WO2024026359A1 - Compounds and methods for the treatment of diseases associated with parasitic worms - Google Patents

Abstract

In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to compounds that are inhibitors for thioredoxin glutathione reductase (TGR), which is key for the survival of parasitic worms. In one aspect, the compounds described herein treat diseases produced by parasitic worms such as, for example, praziquantel-resistant worms.

Description

COMPOUNDS AND METHODS FOR THE TREATMENT OF DISEASES ASSOCIATED WITH PARASITIC WORMS STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0001] This invention was made with government support under grant number R33AI127635 awarded by The National Institutes of Health. The government has certain rights in this invention. CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of and priority to co-pending U.S. Provisional Patent Application No. 63/392,214, filed on July 26, 2022, the contents of which are incorporated by reference herein in their entireties. BACKGROUND [0003] Schistosomiasis is a devastating but neglected tropical disease with more than 200 million people infected resulting in more than 200,000 deaths annually.^{1, 2} In addition, almost everyone infected has a significant degree of disability.³ Female genital schistosomiasis is a common complication, occurring in approximately 40 million girls and women, making it one of the most common gynecologic conditions in Africa, and schistosome infections have been implicated as cofactors in the acquisition and transmission of HIV and are a WHO-recognized risk factor for HIV infection.^{4, 5} Schistosomiasis control strategies rely almost exclusively on mass drug administration (MDA) using praziquantel (PZQ) monotherapy. No alternatives to PZQ are currently available and few drugs or vaccines are in the clinical pipeline for schistosomiasis treatment.^{6, 7, 8} Of immediate concern are results from MDA campaigns finding that PZQ cure rates are often less than 50%.^{9, 10} Modeling studies indicate that MDA using PZQ alone is unlikely to interrupt transmission, and once MDA is suspended, the prevalence of infection is likely to rebound to pre-MDA levels.¹¹ Furthermore, with large-scale drug use it is inevitable that PZQ- resistant parasites will evolve, and PZQ resistance has been induced in laboratory infections.¹² In addition, PZQ has limited activity against juvenile liver-stage worms¹³ and, although progress is being made,¹⁴ it is difficult to administer to children. Therefore, the identification of new drugs for this disease is indispensable. SUMMARY [0004] In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to compounds that are inhibitors for thioredoxin glutathione reductase (TGR), which is key for the survival of parasitic worms and that target TGR in a new regulatory site, named the doorstop pocket. In one aspect, the compounds described herein treat diseases produced by parasitic worms such as, for example, praziquantel- resistant worms. [0005] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments are combinable and interchangeable with one another. BRIEF DESCRIPTION OF THE DRAWINGS [0006] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views. [0007] FIGS. 1-21 show exemplary reaction sequences and conditions for making the compounds described herein. [0008] FIGS.22A-22G show the functional characterization of the inhibitors. (a) Reversibility of TGR inhibitors. Activity (5,5’-dithiobis (2-nitrobenzoic acid) (DTNB) reduction) of the enzyme (3.7 nM) incubated in 250 μM inhibitor for 15 min was determined (red bars). TGR (370 nM) was incubated with 250 μM compound and 100 μM NADPH for 15 min. The sample was diluted 100- fold and the activity was determined immediately (blue bars) and after 60 min (light grey bars). AF = auranofin. Average ± standard deviation (n=3) shown. (b) NADPH dependence of inhibitors. Activity of TGR after exposure to 6 (green circles), 7 (blue squares), or 8 (black triangles) with or without initial incubation with NADPH compared to control TGR incubated with NADPH and without inhibitor. Average ± standard deviation (n=3) shown. (c) Time dependence of inhibition. Inhibition of DTNB reduction by TGR in the presence of 50 μM fast inhibitors 6 (orange), 7 (blue), 8 (black) compared to TGR incubated without compound. Average ± standard deviation (n=3) shown. (d) Time dependence of inhibition. Time-dependent activity (DTNB reduction) of TGR in the presence of 50 μM slow inhibitors 1 (purple), 3 (orange), 4 (black), 5 (blue) compared to TGR activity incubated in the absence of compounds. Average ± standard deviation (n=3) shown. (e) Compound effect on thermal stability of TGR. Melting temperature without (black) or with addition of 500 μM NADPH (red) of TGR alone or with 100 μM inhibitor 1, 3, 5, 7, 8, 9 or control compounds 11 or 12. Average ± standard deviation (n=3) shown. (f) Oxidase activity after incubation with inhibitors. Consumption of NADPH (ƩA₃₄₀/min) by TGR after exposure to inhibitors for 15 min in presence of NADPH. Average ± standard deviation (n=3) shown except control n=12. (g) Production of superoxide by TGR after incubation with inhibitors. Superoxide production was determined by measuring consumption of pyrogallol red (ƩA₅₄₀/min) without added superoxide dismutase (blue circles) and with added superoxide dismutase (black squares) Average ± standard deviation, n=3 except Auranofin n=2, TRi-1 with SOD, n=2, compound 4 without SOD, n=2, and compound 6 with SOD, n=2. [0009] FIGS.23A-23D show the schistosomicidal efficacy in mice. (a) Adult worm and liver egg burdens after compound treatments targeting adult worms 42 days after infection. (b) Adult worm and liver egg burdens after compound treatments targeting juvenile worms 21 days after infection. (c) Images of livers from a mouse treated with compound 2 at 100 mg/kg 42 days after infection and from an untreated mouse, showing reduction in the number of granulomas. (d) Images of livers from a mouse treated with compound 2 at 100 mg/kg 21 days after infection and from an untreated mouse, showing reduction in the number of granulomas. The number of mice in each treatment, n = 5. The student t-test was used to determine significance, p < 0.05 = comparison to mice treated with inhibitors and the controls. [0010] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. DETAILED DESCRIPTION [0011] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein. [0012] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. [0013] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. [0014] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. [0015] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation. [0016] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class. [0017] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein. [0018] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure. Definitions [0019] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of. [0020] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” include, but are not limited to, mixtures or combinations of two or more such excipients, and the like. [0021] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed. [0022] When a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”. [0023] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub- ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range. Thus, for example, if a component is in an amount of about 1%, 2%, 3%, 4%, or 5%, where any value can be a lower and upper endpoint of a range, then any range is contemplated between 1% and 5% (e.g., 1% to 3%, 2% to 4%, etc.). [0024] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise. [0025] As used herein, “IC₅₀,” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process. For example, IC₅₀ refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay. [0026] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH₂CH₂O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more - CO(CH₂)₈CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester. [0027] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted). [0028] The position of a substituent can be defined relative to the positions of other substituents in an aromatic ring. For example, as shown below in relationship to the “R” group, a second substituent can be “ortho,” “para,” or “meta” to the R group, meaning that the second substituent is bonded to a carbon labeled ortho, para, or meta as indicated below. Combinations of ortho, para, and meta substituents relative to a given group or substituent are also envisioned and should be considered to be disclosed.

[0029] In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents. [0030] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0031] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl. [0032] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. [0033] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term. [0034] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. [0035] The term “alkanediyl” as used herein, refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, —CH₂— (methylene), —CH₂CH₂—, —CH₂C(CH₃)₂CH₂—, and —CH₂CH₂CH₂— are non-limiting examples of alkanediyl groups. [0036] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA¹—OA² or —OA¹—(OA²)_a—OA³, where “a” is an integer of from 1 to 200 and A¹, A², and A³ are alkyl and/or cycloalkyl groups. [0037] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A¹A²)C=C(A³A⁴) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. [0038] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. [0039] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. [0040] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. [0041] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized ʌ electrons above and below the plane of the molecule, where the ʌ clouds contain (4n+2) ʌ electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “ Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups. [0042] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ņNH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl. Fused aryl groups including, but not limited to, indene and naphthalene groups are also contemplated. [0043] The term “aldehyde” as used herein is represented by the formula -C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O. _{[0044] The terms “amine” or “amino” as used herein are represented by the formula —NA} ^1A2, where A¹ and A² can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ņNH₂. [0045] The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) and — N(-alkyl)₂, where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like. [0046] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH. [0047] The term “ester” as used herein is represented by the formula —OC(O)A¹ or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [0048] The term “ether” as used herein is represented by the formula A¹OA², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. [0049] The terms “halo,” “halogen” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I. [0050] The terms “pseudohalide,” “pseudohalogen” or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups. [0051] The term “heteroalkyl” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups. [0052] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2- b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl. [0053] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring. [0054] The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro- 1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2- b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl. [0055] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. [0056] The term “hydroxyl” or “hydroxy” as used herein is represented by the formula —OH. [0057] The term “ketone” as used herein is represented by the formula A¹C(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [0058] The term “azide” or “azido” as used herein is represented by the formula —N₃. [0059] The term “nitro” as used herein is represented by the formula —NO2. [0060] The term “nitrile” or “cyano” as used herein is represented by the formula —CN. [0061] The term “silyl” as used herein is represented by the formula —SiA¹A²A³, where A¹, A², and A³ can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [0062] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A¹S(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [0063] The term “thiol” as used herein is represented by the formula -SH. [0064] “R¹,” “R²,” “R³,”... “Rⁿ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R¹ is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group. [0065] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted). [0066] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein. [0067] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH₂)_0–4Rq; –(CH₂)_0–4ORq; -O(CH₂)_0-4R^o, –O–(CH₂)_0–4C(O)OR°; –(CH₂)_0–4CH(ORq)₂; –(CH₂)_0–4SRq; –(CH₂)_0–4Ph, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1-pyridyl which may be substituted with R°; –NO₂; –CN; –N₃; -(CH₂)_0–4N(Rq)₂; –(CH₂)_0–4N(Rq)C(O)Rq; –N(Rq)C(S)Rq; –(CH₂)_0–4N(Rq)C(O)NRq₂; -N(Rq)C(S)NRq₂; –(CH₂)_0–4N(Rq)C(O)ORq; –N(Rq)N(Rq)C(O)Rq; -N(Rq)N(Rq)C(O)NRq₂; -N(Rq)N(Rq)C(O)ORq; –(CH₂)_0–4C(O)Rq; –C(S)Rq; –(CH₂)_0–4C(O)ORq; –(CH₂)_0–4C(O)SRq; -(CH₂)_0–4C(O)OSiRq₃; –(CH₂)_0–4OC(O)Rq; –OC(O)(CH₂)_{0– 4}SR–, SC(S)SR°; –(CH₂)_0–4SC(O)Rq; –(CH₂)_0–4C(O)NRq₂; –C(S)NRq₂; –C(S)SR°; -(CH₂)_{0– 4}OC(O)NRq₂; -C(O)N(ORq)Rq; –C(O)C(O)Rq; –C(O)CH₂C(O)Rq; –C(NORq)Rq; -(CH₂)_0–4SSRq; –(CH₂)_0–4S(O)₂Rq; –(CH₂)_0–4S(O)₂ORq; –(CH₂)_0–4OS(O)₂Rq; –S(O)₂NRq₂; -(CH₂)_{0– 4}S(O)Rq; -N(Rq)S(O)₂NRq₂; –N(Rq)S(O)₂Rq; –N(ORq)Rq; –C(NH)NRq₂; -P(O)₂R°; -P(O)R^O ₂; -OP(O)R^O ₂; -OP(O)(OR^O)₂; SiR°₃; -(Ci-₄ straight or branched alkylene)O- N(R°)₂; or - (C1-4 straight or branched alkylene)C(O)O-N(R°)₂, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH₂Ph, -O(CH₂)₀- iPh, -CH₂-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0068] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen,

-(Ci_₄ straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci^ aliphatic, -CH₂Ph, -0(CH₂)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0069] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*₂, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)₂R*, =NR*, =NOR*, -O(C(R*₂))_2-3O-, or -S(C(R*₂))_2-3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci_₆ aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*₂)_2-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0070] Suitable substituents on the aliphatic group of R* include halogen,

( ) wherein each

is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0071] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R^†, –NR^† ₂, –C(O)R^†, –C(O)OR^†, –C(O)C(O)R^†, –C(O)CH₂C(O)R^†, –S(O)₂R^†, -S(O)₂NR^† ₂, –C(S)NR^† ₂, –C(NH)NR^† ₂, or –N(R^†)S(O)₂R^†; wherein each R^† is independently hydrogen, C_1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0072] Suitable substituents on the aliphatic group of R^† are independently halogen, –R^z, -(haloR^z), –OH, –OR^z, –O(haloR^z), –CN, –C(O)OH, –C(O)OR^z, –NH₂, –NHR^z, –NR^z 2, or –NO₂, wherein each R^z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0073] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate. [0074] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers. [0075] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. [0076] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon. [0077] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds further comprise prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. [0078] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates. [0079] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an Į-hydrogen can exist in an equilibrium of the keto form and the enol form.

Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, the invention includes all such possible tautomers. [0080] It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms. [0081] In some aspects, a structure of a compound can be represented by a formula:

, [0082] which is understood to be equivalent to a formula:

, [0083] wherein n is typically an integer. That is, Rⁿ is understood to represent five independent substituents, R^n(a), R^n(b), R^n(c), R^n(d), and R^n(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R^n(a) is halogen, then R^n(b) is not necessarily halogen in that instance. [0084] As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravireal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia. For example a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition. [0085] As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g. human). "Subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to human and constituents thereof. [0086] As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and/or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as a hematological malignancy, breast cancer, and/or another solid malignancy. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of a hematological malignancy, breast cancer, and/or another solid tumor in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and/or its symptoms or conditions. The term "treatment" as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and/or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain. [0087] As used herein, “therapeutic” can refer to treating, healing, and/or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect. [0088] As used herein, “effective amount” can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function. [0089] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons. [0090] A response to a therapeutically effective dose of a disclosed compound and/or pharmaceutical composition, for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and/or pharmaceutical composition, by changing the disclosed compound and/or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. [0091] As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition. [0092] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. [0093] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner. [0094] The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. [0095] The term “pharmaceutically acceptable prodrug” or “prodrug” represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V.14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). [0096] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and/or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration. [0097] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). [0098] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non- express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification. [0099] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention. [0100] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result. [0101] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. [0102] Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere). Compounds and Methods of Making and Using the Compounds [0103] In one aspect, disclosed herein is a compound having a structure according to structure I or the pharmaceutically acceptable salt thereof [0104] A compound of formula I

or a pharmaceutically acceptable salt thereof wherein

is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted alkenyl;

is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C1-C6 alkyl; R1 and R2 are independently absent, H, halide, azide, nitro, cyano, amino, hydroxyl, carboxy, amido, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 ester, C1-C4 alkenyl, or C1-C6 alkynyl, C1-C6 alkyl amino, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkyl; L₁ is absent or is straight or branched C₁-C₄ alkylene or C₁-C₄ alkenyl optionally substituted with an amide group, an ester group, or a carbonyl group, heteroaryl, aryl, an amide, or an ester; Z is absent or is O, C=O, NR3,

R3 is H, substituted or unsubstituted C1-C6 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or -C(O)R6, wherein R6 is substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted cycloalkyl; and R₄ and R₅ are independently H, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, C₁-C₄ alkyl, oxo, carboxyl, or phenyl. [0105] In one aspect,

in formula I is a unsubstituted heteroaryl, substituted or unsubstituted aryl selected from

_{where L1 in formula} I can be bonded to any position of the aryl or heteroaryl ring. The structure depict unsubstituted groups; however, the ring structure above can be substituted with one or more groups as defined for R₁ and R₂ in formula I above. [0106] In one aspect,

formula I is

wherein R₁ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and R₇ is H or substituted or unsubstituted C₁-C₆ alkyl. In one aspect, R₁ in the structures above is substituted or unsubstituted phenyl. In another aspect, R₇ in the structures above is H or methyl. [0107] In one aspect,

in formula I is wherein

n is an integer from 1 to 4; and R₈ and R₉ are independently absent, H, halide, azide, nitro, cyano, amino, amido, hydroxy, substituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ ester, C₁-C₄ alkenyl, or C₁-C₆ alkynyl, C₁-C₆ alkyl amino, C₁-C₆ alkyl amido, C₁-C₆ alkyl hydroxy, C₁-C₆ alkyl ether, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkyl. [0108] In one aspect, L₁ is absent or is straight or branched C₁-C₄ alkylene or C₁-C₄ alkenyl. In one aspect, L₁ -CH₂-. In another aspect, L₁ is optionally substituted with an amide group, an ester group, or a carbonyl group, heteroaryl, aryl, an amide, or an ester. For example, L₁ can be represented by the formula -(CH₂)_m-X- or -X-(CH₂)_m-, where m is from 1 to 4 and X is an amide group, an ester group, or a carbonyl group, heteroaryl, aryl, an amide, or an ester. [0109] In one aspect,

is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cycloheptyl, substituted or unsubstituted adamantyl, substituted or unsubstituted piperidinyl, or substituted or unsubstituted piperazinyl. In one aspect,

substituted with one or more groups, where R₄ and R₅ in formula I are independently H, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, C₁-C₄ alkyl, oxo, carboxyl, or phenyl. [0110] In one aspect,

is one of the following substituted or unsubstituted groups:

[0111] In one aspect, the compound has the structure IIA or IIB or the pharmaceutically acceptable salt thereof and any stereoisomer thereof [0112]

[0113] In one aspect, R₁ in structure IIA or IIB is substituted or unsubstituted phenyl substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl. In another aspect, L₁ in structure IIA or IIB is -CH₂- or C=O. In another aspect, Z is NH or O in structure IIA or IIB. In another aspect, R₇ is H, methyl, or ethyl in structure IIA or IIB. [0114] In another aspect, the compound has the structure III or the pharmaceutically acceptable salt thereof and any stereoisomer thereof

[0115] In one aspect, R₁ in structure III is substituted or unsubstituted phenyl. In another aspect, L₁ in structure III is -CH₂-. In another aspect, Z is NH or O in structure III. In another aspect, R₂ is H. [0116] In another aspect, the compound has the structure IVA, IVB, VA, or VB or the pharmaceutically acceptable salt thereof and any stereoisomer thereof

[0117] In one aspect, L₁ in structure IVA, IVB, VA, or VB is –(CH₂)_n-, where n is 1, 2, or 3. In another aspect, Z is NH, O, or C(O)NH in structure IVA, IVB, VA, or VB. In another aspect, R₈ in structure IVA, IVB, VA, or VB is H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl. In another aspect, R₉ in structure IVA, IVB, VA, or VB is H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl. [0118] In another aspect, the compound has the following structure

