz, 2 H) 7.98 - 8.08 (m, 3 H) 8.56 (s, 1 H) 10.27 (s, IH).

12 4-Ethyl-N-(l-p-tolyl-l,3-dihvdro-benzofcJfl,2Joxaborol-6-yl)-benzamide

[0289] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with TV- (1 -hydroxy- 1, 3 -dihydro-lH-benzo[b]borol-6-yl)-4-ethyl benzamide replacing TV-(I- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 356 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.20 - 1.29 (m, 6 H) 2.40 (s, 4 H) 2.71 (q, J=7.5 Hz, 2 H) 5.39 (s, 2 H) 7.37 (dd, J=14.1, 7.9 Hz, 6 H) 7.57 (d, J=8.3 Hz, 1 H) 7.95 (d, J=8.2 Hz, 3 H) 7.99 - 8.06 (m, 4 H) 8.57 (d, J=Ll Hz, 1 H) 10.28 (s, 1 H). 13 ^Methoxy-N-d-p-tolyl-U-dihydro-benzofcUUloxaborol-ό-vD-benzamide

3

[0290] The title compound was prepared using a similar procedure to that of 1 replacing TV-( 1 -hydroxy- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethyl benzamide. Data: LCMS m/e: 358 (M+H); ¹U NMR (400 MHz, DMSO-J₆) δ ppm 2.40 (s, 3 H) 3.86 (s, 3 H) 5.38 (s, 2 H) 7.09 (d, J=8.8 Hz,2 H) 7.36 (d, J=7.6 Hz, 2 H) 7.56 (d, J=8.3 Hz, 1 H) 8.02 (d, J=7.2 Hz, 5 H) 8.55 (d, J=l.l Hz, IH) 10.20 (s, 1 H).

14 2-Chloro-N-(l-p-tolyl-l,3-dihvdro-benzofcJfl,2Joxaborol-6-yl)-benzamide

[0291] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with TV- (l-hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-2-chloro benzamide replacing TV-(I- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 378 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 2.39 (s, 3 H) 5.38 (s, 2 H) 7.35 (d, J=7.6 Hz, 2 H) 7.45 - 7.61 (m, 4 H) 7.64 (dd, J=7.3, 1.6 Hz, 1 H) 7.93 (dd, J=8.2, 1.7 Hz, 1 H) 7.98 (d, J=7.8 Hz, 2 H) 8.54 (s, 1 H) 10.60 (s, 1 H).

15 ^Chloro-N-β-p-tolyl-l^-dihydro-benzofcJfUJoxaborol-ό-vD-benzamide

[0292] The title compound was prepared using a similar procedure to that of N-(I- phenyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with TV- (l-hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-4-chloro benzamide replacing TV-(I- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data for 36: LCMS m/e: 362 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 2.40 (s, 3 H) 5.39 (s, 2 H) 7.35 (d, J=7.6 Hz, 2 H) 7.58 (d, J=8.3 Hz, 1 H) 7.64 (d, J=8.5 Hz, 2 H) 8.03 (dd, J=12.5, 8.2 Hz, 5 H) 8.54 (s, 1 H) 10.42 (s, 1 H). 16 N-(l-Phenyl-l,5-dihvdrobenzoIc]Il,2]oxaborol-6-yl)-2-trifluoromethyl benzamide

[0293] A l L round bottom flask was charged with a mixture of 6-amino-l- hydroxy-2,l-benzoxaborolane hydrochloride (10 g, 53.9 mmol, 1 eq) (purchased from Combi-B locks (San Diego, CA)), triethylamine (22.5 ml, 161.7 mmol, 3 eq) and dichloromethane (250 ml). 2-(Trifluoromethyl)benzoyl chloride (8.3 ml, 56.6 mmol, 1.05 eq) was then added and the reaction mixture was allowed to stair at room temperature overnight. IM HCl (200 ml) was added to the mixture and the reaction was stirred for an additional hour. The resulting precipitate was then collected and the off-white powder was dried under vacuum. LCMS (m/e) 322 (M+H). ¹H NMR (400 MHz, DMSO-J₆) d ppm 4.96 (s, 2 H) 7.38 (d, J=8.4 Hz, 1 H) 7.67 (dd, J=8.2, 2.0 Hz, 1 H) 7.68 - 7.75 (m, 2 H) 7.76 - 7.91 (m, 2 H) 8.15 (d, J=2.0 Hz, 1 H) 9.25 (s, 1 H) 10.57 (s, 1 H). Amount Obtained: 14.1 g, 81.5% yield.

[0294] A 40 mL reaction vessel was charged with a solution of iV-(l-hydroxy-l,3- dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (100 mg, 0.31 mmol) in THF (10 mL). The solution was cooled to 0 ⁰C prior to the dropwise addition of p-to\y\ magnesium bromide (1 M in THF, 1 mmol). The reaction was heated to 35 ⁰C for 2 hours, and then allowed to stir at room temperature for an additional 16 hours. The reaction was quenched by dropwise addition of aqueous hydrochloric acid (0.5 mL, 1 M), and then concentrated to dryness. The crude residue was purified by silica gel chromatography to furnish the title compound as a white solid. LCMS (m/z) 396 (M+H); ¹H NMR (400 MHz, acetone- d₆) δ ppm 2.40 (s, 3 H) 5.41 (s, 2 H) 7.33 (d, J=7.6 Hz, 2 H) 7.60 (d, J=8.4 Hz, 1 H) 7.68 - 7.77 (m, 1 H) 7.76 - 7.81 (m, 2 H) 7.85 (d, J=7.8 Hz, 1 H) 8.02 - 8.13 (m, 3 H) 8.62 (d, J=1.8 Hz, 1 H) 9.72 (br. s., 1 H). Amount Obtained: 32 mg, 26% yield. [0295] By proceeding in a similar manner, some of the compounds described herein were prepared from Λ/-(l-hydroxy-l,3-dihydro-benzo[c][l,2]oxaborol-6-yl)-2- trifluoromethylbenzamide and the appropriate aryl, alkyl, or vinyl magnesium halide.

17 4-Fluoro-N-(l-D-tolyl-2,3-dihvdro-lH-benzofblborol-6-yl)-2- trifluoromethylbenzamide

[0296] The title compound was prepared using a similar procedure to that of 4- fluoro-N-( 1 -phenyl-2,3 -dihydro- 1 H-benzo [b]borol-6-yl)-2-trifluoromethyl-benzamide with p-to IyI magnesium bromide replacing phenyl magnesium bromide. Data:

LCMS m/e: 414 (M+H); ¹H NMR (400 MHz, DMSO-J6) δ ppm 2.38 (s, 3 H) 5.38 (s, 2 H) 7.34 (d, J=I.6 Hz, 2 H) 7.57 (d,J=8.4 Hz, 1 H) 7.70 (td, J=8.5, 2.4 Hz, 1 H) 7.81 (dd, J=9.4, 2.5 Hz, 1 H) 7.84 - 7.91 (m, 2 H) 7.97 (d, J=8.0 Hz, 2 H) 8.46 (d, J=I.8 Hz, 1 H) 10.67 (s, 1 H).

