Small molecule compounds for treating parasitic nematode diseases

Abstract

Compounds and methods for treating or reducing the severity of occurrence of a parasitic worm or helminth infection in a subject are described.

Description

[0001] SMALL MOLECULE COMPOUNDS FOR TREATING PARASITIC NEMATODE DISEASES

[0002] RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 568,525 filed on March 22, 2024, which is hereby incorporated herein by reference in its entirety.

[0004] STATEMENT OF FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0005] This invention was made with government support under Grant No. Al 150866 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0006] BACKGROUND

[0007] Human gastrointestinal nematodes (GINs, also known as soil-transmitted helminths) include the roundworm Ascaris lumbricoides, the whipworm Trichuris trichiura, and the hookworms Necator americanus, Ancylostoma duodenale, and Ancylostoma ceylanicum. They are among the most prevalent infections of Neglected Tropical Diseases (NTDs), affecting people in the world’s poorest communities. GINs are successful parasites of vertebrates that have adapted to parasitize humans, livestock, and companion animals. Morbidities associated with GIN infections in humans include anemia, malnutrition, growth stunting, cognitive impairment, pregnancy complications, and lowered immunity against other infectious diseases. GIN infections are responsible for at least 2-3 million disability- adjusted life years (DALY), with hookworms accounting for almost one-half of the DALYs lost due to GIN infections. Children who received hookworm treatment had increased school attendance and adult income. GINs also have enormous impacts on the health and productivity of farm animals.

[0008] The World Health Organization (WHO) has recommended annual or semi-annual Mass Drug Administration (MDA) targeting preschool and school-age children to reduce worm burden and associated morbidity. Four anthelmintics (levamisole, pyrantel pamoate, albendazole, and mebendazole), initially developed for livestock, are currently on the WHO list to control human GINs, with the two benzimidazoles, albendazole and mebendazole, most widely used because of their improved efficacies. In companion and livestock animals, GINs are controlled via frequent and routine treatment using a repertoire of anthelmintics, which has led to widespread and sometimes multi-drug anthelmintic resistance. Benzimidazole resistance is well-established in the veterinary parasites. Single nucleotide polymorphisms (SNPs) in the beta-tubulin gene linked to the benzimidazole resistance in veterinary parasites have been found in human GINs, indicating that with high drug pressure, there is likely to be an emergence for benzimidazole resistance in human GINs. In Haiti and Kenya, the frequency of benzimidazole-resistance codon 200 in T. trichiura was significantly increased following local MDA programs. There are also multiple reports of lowered efficacy of benzimidazoles against human GINs and warnings against drug resistance. Notwithstanding these challenges, WHO has set the ambitious goal to eliminate human GINs by 2030.

[0009] Therefore, potent and broadly active anthelmintics with new modes of action, as well as treatment methods comprising them, are urgently needed for long-term control and elimination of parasitic infections.

[0010] SUMMARY

[0011] Provided herein are benziothiazole ((E)-2-(benzo[d]thiazol-2(3 / 7)-ylidene)-3- oxobutanenitrile) compounds, tyrphostin ((E)-3-(3-(ferf-butyl)-4-hydroxyphenyl)acrylonitrile) compounds, and ESI-09 ((Z)-2-oxo- / V-phenylpropanehydrazonoyl cyanide) analogues. These compounds are useful in the treatment of parasitic infections, including anthelminticresistant parasitic infections.

[0012] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt thereof: wherein the variables are defined herein.

[0013] In an embodiment, the compound of formula I is a compound of formula IA:

[0014] (IA), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0015] In another embodiment, the compound of formula I is a compound of formula IB:

[0016] (IB), a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0017] In an embodiment, the compound of formula I is a compound of formula IC: or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0018] In yet another embodiment, the compound of formula I is a compound of formula IA-1:

[0019] (IA-1), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0020] In still another embodiment, the compound of formula I is a compound of formula IA- II; or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0021] In an embodiment, the compound of formula I is a compound of formula lA-la;

[0022] (lA-la), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein. In yet another embodiment, the compound of formula I is a compound of formula IA- lb;

[0023] (lA-lb), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0024] In still another embodiment, the compound of formula I is a compound of formula IA- lla:

[0025] (lA-lla), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0026] In an embodiment, the compound of formula I is a compound of formula lA-llb; or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0027] In an embodiment, the compound of formula I is a compound of formula IC-I: or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0028] In an aspect, provided herein is a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0029] In an embodiment, the compound of formula II is a compound of formula HA: (HA), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0030] In another embodiment, the compound of formula II is a compound of formula 11 B: (HB), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0031] In yet another embodiment, the compound of formula II is a compound of formula 11 A-

[0032] (HA-i), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0033] In an embodiment, the compound of formula II is a compound of formula IIB-i:

[0034] (HB-i), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein. In another embodiment, the compound of formula II is a compound of formula IIA-ia:

[0035] (IIA-ia), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0036] In yet another embodiment, the compound of formula II is a compound of formula 11 B-

[0037] (IIB-ia), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein. In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of at least one compound of formula III, or a pharmaceutically acceptable salt thereof:

[0038] (HI), wherein the variables are defined herein.

[0039] In an embodiment, the compound of formula III is a compound of formula IIIA:

[0040] (HIA), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0041] In another embodiment, the compound of formula III is a compound of formula HUB:

[0042] (IIIB), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0043] In yet another embodiment, the compound of formula III is a compound of formula

[0044] IIIA-i:

[0045] (IHA-i), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0046] In still another embodiment, the compound of formula III is a compound of formula IIIA-ii:

[0047] (IIIA-ii), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0048] In an embodiment, the compound of formula III is a compound of formula IIIA-iii:

[0049] (IIIA-iii), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0050] In another embodiment, the compound of formula III is a compound of formula IIIA-iv:

[0051] (IIIA-iv), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0052] In yet another embodiment, the compound of formula III is a compound of formula IIIB-i:

[0053] (IIIB-i), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0054] In an embodiment, the compound of formula IIIB-i is a compound of formula IIIB-ia:

[0055] (IIIB-ia), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0056] In still another embodiment, the compound of formula III is a compound of formula IIIB-ii:

[0057] (IIIB-ii), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0058] In an embodiment, the compound of formula IIIB-ii is a compound of formula IIIB-iia: or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0059] In an embodiment, the compound of formula III is a compound of formula IIIB-iii:

[0060] (IIIB-iii), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0061] In another embodiment, the compound of formula III is a compound of formula IIIB-iv:

[0062] (IIIB-iv), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0063] In yet another embodiment, the compound of formula III is a compound of formula IIIB-v: or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0064] In an embodiment, the compound of formula IIIB-v is a compound of formula IIIB-va: or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0065] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of at least one compound of formula IV, or a pharmaceutically acceptable salt thereof: wherein the variables are defined herein.

[0066] In an embodiment, the compound of formula (IV) is a compound of formula (IVA):

[0067] (IVA), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0068] In another embodiment, the compound of formula (IV) is a compound of formula (IVB): or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0069] In yet another embodiment, the compound of formula (IV) is a compound of formula (IVC):

[0070] (IVC), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0071] In still another embodiment, the compound of formula (IV) is a compound of formula (IVD):

[0072] (IVD), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0073] In an embodiment, the compound of formula (IV) is a compound of formula (IVE):

[0074] (IVE), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0075] In another embodiment, the compound of formula (IV) is a compound of formula (IVF):

[0076] (IVF), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein. In an embodiment, the compound of formula (IV) is a compound of formula (IVA-i):

[0077] (IVA-i), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0078] In another embodiment, the compound of formula (IV) is a compound of formula (IVB-i):

[0079] (IVB-i), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0080] In yet another embodiment, the compound of formula (IV) is a compound of formula (IVB-ii):

[0081] (IVB-ii), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

[0082] In still another embodiment, the compound of formula (IV) is a compound of formula (IVE-i):

[0083] (IVE-i), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein. In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound that is or a pharmaceutically acceptable salt thereof.

[0084] BRIEF DESCRIPTION OF THE DRAWINGS

[0085] FIG. 11H NMR spectrum of Compound 159.

[0086] FIG. 21H NMR spectrum of Compound 158.

[0087] FIG. 3 ES mass spectrum of Compound 158.

[0088] FIG. 41H NMR spectrum of Compound 403.

[0089] FIG. 51H NMR spectrum of Compound 402.

[0090] FIG. 6 ES mass spectrum of Compound 402.

[0091] FIG. 71H NMR spectrum of Compound 399.

[0092] FIG. 8 ES mass spectrum of Compound 399.

[0093] FIG. 91H NMR spectrum of Compound 400.

[0094] FIG. 10 ES mass spectrum of Compound 400.

[0095] FIG. 111H NMR spectrum of Compound 398.

[0096] FIG. 12 ES mass spectrum of Compound 398.

[0097] FIG. 131H NMR spectrum of Compound 401.

[0098] FIG. 14 ES mass spectrum of Compound 401.

[0099] FIG. 15 Novel anthelmintic discovery pipeline for human GINs.

[0100] FIG. 16 Primary screening using larval development of A. ceylanicum hookworms.

[0101] FIG. 17 Young adult A. ceylanicum hookworm screens. The top panel shows healthy and motile worms from the DMSO-treated or nonactive test compounds. The lower panel shows dead or intoxicated worms from ivermectin or active compounds. Scale bar 1 mm.

[0102] FIG. 18A - FIG. 18C Adult parasite screening of T. muris whipworm. (A) Adult whipworms, male and female treated with 30pM Levamisole or 1% DMSO. Scale bar 1 mm. (B) Motility readout screenshot from Wormassay-6 software using the Womrinator imaging setup. (C) Example of calculated motility readout, showing adult-parasite actives with at least 50% motility inhibition relative to the DMSO control.

[0103] FIG. 19 Mammalian cells fractional viability of select compounds. Doses tested: 31.6, 10, 3.16, 1 , 0.3, 0.1, 0.03, 0.01, 0.003, and 0.001 pM. FIG. 20 Summary of in vivo validation of anthelmintic candidates tested initially at 50 mg / kg against Ancylostoma ceylanicum hookworm in Syrian hamsters.

[0104] FIG. 21 Tyrphostins and Compound 337 in vivo validation (15 and 5 mg / kg).

[0105] FIG. 22 Cyathostomin L1 survival Assay using sensitive and naturally resistant isolates. Sensitive (circle) and resistant (square).

[0106] FIG. 23 Ancylostoma caninum L1 survival Assay using sensitive and naturally resistant isolates. Sensitive (circle) and resistant (square). * Shows the dose of the drug that induced a significant difference between the two isolates using Sidak’s multiple comparison test. Compound 89 (P-value= 0.0326) and Compound 91 (P-value = 0.0157).

[0107] FIG. 24 Compound 156 safety and in vivo validation.

[0108] FIG. 25 In vivo validation of ESI-09 analogs.

[0109] FIG. 26 ESI-09 (Compound 187) and eight of its analogs were tested in doseresponse against A. ceylanicum hookworms and T. muris whipworms to generate motility IC- 50.

[0110] DETAILED DESCRIPTION

[0111] Provided herein are benziothiazole compounds, tyrphostin compounds, ESI-09 analogues, pharmaceutical compositions that comprise these compounds, and methods of treatment. These compounds are useful in the treatment of parasitic infections including anthelmintic-resistant parasitic infections.

[0112] Definitions

[0113] Listed below are definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0114] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0115] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0116] As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0117] The term “administration” or the like as used herein refers to the providing a therapeutic agent to a subject. Multiple techniques of administering a therapeutic agent exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0118] The term “treat,” “treated,” “treating,” or “treatment” includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated. In certain embodiments, the treatment comprises bringing into contact with a worm an effective amount of a compound disclosed herein for conditions related to parasitic infections.

[0119] As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

[0120] As used herein, the term “patient,” “individual,” or “subject” refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and marine mammals. In an embodiment, the patient, subject, or individual is human.

[0121] As used herein, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0122] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e. , the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0123] As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional nontoxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase “pharmaceutically acceptable salt” is not limited to a mono, or 1 :1, salt. For example, “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0124] As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0125] The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound of the disclosure and a co- agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound of the disclosure and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0126] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0127] The term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C , C1-6 and the like.

[0128] As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e. , C1-6 alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains. The term “Cn-malkyl,” refers to an alkyl group having n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, and hexyl. Other examples of C1-6 alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0129] As used herein, the term “alkenyl” refers to a monovalent group derived from a hydrocarbon moiety containing, in certain embodiments, from two to six, or two to eight carbon atoms having at least one carbon-carbon double bond. The alkenyl group may or may not be the point of attachment to another group. The term “alkenyl” includes, but is not limited to, ethenyl, 1 -propenyl, 1-butenyl, heptenyl, octenyl and the like. The term “Cn-malkenyl” refers to an alkenyl group having n to m carbons.

[0130] The term “alkynyl” employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. The term “Cn-malkynyl” refers to an alkynyl group having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term “haloalkyl” refers to an alkyl group, as defined above, substituted with one or more halo substituents, wherein alkyl and halo are as defined herein. The term “Cn-mhaloalkyl” refers to a Cn-malkyl group having n to m carbon atoms and from at least one up to {2(m)+1} halogen atoms, which may either be the same or different. Haloalkyl includes, by way of example, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like.

[0131] As used herein, the term “alkoxy” refers to the group — O-alkyl, wherein alkyl is as defined herein. The term “Cn-malkoxy” refers to an alkoxy group, the alkyl group of which has n to m carbons. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, sec-butoxy, t-butoxy and the like.

[0132] As used herein, the term “haloalkoxy” refers to an -O-haloalkyl group, wherein haloalkyl is as defined herein. The term “Cn-mhaloalkoxy” refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons. Haloalkoxy includes, by way of example, chloromethoxy, trifluoromethoxy, bromoethoxy, chlorofluoroethoxy, and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0133] As used herein, the term “alkylthio” refers to the group — S-alkyl, wherein alkyl is as defined herein. The term “Cn-malkylthio” refers to an alkylthio group, the alkyl group of which has n to m carbons. Alkylthio includes, by way of example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, t-butylthio and the like.

[0134] As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.

[0135] As used herein, the term “cycloalkyl” means a non-aromatic carbocyclic system that is fully saturated having 1 , 2 or 3 rings wherein such rings may be fused. The term “fused” means that a second ring is present (i.e. , attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 atoms. The term “Cn-mcycloalkyl” refers to a cycloalkyl that has n to m ring member carbon atoms. In an embodiment, “cycloalkyl” is C3-C10 cycloalkyl. The term “cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1 ]pentyl.

[0136] As used herein, the term “heterocyclyl” or “heterocycloalkyl” means a non-aromatic carbocyclic system containing 1 , 2, 3 or 4 heteroatoms selected independently from N, O, and S and having 1 , 2 or 3 rings wherein such rings may be fused, wherein fused is defined above. In an embodiment, “heterocyclyl” or “heterocycloalkyl” is 3-10 membered heterocycloalkyl. Heterocyclyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 atoms, and containing 0, 1, or 2 N, O, or S atoms. The term “heterocyclyl” includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams) and also specifically includes, but is not limited to, epoxidyl, oxetanyl, tetrahydro-furanyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1 ,3-oxazinanyl, 1 ,3-thiazinanyl, 2- azabicyclo[2.1.1]hexanyl, 5-azabicyclo-[2.1.1]hexanyl, 6-azabicyclo[3.1.1] heptanyl, 2- azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]-heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3- azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8- azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3-oxa-9- azabicyclo[3.3.1]nonanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]- heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 2- oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]nonanyl, and 8-oxabicyclo[3.2.1]octanyl.

[0137] As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n + 2) delocalized TT (pi) electrons, where n is an integer.

[0138] As used herein, the term “aryl” means an aromatic carbocyclic system containing 1 (monocyclic), 2 (bicyclic) or 3 rings (tricyclic), wherein such rings may be fused, wherein fused is defined above. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated. The term “Cn-maryl” refers to an aryl group having from n to m ring carbon atoms. In an embodiment, “aryl” is Ce-C aryl. The term “aryl” includes, but is not limited to, phenyl, naphthyl, indanyl, and 1 ,2,3,4-tetrahydronaphthalenyl. In some embodiments, aryl groups have 6 carbon atoms. In some embodiments, aryl groups have from six to ten carbon atoms. In some embodiments, aryl groups have from six to sixteen carbon atoms.

[0139] As used herein, the term “heteroaryl” means an aromatic carbocyclic system containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, and S and having 1, 2, or 3 rings wherein such rings may be fused, wherein fused is defined above. In an embodiment, “heteroaryl” is 5-10 membered heteroaryl. The term “heteroaryl” includes, but is not limited to, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5, 6,7,8- tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta- [c]pyridinyl , 1 ,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2, 4,5,6- tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazolyl, 6,7-dihydro-5H- pyrrolo[1 ,2-b][1 ,2,4]triazolyl , 5,6,7,8-tetrahydro-[1 ,2,4]triazolo[1 , 5-a]pyridinyl , 4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyridinyl, 4,5,6,7-tetrahydro-1 H-indazolyl and 4,5,6,7-tetrahydro- 2H-indazolyl.

[0140] A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more (e.g., 1 , 2 or 3) ring atoms are independently selected from N, O and S. Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1 ,2,3-triazolyl, tetrazolyl, 1 ,2,3- thiadiazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-triazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,3,4- triazolyl, 1 ,3,4-thiadiazolyl and 1 ,3,4-oxadiazolyl.

[0141] A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g., 1 , 2 or 3) ring atoms are independently selected from N, O and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

[0142] It is to be understood that if an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl moiety may be bonded or otherwise attached to a designated moiety through differing ring atoms (i.e., shown or described without denotation of a specific point of attachment), then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term “pyridinyl” means 2-, 3- or 4-pyridinyl, the term “thienyl” means 2- or 3-thienyl, and so forth.

[0143] As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

[0144] As used herein, the term “optionally substituted” means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

[0145] The terms “independently selected” and “independently at each occurrence” are used herein to indicate that, for a variable which occurs in more than one location in a genus, the identity of the variable is determined separately in each instance. For example, if Rxappears as a substituent on two different atoms, the two instances of Rxmay be the same moiety, or different moieties. The same is true if a single atom is substituted with more than one instance of Rx. The identity of Rxin each instance is determined independently of the identity of the other(s).

[0146] In non-limiting embodiments, when a substituent is designated in the form: then it is to be understood that substituent R can occur p number of times on the ring, and R can be a different moiety at each occurrence. It is understood that each R may replace any hydrogen atom attached to a ring atom, including one or both of the (CH2)n hydrogen atoms. Further, in the above example, should the variable Q be defined to include hydrogen atoms, such as when Q is CH2, NH, etc., any floating substituent such as R in the above example, can replace a hydrogen atom of the Q variable as well as a hydrogen atom in any other non-variable component of the ring.

