WO2011019616A1 - Petites molécules contenant du bore à titre d'agents anti-protozoaires - Google Patents

Petites molécules contenant du bore à titre d'agents anti-protozoaires Download PDF

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Publication number
WO2011019616A1
WO2011019616A1 PCT/US2010/044751 US2010044751W WO2011019616A1 WO 2011019616 A1 WO2011019616 A1 WO 2011019616A1 US 2010044751 W US2010044751 W US 2010044751W WO 2011019616 A1 WO2011019616 A1 WO 2011019616A1
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exemplary embodiment
unsubstituted
compound
phenyl
alkyl
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PCT/US2010/044751
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Matthew Orr
Matthew Jenks
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Anacor Pharmaceuticals, Inc.
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Publication of WO2011019616A1 publication Critical patent/WO2011019616A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

Definitions

  • oxaboroles useful as antimicrobials have been described previously, such as in U.S. Pat. Pubs. US20060234981 and US20070155699.
  • an oxaborole has the following structure and substituent numbering system:
  • 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.
  • FIG. 1 Biological data for exemplary compounds of the invention is provided in FIG. 1.
  • 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.
  • Ac is acetyl
  • AcOH is acetic acid
  • ACTBr cetyltrimethylammonium bromide
  • AIBN is azobisisobutyronitrile or 2,2 azobisisobutyronitrile
  • Bn is aqueous; Ar is aryl; B 2 pin 2 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; BoC 2 O is dicarbonate; Bz is, in general, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl or carboxybenzyl;
  • Cs 2 C ⁇ 3 is cesium carbonate
  • CSA camphor sulfonic acid
  • CTAB is
  • Ra Ni or Raney Ni is Raney nickel
  • Ph is phenyl
  • PMB is /?-methoxybenzyl
  • PrOH is 1-propanol
  • iPrOH is 2-propanol
  • POCI 3 is phosphorus chloride oxide
  • PTSA is /? ⁇ r ⁇ -toluene sulfonic acid
  • Pyr. or Pyr or Py as used herein means Pyridine; RT or rt or r.t. is room temperature; sat.
  • Si- amine or Si-NH 2 is amino-functionalized silica, available from SiliCycle; Si-pyr is pyridyl-functionalized silica, available from SiliCycle; TEA or Et 3 N is triethylamine; TFA is trifluoroacetic acid; Tf 2 O is trifluoromethanesulfonic anhydride; THF is tetrahydrofuran; TFAA is trifluoroacetic anhydride; THP is tetrahydropyranyl; TMSI is trimethylsilyl iodide; H 2 O is water; diNO 2 PhSO 2 Cl is dinitrophenyl sulfonyl chloride; 3-F-4-NO 2 -PhSO 2 Cl is 3-fluoro-4-nitrophenylsulfonyl chloride; 2-MeO-4- NO 2 -PhSO 2 Cl is 2-methoxy-4-nitrophenylsulfonyl chloride; and
  • (EtO) 2 POCH 2 COOEt is a triethylester of phosphonoacetic acid known as triethyl phosphonoacetate.
  • Compound of the invention refers to the compounds discussed herein, salts (e.g. pharmaceutically acceptable salts), prodrugs, solvates and hydrates of these compounds.
  • Combination of the invention refers to the compounds and antiprotozoals discussed herein as well as acids, bases, salt forms (such as
  • Boon containing compounds refers to the compounds of the invention that contain boron as part of their chemical formula.
  • 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. , -CH 2 O- is intended to also recite -OCH 2 -.
  • poly as used herein means at least 2.
  • a polyvalent metal ion is a metal ion having a valency of at least 2.
  • Moiety refers to a radical of a molecule that is attached to the remainder of the molecule.
  • 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).
  • 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.
  • 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 (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.
  • 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.
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by
  • 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.
  • alkenylene by itself or as part of another substituent means a divalent radical derived from an alkene.
  • cycloalkylene by itself or as part of another substituent means a divalent radical derived from a cycloalkane.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from an heteroalkane.
  • heterocycloalkylene by itself or as part of another substituent means a divalent radical derived from an heterocycloalkane.
  • arylene by itself or as part of another substituent means a divalent radical derived from an aryl.
  • heteroarylene by itself or as part of another substituent means a divalent radical derived from heteroaryl.
  • 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.
  • 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.
  • 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,
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 .
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
  • no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • the formula -C(O) 2 R'- represents both -C(O) 2 R'- and -R 5 C(O) 2 -.
  • 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.
  • heterocycloalkyl examples 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.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C 4 )alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • 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.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms.
  • 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-
  • aryl when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • 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).
  • a carbon atom e.g., a methylene group
  • an oxygen atom e.g., phenoxymethyl, 2- pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like.
  • heteroaryl are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
  • 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.
  • 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.
  • R' and R" 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.
  • -NR 'R is meant to include, but not be limited to, 1- pyrrolidinyl and 4-morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 ,
  • substituents for the aryl and heteroaryl groups are generically referred to as "aryl group substituents.”
  • 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.
  • each of the R groups is independently selected as are each R', R", R'", R"" and R'"" groups when more than one of these groups is present.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(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.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula
  • a and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- 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.
  • 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) 2 NR'-.
  • the substituents R, R', R" and R'" are preferably independently selected from hydrogen or substituted or unsubstituted Ci or C 2 or C3 or C 4 or C 5 or C 6 alkyl.
  • Ring 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.
  • the term “5- to 7-membered ring” includes, for example phenyl, pyridinyl and piperidinyl.
  • the term “ring” further includes a ring system comprising more than one "ring”, wherein each "ring” is independently defined as above.
  • 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).
  • 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.
  • 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.
  • 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
  • an 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.
  • Topicically 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.
  • 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.
  • 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.
  • organic amino such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine
  • magnesium salt or a similar salt.
  • 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.
  • suitable inert solvent examples include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compounds in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment.
  • Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms.
  • Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the invention.
  • the graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are used to denote the absolute configuration of a stereocenter unless otherwise noted.
  • 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.
  • Compounds of the invention can exist in particular geometric or stereoisomeric forms.
  • the invention contemplates all such compounds, including cis- and trans -isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Optically active (R)- and (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.
  • 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.
  • separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).
  • the compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • 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.
  • 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.
  • “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.
  • compositions refers to preservatives, antioxidants, fragrances, emulsif ⁇ ers, 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.
  • inert fillers 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.
  • 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.
  • excipients is conventionally known to mean carriers, diluents and/or vehicles used in formulating drug compositions effective for the desired use.
  • 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.
  • 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.
  • 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.
  • transdermal delivery is intended to include delivery by permeation through or past the integument, i.e. skin, nail, hair, claw or hoof.
  • 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.
  • active ingredient means a chemical entity which can be effective in treating a targeted disorder, disease or condition.
  • phrases "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.
  • 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.
  • the oral dosage form is one, two or three units. In a particularly preferred embodiment, the oral dosage form is one unit.
  • 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.
  • 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.