or a pharmaceutically acceptable salt thereof. The compounds listed above are also provided in Table 2. General Synthetic Method [0119] Exemplary methods for producing compounds described herein, as well as characterization information, are provided in the Examples. FIGS.1-21 provide several reactions schemes and conditions for making the compounds described herein. Solvents, temperatures, presence or absence of protecting groups, and other reaction conditions may vary according to the specific substituents in the compound being synthesized. Pharmaceutical Compositions [0120] In various aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof. As used herein, “pharmaceutically-acceptable carriers” means one or more of a pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and adjuvants. The disclosed pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy and pharmaceutical sciences. [0121] In a further aspect, the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agent, and optionally one or more adjuvant. The disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. In a further aspect, the disclosed pharmaceutical composition can be formulated to allow administration orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intracranially and intratumorally. [0122] As used herein, “parenteral administration” includes administration by bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrasternal injection and infusion. [0123] In various aspects, the present disclosure also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof. In a further aspect, a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes. [0124] In practice, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the present disclosure, and/or pharmaceutically acceptable salt(s) thereof, can also be administered by controlled release means and/or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation. [0125] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. That is, a “unit dosage form” is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets (including scored or coated tablets), capsules or pills for oral administration; single dose vials for injectable solutions or suspension; suppositories for rectal administration; powder packets; wafers; and segregated multiples thereof. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms. [0126] The pharmaceutical compositions disclosed herein comprise a compound of the present disclosure (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents. In various aspects, the disclosed pharmaceutical compositions can include a pharmaceutically acceptable carrier and a disclosed compound, or a pharmaceutically acceptable salt thereof. In a further aspect, a disclosed compound, or pharmaceutically acceptable salt thereof, can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. [0127] Techniques and compositions for making dosage forms useful for materials and methods described herein are described, for example, in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). [0128] The compounds described herein are typically to be administered in admixture with suitable pharmaceutical diluents, excipients, extenders, or carriers (termed herein as a pharmaceutically acceptable carrier, or a carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The deliverable compound will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration. Carriers include solids or liquids, and the type of carrier is chosen based on the type of administration being used. The compounds may be administered as a dosage that has a known quantity of the compound. [0129] Because of the ease in administration, oral administration can be a preferred dosage form, and tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. However, other dosage forms may be suitable depending upon clinical population (e.g., age and severity of clinical condition), solubility properties of the specific disclosed compound used, and the like. Accordingly, the disclosed compounds can be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques. [0130] The disclosed pharmaceutical compositions in an oral dosage form can comprise one or more pharmaceutical excipient and/or additive. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starches (for example corn starch or amylose), dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talcum, lycopodium, silica gel (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and/or lower saturated, aliphatic oxyalcohols, for example methyl oxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate), fatty acids as well as magnesium, calcium or aluminum salts of fatty acids with 12 to 22 carbon atoms, in particular saturated (for example stearates), emulsifiers, oils and fats, in particular vegetable (for example, peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in each case also optionally hydrated); glycerol esters and polyglycerol esters of saturated fatty acids C₁₂H₂₄O₂ to C₁₈H₃₆O₂ and their mixtures, it being possible for the glycerol hydroxy groups to be totally or also only partly esterified (for example mono-, di- and triglycerides); pharmaceutically acceptable mono- or multivalent alcohols and polyglycols such as polyethylene glycol and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10-18 carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms) or multivalent alcohols such as glycols, glycerol, diethylene glycol, pentacrythritol, sorbitol, mannitol and the like, which may optionally also be etherified, esters of citric acid with primary alcohols, acetic acid, urea, benzyl benzoate, dioxolanes, glyceroformals, tetrahydrofurfuryl alcohol, polyglycol ethers with C1-C12-alcohols, dimethylacetamide, lactamides, lactates, ethyl carbonates, silicones (in particular medium-viscous polydimethyl siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like. [0131] Other auxiliary substances useful in preparing an oral dosage form are those which cause disintegration (so-called disintegrants), such as: cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose. Conventional coating substances may also be used to produce the oral dosage form. Those that may for example be considered are: polymerizates as well as copolymerizates of acrylic acid and/or methacrylic acid and/or their esters; copolymerizates of acrylic and methacrylic acid esters with a lower ammonium group content (for example EudragitR RS), copolymerizates of acrylic and methacrylic acid esters and trimethyl ammonium methacrylate (for example EudragitR RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methyl cellulose phthalate or acetate succinate; cellulose acetate phthalate, starch acetate phthalate as well as polyvinyl acetate phthalate, carboxy methyl cellulose; methyl cellulose phthalate, methyl cellulose succinate, -phthalate succinate as well as methyl cellulose phthalic acid half ester; zein; ethyl cellulose as well as ethyl cellulose succinate; shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer; styrol-maleic acid copolymerizate; 2-ethyl-hexyl-acrylate maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutaminic acid/glutamic acid ester copolymer; carboxymethylethylcellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine. [0132] Plasticizing agents that may be considered as coating substances in the disclosed oral dosage forms are: citric and tartaric acid esters (acetyl-triethyl citrate, acetyl tributyl-, tributyl-, triethyl-citrate); glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl- phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate, di-(2-methoxy- or 2-ethoxyethyl)-adipate; benzophenone; diethyl- and diburylsebacate, dibutylsuccinate, dibutyltartrate; diethylene glycol dipropionate; ethyleneglycol diacetate, -dibutyrate, -dipropionate; tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate (polysorbates such as Polysorbar 50); sorbitan monooleate. [0133] Moreover, suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents may be included as carriers. The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include, but are not limited to, lactose, terra alba, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol talc, starch, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. [0134] In various aspects, a binder can include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. In a further aspect, a disintegrator can include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. [0135] In various aspects, an oral dosage form, such as a solid dosage form, can comprise a disclosed compound that is attached to polymers as targetable drug carriers or as a prodrug. Suitable biodegradable polymers useful in achieving controlled release of a drug include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, caprolactones, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and hydrogels, preferably covalently crosslinked hydrogels. [0136] Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. [0137] A tablet containing a disclosed compound can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. [0138] In various aspects, a solid oral dosage form, such as a tablet, can be coated with an enteric coating to prevent ready decomposition in the stomach. In various aspects, enteric coating agents include, but are not limited to, hydroxypropylmethylcellulose phthalate, methacrylic acid- methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate. Akihiko Hasegawa “Application of solid dispersions of Nifedipine with enteric coating agent to prepare a sustained-release dosage form” Chem. Pharm. Bull. 33:1615-1619 (1985). Various enteric coating materials may be selected on the basis of testing to achieve an enteric coated dosage form designed ab initio to have a preferable combination of dissolution time, coating thicknesses and diametral crushing strength (e.g., see S. C. Porter et al. “The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate”, J. Pharm. Pharmacol. 22:42p (1970)). In a further aspect, the enteric coating may comprise hydroxypropyl-methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate. [0139] In various aspects, an oral dosage form can be a solid dispersion with a water soluble or a water insoluble carrier. Examples of water soluble or water insoluble carrier include, but are not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethyl-cellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, or hydroxypropylmethylcellulose, ethyl cellulose, or stearic acid. [0140] In various aspects, an oral dosage form can be in a liquid dosage form, including those that are ingested, or alternatively, administered as a mouth wash or gargle. For example, a liquid dosage form can include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. In addition, oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients. The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents. [0141] For the preparation of solutions or suspensions it is, for example, possible to use water, particularly sterile water, or physiologically acceptable organic solvents, such as alcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol), oils (for example peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soya bean oil, castor oil, bovine hoof oil), paraffins, dimethyl sulfoxide, triglycerides and the like. [0142] In the case of a liquid dosage form such as a drinkable solutions, the following substances may be used as stabilizers or solubilizers: lower aliphatic mono- and multivalent alcohols with 2- 4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycols with molecular weights between 200-600 (for example 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propylene glycol, organic amides, for example amides of aliphatic C1-C6-carboxylic acids with ammonia or primary, secondary or tertiary C1-C4-amines or C1-C4-hydroxy amines such as urea, urethane, acetamide, N-methyl acetamide, N,N-diethyl acetamide, N,N-dimethyl acetamide, lower aliphatic amines and diamines with 2-6 carbon atoms, such as ethylene diamine, hydroxyethyl theophylline, tromethamine (for example as 0.1 to 20% aqueous solution), aliphatic amino acids. [0143] In preparing the disclosed liquid dosage form can comprise solubilizers and emulsifiers such as the following non-limiting examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or also 1- methyl-3-(2-hydroxyethyl)imidazolidone-(2). In this context, polyoxyethylated means that the substances in question contain polyoxyethylene chains, the degree of polymerization of which generally lies between 2 and 40 and in particular between 10 and 20. Polyoxyethylated substances of this kind may for example be obtained by reaction of hydroxyl group-containing compounds (for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals) with ethylene oxide (for example 40 Mol ethylene oxide per 1 Mol glyceride). Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil. See also Dr. H. P. Fiedler “Lexikon der Hillsstoffe für Pharmazie, Kostnetik und angrenzende Gebiete” 1971, pages 191-195. [0144] In various aspects, a liquid dosage form can further comprise preservatives, stabilizers, buffer substances, flavor correcting agents, sweeteners, colorants, antioxidants and complex formers and the like. Complex formers which may be for example be considered are: chelate formers such as ethylene diamine retrascetic acid, nitrilotriacetic acid, diethylene triamine pentacetic acid and their salts. [0145] It may optionally be necessary to stabilize a liquid dosage form with physiologically acceptable bases or buffers to a pH range of approximately 6 to 9. Preference may be given to as neutral or weakly basic a pH value as possible (up to pH 8). [0146] In order to enhance the solubility and/or the stability of a disclosed compound in a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form, it can be advantageous to employ Į-, ȕ- or Ȗ-cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-ȕ-cyclodextrin or sulfobutyl-ȕ-cyclodextrin. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the present disclosure in pharmaceutical compositions. [0147] In various aspects, a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form can further comprise liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. [0148] Pharmaceutical compositions of the present disclosure suitable injection, such as parenteral administration, such as intravenous, intramuscular, or subcutaneous administration. Pharmaceutical compositions for injection can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms. [0149] Pharmaceutical compositions of the present disclosure suitable for parenteral administration can include sterile aqueous or oleaginous solutions, suspensions, or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In some aspects, the final injectable form is sterile and must be effectively fluid for use in a syringe. The pharmaceutical compositions should be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof. [0150] Injectable solutions, for example, can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In some aspects, a disclosed parenteral formulation can comprise about 0.01-0.1 M, e.g. about 0.05 M, phosphate buffer. In a further aspect, a disclosed parenteral formulation can comprise about 0.9% saline. [0151] In various aspects, a disclosed parenteral pharmaceutical composition can comprise pharmaceutically acceptable carriers such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include but not limited to water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include mannitol, normal serum albumin, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, collating agents, inert gases and the like. In a further aspect, a disclosed parenteral pharmaceutical composition can comprise may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives. Also contemplated for injectable pharmaceutical compositions are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the subject or patient. [0152] In addition to the pharmaceutical compositions described herein above, the disclosed compounds can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt. [0153] Pharmaceutical compositions of the present disclosure can be in a form suitable for topical administration. As used herein, the phrase “topical application” means administration onto a biological surface, whereby the biological surface includes, for example, a skin area (e.g., hands, forearms, elbows, legs, face, nails, anus and genital areas) or a mucosal membrane. By selecting the appropriate carrier and optionally other ingredients that can be included in the composition, as is detailed herein below, the compositions of the present invention may be formulated into any form typically employed for topical application. A topical pharmaceutical composition can be in a form of a cream, an ointment, a paste, a gel, a lotion, milk, a suspension, an aerosol, a spray, foam, a dusting powder, a pad, and a patch. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the present disclosure, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency. [0154] In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. [0155] Ointments are semisolid preparations, typically based on petrolatum or petroleum derivatives. The specific ointment base to be used is one that provides for optimum delivery for the active agent chosen for a given formulation, and, preferably, provides for other desired characteristics as well (e.g., emollience). As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight. [0156] Lotions are preparations that are to be applied to the skin surface without friction. Lotions are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are typically preferred for treating large body areas, due to the ease of applying a more fluid composition. Lotions are typically suspensions of solids, and oftentimes comprise a liquid oily emulsion of the oil-in-water type. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, such as methylcellulose, sodium carboxymethyl-cellulose, and the like. [0157] Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the “internal” phase, is generally comprised of petrolatum and/or a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Reference may be made to Remington: The Science and Practice of Pharmacy, supra, for further information. [0158] Pastes are semisolid dosage forms in which the bioactive agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gel. The base in a fatty paste is generally petrolatum, hydrophilic petrolatum and the like. The pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. Additional reference may be made to Remington: The Science and Practice of Pharmacy, for further information. [0159] Gel formulations are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil. Preferred organic macromolecules, i.e., gelling agents, are crosslinked acrylic acid polymers such as the family of carbomer polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the trademark Carbopol™. Other types of preferred polymers in this context are hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol; modified cellulose, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof. [0160] Sprays generally provide the active agent in an aqueous and/or alcoholic solution which can be misted onto the skin for delivery. Such sprays include those formulated to provide for concentration of the active agent solution at the site of administration following delivery, e.g., the spray solution can be primarily composed of alcohol or other like volatile liquid in which the active agent can be dissolved. Upon delivery to the skin, the carrier evaporates, leaving concentrated active agent at the site of administration. [0161] Foam compositions are typically formulated in a single or multiple phase liquid form and housed in a suitable container, optionally together with a propellant which facilitates the expulsion of the composition from the container, thus transforming it into a foam upon application. Other foam forming techniques include, for example the “Bag-in-a-can” formulation technique. Compositions thus formulated typically contain a low-boiling hydrocarbon, e.g., isopropane. Application and agitation of such a composition at the body temperature cause the isopropane to vaporize and generate the foam, in a manner similar to a pressurized aerosol foaming system. Foams can be water-based or aqueous alkanolic, but are typically formulated with high alcohol content which, upon application to the skin of a user, quickly evaporates, driving the active ingredient through the upper skin layers to the site of treatment. [0162] Skin patches typically comprise a backing, to which a reservoir containing the active agent is attached. The reservoir can be, for example, a pad in which the active agent or composition is dispersed or soaked, or a liquid reservoir. Patches typically further include a frontal water permeable adhesive, which adheres and secures the device to the treated region. Silicone rubbers with self-adhesiveness can alternatively be used. In both cases, a protective permeable layer can be used to protect the adhesive side of the patch prior to its use. Skin patches may further comprise a removable cover, which serves for protecting it upon storage. [0163] Examples of patch configuration which can be utilized with the present invention include a single-layer or multi-layer drug-in-adhesive systems which are characterized by the inclusion of the drug directly within the skin-contacting adhesive. In such a transdermal patch design, the adhesive not only serves to affix the patch to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film. In the multi- layer drug-in-adhesive patch a membrane is disposed between two distinct drug-in-adhesive layers or multiple drug-in-adhesive layers are incorporated under a single backing film. [0164] Examples of pharmaceutically acceptable carriers that are suitable for pharmaceutical compositions for topical applications include carrier materials that are well-known for use in the cosmetic and medical arts as bases for e.g., emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols and the like, depending on the final form of the composition. Representative examples of suitable carriers according to the present invention therefore include, without limitation, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials commonly employed in cosmetic and medicinal compositions. Other suitable carriers according to the present invention include, without limitation, alcohols, such as, for example, monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxes having molecular weight ranging from 200 to 20,000); polyoxyethylene glycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like. [0165] Topical compositions of the present disclosure can, if desired, be presented in a pack or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The dispenser device may, for example, comprise a tube. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser device may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may include labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising the topical composition of the invention formulated in a pharmaceutically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. [0166] Another patch system configuration which can be used by the present invention is a reservoir transdermal system design which is characterized by the inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi- permeable membrane and adhesive. The adhesive component of this patch system can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane. Yet another patch system configuration which can be utilized by the present invention is a matrix system design which is characterized by the inclusion of a semisolid matrix containing a drug solution or suspension which is in direct contact with the release liner. The component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix. [0167] Pharmaceutical compositions of the present disclosure can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds. [0168] Pharmaceutical compositions containing a compound of the present disclosure, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form. [0169] The pharmaceutical composition (or formulation) may be packaged in a variety of ways. Generally, an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, foil blister packs, and the like. The container may also include a tamper proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container typically has deposited thereon a label that describes the contents of the container and any appropriate warnings or instructions. [0170] The disclosed pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Pharmaceutical compositions comprising a disclosed compound formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. [0171] The exact dosage and frequency of administration depends on the particular disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, solvate, or polymorph thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof; the particular condition being treated and the severity of the condition being treated; various factors specific to the medical history of the subject to whom the dosage is administered such as the age; weight, sex, extent of disorder and general physical condition of the particular subject, as well as other medication the individual may be taking; as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the present disclosure. [0172] Depending on the mode of administration, the pharmaceutical composition will comprise from 0.05 to 99 % by weight, preferably from 0.1 to 70 % by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition. [0173] In one aspect, an appropriate dosage level will generally be about 0.01 to 1000 mg of a compound described herein per kg patient body weight per day and can be administered in single or multiple doses. In various aspects, the dosage level will be about 0.1 to about 500 mg/kg per day, about 0.1 to 250 mg/kg per day, or about 0.5 to 100 mg/kg per day. A suitable dosage level can be about 0.01 to 1000 mg/kg per day, about 0.01 to 500 mg/kg per day, about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response. [0174] Such unit doses as described hereinabove and hereinafter can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day. In various aspects, such unit doses can be administered 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration. In a further aspect, dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area. [0175] A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient. The time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release. [0176] It can be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to start, interrupt, adjust, or terminate therapy in conjunction with individual patient response. [0177] The disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological or clinical conditions. [0178] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using. [0179] As already mentioned, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and a pharmaceutically acceptable carrier. Additionally, the present disclosure relates to a process for preparing such a pharmaceutical composition, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to the present disclosure. Methods of Use [0180] Only praziquantel is available for treating parasitic worm infections such as, for example, schistosomiasis, a disease affecting more than 200 million people. Praziquantel-resistant worms have been selected for in the lab and low cure rates from mass drug administration programs, which suggests that resistance is evolving in the field. Not wishing to be bound by theory, thioredoxin glutathione reductase (TGR) is essential for schistosome survival. TGR is a 130 kDa obligate homodimer as the functional stereochemistry of the FAD redox site in each subunit is generated by protein dimerization. TGR inhibitors identified to date are irreversible and/or covalent inhibitors with unacceptable off-target effects. [0181] In one aspect, the compound selectively interacts with the target TGR protein by non- covalent bonds. TGR-based therapeutic approaches is impeded by the lack of non-covalent small molecule inhibitors of TGR. It has been discovered that the compounds described herein interact at the doorstop pocket of thioredoxin glutathione reductase in a non-covalent manner. Not wishing to be bound by theory, the compounds described herein bind at the doorstop pocket, which prevents NADPH oxidation steps. [0182] As demonstrated herein, the compounds described herein are effective TGR inhibitors and. In one aspect, the compounds described herein have an IC₅₀ value for inhibiting TGR of less than about 5 μm, or 0.01 μm, 0.05 μm, 0.10 μm, 0.20 μm, 0.40 μm, 0.60 μm, 0.80 μm, 1.00 μm, 1.50 μm, 2.00 μm, 2.50 μm, 3.00 μm, 3.50 μm, 4.00 μm, 4.50 μm, or 5.00 μm, where any value can be a lower and upper endpoint of a range (e.g., 0.50 μm to 2.00 μm). Methods for determining IC₅₀ values are provided in the Examples. [0183] The compounds described herein are effective in treating diseases in a subject produced by parasitic worms. In one aspect, the compounds can reduce worm burden (i.e., the number of living or viable worms), worm egg burden (i.e., the number of living or viable eggs), or a combination thereof in a subject when compared to the same infected subject prior to the administration of the compound. [0184] The compounds described herein are effective in killing both juvenile (e.g., 23 days old) and adult parasitic worms. In one aspect, the compounds described herein have an LD₅₀ value for killing adult or juvenile parasitic worms of less than about 50 μm, or 0.5 μm, 0.10 μm, 0.50 μm, 1.0 μm, 2.0 μm, 3.0 μm, 4.0 μm, 5.0 μm, 6.0 μm, 7.0 μm, 8.0 μm, 9.0 μm, 10.0 μm, 15.0 μm, 20.0 μm, 25.0 μm, 30.0 μm, 35.0 μm, 40.0 μm, 45.0 μm, or 50.0 μm, where any value can be a lower and upper endpoint of a range (e.g., 1.0 μm to 5.0 μm). Methods for determining LD₅₀ values are provided in the Examples. [0185] In one aspect, the parasitic worm is a flatworm or trematode. In another aspect, the parasitic worm is a blood fluke, a liver fluke, a lung fluke, an intestinal fluke, a pancreatic fluke, a cestode, or tapeworm. [0186] In one aspect, the parasitic worm is a flatworm is from the order Platyhelminthes. In one aspect, the flatworm is from the class Turbellaria, Trematoda, Monogenea and Cestoda. [0187] In another aspect, the parasitic worm is from the genus Schistosoma, Clonorchis, Dicrocoelium, Fasciola, Opisthorchis, Fasciolopsis Metagonimus, Heterophyes, Metorchis, Paragonimus, Eurytrema, Echinostoma, Watsonius, Gastrodiscoides, Gastrodiscus, Heterobilharzia, Paramphistomum, Prosthogonimus, Alaria, Taenia, Hymenolepis, Diphyllobothrium, Echinococcus, Moniezia, Dipylidium, Spirometra, Calicophoron, Nanophytus, Apophallus Cryptocotyle, or Mesocestoides. [0188] In another aspect, the parasitic worm is S. mansoni, S. haematobium, S. japonicum, S. guineensis, S. intercalatum, S. malayensis, S. mekongi, S. bovis, C. sinensis, D. dendriticum, D. hospes, F. gigantica, F. hepatica, O. felineus, O. viverrine, M. conjunctus, F. buski, M. miyatai, M. takahashii, M. yokogawai, H. heterophyes, H. nocens, E. pancreaticum, E. coelomaticum, E. ovis., P. westermani, P. heterotremus, P. kellicoti, P. mexicana, P. skrjabin, P. miyazakii, P. compactus, P. hueit'ungensis, E. ilocanum, W. watsoni, G. hominis, G. aegyptiacus, H. americana, P. macrorchis, P. cervi, A. alata, A. canis, T. saginata, T. solium, T. taeniaeformis, T. multiceps, T. serialis, T. hydatigena, T. pisiformis, T. crassiceps, H. nana, D. latum, E. granulosus, E. multilocularis, E. equinus, E. ortleppi, E. intermedius, E. canadensis, M. expansa, D. caninum, S. mansonoides, C. daubneyi, N. salmincola, A. donicus, C. lingua, or M. variabilis. [0189] The compounds described herein can treat or prevent numerous diseases associated with parasitic worm infection. In one aspect, the compounds described herein can treat schistosomiasis, which is an acute and chronic parasitic disease that has effects millions of people. In other aspects, the compounds described herein can be used to treat renal disease, kidney disease, bladder disease, liver disease, pancreatitis, cholecystitis, cholangiocarcinoma, fever, urticaria, abdominal pain, hepatosplenic disease with periportal fibrosis, glomerular disease (e.g., glomerular lesions are mesangioproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, mesangiocapillary glomerulonephritis, FSGS, and amyloidosis), and urinary tract disease caused by a parasitic worm infection. [0190] In one aspect, the compound is administered orally to the subject. In another aspect, the compound is administered at a dosage of from about 50 mg per day to about 1,000 mg per day, or about 50 mg per day, 50 mg per day, 100 mg per day, 150 mg per day, 200 mg per day, 250 mg per day, 300 mg per day, 350 mg per day, 400 mg per day, 450 mg per day, 500 mg per day, 550 mg per day, 600 mg per day, 650 mg per day, 700 mg per day, 750 mg per day, 800 mg per day, 850 mg per day, 900 mg per day, 950 mg per day, or 1,000 mg per day, where any value can be a lower and upper endpoint of a range (e.g., 100 mg per day to 300 mg per day). Aspects Aspect 1. A compound of formula I

or a pharmaceutically acceptable salt thereof wherein

is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted alkenyl;

is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C1-C6 alkyl; R1 and R2 are independently absent, H, halide, azide, nitro, cyano, amino, hydroxyl, carboxy, amido, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkoxy, C1-C6 ester, C1-C4 alkenyl, or C1-C6 alkynyl, C1-C6 alkyl amino, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkyl; L₁ is absent or is straight or branched C₁-C₄ alkylene or C₁-C₄ alkenyl optionally substituted with an amide group, an ester group, or a carbonyl group, heteroaryl, aryl, an amide, or an ester; Z is absent or is O, NR3, C=O,