18 N-(3,3-Dimethyl-l-p-tolyl-2,3-dihydro-lH-benzo[blborol-6-yl)-4-fluoro-2- trifluoromethylbenzamide

[0297] The title compound was prepared using a similar procedure to that of N- (3,3-dimethyl-l-phenyl-2,3-dihydro-lH-benzo[b]borol-6-yl)-4-fluoro-2- trifluoromethylbenzamide with p-tolyl magnesium bromide replacing phenyl magnesium bromide. Data: LCMS m/e: 442 (M+H); ¹U NMR (400 MHz, DMSO- dβ) δ ppm 1.58 (s, 6 H) 2.38 (s, 3 H) 7.34 (d, J=7.8 Hz, 2 H) 7.54 (d, J= 8.0 Hz, 1 H) 7.71 (td, J=8.3, 2.5 Hz, 1 H) 7.77 - 7.90 (m, 3 H) 7.96 (d, J=7.8 Hz, 2 H) 10.66 (s, 1 H). 19 N-(l-m-Tolyl-13-dihvdrobenzofcUiaioxaborol-6-yl)-2- trifluoromethylbenzamide

[0298] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1 ,3-dihydrobenzo[c][ 1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with m- tolyl magnesium bromide replacing /?-to IyI magnesium bromide. Data: LCMS m/e: 396 (M+H); ¹H NMR (400 MHz, acetone-J₆) δ ppm 2.41 (s, 3 H) 5.42 (s, 2 H) 7.40 (d, J=5.7 Hz, 2 H) 7.62 (d, J=8.3 Hz, 1 H) 7.73 (td, J=8.0, 4.8 Hz, 1 H) 7.76 - 7.82 (m, 2 H) 7.85 (d, J=7.8 Hz, 1 H) 7.98 (s, 2 H) 8.08 (dd, J=8.2, 1.8 Hz, 1 H) 8.61 (d, J=I.4 Hz, I H) 9.72 (br. s., I H).

20 N-(l-o-Tolyl-l,3-dihvdroben7.orcUl,21oxaborol-6-yl)-2- trifluoromethylbenzamide

[0299] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with o- tolyl magnesium bromide replacing p-to\y\ magnesium bromide. Data: LCMS (m/z) : 396 (M+H); ¹H NMR (400 MHz, acetone- d₆) δ ppm 2.63 (s, 3 H) 5.47 (s, 2 H) 7.26

- 7.33 (m, 2 H) 7.36 - 7.43 (m, 1 H) 7.62 (d, J=8.2 Hz, 1 H) 7.67 - 7.73 (m, 1 H) 7.73

- 7.81 (m, 2 H) 7.83 (d, J=7.6 Hz, 1 H) 7.95 - 8.00 (m, 1 H) 8.06 (dd, J=8.2, 2.0 Hz, 1 H) 8.41 (d, J=1.8 Hz, 1 H) 9.71 (br. s., 1 H).

21 N-fl-(4-Methoxy-phenyl)-l,3-dihvdro-benzofclfl,21oxaborol-6-yll- benzamide

[0300] The title compound was prepared using a similar procedure to that of N-(I- phenyl- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- methoxyphenyl magnesium bromide replacing p-to IyI magnesium bromide and N-(I- hydroxy- 1 ,3 -dihydro- 1 H-benzo [b]borol-6-yl)-benzamide replacing N-(I -hydroxy- 1,3- dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 344 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 3.85 (s, 3 H) 5.38 (s, 2 H) 7.10 (d, J=8.5 Hz, 2 H) 7.50 -7.64 (m, 4 H) 8.02 (d, J=7.2 Hz, 3 H) 8.09 (d, J=8.5 Hz, 2 H) 8.60 (s, 1 H) 10.36 (s, 1 H).

22 N-H-(4-Methoxy-phenyl)-l,3-dihvdro-benzofclH,21oxaborol-6-yll-4-methyl- benzamide

[0301] The title compound was prepared using a similar procedure to that of N-(I- phenyl- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- methoxyphenyl magnesium bromide replacing /?-tolyl magnesium bromide and N-(I- hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-/?-tolyl amide replacing TV-(I -hydroxy- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 358 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 2.40 (s, 3 H) 3.85 (s, 3 H) 5.37 (s, 2 H) 7.10 (d, J=8.5 Hz, 2 H) 7.36 (d, J=8.1 Hz, 2 H) 7.56 (d, J=8.2 Hz, 1 H) 7.93 (d, J=8. I Hz, 2 H) 8.01 (dd, J=8.3, 1.7 Hz, 1 H) 8.08 (d, J=8.5 Hz, 2 H) 8.59 (s, 1 H) 10.27 (s, 1 H).

23 4-Ethyl-N-fl-(4-methoxy-phenyl)-l,3-dihvdro-benzofcJfl,2Joxabowl-6-ylJ- benzatnide

[0302] The title compound was prepared using a similar procedure to that of N-(I- phenyl- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- methoxyphenyl magnesium bromide replacing p-to IyI magnesium bromide and TV-(I- hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-4-ethyl benzamide replacing TV-(I- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 372 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.18 - 1.28 (m, 3 H) 2.71 (q, J=7.5 Hz, 2 H) 3.85 (s, 3 H) 5.37 (s, 2 H) 7.10 (d, J=8.5 Hz, 2 H) 7.39 (d, J=8.2 Hz, 2 H) 7.56 (d, J=8.3 Hz, 1 H) 7.95 (d, J=8.2 Hz, 2 H) 8.00 (dd, J=S.2, 1.6 Hz, 1 H) 8.09 (s, 2 H) 8.59 (s, 1 H) 10.28 (s, 1 H).

I l l 24 4-Methoxy-N-tl-(4-methoxy-t)henyl)-l,3-dihvdro-benzotcltl,21oxaborol-6- yll-benzamide

[0303] The title compound was prepared using a similar procedure to that of N-(I- phenyl-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- methoxyphenyl magnesium bromide replacing p-to IyI magnesium bromide and TV-(I- hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-4-methoxy benzamide replacing TV-(I- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: ¹H NMR (400 MHz, DMSO-J₆) δ ppm 3.85 (d, J=3.2 Hz, 6 H) 5.37 (s, 2 H) 7.09 (dd, J=8.5, 6.6 Hz, 4 H) 7.56 (d, J=8.3 Hz, 1 H) 7.97 - 8.05 (m, 3 H) 8.10 (s, 2 H) 8.58 (s, I H) 10.20 (s, I H).