  • the term 'unit' refers to the object which is administered to the animal, not to the interior components of the object.
  • prodrug 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 .
  • the prodrugs are chemically more stable than the active drug, thereby improving formulation and delivery of the parent drug, compared to the drug alone.
  • Prodrugs for carboxylic acid analogs of the invention may include a variety of esters.
  • the pharmaceutical compositions of the invention include a carboxylic acid ester.
  • the prodrug is suitable for treatment /prevention of those diseases and conditions that require the drug molecule to cross the blood brain barrier.
  • the prodrug enters the brain, where it is converted into the active form of the drug molecule.
  • 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.
  • a prodrug can be converted to its parent compound by chemical or biochemical methods in an ex vivo environment.
  • a prodrug can be slowly converted to its parent compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Antibiotic 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.
  • 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.
  • 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).
  • Bio medium refers to both in vitro and in vivo biological milieus.
  • exemplary in vitro “biological media” include, but are not limited to, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.
  • Inhibiting and blocking are used interchangeably herein to refer to the partial or full blockade of an enzyme, such as a beta-lactamase or a leucyl t-RNA synthetase.
  • Boron is able to form additional covalent or dative bonds with oxygen, sulfur or nitrogen under some circumstances in this invention.
  • 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.
  • Salt counterion 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 + , H 3 O + , 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.
  • 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.
  • positively charged counterions include H + , H 3 O + , 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.
  • the invention provides novel boron compounds.
  • 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 invention provides a compound of the invention.
  • the invention is a compound described herein.
  • the invention is a compound according to a formula described herein.
  • the invention provides a compound having a structure according to the following formula: wherein R 1 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 C 2 or C 3 or C 4 or C 5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio, and unsubstituted phenyl.
  • R 1 is alkyl or aryl or heteroaryl, optionally substituted with 1 or 2 or 3
  • 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 C 2 or C 3 or C 4 or C 5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy,
  • halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio, and unsubstituted phenyl.
  • R 3a is selected from the group consisting of H, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl and unsubstituted C 3 or C 4 or C 5 or C 6 cycloalkyl
  • R 3b is selected from the group consisting of H, unsubstituted C 3 or C 4 or C 5 or C 6 alkyl and unsubstituted C 3 or C 4 or C 5 or C 6 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.
  • the compound of the invention has a structure according to the following formula:
  • R 1 , R 3a and R 3b are as described herein, and R 2 , R 3 , R 4 , R 5 and R 6 are members selected from the following table, or a salt thereof.
  • R 1 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • R 3a is H and R 3b is H.
  • R 3a is CH3 and R 3b is CH3.
  • R 1 is methyl.
  • R 1 is vinyl.
  • R 1 is unsubstituted thiophenyl.
  • R 1 is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-fluoro phenyl.
  • R 1 is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-fluoro phenyl. In an exemplary
  • R 1 is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl phenyl.
  • R 1 is meta- unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy phenyl.
  • R 1 is meta- unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para- unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-methoxy phenyl or meta methoxy phenyl or ortho-methoxy phenyl.
  • R 1 is phenyl substituted with Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C 2 or C 3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C 3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 is phenyl substituted with Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or Ce unsubstituted alkoxy.
  • the compound of the invention has a structure according to the following formula:
  • R 1 , R 3a and R 3b are as d escribed herein, and R 2 , R 3 , R 4 , R 5 and R 6 are members selected from the following table, or a salt thereof.
  • Y 1 is Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl.
  • R 3a is H and R 3b is H.
  • R 3a is CH3 and R 3b is CH 3 .
  • Y 1 is methyl.
  • Y 1 is ethyl.
  • Y 1 is unsubstituted C 3 alkyl.
  • Y 1 is isopropyl. In an exemplary embodiment, for any of the entries in the above table, Y 1 is unsubstituted C 4 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y 1 is t-butyl. In an exemplary embodiment, for any of the entries in the above table, Y 1 is unsubstituted C5 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y 1 is unsubstituted C 6 alkyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is
  • R 1 is methyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is vinyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-halo phenyl.
  • R 1 is meta-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-chloro phenyl.
  • R 1 is meta- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-bromo phenyl.
  • R 1 is ortho- unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta- unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl phenyl.
  • R 1 is ortho-unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta- unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy phenyl.
  • R 1 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, R 1 is phenyl substituted with Ci or C 2 or C3 or C 4 or C5 or C 6
  • R 1 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 C 2 or C3 or C 4 or C5 or Ce unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 is phenyl substituted with Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or Ce unsubstituted alkoxy.
  • the compound of the invention has a structure according to the following formula:
  • R 1 , R 3a and R 3b are as d escribed herein, and R 2 , R 3 , R 4 , R 5 and R 6 are members selected from the following table, or a salt thereof.
  • Y is unsubstituted alkoxy.
  • R , 3a a is H and R 3b is H.
  • R 3a is CH3 and R 3b is CH3.
  • Y 2 is unsubstituted Ci alkoxy.
  • Y 2 is unsubstituted C 2 alkoxy.
  • Y 2 is unsubstituted C3 alkoxy.
  • Y 2 is n-propoxy. In an exemplary embodiment, for any of the entries in the above table, Y 2 is isopropoxy. In an exemplary embodiment, for any of the entries in the above table, Y 2 is unsubstituted C 4 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 2 is unsubstituted C 5 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 2 is unsubstituted C 6 alkoxy. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • R 1 is methyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is vinyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-halo phenyl.
  • R 1 is para-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta- chloro phenyl. In an exemplary embodiment,
  • R 1 is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl phenyl.
  • R 1 is meta- unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy phenyl.
  • R 1 is meta- unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para- unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-methoxy phenyl or meta methoxy phenyl or ortho-methoxy phenyl.
  • R 1 is phenyl substituted with Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C 2 or C 3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 is phenyl substituted with Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy.
  • the compound of the invention has a structure according to the following formula:
  • R 1 , R 3a and R 3b are as described herein, and R 2 , R 3 , R 4 , R 5 and R 6 are members selected from the following table, or a salt thereof.
  • Y is halosubstituted alkyl.
  • R , 3a a is H and R , 3b is H.
  • R 3a is CH 3 and R 3b is CH 3 .
  • Y 3 is halosubstituted Ci alkyl.
  • Y 3 is halosubstituted C 2 alkyl.
  • Y 3 is halosubstituted C 3 alkyl.
  • Y is halosubstituted C 4 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 C 6 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y 3 is fluoro-substituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl. In an exemplary embodiment, for any of the entries in the above table, Y 3 is alkyl substituted with one or two or three halogens.
  • Y 3 is trifluoro-substituted Ci or C 2 or C 3 or C 4 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, R 1 is unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is methyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is vinyl.
  • R 1 is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-halo phenyl.
  • R 1 is ortho-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta- chloro phenyl. In an exemplary
  • R 1 is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl phenyl.
  • R 1 is meta- unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy phenyl.
  • R 1 is meta-unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para- unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-methoxy phenyl or meta methoxy phenyl or ortho-methoxy phenyl.