R3 is H, substituted or unsubstituted C1-C6 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or -C(O)R₆, wherein R₆ is substituted or unsubstituted C₁-C₆ alkyl or substituted or unsubstituted cycloalkyl; and R₄ and R₅ are independently H, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, C₁-C₄ alkyl, oxo, carboxyl, or phenyl. Aspect 2. The compound of Aspect 1, wherein

is

Aspect 4. The compound of Aspect 1, wherein

is

wherein R₁ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, and R₇ is H or substituted or unsubstituted C₁-C₆ alkyl. Aspect 5. The compound of Aspect 4, wherein R₁ is substituted or unsubstituted phenyl. Aspect 6. The compound of Aspect 4 or 5, wherein R₇ is H or methyl. Aspect 7. The compound of Aspect 1, wherein

is

wherein n is an integer from 1 to 4; and R₈ and R₉ are independently absent, H, halide, azide, nitro, cyano, amino, amido, hydroxy, substituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ ester, C₁-C₄ alkenyl, or C₁-C₆ alkynyl, C₁-C₆ alkyl amino, C₁-C₆ alkyl amido, C₁-C₆ alkyl hydroxy, C₁-C₆ alkyl ether, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkyl. Aspect 8. The compound of any one of Aspects 1-7, wherein L₁ –(CH₂)n-, n is 1, 2, or 3. Aspect 9. The compound of any one of Aspects 1-8, wherein Z is NH. Aspect 10. The compound of any one of Aspects 1-8, wherein Z is O. Aspect 11. The compound of any one of Aspects 1-10, wherein

is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cycloheptyl, substituted or unsubstituted adamantyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or one of the following substituted or unsubstituted groups

or

Aspect 12. The compound of any one of Aspects 1-10, wherein

Aspect 13. The compound of Aspect 1 having formula IIA or IIB and any stereoisomer thereof

wherein R₁ is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl. Aspect 14. The compound of Aspect 13, wherein R₁ is substituted or unsubstituted phenyl. Aspect 15. The compound of Aspect 13 or 14, wherein L₁ -CH₂- or C=O. Aspect 16. The compound of any one of Aspects 13-15, wherein Z is NH. Aspect 17. The compound of any one of Aspects 13-15, wherein Z is O. Aspect 18. The compound of any one of Aspects 13-17, wherein R₇ is H, methyl, or ethyl. Aspect 19. The compound Aspect 1 having formula III and any stereoisomer thereof

Aspect 20. The compound of Aspect 19, wherein R₁ is substituted or unsubstituted phenyl. Aspect 21. The compound of Aspect 20 or 21, wherein L₁ is -CH₂-. Aspect 22. The compound of any one of Aspects 19-21, wherein Z is NH. Aspect 23. The compound of any one of Aspects 19-21, wherein Z is O. Aspect 24. The compound of any one of Aspects 19-23, wherein R₂ is H. Aspect 25. The compound Aspect 1 having formula IVA, IVB, VA, or VB and any stereoisomer thereof

Aspect 26. The compound of Aspect 25, wherein L₁ –(CH₂)_n-, where n is 1, 2, or 3. Aspect 27. The compound of Aspect 25 or 26, wherein Z is NH or C(O)NH. Aspect 28. The compound of Aspect 25 or 26, wherein Z is O. Aspect 29. The compound of any one of Aspects 25-28, wherein R₈ is H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl with an optional carbonyl group. Aspect 30. The compound of any one of claims 25-29, wherein R₉ is H, halide, azide, nitro, cyano, amino, amido, hydroxy, substituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ ester, C₁-C₄ alkenyl, or C₁-C₆ alkynyl, C₁-C₆ alkyl amino, C₁-C₆ alkyl amido, C₁-C₆ alkyl hydroxy, C₁-C₆ alkyl ether, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkyl. Aspect 31. The compound of Aspect 1 selected from

or a pharmaceutically acceptable salt thereof. Aspect 32. A composition comprising a compound of any one of Aspects 1-31 and a pharmaceutically acceptable excipient. Aspect 33. A method of treating a disease in a subject produced by a parasitic worm comprising administering to the subject an effective amount of a compound of any one of Aspects 1-31. Aspect 34. The method of Aspect 33, wherein the disease is produced from a parasitic flatworm or trematode. Aspect 35. The method of Aspect 33, wherein the disease is produced from a blood fluke, a liver fluke, a lung fluke, an intestinal fluke, a pancreatic fluke, a cestode, or tapeworm. Aspect 36. The method of Aspect 33, wherein the parasitic worm is from the genus Schistosoma, Clonorchis, Dicrocoelium, Fasciola, Opisthorchis, Fasciolopsis Metagonimus, Heterophyes, Metorchis, Paragonimus, Eurytrema, Echinostoma, Watsonius, Gastrodiscoides, Gastrodiscus, Heterobilharzia, Paramphistomum, Prosthogonimus, Alaria, Taenia, Hymenolepis, Diphyllobothrium, Echinococcus, Moniezia, Dipylidium, Spirometra, Calicophoron, Nanophytus, Apophallus Cryptocotyle, or Mesocestoides. Aspect 37. The method of Aspect 33, wherein the parasitic worm is S. mansoni, S. haematobium, S. japonicum, S. guineensis, S. intercalatum, S. malayensis, S. mekongi, S. bovis, C. sinensis, D. dendriticum, D. hospes, F. gigantica, F. hepatica, O. felineus, O. viverrine, M. conjunctus, F. buski, M. miyatai, M. takahashii, M. yokogawai, H. heterophyes, H. nocens, E. pancreaticum, E. coelomaticum, E. ovis., P. westermani, P. heterotremus, P. kellicoti, P. mexicana, P. skrjabin, P. miyazakii, P. compactus, P. hueit'ungensis, E. ilocanum, W. watsoni, G. hominis, G. aegyptiacus, H. americana, P. macrorchis, P. cervi, A. alata, A. canis, T. saginata, T. solium, T. taeniaeformis, T. multiceps, T. serialis, T. hydatigena, T. pisiformis, T. crassiceps, H. nana, D. latum, E. granulosus, E. multilocularis, E. equinus, E. ortleppi, E. intermedius, E. canadensis, M. expansa, D. caninum, S. mansonoides, C. daubneyi, N. salmincola, A. donicus, C. lingua, or M. variabilis. Aspect 38. The method of any one of Aspects 33-37, wherein the compound reduces worm burden, worm egg burden, or a combination thereof in a subject when compared to the same subject prior to the administration of the compound. Aspect 39. A method of inhibiting thioredoxin glutathione reductase (TGR) in a cell comprising administering to the cell an effective amount of a compound of any one of Aspects 1-31. Aspect 40. The method of Aspect 39, wherein the compound selectively interacts with the target TGR protein by non-covalent bonds. Aspect 41. The method of Aspect 40, wherein the interaction occurs at the doorstop pocket of thioredoxin glutathione reductase. [0191] Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure. EXAMPLES [0192] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure. METHODS [0193] Synthesis of 1-12 and PRP [0194] Table 1 provide the structures of compounds 1-12 as referenced below. Table 1

[0195] Structures of additional compounds are provided in Table 2 with biological data. Table 2

[0196] FIGS. 1-21 show exemplary reaction sequences and conditions for making the compounds described herein. All reactions were carried out under inert atmosphere of nitrogen and monitored by thin-layer chromatography with silica gel 60 F₂₅₄ precoated glass plates. Visualization of TLC plates was performed by UV light irradiation (254 nm) or staining with phosphomolybdic acid. All reagents were purchased from commercial suppliers and were used without further purification. Chromatographic purifications were performed using an HPFC Biotage Isolera^TM Four 3.0 system using prepacked flash chromatography cartridges in normal phase (irregular silica, 40-60 μm; hexanes/ethyl acetate gradient) or reverse phase (Biotage KP- C18-HS, water/methanol gradient) modes with UV detection at 254 and 280 nm.¹H NMR spectra were recorded on Bruker spectrometer at 400 MHz.¹³C NMR spectra were recorded on Bruker spectrometer at 100 MHz. Chemical shifts were reported in parts per million (ppm) and calibrated with CDCl₃ residual peak. Coupling constants were reported in Hz and the standard abbreviations indicating multiplicity were used as follows: s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. Chromatographic purities of the final compounds were determined using a Shimadzu HPLC system equipped with CN-propyl column (NUCLEODUR 100-3 CN-RP, 2u50 mm, 3 μm) utilizing water/acetonitrile=90/10+0.1% formic acid eluent system for phase A and methanol+0.1% formic acid for phase B. Purities of all final products were found to be superior to 95% and determined by integration of the chromatogram after subtraction of the background using Labsolutions LCMS software at wavelengths giving the maximum absorbance. High- resolution mass-spectra (HRMS) were performed on Waters Synapt G2-Si ESI/LCMS instrument. Optical rotation was measured on Rudolph Research Analytical AUTOPOL IV automatic polarimeter. [0197] General procedure A: synthesis of oxazole N-oxides 2a-d. Oxazole N-oxides were assembled from commercial benzaldehydes (1a-d) and butane-2,3-dione monoxime similarly to the reported procedure.³ [0198] 1M HCl in acetic acid (2 eq) was added to the mixture of aryl aldehyde (1 eq) and 2,3- butanedione monoxime (1.1 eq) under cooling with ice-water. The resultant mixture was stirred for 12 hrs at ambient temperature. Diethyl ether was then added to the reaction to precipitate the product and the resultant slurry was stirred for 30 min. The precipitate was filtered and washed with ether three times. The cake was suspended in methylene chloride/water and conc. NH₄OH was added to adjust pH of aqueous layer to 8. The resulting mixture was stirred for 20 min and aqueous layer was removed. Organic phase was washed with brine, dried over Na₂SO₄ and the solvent was removed in vacuo to provide target oxazole N-oxides with sufficient purity. If necessary, product can be purified on silica gel using CH₂Cl₂/MeOH=9/1 eluent mixture. [0199] 2-(Benzo[d][1,3]dioxol-5-yl)-4,5-dimethyloxazole 3-oxide (2a): Synthesized according to general method A from piperonal aldehyde. Yellow powder, yield 95%.1H NMR (400 MHz): į 8.10 (dd, J₁=8.32 Hz, J₂=1.65 Hz, 1H), 7.98 (d, J=1.56 Hz, 1H), 6.92 (d, J=8.31 Hz, 1H), 6.03 (s, 2H), 2.34 (d, J=0.76 Hz, 3H), 2.19 (d, J=0.72 Hz, 3H).¹³C NMR (400 MHz, CDCl₃): į 149.1, 147.8, 146.2, 141.0, 128.9, 120.0, 117.5, 108.6, 105.1, 101.5, 11.0, 6.3. HRMS calcd for C₁₂H₁₂NO₄ [M+H]⁺ 234.0766, found 234.0769. [0200] 4,5-Dimethyl-2-phenyloxazole 3-oxide (2b⁴): Synthesized according to general method A from benzaldehyde. Off-white powder, yield 82%. 1H NMR (400 MHz): į 8.44 (d, J=7.68 Hz, 2H), 7.52-7.36 (m, 3H), 2.34 (s, 3H), 2.20 (s, 3H). [0201] 2-(2-Ethylphenyl)-4,5-dimethyloxazole 3-oxide (2c⁵): Synthesized according to general method A from 2-ethylbenzaldehyde. Colorless oil, yield 62%. 1H NMR (400 MHz): į 7.65 (dd, J₁=7.87 Hz, J₂=1.27 Hz, 1H), 7.49 (dt, J₁=7.54 Hz, J₂=1.39 Hz, 1H), 7.35 (d, J=7.75 Hz, 1H), 3.08 (q, J=7.44 Hz, 2H), 2.52 (s, 3H), 2.08 (s, 3H), 1.29 (t, J=1.50 Hz, 3H). [0202] 4,5-Dimethyl-2-(naphthalen-2-yl)oxazole 3-oxide (2d⁶): Synthesized according to general method A from naphthaldehyde. Off-white powder, yield 45%.1H NMR (400 MHz): į 9.33 (s, 1H), 8.26 (dd, J₁=8.74 Hz, J₂=1.62 Hz, 1H), 7.99-7.96 (m, 1H), 7.93 (d, J=8.80 Hz, 1H), 7.87- 7.82 (m, 1H), 7.56-7.50 (m, 2H), 2.41 (d, J=0.68 Hz, 3H), 2.26 (d, J=0.68 Hz, 3H). [0203] General procedure B: synthesis of 2-Aryl-4-(chloromethyl)-5-methyloxazoles (3a-d). Synthesis of compounds 3a-d was performed according to the published literature method.³ POCl₃ (1.1 eq) was added dropwise to a solution of oxazole N-Oxide (2a-d) in anhydrous chloroform (5 ml/mmol) and the resulting mixture was refluxed for 30 min. After cooling reaction mixture was treated with ice/NH₄OH (pH=8) and aqueous layer was extracted with methylene chloride (three times). Combined organic layers were washed with brine, dried over Na₂SO₄ and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using hexanes/ethyl acetate mixture to afford the desired compounds. [0204] 2-(Benzo[d][1,3]dioxol-5-yl)-4-(chloromethyl)-5-methyloxazole (3a): Synthesized according to general method B from compound 2a. White powder, 73%. ¹H NMR (400 MHz, CDCl₃): į 7.55 (dd, J₁=8.17 Hz, J₂=1.69 Hz, 1H), 7.46 (d, J=1.62 Hz, 1H), 6.86 (d, J=8.09 Hz, 1H), 6.02 (s, 2H), 4.53 (s, 2H), 2.40 (s, 3H).¹³C NMR (400 MHz, CDCl₃): į 159.9, 149.5, 148.1, 146.1, 132.7, 121.4, 120.9, 108.5, 106.6, 101.5, 37.3, 10.3. HRMS calcd for C₁₂H₁₁ClNO₃ [M+H]⁺ 252.0427, found 252.0428. [0205] 4-(Chloromethyl)-5-methyl-2-phenyloxazole (3b⁴): Synthesized according to general method B from compound 2b. White solids, 95%. ¹H NMR (400 MHz, CDCl₃): į 8.03-7.98 (m, 2H), 7.47-7.41 (m, 3H), 4.56 (s, 2H), 2.43 (s, 3H). [0206] 4-(Chloromethyl)-2-(2-ethylphenyl)-5-methyloxazole (3c⁵): Synthesized according to general method B from compound 2c. Colorless oil, 58%.¹H NMR (400 MHz): į 7.88 (d, J=7.78 Hz, 1H), 7.39-7.22 (m, 3H), 4.46 (s, 2H), 3.08 (q, J=7.49 Hz, 2H), 2.40 (s, 3H), 1.24 (t, J=7.49 Hz, 3H). [0207] 4-(Chloromethyl)-5-methyl-2-(naphthalen-2-yl)oxazole (3d⁶): Synthesized according to general method B from compound 2d. White solids, 77%.¹H NMR (400 MHz): į 8.51 (s, 1H), 8.10 (dd, J₁=8.59 Hz, J₂=1.69 Hz, 1H), 7.94-7.83 (m, 3H), 7.56-7.49 (m, 2H), 4.59 (s, 2H), 2.48 (s, 3H). [0208] General procedure C: synthesis of N-((2-aryl-5-methyloxazol-4-yl)methyl)amines 8VP70 (compound 1), 8VP83 (compound 3) ,8VP101 (compound 2), 8VP131 (compound 5)). To the solution of amine (2 eq) in methylene chloride (5ml/mmol) were added diisopropylethylamine (1.2 eq) and tetrabutylammonium iodide (0.05 eq). The reaction mixture was cooled down with ice-water bath and the solution of 2-aryl-4-(chloromethyl)-5-methyloxazole (1 eq) in methylene chloride (5ml/mmol) was added dropwise. The resulting mixture was stirred at ambient temperature for 12 hrs, then washed with water, brine and dried over Na₂SO₄. Solvent was evaporated and the residue was purified on reverse phase Biotage KP-C18 cartridge (water/methanol eluent) to afford the final compound. [0209] (1R,2R,3R,5S)-N-((2-(Benzo[d][1,3]dioxol-5-yl)-5-methyloxazol-4-yl)methyl)-2,6,6- trimethylbicyclo[3.1.1]heptan-3-amine (8VP70; compound 1): Synthesized according to general method C from compound 3a and (1R,2R,3R,5S)-(-)-isopinocampheylamine. White solidified oil, 48%.¹H NMR (400 MHz, CDCl₃): į 7.53 (dd, J₁=8.12 Hz, J₂=1.62 Hz, 1H), 7.45 (d, J=1.53 Hz), 6.85 (d, J=8.11 Hz, 1H), 6.01 (s, 2H), 3.65 (AB system, J_AB=13.29 Hz, 2H), 2.93-2.87 (m, 1H), 2.42-2.28 (m, 5H), 1.99-1.93 (m, 1H), 1.89-1.77 (m, 2H), 1.73-1.66 (m, 1H), 1.21 (s, 3H), 1.09 (d, J=7.26 Hz, 3H), 1.02 (d, J=9.58 Hz, 1H), 0.97 (s, 3H). ¹³C NMR (400 MHz, CDCl₃): į 159.5, 149.0, 147.9, 144.0, 134.4, 122.2, 120.6, 108.5, 106.5, 101.4, 56.2, 47.9, 44.8, 42.8, 41.8, 38.6, 36.4, 33.6, 27.8, 23.4, 21.5. HRMS calcd for C₂₂H₂₉N₂O₃ [M+H]⁺ 369.2178, found 369.2170. (c 0.71, CHCl₃).

[0210] (1R,2R,3R,5S)-2,6,6-Trimethyl-N-((5-methyl-2-phenyloxazol-4- yl)methyl)bicyclo[3.1.1]heptan-3-amine (8VP83; compound 3): Synthesized according to general method C from compound 3b and (1R,2R,3R,5S)-(-)-isopinocampheylamine. Colorless oil, 70%.¹H NMR (400 MHz, CDCl₃): į 7.99-7.94 (m, 2H), 7.44-7.35 (m, 3H), 3.70 (AB system, J_AB=13.25 Hz, 2H), 3.00-2.92 (m, 2H), 2.43-2.26 (m, 5H), 1.99-1.84 (m, 2H), 1.80-1.69 (m, 2H), 1.20 (s, 3H), 1.09 (d, J=7.16 Hz, 3H), 1.05 (d, J=9.52 Hz, 1H), 0.95 (s, 3H).¹³C NMR (400 MHz, CDCl₃): į 159.7, 144.6, 134.3, 129.7, 128.6, 127.7, 125.9, 56.1, 47.9, 44.6, 42.6, 41.7, 38.6, 36.1, 33.5, 27.8, 23.4, 21.4, 10.3. HRMS calcd for C₂₁H₂₉N₂O [M+H]⁺ 325.2280, found 325.2275. (c 1.23, CHCl₃).

[0211] (1R,2R,3R,5S)-N-((2-(2-Ethylphenyl)-5-methyloxazol-4-yl)methyl)-2,6,6- trimethylbicyclo[3.1.1]heptan-3-amine (8VP101; compound 2): Synthesized according to general method C from compound 3c and (1R,2R,3R,5S)-(-)-isopinocampheylamine. Colorless oil, 59%.¹H NMR (400 MHz, CDCl₃): į 7.86 (d, J=7.72 Hz, 1H), 7.37-7.19 (3H), 3.69 (AB system, J_AB=13.24 Hz, 2H), 3.07 (q, J=7.43 Hz, 2H), 2.98-2.90 (m, 1H), 2.42-2.29 (m, 5H), 2.00-1.93 (m, 1H), 1.91-1.66 (m, 4H), 1.27-1.18 (m, 6H), 1.09 (d, J=6.84 Hz, 3H), 1.03 (d, J=9.56 Hz, 1H), 0.96 (s, 3H). ¹³C NMR (400 MHz, CDCl₃): į 159.8, 143.9, 143.2, 134.3, 129.7, 129.6, 128.9, 126.4, 125.7, 55.9, 47.9, 44.7, 42.6, 41.7, 38.5, 36.3, 33.5, 27.8, 27.2, 23.3, 21.4, 15.4, 10.2. HRMS calcd for C₂₃H₃₃N₂O [M+H]⁺ 353.2593, found 353.2593. (c 1.1, CHCl ).

₃ [0212] N-((5-Methyl-2-(naphthalen-2-yl)oxazol-4-yl)methyl)cycloheptanamine (8VP131; compound 5). Synthesized according to general method C from compound 3c and cycloheptylamine. Solidified yellow oil, 59%. ¹H NMR (400 MHz, CDCl₃): į 8.46 (d, J=0.89 Hz, 1H), 8.07 (dd, J₁=8.57 Hz, J₂=1.70 Hz, 1H), 7.92-7.79 (m, 3H), 7.52-7.46 (m, 2H), 3.68 (s, 2H), 2.75-2.67 (m, 1H), 2.39 (s, 3H), 1.92-1.85 (m, 2H), 1.72-1.62 (m, 2H), 1.58-1.35 (m, 8H).¹³C NMR (400 MHz, CDCl₃): į 159.9, 145.1, 134.1, 133.9, 133.0, 128.5, 128.4, 127.8, 126.9, 126.6, 125.6, 124.9, 123.2, 58.3, 41.8, 34.3, 28.2, 24.4, 10.4. HRMS calcd for C₂₂H₂₇N₂O [M+H]⁺ 335.2123, found 335.2118. [0213] Synthesis of (1R,2R,3R,5S)-2,6,6-trimethyl-N-((5-methyl-2-phenyloxazol-4- yl)methyl)-N-(prop-2-yn-1-yl)bicyclo[3.1.1]heptan-3-amine (8VP192; compound 6): To 8VP83 (82 mg; 0.252 mmol) in 3 mL acetonitrile was added K₂CO₃ (104 mg; 3 eq) followed by the dropwise addition of propargyl bromide (90 mg; 3 eq) and the resulting mixture was stirred at ambient temperature for 12 hrs. The reaction mixture was partitioned between methylene chloride and water. Aqueous layer was extracted with methylene chloride, and the combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes/EtOAc=90:10) to afford the desired compound as yellow oil which solidified upon standing (77 mg; 82%).¹H NMR (400 MHz, CDCl₃): į 7.99-7.95 (m, 2H), 7.42-7.34 (m, 3H), 3.73 (AB system, J_AB=14.07 Hz, 2H), 3.52-3.41 (m, 2H), 3.40-3.32 (m, 1H), 2.42 (s, 3H), 2.33-2.25 (m, 1H), 2.22-2.13 (m, 2H), 2.12-2.03 (m, 1H), 2.01- 1.93 (m, 2H), 1.83-1.78 (m, 1H), 1.19 (s, 3H), 1.11 (d, J=6.96 Hz, 3H), 0.99 (s, 3H).¹³C NMR (400 MHz, CDCl₃): į 159.4, 145.9, 133.7, 128.5, 127.8, 81.5, 72.4, 60.2, 48.2, 45.1, 41.7, 40.8, 38.9, 33.4, 28.9, 28.0, 23.4, 21.6, 10.5. HRMS calcd for C₂₄H₃₁N₂O [M+H]⁺ 363.2436, found 363.2430. (c 0.97, CHCl₃).