25 2-Chloro-N-H-(4-methoxy-phenyl)-l,3-dihvdro-benzofclH,21oxaborol-6-yll- benzamide

[0304] The title compound was prepared using a similar procedure to that of N-(I- phenyl- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- methoxyphenyl magnesium bromide replacing p-to IyI magnesium bromide and TV-(I- hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-2-chloro benzamide replacing TV-(I- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 378 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 3.84 (s, 3 H) 5.37 (s, 2 H) 7.10 (d, J=8.5 Hz, 2 H) 7.44 - 7.61 (m, 4 H) 7.64 (dd, J=7.3, 1.7 Hz, 1 H) 7.90 (dd, J=8.2, 1.7 Hz, 1 H) 8.07 (s, 2 H) 8.57 (s, 1 H) 10.60 (s, 1 H). 26 4-Chloro-N-fl-(4-methoxy-phenyl)-l,3-dihvdro-benzofcUl,21oxaborol-6-yll- benzamide

[0305] The title compound was prepared using a similar procedure to that of N-(I- phenyl- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- methoxyphenyl magnesium bromide replacing p-to IyI magnesium bromide and TV-(I- hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-4-chloro benzamide replacing TV-(I- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 378 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 3.85 (s, 3 H) 5.38 (s, 2 H) 7.11 (s, 2 H) 7.58 (d, J=8.3 Hz, 1 H) 7.65 (s, 2 H) 7.99 (dd, J=8.3, 1.7 Hz, 1 H) 8.06 (dd, J=14.3, 8.5 Hz, 4 H) 8.57 (s, 1 H) 10.43 (s, 1 H).

27 N-fl-(4-Methoxy-phenyl)-l,3-dihydrobenzofc]fl,2]oxaborol-6-yl]-2- trifluoromethyl-benzamide

[0306] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- methoxyphenyl magnesium bromide replacing p-to\y\ magnesium bromide. Data: LCMS (m/z) : 412 (M+H); ¹H NMR (400 MHz, acetone- d₆) δ ppm 3.88 (s, 3 H) 5.39 (s, 2 H) 7.01 - 7.13 (m, 2 H) 7.59 (d, J=8.2 Hz, 1 H) 7.68 - 7.77 (m, 1 H) 7.76 - 7.81 (m, 2 H) 7.85 (d, J=7.8 Hz, 1 H) 8.02 (dd, J=8.2, 2.0 Hz, 1 H) 8.10 - 8.20 (m, 2 H) 8.65 (d, J=2.0 Hz, 1 H) 9.71 (br. s., 1 H).

28 4-Fluoro-N-fl-(4-methoxyphenyl)-2,3-dihydro-lH-benzofblborol-6-yll-2- trifluoromethylbenzamide

[0307] The title compound was prepared using a similar procedure to that of 4- fluoro-N-( 1 -phenyl-2,3 -dihydro- 1 H-benzo [b]borol-6-yl)-2-trifluoromethyl-benzamide with 4-methoxyphenyl magnesium bromide replacing phenyl magnesium bromide. Data: LCMS m/e: 430 (M+H); ¹U NMR (400 MHz, DMSO-J6) δ ppm 3.84 (s, 3 H) 5.38 (s, 2 H) 7.10 (d, J=8.8 Hz, 2 H) 7.58 (d, J=8.2 Hz, 1 H) 7.71 (td, J=8.3, 2.3 Hz, 1 H) 7.78 - 7.92 (m, 3 H) 8.05 (d, J=8.8 Hz, 2 H) 8.50 (d, J=I.6 Hz, 1 H) 10.68 (s, 1 H).

29 4-Fluoro-N-fl-(4-methoxyphenyl)-3,3-dimethyl-2,3-dihydro-lH- benzotblborol-6-yll-2-trifluoromethylbenzamide

[0308] The title compound was prepared using a similar procedure to that of N- (3,3-dimethyl-l-phenyl-2,3-dihydro-lH-benzo[b]borol-6-yl)-4-fluoro-2- trifluoromethylbenzamide with 4-methoxyphenyl magnesium bromide replacing phenyl magnesium bromide. Data: LCMS m/e: 458 (M+H); ¹H NMR (400 MHz, DMSO-J6) δ ppm 1.58 (s, 6 H) 3.83 (s, 3 H) 7.08 (d, J=8.6 Hz, 2 H) 7.54 (d, J=8.4 Hz, 1 H) 7.65 - 7.76 (m, 1 H) 7.77 - 7.90 (m, 3 H) 8.02 (d, J=8.8 Hz, 2 H) 8.41 (d, J=2.0 Hz, 1 H) 10.66 (s, 1 H). 30 N-fl-(3-Methoxy-phenyl)-l,3-dihvdrobenzofcIfl,2Joxaborol-6-ylI-2- trifluoromethyl-benzamide

[0309] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1 ,3-dihydrobenzo[c] [1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 3- methoxyphenyl magnesium bromide replacing p-to\y\ magnesium bromide. Data:

LCMS (m/z) : 412 (M+H); ¹U NMR (400 MHz, acetone- d₆) δ ppm 3.87 (s, 3 H) 5.43 (s, 2 H) 7.14 (ddd, J=8.2, 2.7, 1.0 Hz, 1 H) 7.44 (t, J=7.7 Hz, 1 H) 7.62 (d, J=8.4 Hz, 1 H) 7.67 - 7.81 (m, 5 H) 7.84 (d, J=8.0 Hz, 1 H) 8.08 (dd, J=SA, 2.0 Hz, 1 H) 8.63 (d, J=I.8 Hz, 1 H) 9.73 (br. s., 1 H). 31 N-fl-(2-Methoxy-phenyl)-l,3-dihvdrobenzofcUl,21oxaborol-6-yll-2- trifluoromethyl-benzamide

[0310] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 2- methoxyphenyl magnesium bromide replacing p-to\y\ magnesium bromide. Data: LCMS (m/z) : 412 (M+H); ¹U NMR (400 MHz, acetone- d₆) δ ppm 4.00 (s, 3 H) 5.39 (s, 2 H) 7.03 (td, J=7.3, 0.8 Hz, 1 H) 7.09 (d, J=8.4 Hz, 1 H) 7.67 - 7.73 (m, 1 H) 7.73 - 7.81 (m, 2 H) 7.83 (d, J=7.8 Hz, 1 H) 7.91 (dd, J=S.2, 2.1 Hz, 1 H) 7.98 (dd, J=7.3, 1.9 Hz, 1 H) 8.80 (d, J=2.0 Hz, 1 H) 9.66 (br. s., 1 H).

32 N-fl-^-Chloro-phenvD-l^-dihvdro-benzofcJfUJoxaborol-ό-ylJ-benzamide

[0311] The title compound was prepared using a similar procedure to that of N-(I- phenyl- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- chlorophenyl magnesium bromide replacing p-to IyI magnesium bromide and TV-(I- hydroxy- 1 ,3 -dihydro- 1 H-benzon[b]borol-6-yl-benzamide replacing TV-( 1 -hydroxy- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 348 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 5.28 (s, 2 H) 7.27 - 7.66 (m, 6 H) 7.81 - 8.05 (m, 5 H) 8.31 (s, 1 H) 10.26 (s, 1 H). 33 N-fl-^-Chloro-phenvD-U-dihydro-benzofcIfl^Ioxaborol-ό-ylI^-methyl- benzatnide

[0312] The title compound was prepared using a similar procedure to that of N-(I- phenyl-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- chlorophenyl magnesium bromide replacing p-to IyI magnesium bromide and TV-(I- hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-/?-tolyl amide replacing TV-(l-hydroxy- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 362 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 2.36 (s, 3 H) 5.28 (s, 2 H) 7.31 (d, J=8.0 Hz, 2 H) 7.45 (d/=8.2 Hz, 1 H) 7.50 (s, 2 H) 7.85 - 7.90 (m, 3 H) 7.93 (d, J=8.2 Hz, 2 H) 8.31 (s, 1 H) 10.17 (s, 1 H).