[0147] In non-limiting embodiments, when a chemical bond is designated in the form: then it is to be understood that the bond is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds. For example, Formula (IA-II) encompasses, at least, Formula lA-lla and Formula lA-llb, where a compound of Formula lA-llb is a cis compound, a trans compound, or a mixture of cis and trans compounds.

[0148] (lA-lla) (lA-llb)

[0149] In non-limiting embodiments, when a chemical bond is designated in the form: then it is to be understood that the bond is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds. For example, Formula (lA-lla) encompasses, at least, Compound 4, Compound 3, and Compound 2, where Compound 2 may be a mixture of Compound 4 and Compound 3.

[0150] (lA-lla)

[0151] In an embodiment, the language “a mixture of cis and trans double bonds,” encompasses, for example, a mixture of:

[0152] Compounds

[0153] Provided herein are tyrphostin compounds. These compounds are useful in the treatment of parasitic infections including anthelmintic-resistant parasitic infections.

[0154] In an aspect, provided herein is a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein: ring D and ring E are each independently selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;

[0155] Y8is selected from the group consisting of O, NH, and N(CI-6 alkyl);

[0156] R9is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R15;

[0157] R10, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, NH2, N(H)(CI-6 alkyl), N(CI-6 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R16;

[0158] R11is selected from the group consisting of H, -CN, OH, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R17;

[0159] R12is selected from the group consisting of H, -CN, OH, C2-6 alkenyl, and C2-6 alkynyl, wherein C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with one, two, or three R18;

[0160] R13is selected from the group consisting of -CN, OH, halo, SO2C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R19;

[0161] R14, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, NH2, N(H)(CI-6 alkyl), N(CI-6 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R20;

[0162] R15, R16, R17, R18, R19and R20, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl^; e and f are each independently 0, 1 , 2, 3, or 4; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0163] In an embodiment, ring D and ring E are each independently selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;

[0164] Y8is selected from the group consisting of NH and N(CI-6 alkyl);

[0165] R9is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or two R15;

[0166] R10, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or two R16;

[0167] R11is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or two R17;

[0168] R12is selected from the group consisting of H, -CN, OH, C2-6 alkenyl, and C2-6 alkynyl, wherein C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with one or two R18; R13is selected from the group consisting of -CN, OH, SO2C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or two R19;

[0169] R14, independently at each occurrence, is selected from the group consisting of -CN, OH, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or two R20;

[0170] R15, R16, R17, R18, R19and R20, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, and NH2; e and f are each independently 0, 1 , 2, or 3; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0171] In another embodiment, ring D and ring E are each independently selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N and O;

[0172] Y8is selected from the group consisting of NH and N(CI-6 alkyl);

[0173] R9is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one R15;

[0174] R10, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, NH2, C1-6 alkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R16;

[0175] R11is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R17;

[0176] R12is selected from the group consisting of H, -CN, OH, C2-6 alkenyl, and C2-6 alkynyl, wherein C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with one R18;

[0177] R13is selected from the group consisting of -CN, OH, SO2C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one R19;

[0178] R14, independently at each occurrence, is selected from the group consisting of -CN, OH, NH2, C1-6 alkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R20;

[0179] R15, R16, R17, R18, R19and R20, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, and NH2; e and f are each independently 0, 1 , or 2; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds. In yet another embodiment, the compound of formula II is a compound of formula HA:

[0180] (HA), or a pharmaceutically acceptable salt thereof.

[0181] In still another embodiment, the compound of formula II is a compound of formula 11 B:

[0182] (IIB), or a pharmaceutically acceptable salt thereof.

[0183] In an embodiment, at least one of ring D and ring E is phenyl.

[0184] In another embodiment, the compound of formula II is a compound of formula HA-i:

[0185] (HA-i), or a pharmaceutically acceptable salt thereof.

[0186] In yet another embodiment, the compound of formula II is a compound of formula 11 B- i:

[0187] (HB-i), or a pharmaceutically acceptable salt thereof. In an embodiment of Formula (II), ring D and ring E are both phenyl.

[0188] In still another embodiment, the compound of formula II is a compound of formula

[0189] IIA-ia:

[0190] (IIA-ia), or a pharmaceutically acceptable salt thereof.

[0191] In an embodiment, the compound of formula II is a compound of formula IIB-ia:

[0192] (IIB-ia), or a pharmaceutically acceptable salt thereof.

[0193] In another embodiment, the compound of formula II is a compound of formula IIA-ii: or a pharmaceutically acceptable salt thereof, wherein:

[0194] Y8is selected from the group consisting of NH and N(CI-6 alkyl);

[0195] R9is selected from the group consisting of H and C1-6 alkyl;

[0196] R10, independently at each occurrence, is selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R16;

[0197] R11is selected from the group consisting of H and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R17; R13is selected from the group consisting of -CN, halo, SO2C1-6 alkyl, C1-6 alkoxy, and

[0198] C2-6 alkynyl, wherein C1-6 alkoxy and C2-6 alkynyl are each optionally substituted with one R19; and

[0199] R16, R17, and R19, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, and NH2.

[0200] In an embodiment of formula IIA-ii,

[0201] Y8is selected from the group consisting of NH and N(CI-6 alkyl);

[0202] R9is selected from the group consisting of H and C1-6 alkyl;

[0203] R10, independently at each occurrence, is selected from the group consisting of C1-6 alkyl and C1-6 alkoxy;

[0204] R11is selected from the group consisting of H and C1-6 alkyl; and

[0205] R13is selected from the group consisting of -CN, halo, SO2C1-6 alkyl, C1-6 alkoxy, and C2-6 alkynyl.

[0206] In an embodiment, the compound of formula II is a compound of formula IIB-ii: or a pharmaceutically acceptable salt thereof. wherein:

[0207] Y8is selected from the group consisting of NH and N(CI-6 alkyl);

[0208] R9is selected from the group consisting of H and C1-6 alkyl;

[0209] R10, independently at each occurrence, is selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R16;

[0210] R11is selected from the group consisting of H and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R17;

[0211] R13is selected from the group consisting of -CN, halo, SO2C1-6 alkyl, C1-6 alkoxy, and C2-6 alkynyl, wherein C1-6 alkoxy and C2-6 alkynyl are each optionally substituted with one R19; and

[0212] R16, R17, and R19, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, and NH2.

[0213] In an embodiment of formula IIB-ii,

[0214] Y8is selected from the group consisting of NH and N(CI-6 alkyl);

[0215] R9is selected from the group consisting of H and C1-6 alkyl; R10, independently at each occurrence, is selected from the group consisting of C1-6 alkyl and C1-6 alkoxy;

[0216] R11is selected from the group consisting of H and C1-6 alkyl; and

[0217] R13is selected from the group consisting of -CN, halo, SO2C1-6 alkyl, C1-6 alkoxy, and C2-6 alkynyl.

[0218] In an embodiment, Y8is NH. In another embodiment, R9is H or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R15. In yet another embodiment, R9is H or C1-6 alkyl. In another embodiment, R9is C1-6 alkyl optionally substituted with one R15. In still another embodiment, R9is H.

[0219] In yet another embodiment, R10, independently at each occurrence, is selected from C1-6 alkyl and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R16. In still another embodiment, R10, independently at each occurrence, is selected from C1-6 alkyl and C1-6 alkoxy. In an embodiment each R10is C1-6 alkyl. In still another embodiment, R11is selected from the group consisting of H and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R17. In an embodiment, R11is selected from the group consisting of H and C1-6 alkyl. In another embodiment, R11is H.

[0220] In an embodiment, R13is selected from the group consisting of -CN, halo, SO2C1-6 alkyl, C1-6 alkoxy, and C2-6 alkynyl, wherein C1-6 alkoxy and C2-6 alkynyl are each optionally substituted with one R19. In an embodiment, R13is selected from the group consisting of - CN, SO2C1-6 alkyl, C1-6 alkoxy, and C2-6 alkynyl, wherein C1-6 alkoxy and C2-6 alkynyl are each optionally substituted with one R19. In another embodiment, R13is selected from the group consisting of -CN, -F, -Br, -I, SO2C1-6 alkyl, and C2-6 alkynyl, wherein C2-6 alkynyl is optionally substituted with one R19. In yet another embodiment, R13is selected from the group consisting of -CN, SO2C1-6 alkyl, and C2-6 alkynyl, wherein C2-6 alkynyl is optionally substituted with one R19. In still another embodiment, R13is selected from the group consisting of -CN, SO2C1-6 alkyl, and C2-6 alkynyl. In an embodiment, R13is selected from the group consisting of SO2C1-6 alkyl and C2-6 alkynyl. In yet another embodiment, R13is SO2C1-6 alkyl. In still another embodiment, R13is C2-6 alkynyl. In an embodiment, R13is halo. In another embodiment, R13is -F, -Br, or I. In yet another embodiment, R13is -F. In still another embodiment, R13is -Br. In an embodiment, R13is -I.

[0221] In another embodiment, R14, independently at each occurrence, is selected from the group consisting of -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R20. In yet another embodiment, R14, independently at each occurrence, is selected from the group consisting of -CN, OH, and C1-6 alkyl. In still another embodiment, R14, independently at each occurrence, is C1-6 alkyl. In yet another embodiment, f is 0 or 1. In still another embodiment, f is 1 and R14is C1-6 alkyl. In an embodiment, f is 0. In still another embodiment, the compound of Formula II is selected from the group consisting of a compound in Table 1, or a pharmaceutically acceptable salt thereof.

[0222] Table 1 In an aspect, provided herein is a compound that is selected from the group consisting of a compound in Table 2, or a pharmaceutically acceptable salt thereof.

[0223] In another aspect, provided herein is a compound of formula II IB: (HIB), or a pharmaceutically acceptable salt thereof, wherein:

[0224] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23;

[0225] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0226] R21and R22are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCi-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6alkyl), C(S)N(H)(CI-6alkyl-N3), C(S)N(CI-6alkyl)2, N(H)C(O)H, N(H)C(O)OH, N(CI-6 alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, phenyl, and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that when is c / s double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =0 and provided that when R16or R18is Br, then R21and R22are both CN; R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6alkyl, and C(O)NH2;

[0227] R24, independently at each occurrence, is selected from the group consisting of -CN, OH, and halo;

[0228] R25is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, NO2, NH2, C(O)OH, C(O)CI-6alkyl, and C(O)NH2; and is a single bond, a c / s double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0229] In an embodiment, the compound of formula 111 B is a compound of formula IIIB-i:

[0230] (IHB-i), or a pharmaceutically acceptable salt thereof, wherein:

[0231] Y16is selected from the group consisting of O and S;

[0232] R15, R17, and R19are each independently selected from the group consisting of H, - CN, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23;

[0233] R16and R18are each independently selected from the group consisting of H, -CN, OH, F, Cl, I, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23;

[0234] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0235] R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6alkyl, and C(O)NH2;

[0236] R24is selected from the group consisting of -CN, OH, and halo;

[0237] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, phenyl, and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21is not =0;

[0238] R25is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, N02, NH2, C(O)OH, C(O)CI-6alkyl, and C(O)NH2;

[0239] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl- N3), and N(CI-6 alkyl)2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0240] In an embodiment of formula IIIB-i,

[0241] Y16is selected from the group consisting of O and S;

[0242] R15, R17, and R19are each independently selected from the group consisting of H, - CN, OH, halo, N02, NH2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R23;

[0243] R16and R18are each independently selected from the group consisting of H, -CN, OH, F, Cl, I, N02, NH2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R23;

[0244] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0245] R23is selected from the group consisting of C(O)OH, C(0)Ci-6 alkyl, and C(O)NH2;

[0246] R24is selected from the group consisting of -CN, OH, and halo;

[0247] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl , OH, -CN, - NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(0)N(CI-6 alkyl)2, C(S)OH, C(S)Ci-6 alkyl, C(S)NH2, phenyl, and 5- or 6-membered heteroaryl;

[0248] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl- N3), and N(CI-6 alkyl)2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0249] In another embodiment of formula IIIB-i,

[0250] Y16is selected from the group consisting of O and S;

[0251] R15, R17, and R19are each independently selected from the group consisting of H, OH, halo, N02, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0252] R16and R18are each independently selected from the group consisting of H, OH, F, Cl, I, N02, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0253] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl; R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl , OH, -CN, - NC, NH2, C(O)OH, C(O)OCI-6 alkyl, C(O)Ci-6alkyl, C(O)NH2, C(S)OH, C(S)Ci-6alkyl, and C(S)NH2;

[0254] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl- N3), and N(CI-6 alkyl)2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0255] In another embodiment of formula IIIB-i,

[0256] Y16is selected from the group consisting of O and S;

[0257] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1- 6 alkoxy are each optionally substituted with one R23;

[0258] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0259] R23is selected from the group consisting of C(O)OH, C(O)Ci-6 alkyl, and C(O)NH2;

[0260] R24is selected from the group consisting of -CN, OH, and halo;

[0261] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl , OH, -CN, - NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6 alkyl)2, C(S)OH, C(S)Ci-6 alkyl, C(S)NH2, phenyl, and 5- or 6-membered heteroaryl; and

[0262] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl- N3), and N(CI-6 alkyl)2.

[0263] In another embodiment of formula IIIB-i,

[0264] Y16is selected from the group consisting of O and S;

[0265] R15, R17, and R19are each independently selected from the group consisting of H, OH, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0266] R16and R18are each independently selected from the group consisting of H, OH, F, Cl, I, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0267] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl;

[0268] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl , OH, -CN, - NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(S)OH, C(S)Ci-6alkyl, and C(S)NH2;

[0269] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl- N3), and N(CI-6 alkyl)2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds. In an embodiment, the compound of formula IIIB-i is a compound of formula IIIB-ia: or a pharmaceutically acceptable salt thereof, wherein:

[0270] Y16is selected from the group consisting of O and S;

[0271] R16and R18are each independently selected from the group consisting of H, OH, F, Cl, I, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0272] R17is selected from the group consisting of H, OH, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0273] R21is selected from the group consisting of H, C1-6 alkyl, OH, -CN, -NC, and NH2;

[0274] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl- N3), and N(CI-6 alkyl^; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0275] In an embodiment of formula IIIB-ia,

[0276] Y16is selected from the group consisting of O and S;

[0277] R16and R18are each independently selected from the group consisting of H, OH, F, Cl, I, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0278] R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0279] R21is selected from the group consisting of OH, -CN, -NC, and NH2;

[0280] R27is selected from the group consisting of NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl-Ns), and N(CI-6 alkyl^; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0281] In an embodiment, the compound of formula IIIB-ia is a compound of formula IIIB-ia-i: (IIIB-ia-i), or a pharmaceutically acceptable salt thereof, wherein:

[0282] Y16is selected from the group consisting of O and S;

[0283] R16and R18are each independently selected from the group consisting of H, OH, F, Cl, I, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0284] R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0285] R21is selected from the group consisting of OH, -CN, -NC, and NH2; and

[0286] R27is selected from the group consisting of NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl-Ns), and N(CI-6 alkyl)2.

[0287] In an embodiment, R18is Br and R27is N(H)(CI-6 alkyl-Ns).

[0288] In an embodiment, at least one of R15, R16, R17, R18, and R19is selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with C(O)OH or C(O)NH2. In another embodiment, R15and R19are H. In yet another embodiment, R16is selected from the group consisting of H, OH, NO2, C1-6 alkyl, and C1-6 alkoxy. In another embodiment, R16is H. In yet another embodiment, R16is C1-6 alkyl. In still another embodiment, R16is C1-6 alkoxy. In an embodiment, R16is OH. In another embodiment, R16is NO2.

[0289] In yet another embodiment, R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23. In still another embodiment, R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, and C1-6 alkoxy. In another embodiment, R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, and O-C2-6 alkynyl. In an embodiment, R17is selected from the group consisting of H, OH, and C1-6 alkyl. In another embodiment, R17is H. In yet another embodiment, R17is OH. In still another embodiment, R17is C1-6 alkyl. In an embodiment, R17is NO2. In another embodiment, R17is O-C2-6 alkynyl.

[0290] In an embodiment, R18is selected from the group consisting of H, OH, halo, NO2, C1-6 alkyl, and C1-6 alkoxy. In another embodiment, R18is H. In yet another embodiment, R18is OH. In still another embodiment, R18is halo. In another embodiment, R18is selected from F, Cl, and I. In an embodiment, R18is NO2. In another embodiment, R18is C1-6 alkyl. In yet another embodiment, R18is C1-6 alkoxy.

[0291] In still another embodiment, R20is selected from the group consisting of H and C1-6 alkyl. In an embodiment, R20is H. In another embodiment, R21is selected from the group consisting of OH, -CN, -NC, and NH2. In yet another embodiment, R21is selected from the group consisting of -CN and - NC. In an embodiment, R21is -CN. In another embodiment, R21is -NC.

[0292] In yet another embodiment, R22is selected from C(S)NH2, C(S)N(H)(CI-6 alkyl), and C(S)N(CI-6 alkyl)2. In still another embodiment, R22is C(S)NH2. In an embodiment, R22is C(S)N(CI-6alkyl)2.

[0293] In another embodiment, Y16is S. In yet another embodiment, R27is selected from the group consisting of NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl-Ns), and N(CI-6 alkyl)2. In an embodiment, R27is selected from the group consisting of NH2, N(H)(CI-6 alkyl), and N(H)(CI-6 alkyl-Ns). In another embodiment, R27is NH2. In yet another embodiment, R27is N(H)(CI-6 alkyl). In still another embodiment, R27is N(H)(CI-6 alkyl-Ns),

[0294] In another embodiment, the compound is selected from the group consisting of a compound in Table 3, or a pharmaceutically acceptable salt thereof. Table 3

[0295] In an embodiment, the compound of formula III is a compound of formula IIIB-iia:

[0296] (IIIB-iia) or a pharmaceutically acceptable salt thereof, wherein:

[0297] R16, R17, and R18are each independently selected from the group consisting of H, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and O-C2-6 alkynyl.

[0298] In an embodiment of IIIB-iia,

[0299] R16and R17are each independently selected from the group consisting of H, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and O-C2-6 alkynyl; and

[0300] R18is halo.

[0301] In an embodiment, the compound of formula III is a compound of formula IIIB-va:

[0302] (IIIB-va) or a pharmaceutically acceptable salt thereof, wherein:

[0303] R16and R17are each independently selected from the group consisting of H, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and O-C2-6 alkynyl.

[0304] In an embodiment of IIIB-va,

[0305] R16is selected from the group consisting of H, OH, C1-6 alkyl, C1-6 haloalkyl, and O-

[0306] C2-6 alkynyl; and

[0307] R17is O-C2-6 alkynyl.