  • R 1 is phenyl substituted with Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy.
  • R 1 is phenyl substituted with Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or Ce unsubstituted alkoxy.
  • the compound of the invention has a structure according to the following formula:
  • R 1 , R 3a and R 3b are as d escribed herein, and R 2 , R 3 , R 4 , R 5 and R 6 are members selected from the following table, or a salt thereof.
  • Y 4 is halosubstituted alkoxy.
  • R 3a is H and R 3b is H.
  • R 3a is CH3 and R 3b is CH3.
  • Y 4 is halosubstituted Ci alkoxy.
  • Y 4 is halosubstituted C 2 alkoxy.
  • Y 4 is halosubstituted C3 alkoxy.
  • Y 4 is halosubstituted C 4 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 4 is halosubstituted C5 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 4 is halosubstituted C 6 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 4 is fluoro-substituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 4 is alkoxy substituted with one or two or three halogens.
  • Y 4 is trifluoro-substituted Ci or C 2 or C3 or C 4 or C5 or Ce alkoxy. In an exemplary embodiment, for any of the entries in the above table, Y 4 is trifluoromethoxy. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is methyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is vinyl.
  • R 1 is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-halo phenyl.
  • R 1 is ortho-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta- chloro phenyl. In an exemplary
  • R 1 is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl phenyl.
  • R 1 is meta- unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy phenyl.
  • R 1 is meta- unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para- unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-methoxy phenyl or meta methoxy phenyl or ortho-methoxy phenyl.
  • R 1 is phenyl substituted with Ci or C 2 or C 3 or C 4 or C5 or C 6 unsubstituted alkoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C 2 or C 3 or C 4 or C5 or Ce unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C3 or C 4 or C5 or Ce unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 is phenyl substituted with Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C 5 or Ce unsubstituted alkoxy.
  • the compound of the invention has a structure according to the following formula:
  • R 1 , R 3a and R 3b are as d escribed herein, and R 2 , R 3 , R 4 , R 5 and R 6 are members selected from the following table, or a salt thereof.
  • Y is halosubstituted alkylthio.
  • R 3a is H and R 3b is H.
  • R 3a is CH3 and R 3b is CH3.
  • Y is halosubstituted C alkylthio.
  • Y 5 is halosubstituted C 2 alkylthio.
  • Y 5 is halosubstituted C3 alkylthio.
  • Y 5 is halosubstituted C 4 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y 5 is halosubstituted C5 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y 5 is halosubstituted C 6 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y 5 is fluoro-substituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio.
  • Y 5 is alkylthio substituted with one or two or three halogens. In an exemplary embodiment, for any of the entries in the above table, Y 5 is trifluoro-substituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio. In an exemplary embodiment, for any of the entries in the above table, Y 5 is trifluoromethylthio. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or Ce alkyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is methyl.
  • R 1 is vinyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is substituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-halo phenyl.
  • R 1 is para-halo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-fluoro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-chloro phenyl. In an exemplary
  • R 1 is meta- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para- chloro phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is meta-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-bromo phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl phenyl.
  • R 1 is meta- unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para- unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is ortho-unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy phenyl.
  • R 1 is meta- unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is para-methoxy phenyl or meta methoxy phenyl or ortho-methoxy phenyl.
  • R 1 is phenyl substituted with Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy.
  • R 1 is phenyl substituted with Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl and substituted at a second position on said phenyl with a member selected from the group consisting of halogen, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkyl, Ci or C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkoxy.
  • R 1 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 C 2 or C 3 or C 4 or C 5 or C 6 unsubstituted alkyl, Ci or C 2 or C3 or C 4 or C5 or C 6 unsubstituted alkoxy.
  • the compound of the invention has a structure according to the following formula:
  • R la , R lb , R lc , R ld and R le are members selected from the following table, or a salt thereof.
  • R 3 a a is H
  • R > 3b is H.
  • R 3 a a is
  • CH 3 and R 3 'b D is CH 3 .
  • the compound has a structure according to the following formula:
  • R 1 , R 3a , and R 3b are as described herein, and R 2 , R 3 , R 4 , R 5 and R 6 are members selected from the following table, or a salt thereof.
  • R 1 is unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, and Y 2 is as described herein and Y 3 is as described herein.
  • R 3a is H and R 3b is H.
  • R 3a is CH3 and R 3b is CH3.
  • R 1 is methyl.
  • R 1 is vinyl.
  • R 1 is unsubstituted thiophenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is unsubstituted phenyl. In an exemplary embodiment, for any of the entries in the above table, R 1 is substituted phenyl.
  • the compound has a structure according to the following formula:
  • R la , R lb , R lc , R ld and R le are members selected from the following table, or a salt thereof.
  • the compound has a structure according to the following formula:
  • R la , R lb , R lc , R ld and R le are members selected from the following table, or a salt thereof.
  • each Y 1 is as described herein and are the same or different from other Y 1 S.
  • the compound has a structure according to the following formula:
  • R 2 , R 3 , R 4 , R 5 and R 6 is a member selected from halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio, unsubstituted phenyl, and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 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 C 2
  • the compound has a structure according to the following formula:
  • X is as described herein and one member selected from R la , R lb , R lc , R ld and R le is NR lf R lg , wherein R lf is H or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl and R lg is H or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, and the remaining members of R la , R lb , R lc , R ld and R le are H.
  • NR lf R lg is NH 2 .
  • NR lf R lg is NHR lg , wherein R lg is unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • each R lf andR lg are the same or different and are each selected from unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • each R lf andR lg are the same or different and are each selected from unsubstituted Ci or C 2 or C3 alkyl.
  • NR lf R lg is N(CHs) 2 .
  • NR lf R lg is N(CH 3 )R lg , wherein R lg is unsubstituted Ci or C 2 or C 3 alkyl.
  • the compound has a structure according to the following formula:
  • R 2 , R 3 , R 4 , R 5 and R 6 is a member selected from halogen, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkylthio, unsubstituted phenyl, and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H; and wherein one member selected from R la , R lb , R lc , R ld and R le is NR lf R lg , wherein R lf is H
  • the compound has a structure according to the following formula:
  • R is a member selected from halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio, unsubstituted phenyl, and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H; and R lc is a member selected from halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy and
  • R 2 , R 3 , R 4 , R 5 and R 6 is a member selected from halogen, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, unsubstituted Ci or C 2 or C3 or C 4 or C 5 or C 6 alkylthio, unsubstituted phenyl, and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 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 C 2
  • the compound of the invention has a structure which is: or or , wherein
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 1 is as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • R 1 is as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 5 is unsubstituted pyrimidinyl or unsubstituted pyrazinyl or unsubstituted pyridazinyl
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 5 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 5 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure which is:
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 1 is as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • R 1 is as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 6 is halosubstituted pyridazinyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 6 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 6 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • Z 6 is pyridazinyl, substituted with one halogen, and R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 6 is pyridazinyl, substituted with two halogens, and R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 6 is pyridazinyl, substituted with two chlorines, and R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure which is: wherein each R 14 is chlorine or fluorine, and R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • each R 14 is chlorine, and R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • each R 13 are the same or different and are each selected from H or -SH or - OH, wherein R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 13 and R 1 are as described herein
  • R 3a is H and R 3b is H, or a salt thereof.