34 N-fl-(4-Chloro-phenyl)-13-dihvdro-benzoIclfl,21oxaborol-6-yll-4-methoxy- benzamide

[0313] The title compound was prepared using a similar procedure to that of N-(I- phenyl-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- chlorophenyl magnesium bromide replacing p-to\y\ magnesium bromide and TV-( 1 - hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-4-methoxy benzamide replacing TV-(I- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 179 (M/2H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 3.85 (s, 3 H) 5.14 - 5.43 (m, 2 H) 5.32 (s, 2 H) 7.06 (s, 3 H) 7.47 (s, 1 H) 7.54 (s, 3 H) 7.92 (dd, J=S.2, 1.5 Hz, 1 H) 7.94 - 8.04 (m, 5 H) 8.35 (s, 1 H) 10.14 (s, 1 H).

35 2-Chloro-N-fl-(4-chloro-phenyl)-l,3-dihvdro-benzofcJfl,2Joxaborol-6-ylJ- benzatnide

[0314] The title compound was prepared using a similar procedure to that of N-(I- phenyl-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- chlorophenyl magnesium bromide replacing p-to IyI magnesium bromide and TV-(I- hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-2-chloro benzamide replacing TV-(I- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: 384 (M+H); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 5.30 (s, 2 H) 7.43 - 7.54 (m, 5 H) 7.55 - 7.63 (m, 2 H) 7.81 (dd, J=8.2, 1.6 Hz, 1 H) 7.91 (d, J=8.2 Hz, 2 H) 8.29 (s, 1 H) 10.51 (s, 1 H). 36 ^Chloro-N-fl-M-chloro-phenvD-U-dihydro-benzofcimioxaborol-ό-yll- benzamide

[0315] The title compound was prepared using a similar procedure to that of N-(I- phenyl- l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- chlorophenyl magnesium bromide replacing p-to IyI magnesium bromide and TV-(I- hydroxy-l,3-dihydro-lH-benzo[b]borol-6-yl)-4-chloro-benzamide replacing TV-(I- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide. Data: LCMS m/e: 191 (M/2H); ¹U NMR (400 MHz, DMSO-J₆) δ ppm 5.31 (s, 2 H) 7.46 - 7.55 (m, 3 H) 7.62 (d, J=8.5 Hz, 2 H) 7.90 (dd, J=S.2, 1.4 Hz, 1 H) 7.95 (d, J=8.1 Hz, 2 H) 8.02 (d, J=8.5 Hz, 3 H) 8.31 (s, 1 H) 10.35 (s, 1 H).

37 N-fl-(4-Chloro-phenyl)-l,3-dihvdrobenzofcIfl,2Ioxaborol-6-ylI-2- trifluoromethyl-benzamide

[0316] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- chlorophenyl magnesium bromide replacing p-to IyI magnesium bromide. Data:

LCMS (mix) : 416 (M+H); ¹H NMR (400 MHz, acetone- d₆) δ ppm 5.43 (s, 2 H) 7.52 - 7.59 (m, 2 H) 7.62 (d, J=8.2 Hz, 1 H) 7.67 - 7.75 (m, 1 H) 7.75 - 7.81 (m, 2 H) 7.84 (d, J=7.8 Hz, 1 H) 8.04 (dd, J=8.2, 2.0 Hz, 1 H) 8.11 - 8.21 (m, 2 H) 8.60 (d, J=I.8 Hz, 1 H) 9.73 (br. s., 1 H).

38 N-fl-(4-Chlorophenyl)-2,3-dihvdro-lH-benzofb]borol-6-yl]-4-fluoro-2- trifluoromethylbenzatnide

[0317] The title compound was prepared using a similar procedure to that of 4- fluoro-N-( 1 -phenyl-2,3 -dihydro- 1 H-benzo [b]borol-6-yl)-2-trifluoromethyl-benzamide with 4-chlorophenyl magnesium bromide replacing phenyl magnesium bromide. Data: LCMS m/e: 434 (M+H); ¹U NMR (400 MHz, DMSO- dβ) δ ppm 5.29 (s, 2 H) 7.47 (d, J=8.2 Hz, 1 H) 7.50 (d, J=8.2 Hz, 2 H) 7.69 (td, J=8.4, 2.6 Hz, 1 H) 7.74 - 7.86 (m, 3 H) 7.89 (d, J=8.4 Hz, 2 H) 8.20 (d, J=I.4 Hz, 1 H) 10.58 (s, 1 H).

39 N-ri-(4-ChloroDhenyl)-3,3-dimethyl-2,3-dihvdro-lH-ben7.ofblborol-6-yll-4- fluoro-2-trifluoromethylbenzamide

[0318] The title compound was prepared using a similar procedure to that of N- (3,3-dimethyl-l-phenyl-2,3-dihydro-lH-benzo[b]borol-6-yl)-4-fluoro-2- trifluoromethylbenzamide with 4-chlorophenyl magnesium bromide replacing phenyl magnesium bromide. Data: LCMS m/e: 462 (M+H); ¹H NMR (400 MHz, acetone) δ ppm 1.64 (s, 6 H) 7.50 - 7.68 (m, 5 H) 7.89 (dd, J=8.4, 5.5 Hz, 1 H) 8.01 (dd, J=8.3, 2.1 Hz, 1 H) 8.09 - 8.18 (m, 2 H) 8.50 (d, J=2.0 Hz, 1 H) 9.79 (br. s., 1 H).