[0308] In another embodiment of IIIB-va,

[0309] R16is selected from the group consisting of H, OH, C1-6 alkyl, and O-C2-6 alkynyl; and R17is O-C2-6 alkynyl.

[0310] In an embodiment, R16is selected from the group consisting of H, OH, and C1-6 alkyl. In another embodiment, R16is C1-6 alkyl. In yet another embodiment, R17is O-C2-6 alkynyl.

[0311] In yet another embodiment, R16is selected from the group consisting of H, OH, NO2, C1-6 alkyl, and C1-6 alkoxy. In another embodiment, R16is H. In yet another embodiment, R16is C1-6 alkyl. In still another embodiment, R16is C1-6 alkoxy. In an embodiment, R16is OH. In another embodiment, R16is NO2.

[0312] In still another embodiment, R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, and C1-6 alkoxy. In another embodiment, R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, and O-C2-6 alkynyl. In an embodiment, R17is selected from the group consisting of H, OH, and C1-6 alkyl. In another embodiment, R17is H. In yet another embodiment, R17is OH. In still another embodiment, R17is C1-6 alkyl. In an embodiment, R17is C1-6 alkoxy. In an embodiment, R17is NO2. In another embodiment, R17is O-C2-6 alkynyl.

[0313] In an embodiment, R18is selected from the group consisting of H, OH, halo, NO2, C1-6 alkyl, and C1-6 alkoxy. In another embodiment, R18is H. In yet another embodiment, R18is OH. In still another embodiment, R18is halo. In another embodiment, R18is selected from F, Cl, and I. In an embodiment, R18is NO2. In another embodiment, R18is C1-6 alkyl. In yet another embodiment, R18is C1-6 alkoxy.

[0314] In another embodiment, the compound is selected from the group consisting of a compound in Table 4, or a pharmaceutically acceptable salt thereof.

[0315] Table 4

[0316] In an aspect, provided herein is a pharmaceutical composition comprising any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0317] The compounds disclosed herein may exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, and the like).

[0318] It is generally well known in the art that any compound that will be converted in vivo to provide a compound disclosed herein is a prodrug within the scope of the present disclosure. Compounds provided herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the disclosure can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can used in various studies such as NMR spectroscopy, metabolism experiments, and / or assays.

[0319] In the compounds provided herein, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Also, unless otherwise stated, when a position is designated specifically as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e. , at least 45% incorporation of deuterium).

[0320] Methods of Treatment

[0321] Provided herein are methods of treating parasitic infections with, inter alia, benziothiazole compounds, tyrphostin compounds, and ESI-09 analogues. These methods are useful in the treatment of anthelmintic-resistant parasitic infections.

[0322] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof:

[0323] wherein: ring A is selected from the group consisting of Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl, wherein Ce-io aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, three, or four R4, and wherein 5-10 membered heteroaryl and 3-11 membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S; ring B is selected from the group consisting of absent, Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl, wherein Ce-io aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, three, or four R5, and wherein 5-10 membered heteroaryl and 3-11 membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S;

[0324] Y1is selected from the group consisting of C(R6)2, NR7, O, and S;

[0325] Y2is CR8or N;

[0326] Y3is selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, O, S, and SO2;

[0327] R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, OH, -CN, halo, NH2, N(H)(CI-6alkyl), and N(CI-6alkyl)2;

[0328] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2, provided that when is c / s double bond, a trans double, or a mixture of cis and trans double bonds, then R2and R3are not =0;

[0329] R6and R8, independently at each occurrence, are selected from the group consisting of H, OH, -CN, halo, NH2, N(H)(CI-6alkyl), and N(CI-6alkyl)2;

[0330] R7is selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2- 6 alkenyl, and C2-6 alkynyl; a is 0, 1 , 2, 3, or 4; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0331] In an embodiment, ring A is selected from the group consisting of Ce- aryl and 5-10 membered heteroaryl, wherein Ce-io aryl and 5-10 membered heteroaryl are each optionally substituted with one, two, three, or four R4, and wherein 5-10 membered heteroaryl contains one, two, or three ring heteroatoms selected from the group consisting of N, O, and S; ring B is selected from the group consisting of absent, Ce- aryl, and 3-11 membered heterocycloalkyl, wherein Ce- aryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, or three R5, and wherein 3-11 membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;

[0332] Y1is selected from the group consisting of C(R6)2, NR7, O, and S;

[0333] Y2is CR8or N;

[0334] Y3is selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, O, S, and SO2;

[0335] R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, OH, -CN, halo, NH2, N(H)(CI-6alkyl), and N(CI-6alkyl)2;

[0336] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R2and R3are not =0;

[0337] R6and R8, independently at each occurrence, are selected from the group consisting of H, OH, -CN, halo, and NH2;

[0338] R7is selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl; a is 0, 1 , 2, or 3; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0339] In another embodiment, ring A is selected from the group consisting of phenyl and 5-10 membered heteroaryl, wherein phenyl and 5-10 membered heteroaryl are each optionally substituted with one, two, or three R4, and wherein 5-10 membered heteroaryl contains one or two ring heteroatoms selected from the group consisting of N, O, and S; ring B is selected from the group consisting of absent, phenyl, and 3-6 membered heterocycloalkyl, wherein phenyl, and 3-6 membered heterocycloalkyl are each optionally substituted with one or two R5, and wherein 3-6 membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;

[0340] Y1is selected from the group consisting of NR7, O, and S;

[0341] Y2is CR8or N;

[0342] Y3is selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, O, S, and SO2;

[0343] R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2;

[0344] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R2and R3are not =0;

[0345] R7is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;

[0346] R8is selected from the group consisting of H, OH, -CN, halo, and NH2; a is 0, 1 , or 2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0347] In an embodiment of formula I, ring A is phenyl.

[0348] Thus, in yet another embodiment, the compound of formula I is a compound of formula IA: or a pharmaceutically acceptable salt thereof, wherein: b is 0, 1 , 2, or 3.

[0349] In an embodiment of formula I, ring A is 9- or 10-membered heteroaryl, ring B is absent, and Y3is absent, wherein 9- or 10-membered heteroaryl is optionally substituted with one, two, or three R4and wherein 9- or 10-membered heteroaryl contains one or two ring heteroatoms selected from the group consisting of N, O, and S.

[0350] Thus, in still another embodiment, the compound of formula I is a compound of formula IB: a pharmaceutically acceptable salt thereof, wherein:

[0351] Y4and Y5are each independently selected from the group consisting of CH2, NH, N(CI-6 alkyl), O, and S, provided that at least one of Y4and Y5is selected from the group consisting of NH, N(CI-6 alkyl), O, and S; b is 0, 1 , 2, or 3; and c is 0 or 1.

[0352] In an embodiment of formula I, ring A is 5-membered heteroaryl, ring B is absent, and Y3is absent, wherein 5-membered heteroaryl is optionally substituted with one, two, or three R4and wherein 5-membered heteroaryl contains one ring heteroatom selected from the group consisting of N, O, and S.

[0353] Thus, in an embodiment, the compound of formula I is a compound of formula IC: or a pharmaceutically acceptable salt thereof, wherein:

[0354] Y1is selected from the group consisting of NR7, O, and S;

[0355] Y2is CR8or N;

[0356] Y33is selected from the group consisting of NH, O, and S;

[0357] R1and R4, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2;

[0358] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2, provided that when is c / s double bond, a trans double bond, or a mixture of cis and trans double bonds, then R2and R3are not =0;

[0359] R7is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy; R8is selected from the group consisting of H, OH, -CN, halo, and NH2; a is 0, 1 , or 2; b is 0, 1 , 2, or 3; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0360] In an embodiment of formula IC,

[0361] Y1is selected from the group consisting of NH, O, and S;

[0362] Y2is CH or N;

[0363] Y33is selected from the group consisting of NH, O, and S;

[0364] R1and R4, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2;

[0365] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2; a is 0, or 1 ; b is 0, 1 , or 2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0366] In an embodiment of formula I A, ring B is phenyl or 6-membered heterocycloalkyl and Y3is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, O, S, and SO2, wherein phenyl and 6-membered heterocycloalkyl are each optionally substituted with one or two R5and wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S.

[0367] Thus, in another embodiment, the compound of formula I is a compound of formula IA-I:

[0368] (IA-I), or a pharmaceutically acceptable salt thereof, wherein: ring B is phenyl or 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S; b is 0, 1 , 2, or 3; and d is 0, 1 , or 2.

[0369] In an embodiment of formula IA-I, ring B is phenyl or 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;

[0370] Y1is selected from the group consisting of NR7, O, and S;

[0371] Y2is CR8or N;

[0372] Y3is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, O, S, and SO2;

[0373] R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2;

[0374] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2;

[0375] R7is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;

[0376] R8is selected from the group consisting of H, OH, -CN, halo, and NH2; a is 0, 1 , or 2; b is 0, 1 , 2, or 3; d is 0, 1 , or 2; and is a c / s double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0377] In another embodiment of formula IA-I, ring B is phenyl or 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N and O;

[0378] Y1is O or S;

[0379] Y2is N;

[0380] Y3is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, O, S, and SO2;

[0381] R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, OH, -CN, and halo;

[0382] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, OH, -CN, halo, and NH2;

[0383] R7is selected from the group consisting of H, C1-6 alkyl and C1-6 alkoxy;

[0384] R8is H or halo; a is 0 or 1 ; b is 0, 1 , or 2; d is 0 or 1 ; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds. In an embodiment of formula I or formula I A, ring A is phenyl, ring B is absent, and Y3is absent, wherein phenyl is optionally substituted with one, two, or three R4.

[0385] In an embodiment of formula IA, ring B is absent and Y3is absent.

[0386] Thus, in yet another embodiment, the compound of formula I is a compound of formula IA-II;

[0387] (IA-II), or a pharmaceutically acceptable salt thereof, wherein: b is 0, 1 , 2, or 3.

[0388] In an embodiment of formula IA-II,

[0389] Y1is selected from the group consisting of NR7, O, and S;

[0390] Y2is CR8or N;

[0391] R1and R4, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2;

[0392] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R2and R3are not =0;

[0393] R7is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;

[0394] R8is selected from the group consisting of H, OH, -CN, halo, and NH2; a is 0, 1 , or 2; b is 0, 1 , 2, or 3; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0395] In another embodiment of formula IA-II,

[0396] Y1is O or S;

[0397] Y2is N;

[0398] R1and R4, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, OH, -CN, and halo; R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, =0, OH, -CN, halo, and NH2, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R2and R3are not =0;

[0399] R7is selected from the group consisting of H, C1-6 alkyl and C1-6 alkoxy;

[0400] R8is H or halo; a is 0 or 1 ; b is 0, 1 , 2, or 3; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0401] In an embodiment of formula I C, b is 1 and is a a trans double bond.

[0402] Thus, in an embodiment, the compound of formula I is a compound of formula IC-I: or a pharmaceutically acceptable salt thereof, wherein:

[0403] Y1is selected from the group consisting of NH, O, and S;

[0404] Y2is CH or N;

[0405] Y33is selected from the group consisting of NH, O, and S;

[0406] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2; and

[0407] R4is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, - CN, halo, and NH2.

[0408] In still another embodiment, the compound of formula I is a compound of formula IA- la;

[0409] (lA-la), or a pharmaceutically acceptable salt thereof, wherein b is 0, 1 , 2, or 3; and d is 0 or 1.

[0410] In an embodiment of formula I A- la,

[0411] Y1is selected from the group consisting of NR7, O, and S;

[0412] Y2is CR8or N;

[0413] Y3is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, O, S, and SO2;

[0414] R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2;

[0415] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2;

[0416] R7is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;

[0417] R8is selected from the group consisting of H, OH, -CN, halo, and NH2; a is 0, 1 , or 2; b is 0, 1 , 2, or 3; d is 0 or 1 ; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0418] In another embodiment of formula lA-la,

[0419] Y1is O or S;

[0420] Y2is N;

[0421] Y3is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, O, S, and SO2;

[0422] R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, OH, -CN, and halo;

[0423] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, OH, -CN, halo, and NH2;

[0424] R7is selected from the group consisting of H, C1-6 alkyl and C1-6 alkoxy;

[0425] R8is H or halo; a is 0 or 1 ; b is 0, 1 , or 2; d is 0 or 1 ; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0426] In an embodiment, the compound of formula I is a compound of formula lA-lb;

[0427] or a pharmaceutically acceptable salt thereof, wherein:

[0428] Y6is selected from the group consisting of CH2, NH, O, and S;

[0429] Y7is selected from the group consisting of CH and N, provided that at least one of Y6and Y7is selected from the group consisting of N, NH, O, and S; b is 0, 1 , 2, or 3; and d is 0 or 1.

[0430] In an embodiment of formula lA-lb, d is 0, 1 , or 2.

[0431] In another embodiment of formula lA-lb,

[0432] Y1is selected from the group consisting of NR7, O, and S;

[0433] Y2is CR8or N;

[0434] Y3is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, O, S, and SO2;

[0435] Y6is selected from the group consisting of CH2, NH, O, and S;

[0436] Y7is selected from the group consisting of CH and N, provided that at least one of Y6and Y7is selected from the group consisting of N, NH, O, and S;

[0437] R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2;

[0438] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6alkyl)2;

[0439] R7is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;

[0440] R8is selected from the group consisting of H, OH, -CN, halo, and NH2; a is 0, 1 , or 2; b is 0, 1 , 2, or 3; d is 0, 1 , or 2; and is a c / s double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0441] In yet another embodiment of formula lA-lb, Y1is O or S;

[0442] Y2is N;

[0443] Y3is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, O, S, and SO2;

[0444] Y6is CH2or NH;

[0445] Y7is CH or N, provided that at least one of Y6and Y7is N or NH;

[0446] R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, OH, -CN, and halo;

[0447] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, OH, -CN, halo, and NH2;

[0448] R7is selected from the group consisting of H, C1-6 alkyl and C1-6 alkoxy;

[0449] R8is H or halo; a is 0 or 1 ; b is 0 or 1 ; d is 0, 1 , or 2; and is a c / s double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0450] In another embodiment, the compound of formula I is a compound of formula lA-lla:

[0451] (lA-lla), or a pharmaceutically acceptable salt thereof, wherein: b is 0, 1 , 2, or 3.

[0452] In an embodiment of formula I A- 1 la,

[0453] Y1is selected from the group consisting of NR7, O, and S;

[0454] Y2is CR8or N;

[0455] R1and R4, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2;

[0456] R2is selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2.

[0457] 6alkenyl, C2.6alkynyl, OH, -CN, halo, NH2, N(H)(CI-6alkyl), and N(CI-6alkyl)2; a is 0, 1 , or 2; and b is 0, 1 , 2, or 3.

[0458] In another embodiment of formula lA-lla, Y1is O or S;

[0459] Y2is N;

[0460] R1and R4, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, OH, -CN, and halo;

[0461] R2is selected from the group consisting of H, C1-6 alkyl, OH, -CN, halo, and NH2;

[0462] R7is selected from the group consisting of H, C1-6 alkyl and C1-6 alkoxy;

[0463] R8is H or halo; a is 0 or 1 ; and b is 0 or 1.

[0464] In yet another embodiment, the compound of formula I is a compound of formula IA- llb; or a pharmaceutically acceptable salt thereof, wherein: b is 0, 1 , 2, or 3; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0465] In an embodiment of formula lA-llb,

[0466] Y1is selected from the group consisting of NR7, O, and S;

[0467] Y2is CR8or N;

[0468] R1and R4, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, OH, -CN, and halo;

[0469] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R2and R3are not =0;

[0470] R7is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;

[0471] R8is selected from the group consisting of H, OH, -CN, halo, and NH2; a is 0, 1 , or 2; b is 0, 1 , 2, or 3; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0472] In another embodiment of formula lA-llb,

[0473] Y1is O or S;

[0474] Y2is N;

[0475] R1and R4, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2;

[0476] R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, =0, OH, -CN, halo, and NH2, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R2and R3are not =0;

[0477] R7is selected from the group consisting of H, C1-6 alkyl and C1-6 alkoxy;

[0478] R8is H or halo; a is 0 or 1 ; b is 0, 1 , or 2; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0479] In still another embodiment, Y1is O or S. In another embodiment, Y1is S. In an embodiment, Y2is N. In another embodiment, Y3is selected from the group consisting of absent, C1-6 alkyl, O, and SO2. In yet another embodiment, Y3is absent. In still another embodiment, Y3is selected from the group consisting of C1-6 alkyl, O, and SO2. In an embodiment, Y3is selected from the group consisting of C1-3 alkyl, O, and SO2. In yet another embodiment, Y4and Y5are each independently selected from the group consisting of NH, O, and S. In still another embodiment, Y6is selected from the group consisting of CH2, NH, and O.

[0480] In an embodiment, R1is selected from the group consisting of C1-6 alkyl, OH, -CN, halo, and NH2. In another embodiment, R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2. In yet another embodiment, R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, OH, -CN, halo, and NH2. In still another embodiment, R2is selected from the group consisting of H, C1-6 alkyl, OH, -CN, halo, and NH2.

[0481] In an embodiment, R4, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, OH, -CN, and halo. In another embodiment, R5, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, OH, - CN, and halo. In an embodiment, R7is selected from the group consisting of H, C1-6 alkyl, C1- 6 alkoxy, and C1-6 haloalkyl. In yet another embodiment, a is 0 or 1. In still another embodiment, c is 1. In an embodiment, ring A is selected from the group consisting of phenyl and 6-10 membered heteroaryl, wherein phenyl and 6-10 membered heteroaryl are each optionally substituted with one, two, or three R4, and wherein 6-10 membered heteroaryl contains one or two ring heteroatoms selected from the group consisting of N, O, and S.

[0482] In an embodiment, ring A is selected from the group consisting of phenyl and 8-10 membered heteroaryl, wherein phenyl and 8-10 membered heteroaryl are each optionally substituted with one, two, or three R4, and wherein 8-10 membered heteroaryl contains one or two ring heteroatoms selected from the group consisting of N, O, and S. In another embodiment, 8-10 membered heteroaryl is a bicyclic 8-10 membered heteroaryl.

[0483] In yet another embodiment, the compound of Formula I is selected from the group consisting of a compound in Table 5, or a pharmaceutically acceptable salt thereof. Table 5

[0484]

[0485]

[0486] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound of Table 6, or a pharmaceutically acceptable salt thereof, wherein: As a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0487] Table 6

[0488]

[0489] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0490] In an embodiment, the parasitic infection is a parasitic worm infection. In another embodiment, the parasitic worm infection is selected from the group consisting of roundworm infection, whipworm infection, hookworm infection, flatworm infection, tapeworm infection, fluke infection, and pinworm (threadworm) infection.