  • R 13 and R 1 and as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • each R 13 are the same or different and are each selected from -SH or -OH, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z is thiophenyl
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure which is:
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 1 is as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • R 1 is as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 1 is unsubstituted alkylthiophenyl
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 1 and R 1 are as described herein
  • R 3a is H and R 3b is H, or a salt thereof.
  • Z 1 and R 1 are as described herein
  • R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure which is:
  • R 15 is unsubstituted alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 15 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • R 15 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • R 15 is unsubstituted Ci alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 15 is unsubstituted C 2 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 15 is unsubstituted C3 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 15 is unsubstituted C 4 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 15 is unsubstituted C 5 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 15 is unsubstituted C 6 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 2 is unsubstituted benzothiophenyl
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 2 and R 1 are as described herein
  • R 3a is H and R 3b is H, or a salt thereof.
  • Z 2 and R 1 are as described herein
  • R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 2 is halosubstituted benzothiophenyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 2 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 2 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • Z 2 is benzothiophenyl substituted with chloro, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 2 is
  • Z 2 is benzothiophenyl substituted with fluoro, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 2 is benzothiophenyl substituted with one halogen, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 2 is benzothiophenyl substituted with two halogens, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 2 is
  • Z 2 is benzothiophenyl substituted with two chlorines, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 2 is benzothiophenyl substituted with a fluorine and a chlorine, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention is:
  • R 16 is halogen
  • R 17 is halogen
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 16 , R 17 , and R 1 are as described herein
  • R 3a is H and R 3b is H, or a salt thereof.
  • R 16 , R 17 , and R 1 are as described herein
  • R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention is: wherein each R 16 and R 17 are each the same or different and are each selected from halogen, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 16 , R 17 , and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof. In an exemplary embodiment, R 16 , R 17 , and R 1 are as described herein, R 3a is CH3 and R 3b is CH3, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted oxazo are as described herein, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure which is: or wherein R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted alkyl oxazolyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure which is: or wherein R 18 is unsubstituted alkyl, R 1 ,
  • R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula: wherein R 18 is unsubstituted alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 18 is Ci or C 2 or C 3 or C 4 or C5 or Ce alkyl, and R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted isoxazolyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure which is:
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted alkyl isoxazolyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure which is:
  • R 19 is unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • R 19 is unsubstituted as described herein, or a salt thereof.
  • R 19 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • R 19 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • R 19 is unsubstituted Ci alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 19 is unsubstituted C 2 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 19 is unsubstituted C 3 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 19 is unsubstituted C 4 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 19 is unsubstituted C 5 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 19 is unsubstituted C 6 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted thiazolyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure which is:
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted alkyl
  • R 3b are as described herein, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure which is:
  • R 20 is unsubstituted alkyl, R 1 ,
  • R 3a , R 3b are as ddeessccrriibbeedd hheerreeiinn,, oorr aa ssaalltt tthheerreeooff.
  • the compound of the invention has a structure which is: , wherein R 20 is unsubstituted alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 20 is Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl, R . 1 , r R> 3a a , r R> 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted pyrazolyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 and as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure which is:
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted alkyl pyrrolyl or unsubstituted phenyl pyrrolyl or unsubstituted phenyl (unsubstituted alkyl) pyrrolyl
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is CH3 and R 3b is CH3, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • each R are the same or different and are each selected from unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl or phenyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure which is:
  • the compound of the invention has a structure which is: wherein R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • each R 21 is unsubstituted Ci alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 21 is unsubstituted C 2 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 21 is unsubstituted C 3 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 21 is unsubstituted C 4 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 21 is unsubstituted C5 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 21 is unsubstituted C 6 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 21 is unsubstituted phenyl, R 1 , 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:
  • R 21 is as described herein, R 1 , R , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted furanyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound is:
  • R . 1 , r R> 3a a , r R> 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted alkylfuranyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention is :
  • Y 7 is unsubstituted as described herein, or a salt thereof.
  • Y 7 is unsubstituted Ci alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Y 7 is unsubstituted C 2 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Y 7 is unsubstituted C3 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Y 7 is unsubstituted C 4 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, Y 7 is unsubstituted C5 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, Y 7 is unsubstituted C 6 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted pyrrole, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound is:
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 3 is unsubstituted alkyl pyrrole, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 3 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound is: or wherein R 22 is unsubstituted alkyl, R 1 ,
  • R 3a , R 3b are as described herein, or a salt thereof.
  • the compound is:
  • R 22 is unsubstituted alkyl, R 1 ,
  • R 3a , R 3b are as described herein, or a salt thereof.
  • R 22 is unsubstituted Ci alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 22 is unsubstituted C 2 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 22 is unsubstituted C 3 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 22 is unsubstituted C 4 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 22 is unsubstituted C 5 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 22 is unsubstituted C 6 alkyl, R 1 , 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:
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 1 is as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • R 1 is as described herein, R 3a is CH3 and R 3b is CH3, or a salt thereof.
  • the compound of the invention has a structure which is:
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 1 is as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • R 1 is as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 9 is unsubstituted alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 9 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 9 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • Z 9 is unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 9 is methyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 9 is
  • Z 9 is n-butyl or sec-butyl or isobutyl or tert-butyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 9 is tert- butyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • R 15 is unsubstituted alkyl
  • R 16 is H or phenyl substituted alkyl
  • R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • R 1 , R 15 , R , 1 1 6 are as described herein
  • R 3a is H and R 3b is H, or a salt thereof.
  • R 1 , R 15 , R 16 are as described herein
  • R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • R 15 is unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 15 is unsubstituted C 3 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 16 is benzyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof. In an exemplary embodiment, R 16 is H, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the compound of the invention has a structure according to the following formula:
  • Z 10 is hydroxy-substituted alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • Z 10 and R 1 are as described herein, R 3a is H and R 3b is H, or a salt thereof.
  • Z 10 and R 1 are as described herein, R 3a is CH 3 and R 3b is CH 3 , or a salt thereof.
  • Z 10 is hydroxysubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, R 1 , R 3a , R 3b are as described herein, or a salt thereof.
  • the cytotoxicity on murine L929 IC50 of a compound of the invention is a member selected from about 1 ⁇ M to 20 ⁇ M.
  • 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.
  • 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.
  • 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.
  • the cytochrome P450 enzyme is a member selected from CP1A2, 2C9, 2D6 and 3A4. In an exemplary embodiment, the cytochrome P450 enzyme is
  • 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.
  • the invention provides a compound described herein, or a solvate thereof.
  • the invention provides a compound described herein, or a prodrug thereof.
  • the invention provides a salt of a compound described herein.