40 N-fl-(3-Chlorophenyl)-l,3-dihvdrobenzorcIfl,2Ioxaborol-6-ylI-2- trifluoromethyl-benzamide

[0319] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1 ,3-dihydrobenzo[c] [1 ,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 3- chlorophenyl magnesium bromide replacing p-to IyI magnesium bromide. Data:

LCMS m/e: 416 (M+H); ¹H NMR (400 MHz, acetone-<4) δ ppm 5.47 (s, 2 H) 7.53 - 7.68 (m, 3 H) 7.69 - 7.77 (m, 1 H) 7.79 (s, 2 H) 7.85 (d, J=7.8 Hz, 1 H) 8.10 (d, J=1.0 Hz, 2 H) 8.12 (s, 1 H) 8.58 (d, J=I.4 Hz, 1 H) 9.76 (br. s., 1 H). 41 N-fl-(3,4-Dichlow-phenyl)-l,3-dihvdrobenzofcIfl,2Ioxabowl-6-ylI-2- trifluoromethylbenzamide

[0320] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 3,4- dichlorophenyl magnesium bromide replacing p-to IyI magnesium bromide. Data: ¹H NMR (400 MHz, acetone- d₆) δ ppm 5.45 (s, 2 H) 7.63 (d, J=8.2 Hz, 1 H) 7.66 - 7.76 (m, 2 H) 7.76 - 7.82 (m, 2 H) 7.85 (d, J=7.8 Hz, 1 H) 8.03 - 8.14 (m, 2 H) 8.21 (d, J=0.8 Hz, 1 H) 8.55 (s, 1 H) 9.76 (br. s., 1 H). 42 N-fl-(2,6-Dimethylphenyl)-l,3-dihydrobenzofc]fl,2]oxaborol-6-yl]-2- trifluoromethylbenzamide

[0321] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 2,6- dimethylphenyl magnesium bromide replacing p-to IyI magnesium bromide. Data: LCMS m/e: 410 (M+H); ¹H NMR (400 MHz, acetone-d₆) δ ppm 2.28 (s, 6 H) 5.50 (s, 2 H) 7.03 (d, J=7.6 Hz, 2 H) 7.19 (t, J=7.6 Hz, 1 H) 7.64 (d, J=8.2 Hz, 1 H) 7.67 - 7.79 (m, 3 H) 7.81 (d, J=7.7 Hz, 1 H) 7.99 (dd, J=S.2, 1.9 Hz, 1 H) 8.07 (d, J=I.4 Hz, 1 H) 9.61 (br. s., 1 H). 43 N-fl-(4-Methoxy-2-methylphenyl)-l,3-dihvdrobenzofclfl,21oxaborol-6-yll-2- trifluoromethylbenzamide

[0322] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- methoxy-2-methylphenyl magnesium bromide replacing p-to IyI magnesium bromide. Data: LCMS m/e: 426 (M+H); ¹H NMR (400 MHz, acetone-*/*) δ ppm 2.64 (s, 3 H) 3.84 (s, 3 H) 5.43 (s, 3 H) 6.86 (s, 2 H) 7.60 (d, J=8.2 Hz, 1 H) 7.67 - 7.76 (m, 1 H) 7.75 - 7.81 (m, 2 H) 7.84 (d, J=7.9 Hz, 1 H) 8.04 (dd, J=8.6, 3.3 Hz, 2 H) 8.47 (s, 1 H) 9.70 (br. s., 1 H).

44 N-tl-(3,4-Dimethoxyphenyl)-l,3-dihvdrobenzotcltl,21oxaborol-6-yll-2- trifluoromethylbenzamide

[0323] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 3,4- dimethoxyphenyl magnesium bromide replacing p-to IyI magnesium bromide. Data: LCMS m/e: 442 (M+H); ¹H NMR (400 MHz, acetone-<4) δ ppm 3.89 (s, 3 H) 3.90 (s, 3 H) 5.40 (s, 2 H) 7.60 (d, J=8.2 Hz, 1 H) 7.68 (s, 1 H) 7.70 - 7.76 (m, 1 H) 7.76 - 7.81 (m, 2 H) 7.84 (t, J=7.7 Hz, 2 H) 8.01 (dd, J=8.2, 1.8 Hz, 1 H) 8.68 (d, J=1.3 Hz, 1 H) 9.70 (br. s., 1 H). 45 2-Trifluoromethyl-N-fl-(2,4,6-trimethylphenyl)-l,3- dihvdrobenzotcπi,21oxaborol-6-yll-benzamide

[0324] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 2,4,6-trimethylphenyl magnesium bromide replacing p-to\y\ magnesium bromide. Data: LCMS m/e: 424 (M+H); ¹U NMR (400 MHz, acetone-d₆) δ ppm 2.19 - 2.38 (m, 9 H) 6.86 (s, 2 H) 7.63 (d, J=8.2 Hz, 1 H) 7.65 - 7.78 (m, 3 H) 7.81 (d, J=7.8 Hz, 1 H) 7.96 (dd, J=8.2, 1.9 Hz, 1 H) 8.09 (d, J=I.4 Hz, 1 H) 9.60 (br. s., 1 H). 46 N-fl-(4-Dimethylamino-phenyl)-l,3-dihvdro-benzofclfl,21oxaborol-6-yll-2- trifluoromethyl-benzamide

[0325] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with 4- (/V,Λ/-dimethyl)aniline magnesium bromide replacing p-to IyI magnesium bromide. Data: LCMS (m/z) : 425 (M+H); ¹U NMR (400 MHz, acetone- d₆) δ ppm 3.18 (s, 6 H) 5.44 (s, 2 H) 7.62 (d, J=8.2 Hz, 1 H) 7.70 - 7.81 (m, 5 H) 7.82 - 7.89 (m, 1 H) 8.04 (dd, J=8.3, 1.7 Hz, 1 H) 8.24 (d, J=8.2 Hz, 2 H) 8.65 (s, 1 H) 9.75 (br. s., 1 H). 47 N-(l-Thiophen-2-yl-l,3-dihydrobenzofcUl,21oxaborol-6-yl)-2- trifluoromethyl-benzamide

[0326] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with thiophen-2-yl magnesium bromide replacing p-to\y\ magnesium bromide. Data:

LCMS (m/z) : 388 (M+H); ¹H NMR (400 MHz, acetone- d₆) δ ppm 5.43 (s, 2 H) 7.39 (dd, J=4.7, 3.5 Hz, 1 H) 7.61 (d, J=8.2 Hz, 1 H) 7.67 - 7.76 (m, 1 H) 7.76 - 7.81 (m, 2 H) 7.85 (d, J=8.0 Hz, 1 H) 7.99 (d, J=4.7 Hz, 1 H) 8.04 (dd, J=8.2, 2.0 Hz, 1 H) 8.07 (d, J=3.5 Hz, 1 H) 8.61 (d, J=I.8 Hz, 1 H) 9.74 (br. s., 1 H). 48 N-(l-Methyl-l,3-dihvdrobenzofcJfl,2Joxabowl-6-yl)-2- trifluoromethylbenzatnide

[0327] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with methyl magnesium bromide replacing p-to IyI magnesium bromide. Data: LCMS (m/z) : 320 (M+H); ¹H NMR (400 MHz, acetone- d₆) δ ppm 0.75 (s, 3 H) 5.23 (s, 2 H) 7.51 (d, J=8.2 Hz, 1 H) 7.66 - 7.81 (m, 3 H) 7.83 (d, J=7.8 Hz, 1 H) 7.90 (dd, J=8.2, 2.0 Hz, 1 H) 8.20 (d, J=2.0 Hz, 1 H) 9.63 (br. s., 1 H).