[0491] In yet another embodiment, the parasitic worm infection is selected from the group consisting of whipworm infection, hookworm infection, flatworm infection, tapeworm infection, fluke infection, and pinworm (threadworm) infection. In still another embodiment, the parasitic worm is resistant to one or more anthelmintic treatment.

[0492] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof:

[0493] (HI), wherein: ring F is selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;

[0494] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, NO2, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, Ci-6alkyl, Ci-6haloalkyl, Ci-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, and O-C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, and O-C2-6 alkynyl are each optionally substituted with one, two, or three R23; alternatively, R18and R19, together with the atom to which they are attached, form a ring selected from the group consisting of phenyl and 5- or 6-membered heteroaryl;

[0495] R20is selected from the group consisting of H, -CN, OH, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R24;

[0496] R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6 alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), and C(O)N(CI-6alkyl)2;

[0497] R24, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;

[0498] R21and R22are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, -NC, halo, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C(O)OH, C(O)OCi-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6alkyl), C(S)N(H)(CI-6alkyl-N3), C(S)N(CI-6alkyl)2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl, wherein Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, or three R25, provided that when is c / s double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =0; or one of R21and R22has the structure: wherein: ring G is selected from the group consisting of absent, Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl, wherein Ce-io aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, three, or four R26;

[0499] Y9and Y11are each independently selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O), and C(S), provided that at least one of Y9and Y11is selected from the group consisting of C(O), C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;

[0500] Y10is selected from the group consisting of absent, O, NH, and N(CI-6 alkyl); R25, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NO2, NH2, N(H)(CI-6 alkyl), N(CI-6alkyl)2, C(O)OH, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(0)N(CI-6 alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6alkyl), and C(S)N(CI-6alkyl)2;

[0501] R26, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NO2, NH2, N(H)(CI-6 alkyl), N(CI-6alkyl)2, C(O)OH, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(0)N(CI-6 alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6alkyl), and C(S)N(CI-6alkyl)2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0502] In an embodiment,

[0503] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, N02, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C1-6 alkyl, Ci-6haloalkyl, Ci-6alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R23; alternatively, R18and R19, together with the atom to which they are attached, form a ring selected from the group consisting of phenyl and 5- or 6-membered heteroaryl; and

[0504] R21and R22are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, -NC, halo, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C(O)OH, C(O)OCi-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6alkyl), C(S)N(H)(CI-6alkyl-N3), C(S)N(CI-6alkyl)2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl, wherein Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, or three R25, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =0; or one of R21and R22has the structure:

[0505] In another embodiment, R18is halo and the subject is resistant to one or more anthelmintic treatment.

[0506] In an embodiment, ring F is selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N and O;

[0507] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one or two R23; alternatively, R18and R19, together with the atom to which they are attached, form a ring selected from the group consisting of phenyl and 5- or 6-membered heteroaryl;

[0508] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or two R24;

[0509] R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6 alkyl, and C(O)NH2;

[0510] R24, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, and C1-6 alkyl;

[0511] R21and R22are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCi-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6alkyl), C(S)N(CI-6alkyl)2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, Ce- aryl, and 5-10 membered heteroaryl, wherein Ce- aryl and 5-10 membered heteroaryl are each optionally substituted with one or two R25, provided that when is c / s double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =0; or one of R21and R22has the structure: wherein: ring G is selected from the group consisting of absent, Ce- aryl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl, wherein Ce- aryl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, or three R26;

[0512] Y9and Y11are each independently selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C(O), and C(S), provided that at least one of Y9and Y11is selected from the group consisting of C(O), C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;

[0513] Y10is selected from the group consisting of absent, O, NH, and N(CI-6 alkyl); R25, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, Ci-6alkoxy, Ci-6haloalkyl, OH, -CN, halo, NO2, NH2, C(O)OH, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6 alkyl), C(O)N(CI-6alkyl)2, C(S)OH, and C(S)NH2;

[0514] R26, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, Ci-6haloalkyl, =0, OH, -CN, halo, N02, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C(O)OH, C(0)Ci-6 alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, and C(S)NH2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0515] In an embodiment, R18is halo and the subject is resistant to one or more anthelmintic treatment.

[0516] In another embodiment, ring F is selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N and O;

[0517] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, N02, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23; alternatively, R18and R19, together with the atom to which they are attached, form a ring selected from the group consisting of phenyl and 6-membered heteroaryl;

[0518] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0519] R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6alkyl, and C(O)NH2;

[0520] R24, independently at each occurrence, is selected from the group consisting of -CN, OH, and halo;

[0521] R21and R22are each independently selected from the group consisting of H, C1-6 alkyl, Ci-6haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCi-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6alkyl)C(O)H, phenyl, and 5- or e- membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =0; or one of R21and R22has the structure: wherein: ring G is selected from the group consisting of absent, phenyl, 5- or 6-membered heteroaryl, and 5-7 membered heterocycloalkyl, wherein phenyl, 5- or 6-membered heteroaryl, and 5-7 membered heterocycloalkyl are each optionally substituted with one or two R26;

[0522] Y9and Y11are each independently selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C(O), and C(S), provided that at least one of Y9and Y11is selected from the group consisting of C(O), C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;

[0523] Y10is selected from the group consisting of absent, O, NH, and N(CI-6 alkyl);

[0524] R25is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, NO2, NH2, C(O)OH, C(O)CI-6alkyl, and C(O)NH2;

[0525] R26, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, Ci-6haloalkyl, =0, OH, -CN, halo, N02, NH2, C(O)OH, C(O)Ci-6alkyl, C(O)NH2, C(0)N(H)(CI-6 alkyl), and C(O)N(CI-6alkyl)2; and is a single bond, a c / s double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0526] In an embodiment, R18is halo and the subject is resistant to one or more anthelmintic treatment.

[0527] In yet another embodiment, the compound of formula III is a compound of formula IIIA:

[0528] (HIA), or a pharmaceutically acceptable salt thereof.

[0529] In an embodiment of formula IIIA, ring F is selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N and O;

[0530] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, N02, NH2, CI-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23; alternatively, R18and R19, together with the atom to which they are attached, form a ring selected from the group consisting of phenyl and 6-membered heteroaryl;

[0531] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0532] R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6 alkyl, and C(O)NH2;

[0533] R24, independently at each occurrence, is selected from the group consisting of -CN, OH, and halo;

[0534] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, phenyl, and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21is are not =0; ring G is selected from the group consisting of absent, phenyl, 5- or 6-membered heteroaryl, and 5-7 membered heterocycloalkyl, wherein phenyl, 5- or 6-membered heteroaryl, and 5-7 membered heterocycloalkyl are each optionally substituted with one or two R26;

[0535] Y9and Y11are each independently selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C(0), and C(S), provided that at least one of Y9and Y11is selected from the group consisting of C(0), C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;

[0536] Y10is selected from the group consisting of absent, O, NH, and N(CI-6 alkyl);

[0537] R25is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, N02, NH2, C(O)OH, C(O)CI-6alkyl, and C(O)NH2;

[0538] R26, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, =0, -CN, halo, N02, NH2, C(O)OH, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), and C(O)N(CI-6alkyl)2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0539] In still another embodiment, the compound of formula III is a compound of formula IIIB: (IIIB), or a pharmaceutically acceptable salt thereof, wherein:

[0540] R21and R22are each independently selected from the group consisting of H, C1-6 alkyl, Ci-6haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(0)0Ci-6alkyl, C(0)Ci-6alkyl, C(O)NH2, C(0)N(H)(CI-6 alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6 alkyl), C(S)N(H)(CI-6alkyl-N3), C(S)N(CI-6alkyl)2, N(H)C(O)H, N(H)C(O)OH, N(CI-6 alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, phenyl, and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =0.

[0541] In another embodiment, R18is halo and the subject is resistant to one or more anthelmintic treatment.

[0542] In an embodiment of formula IIIB,

[0543] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, N02, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23;

[0544] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0545] R21and R22are each independently selected from the group consisting of H, C1-6 alkyl, Ci-6haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCi-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6alkyl), C(S)N(H)(CI-6alkyl-N3), C(S)N(CI-6alkyl)2, N(H)C(O)H, N(H)C(O)OH, N(CI-6 alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, phenyl, and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =0 and provided that when R16or R18is Br, then R21and R22are both CN, or when R18is Br, then R22is C(S)N(H)(CI-6 alkyl-N3);

[0546] R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6alkyl, and C(O)NH2; R24, independently at each occurrence, is selected from the group consisting of -CN, OH, and halo;

[0547] R25is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, NO2, NH2, C(O)OH, C(O)CI-6alkyl, and C(O)NH2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0548] In an embodiment,

[0549] R21and R22are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCi-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6alkyl)C(O)H, phenyl, and 5- or 6- membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =O.ln an embodiment, the compound of formula III is a compound of formula IIIA-i:

[0550] (IHA-i), or a pharmaceutically acceptable salt thereof, wherein: g is 0, 1 , or 2.

[0551] In an embodiment of formula IIIA-i, ring F is selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N and O;

[0552] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23; alternatively, R18and R19, together with the atom to which they are attached, form a ring selected from the group consisting of phenyl and 6-membered heteroaryl;

[0553] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24; R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6alkyl, and C(O)NH2;

[0554] R24, independently at each occurrence, is selected from the group consisting of -CN, OH, and halo;

[0555] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(0)0CI-6 alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(0)N(CI-6 alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, phenyl, and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21is are not =0; ring G is selected from the group consisting of absent, phenyl, 5- or 6-membered heteroaryl, and 5-7 membered heterocycloalkyl, wherein phenyl, 5- or 6-membered heteroaryl, and 5-7 membered heterocycloalkyl are each optionally substituted with one or two R26;

[0556] Y9and Y11are each independently selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C(0), and C(S), provided that at least one of Y9and Y11is selected from the group consisting of C(0), C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;

[0557] Y10is selected from the group consisting of absent, O, NH, and N(CI-6 alkyl);

[0558] R25is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, N02, NH2, C(O)OH, C(O)CI-6alkyl, and C(O)NH2;

[0559] R26, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, =0, -CN, halo, N02, NH2, C(O)OH, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), and C(O)N(CI-6alkyl)2; g is 0, 1 , or 2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0560] In another embodiment, the compound of formula III is a compound of formula IIIA-ii:

[0561] (IIIA-ii), or a pharmaceutically acceptable salt thereof, wherein: Y12is selected from the group consisting of CH2, NH, O, and S;

[0562] Y13is selected from the group consisting of CH and N, provided that at least one of Y12and Y13is selected from the group consisting of N, NH, O, and S; and g is 0, 1 , or 2.

[0563] In yet another embodiment, the compound of formula III is a compound of formula IIIA-iii:

[0564] (IIIA-iii), or a pharmaceutically acceptable salt thereof, wherein:

[0565] Y14and Y15are each independently selected from the group consisting of CH2, NH, O, S, and SO2 provided that at least one of Y14and Y15is selected from the group consisting of N, NH, O, S, and SO2; and g is 0, 1 , or 2.

[0566] In still another embodiment, the compound of formula III is a compound of formula IIIA-iv:

[0567] (IIIA-iv), or a pharmaceutically acceptable salt thereof.

[0568] In an embodiment, the compound of formula III is a compound of formula IIIB-i:

[0569] (IHB-i), or a pharmaceutically acceptable salt thereof, wherein:

[0570] Y16is selected from the group consisting of O and S;

[0571] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23; alternatively, R18and R19, together with the atom to which they are attached, form a ring selected from the group consisting of phenyl and 6-membered heteroaryl;

[0572] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0573] R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6 alkyl, and C(O)NH2;

[0574] R24is selected from the group consisting of -CN, OH, and halo;

[0575] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, phenyl, and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that when is c / s double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21is not =0;

[0576] R25is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, N02, NH2, C(O)OH, C(O)CI-6alkyl, and C(O)NH2; and

[0577] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), C(S)N(H)(CI-6 alkyl-Ns) , and N(CI-6 alkyl)2.

[0578] In an embodiment of formula IIIB-i,

[0579] Y16is selected from the group consisting of O and S;

[0580] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R23;

[0581] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0582] R23is selected from the group consisting of C(O)OH, C(0)Ci-6 alkyl, and C(0)NH2;

[0583] R24is selected from the group consisting of -CN, OH, and halo;

[0584] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl , OH, -CN, - NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(0)N(CI-6 alkyl)2, C(S)OH, C(S)Ci-6 alkyl, C(S)NH2, phenyl, and 5- or 6-membered heteroaryl; and R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), C(S)N(H)(CI-6 alkyl-Ns) , and N(CI-6 alkyl)2.

[0585] In another embodiment of formula IIIB-i,

[0586] Y16is selected from the group consisting of O and S;

[0587] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, OH, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0588] R20is selected from the group consisting of H, -ON, OH, and C1-6 alkyl;

[0589] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl , OH, -ON, - NO, NH2, C(O)OH, C(O)OCI-6 alkyl, C(O)Ci-6alkyl, C(O)NH2, C(S)OH, C(S)Ci-6alkyl, and C(S)NH2; and

[0590] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), C(S)N(H)(CI-6 alkyl-Ns) , and N(CI-6 alkyl)2.

[0591] In yet another embodiment of formula IIIB-i, R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6alkyl)2-

[0592] In an embodiment of formula IIIB-i,

[0593] Y16is selected from the group consisting of O and S;

[0594] R15, R17, and R19are each independently selected from the group consisting of H, - ON, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23;

[0595] R16and R18are each independently selected from the group consisting of H, -ON, OH, F, Cl, I, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23;

[0596] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0597] R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6 alkyl, and C(O)NH2;

[0598] R24is selected from the group consisting of -CN, OH, and halo;

[0599] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, phenyl, and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that when is c / s double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21is not =0;

[0600] R25is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, N02, NH2, C(O)OH, C(O)CI-6alkyl, and C(O)NH2; R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0601] In another embodiment of formula IIIB-i,

[0602] Y16is selected from the group consisting of O and S;

[0603] R15, R17, and R19are each independently selected from the group consisting of H, - CN, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R23;

[0604] R16and R18are each independently selected from the group consisting of H, -CN, OH, F, Cl, I, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R23;

[0605] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0606] R23is selected from the group consisting of C(O)OH, C(O)Ci-6 alkyl, and C(O)NH2;

[0607] R24is selected from the group consisting of -CN, OH, and halo;

[0608] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl , OH, -CN, - NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6 alkyl)2, C(S)OH, C(S)Ci-6 alkyl, C(S)NH2, phenyl, and 5- or 6-membered heteroaryl;

[0609] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0610] In yet another embodiment of formula IIIB-i,

[0611] Y16is selected from the group consisting of O and S;

[0612] R15, R17, and R19are each independently selected from the group consisting of H, OH, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0613] R16and R18are each independently selected from the group consisting of H, OH, F, Cl, I, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0614] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl;

[0615] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl , OH, -CN, - NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(S)OH, C(S)Ci-6alkyl, and C(S)NH2;

[0616] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0617] In another embodiment of formula IIIB-i, R18is Br and R27is N(H)(CI-6 alkyl-Ns).

[0618] In still another embodiment of formula IIIB-i,

[0619] Y16is selected from the group consisting of O and S;

[0620] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1- 6 alkoxy are each optionally substituted with one R23;

[0621] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0622] R23is selected from the group consisting of C(O)OH, C(O)Ci-6 alkyl, and C(O)NH2;

[0623] R24is selected from the group consisting of -CN, OH, and halo;

[0624] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl , OH, -CN, - NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6 alkyl)2, C(S)OH, C(S)Ci-6 alkyl, C(S)NH2, phenyl, and 5- or 6-membered heteroaryl; and

[0625] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2.

[0626] In another embodiment of formula IIIB-i,

[0627] Y16is selected from the group consisting of O and S;

[0628] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, OH, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0629] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl;

[0630] R21is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl , OH, -CN, - NC, NH2, C(O)OH, C(O)OCI-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(S)OH, C(S)Ci-6alkyl, and C(S)NH2; and

[0631] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2.

[0632] In an embodiment, the compound of formula IIIB-i is a compound of formula IIIB-ia:

[0633] (IIIB-ia), or a pharmaceutically acceptable salt thereof, wherein:

[0634] Y16is selected from the group consisting of O and S;

[0635] R16, R17, and R18are each independently selected from the group consisting of H, OH, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0636] R21is selected from the group consisting of H, C1-6 alkyl, OH, -ON, -NO, and NH2;

[0637] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl- N3), and N(CI-6 alkyl^; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0638] In an embodiment, R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2.

[0639] In an embodiment of formula IIIB-ia,

[0640] Y16is selected from the group consisting of O and S;

[0641] R16and R18are each independently selected from the group consisting of H, OH, F, Cl, I, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0642] R17is selected from the group consisting of H, OH, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0643] R21is selected from the group consisting of H, C1-6 alkyl, OH, -CN, -NC, and NH2;

[0644] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0645] In another embodiment of formula IIIB-ia,

[0646] Y16is selected from the group consisting of O and S;

[0647] R16and R18are each independently selected from the group consisting of H, OH, F, Cl, I, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0648] R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0649] R21is selected from the group consisting of OH, -CN, -NC, and NH2;

[0650] R27is selected from the group consisting of NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl^; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0651] In an embodiment formula IIIB-ia, R18is Br and R27is N(H)(CI-6 alkyl-Ns).

[0652] In yet another embodiment of formula IIIB-ia:

[0653] Y16is selected from the group consisting of O and S; R16, R17, and R18are each independently selected from the group consisting of H, OH, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0654] R21is selected from the group consisting of H, C1-6 alkyl, OH, -ON, -NO, and NH2;

[0655] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2; and is a c / s double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0656] In an embodiment, the compound of formula IIIB-ia is a compound of formula IIIB-ia-i:

[0657] (IIIB-ia-i), or a pharmaceutically acceptable salt thereof, wherein:

[0658] Y16is selected from the group consisting of O and S;

[0659] R16and R18are each independently selected from the group consisting of H, OH, F, Cl, I, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0660] R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;

[0661] R21is selected from the group consisting of OH, -CN, -NC, and NH2; and

[0662] R27is selected from the group consisting of NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl-Ns), and N(CI-6 alkyl)2.

[0663] In an embodiment formula IIIB-ia-i, R18is Br and R27is N(H)(CI-6 alkyl-Ns).

[0664] In an embodiment, the compound of formula III is a compound of formula IIIB-ii:

[0665] (IIIB-ii), or a pharmaceutically acceptable salt thereof, wherein:

[0666] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, and O-C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, and O-C2-6 alkynyl are each optionally substituted with one R23;

[0667] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0668] R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6 alkyl, and C(O)NH2; and

[0669] R24is selected from the group consisting of -CN, OH, and halo.

[0670] In an embodiment of formula IIIB-ii,

[0671] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23.