[0214] Synthesis of 8VP71 (FIG.1)Error! Reference source not found.Error! Reference source not found.Error! Reference source not found.Error! Reference source not found.Error! Reference source not found. [0215] (5-Phenyl-1H-pyrazole-3-yl) methanol (5). Compound 5 was synthesized according to the literature method.⁷ White solids, 51 %.¹H NMR (400 MHz, CDCl₃): į 12.99, 12.72 (total 1H, each br s), 7.81-7.68 (m, 2H), 7.46-7.21 (m, 3H), 6.62-6.52 (m, 1H), 5.29-4.94 (m, 1H), 4.53-4.38 (m, 2H). [0216] General procedure D: synthesis of 3-(bromomethyl)-5-phenyl-1H-pyrazole (6⁸). To compound 5 (100 mg; 0.57 mmol) in 3 mL methylene chloride under cooling with ice-water bath was added CBr₄ (286 mg; 0.86 mmol) followed by portion wise addition of triphenyl phosphine (226 mg; 0.86 mmol). Reaction mixture was stirred at ambient temperature for 12 hrs and then solvent was removed in vacuo. The crude residue was purified by flash chromatography (hexanes/EtOAc=90:10) to afford previously reported compound 6 as white solids. (47 mg; 36%). 1H NMR (400 MHz, CDCl₃): į 8.32 (s, 1H), 7.63-7.58 (m, 2H), 7.44-7.31 (m, 3H), 6.59 (s, 1H), 4.51 (s, 2H). [0217] (1R,2R,3R,5S)-2,6,6-trimethyl-N-((5-phenyl-1H-pyrazol-3- yl)methyl)bicyclo[3.1.1]heptan-3-amine (8VP71; compound 11). Synthesized according to general method C from compound 6 and (1R,2R,3R,5S)-(-)-isopinocampheylamine. Colorless oil, 45%.¹H NMR (400 MHz, CDCl₃): į 7.74 (d, J=7.53 Hz, 2H), 7.40 (t, J=7.53 Hz, 2H), 7.32 (m, 1H), 6.48 (s, 1H), 3.93 (AB system, J_AB=14.12 Hz, 2H), 2.97-2.88 (m, 1H), 2.46-2.28 (m, 2H), 2.00- 1.92 (m, 1H), 1.89-1.76 (m, 2H), 1.69-1.59 (m, 1H), 1.21 (s, 3H), 1.11 (d, J=7.11 Hz), 3H), 0.94 (s, 3H).¹³C NMR (400 MHz, CDCl₃): į 149.7, 146.1, 132.6, 128.6, 127.7, 125.6, 56.4, 47.9, 45.0, 43.4, 41.7, 38.5, 36.5, 33.8, 27.7, 23.4, 21.5. HRMS calcd for C₂₀H₂₈N₃ [M+H]⁺ 310.2283, found 310.2289. (c 1.19, CHCl₃).

[0218] Synthesis of 8VP121-1 and 9VP108 (FIG.2) [0219] (2-Cyclohexyl-5-methyloxazol-4-yl)-methanol (10). Compound 10 was synthesized according to a literature method.⁹ Yellowish oil, 90 %.¹H NMR (400 MHz, CDCl₃): į 4.46 (s, 2H), 2.72-2.64 (m, 1H), 2.26 (s, 3H), 2.04-1.96 (m, 2H), 1.82-1.61 (m, 4H), 1.57-1.45 (m, 2H), 1.40- 1.13 (m, 2H). [0220] 4-(Bromomethyl)-2-cyclohexyl-5-methyloxazole (11). Synthesized according to general procedure D from compound 10. Colorless oil, 55%.¹H NMR (400 MHz, CDCl₃): į 4.34 (s, 2H), 2.73-2.64 (m, 1H), 2.25 (s, 3H), 2.05-1.98 (m, 2H), 1.82-1.75 (m, 2H), 1.70-1.64 (m, 1H), 1.57-1.47 (m, 2H), 1.38-1.18 (m, 3H).¹³C NMR (400 MHz, CDCl₃): į 166.4, 145.3, 131.0, 37.4, 30.5, 25.7, 25.6, 24.2, 10.2. HRMS calcd for C₁₁H₁₇BrNO [M+H]⁺ 258.0494, found 258.0497. [0221] (1R,2R,3R,5S)-N-((2-Cyclohexyl-5-methyloxazol-4-yl)methyl)-2,6,6- trimethylbicyclo[3.1.1]heptan-3-amine (8VP121-1; compound 4). Synthesized according to general method C from compound 11 and (1R,2R,3R,5S)-(-)-isopinocampheylamine. Colorless oil, 64%.¹H NMR (400 MHz, CDCl₃): į 3.54 (AB system, J_AB=12.99 Hz, 2H), 2.86-2.79 (m, 1H), 2.72-2.63 (m, 1H), 2.36-2.24 (m, 2H), 2.23 (s, 3H), 2.02-1.89 (m, 3H), 1.85-1.74 (m, 3H), 1.70- 1.59 (m, 3H), 1.57-1.45 (m, 2H), 1.38-1.21 (m, 3H), 1.19 (s, 3H), 1.05 (d, J=7.24 Hz, 3H), 0.99 (d, J=9.68 Hz, 1H), 0.94 (s, 3H).¹³C NMR (400 MHz, CDCl₃): į 166.2, 143.5, 131.9, 56.0, 47.9, 44.4, 43.4, 42.5, 41.7, 38.6, 37.5, 35.9, 33.4, 30.7, 30.6, 27.8, 25.8, 25.7, 23.4, 21.4, 10.1. HRMS calcd for C₂₁H₃₅N₂O [M+H]⁺ 331.2749, found 331.2745. (c 0.80, CHCl₃).

[0222] 2-Cyclohexyl-5-methyloxazole-4-carboxylic acid (12). Compound 12 was synthesized according to literature method.¹⁰ Off-white solids, 90 %.¹H NMR (400 MHz, CDCl₃): į 2.78-2.70 (m, 1H), 2.58 (s, 3H), 2.07-1.97 (m, 2H), 1.84-1.63 (m, 3H), 1.61-1.49 (m, 2H), 1.41-1.19 (m, 3H). [0223] General procedure E: 2-cyclohexyl-5-methyl-N-((1R,2R,3R,5S)-2,6,6- trimethylbicyclo[3.1.1]heptan-3-yl)oxazole-4-carboxamide (9VP108; compound 7). To compound 12 (155 mg; 0.74 mmol) in 6 mL methylene chloride under cooling with ice-water bath was added 1-hydroxybenzotriazole (120 mg; 0.89 mmol), followed by the addition of 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (170 mg; 0.89 mmol). After 10 min of stirring (1R,2R,3R,5S)-(-)-isopinocampheylamine (150 mg; 0.98 mmol) and diisopropylethylamine amine (115 mg; 0.89 mmol) were added and the resulting mixture was stirred at ambient temperature for 12 hrs. Then reaction mixture was diluted with methylene chloride/water=5mL/5mL and pH of an aqueous layer was adjusted to 3 with 1M HCl. Aqueous layer was extracted with methylene chloride three times. Combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc=90:10) to afford the desired compound as solidified white oil (208 mg; 82%).¹H NMR (400 MHz, CDCl₃): į 6.79 (d, J=9.16 Hz, 1H), 4.44-4.35 (m, 1H), 2.75-2.59 m, 2H), 2.59 (s, 3H), 2.45-2.37 (m, 1H), 2.04-1.86 (m, 3H), 1.85-1.76 (m, 2H), 1.72-1.47 (m, 7H), 1.41-1.23 (m, 2H), 1.22 (s, 3H), 1.12 (d, J=7.08 Hz, 3H), 1.07 (s, 3H), 0.95 (d, J=9.75 Hz, 1H).¹³C NMR (400 MHz, CDCl₃): į 164.9, 161.8, 151.9, 128.7, 47.8, 47.1, 45.9, 41.6, 38.5, 37.4, 37.1, 35.2, 30.5, 28.1, 25.7, 25.5, 23.3, 20.7, 11.5. HRMS calcd for C₂₁H₃₃N₂O₂ [M+H]⁺ 345.2542, found 345.2538.

(c 1.18, CHCl₃). [0224] (1R,2R,3R,5S)-2,6,6-trimethyl-N-((1-methyl-1H-benzo[d]imidazol-2- yl)methyl)bicyclo[3.1.1]heptan-3-amine (9VP51; compound 12) was synthesized according to the reported procedure.¹¹ Solidified white oil, 38 %.¹H NMR (400 MHz, CDCl₃): į 7.73-7.68 (m, 1H), 7.33-7.29 (m, 1H), 7.27-7.19 (m, 2H), 4.07 (AB system, J_AB=13.62 Hz, 2H), 3.84 (s, 3H), 3.00-2.93 (m, 1H), 2.48-2.39 (m, 1H), 2.36-2.28 (m, 1H), 1.99-1.93 (m, 1H), 1.88-1.77 (m 2H), 1.74-1.66 (m 1H), 1.20 (s, 3H), 1.11 (d, J=7.23 Hz, 3H), 0.98-0.93 (m, 4H).¹³C NMR (400 MHz, CDCl₃): į 153.0, 142.3, 136.1, 122.4, 121.8, 119.4, 109.0, 57.3, 47.8, 45.0, 44.8, 41.7, 38.5, 36.3, 33.7, 29.9, 27.8, 23.4, 21.5. HRMS calcd for C₁₉H₂₈N₃ [M+H]⁺ 298.2283, found 298.2283. (c 1.25, CHCl

3). [0225] Synthesis of 9VP128-2 (FIG.3) [0226] (2S,3R,4S,5R)-2-(3-formyl-1H-indol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (13). Compound 13 was synthesized according to reported literature method.¹² Yellow oil, 56 %. ¹H NMR (400 MHz, CDCl₃): į 10.01 (s, 1H), 8.30-8.26 (m, 1H), 7.86 (s, 1H), 7.45-7.41 (m, 1H), 7.37-7.28 (m, 2H), 5.56 (d, J=8.68 Hz, 1H), 5.49-5.38 (m, 2H), 5.24-5.16 (m, 1H), 4.33 (dd, J₁=11.78 Hz, J₂=5.74 Hz, 1H), 3.61 (t, J=11.20 Hz, 1H), 2.94 (s, 3H), 2.86 (s, 3H), 2.04 (s, 3H). [0227] (2S,3R,4S,5R)-2-(3-((((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3- yl)amino)methyl)-1H-indol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (14). To compound 13 (80 mg; 0.198 mmol) in 3 mL methylene chloride was added (1R,2R,3R,5S)-(-)- isopinocampheylamine (36 mg; 0.223 mmol) and 4A powdered sieves (100 mg). After 10 min stirring sodium triacetoxyborohydride (84 mg; 0.398 mmol) was added and the resulting mixture was stirred at ambient temperature for 12 hrs. Then reaction mixture was diluted with 6 mL methylene chloride and washed with saturated NaHCO₃ solution, brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography (EtOAc/MeOH=90/10) to afford the desired compound as colorless oil (82 mg; 77%).¹H NMR (400 MHz, CDCl₃): į 7.66 (d, J=7.88 Hz, 1H), 7.36 (d, J=7.92 Hz, 1H), 7.25-7.19 (m, 1H), 7.18 (s, 1H), 7.15-7.10 (m, 1H), 5.53-5.39 (m, 3H), 5.20-5.12 (m, 1H), 4.24 (dd, J₁=11.56 Hz, J₂=5.76 Hz, 1H), 3.94 (AB system, J_AB=13.41 Hz, 2H), 3.56 (t, J=11.04 Hz, 1H), 2.98-2.90 (m, 1H), 2.43-2.26 (m, 2H), 2.06 (s, 3H), 2.03 (s, 3H), 1.98-1.92 (m, 1H), 1.88-1.79 (m, 1H), 1.79-1.74 (m, 1H), 1.74-1.67 (m, 1H), 1.66 (s, 3H), 1.19 (s, 3H), 1.05-0.98 (m, 4H), 0.94 (s, 3H).¹³C NMR (400 MHz, CDCl₃): į 170.2, 169.8, 168.8, 136.9, 128.4, 122.9, 122.6, 120.6, 119.6, 116.0, 109.6, 83.7, 73.0, 70.6, 68.9, 65.5, 56.0, 47.9, 44.6, 42.4, 41.7, 38.6, 35.9, 33.6, 27.8, 23.5, 21.4, 20.7, 20.2. HRMS calcd for C₃₀H₄₁N₂O₇ [M+H]⁺ 541.2914, found 541.2914.

(c 1.60, CHCl₃). [0228] (2S,3R,4S,5R)-2-(3-((((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3- yl)amino)methyl)-1H-indol-1-yl)tetrahydro-2H-pyran-3,4,5-triol (9VP128-2; compound 9). [0229] To 14 (60 mg; 0.111 mmol) in MeOH/DCM=1mL/0.5mL under cooling with ice-water bath was added 1M NaOMe (0.4 mL; 3.6 eq). The mixture was slowly warmed up to room temperature and neutralized with saturated solution of NH₄Cl after 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography in water/MeOH=90/10-0/100 gradient to provide the desired compound as white solids. (27 mg; 59%). %).¹H NMR (400 MHz, CD₃OD): į 7.74 (d, J= 7.76 Hz, 1H), 7.69 (s, 1H), 7.60 (d, J=8.08 Hz, 1H), 7.28 (t, J=7.46 Hz, 1H), 7.21 (t, J=7.62 Hz, 1H), 5.49 (s, 1H), 5.43 (d, J=9.28 Hz, 1H), 4.46 (AB system, J_AB=13.82 Hz, 2H), 3.99 (dd, J₁=11.22 Hz, J₂=5.10 Hz), 3.90 (t, J=8.98 Hz, 1H), 3.74-3.65 (m, 1H), 3.60-3.46 (m, 3H), 2.70-2.59 (m, 1H), 2.52-2.41 (m, 1H), 2.16-2.05 (m, 2H), 2.01-1.93 (m, 1H), 1.92-1.86 (m, 1H), 1.32-1.24 (m, 4H), 1.19-1.11 (m, 4H), 0.95 (s, 3H).¹³C NMR (400 MHz, CD₃OD, DEPTQ135 with quaternary carbons pulse sequence): į peaks down (CH, CH₃): 128.9, 123.9, 122.0, 119.3, 112.2, 87.5, 79.1, 73.6, 71.1, 48.7, 42.5, 42.3, 27.9, 23.8, 21.1; peaks up (C, CH₂): 138.2, 129.0, 106.9, 69.6, 41.5, 39.8, 33.9, 32.9, 41.5, 39.8, 33.9, 32.9. HRMS calcd for C₂₄H₃₅N2O₄ [M+H]⁺ 415.2597, found 415.2580 (c 1.83, EtOH).

[0230] Synthesis of 9VP173 (FIG.4) [0231] 1-Cycloheptyl-1H-benzo[d]imidazole-2-carbaldehyde (19). Compound 19 was synthesized similarly to reported literature method.¹³ Solidified white oil, 68 %.¹H NMR (400 MHz, CDCl₃): į 10.09 (s, 1H), 7.91-7.88 (m, 1H), 7.63-7.59 (m, 1H), 7.41-7.32 (m, 2H), 5.59 (m, 1H), 2.39-2.28 (m, 2H), 2.06-1.97 (m, 2H), 1.90-1.60 (m, 8H).¹³C NMR (400 MHz, CDCl₃): į 185.1, 145.5, 143.5, 135.3, 126.1, 123.6, 122.5, 113.6, 58.2, 33.9, 27.4, 25.8. HRMS calcd for C₁₅H₁₉N₂O [M+H]⁺ 243.1497, found 243.1494. [0232] (1R,2R,3R,5S)-N-((1-Cycloheptyl-1H-benzo[d]imidazol-2-yl)methyl)-2,6,6- trimethylbicyclo[3.1.1]heptan-3-amine (9VP173; compound 8). To compound 19 (144 mg; 0.594 mmol) in 6 mL methylene chloride was added (1R,2R,3R,5S)-(-)-isopinocampheylamine (118 mg; 0.772 mmol) and 4 A powdered sieves (140 mg). After 10 min stirring sodium triacetoxyborohydride (252 mg; 1.190 mmol) was added and the resulting mixture was stirred at ambient temperature for 12 hrs. Then reaction mixture was diluted with 6 mL methylene chloride and washed with saturated NaHCO₃ solution, brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc=70/30 containing 0.1% triethylamine) to afford the desired compound as colorless oil (170 mg; 76%).¹H NMR (400 MHz, CDCl₃): į 7.71-7.66 (m, 1H), 7.50-7.44 (m, 1H), 7.20-7.15 (m, 2H), 4.76-4.68 (m, 1H), 4.04 (AB system, J_AB=13.36 Hz, 2H), 2.98-2.91 (m, 1H), 2.47-2.39 (m, 1H), 2.38-2.27 (m, 3H), 2.07-1.94 (m, 3H), 1.89-1.77 (m, 4H), 1.75-1.58 (m, 7H), 1.21 (s, 3H), 1.11 (d, J=7.21 Hz, 3H), 0.96 (s, 1H), 0.96 (d, J=9.32 Hz, 1H).¹³C NMR (400 MHz, CDCl₃, DEPTQ135 with quaternary carbons pulse sequence): į peaks down (CH, CH₃): 121.9, 121.4, 119.7, 58.2, 57.3, 47.9, 45.3, 41.8, 27.8, 23.4, 21.6; peaks up (C, CH₂): 152.3, 143.0, 133.9, 45.7, 38.6, 36.5, 33.8, 33.7, 27.6, 27.5, 26.1, 26.0. HRMS calcd for C₂₅H₃₈N₃ [M+H]⁺ 380.3066, found 380.3074.

[0233] Synthesis of 10VP91 (FIG.5) [0234] Cyclohexylbenzene-1,2-diamine (20). Compound 20 was synthesized analogously to reported literature method.^{14, 15} Red solids, 95 %.¹H NMR (400 MHz, CDCl₃): į 6.80-6.74 (m, 1H), 6.72-6.59 (m, 3H), 3.25-3.16 (m, 1H), 2.09-2.00 (m, 2H), 1.80-1.70 (m, 2H), 1.68-1.59 (m, 1H), 1.42-1.29 (m, 2H), 1.28-1.12 (m, 3H). [0235] Methyl 3-((2-(cyclohexylamino)phenyl)amino)-3-oxopropanoate (21). Synthesized according to general method E from compound 20 and methyl hydrogen malonate. Off-white solids, 40%. Compound 21 was used in the next step without purification. ¹H NMR (400 MHz, CDCl₃): į 8.49 (br s, 1H), 7.37 (dd, J₁=7.72 Hz, J₂=1.28 Hz), 7.11-7.06 (m 1H), 6.81-6.70 (m, 2H), 3.79 (s, 3H), 3.50 (s, 2H), 3.26-3.17 (m, 1H), 2.06-1.97 (m, 2H), 1.80-1.70 (m, 2H), 1.67-1.57 (m, 1H), 1.41-1.15 (m, 5H). [0236] Methyl 2-(1-cyclohexyl-1H-benzo[d]imidazole-2-yl)acetate (22). A solution of crude 21 (100 mg; 0.341 mmol) in 1.5 mL acetic acid was stirred at 70° C for 12 hrs. After cooling to room temperature, volatiles were evaporated under reduced pressure and the residue was partitioned between methylene chloride and NaHCO_3sat. Aqueous phase was extracted with methylene chloride three times and the combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc=50/50-10/90) to afford the desired compound as colorless oil (84 mg; %).¹H NMR (400 MHz, CDCl₃): į 7.73-7.68 (m, 1H), 7.58-7.53 (m, 1H), 7.23-7.17 (m, 2H), 4.18-4.08 (m, 1H), 4.05 (s, 2H), 3.71 (s, 3H), 2.29-2.16 (m, 2H), 2.00-1.89 (m, 4H), 1.83-1.75 (m, 1H), 1.49-1.27 (m, 3H).¹³C NMR (400 MHz, CDCl₃): į 168.9, 147.1, 143.2, 133.8, 122.2, 121.7, 120.0, 112.2, 57.1, 52.6, 35.1, 31.2, 26.1, 25.4. HRMS calcd for C₁₆H₂₁N₂O₂ [M+H]⁺ 273.1603, found 273.1608. [0237] 2-(1-Cyclohexyl-1H-benzo[d]imidazole-2-yl)-N-((1R,2R,3R,5S)-2,6,6- trimethylbicyclo[3.1.1]heptan-yl)acetamide (10VP91; compound 10). A mixture of 22 (84 mg; 0.308 mmol) and LiOH (18 mg; 0.771 mmol) in tetrahydrofuran/water=0.5 mL/0.5 mL was stirred at room temperature for 1.5 hrs. Then 2M HCl in ether (0.5 mL;1.00 mmol) was added to the reaction mixture and it was concentrated and dried in vacuo. To this residue in 3 mL methylene chloride under cooling with ice-water bath was added 1-hydroxybenzotriazole (63 mg; 0.465 mmol), followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (89 mg; 0.465 mmol). After 10 min of stirring (1R,2R,3R,5S)-(-)-isopinocampheylamine (62 mg; 0.403 mmol) and diisopropylethylamine amine (80 mg; 0.619 mmol) were added and the resulting mixture was stirred at ambient temperature for 12 hrs. Then reaction mixture was diluted with methylene chloride and water and pH of an aqueous layer was adjusted to 8 with NaHCO_3sat. Aqueous layer was extracted with methylene chloride three times. Combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography (EtOAc, EtOAc/MeOH=90:10) to afford the desired compound as white solids (69 mg; 57%).¹H NMR (400 MHz, CDCl₃): į 7.73-7.67 (m, 1H), 7.59-7.54 (m, 1H), 7.27-7.15 (3H), 4.39-4.29 (m, 1H), 4.28-4.19 (m, 1H), 3.91 (s, 3H), 2.56-2.47 (m, 1H), 2.38-2.299m, 1H), 2.28- 2.13 (m, 2H), 2.00-1.85 (m, 5H), 1.84-1.69 (m, 3H), 1.55-1.41 (m, 3H), 1.38-1.27 (m, 1H), 1.18 (s, 3H), 1.03 (d, J=7.28 Hz, 3H), 1.00 (s, 3H), 0.82 (d, J=9.64 Hz, 1H).¹³C NMR (400 MHz, CDCl₃): į 166.0; 148.7; 142.7; 133.6; 122.1; 121.7; 119.5; 112.1; 56.5; 47.9; 47.6; 45.7; 41.4; 38.2; 36.7; 36.5; 34.8; 31.2; 27.8; 25.9; 25.2; 23.3; 20.6. HRMS calcd for C₂₅H₃₆N₃O [M+H]⁺ 394.2858, found 394.2858. (c 0.93, CHCl₃).