49 2-Trifluoromethyl-N-(l-vinyl-l,3-dihydrobenzotcltl,21oxaborol-6-yl)- benzatnide

[0328] The title compound was prepared using a procedure similar to that of N-(I- phenyl- 1, 3 -dihydrobenzo[c][l,2]oxaborol-6-yl)-2-trifluoromethylbenzamide with vinyl magnesium bromide replacing p-to IyI magnesium bromide. Data: LCMS (m/z) : 332 (M+H); ¹H NMR (400 MHz, acetone- d₆) δ ppm 5.30 (s, 2 H) 6.27 (dd, J=I 1.8, 5.8 Hz, 1 H) 6.46 - 6.58 (m, 2 H) 7.55 (d, J=8.4 Hz, 1 H) 7.65 - 7.81 (m, 3 H) 7.83 (d, J=7.8 Hz, 1 H) 7.97 (dd, J=8.2, 2.0 Hz, 1 H) 8.37 (d, J=I.8 Hz, 1 H) 9.66 (br. s., 1 H).

EXAMPLE 2

Trypanosoma brucei brucei High-Throughput Screening Assay Procedure

[0329] All experiments were conducted with the bloodstream- form trypanosome T. brucei brucei All strain obtained from Seattle Biomedical Research Institute.

Parasites were cultured in T-25 vented cap flasks and kept in humidified incubators at 37°C and 5% CO₂. The parasite culture media was complete HMI- 9 medium (c.f. Hirumi, Journal of Parasitology 1989, Volume 75, page 985 et seq) containing 10% FBS, 10% Serum Plus medium and penicillin/streptomycin. To ensure log growth phase, trypanosomes were sub-cultured at appropriate dilutions every 2-3 days.

In Vitro Drug Sensitivity Assays

[0330] Approximately 50 microliters of log phase cultures were diluted 1 : 10 in HMI-9 and 10 uL of the diluted culture was removed and counted using a

hemocytometer to determine parasite concentration. Parasites were diluted by addition of an appropriate volume of HMI-9 to achieve a final parasite concentration of 2 x 10⁵ ImL. Compounds of the invention to be tested were serially diluted in DMSO and 0.5 uL added to 49.5 uL HMI-9 in triplicate 96-well plates using a Biomek NX liquid handler. Parasites from the diluted stock were added to each well (50 uL) using a Multidrop 384 dispenser to give a final concentration of 1.0x105/ml parasites in 0.4% for DMSO. Trypanosomes were incubated with compounds for 72 hrs at 37°C with 5% CO₂. Resazurin (20 uL of 12.5 mg/ml stock) from Sigma- Aldrich was added to each well and plates were incubated for an additional 2-4 hrs. Assay plates were read using an En Vision plate reader at an excitation wavelength of 544 nm and emission of 590 nm. Triplicate data points were averaged to generate sigmoidal dose response curve and determine IC50 values using XLfit curve fitting software from IDBS (Guildford, UK).

[0331] Biological data for exemplary compounds of the invention is provided in FIG. 1.

EXAMPLE 3

Method for Estimation of Kinetic Solubility of Compounds of the Invention

[0332] The kinetic solubilities of compounds were estimated using a nephelometric (light scattering) method. Briefly, compounds of the invention were serially diluted in DMSO, followed by dilution in PBS pH 7.4. After incubation, the amount of light scattered by a compound at each concentration was measured. Clear solutions of soluble compounds do not scatter a light beam passed through the sample well and produce no signal. At concentrations above the solubility limit, the compound precipitates and the precipitant in the well scatters the light, generating a signal. Higher levels of precipitant in a well scatter more light and produce a stronger signal.

[0333] A stock solution of a compound of the invention (25 mM in DMSO) was prepared, and was serially diluted in DMSO in two-fold increments in a row of a 96 well plate to a lowest concentration of 24 μM. A duplicate plate was prepared by transfer of half of the volume of each well to a new plate. Each well containing DMSO solution of the test compound was then diluted further (1 : 100) with phosphate buffered saline (pH 7.4) to provide aqueous solutions of compound at the following final concentrations: 250, 125, 62.5, 31.3, 15.6, 7.8, 3.9, 2.0, 1.0, 0.5 and 0.2 μM. All liquid handling stages were performed on a Beckman Coulter Biomek NX

Laboratory Automation Workstation. Each compound was diluted and tested in duplicate, providing four separate wells at each test concentration.

[0334] The test solutions of compound were incubated at room temperature for 90 minutes and then analyzed using a Thermoskan Ascent nephelometric plate reader. The nephelometer protocol included two steps: first, the plate was shaken for 60 seconds at 1200 rpm, then each well of the plate was read in succession with an 800 ms settling delay between measurements. The total measurement time for a single plate was less than 4 minutes.

[0335] The four values (in nephelometric units) obtained for each compound at each concentration were averaged and plotted on a log scale versus concentration. The concentration at which the nephelometric signal is > 110% of the value obtained for a DMSO/PBS blank is reported as the limit of solubility .

[0336] Biological data for exemplary compounds of the invention is provided in FIG. 1. EXAMPLE 4

L929 Cells and Cultivation

[0337] For evaluation of compound effects on mammalian cells, L929 mouse fibroblast cells were used. Cells were maintained as adherent cultures in T-25 vented cap flasks in a humidified incubator at 37 ⁰C in the presence of 5% CO₂. Culture media was D-MEM supplemented with 10% fetal bovine serum and 1%

penicillin/streptomycin. L929 cells were maintained below confluent levels by sub- culturing at 1 :10 dilution twice weekly using 0.05% trypsin for detachment.

Cytotoxicity Evaluation

[0338] Sub-confluent L929 cells were trypsinized, resuspended in fresh media and 10 uL was counted using hemocytometer to determine cell concentration. Cells were diluted to 1 x 10⁴ /mL in DMEM, dispensed (100 uL) into 96-well plates using a Multidrop 384 dispenser and allowed to attach overnight. Spent media was replaced with 99.5 uL fresh D-MEM and compounds to be tested were serially diluted in DMSO and 0.5 uL added using a Biomek NX liquid handler. Plates were incubated with compounds for 72 hrs at 37 ⁰C with 5% CO₂. Resazurin (20 uL of 12.5 mg/ml stock) from Sigma- Aldrich was added to each well and plates were incubated for an additional 3-4 hrs. Assay plates were read using an En Vision plate reader at an excitation wavelength of 544 nm and emission of 590 nm. Single data points were used to generate sigmoidal dose response curves and determine IC50 values using XLfit curve fitting software from IDBS (Guildford, UK). [0339] Biological data for exemplary compounds of the invention is provided in FIG. 1.

EXAMPLE 5

Acute Murine Model A

[0340] Female Swiss Webster mice can be inoculated with 250,000 parasites of the LAB 110 Eatro strain of T. b. brucei. 24 hrs post-infection, treatment can be initiated BID for 4 days with 20 mg/kg/dose of a compound of the invention (40 mg/kg/day) intraperitoneally (IP) or orally (PO), 5 mg/kg BID or 10 mg/kg BID orally (PO). N=3 mice/group. Mice can be monitored for 30 days for survival. Pentamidine at 2 mg/kg IP can be used as the positive control.