[0672] In another embodiment of formula IIIB-ii,

[0673] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1- 6 alkoxy are each optionally substituted with one R23;

[0674] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0675] R23is selected from the group consisting of C(O)OH, C(O)Ci-6 alkyl, and C(O)NH2;

[0676] R24is selected from the group consisting of -CN, OH, and halo;

[0677] In yet another embodiment of formula IIIB-ii,

[0678] R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, OH, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy; and

[0679] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl.

[0680] In an embodiment, the compound is a compound of formula IIIB-ii and the subject is resistant to one or more anthelmintic treatment. In an embodiment, R18is halo and the subject is resistant to one or more anthelmintic treatment.

[0681] In an embodiment, the compound of formula IIIB-ii is a compound of formula IIIB-iia:

[0682] (IIIB-iia) or a pharmaceutically acceptable salt thereof, wherein: R16, R17, and R18are each independently selected from the group consisting of H, OH, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkynyl, and O-C2-6 alkynyl.

[0683] In an embodiment of IIIB-iia,

[0684] R16, R17, and R18are each independently selected from the group consisting of H, OH, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy.

[0685] In an embodiment of IIIB-iia,

[0686] R16and R17are each independently selected from the group consisting of H, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and O-C2-6 alkynyl;

[0687] R18is halo; and the subject is resistant to one or more anthelmintic treatment.

[0688] In an embodiment, the compound of formula III is a compound of formula IIIB-iii:

[0689] (IIIB-iii), or a pharmaceutically acceptable salt thereof, wherein:

[0690] Y16is selected from the group consisting of O and S;

[0691] Y17and Y18are each independently selected from the group consisting of CH and N, provided that at least one of Y17and Y18is CH; and

[0692] R27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2.

[0693] In another embodiment, the compound of formula III is a compound of formula IIIB-iv: or a pharmaceutically acceptable salt thereof, wherein:

[0694] Y19and Y20are each independently selected from the group consisting of O and S; and R28and R29are each independently selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 alkoxy.

[0695] In yet another embodiment, the compound of formula III is a compound of formula

[0696] IIIB-v:

[0697] (IIIB-v), or a pharmaceutically acceptable salt thereof, wherein:

[0698] R15, R16, R17, and R19are each independently selected from the group consisting of H, -CN, OH, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, and O-C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, and O- C2-6 alkynyl are each optionally substituted with one R23;

[0699] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0700] R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6 alkyl, and C(O)NH2; and

[0701] R24is selected from the group consisting of -CN, OH, and halo.

[0702] In an embodiment of formula IIIB-v,

[0703] R15, R16, R17, and R19are each independently selected from the group consisting of H, -CN, OH, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23;

[0704] In an embodiment of formula IIIB-v,

[0705] R15, R16, R17, and R19are each independently selected from the group consisting of H, -CN, OH, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and O-C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, and O-C2-6 alkynyl are each optionally substituted with one R23;

[0706] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R24;

[0707] R23is selected from the group consisting of C(O)OH, C(O)Ci-6 alkyl, and C(O)NH2; and

[0708] R24is selected from the group consisting of -CN, OH, and halo.

[0709] In another embodiment of formula IIIB-v, R15, R16, R17, and R19are each independently selected from the group consisting of H, -CN, OH, NH2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R23.

[0710] In yet another embodiment of formula IIIB-v,

[0711] R15, R16, R17, and R19are each independently selected from the group consisting of

[0712] H, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and O-C2-6 alkynyl; and

[0713] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl.

[0714] In still another embodiment of formula IIIB-v,

[0715] R15, R16, R17, and R19are each independently selected from the group consisting of

[0716] H, OH, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy; and

[0717] R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl.

[0718] In an embodiment, the compound is a compound of formula IIIB-v, and the subject is resistant to one or more anthelmintic treatment.

[0719] In an embodiment, the compound of formula IIIB-v is a compound of formula IIIB-va:

[0720] (IIIB-va) or a pharmaceutically acceptable salt thereof, wherein:

[0721] R16and R17are each independently selected from the group consisting of H, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and O-C2-6 alkynyl.

[0722] In an embodiment of IIIB-va,

[0723] R16is selected from the group consisting of H, OH, C1-6 alkyl, C1-6 haloalkyl, and O-

[0724] C2-6 alkynyl; and

[0725] R17is O-C2-6 alkynyl.

[0726] In another embodiment of IIIB-va,

[0727] R16is selected from the group consisting of H, OH, C1-6 alkyl, and O-C2-6 alkynyl; and

[0728] R17is O-C2-6 alkynyl.

[0729] In yet another embodiment of formula IIIB-va,

[0730] R16and R17are each independently selected from the group consisting of H, OH, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy.

[0731] In an embodiment, R16is selected from the group consisting of H, OH, and C1-6 alkyl. In another embodiment, R16is C1-6 alkyl. In yet another embodiment, R17is O-C2-6 alkynyl. In an embodiment, the compound is a compound of formula IIIB-va, and the subject is resistant to one or more anthelmintic treatment.

[0732] In another embodiment, at least two of R15, R16, R17, R18, and R19are selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy. In yet another embodiment, at least three of R15, R16, R17, R18, and R19are selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy. In still another embodiment, at least one of R15, R16, R17, R18, and R19is selected from the group consisting of H, OH, and halo.

[0733] In an embodiment, at least one of R15, R16, R17, R18, and R19is selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with C(O)OH or C(O)NH2. In yet another embodiment, R16is selected from the group consisting of H, OH, NO2, C1-6 alkyl, and C1-6 alkoxy. In another embodiment, R16is H. In yet another embodiment, R16is C1-6 alkyl. In still another embodiment, R16is C1-6 alkoxy. In an embodiment, R16is OH. In another embodiment, R16is NO2.

[0734] In yet another embodiment, R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23. In still another embodiment, R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, and C1-6 alkoxy. In another embodiment, R17is selected from the group consisting of H, OH, NO2, C1-6 alkyl, and O-C2-6 alkynyl. In an embodiment, R17is selected from the group consisting of H, OH, and C1-6 alkyl. In another embodiment, R17is H. In yet another embodiment, R17is OH. In still another embodiment, R17is C1-6 alkyl. In an embodiment, R17is NO2. In another embodiment, R17is O-C2-6 alkynyl.

[0735] In an embodiment, R16is selected from the group consisting of H, OH, halo, NO2, C1-6 alkyl, and C1-6 alkoxy. In another embodiment, R16is H. In yet another embodiment, R16is OH. In still another embodiment, R16is halo. In an embodiment, R16is NO2. In another embodiment, R16is C1-6 alkyl. In yet another embodiment, R16is C1-6 alkoxy.

[0736] In an embodiment, R18is selected from the group consisting of H, OH, halo, NO2, C1-6 alkyl, and C1-6 alkoxy. In another embodiment, R18is H. In yet another embodiment, R18is OH. In still another embodiment, R18is halo. In an embodiment, R18is NO2. In another embodiment, R18is C1-6 alkyl. In yet another embodiment, R18is C1-6 alkoxy.

[0737] In still another embodiment, R20is selected from the group consisting of H and C1-6 alkyl. In an embodiment, R20is H.

[0738] In another embodiment, R21is selected from the group consisting of =0, OH, -ON, - NO, NH2, and phenyl optionally substituted with R25. In yet another embodiment, R21is selected from the group consisting of =O,-CN, and -NO. In still another embodiment, R21is =0. In an embodiment, R21is -ON. In another embodiment, R21is -NO. In yet another embodiment, R22is selected from C(S)NH2, C(S)N(H)(CI-6 alkyl), and C(S)N(CI-6 alkyl)2. In still another embodiment, R22is C(S)NH2. In an embodiment, R22is C(S)N(CI-6alkyl)2.

[0739] In another embodiment, Y16is S. In yet another embodiment, Y9and Y11are each independently selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, and C(O), provided that at least one of Y9and Y11is selected from the group consisting of C(O), C1-6 alkyl, and C1-6 alkoxy. In still another embodiment, Y9is C(O).

[0740] In an embodiment, Y11is absent. In another embodiment, Y11is C1-6 alkyl. In yet another embodiment, Y11is C1-6 alkoxy. In still another embodiment, Y10is selected from the group consisting of NH and N(CI-6 alkyl).

[0741] In an embodiment, R23is C(O)OH. In another embodiment, R23is C2-6 alkynyl

[0742] In yet another embodiment, R25is selected from the group consisting of OH, -CN, halo, NO2, and NH2. In still another embodiment, R25is NO2.

[0743] In still another embodiment, R26, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, =0, halo, and NO2. In an embodiment R26is =0. In an embodiment, R26, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, halo, and NO2.

[0744] In yet another embodiment, R27is selected from the group consisting of NH2, N(H)(CI-6 alkyl), N(H)(CI-6 alkyl-Ns), and N(CI-6 alkyl)2. In an embodiment, R27is selected from the group consisting of NH2, N(H)(CI-6 alkyl), and N(H)(CI-6 alkyl-Ns). In another embodiment, R27is NH2. In yet another embodiment, R27is N(H)(CI-6 alkyl). In still another embodiment, R27is N(H)(CI-6 alkyl-Ns).

[0745] In another embodiment, the compound is selected from the group consisting of a compound in Table 7, or a pharmaceutically acceptable salt thereof, wherein: s a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0746] Table 7

[0747]

[0748] In an embodiment, the compound is compound 90, and the subject is resistant to one or more anthelmintic treatment.

[0749] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound in Table 8, or a pharmaceutically acceptable salt thereof, wherein: s a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0750] Table 8

[0751]

[0752] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound of formula IV, or a pharmaceutically acceptable salt thereof:

[0753] (IV), wherein: ring H and ring I are each independently selected from the group consisting of Ce- aryl, 5-11 membered heteroaryl, C3-11 cycloalkyl, and 5-11 membered heterocycloalkyl, wherein 5-11 membered heteroaryl, and 5-11 membered heterocycloalkyl each contain one or two ring heteroatoms selected from the group consisting of N, O, and S;

[0754] Y21is selected from the group consisting of CH2, C(H)(CI-6 alkyl), C(Ci-6 alkyl)2, 0, and S;

[0755] R30, independently at each occurrence, is selected from the group consisting of =0, - CN, OH, halo, N02, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C1-6 alkyl, Ci-6alkylthio, Ci-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Ce- aryl, 5-11 membered heteroaryl, C3-11 cycloalkyl, and 5-11 membered heterocycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ce- aryl, 5-11 membered heteroaryl, C3-11 cycloalkyl, and 5-11 membered heterocycloalkyl are each optionally substituted with one, two, or three R34, and wherein 5-11 membered heteroaryl and 5-11 membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S; alternatively, two adjacent R30, together the atom to which they are attached, form a ring selected from the group consisting of phenyl and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one, two, or three R35, and wherein 5- or 6-membered heteroaryl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;

[0756] R31is selected from the group consisting of H, -CN, OH, halo, NH2, N(H)(CI-6 alkyl), N(CI-6 alkyl)2, C1-6 alkyl, C1.6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)OCi-6 alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), and C(O)N(CI-6alkyl)2;

[0757] R32is selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;

[0758] R33, independently at each occurrence, is selected from the group consisting of =0, - CN, OH, halo, N02, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C1-6 alkyl, Ci-6haloalkyl, Ci-6alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Ce- aryl, 5-11 membered heteroaryl, C3-11 cycloalkyl, and 5-11 membered heterocycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ce- aryl, 5-11 membered heteroaryl, C3-11 cycloalkyl, and 5-11 membered heterocycloalkyl are each optionally substituted with one, two, or three R36’, and wherein 5-11 membered heteroaryl and 5-11 membered heterocycloalkyl each contain one or two ring heteroatoms selected from the group consisting of N, O, and S;

[0759] R34, R35, and R36, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, N(H)(CI-6 alkyl), N(CI-6 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl; h and I are each independently 0, 1 , 2, 3, or 4; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0760] In an embodiment, ring H and ring I are each independently selected from the group consisting of Ce- aryl, 5-7 membered heteroaryl, C3-6 cycloalkyl, and 5-7 membered heterocycloalkyl, wherein 5-7 membered heteroaryl, and 5-7 membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S; Y21is selected from the group consisting of CH2, C(H)(CI-6 alkyl), C(Ci-6 alkyl)2, 0, and S;

[0761] R30, independently at each occurrence, is selected from the group consisting of =0, - CN, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, C6-10 aryl, and C3-11 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, Ce- aryl, and C3-11 cycloalkyl are each optionally substituted with one or two R34; alternatively, two adjacent R30, together the atom to which they are attached, form a ring selected from the group consisting of phenyl and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one, two, or three R35, and wherein 5- or 6-membered heteroaryl contains one or two ring heteroatoms selected from the group consisting of N and O;

[0762] R31is selected from the group consisting of H, -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)OCi-6 alkyl, C(O)Ci-6 alkyl, and C(O)NH2;

[0763] R32is selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;

[0764] R33, independently at each occurrence, is selected from the group consisting of =0, - CN, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, Ce-w aryl, 5-11 membered heteroaryl, and C3-11 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, Ce- 10 aryl, 5-11 membered heteroaryl, and C3-11 cycloalkyl are each optionally substituted with one or two R36;

[0765] R34, R35, and R36, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl; h and I are each independently 0, 1 , 2, 3, or 4; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0766] In another embodiment, ring H and ring I are each independently selected from the group consisting of phenyl, 5- or 6-membered heteroaryl, C3-5 cycloalkyl, and 5- or 6-membered heterocycloalkyl, wherein 5- or 6-membered heteroaryl and 5- or 6-membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S;

[0767] Y21is selected from the group consisting of CH2, O, and S;

[0768] R30, independently at each occurrence, is selected from the group consisting of =0, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, and C3-6 cycloalkyl are each optionally substituted with one R34; alternatively, two adjacent R30, together the atom to which they are attached, form a ring selected from the group consisting of phenyl and 6-membered heteroaryl, wherein phenyl and 6-membered heteroaryl are each optionally substituted with one or two R35, and wherein 6-membered heteroaryl contains one ring heteroatom selected from the group consisting of N and O;

[0769] R31is selected from the group consisting of H, -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl;

[0770] R32is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;

[0771] R33, independently at each occurrence, is selected from the group consisting of =0, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, 5- or e- membered heteroaryl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, 5- or e- membered heteroaryl, and C3-6 cycloalkyl are each optionally substituted with one R36;

[0772] R34, R35, and R36, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, and C1-6 alkyl; h and I are each independently 0, 1 , 2, 3, or 4; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0773] In yet another embodiment, ring H is selected from the group consisting of phenyl, 5-membered heteroaryl, C3-5 cycloalkyl, and 5-membered heterocycloalkyl, wherein 5-membered heteroaryl and 5- membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S; and ring I is selected from the group consisting of phenyl, 5-membered heteroaryl, and 5- membered heterocycloalkyl, wherein 5-membered heteroaryl and 5-membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S.

[0774] In still another embodiment, ring H is selected from the group consisting of phenyl, cyclopropyl, isoxazolyl, thiophenyl, pyrazolyl, benzothiophenyl, and benzothiazolyl; ring I is selected from the group consisting of phenyl, 5-membered heteroaryl, and 5- membered heterocycloalkyl, wherein 5-membered heteroaryl and 5-membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S;

[0775] Y21is selected from the group consisting of CH2, O, and S;

[0776] R30, independently at each occurrence, is selected from the group consisting of =0, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, and C3-6 cycloalkyl are each optionally substituted with one R34; alternatively, two adjacent R30, together the atom to which they are attached, form a ring selected from the group consisting of phenyl and 6-membered heteroaryl, wherein phenyl and 6-membered heteroaryl are each optionally substituted with one or two R35, and wherein 6-membered heteroaryl contains one ring heteroatom selected from the group consisting of N and O;

[0777] R31is selected from the group consisting of H, -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl;

[0778] R32is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;

[0779] R33, independently at each occurrence, is selected from the group consisting of =0, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, 5- or e- membered heteroaryl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, 5- or e- membered heteroaryl, and C3-6 cycloalkyl are each optionally substituted with one R36;

[0780] R34, R35, and R36, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, and C1-6 alkyl; h and I are each independently 0, 1 , 2, 3, or 4; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0781] In an embodiment, h is 0, R30is Cl, i is 1 , and R33is NO2 or C1-6 alkyl.

[0782] In another embodiment, ring H is selected from the group consisting of phenyl, cyclopropyl, isoxazolyl, thiophenyl, pyrazolyl, benzothiophenyl, and benzothiazolyl; ring I is selected from the group consisting of phenyl, 5-membered heteroaryl, and 5- membered heterocycloalkyl, wherein 5-membered heteroaryl and 5-membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S;

[0783] Y21is selected from the group consisting of CH2, O, and S;

[0784] R30, independently at each occurrence, is selected from the group consisting of =0, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, and C3-6 cycloalkyl are each optionally substituted with one R34; alternatively, two adjacent R30, together the atom to which they are attached, form a ring selected from the group consisting of phenyl and 6-membered heteroaryl, wherein phenyl and 6-membered heteroaryl are each optionally substituted with one or two R35, and wherein 6-membered heteroaryl contains one ring heteroatom selected from the group consisting of N and O;

[0785] R31is selected from the group consisting of H, -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl;

[0786] R32is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;

[0787] R33, independently at each occurrence, is selected from the group consisting of =0, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, 5- or 6- membered heteroaryl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, 5- or 6- membered heteroaryl, and C3-6 cycloalkyl are each optionally substituted with one R36;

[0788] R34, R35, and R36, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, and C1-6 alkyl; h and I are each independently 0, 1 , 2, 3, or 4; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0789] In still another embodiment, the compound of formula (IV) is a compound of formula (IVA):

[0790] (IVA), or a pharmaceutically acceptable salt thereof, wherein:

[0791] Y21is selected from the group consisting of CH2, O, and S;

[0792] R30, independently at each occurrence, is selected from the group consisting of =0, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, and C3-6 cycloalkyl are each optionally substituted with one R34; alternatively, two adjacent R30, together the atom to which they are attached, form a ring selected from the group consisting of phenyl and 6-membered heteroaryl, wherein phenyl and 6-membered heteroaryl are each optionally substituted with one or two R35, and wherein 6-membered heteroaryl contains one ring heteroatom selected from the group consisting of N and O;

[0793] R31is selected from the group consisting of H, -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl;

[0794] R32is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy; R33, independently at each occurrence, is selected from the group consisting of =0, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, 5- or 6- membered heteroaryl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, 5- or 6- membered heteroaryl, and C3-6 cycloalkyl are each optionally substituted with one R36;

[0795] R34, R35, and R36, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, and C1-6 alkyl; h and I are each independently 0, 1 , 2, or 3; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0796] In an embodiment of formula (IVA),

[0797] Y21is selected from the group consisting of O and S;

[0798] R30, independently at each occurrence, is selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R34;

[0799] R31is selected from the group consisting of -CN, OH, halo, and NH2;

[0800] R32is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;

[0801] R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R36;

[0802] R34and R36, independently at each occurrence, are selected from the group consisting of -CN, OH, and NH2; h and I are each independently 0, 1 , or 2; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0803] In another embodiment of formula (IVA),

[0804] Y21is selected from the group consisting of O and S;

[0805] R30is selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;

[0806] R31is selected from the group consisting of -CN and OH;

[0807] R32is selected from the group consisting of H and C1-6 alkyl;

[0808] R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy; h is 0 or 1 ; i is 0, 1 , or 2; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0809] In still another embodiment of formula (IVA),

[0810] Y21is selected from the group consisting of O and S;

[0811] R30is selected from the group consisting of F, Br, I, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;

[0812] R31is selected from the group consisting of -CN and OH;

[0813] R32is selected from the group consisting of H and C1-6 alkyl;

[0814] R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy; h is 0 or 1 ; i is 0, 1, or 2; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0815] In yet another embodiment of formula (IVA), R30is selected from the group consisting of halo, C1-6 alkyl, and C1-6 haloalkoxy. In still another embodiment of formula (IVA), h is 0, R30is Cl, i is 1 , and R33is NO2 or C1-6 alkyl. In an embodiment of formula (IVA), R30is selected from the group consisting of C1-6 alkyl and C1-6 haloalkoxy. In still another embodiment of formula (IVA), R33, independently at each occurrence, is selected from the group consisting of halo, NO2, and C1-6 alkyl.