  • the invention provides a pharmaceutically acceptable salt of a compound described herein.
  • the invention provides a hydrate of a compound described herein.
  • the invention provides a solvate of a compound described herein.
  • the invention provides a prodrug of a compound described herein.
  • alkyl is linear alkyl. In another exemplary embodiment, alkyl is branched alkyl.
  • heteroalkyl is linear heteroalkyl. In another exemplary embodiment, heteroalkyl is branched heteroalkyl.
  • 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.
  • the additional therapeutic agent is a compound of the invention.
  • the additional therapeutic agent includes a boron atom.
  • the additional therapeutic agent does not contain a boron atom.
  • the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
  • the additional therapeutic agent is berenil.
  • the additional therapeutic agent is berenil.
  • the additional therapeutic agent is diminazene.
  • the additional therapeutic agent is an antiprotozoa.
  • the additional therapeutic agent is selected from the group consisting of benznidazole, buparvaquone, carbarsone, clioquinol, disulf ⁇ ram, eflornithine, emetine, etofamide, furazolidone, meglumine antimoniate, melarsoprol, metronidazole, miltefosine, nifurtimox, nimorazole, nitazoxanide, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, secnidazole and tinidazole.
  • benznidazole buparvaquone
  • carbarsone clioquinol
  • disulf ⁇ ram eflornithine
  • emetine etofamide
  • furazolidone meglumine antimoniate
  • the additional therapeutic agent is pentamidine. In an exemplary embodiment, the additional therapeutic agent is suramin. In an exemplary
  • 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
  • the additional therapeutic agent is an antiparasitic.
  • the additional therapeutic agent is selected from the group consisting of amitraz, avermectin, carbadox,
  • the additional therapeutic agent is selected from the group consisting of antimony, meglumine antimoniate, sodium stibogluconate,
  • amphotericin miltefosine and paromomycin.
  • 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 (PEGINTRONTM; 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.
  • interferon such as interferon alfa-2a (ROFERONd)-A; Hoffmann-La Roche), interferon alpha-2b (INTRONd)-A; Schering-Plough
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical formulation is a unit dosage form.
  • the pharmaceutical formulation is a single unit dosage form.
  • the pharmaceutical formulation is a two unit dosage form.
  • 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.
  • 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 Et 3 N in an appropriate solvent and is stirred for an appropriate period of time at an appropriate temperature to form the product.
  • the compound of the invention can be synthesized according to the following scheme:
  • 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
  • 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.
  • 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 .
  • 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.
  • the microorganism is a protozoa.
  • the microorganism is a kinetoplastid.
  • the protozoa is a Trypanosoma.
  • 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.
  • the protozoa is a Trypanosoma brucei.
  • 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
  • the protozoa is Trypanosoma cruzi.
  • the protozoa is a member of the genus Leishmania.
  • the protozoa is a member of Leishmania Viannia.
  • 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.
  • the protozoa is L. donovani.
  • the protozoa is L.
  • the compound is described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof.
  • the invention provides a compound described herein, or a salt, hydrate or solvate thereof.
  • the invention provides a compound described herein, or a prodrug thereof.
  • the invention provides a compound described herein, or a salt thereof.
  • the compound of the invention is a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the compound is described by a formula listed herein, or a pharmaceutically acceptable salt thereof.
  • the compound is part of a pharmaceutical formulation described herein.
  • 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.
  • the microorganism is inside, or on the surface of an animal.
  • 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.
  • the animal is a human.
  • the microorganism is killed or its growth is inhibited through oral administration of the compound of the invention.
  • 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
  • the compound of the invention is administered in a topically effective amount.
  • the compound is administered in a cosmetically effective amount.
  • the pharmaceutical formulation is administered in an orally effective amount.
  • 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.
  • 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.
  • the compound of the invention can be used in human or veterinary medical therapy, particularly in the treatment or prophylaxis of protozoa-associated disease.
  • the compound of the invention can be used in human or veterinary medical therapy, particularly in the treatment or prophylaxis of protozoa-associated disease.
  • the compound of the invention can be used in human or veterinary medical therapy, particularly in the treatment or prophylaxis of kinetoplastid- associated disease.
  • the disease is associated with a Trypanosoma.
  • 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.
  • the disease is associated with a Trypanosoma brucei.
  • the disease is associated with a member selected from Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense.
  • 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
  • the disease is a trypanosomiasis.
  • the disease is a human trypanosomiasis.
  • the disease is an animal trypanosomiasis.
  • 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.
  • nagana surra
  • mal de caderas murrina de caderas
  • dourine cachexial fevers
  • Gambian horse sickness baleri, kaodzera, tahaga, galziekte or galzietzke and peste-boba.
  • 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).
  • the disease is Chagas disease.
  • the disease is sleeping sickness (or African sleeping sickness).
  • the disease is acute phase sleeping sickness.
  • the disease is chronic phase sleeping sickness.
  • the disease is an acute phase of a trypanosomiasis.
  • the disease is a chronic phase of a trypanosomiasis.
  • 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.
  • 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 associated with L. infantum. In an exemplary
  • 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.
  • 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.
  • the compound of the invention is a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the compound is described by a formula listed herein, or a pharmaceutically acceptable salt thereof.
  • the compound is part of a pharmaceutical formulation described herein.
  • 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.
  • 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.
  • the animal is a human.
  • the animal is a mouse.
  • 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.
  • the animal is a human.
  • the disease is treated through oral
  • the disease is treated through intravenous administration of the compound of the invention.
  • the disease is treated through topical administration of the compound of the invention.
  • the disease is treated through intraperitoneal administration of the compound of the invention.
  • the compound is administered in a topically effective amount.
  • the compound is administered in a cosmetically effective amount.
  • the pharmaceutical formulation is administered in an orally effective amount.
  • 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.
  • the invention is a pharmaceutical formulation which includes: (a) a pharmaceutically acceptable excipient; and (b) a compound of the invention.
  • the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound according to a formula described herein.
  • 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.
  • 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.
  • the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, hydrate or solvate thereof.
  • the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a salt of a compound described herein.
  • the salt is a pharmaceutically acceptable salt.
  • the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a prodrug of a compound described herein.
  • the pharmaceutical formulation includes: (a) a) a
  • the pharmaceutical formulation is a unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a single unit dosage form.
  • 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).
  • DMSO dimethylsulfoxide
  • 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.
  • parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques.
  • the pharmaceutical formulation is administered orally.
  • the pharmaceutical formulation is administered intravenously.
  • the pharmaceutical formulation is administered in a topically effective dose. In an exemplary embodiment, the pharmaceutical formulation is administered in a cosmetically effective dose. In an exemplary embodiment, the pharmaceutical formulation is administered in an orally effective dose.
  • the pharmaceutical formulations containing compounds of the invention are preferably in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical formulations, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • 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.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents, which may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or
  • condensation products of ethylene oxide with long chain aliphatic alcohols for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium EDTA
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium EDTA, sodium bicarbonate, sodium bicarbonate
  • compositions of the invention may also be in the form of oil-in-water emulsions and water-in-oil emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth; naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol; anhydrides, for example sorbitan monooleate; and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • the pharmaceutical formulations may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • composition of the invention may also be administered in the form of suppositories, e.g., for rectal administration of the drug.