[0238] Synthesis of 9VP40 (FIG.6) [0239] tert-Butyl (3-oxopropyl)carbamate (24). Compound 24 was synthesized according to the literature method.¹⁶ Colorless oil, 97%.¹H NMR (400 MHz, CDCl₃): į 9.79 (s, 1H), 4.86 (1H, br. s), 3.42-3.37 (m, 2H), 2.68 (t, J=5.8 Hz, 2H), 1.45 (s, 9H). [0240] tert-Butyl (3-(prop-2-yn-1-yl((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3- yl)amino)propyl)carbamate (26). To compound 24 (115 mg; 0.664 mmol) in 5 mL methylene chloride was added (1R,2R,3R,5S)-(-)-isopinocampheylamine (122 mg; 0.797 mmol) and 4 A powdered sieves (80 mg). After 10 min stirring sodium triacetoxyborohydride (281 mg; 1.330 mmol) was added and the resulting mixture was stirred at ambient temperature for 12 hrs. Then reaction mixture was diluted with 6 mL methylene chloride and washed with saturated NaHCO₃ solution, brine, dried over Na₂SO₄ and concentrated. The residue in 5 mL acetonitrile was added K₂CO₃ (276 mg; 1.990 mmol) followed by the dropwise addition of propargyl bromide (237 mg; 1.990 mmol) and the resulting mixture was stirred at ambient temperature for 12 hrs. The reaction mixture was partitioned between methylene chloride and water. Aqueous layer was extracted with methylene chloride, and the combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes/EtOAc=90/10-70/30) to afford the desired compound as colorless oil (200 mg; 87%).¹H NMR (400 MHz, CDCl₃): į 5.40 (br s, 1H), 3.47-3.34 (m, 2H), 3.31-3.09 (m, 3H), 2.77-2.68 (m, 1H), 2.67-2.58 (m, 1H), 2.31-2.22 (m, 1H), 2.18-2.14 (m, 1H), 2.12-2.03 (m, 1H), 1.94-1.84 (m, 2H), 1.83-1.74 (m, 2H), 1.68-1.58 (m, 2H), 1.41 (s, 9H), 1.18 (s, 3H), 1.08 (d, J=7.02 Hz, 3H), 0.98 (s, 3H), 0.85 (d, J=9.86 Hz, 1H).¹³C NMR (400 MHz, CDCl₃): į 156.1, 81.5, 78.7, 72.0, 60.8, 48.1, 47.4, 41.7, 40.8, 40.3, 39.9, 39.1, 33.4, 28.5, 28.2, 28.0, 27.0, 23.4, 21.4. HRMS calcd for C₂₁H₃₇N₂O₂ [M+H]⁺ 349.2855, found 349.2853.

(c 0.75, CHCl₃). [0241] N¹-(Prop-2-yn-1-yl)-N¹-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3- yl)propane-1,3-diamine (27). To compound 26 (186 mg; 0.533 mmol) in 5 mL methylene chloride was added 4M HCl in 1,4-dioxane (1.33 mL, 10 eq) and the resulting mixture was stirred at ambient temperature for 12 hrs. Reaction mixture was diluted with methylene chloride and water and pH of an aqueous layer was adjusted to 9 with aqueous ammonia. Aqueous layer was extracted with methylene chloride three times. Combined organic layers were dried over Na₂SO₄ and concentrated. The residue was dried in vacuo to afford the desired compound as yellow oil (132 mg, quant). Compound 27 was used in the next step without purification.¹H NMR (400 MHz, CDCl₃): į 3.48-3.36 (m, 2H), 3.29-3.21 (m, 1H), 2.79-2.67 (m, 3H), 2.63-2.55 (m, 1H), 2.30-2.22 (m, 1H), 2.16-2.13 (m, 1H), 2.11-2.03 (m, 1H), 1.94-1.74 (m, 4H), 1.63-1.55 (m, 2H), 1.18 (s, 3H), 1.07 (d, J=7.00 Hz, 3H), 0.98 (s, 3H), 0.85 (d, J=9.85 Hz, 1H). [0242] 2,3,4,5,6-Pentafluoro-N-(3-(prop-2-yn-1-yl((1R,2R,3R,5S)-2,6,6- trimethylbicyclo[3.1.1]heptan-3-yl)amino)propyl)benzamide (28). To pentafluorobenzoic acid (68 mg; 0.320 mmol) in 3 mL methylene chloride was added 1-hydroxybenzotriazole (48 mg; 0.353 mmol), followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg; 0.353 mmol). After 10 min of stirring, crude compound 27 (79 mg; 0.320 mmol) was added and the resulting mixture was stirred at ambient temperature for 12 hrs. Then reaction mixture was diluted with methylene chloride and water and pH of an aqueous layer was adjusted to 8 with NaHCO_3sat. Aqueous layer was extracted with methylene chloride three times. Combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc=90/10-70/30) to afford the desired compound as yellow oil (98 mg; 70%).¹H NMR (400 MHz, CDCl₃): į 8.06 (br s, 1H), 3.86-3.76 (m, 1H), 3.45-3.25 (m, 4H), 2.88-2.79 (m, 1H), 2.75-2.67 (m, 1H), 2.31-2.23 (m, 1H), 2.07-1.98 (m, 2H), 1.94-1.67 (m, 6H), 0.95 (s, 3H), 0.91 (d, J=7.03 Hz, 3H), 0.78 (d, J=9.99 Hz, 1H). ¹³C NMR (400 MHz, CDCl₃): į 156.8; 143.8 (dm, J_C-F=251.8 Hz), 141.9 (dm, J_C-F=256.5 Hz), 137.44 (dm, J_C-F=255.2 Hz), 112.5 (br t, J_C-F=20.9 Hz), 80.7; 72.0; 60.0; 48.5; 47.9; 41.5; 40.5; 40.4; 39.1; 33.2; 27.9; 27.3; 25.2; 23.3; 20.9.¹⁹F NMR (400 MHz, CDCl₃): į -140.60 (m, 2F), -152.20 (br t, J=20.56 Hz, 1F), -160.77 (m, 2F). HRMS calcd for C₂₃H₂₈N₂OF₅ [M+H]⁺ 443.2122, found 443.2127. (c 1.62, CHCl₃).

[0243] 4-Azido-2,3,5,6-tetrafluoro-N-(3-(prop-2-yn-1-yl((1R,2R,3R,5S)-2,6,6- trimethylbicyclo[3.1.1]heptan-3-yl)amino)propyl)benzamide (9VP40; PRP). To compound 28 (59 mg; 0.133 mmol) in 0.5 mL of dimethylformamide were added sodium azide (10.4 mg; 0.160 mmol) and tetrabutylammonium azide (3.8 mg; 0.013 mmol). Reaction flask was wrapped with tin foil and reaction mixture was stirred at ambient temperature for 12 hrs. Then reaction mixture was poured onto ice/water mixture and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na₂SO₄ and concentrated. The residue was immediately purified by flash chromatography (hexanes/EtOAc=80/20-70/30) to afford the desired compound as clear oil (30 mg; 48%). The product was stored under nitrogen in air-tight container at -20°C.¹H NMR (400 MHz, CDCl₃): į 7.95 (br s, 1H), 3.83-3.74 (m, 1H), 3.46-3.27 (m, 4H), 2.88-2.79 (m, 1H), 2.76- 2.68 (m 1H), 2.31-2.23 (m, 1H), 2.08-1.98 (m, 2H), 1.95-1.68 (m, 6H), 1.18 (s, 3H), 0.98 (s, 3H), 0.93 (d, J=7.04 Hz, 3H), 0.78 (d, J=10.00 Hz, 1H).¹⁹F NMR (400 MHz, CDCl₃): į -140.79 (m, 2F), -150.91 (m, 2F). ¹³C NMR (400 MHz, CDCl₃): į 157.2; 143.9 (doublet of multiplets, J_C-F=252.0 Hz), 140.4 (doublet of multiplets, J_C-F=251.7 Hz), 121.3 (br t, J_C-F=12.3 Hz), 112.5 (t, J_C-F=19.5 Hz), 80.7, 72.2, 60.2, 48.5, 47.9, 41.5, 40.6, 40.5, 40.1, 39.1, 33.2, 27.9, 27.5, 25.2, 23.3, 21.0. HRMS calcd for C₂₃H₂₈N₅OF₄ [M+H]⁺ 466.2230, found 466.2237. 4 (c 1.52, CHCl₃).