[0816] In an embodiment, the compound of formula (IV) is a compound of formula (IVB):

[0817] (IVB), or a pharmaceutically acceptable salt thereof, wherein:

[0818] Y21is selected from the group consisting of CH2, O, and S;

[0819] Y22is selected from the group consisting of CH2, NH, O, and S;

[0820] Y23is selected from the group consisting of CH and N, provided that at least one of Y22and Y23is selected from the group consisting of N, NH, O, and S;

[0821] R30, independently at each occurrence, is selected from the group consisting of =0, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, and C3-6 cycloalkyl are each optionally substituted with one R34; alternatively, two adjacent R30, together the atom to which they are attached, form a ring selected from the group consisting of phenyl and 6-membered heteroaryl, wherein phenyl and 6-membered heteroaryl are each optionally substituted with one or two R35, and wherein 6-membered heteroaryl contains one ring heteroatom selected from the group consisting of N and O;

[0822] R31is selected from the group consisting of H, -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl;

[0823] R32is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;

[0824] R33, independently at each occurrence, is selected from the group consisting of =0, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, 5- or e- membered heteroaryl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, 5- or e- membered heteroaryl, and C3-6 cycloalkyl are each optionally substituted with one R36;

[0825] R34, R35, and R36, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, and C1-6 alkyl; h is 0, 1 , 2, or 3; i is 0, 1 , 2, 3, or 4; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0826] In an embodiment of formula (IVB),

[0827] Y21is selected from the group consisting of O and S;

[0828] Y22is selected from the group consisting of NH, O, and S;

[0829] Y23is selected from the group consisting of CH and N, provided that at least one of Y22and Y23is selected from the group consisting of N, NH, O, and S;

[0830] R30, independently at each occurrence, is selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and phenyl, wherein C1-6 alkyl, C1-6 alkoxy, and phenyl are each optionally substituted with one R34; alternatively, two adjacent R30, together the atom to which they are attached, form a phenyl ring optionally substituted with one R35;

[0831] R31is selected from the group consisting of H, -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl;

[0832] R32is selected from the group consisting of H and C1-6 alkyl;

[0833] R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, and C1-6 haloalkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R36;

[0834] R34, R35, and R36, independently at each occurrence, are selected from the group consisting of OH, halo, and NH2; h and i are each independently 0, 1 , 2, or 3; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0835] In another embodiment of formula (I VB) ,

[0836] Y21is selected from the group consisting of O and S;

[0837] Y22is selected from the group consisting of NH, O, and S;

[0838] Y23is selected from the group consisting of CH and N, provided that at least one of Y22and Y23is selected from the group consisting of N, NH, O, and S;

[0839] R30, independently at each occurrence, is selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and phenyl, wherein C1-6 alkyl, C1-6 alkoxy, and phenyl are each optionally substituted with one R34; alternatively, two adjacent R30, together the atom to which they are attached, form a phenyl ring optionally substituted with one R35;

[0840] R31is selected from the group consisting of H, -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl;

[0841] R32is selected from the group consisting of H and C1-6 alkyl;

[0842] R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, and C1-6 haloalkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R36;

[0843] R34, R35, and R36, independently at each occurrence, are selected from the group consisting of OH, halo, and NH2; h and i are each independently 0, 1 , 2, or 3; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0844] In another embodiment of formula (IVB),

[0845] Y21is selected from the group consisting of O and S;

[0846] Y22is selected from the group consisting of O and S;

[0847] Y23is selected from the group consisting of CH and N, provided that at least one of Y22and Y23is selected from the group consisting of N, O, and S;

[0848] R30, independently at each occurrence, is selected from the group consisting of halo, C1-6 alkyl, and C1-6 haloalkyl;

[0849] R31is selected from the group consisting of -CN, OH, halo, and NH2;

[0850] R32is selected from the group consisting of H and C1-6 alkyl;

[0851] R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; h is 0 or 1 ; i is 0, 1 , or 2; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0852] In yet another embodiment of formula IVB,

[0853] Y22is selected from the group consisting of NH, NC1-6 alkyl, O, and S; and

[0854] Y23is selected from the group consisting of CH and N, provided that at least one of Y22and Y23is selected from the group consisting of N, O, and S.

[0855] In an embodiment, the compound of formula (IV) is a compound of formula (IVC):

[0856] (IVC), or a pharmaceutically acceptable salt thereof, wherein:

[0857] Y22is selected from the group consisting of CH2, NH, O, and S;

[0858] Y23is selected from the group consisting of CH and N;

[0859] Y24is selected from the group consisting of CH2, NH, O, and S;

[0860] Y25and Y26are each independently selected from the group consisting of CH and N, provided that at least one of Y24, Y25, and Y26is selected from the group consisting of N, NH, O, and S; h is 0, 1 , 2, or 3; and i is 0 or 1.

[0861] In another embodiment, the compound of formula (IV) is a compound of formula

[0862] (IVD):

[0863] (IVD), or a pharmaceutically acceptable salt thereof, wherein: h is 0, 1 , or 2; and i is 0, 1 , 2, 3, or 4.

[0864] In yet another embodiment, the compound of formula (IV) is a compound of formula

[0865] (IVE):

[0866] (IVE), or a pharmaceutically acceptable salt thereof, wherein:

[0867] Y27and Y28are each independently selected from the group consisting of CH2, NH, O, and S, provided that at least one of Y27and Y28is selected from the group consisting of NH, O, and S; h is 0, 1 , 2, 3, or 4; i is 0 or 1 ; and is a single bond or a double bond.

[0868] In still another embodiment, the compound of formula (IV) is a compound of formula (IVF):

[0869] (IVF), or a pharmaceutically acceptable salt thereof, wherein:

[0870] Y29is selected from the group consisting of CH2, C(H)(R30), NH, NR30, O, and S;

[0871] Y30is selected from the group consisting of CH, CR30, and N, provided that at least one of Y29and Y30is selected from the group consisting of N, NH, NR30, O, and S; i is 0, 1 , 2, 3, or 4; and j is 0, 1 , or 2.

[0872] In an embodiment, the compound of formula (IV) is a compound of formula (IVA-i):

[0873] (IVA-i), or a pharmaceutically acceptable salt thereof, wherein: Y31and Y32are each independently selected from the group consisting of CH and N, provided that at least one of Y31and Y32is N; and

[0874] R36is selected from the group consisting of -CN, OH, halo, NH2, and C1-6 alkyl.

[0875] In another embodiment, the compound of formula (IV) is a compound of formula (IVB-i):

[0876] (IVB-i), or a pharmaceutically acceptable salt thereof, wherein:

[0877] Y21is selected from the group consisting of O and S;

[0878] Y22is selected from the group consisting of O and S;

[0879] R31is selected from the group consisting of -CN, OH, halo, and NH2;

[0880] R32is selected from the group consisting of H and C1-6 alkyl;

[0881] R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; i is 0, 1, or 2; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0882] In an embodiment of formula (IVB-i),

[0883] Y21is selected from the group consisting of O and S;

[0884] Y22is S;

[0885] R31is selected from the group consisting of -CN, OH, halo, and NH2;

[0886] R32is selected from the group consisting of H and C1-6 alkyl;

[0887] R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; i is 0, 1, or 2; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0888] In another embodiment of formula (IVB-i),

[0889] Y21is selected from the group consisting of O and S;

[0890] Y22is S;

[0891] R31is selected from the group consisting of -CN, OH, halo, and NH2;

[0892] R32is selected from the group consisting of H and C1-6 alkyl; R33, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; i is 0 or 1 ; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0893] In yet another embodiment, the compound of formula (IV) is a compound of formula (IVB-ii):

[0894] (IVB-ii), or a pharmaceutically acceptable salt thereof, wherein:

[0895] Y22is selected from the group consisting of CH2, NH, O, and S;

[0896] Y23is selected from the group consisting of CH and N; h is 0, 1 , or 2; and i is 0, 1 , 2, 3, or 4.

[0897] In an embodiment of formula (IVB-ii), R30is selected from the group consisting of halo, C1-6 alkyl, and C1-6 haloalkyl.

[0898] In yet another embodiment, the compound of formula (IV) is a compound of formula (IVB-iii):

[0899] (IVB-iii), or a pharmaceutically acceptable salt thereof, wherein:

[0900] Y21is selected from the group consisting of O and S;

[0901] Y22is selected from the group consisting of NH, NC1-6 alkyl, O, and S;

[0902] R30, independently at each occurrence, is selected from the group consisting of halo, C1-6 alkyl, and C1-6 haloalkyl;

[0903] R31is selected from the group consisting of -CN, OH, halo, and NH2;

[0904] R32is selected from the group consisting of H and C1-6 alkyl; R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; h is 0, 1 , or 2; and i is 0, 1 , 2, 3, or 4. In yet another embodiment, the compound of formula (IV) is a compound of formula (IVE-i):

[0905] (IVE-i), or a pharmaceutically acceptable salt thereof, wherein:

[0906] Y28is selected from the group consisting of CH2, C(H)(R33), C(R33)2, NH, NR33, O, and S; h is 0, 1 , 2, 3, or 4; i is 0 or 1 ; and is a single bond, a c / s double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0907] In still another embodiment, the compound of formula (IVB-ii) is a compound of formula (IVB-iia):

[0908] (IVB-iia), or a pharmaceutically acceptable salt thereof, wherein:

[0909] Y21is selected from the group consisting of O and S;

[0910] R30is selected from the group consisting of halo, C1-6 alkyl, and C1-6 haloalkyl;

[0911] R31is selected from the group consisting of -CN and OH;

[0912] R32is selected from the group consisting of H and C1-6 alkyl;

[0913] R33is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; h is 0 or 1 ; and i is 0 or 1.

[0914] In still another embodiment, Y21is selected from the group consisting of O and S. In an embodiment, R30, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and phenyl.

[0915] In another embodiment, R31is selected from the group consisting of H, -CN, OH, and C2-6 alkynyl.

[0916] In yet another embodiment, R32is selected from the group consisting of H and C1-6 alkyl. In still another embodiment, R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, and phenyl. In an embodiment, R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, and phenyl.

[0917] In another embodiment, Y22is selected from the group consisting of NH, O, and S. In yet another embodiment, Y23is selected from the group consisting of CH and N. In still another embodiment, Y24is selected from the group consisting of O and S. In an embodiment, Y25and Y26are N. In another embodiment, Y28is selected from the group consisting of NH and NR33. In yet another embodiment, wherein Y29is selected from the group consisting of O and S. In still another embodiment, Y30is selected from the group consisting of CR30and N.

[0918] In an embodiment, h is 0, 1 , or 2. In another embodiment, h is 0 or 1. In yet another embodiment, i is 0, 1 , 2, or 3. In still another embodiment, i is 0, 1 , or 2. In an embodiment, ] is 0 or 1.

[0919] In another embodiment, the compound is selected from the group consisting of a compound in Table 9, or a pharmaceutically acceptable salt thereof, wherein: s a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0920] Table 9 In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound in Table 10, or a pharmaceutically acceptable salt thereof, wherein: As a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0921] Table 10

[0922]

[0923] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound in 11, or a pharmaceutically acceptable salt thereof, wherein:

[0924] As a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

[0925] Table 11

[0926]

[0927] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound that is or a pharmaceutically acceptable salt thereof.

[0928] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound of Table 1 , T able 2, T able 5, T able 6, T able 7, T able 8, T able 9, or T able 11, or a pharmaceutically acceptable salt thereof.

[0929] In an aspect, provided herein is a method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound of Table 1 , Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, or Table 11 , or a pharmaceutically acceptable salt thereof.

[0930] In an embodiment, the parasitic infection is a parasitic worm infection.

[0931] In another embodiment, the parasitic worm infection is selected from the group consisting of roundworm infection, whipworm infection, hookworm infection, flatworm infection, tapeworm infection, fluke infection, and pinworm (threadworm) infection.

[0932] In yet another embodiment, the parasitic worm infection is selected from the group consisting of whipworm infection, hookworm infection, flatworm infection, tapeworm infection, fluke infection, and pinworm (threadworm) infection.

[0933] In still another embodiment, the parasitic worm is resistant to one or more anthelmintic treatment.

[0934] In an embodiment, the compound or pharmaceutical composition is administered orally.

[0935] Administration / Dosages / Formulations

[0936] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0937] Injectable preparations (for example, sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0938] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0939] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0940] Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0941] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this disclosure.

[0942] The ointments, pastes, creams and gels may contain, in addition to an active compound of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0943] Powders and sprays can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[0944] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0945] According to the methods of treatment of the present disclosure, disorders are treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the disclosure, in such amounts and for such time as is necessary to achieve the desired result. The term “therapeutically effective amount” of a compound of the disclosure, as used herein, means a sufficient amount of the compound so as to decrease the symptoms of a disorder in a subject. As is well understood in the medical arts a therapeutically effective amount of a compound of this disclosure will be at a reasonable benefit / risk ratio applicable to any medical treatment.

[0946] In general, compounds of the disclosure will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg / kg per body weight. An indicated daily dosage in the larger mammal, e.g., humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, e.g., in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient. In certain embodiments, a therapeutic amount or dose of the compounds of the present disclosure may range from about 0.1 mg / Kg to about 500 mg / Kg, alternatively from about 1 to about 50 mg / Kg. In general, treatment regimens according to the present disclosure comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this disclosure per day in single or multiple doses. Therapeutic amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.

[0947] Upon improvement of a subject’s condition, a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained; when the symptoms have been alleviated to the desired level, treatment should cease. The subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

[0948] It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

[0949] Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylenepolyoxypropylene-block polymers; wool fat; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such a propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; and phosphate buffer solutions. Further, non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition and a pharmaceutically acceptable carrier, are other embodiments of the present disclosure.

[0950] Equivalents and scope

[0951] The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[0952] EXAMPLES

[0953] The application is further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of the art.

[0954] Ethics Statement

[0955] All experiments involving animals were conducted per the recommendation of the National Institute of Health (USA) Guide for Care and Use of Laboratory Animals and the Animal Welfare Act. The animal protocols used in this study (PROT0202000044 and PRGT0202000071) were approved by the Institutional Animal Care and Use Committee (IACUC) of UMASS Chan Medical School. Example 1 : Tyrphostin Compound Synthesis

[0956] General Procedure

[0957] 397 H Methylsulfonyl

[0958] Scheme 1. Synthesis scheme of (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)- / \ / - phenylacrylamide derivatives

[0959] Commercially available cinnamic acid derivatives, thionyl chloride and triethylamine were purchased from Sigma Aldrich, Co., St. Louis, MO. 4-substituted aniline derivatives were purchased from AK Scientific, Inc. 30023 Ahern Avenue Union City, CA 94587, USA. Thionyl chloride (3 eq) was added dropwise to a suspension of cinnamic acid derivative (1 eq) in an anhydrous dichloromethane with vigorous stirring. Next, the reaction mixture was refluxed for 6 h. The organic solvent and excess thionyl chloride were evaporated under reduced pressure to afford the acyl chloride. Triethylamine (5 eq) was added to a suspension of a 4-substituted aniline derivative (1.20 eq) and acyl chloride (1.0 eq) in THF, and the resulting mixture was allowed to stir at room temperature for 12 h. THF was evaporated under reduced pressure and the residue was extracted twice with dichloromethane. The combined organic extract was washed with water, dried over anhydrous sodium sulphate and concentrated in vacuo to afford the (E)-3-(3,5-di-tert-butyl-4- hydroxyphenyl)- / V-phenylacrylamide derivative. The resultant solid product was then dissolved in methanol and the crude product purified by reverse phase HPLC using a semipreparative C18 column and water / acetonitrile gradient supplemented with 0.05% TFA.

[0960] 1H NMR spectra were recorded at 500 MHz using a Bruker BioSpin 500 MHz Avance AV-HI digital NMR spectrometer, and13C NMR spectra were recorded at 125 MHz. Chemical shifts are reported in 5 (ppm) relative to the internal chloroform-d (CDCI3, 7.26 ppm) and DMSO-cfe ((CD3)2SO, 2.50 ppm). Coupling constants are given in Hz. The purity of all compounds was determined to be > 95% by1H NMR and13C NMR spectra. All solvents were purchased from Sigma Aldrich or Fisher Scientific (HPLC grade). Concentrations of solutions after reactions and extractions involved the use of a rotary evaporator operating at reduced pressure. Reactions were analyzed by TLC with spots visualized by UV light and LC-MS (Agilent). Reverse-phase HPLC was conducted with an Agilent Prep Star model P21402M404 using Agilent prep - C18 column (10 pm, 250 x 21.2 mm) (solvent A: water with 0.05% (v / v) TFA, solvent B: acetonitrile with 0.05% (v / v) TFA).