  • 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.
  • 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.
  • 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.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • the composition containing the therapeutic compound may be added to the animal's feed or drinking water. Also, it will be convenient to formulate animal feed and drinking water products so that the animal takes in an appropriate quantity of the compound in its diet. It will further be convenient to present the compound in a composition as a premix for addition to the feed or drinking water. The composition can also added as a food or drink supplement for humans.
  • Dosage levels of the order of from about 5 mg to about 250 mg per kilogram of body weight per day and more preferably from about 25 mg to about 150 mg per kilogram of body weight per day, are useful in the treatment of the above- indicated conditions.
  • the amount of active ingredient that may be combined with the carrier materials to produce a unit dosage form will vary depending upon the condition being treated and the particular mode of administration. Unit dosage forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al. (Journal of
  • 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).
  • compositions 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.
  • 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).
  • 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 ED 50 (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 therapeutically effective dose can be estimated initially from cell culture assays, as disclosed herein.
  • 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.
  • EC50 effective dose for 50% increase
  • 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.
  • 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.
  • 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/m 2 /day.
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • 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.
  • the compound is present at a level of about 0.1-3.0 wt%, more preferably, about 1.0 wt%.
  • the invention provides a compound having a structure according to the following formula:
  • R 1 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 C 2 or C3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 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 C
  • X is phenyl or heteroaryl, in which one substituent on said phenyl or said heteroaryl is selected from the group consisting of F, Cl, -CH 3 , -CH 2 CHs, CH(CHs) 2 , C(CHs) 3 , CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , and -SCH 3 .
  • the compound has a structure according to the following formula:
  • R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are each selected from the group consisting of H, halogen, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C3 or C 4 or C 5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio, and unsubstituted phenyl with the proviso that R 2 , R 3 , R 4 , R 5 and R 6 cannot all be H.
  • the compound has a structure according to the following formula:
  • R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are each selected from the group consisting of H, F, Cl, -CH 3 , -CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , -OCH 3 , - OCH 2 CH 3 , -OCF 3 , and -SCH 3 with the proviso that R 2 , R 3 , R 4 , R 5 and R 6 cannot all be H.
  • the compound has a structure according to the following formula:
  • R 2 , R 3 , R 4 , R 5 and R 6 is selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkylthio, unsubstituted phenyl, and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure according to the following formula:
  • R 2 , R 3 , R 4 , R 5 and R 6 is selected from the group consisting of F, Cl, -CH 3 , -CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , -OCH 3 , -OCH 2 CH 3 , - OCF 3 and -SCH 3 and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 is halogen or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 is selected from the group consisting of F, Cl, Br, I, CH 3 , CF 3 and OCH 3 ; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 is F or Cl or CH 3 or CF 3 ; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein two members selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are each selected from F or Cl or Br or I; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 is F or Cl or Br or I; one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 is halogen or unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl or halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl; and the remaining members of R 2 , R 3 , R 4 , R 5 , and R 6 are H.
  • the compound has a structure wherein one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 , and R 6 is halogen; one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 , and R 6 is F or Cl or Br or I or CH 3 or CF 3 or OCH 3 ; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 is F; one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 is halogen or unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl or halosubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure wherein one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 is F; and one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 is Cl or CH 3 or CF 3 ; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure according to the following formula:
  • R 2 is a member selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio, and unsubstituted phenyl.
  • the compound has a structure according to the following formula:
  • R 2 is a member selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, and halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • the compound has a structure wherein R 2 is a member selected from the group consisting of F, Cl, CH 3 and CF 3 .
  • the compound has a structure according to the following formula:
  • R is a member selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkylthio, and unsubstituted phenyl.
  • the compound has a structure according to the following formula:
  • R is a member selected from the group consisting of halogen, unsubstituted
  • the compound has a structure wherein R 3 is selected from the group consisting of F, Cl, CH 3 , and CF 3 .
  • the compound has a structure wherein R 3 is selected from the group consisting of F, Cl, CH 3 , and CF 3 . [0195] In an exemplary embodiment, according to any of the above paragraphs, the compound has a structure according to the following formula:
  • R 4 is selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio, and unsubstituted phenyl.
  • the compound has a structure according to the following formula:
  • R 4 is selected from the group consisting of halogen, unsubstituted Ci or C 2 or
  • the compound has a structure wherein R 4 is selected from the group consisting of F, Cl, CH 3 , and CF 3 .
  • the compound has a structure according to the following formula:
  • R 4 is halogen; and R 2 is selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or Ce alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl,
  • the compound has a structure according to the following formula:
  • R 4 is halogen; and R 2 is selected from the group consisting of F, Cl, -CH 3 , - CH 2 CH 3 , CH(CHs) 2 , C(CH 3 ) 3 , CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 and -SCH 3 .
  • the compound has a structure according to the following formula:
  • R 4 is halogen; and R 3 is selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or Ce alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl,
  • Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio, and unsubstituted phenyl.
  • the compound has a structure according to the following formula:
  • R 4 is F or Cl or Br or I; and R J is selected from the group consisting of F, Cl, -CH 3 , -CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 and -SCH 3 .
  • the compound has a structure according to the following formula:
  • R 2 is selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkylthio, and unsubstituted phenyl.
  • the compound has a structure according to the following formula:
  • R is selected from the group consisting of F, Cl, -CH 3 , -CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , and -SCH 3 .
  • the compound has a structure according to the following formula:
  • R is selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkylthio, and unsubstituted phenyl.
  • the compound has a structure according to the following formula:
  • R is selected from the group consisting of F, Cl, -CH 3 , -CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , and -SCH 3 .
  • the compound has a structure according to the following formula:
  • R 2 is selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkylthio, and unsubstituted phenyl [0207]
  • the compound has a structure according to the following formula:
  • R 2 is selected from the group consisting of F, Cl, -CH 3 , -CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , and -SCH 3 .
  • the compound has a structure according to the following formula:
  • R is selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or Cs or C 6 alkylthio, and unsubstituted phenyl.
  • the compound has a structure according to the following formula:
  • R is selected from the group consisting of F, Cl, -CH 3 , -CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , and -SCH 3 .
  • the compound has a structure according to the following formula:
  • the compound has a structure according to the following formula: wherein R 4 is halogen; and R 2 is selected from the group consisting of halogen, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, and halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • the compound has a structure according to the following formula:
  • R 4 is halogen and R 2 is halogen.
  • the compound has a structure according to the following formula:
  • R 4 is F; and R 2 is selected from the group consisting of Cl, CH 3 and CF 3 .
  • the compound has a structure according to the following formula:
  • the compound has a structure according to the following formula:
  • the compound has a structure according to the following formula:
  • the compound has a structure according to the following formula:
  • Ci trifluorosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl.