[0244] Computer-aided molecular design, synthesis, and characterization [0245] All the computer-aided molecular design studies were performed in SZMAP/GamePlan³⁷ and vBrood³⁸ modules in OpenEye software and Molecular Operating Environment, MOE.³⁹ The 3D structures of TGR in biological assembly (i.e., dimers) PDB:6FP4 (https://www.rcsb.org/structure/6FP4) and PDB:6FTC (https://www.rcsb.org/structure/6FTC) were downloaded from PDB. The proteins were subjected to the Structure Preparation procedure followed by addition of hydrogen atoms using the Protonate 3D application⁷¹ with all the default settings in MOE. The energy of the resulting structure was minimized utilizing AMBER14:EHT forcefield in MOE^{72, 73} with all the settings set default until the RMS gradient reached 0.001 kcal/mol/ Ų. The resulting ligand-proteins complexes were aligned to match the position of the co-crystallized small molecule fragments. At this step, the water molecules found in the X-ray structures were removed. The co-crystallized fragments found in sub-pockets A-C and the protein were used as input for the SZMAP, Gameplan, and vBrood applications and visualization in MOE. To facilitate the calculations and analysis, an artificial chimera molecule was built using the X-ray fragments found in subpockets A-C in PDB:6FP4 (https://www.rcsb.org/structure/6FP4) and PBD:6FTC (https://www.rcsb.org/structure/6FTC) and connected by a short CH₂CH₂ linker. The resulting complex was additionally minimized as described above. The default settings for the SZMAP and Gameplan applications were used in all the calculations. SZMAP was used for analysis of energetics of stabilizing and destabilizing effects of water. The szmap command with keyword -stbl resulted in complex, apo, and ligand grids. Additional grids were generated using - results_set max keyword. To break-out the region displaced by the ligand, the grid_comp command was run on the results of the previous step. WaterColor and WaterOrientation VIDA extensions were applied to the results of SZMAP calculations to visualize the regions that favor polar and non-polar substituents. The water probes position, orientation, and energetics were determined for the chimera-TGR complex. The -1.5 kcal/mol and 0.75 kcal/mol cutoffs were used for the lower and upper cutoffs in the “Exclude free energy range” settings, the water molecules were visualized by energy. The grid point pruning was set to “more”. The positions of the probes and the free energy values were exported in a PDB file and visualized in Pymol.⁷⁴ The S. mansoni X-ray structures of TGR 2X99 [httpshttps://www.rcsb.org/structure/3X99], 2X8G [https://www.rcsb.org/structure/2X8G], 2X8H [https://www.rcsb.org/structure/2X8H],⁷⁵6FP4 [https://www.rcsb.org/structure/6FP4], 6FTC [https://www.rcsb.org/structure/6FTC],³³ 6ZST [https://www.rcsb.org/structure/6ZST], 6ZP3 [https://www.rcsb.org/structure/6ZP3], 6ZLP [https://www.rcsb.org/structure/6ZLP], 6FMU [https://www.rcsb.org/structure/6FMU], 6ZLB [https://www.rcsb.org/structure/6ZLB], 7B02 [https://www.rcsb.org/structure/7B02], 7NPX [https://www.rcsb.org/structure/7NPX],³⁴ 2V6O [https://www.rcsb.org/structure/2V6O],⁷⁵6RTJ [https://www.rcsb.org/structure/6RTJ], 6RTO [https://www.rcsb.org/structure/6RTO], 6RTM [https://www.rcsb.org/structure/6RTM],³⁶ 3H4K [https://www.rcsb.org/structure/3H4K]⁷⁶ were downloaded from PDB, aligned in MOE, water molecules in the doorstop pocket were extracted and saved for visualization in Pymol. The same color scheme was used to visualize the water probes. Gameplan was used to generate a set of hypotheses for polar and non-polar ligand modifications. All the settings in Gameplan were set default. The fragment library for the vBrood application was prepared using the CHOMP application to fragment the ChEMBL database⁷⁷ version CHEMBL25.⁷⁸ In the CHOMP application, no additional parameters were used except for the minimal required to run it (i.e. -in and -out). The total number of fragments in the resulting database was 17,697,078. vBrood was run to replace the piperazine portion of the molecule using the default settings in vBrood. [0246] Photolabeling of TGR with PRP [0247] TGR (1 μM) or SmHDAC8 (1 μM) was incubated at concentrations of either 5 or 50 μM PRP with or without 100 μM NADPH totaling eight samples. The photocrosslinking and CuAAC click biotinylation were performed as previously described by our group.⁵² After resolving samples on SDS-PAGE and nitrocellulose membrane transfer, western blot normalization was performed with the Licor Revert™ 700 Total Protein Stain Kit as described in their protocol. Protein was finally imaged with the Licor IRDye® 800CW streptavidin on the Odyssey Sa imager. [0248] Enzyme inhibition, kinetics, ex vivo and in vivo activity [0249] Enzyme preparation and activity determination: Recombinant TGR, human TrxR1, B. malayi (Bm)TrxR and human GR proteins were expressed and purified as described.^{20, 69, 79} The codon optimized sequence for P. falciparum (PfTrxR, https://www.ncbi.nlm.nih.gov/protein/CAA60574.1/) with an N-terminal 6-His tag was synthesized and inserted into pET15b (GenScript) and expressed in BL21 (DE3) cells and purified as described for human GR.²⁰ TGR and TrxR enzyme inhibition assays were performed in triplicate at 25 °C as described²⁰ in 0.1 M potassium phosphate (pH 7.4), 10 mM EDTA, 100 μM NADPH and 0.01% Tween-20. TGR, human TrxR1 and BmTrxR (all at 4 nM) and PfTrxR (50 nM) were preincubated with the compounds for 15 min. The reaction was started with addition of an equal volume of DTNB (6 mM) and NADPH (100 μM) and the increase in A₄₁₂ during the first 3 min was recorded. To determine inhibition of GR, GR (120 pM) was added to an assay mixture (100 ^M NADPH, 0.1 M potassium phosphate (pH 6.9), 200 mM KCl, and 1 mM EDTA). The reaction was preincubated for 15 min. Activity was initiated with the addition of 1 mM GSSG and 100 ^M NADPH and initial rates of NADPH oxidation were monitored at 340 nm. The reactions were done in triplicate. The IC₅₀ was calculated in GraphPad Prism. [0250] Thermal Shift Assay (TSA): Samples were prepared by using a final concentration of 0.25 mg/ml TGR diluted in TGR reaction buffer to the desired volume. To evaluate reduced TGR, 500 μM NADPH was added. Inhibitors were added at a concentration dependent on the compound’s IC₅₀, from 125-500 μM. The mixtures containing inhibitors 1-5 were incubated for 6 h and for 30 min for treatments with 6-8 at room temperature. After the preincubation period, 20 μL samples were pipetted into a BioRad un-skirted PCR 96 well plate and sealed with MicroAmp^TM Optical Adhesive film. The plate was then centrifuged for 5 min at 1000 u g. TSA was carried out using a BioRad CFX Connect qPCR instrument with a melt curve setting of 25 - 95 ^, in increments of 0.5 ^/10 seconds. The SYBR green channel was used to detect fluorescence as the wavelength of flavin fluorescence overlaps with that of SYBR green. BioRad CFX Maestro 5.2 was used to analyze TSA data. [0251] NADPH Dependence of Inhibition: TGR was incubated at room temperature with inhibitor in the presence or absence of 100 μM NADPH for 15 min. DTNB (3 mM) and NADPH (100 μM) were added, and the reaction was monitored at A₄₁₂ for 5 min to determine reaction rate. The assay was done in triplicate. [0252] Time Dependence of Inhibition: TGR was incubated at room temperature (up to 6 h) and at 4 ^ for 6 to 24 h with 50 μM inhibitor and 100 μM NADPH for the indicated times. Then DTNB (3 mM) and NADPH (100 μM) were added, and the reaction was monitored at A₄₁₂ for 5 min. The assay was done in triplicate. [0253] Reversibility by jump dilution: A reaction of 370 nM TGR, 100 μM NADPH, and 250 μM inhibitor was incubated for 15 min at room temperature. A 100x dilution of the reaction was made and the activity was determined immediately and after 60 min. The inhibition of 3.7 nM TGR with 250 μM inhibitor, 100 μM NADPH, and a 15 min pre-incubation at RT was measured to compare to the inhibition after the jump dilution. [0254] NADPH Competition: Master mixes with varying concentrations of NADPH were made, each with 2 nM TGR in reaction buffer. Inhibitor (2 μl) was added to a 96 well microplate in triplicate for each NADPH and inhibitor concentration, and 192 μl of the master buffer was added to each well. The reaction incubated for 15 minutes and 6 μl of 50 mM DTNB was added to each well. The kinetic rate was measured at A₄₁₂ for 5 min. [0255] Superoxide Production: The production of superoxide by TGR was determined by monitoring reaction of superoxide with pyrogallol red.⁸⁰ Briefly, a 1 ml reaction mix (500 nM TGR, 100 μM NADPH, and 20-50 μM inhibitor) was incubated at room temperature for 30 min for fast inhibitors, or 2 h for slow inhibitors. For irreversible inhibitor controls TRi-1, Stattic, and AF, the samples were desalted using a Zeba spin desalting column.100 μL of sample was combined with pyrogallol buffer with and without superoxide dismutase (SOD) (50 μM pyrogallol red, 300 μM NADPH; ± 10 units SOD). The reaction was measured at A₃₄₀ and A₅₄₀ simultaneously for 2 h. [0256] NADPH Consumption: TRi-1, Stattic (both at 50 μM) and AF (20 μM) were incubated with 1 ml of 500 nM TGR and 100 μM NADPH in TGR reaction buffer for 30 min. The samples were desalted using a Zeba spin desalting column (Thermo Fisher Scientific) and 100 μl of the desalted sample was combined with 100 μl of 100 μM NADPH. NADPH consumption was monitored at 340 nm in triplicate. Compounds 1, 4, 6, and 7 (50 μM) were tested in the same fashion without the desalting step and with a first incubation step of 30 min for 6 and 7 and 2 h for 1 and 4. [0257] Evaluation of Schistosomicidal Activity [0258] Preparation of NTS [0259] Oncomelania hupensis subsp. hupensis, Chinese strain, infected with S. japonicum, Chinese strain, and Biomphalaria glabrata, strain NMRI, infected with S. mansoni, strain NMRI, were provided by the NIAID Schistosomiasis Resource Center for distribution through BEI Resources, NIAID, NIH. After infections were patent, snails were exposed to bright light for 1 hr to obtain cercariae. Cercariae were mechanically transformed to schistosomula.⁵⁴ Briefly, cercariae were placed on ice for 30 min and then centrifuged at 350 u g for 10 mins. The supernatant was decanted and 2 ml of serum-free M199 medium was added to cercarial pellets and vortexed for 1 min until cercarial tails were detached. NTS were purified by layering on 4 °C Percoll gradient suspension containing Eagle’s minimum essential medium, penicillin- streptomycin (10,000 U per ml penicillin/10,000 U per ml streptomycin), and 1 M HEPES in 0.85% NaCl with cercariae suspension and centrifuged at 500 u g for 15 min. Cercarial pellets were resuspended and washed thrice in serum-free M199 medium and collected at 100 u g for 5 min. NTS (240) were transferred to U-bottom 96 well assay plates containing 200 μl of M199 medium supplemented with 5.5 mM D-glucose, penicillin-streptomycin and 5% heat inactivated fetal bovine serum and incubated at 37 °C in a 5% CO₂ incubator overnight. [0260] Preparation of juvenile and adult worms [0261] All animal studies at Rush University Medical Center were approved by the Institutional Animal Care and Use Committee of the Rush University Medical Center (Department of Health and Human Services animal welfare assurance number A-3120í01) with protocol ID: 20-069. Three-week old, female Swiss-Webster mice obtained from the Charles River were housed in the Comparative Research Center of Rush University Medical Center. Mice were infected by percutaneous tail exposure to about 200 S. mansoni or 50 S. japonicum cercaria for adult worms and about 1000 cercaria for juvenile S. mansoni worms through natural transdermal penetration of the cercariae for 1 h.⁸¹ Mice were euthanized three-and seven-weeks post infection for juvenile and adult worms, respectively, using a lethal dose of 0.018 ml of Euthasol and 5.85 mg/ml heparin to prevent blood coagulation (injection volume of 400 μl). Perfusion was performed by flushing pre-warmed RPMI containing phenol red and L-glutamine through a 25- and 3/8-gauge needle placed into the aorta attached to Tygon tubing aided by the Masterflex L/S perfusion pump as described.⁸¹ Juvenile and adult worms were carefully washed in phenol red free RPMI medium and subsequently incubated in phenol red free RPMI medium supplemented with 5.5 mM D- glucose, penicillin-streptomycin and 5% heat inactivated fetal bovine serum and at 37 °C in a 5% CO₂ incubator overnight. [0262] Schistosomicidal activity of compounds against NTS, juvenile and adult worms [0263] DMSO formulated compounds were diluted with phenol red free M199 medium or RPMI medium for NTS or juvenile and adult worms, respectively, at < 1% DMSO final concentrations. NTS, juvenile and adult worms from overnight cultures were tested against compounds in triplicate. Controls were treated with DMSO alone or 5 μM AF as a positive control in appropriate medium.¹⁸ Worm viability was assessed at 24 or 72 h by measuring ATP content of worms using Cell Titer Glo Assay (Promega) as described.⁸² Schistosome viabilities in the presence of the compounds were assessed using this formula: % Viability = Averages of Test / Averages of DMSO Control x 100. [0264] Channel blockers enhanced schistosomicidal activity of compounds. [0265] To assess the involvement of efflux pumps in the diminished schistosomicidal activity observed in selected compounds (7-9) against S. mansoni adult worms, we treated adult worms with these compounds in the presence of channel blockers Tariquidar (T, 10 PM) and Ko143 (K, 10 PM) as described above. [0266] Phenotypic Assessment of PZQ activity on NTS [0267] About 200 NTS incubated at 37 °C in a 5% CO₂ incubator overnight were exposed to different concentrations of PZQ (1, 5, 10, 20, 30, 40 and 50 μM) and control without treatment for 24 h in triplicate. Worm images were acquired using Keyence BZ-X800 microscope and PZQ activity evaluated phenotypically.⁶² NTS viability was assessed by scoring worms based on morphological changes and motility. Viability scores of 3 = motile, no changes to morphology and transparency, 2 = reduced motility and/or some damage to tegument as well as reduced transparency and increased granularity, 1 = severe reduction of motility and/or damage to tegument with high opacity and high granularity, and 0 = dead. The effect of PZQ on NTS was determined using the formula % Effect = 100 – (Average (Test) x 100 / Average (Control)) and LD₅₀ determined in GraphPad Prism. [0268] Cytotoxicity in Mammalian Cells. [0269] Vero cells (African Green Monkey Kidney cells, ATCC CCL-81) were grown in Dulbecco's modified Eagle's medium (DMEM) containing glucose, L-glutamine and sodium pyruvate and supplemented with 10% fetal bovine serum and 1X penicillin–streptomycin (Sigma) at 37 °C in culture flasks (TPT-90025) until confluent growth was attained. Vero cells were detached from the flasks by treatment with trypsin (0.5 mg/ml)/EDTA (0.2 mg/ml) in PBS for 5 min at 37 °C. Detached cells were suspended in the modified DMEM medium and seeded at 10⁴ cells/well in 96-well microtiter plates (Costar, Corning) and incubated in the presence of 5% CO₂ at 37 °C for 24ௗh. Following overnight incubation, formulated DMSO-compound stock solutions were diluted with DMEM at < 1% DMSO final concentrations. Vero cells were treated with different concentrations of compounds with DMSO as control and incubated in the presence of 5% CO₂ at 37 °C for 24ௗh. Vero cells treated similarly with different concentrations of PZQ, MZM and AF (Cayman Chemicals) were used as positive controls. Vero cell viability was assessed at 24 h by measuring ATP content using Cell Titer Glo Assay as described.⁸³ [0270] Assessment of Schistosomicidal Activity in Mice [0271] To assess the efficacy of the compounds in vivo against juvenile and adult worms, five female Swiss-Webster mice were randomly assigned for the control and experiment groups using a randomization tool embedded in GraphPad Prism. Mice were percutaneously exposed for 1 h to about 80 S. mansoni cercariae. Three- and six-weeks post infection, respectively, for juvenile and adult worms, mice were treated depending on their weight with formulations of the compounds, while the control mice received only the vehicle. Compounds were formulated with 10% DMSO and 10% Tween-80, and vortexed to obtain a uniform mixture. The mixture was sonicated twice for 5 min each time using a digital ultrasonic cleaner heated to 50 °C. Sodium chloride 0.9% (80% normal saline) was added to the mixture, briefly vortexed and sonicated one more time using the same conditions as previous. The investigators were blinded by which group of mice received a treatment and the vehicle, as injection was done by technicians from the Comparative Research Center of Rush University Medical Center. Using a 26 G, Ǫ in intradermal bevel needle, each mouse was administered intraperitoneally with 100 μl of the formulated compound suspension at 50 mg/kg, 100 mg/kg and 200 mg/kg. Mice treated three weeks post infection for juvenile worms were euthanized three weeks post treatment and mice treated six weeks post infection were euthanized one week post treatment with 0.018 ml of Euthasol and 5.85 mg/ml heparin and perfused.⁸¹ The mesenteric and hepatic portal veins of the mice were carefully scanned under the microscope to extract any remaining S. mansoni adult worms and worm burdens were determined. Egg burden was determined by weighing 50 mg of liver tissue from each of treated and control mice. The liver tissues were digested with 5% KOH at 37 °C overnight and washed twice with PBS. The number of eggs per 50 mg of liver tissue was determined using a Keyence BZ-X800 microscope using the egg autofluorescence.⁸⁴ [0272] TGR inhibition in worms: TRFS-Green fluorescence quantification and GSH/GSSG determination [0273] TGR inhibition in NTS was assessed using a fluorescent probe TRFS-Green.⁴³ NTS prepared as previously described and cultured in M199 supplemented with 5.5 mM D-glucose, penicillin-streptomycin and 5% heat inactivated fetal bovine serum were incubated at 37 °C in a clear bottom flat well plate in a 5% CO₂ incubator overnight. To inhibit TGR activity, NTS were treated with compounds (30 μM) or auranofin (5 μM) for 2 h. NTS were further treated with TRFS- Green (10 μM) for additional 4 h and rinsed with M199 medium to remove residual TRFS-Green. Fluorescence images were obtained using Keyence BZ-X800. The quantification of fluorescence intensity upon the uptake of TRFS-Green by NTS was performed by a fluorescent microplate imager (BioTek Cytation3) (excitation, 438 nm; emission, 538 nm) hourly for 5 h and after 24 h. [0274] We assessed GSH/GSSG levels experimentally by treating S. mansoni adult worms with 50 μM of compounds, or respective controls 5 μM Auranofin, 50 μM PZQ or 50 μM MZM and 0.01% DMSO for 3 h. Worm homogenate was prepared by washing three times with PBS to remove residual compounds and ten volumes of ice cold 5% sulfosalicylic acid was added. Worms were manually homogenized on ice using VWR Pellet Mixer Adaptor. The worm suspension was centrifuged at 14000 u g, 4 °C for 10 min and the acid supernatants transferred. An equal volume of ice-cold neutralization buffer (500 mM HEPES, pH 8.0) was added to the acid supernatants. [0275] GSH/GSSG assay was performed by diluting the acid supernatant (5-fold) with ice-cold dilution buffer (250 mM HEPES, pH 7.5). Using white opaque luminescence plate on ice, 25 μl of the diluted worm acid supernatant was added each well in triplicates. Total glutathione lysis reagent and GSSG lysis reagent, which contains alkylating agent N-ethylmaleimide (25 mM) were prepared following manufactures protocol and added to respective wells along with blank for background. Total glutathione lysis reagent or oxidized glutathione lysis reagent (25 μl) was added to respective wells containing worm acid supernatants and the plate was shaken for 5 min. Luciferin generation reagent (LGR) (50 μl) was added to all wells, briefly shaken and incubated at room temperature for 30 min. Luciferin detection reagent (LDR) (100 μl) was added to all wells, briefly shaken and incubated for 15 min at room temperature and the luminescence measured using microplate imager (BioTek Cytation3). GSH/GSSH ratio for DMSO control and compounds were calculated using (Net DMSO total glutathione RFU) – (Net DMSO GSSG RFU)/ (Net DMSO GSSG RFU)/2 and (Net inhibitor total glutathione RFU) – (Net inhibitor GSSG RFU)/ (Net inhibitor GSSG RFU)/2 respectively. [0276] Pharmacokinetics of 1 and 2 in vivo: Intraperitoneal administration [0277] Chemicals and Reagents: HPLC-grade water was prepared by an in-house PURELAB Option filtration system (Elga lab water solution, UK). All reagents and solvents used were of HPLC grade. Methanol (VWR Chemicals), formic acid (Sigma-Aldrich, West Chester, PA, USA) & DMSO Sigma-Aldrich (West Chester, PA, USA), NADPH (Merk, USA). [0278] Animals: Swiss Webster male mice were purchased from Charles River Laboratories (Wilmington, MA, US). At 6 weeks of age, mice were housed in plastic cages and received standard chow (AIN-76) and water ad libitum prior to experiment maintained on a 12 h/12 h light/dark cycle. All the mice were weighed and dosed intraperitoneally accordingly at 100 mg/kg body weight with freshly prepared 1 or 2. [0279] Blood was collected by submandibular puncture into 1mL Eppendorf tubes, the plasma was separated and stored in -80 °C until used. A 25 μl of mouse plasma was transferred into 1.5 ml centrifuge tube which was spiked with 2.5 μl of internal standard (IS) working standard solution (100 μg/ml) to get final IS contraction of 250 ng/ml and the solution was vortexed. An aliquot of 75 μl of methanol/0.15 formic acid was added and gently vortexed for 2 minutes. The samples then centrifuged for 20 minutes at 4 °C and 15000 u g. A clear supernatant (50 μl) with added 50 μl mobile phase (reconstitution solution) from each extraction was then transferred into a 250 μl autosampler vial. A 3μl aliquot of each sample was injected for LC-MSMS analysis. [0280] Animal experiments were performed according to the policies and guidelines of the Institutional Animal Care and Use Committee (IACUC) of the University of Illinois at Chicago (Protocol 19-049). [0281] LC-MS/MS Conditions: The analyte molecules were eluted on Zorbax XDB-C18 column (3.5 ^m, 2.1x20 mm) with the mobile phase composed of water/0.1% formic acid and methanol/0.1% formic acid in the ratio of 70:30 V/V with the flow rate of 0.2 ml/min. The total run time of 2 min with an injection volume of 3 Pl at column temperature 40 qC were efficient to achieve accepted results. [0282] A Shimadzu LC20AD, Ultra Performance Liquid Chromatography (UPLC) system (Shimadzu Corporation, Kyoto, Japan) equipped with Shimadzu 8040 triple quadrupole (QqQ) mass analyzer (Shimadzu Corporation, Kyoto, Japan) with an electrospray ionization source (ESI) operated in the positive charge mode for the quantification of 1 and 2. [0283] Instrument control and data acquisition was achieved via LabSolutioFns software (Shimadzu Corporation, Kyoto, Japan). [0284] Pharmacokinetics of 2 in vivo: Oral Gavage [0285] Chemicals and Reagents: HPLC-grade water was prepared by an in-house PURELAB Option filtration system (Elga lab water solution, UK). All reagents and solvents used were of HPLC grade. Methanol (VWR Chemicals), formic acid (Sigma-Aldrich, West Chester, PA, USA) & DMSO Sigma-Aldrich (West Chester, PA, USA), NADPH (Merk, USA). [0286] Animals: Compound 2 was dissolved in DMSO. Tween 80 and saline were then added to the DMSO solution in that order. Final solution was 10% DMSO:10% Tween 80:80% saline. [0287] Swiss Webster female mice were purchased from Charles River Laboratories (Wilmington, MA, USA). At 6 weeks of age, mice were housed in plastic cages and received standard chow (AIN-76) and water ad libitum prior to experiment maintained on a 12 h/12 h light/dark cycle. All the mice were weighed and gavaged orally at 200 mg/kg body weight with freshly prepared 2. Blood was collected by submandibular puncture at 0, 0.25, 0.5, 1, and 2 h. [0288] Animal experiments were performed according to the policies and guidelines of the Institutional Animal Care and Use Committee (IACUC) of the University of Illinois at Chicago (Protocol 19-049). [0289] Analytical standard preparation: The multiplexed working standards were prepared by dilution from stock solutions in methanol at concentrations from 2.5 ng/ml – 2000 ng/ml. The working internal standards were also diluted from stock solutions in methanol with 0.1% formic acid. The working concentration of internal standard compound 1 was 750 ng/ml. [0290] Sample Preparation: Calibration curve for 2 was prepared by spiking 40 μl of blank mouse plasma with 10 μl of working standard solution to get final concentration ranging from 2.5 ng/ml – 2000 ng/ml. Samples were deproteinized with 150 μl of internal standard solution. This mixture was vortexed to mix properly and centrifuged at 13000 u g for 30 min. 160 μl of the supernatant was transferred to another set of tubes and dried using a nitrogen evaporator. Samples were reconstituted in 100 μl of methanol, vortexed and centrifuged at 13000 u g for 20 min.30 μl of supernatant was transferred to autosampler vials. [0291] LC-MS/MS Conditions: Experiments were carried out on ThermoFisher Scientific Vanquish high-performance liquid chromatography connected to ThermoFisher Scientific TSQ Quantis – triple quadrupole mass spectrometer. The analyte molecules were separated on Phenomenex kinetex C18 column 100 Å (2.6 ^m, 50 u 3 mm) with the mobile phase composed of Water/0.1% formic acid (A) and Acetonitrile (B) at the flow rate of 0.5 ml/min with the column temperature maintained at 40 °C and the sample of injection was 5 μl. The gradient program was set as follows: 0.1 min, 5% B; 0.1-0.5 min, 5%-95% B; 0.5-2.5 min, 95% B; 2.5-3.5 min, 95%-5%; 3.5-4 min and stop at 5 min. [0292] Quantification was performed using electrospray in the positive mode with the spray voltage of 3500 V. Sheath gas (Arb) 20, Auxiliary gas (Arb) 8 and Sweep gas (Arb) 5.7. The ion transfer tube has a temperature of 325 °C and vaporizer temperature of 350 °C. [0293] A Shimadzu LC20AD, Ultra Performance Liquid Chromatography (UPLC) system (Shimadzu Corporation, Kyoto, Japan) equipped with Shimadzu 8040 triple quadrupole (QqQ) mass analyzer (Shimadzu Corporation, Kyoto, Japan) with an electrospray ionization source (ESI) operated in the positive charge mode for the quantification of 2. [0294] Instrument control and data acquisition was achieved via LabSolutions software (Shimadzu Corporation, Kyoto, Japan). [0295] Evaluation of compound 2 stability under the biochemical assay conditions with recombinant TGR [0296] TGR assay solutions (1 ml each) were prepared as described in the main manuscript. Compound 2, NADPH, and incubation time was varied as following: 1) TGR and 2, no preincubation, 2) TGR, 2, and NADPH, no preincubation, 3) TGR and 2, 15 min preincubation, 4) TGR, 2, and NADPH, 15 min preincubation, 5) TGR and NADPH followed by 15 min preincubation, 2 was added after 15 min preincubation, 6) TGR and 2 followed by 15 min preincubation, NADPH was added after 15 min preincubation. Each of the reaction mixtures were terminated by the addition of 250 μl of ethyl acetate, extracted with 1 ml of methyl tert-butyl ether. The organic layer was evaporated in vacuo, and the residue was redissolved in 0.5 mL of 50% MeOH before injection onto LC column. LC-MS analysis was done on a Waters SYNAPT quadrupole/time-of-flight mass spectrometer operated in positive ion electrospray mode. The column was Waters XBridge C8 column and gradient was from 20-90% MeCN/0.1% formic acid over 12 minutes. No additional ions except for those corresponding to 2 were detected. [0297] Assessment of reactivity of 2 and TRi-1 with N-Boc protected methyl ester of L- selenocysteine [0298] Dimethyl bis(N-tert-butoxycarbonyl)-L-selenocystine was synthesized as reported previously.⁸⁵ (N-tert-butoxycarbonyl)-L-selenocysteine methyl ester was prepared in situ⁸⁶ in methanol or phosphate buffer. Compound 2 was added to the solution of (N-tert-butoxycarbonyl)- L-selenocysteine methyl ester in either methanol or phosphate buffer and incubated for 40 min, 24 h, and 120 h under N₂ gas balloon. Additional amounts of NaBH₄ were added at 12 h and 96 h to maintain the reducing conditions. Aliquots taken from methanol solution at each of the time points were concentrated in vacuo, mixed with water, and extracted with ethyl acetate. The organic layer was separated, concentrated in vacuo, re-dissolved in methanol and analyzed by LCMS. Aliquots taken from the phosphate buffer solution were extracted with ethyl acetate. The resulting organic layer was separated and concentrated in vacuo. The residue was re-dissolved in methanol and analyzed by LCMS. No additional peaks were detected either by UV or MS detection. No additional spots were detected by TLC as well. [0299] Covalent TGR inhibitor TRi-1 was used as a positive control for the reaction with (N-tert- butoxycarbonyl)-L-selenocysteine methyl ester. The reactivity of TRi-1 was tested similarly as described above for compound 2. An adduct between TRi-1 was detected by TLC and LCMS analysis. [0300] Cryo-Em Methods [0301] Negative staining Transmission electron microscopy: The homogeneity of the protein before structural determination was assessed by negative staining electron microscopy. Around 4 μl of the mixture of 0.02 mg/ml TGR in 0.15% DMSO and 5 mM inhibitor was applied to home- made carbon film evaporated a mica film, which was floated off in about 200 μl of 2% sodium silicotungstate (SST) and recovered by a Cu grid. The stained sample was then air dried. The images were acquired on a Tecnai 12 (Thermo Fisher Scientific) LaB₆ electron microscope operating at 120 kV using a Gatan Orius 1000 CCD camera or on a Tecnai F20 (Thermo Fisher Scientific) FEG electron microscope operating at 200 kV using a Ceta CMOS camera (Thermo Fisher Scientific). [0302] Cryogenic Electron Microscopy: The specimens for cryogenic electron microscopy (Cryo-EM) have been prepared onto 300 mesh Ultrafoil Au R1.2/1.3 grids (Quantifoil Micro Tools GmbH, Germany). First, 0.4 mg/ml TGR protein was mixed with 5 mM of inhibitor (9VP128-2) in buffer solution containing 0.15% DMSO and incubated 30 min at room temperature (20 °C). Then, 3.5 μl of the sample was applied onto 45 s glow-discharged quantifoil grids and vitrified in liquid ethane using a Vitrobot Mark IV (ThermoFisher Scientific) at 100% humidity, 7 s blotting time and 10 s waiting time. A total number of 2635 raw movie stacks made of 50 frames each were collected with SerialEM⁸⁷ from a single individual session with a GLACIOS 200 kV FEG Cryo- TEM (ThermoFisher Scientific) using a K2 Summit detector (Gatan Inc., USA) at 36000× magnification and pixel size of 1.145 Å/pixel without pre-exposure and using a defocus of –2.6 to –1.8 μm and 50 e-/Ų total dose per stack (1 e-/Ų per frame). Single-particle structure determination has been carried out with Relion v3.1.2⁸⁸ after motion-correction using 5×5 patches⁸⁹ and CTF estimation.⁹⁰ About 10000 particles were picked using a Laplacian-of- Gaussian approach to build 2D templates from eleven selected motion-corrected micrographs for further template-based picking to reach more than 1.7×10⁶ particles. After extraction with 2-fold binning (216 to 108 pixels), 2D classification was used to eliminate wrongly picked particles. An initial 3D model was built in Relion with both C1 and C2 symmetry and used for subsequent 3D classifications and refinements. All classes obtained after 3D classification and refinement showed the best results in terms of overall resolution and appearance of electron density. The final rounds of 3D classification and 3D refinement were performed using a larger box size (300 pixels) without binning along with CTF refinements and particle polishing. The final 3D map has an average resolution of 3.6 Å at FSC = 0.143. The crystal structure of TGR (PDB ID: 2V6O [https://www.rcsb.org/structure/2V6O])³² was docked manually in the cryo-EM map using COOT⁹¹.⁹⁰ Map local anisotropic sharpening and real space refinement was carried out with Phenix,⁹² while manual model building was done with COOT. After several cycles of refinement and model building, the inhibitor was placed into the cryo-EM map. [0303] Data Availability [0304] Source data are provided with this paper. The cryo-EM data generated in this study have been deposited in the PDB and in the EM data bank under accession codes 8A1R [https://www.rcsb.org/structure/8A1R] and EMD-15084 [https://www.ebi.ac.uk/emdb/EMD- 15084], respectively. The cryo-EM data will be released immediately upon publication. The X-ray- derived data of small molecular fragments in complex with TGR used in this study to design the compounds here described are available in the PDB under accession codes 6FTC [https://www.rcsb.org/structure/6FTC], 6FMU [https://www.rcsb.org/structure/6FMU], 6FMZ [https://www.rcsb.org/structure/6FMZ] and 6FP4 [https://www.rcsb.org/structure/6FP4], 2X99 [https://www.rcsb.org/structure/3X99], 2X8G [https://www.rcsb.org/structure/2X8G], 2X8H [https://www.rcsb.org/structure/2X8H], 6ZST [https://www.rcsb.org/structure/6ZST], 6ZP3 [https://www.rcsb.org/structure/6ZP3], 6ZLP [https://www.rcsb.org/structure/6ZLP], 6ZLB [https://www.rcsb.org/structure/6ZLB], 7B02 [https://www.rcsb.org/structure/7B02], 7NPX [https://www.rcsb.org/structure/7NPX], 2V6O [https://www.rcsb.org/structure/2V6O], 6RTJ [https://www.rcsb.org/structure/6RTJ], 6RTO [https://www.rcsb.org/structure/6RTO], 6RTM [https://www.rcsb.org/structure/6RTM], 3H4K [https://www.rcsb.org/structure/3H4K]. [0305] The ChEMBL25 data used in this study are available in the ChEMBL25 database under accession code [http://doi.org/10.6019/CHEMBL.database.25] RESULTS [0306] Fragment-based drug design and chemistry: [0307] Utilizing “actives” identified in a quantitative high-throughput screen against Schistosoma mansoni TGR,^20,3592 commercially available low molecular weight (MW) compounds/fragments were tested by X-ray crystallography.^{33, 34, 36} Some of the fragments, for which X-ray structures were obtained, were found in the doorstop pocket expected to be critical for TGR inhibition and adjacent to the NADPH binding site.³³ In the doorstop pocket, subpocket A binds 2- carboxynaphthyridine and subpockets B and C bind 4-(2-hydroxyethyl)-1-piperazineethane (HEPE). TGR IC₅₀s for these low MW fragments varied from 0.76 mM to 4.4 mM. Considering their low MW and non-covalent nature of inhibition of TGR, these compounds were deemed appropriate for fragment-based design. [0308] Further structure-based iterative optimization resulting in inhibitors was driven by bioisosteric replacement of the fragments bound to subpockets A-C, scaffold-hopping, de novo design, and medicinal chemistry and was facilitated by SZMAP/GamePlan,³⁷ vBrood,³⁸ and MOE software.³⁹ The computational analysis was facilitated by combining two X-ray fragments found in subpockets A-C in PDB:6FP4 (https://www.rcsb.org/structure/6FP4) and PBD:6FTC (https://www.rcsb.org/structure/6FTC) via a short CH₂CH₂ linker in a putative chimera molecule. Since all the fragments crystallized in subpocket C contained HEPE moiety with an additional polar substituent, it was tempting to think that a similar polar moiety should be placed in subpocket C. We noticed, however, that the bottom part of subpocket C in the vicinity of the fragments found in the X-ray structures is formed by the hydrophobic portions of D325, Y479, A481, H538, G483, V469, T471 and is likely to prefer bulky hydrophobic substituents. Consistent with this observation, all non-polar attachments proposed by GamePlan in subpocket C congregated near the piperazine ring of HEPE at the bottom of subpocket C. The published TGR X-ray structures also contained several water molecules in subpockets A and C. Considering that the water molecules were trapped largely in the hydrophobic pockets, often made contacts with or were displaced by the fragments, and did not appear to play a structural role, we anticipated that their displacement with larger non-polar moieties would improve binding of newly designed inhibitors. An analysis of the free energy minima and maxima for the water probe in subpockets A-C using SZMAP³⁷ and WaterOrientation extension in VIDA⁴⁰. The bottom of subpocket C in proximity to the chimera ligand contained several mostly non-polar (purple) probes with positive free energy values, indicating that it may be filled with additional non-polar substituents. The locations of waters found in the X-ray structures either overlapped or were very close to the locations of the probes placed by SZMAP. This observation further strengthened the notion that additional binding free energy could be gained not only by forming meaningful interactions with the doorstop pocket but also by liberating the trapped waters. [0309] Further visual inspection in VIDA of the vBrood search for candidates that can fill the doorstop pocket led us, among other possible scaffolds, to pinane in subpocket C. The sp³ carbon scaffold of the pinane rings offered an effective way to capture interactions with the hydrophobic portions of subpocket C while also displacing likely trapped waters. Subpockets A and B are also mostly hydrophobic and with only a few polar groups available to make polar interactions with the ligand. While subpockets B and C are rather large, subpocket A is narrow and restricted in depth by FAD at the bottom of the pocket, limiting the choice of modifications of the inhibitor in subpocket A. Although the SZMAP and GamePlan analyses suggested placement of polar and non-polar substituents in multiple locations, including those that were relatively remote, we intentionally limited the modifications to those in proximity or to the putative chimera molecule itself to maximize the potential for further improvements during structure-activity relationship (SAR) studies. By advancing through several generations of inhibitors, a series of inhibitors of TGR was obtained with activity against recombinant TGR improving from the mM range for the fragments alone to the single digit μM range. Of more than 100 compounds synthesized and tested for TGR inhibition (a more thorough description of compound design will form the basis of a future manuscript), the most promising were selected to be extensively characterized in the in vitro and in vivo studies described below. The candidates selected are predicted to be orally bioavailable according to the analysis of Lipinski et al⁴¹ (Table 3). Table 3. Biochemical characterization of 1-10, controls 11, 12, auranofin (AF), praziquantel (PZQ), meclonazepam (MZM) and photoreactive probe (PRP). Data are represented by n = 3 independent experiments as mean ± SD. Source data are provided as a Source Data file.