[0961] Characterization

[0962] (E)-2-cyano-3-(3,5-di-tert-butyl-4-hydroxyphenyl)- / \ / -(4-ethynylphenyl)acrylamide (Compound 34), off-white solid, 76 mg, 80%,1H NMR (CDCh, 500 MHz): 5 = 8.28 (s, 1 H), 7.83 (s, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 5.85 (s, 1 H), 3.00 (s, 1 H), 1.41 (s, 18H);13C NMR (CDCh, 125 MHz) 5 = 159.2, 158.9, 155.2, 137.6, 136.9, 133.1 , 129.4, 123.7, 119.9, 118.6, 117.9, 99.1 , 83.2, 53.4, 34.6, 30.1. LC-MS (ESI) m / z calculated for C26H27N2O2" [M-H]- 399.20, observed 399.20

[0963] (E)-2-cyano-3-(3,5-di-tert-butyl-4-hydroxyphenyl)- / \ / -(4-fluorophenyl)acrylamide (Compound 35), off-white solid, 60 mg, 76%,1H NMR (CDCh, 500 MHz): 5 = 8.28 (s, 1 H), 7.89 (s, 1 H), 7.82 (s, 1 H), 7.53 - 7.50 (m, 2H), 7.02 - 6.98 (m, 2H), 5.84 (s, 1 H), 1.42 (s, 18H);13C NMR (CDCh, 125 MHz) 5 = 160.9, 159.3, 158.9, 158.9, 154.9, 136.9, 133.2,

[0964] 129.3, 123.5, 122.5, 122.4, 118.0, 115.8, 99.1 , 34.6, 30.1. LC-MS (ESI) m / z calculated for C24H26FN2O2- [M-H]- 393.20, observed 393.20

[0965] (E)-2-cyano-3-(3,5-di-tert-butyl-4-hydroxyphenyl)- / \ / -(4- (methylsulfonyl)phenyl)acrylamide (Compound 36), off-white solid, 45 mg, 68%,1H NMR (CDCh, 500 MHz): 5 = 8.31 (s, 1 H), 8.16 (s, 1 H), 7.88 (d, J = 8.7, 2H), 7.85 (s, 1 H), 7.80 (d, J = 8.7, 2H), 5.91 (s, 1 H), 3.00 (s, 3H0, 1.41 (s, 18H);13C NMR (CDCh, 125 MHz) 5 = 159.8,

[0966] 159.4, 156.1 , 142.1 , 137.1 , 136.2, 129.6, 128.8, 123.4, 120.4, 117.8, 98.4, 44.7, 34.6, 30.1. LC-MS (ESI) m / z calculated for C25H3IN2O4S+[M+H]+455.20, observed 455.20

[0967] (E)-2-cyano-3-(3,5-di-tert-butyl-4-hydroxyphenyl)- / \ / -(4-methoxyphenyl)acrylamide (Compound 37), off-white solid, 36 mg, 60%,1H NMR (CDCh, 500 MHz): 5 = 8.27 (s, 1 H), 7.82 (s, 2H), 7.44 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 5.82 (s, 1 H), 3.75 (s, 3H), 1.41 (s, 18H);13C NMR (CDCh, 125 MHz) 5 = 159.1 , 158.7, 157.1 , 136.8, 136.7, 130.2, 129.2, 123.7, 122.4, 122.2, 118.1 , 114.3, 99.5, 55.5, 34.6, 30.1. LC-MS (ESI) m / z calculated for C25H31N2C [M+H]+407.23, observed 407.20

[0968] (E)-2-cyano- / V-(4-cyanophenyl)-3-(3,5-di-ferf-butyl-4-hydroxyphenyl)acrylamide (Compound 38), off-white solid, 40 mg, 56%,1H NMR (CDCI3, 500 MHz): 5 = 8.30 (s, 1 H), 8.09 (s, 1 H), 7.84 (s, 2H), 7.71 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 5.91 (s, 1 H), 1.41 (s, 18H);13C NMR (CDCI3, 125 MHz) 5 = 159.7, 159.4, 156.0, 141.2, 137.1 , 133.4, 129.7, 123.4, 120.3, 118.6, 117.8, 108.1 , 98.3, 34.6, 30.1. LC-MS (ESI) m / z calculated for C25H26N3O2" [M-H]- 400.20, observed 400.20

[0969] (E)-2-cyano-3-(3,5-di-tert-butyl-4-hydroxyphenyl)- / \ / -(4-iodophenyl)acrylamide (Compound 39), off-white solid, 41 mg, 71%,1H NMR (CDCI3, 500 MHz): 5 = 8.27 (s, 1 H), 7.84 (d, J = 8.7 Hz, 2H), 7.61 (s, 1 H), 7.20 (d, J = 8.7 Hz, 2H), 5.85 (s, 1 H), 1.41 (s, 18H);13C NMR (CDCI3, 125 MHz) 5 = 159.3, 159.0, 155.2, 138.1 , 136.9, 136.9, 129.4, 123.5,

[0970] 122.3, 117.9, 99.0, 34.6, 30.1. LC-MS (ESI) m / z calculated for C24H26lN2O2- [M-H]- 501.10, observed 501.00

[0971] (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)- / \ / -(4-ethynylphenyl)acrylamide (Compound

[0972] 40), off-white solid, 70 mg, 90%,1H NMR (DMSO-d6, 500 MHz): 5 = 10.27 (s, 1 H), 7.72 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 15.6 Hz, 1 H), 7.46 - 7.41 (m, 5H), 6.66 (d, J = 15.6 Hz, 1 H), 4.10 (s, 1 H), 1.42 (s, 18H);13C NMR (DMSO-d6, 125 MHz) 5 = 164.6, 156.5, 142.4, 140.5, 139.7, 132.9, 126.4, 125.2, 119.3, 118.8, 116.4, 84.1 , 80.3, 34.9, 30.6. LC-MS (ESI) m / z calculated for C25H30NC [M+H]+376.23, observed 376.20

[0973] (E)- / V-(4-bromophenyl)-3-(3,5-di-terf-butyl-4-hydroxyphenyl)acrylamide (Compound

[0974] 41), off-white solid, 40 mg, 81%,1H NMR (DMSO-d6, 500 MHz): 5 = 10.21 (s, 1 H), 7.67 (d, J = 8.7 Hz, 2H), 7.55 - 7.39 (m, 6H), 6.64 (d, J = 15.6 Hz, 1 H), 1.42 (s, 18H);13C NMR (DMSO-d6, 125 MHz) 5 = 164.6, 156.5, 142.3, 140.5, 139.7, 139.4, 132.0, 126.4, 125.1 ,

[0975] 121.4, 118.8, 115.1 , 55.4, 34.9, 30.6. LC-MS (ESI) m / z calculated for C23H29BrNO2+[M+H]+430.14, observed 432.00

[0976] (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)- / \ / -(4-fluorophenyl)acrylamide (Compound

[0977] 42), off-white solid, 56 mg, 77%,1H NMR (DMSO-d6, 500 MHz): 5 = 10.13 (s, 1 H), 7.73 - 7.70 (m, 2H), 7.50 (d, J = 8.7 Hz, 1 H), 7.40 - 7.15 (m, 5H), 6.64 (d, J = 15.6 Hz, 1 H), 1.42 (s, 18H);13C NMR (DMSO-d6, 125 MHz) 5 = 164.3, 159.3, 157.4, 156.4, 141.9, 139.7, 136.4,

[0978] 126.4, 125.1 , 121.1 , 118.9, 115.9, 34.9, 30.6. LC-MS (ESI) m / z calculated for C23H27FNO2- [M-H]- 368.20, observed 368.20

[0979] (E)-3-(3,5-di-terf-butyl-4-hydroxyphenyl)- / \ / -(4-(methylsulfonyl)phenyl)acrylamide (Compound 397), off-white solid, 52 g, 90%,1H NMR (DMSO-d6, 500 MHz): 5 = 10.54 (s, 1 H), 7.96 - 7.89 (m, 4H), 7.60 (d, J = 8.7 Hz, 1 H), 7.47 - 7.43 (m, 3H), 6.70 (d, J = 15.6 Hz, 1 H), 3.19 (s, 3H), 1.44 (s, 18H);13C NMR (DMSO-d6, 125 MHz) 5 = 165.0, 156.7, 144.5, 143.1 , 139.7, 134.9, 128.7, 126.2, 125.3, 119.3, 118.4, 44.3, 34.9, 30.6. LC-MS (ESI) m / z calculated for C24H32NC>4S+[M+H]+430.20, observed 430.20

[0980] Additional NMR and MS characterization data is shown in FIG. 1 through FIG. 14.

[0981] Example 2: Materials and Methods

[0982] Parasite Maintenance in Laboratory Animals

[0983] A. ceylanicum hookworm parasites were maintained in golden Syrian hamsters (PloS Negl Trop Dis 2012, 6 (11), e1900). Following standard protocols, T. muris whipworm parasites were maintained in STAT6- / - mice (PloS One 8432013, 8 (7), e70702).

[0984] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0985] All references e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference {e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

[0986] Example 3: Screening Methods

[0987] A screening model (FIG. 15) based on the larval stages of human hookworm parasites was used as described in Sci Rep 2019, 9(1), 12347, incorporated herein by reference in its entirety. The primary screen was scaled up with modifications to include 30,000+ compounds in chemical libraries (FIG. 16).

[0988] Primary Screening Using Larval Developmental Assay

[0989] Feces from A. ceylanicum-' ected hamsters were collected ~18 days post-infection and about 20 grams of feces were processed for egg isolation and purification following salt / sugar flotation protocol (Parasitology 2001 , 123 (Pt 3), 309-14 and 10.1101 / 2023.02.01.526637). Purified and surface sterilized eggs were incubated in S- medium (WormBook 2006, 1-11) at 28 °C, without any food source for about 20 hours, allowing eggs to hatch into synchronized first-stage larvae (10.1101 / 2023.02.01.526637). Newly hatched L1 were washed three times in a S-medium. About 30-35 L1 larvae were dispensed into each well of 96-well assay plates containing 90|JL of S-media supplemented with 100U / ml of penicillin, 100|jg / ml streptomycin, and 2.5pg / ml amphotericin, Escherichia coli OP50 with final GD600 of 0.3 and 0.15 l Dimethylsulfoxide (DMSO). Library plates were diluted in S-media to 100pM and 1%DMSO. Using a multichannel pipette, 1OpL of the library plates were transferred into each well of the assay plates, giving a final concentration of 10pM of test drug and 0.25% DMSO. Plates were prepared in duplicates. Test plates were incubated at 28 °C for seven days and then scored for development under a dissecting microscope. Test drugs were considered hit if > 90% of L1 larvae failed to develop in duplicate wells. Each assay plate includes four wells of 10pM ivermectin as positive control and four wells of 0.25% DMSO as negative control.

[0990] Secondary Screening Using young Adults of Hookworm Parasites

[0991] Hits were then screened from the primary screening (larval development) against the adult stages of hookworm parasites. A. ceylanicum hookworm young adults were harvested 10-11 days post-inoculation from the small intestines of infected hamsters. Harvested worms were washed and incubated in prewarmed hookworm culture medium (RPMI1640 of pH 7.2 supplemented with 10% fetal bovine serum, 100U penicillin, 100pg / ml streptomycin, 2.5pg / ml amphotericin). Two adults of A. ceylanicum hookworm were manually picked into each well of the 96-well assay plates, containing 70pL of hookworm medium supplemented with 0.7pl DMSO. Using a multichannel pipette, 30pL from the library plates diluted in hookworm medium to a final concentration of 100pM and 1% DMSO were dispensed into screening wells, giving a final concentration in assay plates of 30pM of test compounds and 1% DMSO with duplicate wells / drug. Assay plates were incubated for 48 hours at 37 °C and 5% CO2. Drug activity was determined using the standard motility index (Sci Rep 2019, 9 (1), 12347 and PloS One 2013, 8 (7), e70702). A motility index of 3 was given to vigorous healthy adults, 2 for motile but slow adults, 1 for immotile adults that moved after stimulation by touching, and 0 for non-motile adults even after touching. The drug was considered a hit if the motility index of at least three of the four A. ceylanicum hookworm adults were scored <1 and / or if all the parasites in the well had significant morphological defects {e.g., shrunken cuticles, darkened intestines (FIG. 17). Each assay plate included four positive control wells (30pM ivermectin) and four negative control wells (1% DMSO).

[0992] Tertiary Screening Using Adult Whipworm Parasites

[0993] A. ceylanicum hookworm adult hits were then screened against T. muris whipworm parasites. T. muris adult whipworms were harvested from the cecum and large intestines of infected STAT6- / - mice. Single worms were manually picked into each well of a 48-well plate, six wells / test drug, and a final volume of 291 pL of whipworm culture medium with 2.1 pl DMSO (like hookworm culture medium but supplemented with 5% fetal bovine serum). 9pL from library plates diluted in whipworm medium to a final concentration of 1mM and 10% DMSO were dispensed into each well of the screening plates, giving a final concentration of 30|JM test drug and 1% DMSO. Assay plates were incubated at 37 °C, and 5% CO2. T. muris whipworm motility was measured using an in-house assembled worminator and worm assay software (PloS Negl Trop Dis 2012, 6 (1), e1494) for 3 minutes after 24 and 48 hours. Drug activity was determined using the percent motility inhibition compared to DMSO control. Drugs were considered active if the 24- and / or 48-hour motility was reduced by at least 50% compared to negative control (FIG. 18).

[0994] Example 4: Chemical Libraries Screened

[0995] Life Chemical 15K diversity set:

[0996] Life Chemical pre-plated diversity set library was obtained from the Small Molecules Screening Facility (SMSF), UMASS Chan Medical School. The library contains 15,360 compounds representing 1 ,717 chemical scaffolds with an average Tanimoto similarity index of 0.409. Library compounds were plated in 96-well plates with 1 ul of 10mM stock concentration. Hits from the primary and secondary screening were cherrypicked into 96-well plates for A. ceylanicum hookworms or T. muris whipworms screening.

[0997] Broad Institute Repurposing Hub

[0998] The drug repurposing hub includes 6,743 compounds which were from a curated and annotated collection of preclinical drugs in phase 1 (REPO 1) or phases 2-3 (REPO 2) and FDA-approved and launched drugs (REPO 3). REPO drugs cover a wide range of disease areas, including but not limited to infectious diseases, allergies, cardiology, dermatology, endocrinology, metabolism, neurology, and gastroenterology. The library covers 1,133 different modes of action and 2,183 different drug targets (Nat Med 2017, 23 (4), 405-408).

[0999] ICCB Screening libraries

[1000] The Institute of Chemistry and Cell Biology-Longwood (ICCB-L) Screening Program at Harvard Medical School offers a wide range of well-annotated drug screening libraries. Multiple ICCB-L libraries were screened, including mechanism of action, neuronal targets, GPCR-based inhibitors, and six libraries of kinase inhibitors.

[1001] ICCB-L MCA: the mechanism of the action library is a collection of high-quality annotated compounds with biological activity against known targets with target-compound pairs based on high target specificity and potency. The library contains 1 ,245 unique compounds, each plated in 4 doses.

[1002] ICCB-L Selleck Neuronal Targets: the neuronal targets library was initially composed of Selleck chemicals from FDA-approved compound sets that were determined to have biological activity in neurologic research and neurological assays. ICCB-L ChemBridge focused GPCR: this focused library of 250 GPCR inhibitors was selected from 13,000 GPCR inhibitors assembled by ChemBridge. The library has 11 different scaffolds, each containing 19-24 compounds.

[1003] Kinase inhibitor libraries: in total, we screened focused sets of 1428 kinase inhibitors from 7 different kinase libraries, some of which were screened at multiple doses.

[1004] ICCB-L SYNthesis kinase inhibitor: this library was assembled by SYNthesis Med Chem of 96 compounds known to inhibit different kinases.

[1005] ICCB-L EMD Kinase inhibitors: this library was built by EMD of 244 protein kinase inhibitors.

[1006] ICCB-L ChemBridge Focused Kinase inhibitors: this library of 250 compounds was created and selected from the ChemBridge kinase-biased library of 6000 compounds. These compounds were selected based on the pharmacophore properties of known kinase inhibitors or from compounds predicted to interact with the ATP binding site of kinases. In total, these compounds represent 16 different scaffolds that cover 34 kinase targets.

[1007] ICCB-L LINCS 1,2 and 4 Kinase inhibitors: these three libraries were assembled by LINCS together, including 345 compounds with known or predicted kinase inhibitors.

[1008] SMSF Kinase Inhibitor Library

[1009] This library includes 429 kinase inhibitors with activity and safety confirmed by preclinical research and clinical trials.

[1010] Natural Products:

[1011] The TimTec library of 4240 purified compounds from natural products or derivatives was screened. The TimTec library was obtained from the SMSF and includes two types of compounds.

[1012] Natural Products Library (NPL): the NPL library includes 1200 purified natural compounds from plant, bacteria, fungi, and animal sources.

[1013] Natural Derivatives Library (NDL): the NDL library includes 3040 semi-natural compounds derived from natural molecules or synthetic compounds with natural-like structures.

[1014] Structure-Activity Relationship (SAR) of Anthelmintic Hits:

[1015] Vendors’ databases and online tools were used to identify analogs of Compound 1, which were purchased from Life Chemicals. These analogs were tested against the adult stages of T. muris whipworm and A. ceylanicum hookworm parasites at 30pM and scored using the Worminator at 24 and 48 hours. Hence, A. ceylanicum hookworm parasites used in testing Compound 1 analogs for SAR model were mature adults harvested 18 days postinfection

[1016] Example 5: Screening Summary In total, 30,238 unique compounds were screened in duplicate. Some compounds were screened at multiple doses due to plate format availability, making the total number of conditions screened 76,586. All libraries were initially screened in duplicate at 10 pM. As per our pipeline, primary screen hits (in both duplicate wells) were screened at 30 pM against adult A. ceylanicum hookworms. Adult hookworm hits were then screened at 30 pM against adult T. muris whipworms. A breakdown of hits “library by library” is shown below in Table 12.

[1017] Table 12

[1018] Hits from the Generic Diversity Set Library:

[1019] Of the 15,360 compounds in the generic diversity set tested against A. ceylanicum hookworm larvae, 491 were active, with a hit rate of 3.2%. These 491 larval hits were tested against the early adult stages of A. ceylanicum hookworm, yielding 33 hookworm adultactive compounds. An example of screening against the early adult stages of A. ceylanicum hookworms is shown in FIG. 17. These 33 A. ceylanicum hookworm adult-active compounds were screened against T. muris adult whipworms, yielding seven hits active against the two evolutionarily divergent parasites. An example of screening against adult T. muris whipworms is shown in FIG. 18.