  • the invention provides a compound having a structure according to the following formula:
  • X 1 is selected from the group consisting of substituted and unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 or C 7 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 C 2 or C 3 or C 4 or C 5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkylthio, and unsubstituted phenyl, or a salt thereof.
  • X 1 is Ci or C 2 or C3 or C 4 or C5 or C 6 or C 7 or Cs or C9 or C 10 alkyl, optionally substituted with a member selected from the group consisting of halogen, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl,
  • Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkylthio, and unsubstituted phenyl on the carbon adjacent to the carbonyl carbon.
  • the compound has a structure according to the following formula:
  • n is 1 or 2 or 3 or 4 or 5 or 6, at least one member selected from R , R , R , R 5 and R 6 is selected from the group consisting of halogen, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio, and unsubstituted phenyl, and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure according to the following formula:
  • n is 1 or 2 or 3 or 4 or 5 or 6; and one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 is selected from the group consisting of F, Cl, - CH 3 , -CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 and -SCH 3 and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure according to the following formula:
  • R 2 , R 3 , R 4 , R 5 and R 6 is halogen; one member selected from the group consisting of R 2 , R 3 , R 4 , R 5 and R 6 is halogen or unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl or halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl; and the remaining members of R 2 , R 3 , R 4 , R 5 and R 6 are H.
  • the compound has a structure according to the following formula:
  • R 4 is halogen
  • R 2 is a member selected from the group consisting of halogen, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, and halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • 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 R 1 is unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl.
  • the compound has a structure wherein R 1 is methyl.
  • the compound has a structure wherein R 1 is vinyl.
  • the compound has a structure wherein R 1 is unsubstituted phenyl.
  • the compound has a structure wherein R 1 is phenyl, substituted with a member selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, and unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio.
  • R 1 is phenyl, substituted with a member selected from the group consisting of halogen, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkyl, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, halosubsti
  • the compound has a structure according to the following formula:
  • R le is selected from the group consisting of halogen, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C 5 or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkoxy, unsubstituted Ci or C 2 or C3 or C 4 or C5 or C 6 alkylthio, and unsubstituted phenyl, and the remaining members of R la , R lb , R lc , R ld and R le are H.
  • the compound has one substituent on said phenyl which is selected from the group consisting of Cl, -CH 3 and -OCH 3 .
  • the compound having a structure according to the following formula:
  • 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 C 2 or C 3 or C 4 or C5 or C 6 alkyl, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy, halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl, halosubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkoxy, unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkylthio, and unsubstituted phenyl, and the remaining members of R la , R lb , R lc , R ld and R le are H.
  • 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, -CH 3 and -OCH 3 .
  • R ld and R le are the same or different and are each selected from unsubstituted Ci or C 2 or C 3 or C 4 or C5 or C 6 alkyl, and the remaining members of R la , R lb , R lc , R ld and R le are H.
  • the compound has a structure wherein R 1 is unsubstituted heteroaryl.
  • the compound has a structure wherein the unsubstituted heteroaryl is thiophenyl.
  • the invention provides a combination comprising the compound according to any of the above paragraphs, together with at least one other therapeutically active agent.
  • 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.
  • the pharmaceutical formulation is a unit dosage form.
  • the salt of the compound according to any of the above paragraphs is a
  • 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.
  • the compound has a structure described herein.
  • 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.
  • the protozoa is Trypanosoma brucei.
  • the Trypanosoma brucei is a member selected from Trypanosoma brucei brucei, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense.
  • 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.
  • the protozoa is Leishmania donovani.
  • 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.
  • the compound has a structure described herein.
  • the disease is African sleeping sickness.
  • the disease is leishmaniasis.
  • the leishmaniasis is a member selected from visceral leishmaniasis, cutaneous leishmaniasis, diffuse cutaneous leishmaniasis and mucocutaneous leishmaniasis.
  • the leishmaniasis is visceral leishmaniasis.
  • the leishmaniasis is cutaneous leishmaniasis.
  • the animal is a human.
  • 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.
  • LCMS spectra were obtained using a ThermoFinnigan AQA MS ESI instrument utilizing a Phenomenex Aqua 5 micron C 18 125 A 50 x 4.60 mm column.
  • the spray setting for the MS probe was at 350 ⁇ L/min with a cone voltage at 25 mV and a probe temperature at 450 0 C.
  • the spectra were recorded using ELS and UV (254 nm) detection.
  • LCMS spectra were obtained using an Agilent 1200SL HPLC equipped with a 6130 mass spectrometer operating with electrospray ionization.
  • the eluent was 0-100% EtOAc in heptane or 0-10% MeOH in CH 2 Cl 2 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.
  • HPLC purification was performed using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C 18 column, Dyonex Chromeleon operating system coupled with a Varian Prostar 320 UV-vis detector (254 nm) and a Sedex55 ELS detector. Conditions: Solvent A: H 2 O/1% acetonitrile/0.1% HCO 2 H; 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.
  • reaction solution was stirred for 20 min at -78 0 C 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 0 C.
  • acetone 7.5 mL, 124.8 mmol, 1.4 equiv.
  • the resulting mixture was allowed to stir for 20 min at -78 0 C then warm to room temperature gradually.
  • 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 Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • reaction solution was diluted with DCM, washed with IN HCl, H 2 O, brine and then dried over Na 2 SO 4 , 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.
  • 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 0 C prior to the dropwise addition of p-to ⁇ y ⁇ magnesium bromide (1 M in THF, 1 mmol).
  • the reaction was heated to 35 0 C 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.
  • Parasites were cultured in T-25 vented cap flasks and kept in humidified incubators at 37°C and 5% CO 2 .
  • 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.
  • 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).
  • FIG. 1 Biological data for exemplary compounds of the invention is provided in FIG. 1.
  • 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.
  • 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 ⁇ M.
  • 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 ⁇ M. All liquid handling stages were performed on a Beckman Coulter Biomek NX
  • 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.
  • L929 mouse fibroblast cells were used. Cells were maintained as adherent cultures in T-25 vented cap flasks in a humidified incubator at 37 0 C in the presence of 5% CO 2 . Culture media was D-MEM supplemented with 10% fetal bovine serum and 1%
  • L929 cells were maintained below confluent levels by sub- culturing at 1 :10 dilution twice weekly using 0.05% trypsin for detachment.
  • 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 10 4 /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 0 C with 5% CO 2 .
  • 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).
  • Biological data for exemplary compounds of the invention is provided in FIG. 1.
  • mice 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).
  • IP intraperitoneally
  • PO orally
  • 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.
  • 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.”
  • mice weighing approximately 25 g can receive the compound of the invention by either intravenous (IV), oral gavage (OG) or intra-peritoneal (IP) routes.
  • 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).
  • 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.
  • 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.
  • 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.
  • PBS phosphate-buffered saline
  • 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 3 ⁇ C8 50 x 2mm, with an online sample purification step performed on a Phenomenex Synergi 4 ⁇ Polar RP 50 x 2mm column.