a – IC50 after 15 min preincubation (enzyme + 100 μM NADPH + compound). ^b – IC50 (μM) or inhibition (%) at 66.7 μM (enzyme + 100 μM NADPH + compound) after 6 h preincubation. Inhibition (%) of TGR activity after 6 h incubation are given and not IC₅₀s because equilibrium between enzyme and inhibitor was not obtained in this time frame (FIG.22d). ^c n.i. - no inhibition at 67 PM in 6 h. ^d n.d. - not determined. ^e – ratio of GSH/GSSG in adult worms determined after 3 h exposure to compounds at 50 PM. ^f – PRP is a “slow” inhibitor. Auranofin (AF), praziquantel (PZQ), meclonazepam (MZM) and photoreactive probe (PRP). [0310] TGR is inhibited in S. mansoni worms [0311] The activities against recombinant TGR of the inhibitors ranged from a modest 28.7% inhibition at 67 μM to robust activity with IC₅₀ = 2.5 μM (Table 3). A predicted outcome of TGR inhibition in worms is the accumulation of oxidized GSH (GSSG) because of attenuated reduction to GSH by TGR, leading to decreases in the GSH/GSSG ratio. To characterize compound engagement of TGR in adult worms ex vivo, the GSH/GSSG ratio was measured for compounds in Table 3. After a 3 h exposure to compounds at 50 μM, large decreases in GSH/GSSG of 20 to 75% were observed. Under the same conditions, treatment with the current drug of choice, PZQ, or the clinically tested and now discontinued meclonazepam (MZM),⁴² which have different schistosomicidal mechanisms and do not inhibit TGR, resulted in no change of that ratio. Treatment with positive control auranofin (AF), a covalent TGR inhibitor with schistosomicidal activity,¹⁸ decreased GSH/GSSG ratio by 90%. Treatment with inactive, negative control compounds (11 and 12), structurally related to the active inhibitors 1-10, had minimal effect on the GSH/GSSG in treated worms. [0312] To further characterize compound engagement of TGR in ex vivo worms using an orthogonal assay, inhibition of TGR activity in newly transformed schistosomula (NTS, skin-stage worms) was assessed using a TrxR-selective fluorescent probe,^{43, 44} TRFS-Green. The fluorescence of TRFS-Green is induced by the TGR (or TrxR)-mediated disulfide cleavage followed by intramolecular cyclization to liberate the masked naphthalimide fluorophore. Treatment of NTS with inhibitors 1, 2, 4, 7, and 8, positive control AF, or negative control 12 for 2 h was followed by addition of TRFS-Green. Fluorescence in wells was determined hourly for the first 5 h and at the terminal point of 24 h after addition of probe. NTS treated with TRFS-Green only were clearly fluorescent after 2 h incubation. Treatment with inhibitors 1, 2, 4, 7, and 8, and AF led to significant decreases in fluorescence. Consistent with the outcome of the measurements of the GSH/GSSG ratio, negative control 12 had negligible effects on TRFS-Green fluorescence. Overall, these findings indicate that the TGR inhibitors engage TGR in ex vivo worms. [0313] TGR inhibitors do not react covalently with GSH, selenocysteine, or TGR, and inhibition of TGR is reversible [0314] To evaluate stability of the TGR inhibitors in the presence of GSH and selenocysteine, compound 2 and a known covalent inhibitor of TGR, TRi-1,^{20, 45} were incubated with GSH or the N-Boc protected methyl ester of selenocysteine, and the reaction mixtures were analyzed by LCMS. Unlike TRi-1, no reaction of 2 with either thiol or selenol groups in GSH or protected selenocysteine was observed. Incubation of inhibitor 2 under the biochemical assay conditions with TGR and with or without NADPH resulted in no formation of derivatives of 2. To evaluate reversibility, TGR inhibitors were tested in the jump dilution assay.^{46, 47} In the jump dilution assay, after incubation of enzyme, NADPH, and inhibitor, the reactions are diluted to well below the IC₅₀ for the inhibitor allowing its release from the enzyme and activity is determined. We find that our inhibitors are reversible, while known covalent TGR inhibitors,^{20, 45} including AF, Stattic, and TRi- 1, are irreversible (FIG.22a). [0315] TGR inhibitors target a reduced form of TGR [0316] Next, we investigated if the TGR redox state affects the binding and activity of the inhibitors. Inhibitors 6-8 were incubated with TGR with and without NADPH, and the inhibition of TGR activity was determined after adding a second aliquot of NADPH and 5,5’-dithiobis (2- nitrobenzoic acid) (DTNB). Incubation of these inhibitors with TGR in the absence of NADPH led to significantly attenuated enzyme inhibition compared to inhibition resulting from incubation in the presence of NADPH (FIG.22b). [0317] Typical TGR inhibitor studies utilize a 15-minute preincubation step of enzyme, NADPH, and inhibitor. The reaction is started by the addition of substrate, DTNB or GSSG, and a second aliquot of NADPH. While compounds 6-8 caused maximal inhibition of TGR within 15 minutes (referred to here as fast inhibitors; Table 3, FIG. 22c), compounds 1-5 were found to be slow inhibitors as they displayed little to no inhibition after 15 minutes, but time-dependent inhibition of TGR over 25 h (FIG.22d and Table 3). [0318] Steady state studies varying NADPH and inhibitor concentrations indicate that treatment with the fast inhibitors 7 and 8 or the slow inhibitor 3, (the only slow inhibitor reaching equilibrium in 6 h), resulted in decreases in both K_m and V_max values consistent with uncompetitive inhibition of TGR, while treatment with 9, a derivative of compound 8 synthesized ad hoc to facilitate structural studies (see below), changed only the V_max indicating noncompetitive inhibition. Determination of steady state parameters for all the compounds was not possible due to low solubility at high micromolar concentrations. The change from uncompetitive to non-competitive mechanism induced by chemical modifications of the inhibitors is not rare in drug design studies.^{48, 49, 50} In general, both uncompetitive and noncompetitive inhibitors exert their action through the binding of the ES complex and/or downstream catalytic species, with the difference that noncompetitive ones bind also to free enzyme. In TGR, and more generally in TrxRs, electron transfer from NADPH to the enzyme is fast and practically irreversible and so an actual ES complex (NADPH-TGR) is not significantly populated during the catalytic cycle.¹⁷ We refer to the species formed after NADPH binding (the ES downstream species) as NADP⁺-TGR(H) reduced complexes, indicating that electrons are inside the polypeptide chain of the enzyme giving rise to the EH₂ and the EH₄ species. To obtain orthogonal proof that our inhibitors bind to the NADP⁺- TGR(H) forms, we evaluated their effect on thermal stability of TGR using the thermal shift assay (TSA or differential scanning fluorometry). A modification of the assay developed for flavoproteins has been reported and was utilized here.⁵¹ Oxidized TGR had a T_m of 73.7 °C, whereas TGR reduced with NADPH displayed a T_m of 66.5 °C (FIG. 22e), indicating destabilization of the polypeptide chain upon enzyme reduction. Neither fast 6-9 nor slow TGR inhibitors 1, 3, 5 affected the T_m of oxidized TGR. On the other hand, in the presence of NADPH there was an increase in the T_m of 3.5 – 7.2 °C providing further evidence that the ES complex is the target of the inhibitors. The same time dependence on the shift in T_m was seen for the compounds; fast inhibitors affected the T_m in 15 min., while the slow inhibitors required >2 h to cause a shift in T_m. Structurally similar non-inhibitors 11 and 12 had no effect on the T_m of either oxidized or reduced TGR. Next, we evaluated photocrosslinking between a photoreactive probe (PRP) (a slow inhibitor of TGR, Table 3) and recombinant TGR in the presence or absence of NADPH using procedures we published previously.⁵² In the presence of NADPH, labeling of TGR was more effective at both 5 and 50 PM of PRP than that without NADPH, indicating a higher yield of TGR-PRP adduct when NADPH was present. A control protein, S. mansoni histone deacetylase 8, was not labeled with or without NAPDH. Overall, the experiments clearly demonstrate preferable binding of our inhibitors to the NADP⁺-TGR(H) complexes. [0319] Inhibitors do not convert TGR into an NADPH oxidase [0320] Several covalent inhibitors of TGR are electrophilic compounds reacting with the Sec residue at the C-terminus, which induce a transition in the enzyme from an antioxidant to a pro- oxidant with increased NADPH consumption.^{20, 45} As expected, Stattic and TRi-1 converted TGR to a pro-oxidant enzyme, whereas our non-covalent inhibitors did not increase NADPH consumption or superoxide production (FIG.22f,g), indicating again the lack of involvement of the Sec-containing C-terminus in the mechanism of action of the newly described TGR inhibitors. [0321] TGR inhibitors bind to the doorstop pocket [0322] To gain additional insights into the mechanism of inhibition, we conducted a series of structural studies. Our attempts to obtain X-ray co-crystal structures of TGR and inhibitors resulted in structures with no detectable density of the inhibitors, possibly owing to the limited solubility of the compounds in the crystallization conditions. To increase aqueous solubility of the compounds to facilitate structural studies, the cycloheptyl substituent in TGR uncompetitive inhibitor 8 was replaced with a sugar moiety, resulting in compound 9, a noncompetitive inhibitor and thus capable of binding the enzyme in absence of NADPH. However, co-crystallization trials failed again. We, therefore, used alternative approaches and have determined the structure of a high molecular weight TrxR subfamily member using cryo-EM, demonstrating the feasibility of this methodology to study this protein subfamily of importance in several human diseases (PDB ID 8A1R, EMD-15084). First, the TGR-9 complex was subjected to negative staining TEM to assess quality of TGR particles and then, upon sample vitrification, to a cryo-EM operating at 200 kV. After structural refinement of the X-ray structure of TGR into the cryo-EM map obtained at 3.6 Å resolution, additional electron density ascribable to the compound is present in the doorstop pocket. Upon placement of the compound into the cryo-EM map and structural refinement we find that 9 adopts two conformations in both subunits, spanning the three subpockets A, B and C. Conformational changes induced by compound binding are not detected at this resolution. The correlation coefficient (CC) of 9 in the two different conformations is in the 0.67-0.71 range, close to the CCs of the FAD cofactor in each subunit (CC = 0.73-0.74). The two conformations differ in the position of the polar sugar moiety and in the orientation of the indole that is 180° rotated with respect to each other. In both conformations, the pinane ring of the compound interacts with F324, V469, T471, A481 and L484 in subpocket C, the indole interacts with F324, G325, P439 and L441 present in subpocket B, while the sugar moiety, through its hydroxyl groups, is close to the main chain carbonyls of G323 and R322 in one conformation and with the analogous groups of G437 and Q440 occupying the hydrophilic portion of subpocket A in the other conformation. In agreement with the noncompetitive behavior of 9 and as determined by structural superposition of the cryo-EM structure and the X-ray NADPH-TGR- complex,¹⁷ inhibitor 9 does not sterically interfere with NADPH binding. Instead, it contacts F324, a conserved residue in GRs and high molecular weight TrxRs involved in the recognition of the oxidized nicotinamide moiety of NADP⁺,⁵³ suggesting that 9 may interfere with NADP⁺ release and/or with the structural changes associated with it, slowing down the oscillations between EH₂ and EH₄ during enzyme turn-over. [0323] TGR inhibitors can achieve selectivity over mammalian enzymes [0324] Compounds 1-8 affected viability of Vero cells (EC₅₀) mostly at concentrations >50 μM (Table 4). An analysis of the raw data shows that for 1, 4-7, and 9, EC₅₀ against Vero cells is likely to be >200 μM. A more accurate assessment of these values was not possible due to low solubility of these compounds at high micromolar concentrations. To gain insights into the mechanism of VERO cell toxicity at high compound concentrations, the compounds were tested for inhibition of human cytoplasmic TrxR1 and GR. While none of the compounds show any appreciable inhibition of GR, TrxR1 IC₅₀ values varied from 4.9 to >50 μM (Table 3). Compound 6 is at least 25 times more potent against TGR than human TrxR1 indicating that selective enzyme inhibition is possible. Table 4. Ex vivo characterization of 1-10, controls 11, 12, auranofin (AF), praziquantel (PZQ), and meclonazepam (MZM). Schistosomicidal activity (LD₅₀, μM) of 1-12, AF, PZQ and MZM determined against S. mansoni newly transformed schistosomula (NTS) (n = 200, at 24 h exposure), adult worms (n = 10, at 24 h exposure) and juvenile worms (23 days) (n = 10, at 48 h exposure) and S. japonicum adult worms (n = 10, at 48 h exposure). Cytotoxic activity of 1-9, AF, PZQ and MZM against Vero cells (African Green Monkey Kidney cells, ATCC CCL-81) (n = 104 cells/well) after 24-hour exposure. Data are represented by n = 3 independent experiments as mean ± SD. ^a

– greater than highest concentration tested (μM). ^b n.d. - not determined. Auranofin (AF), praziquantel (PZQ), meclonazepam (MZM). [0325] TGR inhibitors are potent schistosomicidal agents ex vivo [0326] Compounds in Table 3 were tested for schistosomicidal activity against S. mansoni and S. japonicum adult worms and S. mansoni NTS and 21-day juvenile worms ex vivo (Table 4) Schistosomicidal LD₅₀s against both species of adult worms were between 9.36 and 32.6 μM, juvenile worms 7.2 to >30 μM, and 0.6 μM to 17.5 μM against NTS, with most NTS LD₅₀ values below 6 μM. No differences in response were observed between male and female adult worms for any of the compounds tested. TGR inhibitors 1-6 were found to have higher potency against S. mansoni adult and NTS worm stages than PZQ and MZM, drugs with schistosomicidal activity. The PZQ LD₅₀ for NTS was determined after just 24 h exposure using both the Cell TiterGlo (27.1 ± 2.27 μM, Table 4) and the phenotypic analysis (42.9 ± 0.83 μM), which is also used by others⁵⁴. If incubation with compounds is prolonged, superior efficacies can be reached: after 72 h exposure of NTS to compounds 1 and 6 had LD₅₀s of 2.2 ± 0.19 and 7.8 ± 2.36 μM respectively, whereas 2 had 0.18 ± 0.007 μM. In the assay with juvenile S. mansoni worms, TGR inhibitors 1- 5 displayed potency comparable to that against adult worms and superior to PZQ and MZM, whereas LD₅₀ for 6-8, PZQ and MZM were all >30 μM. Potency of inhibitors 1-4, 7, and 8 against S. mansoni and S. japonicum adult worms was generally comparable. [0327] Efflux may affect efficacy of TGR inhibitors ex vivo [0328] Compounds 7-9 were found to have significant NTS killing activity, but the decrease in GSH/GSSG ratio was attenuated and less adult schistosomicidal activity was observed. Helminths are known to possess ABC/MDR transporters, P-glycoprotein, and other efflux transporters that mediate the transport of molecules and antimicrobials across the membrane modulating drug susceptibility.⁵⁵ To enhance the level of uptake and retention, we coupled treatments of 7-9 with channel blockers in ex vivo worms. Treatment with combinations of channel blockers, tariquidar (10 PM) and Ko143 (10 PM), resulted in increased adult worm killing compared to treatments without channel blockers (Table 5). Likewise, significant decreases in GSH/GSSG ratio in combination treatments compared to TGR inhibitors alone were also seen. Treatment with the channel blockers alone or in combination with negative control 11 resulted in insignificant decrease of the GSH/GSSG ratio and no effect on adult worm viability. Table 5. Biological activity of compounds 7-9 and 11 alone and with channel blockers tariquidar (T) and Ko143 (K) both at 10 μM. Adult worm data presented by three independent experiments as mean ± SD of biological replicates. Source data are provided as a Source Data file.