EXAMPLE 6

Chronic CNS Model

[0341] Mice can be infected with 10,000 parasites of the TREU 667 strain of T. b. brucei. Twenty one days post-infection mice can be treated with a dose of between 6 and 100 mg/kg of the compound of the invention, either BID or QD for 7 days intraperitoneally (IP) or orally (PO). Positive control mice can be treated with Diminazene (10 mg/kg, IP) on Day 4 post-infection. Negative control mice can be treated with Diminazene (10 mg/kg, PO) on Day 21. Since Diminazene is not able to penetrate the CNS, mice treated at Day 21 are not able to cure the infection. Starting 1 week after the end of treatment, mice can be monitored for parasitemia and sacrificed if parasites are detected in the blood. Mice that survive 6 months are considered "cured."

EXAMPLE 7

Pharmacokinetic studies in mice

[0342] Male CD-I mice weighing approximately 25 g can receive the compound of the invention by either intravenous (IV), oral gavage (OG) or intra-peritoneal (IP) routes. Animals in IV group (6-10 animals, 1-2 per time point) received a single bolus injection of approximately 2mg/kg of the compound of the invention. Animals receiving extra- vascular doses can be administered the compound of the invention as either single OG doses (6-10 animals, 1-2 per time point) of approximately 8mg/kg, or as 4 repeat doses (over 2 days) of approximately 25 mg/kg or 50 mg/kg by the IP route (6-10 animals, 1-2 per time point).

[0343] All doses can be administered as clear colorless solutions in either: 50% (v/v)PEG400 : 20% (v/v) ethanol : 30% (v/v) carboxymethylcellulose (0.5% w/v in sterile water for injection, WFI), or as in situ sodium salts in 5% (m/v) dextrose : 2% (v/v) ethanol in DWI. All dose solutions can be delivered at 4 mL/kg. Animals can be fasted for at least 4 hours before dosing, and for 2 hours after dosing.

[0344] Blood samples and brain tissue can be sampled from 1 or 2

animals/timepoint/group immediately before dosing and approximately 0.17, 0.5, 1, 2, 3, 4, 6, 8, 12, 18 and 24hr after dosing for full pharmacokinetic and tissue analysis, or at 0.5, 2 and 4 hours post dosing to assess early-phase CNS disposition.

[0345] Bioanalysis for the compound of the invention in whole blood, plasma or brain tissue can be performed by HPLC with tandem mass spectrometry (LC-MSMS). Whole blood and plasma samples can be treated with 3 volumes of either acetonitrile or methanol to precipitate plasma proteins. Treated samples can be centrifuged and supernatants removed for analysis. Brain tissues can be weighed and homogenized mechanically in the presence of 1 volume of phosphate-buffered saline (PBS). The resulting tissue suspensions can be then diluted with a further volume of PBS, and then treated in the same manner as whole blood or plasma. [0346] Extracted samples can be assayed for compound of the invention by means of LC-MSMS employing reversed-phase chromatography coupled to a triple quadrupole mass spectrometer employing electrospray ionization in the positive ion mode. The analytical column can be a Phenomenex Luna 3μ C8 50 x 2mm, with an online sample purification step performed on a Phenomenex Synergi 4μ Polar RP 50 x 2mm column.

[0347] Test articles can be eluted using a binary mobile phase gradient comprising 5 mM Ammonium Acetate: 0.1% formic acid in either MeOH or H2O.

[0348] Non-compartmental analysis of plasma compound of the invention concentration versus time can be performed in Microsoft Excel to generate

pharmacokinetic parameters including: area under the curve (AUC), clearance (as Cl or Cl/F), volume of distribution (Vdss), half-life (tl/2), and bioavailability (F). Pharmacokinetic studies in rats

[0349] Male Sprague Dawley rats weighing approximately 20Og can receive a compound of the invention as a single oral gavage (OG) dose of approximately 25 mg/kg (approximately 10 animals per group). [0350] All doses can be administered as clear colorless solutions as in situ sodium salts in 5% (m/v) dextrose : 2% (v/v) ethanol in DWI. All dose solutions can be delivered at 2 mL/kg. Animals can be fasted for at least 4 hours before dosing, and for 2 hours after dosing.

[0351] Blood and CSF samples and brain tissue can be sampled from 1 animal/timepoint/group immediately before dosing and approximately 0.5, 1, 2, 3, 4, 6, 8, 12, 18 and 24hr after dosing for full pharmacokinetic (plasma and CSF) and tissue (Brain) analysis.

EXAMPLE 8

Leishmania donovani High Throughput Screening Assay Procedure

Leishmania donovani Strain and Cultivation

[0352] All experiments were conducted with the Leishmania donovani strain IS- CL2D from Sudan, World Health Organization (WHO) designation:

(MHOM/SD/62/1S-CL2D). The parasite (obtained from Dr. Stephen Beverley, Washington University, St. Louis, MO) contained the luciferase trans-gene stably integrated in the genome to enable viability detection using luminescence signal.

Parasites were routinely maintained as promastigote stages at 26 ⁰C in standard M 199 medium supplemented with 10% fetal calf serum as described by Kapler {Molecular and Cellular Biology vol. 10, 1084-1094, 1990) For transformation from

promastigote to axenic amastigote stages, parasites were transferred into T-25 vented cap flasks and kept at 37°C and 5% CO₂. Axenic parasite culture media was RPMI- 1640/MES/pH 5.5 formulated and prepared as described by Debrabant et. al.

(InternationalJournal for Parasitology Vol. 34, 205-217, 2005). To ensure log growth phase, L. donovani parasites were sub-cultured at appropriate dilutions every 2-3 days. The J774A.1 mouse macrophages obtained from American Type Culture Collection (ATCC) were used as host cells for infection with axenic amastigotes. Macrophages were cultured in Dulbecco's Modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum in T-75 vented cap flasks and kept in humidified incubators at 37°C and 5% CO₂. For sub-culture, macrophages were passed twice weekly by scraping and dilution (1 :10) into fresh media.

In Vitro Intracellular Amastigote Assay

[0353] For assay, cultures of J774A.1 macrophages were scraped, suspended in DMEM medium and counted using a 0.1 mm deep Hauser Scientific hemocytometer to determine cell concentration. Macrophages were diluted to 2.5 x 10⁵ /mL in DMEM medium and seeded (100 μL/well) into 96-well white-walled assay plates and allowed to adhere overnight at 37°C and 5% CO₂. Cultures of axenic amastigotes growing in the log phase were passed through a 22 gauge blunt needle to break up the clumps, diluted 1 : 10 in RPMI- 1640 medium and counted using the hemocytometer to determine parasite concentration. Amastigotes were diluted to 2.5 x 10⁶ /mL in RPMI- 1640 medium and used to infect macrophages at a 1 :10 ratio. Assay plates were incubated for 2-3 hours to allow amastigote uptake then washed with Dulbecco's phosphate buffered saline to remove non-internalized amastigotes and 100 μL D- MEM was added. Compounds to be tested were serially diluted in DMSO to generate a top concentration of 50 ug/ml when 0.5 μL was in each well of the assay plates using a Biomek NX liquid handler. Infected macrophages were incubated with compounds for 72 hrs at 37°C with 5% CO₂. Spent culture media was replaced with 50 μL Dulbecco's PBS followed by addition of 50 μL of luciferin (luciferase substrate) reconstituted in lysis buffer (Promega Corporation). Plates were gently mixed by pipetting up and down and luminescence was read in the En Vision plate reader (Perkin Elmer). Data points were averaged to generate sigmoidal dose response curve and IC50 values for intracellular amastigote killing were determined using XLfit curve fitting software from IDBS (Guildford, UK).