  • 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.
  • Non-compartmental analysis of plasma compound of the invention concentration versus time can be performed in Microsoft Excel to generate
  • AUC area under the curve
  • Vdss volume of distribution
  • tl/2 half-life
  • F bioavailability
  • a compound of the invention can receive a compound of the invention as a single oral gavage (OG) dose of approximately 25 mg/kg (approximately 10 animals per group).
  • 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.
  • 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.
  • the parasite (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.
  • Axenic parasite culture media was RPMI- 1640/MES/pH 5.5 formulated and prepared as described by Debrabant et. al.
  • 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% CO 2 . For sub-culture, macrophages were passed twice weekly by scraping and dilution (1 :10) into fresh media.
  • DMEM Dulbecco's Modified Eagle's medium
  • Amastigotes were diluted to 2.5 x 10 6 /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 ⁇ L 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 ⁇ L 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% CO 2 .
  • Spent culture media was replaced with 50 ⁇ L Dulbecco's PBS followed by addition of 50 ⁇ L 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).
  • FIG. 1 Biological data for exemplary compounds of the invention is provided in FIG. 1.
  • the macrophage cell line J774A.1 was used for evaluation of compound effects on mammalian cells.
  • Cells were maintained as adherent cultures in T-25 vented cap flasks in a humidified incubator at 37 0 C in the presence of 5% CO 2 .
  • 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.
  • J774A.1 cells were detached by scraping, resuspended in fresh media and 10 ⁇ L was counted using hemocytometer to determine cell concentration. Cells were diluted to lxlO 4 /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 (2.5xlO 5 /ml) to serve as controls.
  • Serial drug dilutions of seven 3-fold dilution steps covering a range from 90 to 0.123 ⁇ g/ml can be prepared. Then 10 4 bloodstream forms of T. b. rhodesiense STIB 900 in 50 ⁇ l can be added to each well and the plate can be incubated at 37 0 C under a 5 % CO 2 atmosphere for 72 h. 10 ⁇ l 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).
  • 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).
  • Rat skeletal myoblasts (L-6 cells) can be seeded in 96-well microtitre plates at 2000 cells/well in 100 ⁇ L RPMI 1640 medium with 10% FBS and 2 mM 1- glutamine. After 24 h the medium can be removed and replaced by 100 ⁇ l per well containing 5000 trypomastigote forms of T. cruzi Tulahuen strain C2C4 containing the ⁇ -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).
  • Lac Z ⁇ -galactosidase
  • the medium can be removed from the wells and replaced by 100 ⁇ l fresh medium with or without a serial drug dilution of seven 3-fold dilution steps covering a range from 90 to 0.123 ⁇ g/ml.
  • the plates can be inspected under an inverted microscope to assure growth of the controls and sterility.
  • the substrate CPRG/Nonidet 50 ⁇ l can be added to all wells.
  • a color reaction can be within 2-6 h and can be read

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Abstract

Cette invention concerne, entre autres, de nouveaux composés utiles pour traiter les infections à protozoaires, des compositions pharmaceutiques les contenant, ainsi que des associations de ces composés avec au moins un autre agent thérapeutiquement efficace. Les composés présentent la formule suivante (1) dans laquelle R1 représente un élément sélectionné parmi alkyle ou aryle ou hétéroaryle, dans lequel au moins un substituant sur ledit alkyle ou ledit aryle ou ledit hétéroaryle est éventuellement substitué par un élément sélectionné parmi halogène, alkyle non substitué C1 ou C2 ou C3 ou C4 ou C5 ou C6, alcoxy non substitué C1 ou C2 ou C3ou C4 ou C5 ou C6, alkyle C1 ou C2 ou C3ou C4 ou C5 ou C6 halosubstitué, alcoxy C1 ou C2 ou C3 ou C4 ou C5 ou C6 halosubstitué, alkylthio C1 ou C2 ou C3 ou C4ou C5 ou C6 , phényle non substitué; et X représente aryle ou hétéroaryle, dans lequel un substituant sur ledit aryle ou ledit hétéroaryle est un élément sélectionné parmi halogène, alkyle C1 ou C2 ou C3 ou C4 ou C5 ou C6 non substitué, alcoxy C1 ou C2 ou C3 ou C4 ou C5 ou C6 non substitué, alkyle C1 ou C2 ou C3 ou C4 ou C5 ou C6 halosubstitué, alcoxy C1 ou C2 ou C3 ou C4 ou C5 ou C6 halosubstitué, alkylhtio C1 ou C2 ou C3 ou C4 ou C5 ou C6 non substitué, phényle non substitué ou un sel associé.
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WO2011116348A1 (fr) * 2010-03-19 2011-09-22 Anacor Pharmaceuticals, Inc. Petites molécules borées en tant qu'agent anti-protozoaire
US11039617B2 (en) 2013-01-30 2021-06-22 Agrofresh Inc. Large scale methods of uniformly coating packaging surfaces with a volatile antimicrobial to preserve food freshness
US9138002B2 (en) 2013-01-30 2015-09-22 Agrofresh Inc. Compounds and compositions
US11917997B2 (en) 2013-01-30 2024-03-05 Agrofresh Inc. Volatile applications against pathogens
US9426996B2 (en) 2013-01-30 2016-08-30 Agrofresh Inc. Use of benzoxaboroles as volatile antimicrobial agents on meats, plants, or plant parts
US9585396B2 (en) 2013-01-30 2017-03-07 Agrofresh Inc. Volatile applications against pathogens
US10070649B2 (en) 2013-01-30 2018-09-11 Agrofresh Inc. Volatile applications against pathogens
US11771089B2 (en) 2013-01-30 2023-10-03 Agrofresh Inc. Large-scale methods of uniformly coating packaging surfaces with a volatile antimicrobial to preserve food freshness
US10765117B2 (en) 2013-01-30 2020-09-08 Agrofresh Inc. Volatile applications against pathogens
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WO2014173880A1 (fr) 2013-04-22 2014-10-30 Syngenta Participations Ag Nouveaux microbiocides
GB2531098A (en) * 2014-05-28 2016-04-13 Syngenta Participations Ag Novel microbiocides
WO2016001834A1 (fr) 2014-07-01 2016-01-07 Daiichi Sankyo Company, Limited Benzoxaboroles tricycliques en tant qu'agents antibactériens
US10966429B2 (en) 2016-03-07 2021-04-06 Agrofresh Inc. Synergistic methods of using benzoxaborole compounds and preservative gases as an antimicrobial for crops
CN110183477B (zh) * 2019-07-03 2022-03-04 石家庄诚志永华显示材料有限公司 有机电致发光化合物及其应用
CN110183477A (zh) * 2019-07-03 2019-08-30 北京诚志永华显示科技有限公司 有机电致发光化合物及其应用
WO2024094235A1 (fr) 2022-11-03 2024-05-10 Univerzita Karlova Utilisation de composés à base de benzoxaborole dans le traitement de maladies causées par des amibes du genre naegleria

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