[0329] TGR inhibitors have efficacy as schistosomicidal agents in vivo [0330] Encouraged by the activity of our non-covalent TGR inhibitors against ex vivo worms, we evaluated the schistosomicidal activity of these compounds in mice infected with S. mansoni (FIG. 23). A single treatment of mice 42 days post infection (d.p.i.) with 1 (100 mg/kg i.p.) resulted in a 44% decrease in worm and a 40% reduction in egg burdens, respectively. Administration, at 42 d.p.i., of two doses of 1 (100 mg/kg i.p. bid) resulted in 54% and 48% decrease in worm and egg burdens, respectively. A single dose of 2 (100 mg/kg i.p.) at 42 d.p.i. resulted in a 85% decrease in worm burden and 73% decrease in egg burden. Decreased efficacy was observed when this dose was spread over two administrations (50 mg/kg i.p. at 42 d.p.i. and 50 mg/kg i.p. at 45 d.p.i.), resulting in a 43% decrease in worm burden and a 69% decrease in egg production. A single dose of 6 (100 mg/kg i.p.) at 42 d.p.i. resulted in a 34% decrease in worm and 3% decrease in egg burdens, respectively, while two doses (100 mg/kg i.p. at 42 d.p.i. and 100 mg/kg i.p. at 45 d.p.i.), did not result in increased efficacy (38% decrease in worm and 18% reduction in egg burdens, respectively). A single administration of 8 at 42 d.p.i (200 mg/kg i.p.) resulted in a 19% and 7% decrease in worm and egg burdens, respectively. [0331] The three TGR inhibitors with significant in vivo efficacy (1, 2, and 6) against adult worms were tested for efficacy against juvenile worms 21 d.p.i. (FIG.23). As shown in previous studies, PZQ has very little activity in this context.¹³ Treatment with either compound 1 (2 x 100 mg/kg) or 2 (1 x 100 mg/kg) resulted in significant decreases in both worm and egg burdens of 61% and 57% for 2 and 28% and 31% for 1, respectively. Compound 6 exhibited only marginal efficacy of 16% and 7% decrease in worm and egg burdens, respectively. Thus, the greater efficacy of inhibitor 2 observed against adult worms, translated to the greater efficacy in mice against juvenile worms. [0332] Pharmacokinetic (PK) studies [0333] Administration of 1 (100 mg/kg i.p.) achieved a C_max of 4.1 PM at 30 minutes and maintained plasma concentrations >2 PM at 2 h post administration: 4.1, 3.3, and 2.4 PM at 30, 60, and 120 minutes. A similar PK profile was observed for inhibitor 2 (100 mg/kg i.p.), with 4.8, 3.9, and 3.0 PM concentrations measured at 30, 60, and 120 minutes, respectively. Plasma exposure of mice to both 1 and 2 is compatible with observed efficacy and no overt toxicity was observed. Based on the time points available, the half-lives of 1 and 2 can be estimated at 90 min. The TGR inhibitor demonstrating greatest efficacy in treating infected mice, 2, was also studied after oral administration: 2 (200 mg/kg p.o.) gave plasma concentrations of 0.71, 0.77, and 0.40 μM at 30, 60, and 120 min, respectively. [0334] Non-covalent inhibitors of TrxR class of redox proteins may have broad application [0335] One of our recently synthesized TGR inhibitors compound 10 with IC₅₀ = 18.6 PM for TGR is even more potent against TrxR from Brugia malayi (BmTrxR; IC₅₀ = 2.5 PM) and is a weak inhibitor of TrxR from Plasmodium falciparum (PfTrxR; IC₅₀ = 32.5 PM) (Table 3). Both BmTrxR and PfTrxR are validated drug targets against lymphatic filariasis and malaria, respectively.^{56, 57} These results and the differences in the composition of the doorstop pockets suggest that selectivity for individual TrxRs can be attainable, which may result in lower toxicity. DISCUSSION [0336] We have identified compounds (1-10) that act as first-in-class, non-covalent inhibitors of TGR with druglike properties as demonstrated by efficacy in mice infected with S. mansoni. Inhibition of TGR was shown in biochemical assays with recombinant protein, and in ex vivo worms by measurement of both TGR-generated fluorescent products from TRFS-Green and the decrease in the GSH/GSSG ratio. Herein, we demonstrate that single particle cryo-EM can be applied to a member of the pyridine nucleotide-disulfide oxidoreductase protein family, which includes crucial drug targets for several human diseases. The cryo-EM data show inhibitor 9 bound in the doorstop pocket, indicating that the design strategy, based on the initial fragments found in X-ray co-crystal structures, is successful. We propose that this class of inhibitors trap the NADP⁺-TGR(H) species, preventing NADP⁺ release. The evidence is provided by: (i) the inhibitors are found in the secondary site known to interact with outgoing NADP⁺ in related pyridine nucleotide–disulfide oxidoreductases;⁵³ (ii) inhibition is reversible; and (iii) inhibition is exerted by binding to the NADP⁺-TGR(H) reduced species. One advantage of noncompetitive and uncompetitive inhibitors over competitive inhibitors in disruption of metabolic pathways, is the lack of competition with endogenous substrates that may be present at high cellular concentrations as a result of enzyme inhibition, making uncompetitive inhibitors, in particular, ideal for drug development.⁵⁸ [0337] All lines of evidence indicate that fast and slow TGR inhibitors bind different conformational states present in the TGR enzymatic cycle induced by both NADPH-dependent reduction and the concomitant destabilization of the polypeptide chain, as shown by TSA. We hypothesize that (i) the slow inhibition observed in the biochemical assay with the recombinant protein with some of the compounds is due to their preferential binding to a slowly populated conformer of the NADP⁺-TGR(H) complex and (ii) this conformer is already populated in the worm cell interior accounting for the more rapid inhibition of TGR observed in ex vivo worms with the slow inhibitors. To the best of our knowledge, the assays where DTNB, GSSG, Trx, and NADPH (at saturating concentrations) are utilized as substrates are the only assays used to measure activity of TGR and related enzymes, including human TrxR and GR.⁵⁹ Considering that very little is known about the local and temporal concentrations of NADPH and TGR and the multiple redox- associated conformational states, it is difficult to assess how accurately the biochemical assay with recombinant TGR models the inhibition of TGR in worms ex vivo or in vivo. A comprehensive characterization of enzyme inhibition by slow inhibitors, which are well documented in the literature,⁵⁸ is not straightforward. Hence, it certainly appears that measurements in worms ex vivo of GSH/GSSG ratio and fluorescent product from TRFS-Green are more reliable in assessing endogenous inhibition of TGR. The observed inhibition of GSSG reduction likely leads to redox stress resulting in the potent schistosomicidal activity observed. Despite similarity, TrxR and TGR proteins appear to be sufficiently different, as evidenced by the differential activity of our inhibitors against TGR and human, B. malayi, and P. falciparum TrxRs, and inhibitors selective for individual enzymes could be developed. Human TrxR1 (the cytosolic isoform) displays 74% sequence identity in the doorstop pocket residues with respect to TGR. Remarkably, the charge distribution and shape of TrxR1 in this site is different with respect to TGR³³ due to the presence of charged and bulky residues, i.e., E337, D338, E341, E368 and K389 in human TrxR1 in place of A436, G437, Q440, S467 and D488 in TGR. These structural differences suggest that selective inhibition of TGR over human TrxR may be attainable. Indeed, compound 6 has IC₅₀ = 2.5 μM against TGR and against human TrxR1 it is > 66.7 μM, at least 25 times more potent against TGR than human TrxR1. Human Trx and GSH systems have compensatory activities so that inhibition of one arm can be supplemented by the other,⁶⁰ suggesting that the inhibition of hTrxR by some of the compounds presented here will not be detrimental for humans as it is for schistosomes. Better understanding of the mechanism and TGR/TrxR reduced species involved in the binding of inhibitors depending on microenvironment may offer an additional avenue to control inhibitor selectivity in organism, tissue, and cell type specific manner. [0338] The TGR inhibitors, reported herein, are schistosomicidal both ex vivo and in vivo. These inhibitors outperform PZQ, the drug of choice to fight schistosomiasis. Disease eradication using PZQ monotherapy is severely limited by the low activity of this drug against juvenile worms. Against ex vivo S. mansoni juvenile worms, the LD₅₀ of PZQ (413 μM) is inferior to that of inhibitors 1-5 (7.2 < LD₅₀ < 26 μM).⁶¹ Under the assay conditions used herein (ex vivo worm viability assessed after 24 h exposure), all compounds had equal or superior potency to PZQ and all, except 9, were more active than MZM against S. mansoni adult worms and NTS (Table 4). The reported LD₅₀ for NTS after exposure to PZQ for 3 days is 1-2 μM.⁶² After 3-days exposure of NTS, the LD₅₀ of compound 1 was similar to that of PZQ, whereas 2 was 5-fold more potent than PZQ. In other studies, the LD₅₀ for PZQ against adult worms has been reported as 1.5 μM and 5.1 μM for male and female worms, respectively;⁶¹ however, these LD₅₀s were determined after overnight exposure to PZQ followed by 8 days culture. Our comparison of PZQ activity against NTS in the phenotypic and Cell Titer Glo assays found similar LD₅₀s immediately after 24 h exposure. The compounds presented herein have similar activities against both S. mansoni and S. japonicum adult worms and show no differences between male and female parasites. The similar effect observed against S. japonicum can be rationalized by the 100% homology of the residues in the doorstop pocket of TGR from the two species. The complete reliance of all schistosome species¹⁵ on TGR for regulation of the redox defense network, and our previous results with several covalent TGR inhibitors,^{19, 20} are compatible with species and sex concordance. Although some inhibitors (7-9), on the basis of adult schistosomicidal activity in combination with efflux transport blockers, appear to be substrates for efflux pumps, this does not cause species nor sex differences. [0339] When targeting adult worms in mice, administration of inhibitors 1, 2, and 6, resulted in significant reductions in both worm and egg burdens. Treatment with a single dose of compound 2 (100 mg/kg) resulted in an 85% reduction in adult worm burdens. The WHO criterion for lead progression is ^ 80% reduction in worm burden after five doses (100 mg/kg qd) over multiple days.⁶³ This criterion is somewhat at odds with the current SOP for MDA, which does not entertain multiple doses over multiple days.²⁷ Compound 2 is therefore a viable development lead for treatment of schistosome infection. Earlier studies found that the ED₅₀ for PZQ against adult worms in mice was 80 mg/kg;⁶¹ the activity for 2 reported here of 85% reduction at 100 mg/kg indicates similar activity. Targeting juvenile worms at 21 d.p.i. with a single injection of 2 (100 mg/kg) resulted in >60% reduction in worm burden, a significantly higher efficacy than observed for treatment with PZQ in previous studies,¹³ which had 0% reduction at 21 and 28 d.p.i. (500 mg/kg) and reductions of 50 % and 17% at 21 and 28 d.p.i. (1,000 mg/kg), respectively. Titrating PZQ doses 28 d.p.i. resulted in ED₅₀ = 2,456 mg/kg.⁶¹ Based on the single dose tested for 2, the estimated ED₅₀ is below 100 mg/kg. Comparing the schistosomicidal activity against juvenile worms with that of PZQ reported in previous in vivo studies,⁶¹ the inhibitors reported herein show superior schistosomicidal activity to PZQ at the worm developmental stage in mice. Overall, treatment targeting juvenile worms resulted in smaller decreases in worm and egg burdens, which could be associated with higher ABC and MDR transporter activity in juvenile worms than adult worms.⁵⁵ [0340] The maximum plasma concentration (C_max) reached for a standard dose of PZQ (1,500 mg), in healthy volunteers, is 0.16 Pg/ml or 513 nM.⁶⁴ The PZQ plasma exposure, measured by C_max, is substantially lower than the LD₅₀ against adult worms and NTS reported by others,^{61, 62} and substantially below the LD₅₀ for NTS killing measured herein (27-43 μM). The half-life of PZQ in healthy volunteers (1.6 h)⁶⁴ is also much shorter than the 3-8 days assays used by others to determine LD₅₀ for worms and NTS ex vivo. Discordance between ex vivo potency and in vivo PK/PD has many potential causes, one of which, in the case of schistosomicidal agents, is the involvement of the host immune response. The schistosomicidal activities of PZQ and of potassium antimonial tartrate, a drug used in the past for schistosomiasis and a TGR inhibitor, are reduced in immunosuppressed mice,⁶⁵ indicating a crucial role of the host immune system in the mechanism of action of schistosomicidal agents in vivo. There is every reason to argue that the efficacy observed for compounds 1 and 2 in vivo incorporates a similar role for the host immune response as seen for other schistosomicidal agents. It is therefore unsurprising that the LD₅₀ values for compounds 1 and 2 determined ex vivo have a similar discordance to that seen for PZQ when considering in vivo PK/PD: much like PZQ these compounds are schistosomicidal in vivo at sub LD₅₀ concentrations. Although the maximum plasma concentration is lower when compound 2 is administered PO (0.77 μM) instead of IP (4.8 μM), it is still 4.3-fold higher than LD₅₀ for ex vivo NTS determined in the commonly used 72 h assay, also indicating that TGR inhibitor 2 is orally bioavailable and the initial prediction of oral bioavailability based on the Lipinski et al.⁴¹ criteria is correct. The observation that higher plasma concentrations of 2 can be achieved after oral delivery than for PZQ, coupled with the greater ex vivo potency of compound 2, strongly suggest that further optimization will yield an orally bioavailable schistosomicidal agent that will be transformative in the clinical setting. Inhibitors reported herein are effective against all stages of schistosome development, decrease egg production, improve liver pathology, and are orally bioavailable. [0341] All parasitic flatworms have a redox system similar to that of S. mansoni with TGR serving an obligate role in the absence of TrxR and GR; therefore, our therapeutic approach can be extended to other human and veterinary flatworms.⁶⁶ Given the mechanism of enzyme inhibition, our non-covalent inhibitors can be targeted to TrxR and can be applicable to development of therapeutics for a broad range of diseases. All TrxR enzymes require an NADPH-dependent reduction step to exert their function in vivo and TrxR is a therapeutic target for cancer and infectious diseases.^{21, 67} Several currently used cancer drugs exert their anticancer activity in part through covalent inhibition of TrxR²¹ and two covalent TrxR inhibitors are currently in clinical trials.⁶⁸ TrxRs from filarial nematodes and malaria parasites have been validated as druggable^{56, 57} and have structures available.^{69, 70} The druglike and orally bioavailable compounds identified herein are active in animal models of schistosomiasis with a broader range of developmental stages targeted than the drug of choice, PZQ. Their mechanism of action is different from that of PZQ and combinations of PZQ and TGR inhibitors represent a promising approach to develop combination therapies essential for schistosomiasis elimination. [0342] It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations set forth for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the above- described embodiment(s) without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.

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Claims

CLAIMS 1. A compound of formula I

or a pharmaceutically acceptable salt thereof wherein

is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted alkenyl;

is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C1-C6 alkyl; R1 and R2 are independently absent, H, halide, azide, nitro, cyano, amino, hydroxyl, carboxy, amido, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkoxy, C1-C6 ester, C1-C4 alkenyl, or C1-C6 alkynyl, C1-C6 alkyl amino, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkyl; L₁ is absent or is straight or branched C₁-C₄ alkylene or C₁-C₄ alkenyl optionally substituted with an amide group, an ester group, or a carbonyl group, heteroaryl, aryl, an amide, or an ester; Z is absent or is O, NR3, C=O,

R3 is H, substituted or unsubstituted C1-C6 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or -C(O)R6, wherein R6 is substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted cycloalkyl; and R₄ and R₅ are independently H, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, C₁-C₄ alkyl, oxo, carboxyl, or phenyl. 2. The compound of claim 1, wherein

is

3. The compound of claim 1 wherein

is selected from

N and

4. The compound of claim 1, wherein is

wherein R₁ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, and R₇ is H or substituted or unsubstituted C₁-C₆ alkyl.

5. The compound of claim 4, wherein R₁ is substituted or unsubstituted phenyl.

6. The compound of claim 4 or 5, wherein R₇ is H or methyl.

7. The compound of claim 1, wherein

is wher

ein n is an integer from 1 to 4; and R₈ and R₉ are independently absent, H, halide, azide, nitro, cyano, amino, amido, hydroxy, substituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ ester, C₁-C₄ alkenyl, or C₁-C₆ alkynyl, C₁-C₆ alkyl amino, C₁-C₆ alkyl amido, C₁-C₆ alkyl hydroxy, C₁-C₆ alkyl ether, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkyl.

8. The compound of any one of claims 1-7, wherein L₁ –(CH₂)n-, n is 1, 2, or 3.

9. The compound of any one of claims 1-8, wherein Z is NH.

10. The compound of any one of claims 1-8, wherein Z is O.

11. The compound of any one of claims 1-10, wherein

is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cycloheptyl, substituted or unsubstituted adamantyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or one of the following substituted or unsubstituted groups:

, ,

12. The compound of any one of claims 1-10, wherein

13. The compound of claim 1 having formula IIA or IIB and any stereoisomer thereof

wherein R₁ is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl.

14. The compound of claim 13, wherein R1 is substituted or unsubstituted phenyl.

15. The compound of claim 13 or 14, wherein L1 -CH2- or C=O.

16. The compound of any one of claims 13-15, wherein Z is NH.

17. The compound of any one of claims 13-15, wherein Z is O.

18. The compound of any one of claims 13-17, wherein R₇ is H, methyl, or ethyl.

19. The compound claim 1 having formula III and any stereoisomer thereof

20. The compound of claim 19, wherein R₁ is substituted or unsubstituted phenyl.

21. The compound of claim 20 or 21, wherein L1 is -CH2-.

22. The compound of any one of claims 19-21, wherein Z is NH.

23. The compound of any one of claims 19-21, wherein Z is O.

24. The compound of any one of claims 19-23, wherein R₂ is H.

25. The compound claim 1 having formula IVA, IVB, VA, or VB and any stereoisomer thereof

26. The compound of claim 25, wherein L1 –(CH2)n-, where n is 1, 2, or 3.

27. The compound of claim 25 or 26, wherein Z is NH or C(O)NH.

28. The compound of claim 25 or 26, wherein Z is O.

29. The compound of any one of claims 25-28, wherein R₈ is H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl with an optional carbonyl group.

30. The compound of any one of claims 25-29, wherein R9 is H, halide, azide, nitro, cyano, amino, amido, hydroxy, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 ester, C1-C4 alkenyl, or C1-C6 alkynyl, C1-C6 alkyl amino, C1-C6 alkyl amido, C₁-C₆ alkyl hydroxy, C₁-C₆ alkyl ether, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkyl.

31. The compound of claim 1 selected from

or a pharmaceutically acceptable salt thereof.

32. A composition comprising a compound of any one of claims 1-31 and a pharmaceutically acceptable excipient.

33. A method of treating a disease in a subject produced by a parasitic worm comprising administering to the subject an effective amount of a compound of any one of claims 1- 31.

34. The method of claim 33, wherein the disease is produced from a parasitic flatworm or trematode.

35. The method of claim 33, wherein the disease is produced from a blood fluke, a liver fluke, a lung fluke, an intestinal fluke, a pancreatic fluke, a cestode, or tapeworm.

36. The method of claim 33, wherein the parasitic worm is from the genus Schistosoma, Clonorchis, Dicrocoelium, Fasciola, Opisthorchis, Fasciolopsis Metagonimus, Heterophyes, Metorchis, Paragonimus, Eurytrema, Echinostoma, Watsonius, Gastrodiscoides, Gastrodiscus, Heterobilharzia, Paramphistomum, Prosthogonimus, Alaria, Taenia, Hymenolepis, Diphyllobothrium, Echinococcus, Moniezia, Dipylidium, Spirometra, Calicophoron, Nanophytus, Apophallus Cryptocotyle, or Mesocestoides.

37. The method of claim 33, wherein the parasitic worm is S. mansoni, S. haematobium, S. japonicum, S. guineensis, S. intercalatum, S. malayensis, S. mekongi, S. bovis, C. sinensis, D. dendriticum, D. hospes, F. gigantica, F. hepatica, O. felineus, O. viverrine, M. conjunctus, F. buski, M. miyatai, M. takahashii, M. yokogawai, H. heterophyes, H. nocens, E. pancreaticum, E. coelomaticum, E. ovis., P. westermani, P. heterotremus, P. kellicoti, P. mexicana, P. skrjabin, P. miyazakii, P. compactus, P. hueit'ungensis, E. ilocanum, W. watsoni, G. hominis, G. aegyptiacus, H. americana, P. macrorchis, P. cervi, A. alata, A. canis, T. saginata, T. solium, T. taeniaeformis, T. multiceps, T. serialis, T. hydatigena, T. pisiformis, T. crassiceps, H. nana, D. latum, E. granulosus, E. multilocularis, E. equinus, E. ortleppi, E. intermedius, E. canadensis, M. expansa, D. caninum, S. mansonoides, C. daubneyi, N. salmincola, A. donicus, C. lingua, or M. variabilis.

38. The method of any one of claims 33-37, wherein the compound reduces worm burden, worm egg burden, or a combination thereof in a subject when compared to the same subject prior to the administration of the compound.

39. A method of inhibiting thioredoxin glutathione reductase (TGR) in a cell comprising administering to the cell an effective amount of a compound of any one of claims 1-31.

40. The method of claim 39, wherein the compound selectively interacts with the target TGR protein by non-covalent bonds.

41. The method of claim 40, wherein the interaction occurs at the doorstop pocket of thioredoxin glutathione reductase.