[0354] Biological data for exemplary compounds of the invention is provided in FIG. 1.

EXAMPLE 9

J774A.1 Cells and Cultivation

[0355] For evaluation of compound effects on mammalian cells, the macrophage cell line J774A.1 was used. Cells were maintained as adherent cultures in T-25 vented cap flasks in a humidified incubator at 37 ⁰C in the presence of 5% CO₂. Culture media was D-MEM supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. The J774A.1 cells were maintained below confluent levels by sub-culturing at 1 :10 dilution twice weekly using a cell scraper for detachment.

Cytotoxicity Evaluation

[0356] Sub-confluent J774A.1 cells were detached by scraping, resuspended in fresh media and 10 μL was counted using hemocytometer to determine cell concentration. Cells were diluted to lxlO⁴/ml in DMEM, dispensed into 96-well plates using a Multidrop 384 dispenser and allowed to attach overnight. Because compounds that disrupt or are cytotoxic to the macrophage monolayer would appear as actives or positives in intracellular amastigote assay, a parallel set of plates was seeded with J774A.1 at higher density (2.5xlO⁵/ml) to serve as controls. After attachment, spent media was replaced with 99.5 uL fresh D-MEM and compounds to be tested were serially diluted in DMSO and 0.5 uL added using a Biomek NX liquid handler. Plates were incubated with a compound of the invention for 72 hrs at 37°C with 5% CO₂. Resazurin (20 uL of 12.5 mg/ml stock) from Sigma-Aldrich was added to each well and plates were incubated for an additional 3-4 hrs. Assay plates were read using an En Vision plate reader at an excitation wavelength of 544 nm and emission of 590 nm. Single data points were used to generate sigmoidal dose response curves and determine IC₅₀ values for low density and high density seeded J774A.1 cells using XLfϊt curve fitting software from IDBS (Guildford, UK). [0357] Biological data for exemplary compounds of the invention is provided in FIG. 1.

EXAMPLE 10

Activity against Trypanosoma brucei rhodesiense

[0358] This stock was isolated in 1982 from a human patient in Tanzania and after several mouse passages cloned and adapted to axenic culture conditions (Baltz et al (1985) EMBO Journal 4: 1273-1277; Thuita et al (2008) Acta Tropica 108:6-10.) Minimum Essential Medium (50 μl) supplemented with 25 mM HEPES, lg/1 additional glucose, 1% MEM non-essential amino acids (10Ox), 0.2 mM 2- mercaptoethanol, ImM Na-pyruvate and 15% heat inactivated horse serum can be added to each well of a 96-well microtiter plate. Serial drug dilutions of seven 3-fold dilution steps covering a range from 90 to 0.123 μg/ml can be prepared. Then 10⁴ bloodstream forms of T. b. rhodesiense STIB 900 in 50 μl can be added to each well and the plate can be incubated at 37 ⁰C under a 5 % CO₂ atmosphere for 72 h. 10 μl Alamar Blue (resazurin, 12.5 mg in 100 ml double-distilled water) can be then added to each well and incubation continued for a further 2-4 h (Raz et al. (1997) Acta Trop 68: 139-47). Then the plates can be read with a Spectramax Gemini XS microplate fluorometer (Molecular Devices Cooperation, Sunnyvale, CA, USA) using an excitation wave length of 536 nm and an emission wave length of 588 nm. Data can be analyzed using the microplate reader software Softmax Pro (Molecular Devices Cooperation, Sunnyvale, CA, USA).

EXAMPLE 11

Activity against T. cruzi

[0359] Rat skeletal myoblasts (L-6 cells) can be seeded in 96-well microtitre plates at 2000 cells/well in 100 μL RPMI 1640 medium with 10% FBS and 2 mM 1- glutamine. After 24 h the medium can be removed and replaced by 100 μl per well containing 5000 trypomastigote forms of T. cruzi Tulahuen strain C2C4 containing the β-galactosidase (Lac Z) gene (Buckner et al. (1996) Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing beta-galactosidase, p. 2592-2597, vol. 40). After 48 h the medium can be removed from the wells and replaced by 100 μl fresh medium with or without a serial drug dilution of seven 3-fold dilution steps covering a range from 90 to 0.123 μg/ml. After 96 h of incubation the plates can be inspected under an inverted microscope to assure growth of the controls and sterility. Then the substrate CPRG/Nonidet (50 μl) can be added to all wells. A color reaction can be within 2-6 h and can be read

photometrically at 540 nm. Data can be transferred into the graphic programme Softmax Pro (Molecular Devices), to calculated IC₅₀ values. [0360] 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 entiret y for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A compound having a structure according to the following formula:

wherein

R¹ is a member selected from alkyl or aryl or heteroaryl, in which at least one substituent on said alkyl or said aryl or said heteroaryl is optionally substituted with a member selected from halogen, Ci or C₂ or C3 or C₄ or C₅ or Ce unsubstituted alkyl, Ci or C₂ or C₃ or C₄ or C₅ or C₆ unsubstituted alkoxy, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkylthio, unsubstituted phenyl; and

X is aryl or heteroaryl, in which one substituent on said aryl or said heteroaryl is a member selected from halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkylthio, unsubstituted phenyl or a salt thereof.

2. The compound of claim 1, having a structure according to the following formula:

wherein

R⁴ is halogen; and

R² is a member selected from halogen, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkyl, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, halosubstituted Ci or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, halosubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkoxy, unsubstituted Ci or C₂ or C3 or C₄ or C5 or C₆ alkylthio and unsubstituted phenyl.

3. The compound of claim 1, having a structure according to the following formula:

wherein

R⁴ is halogen; and

R² is a member selected from F, Cl, -CH₃, -CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CF₃, -OCH₃, -OCH₂CH₃, -OCF₃ and -SCH₃.

4. The compound of claim 1, having a structure according to the following formula:

wherein

R⁴ is halogen; and

R² is a member selected from Cl, CH₃ and CF₃.

5. A pharmaceutical formulation comprising:

a) the compound of claim 1, or a salt thereof; and

b) a pharmaceutically acceptable excipient.

6. A method of killing and/or preventing the growth of a protozoa, comprising: contacting the protozoa with an effective amount of the compound of claim 1, thereby killing and/or preventing the growth of the protozoa.

7. A method of treating and/or preventing a disease in an animal, comprising: administering to the animal a therapeutically effective amount of the compound of claim 1, thereby treating and/or preventing the disease.