[1020] Hits from the Repurposing and Mechanism of Action (MoA) Libraries

[1021] Of the 6,743 compounds tested from the repurposing library, 230 A. ceylanicum hookworm larval-active compounds were identified (hit rate of 3.4%), of which 96 showed activity against adult A. ceylanicum hookworms (hit rate 1.42%). Of these 96 compounds, 36 were active against adult T. muris whipworms with a final hit rate of 0.53%. Similarly, The ICCB-Longwood MoA library contained 1 ,245 high-quality compounds with known mechanisms of action. Sixty-five A. ceylanicum hookworm larval-active compounds were identified with a 5.2% hit rate, the highest among all tested libraries. Seventeen of these compounds carried adulticidal activity against A. ceylanicum hookworms, from which nine were active against T. muris whipworm adults, with a final hit rate of 0.72% Hits from the Neuronal and the GPCR libraries:

[1022] Of the 1031 compounds with known modulation of neuronal signaling, we identified 29 A. ceylanicum hookworm larval-active compounds (hit rate of 2.8%). Of these 29 compounds, 12 showed activity against adult A. ceylanicum hookworms (1.1% of the total), of which two were active against T. muris whipworm adults with a final hit rate of 0.19%. We also screened 250 known GPCR inhibitors and identified two compounds with larval activity against A. ceylanicum; however, these compounds did not show activity against the adult stages of parasites. One explanation for the lack of success with this library is that these inhibitors were tailored initially for selective binding to human GPCRs.

[1023] Hits from the Kinase Inhibitor Libraries:

[1024] Of seven kinase inhibitor libraries with 1427 compounds (Table 12), 47 compounds were identified with A. ceylanicum larval activity, giving a hit rate of 3.2%. Of those 47 compounds, 13 showed activities against the adult stages of A. ceylanicum hookworms (0.9%), of which 10 compounds were also active against T. muris whipworm adults with a hit rate of 0.7%.

[1025] Hits from the Natural Products Library:

[1026] Of 4,240 purified compounds from natural products or derived from natural products, 14 compounds were identified with A. ceylanicum larval activity, giving the lowest primary screen hit rate of 0.33%. None of these 14 larvicidal compounds showed activity against the adult stages of A. ceylanicum hookworms.

[1027] Example 6: In Vitro Anthelmintic Activity

[1028] Provided below in Table 13 are 55 active compounds including chemical structure, source library, in vitro activity against A. ceylanicum hookworms (HW M. index where 3 is healthy and 0 is completely immotile), in vitro activity against T. muris whipworms (WW % M.I., motility inhibition), known mode of action in eukaryotic organisms, and the orthologous targets in nematodes if any. (-) no known target.

[1029] Table 13

[1030]

[1031] Collectively, 878 compounds were identified with A ceylanicum larval activity, giving an overall primary screen hit rate of 2.9% (Table 12). In the secondary screen, all larval- active compounds were tested at 30 pM against the adult stages of A. ceylanicum hookworm parasites. Of those, 171 (19.5% of the larval hits) had anthelmintic activity toward adult hookworms, representing a hit rate of 0.5% based on the total number of compounds in the initial libraries. These 171 hookworm-adult actives were tested against adult T. muris whipworms at 30 pM. Sixty-four compounds (37% of the adult hookworm hits and 0.21% based on the total number of compounds in all the libraries) showed activity against whipworm adults (Table 12). Of the 64 compounds identified from all libraries, nine were redundant (included independently in multiple libraries), yielding 55 unique active compounds listed in Table 11. Anthelmintic compounds that showed activity at 30pM against A. ceylanicum and T. muris are shown in Table 13.

[1032] Seven compounds with anthelmintic activity were identified from the Life Chemical Diversity Set, which is compiled of de novo and newly synthesized molecules developed for initial phenotypic screening. To further investigate, 28 analogs were identified using structural similarity online searching tools and purchased from a commercial vendor (Life Chemical), which could serve as training sets for ligand-based optimization and generate the SAR model. This set of analogs was screened against adult T. muris whipworms, followed by older A. ceylanicum hookworm adults, which could read more easily in the Worminator.

[1033] In vitro activity against A. ceylanicum hookworms (HW) and T. muris whipworms (WW) are shown below in Table 14.

[1034] Table 14

[1035] 1Not Determined

[1036] The in vitro activity of the tyrphostin compounds against A. ceylanicum hookworms (HW) and T. muris whipworms (WW) is shown below in Table 15.

[1037] Table 15

[1038] 1Not Determined

[1039] The in vitro activity of the ESI-09 analogues against A. ceylanicum hookworms (HW) and T. muris whipworms (WW) is shown below in Table 16.

[1040] Table 16

[1041] 1Not Determined

[1042] Mammalian cells (LI20S) fractional viability of select compounds is shown in FIG. 19. Doses tested were 31.6, 10, 3.16, 1 , 0.3, 0.1, 0.03, 0.01, 0.003, and 0.001 pM. Example 7: In Vivo Anthelmintic Activity

[1043] The in vivo activity of particular compounds against A. ceylanicum hookworms (HW) is shown below in Table 17.

[1044] Table 17

[1045] Example 8: Compound Potency

[1046] The IC-50 values of the ESI-09 analogues against A ceylanicum hookworms and T. muris whipworms is shown below in Table 18.

[1047] Table 18 in vivo active The IC-50 values of the tyrphostin compounds against A ceylanicum hookworms and T. muris whipworms is shown below in Table 19.

[1048] Table 19

[1049] Example 9: Tyrphostins Overcome Anthelmintic Drug Resistance

[1050] Cyathostomin and Ancylostoma caninum L1 survival Assay using sensitive and naturally resistant isolates.

[1051] Cyathostomin

[1052] Using two-way ANOVA, the dose-response between resistant and sensitive isolates were compared (FIG. 22). The three drugs generated different response curves and the differences in dose-response between the three drugs on L1 survival were highly significant (P < 0.0001). However, no significant differences between the two isolates (sensitive and double resistant) to the dose-response of the three drugs were observed.

[1053] A. caninum

[1054] Using two-way ANOVA, the dose-response between triple resistant and sensitive isolates were compared (FIG. 23). Similarly, to cyathstomins, the differences in doseresponse between the three drugs were highly significant (P < 0.0001). It is worth noting that Compound 89, and Compound 91 showed significant differences in dose-response between the sensitive and triple resistant isolate, indicating that the triple resistant isolate were more susceptible to Compound 89 and Compound 91 than the sensitive strain.

[1055] Example 10: In Vivo Validation

[1056] In vivo validation for select compounds in shown in FIG. 20 and FIG. 21. Compound 156 safety and in vivo validation is shown in FIG. 24. ESI-09 analogs in vivo validation is shown in FIG. 25.

[1057] Example 11 : Dose Response

[1058] ESI-09 (Compound 187) and select analogs dose response is shown in FIG. 26.

[1059] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[1060] All references {e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference {e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

CLAIMS1 . A method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt thereof:(I), wherein: ring A is selected from the group consisting of Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl, wherein Ce-io aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, three, or four R4, and wherein 5-10 membered heteroaryl and 3-11 membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S; ring B is selected from the group consisting of absent, Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl, wherein Ce-io aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, three, or four R5, and wherein 5-10 membered heteroaryl and 3-11 membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S;Y1is selected from the group consisting of C(R6)2, NR7, O, and S;Y2is CR8or N;Y3is selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, O, S, and SO2;R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, OH, -CN, halo, NH2, N(H)(CI-6alkyl), and N(CI-6alkyl)2;R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2, provided that when is c / s double bond, a trans double bond, or a mixture of cis and trans double bonds, then R2and R3are not =0;R6and R8, independently at each occurrence, are selected from the group consisting of H, OH, -CN, halo, NH2, N(H)(CI-6alkyl), and N(CI-6alkyl)2;R7is selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2. 6 alkenyl, and C2-6 alkynyl; a is 0, 1 , 2, 3, or 4; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

2. The method of claim 1 , wherein: ring A is selected from the group consisting of Ce- aryl and 5-10 membered heteroaryl, wherein Ce-io aryl and 5-10 membered heteroaryl are each optionally substituted with one, two, three, or four R4, and wherein 5-10 membered heteroaryl contains one, two, or three ring heteroatoms selected from the group consisting of N, O, and S; ring B is selected from the group consisting of absent, Ce- aryl, and 3-11 membered heterocycloalkyl, wherein Ce- aryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, or three R5, and wherein 3-11 membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;Y1is selected from the group consisting of C(R6)2, NR7, O, and S;Y2is CR8or N;Y3is selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, O, S, and SO2;R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, OH, -CN, halo, NH2, N(H)(CI-6alkyl), and N(CI-6alkyl)2;R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2, provided that whenis cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R2and R3are not =0;R6and R8, independently at each occurrence, are selected from the group consisting of H, OH, -CN, halo, and NH2;R7is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl; a is 0, 1 , 2, or 3; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

3. The method of claim 1 or 2, wherein:ring A is selected from the group consisting of phenyl and 5-10 membered heteroaryl, wherein phenyl and 5-10 membered heteroaryl are each optionally substituted with one, two, or three R4, and wherein 5-10 membered heteroaryl contains one or two ring heteroatoms selected from the group consisting of N, O, and S; ring B is selected from the group consisting of absent, phenyl, and 3-6 membered heterocycloalkyl, wherein phenyl, and 3-6 membered heterocycloalkyl are each optionally substituted with one or two R5, and wherein 3-6 membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;Y1is selected from the group consisting of NR7, O, and S;Y2is CR8or N;Y3is selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, O, S, and SO2;R1, R4, and R5, independently at each occurrence, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, and NH2;R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2, provided that whenis cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R2and R3are not =0;R7is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;R8is selected from the group consisting of H, OH, -CN, halo, and NH2; a is 0, 1 , or 2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

4. The method of any one of claims 1-3, wherein the compound of formula I is a compound of formula IA:or a pharmaceutically acceptable salt thereof, wherein: b is 0, 1 , 2, or 3.

5. The method of any one of claims 1-3, wherein the compound of formula I is a compound of formula IB:(IB), a pharmaceutically acceptable salt thereof, wherein:Y4and Y5are each independently selected from the group consisting of CH2, NH, N(CI-6 alkyl), O, and S, provided that at least one of Y4and Y5is selected from the group consisting of NH, N(CI-6 alkyl), O, and S; b is 0, 1 , 2, or 3; and c is 0 or 1.

6. The method of any one of claims 1-3, wherein the compound of formula I is a compound of formula IC:or a pharmaceutically acceptable salt thereof, wherein:Y33is selected from the group consisting of NH, O, and S; and b is 0, 1 , 2, or 3.

7. The method of any one of claims 1-4, wherein the compound of formula I is a compound of formula IA-I:(IA-I), or a pharmaceutically acceptable salt thereof, wherein: ring B is phenyl or 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S; b is 0, 1 , 2, or 3; and d is 0, 1 , or 2.

8. The method of any one of claims 1-4, wherein the compound of formula I is a compound of formula IA-II;(IA-II), or a pharmaceutically acceptable salt thereof, wherein: b is 0, 1 , 2, or 3.

9. The method of any one of claims 1-4 and 7, wherein the compound of formula I is a compound of formula lA-la;(lA-la), or a pharmaceutically acceptable salt thereof, whereinb is 0, 1 , 2, or 3; and d is 0 or 1.

10. The method of any one of claims 1-4 and 7, wherein the compound of formula I is a compound of formula lA-lb;(IA-lb), or a pharmaceutically acceptable salt thereof, wherein:Y6is selected from the group consisting of CH2, NH, O, and S;Y7is selected from the group consisting of CH and N, provided that at least one of Y6and Y7is selected from the group consisting of N, NH, O, and S; b is 0, 1 , 2, or 3; and d is 0 or 1.

11. The method of any one of claims 1-4 and 8, wherein the compound of formula I is a compound of formula lA-lla:(lA-lla), or a pharmaceutically acceptable salt thereof, wherein: b is 0, 1 , 2, or 3.

12. The method of any one of claims 1-4 and 8, wherein the compound of formula I is a compound of formula lA-lib;(lA-lib), or a pharmaceutically acceptable salt thereof, wherein: b is 0, 1 , 2, or 3; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

13. The method of any one of claims 1-12, wherein Y1is O or S.

14. The method of any one of claims 1-13, wherein Y2is N.

15. The method of any one of claims 1-4, 7, 9, 10, 11 , and 12, wherein Y3is selected from the group consisting of absent, C1-6 alkyl, O, and SO2.

16. The method of claim 5, wherein Y4and Y5are each independently selected from the group consisting of NH, O, and S.

17. The method of claim 10, wherein Y6is selected from the group consisting of CH2, NH, and O.

18. The method of any one of claims 1-17, wherein R1is selected from the group consisting of C1-6 alkyl, OH, -CN, halo, and NH2.

19. The method of any one of claims 1-10 and 12-18, wherein R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, NH2, N(H)(CI-6alkyl), and N(CI-6alkyl)2.

20. The method of any one of claims 1-10 and 12-19, wherein R2and R3are each independently selected from the group consisting of H, C1-6 alkyl, OH, -CN, halo, and NH2.

21. The method of any one of claims 1-20, wherein R2is selected from the group consisting of H, C1-6 alkyl, OH, -CN, halo, and NH2.

22. The method of any one of claims 1-21 , wherein R4, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, OH, -CN, and halo.

23. The method of any one of claims 1-4, 7, 9, 10, 13-15, and 17-22, wherein R5, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, OH, - CN, and halo.

24. The method of any one of claims 1-23, wherein a is 0 or 1.

25. The method of any one of claims 5 and 13, 14, 16, 18-22, and 24, wherein c is 1.

26. The method of any one of claims 1-3, wherein ring A is selected from the group consisting of phenyl and 6-10 membered heteroaryl, wherein phenyl and 6-10 membered heteroaryl are each optionally substituted with one, two, or three R4, and wherein 6-10 membered heteroaryl contains one or two ring heteroatoms selected from the group consisting of N, O, and S.

27. The method of any one of claims 1-3 and 26, wherein ring A is selected from the group consisting of phenyl and 8-10 membered heteroaryl, wherein phenyl and 8-10 membered heteroaryl are each optionally substituted with one, two, or three R4, and wherein 8-10 membered heteroaryl contains one or two ring heteroatoms selected from the group consisting of N, O, and S.

28. The method of claim 27, wherein 8-10 membered heteroaryl is a bicyclic 8-10 membered heteroaryl.

29. The method of any one of claims 1-28, wherein the compound is selected from the group consisting of a compound in Table 5, or a pharmaceutically acceptable salt thereof.

30. A compound of formula II:or a pharmaceutically acceptable salt thereof, wherein: ring D and ring E are each independently selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;Y8is selected from the group consisting of O, NH, and N(CI-6 alkyl);R9is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R15;R10, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, NH2, N(H)(CI-6 alkyl), N(CI-6 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R16;R11is selected from the group consisting of H, -CN, OH, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R17;R12is selected from the group consisting of H, -CN, OH, C2-6 alkenyl, and C2-6 alkynyl, wherein C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with one, two, or three R18;R13is selected from the group consisting of -CN, OH, halo, SO2C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R19;R14, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, NH2, N(H)(CI-6 alkyl), N(CI-6 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R20;R15, R16, R17, R18, R19and R20, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl^; e and f are each independently 0, 1 , 2, 3, or 4; andis a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

31. The compound of claim 30, wherein: ring D and ring E are each independently selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;Y8is selected from the group consisting of NH and N(CI-6 alkyl);R9is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or two R15;R10, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or two R16;R11is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or two R17;R12is selected from the group consisting of H, -CN, OH, C2-6 alkenyl, and C2-6 alkynyl, wherein C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with one or two R18;R13is selected from the group consisting of -CN, OH, SO2C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or two R19;R14, independently at each occurrence, is selected from the group consisting of -CN, OH, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or two R20;R15, R16, R17, R18, R19and R20, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, and NH2; e and f are each independently 0, 1 , 2, or 3; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

32. The compound of claim 30 or 31 , wherein: ring D and ring E are each independently selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N and O;Y8is selected from the group consisting of NH and N(CI-6 alkyl);R9is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one R15;R10, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, NH2, C1-6 alkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R16;R11is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R17;R12is selected from the group consisting of H, -CN, OH, C2-6 alkenyl, and C2-6 alkynyl, wherein C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with one R18;R13is selected from the group consisting of -CN, OH, SO2C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one R19;R14, independently at each occurrence, is selected from the group consisting of -CN, OH, NH2, C1-6 alkyl, and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R20;R15, R16, R17, R18, R19and R20, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, and NH2; e and f are each independently 0, 1 , or 2; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

33. The compound of any one of claims 30-32, wherein the compound of formula II is a compound of formula IIA:(HA), or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 30-32, wherein the compound of formula II is a compound of formula IIB:(HB), or a pharmaceutically acceptable salt thereof.

35. The compound of any one of claims 30-34, wherein at least one of ring D and ring E is phenyl.

36. The compound of any one of claims 30-33 and 35, wherein the compound of formulaII is a compound of formula IIA-i:(HA-i), or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 30-32, 34, and 35, wherein the compound of formula II is a compound of formula IIB-i:(HB-i), or a pharmaceutically acceptable salt thereof.

38. The compound of any one of claims 30-33, 35, and 36, wherein the compound of formula II is a compound of formula IIA-ia:(IIA-ia), or a pharmaceutically acceptable salt thereof.

39. The compound of any one of claims 30-32, 34, 35, and 37, wherein the compound of formula II is a compound of formula IIB-ia:(IIB-ia), or a pharmaceutically acceptable salt thereof.

40. The compound of any one of claims 30-39, wherein R9is H or C1-6 alkyl optionally substituted with one R15.

41. The compound of any one of claims 30-40, wherein R9is H.

42. The compound of any one of claims 30-40, wherein R9is C1-6 alkyl optionally substituted with one R15.

43. The compound of any one of claims 30-42, wherein R10, independently at each occurrence, is selected from C1-6 alkyl and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with one R16.

44. The compound of any one of clams 30-43, wherein R11is selected from the group consisting of H and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R17.

45. The compound of any one of claims 30-44, wherein R13is selected from the group consisting of -CN, SO2C1-6 alkyl, C1-6 alkoxy, and C2-6 alkynyl, wherein C1-6 alkoxy and C2-6 alkynyl are each optionally substituted with one R19.

46. The compound of any one of claims 30-45, wherein R14, independently at each occurrence, is selected from the group consisting of -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one R20.

47. The compound of any one of claims 30-46, wherein f is 0 or 1.

48. The compound of any one of claim 30-47, wherein the compound is selected from the group consisting of a compound in Table 1 , or a pharmaceutically acceptable salt thereof.

49. A pharmaceutical composition comprising a compound of any one of claims 30-48, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

50. A method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof:(HI), wherein: ring F is selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R23; alternatively, R18and R19, together with the atom to which they are attached, form a ring selected from the group consisting of phenyl and 5- or 6-membered heteroaryl;R20is selected from the group consisting of H, -CN, OH, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one, two, or three R24;R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6 alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), and C(O)N(CI-6alkyl)2;R24, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;R21and R22are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, -NC, halo, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C(O)OH, C(O)OCi-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6alkyl), C(S)N(CI-6alkyl)2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6alkyl)C(O)H, Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl, wherein Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, or three R25, provided that whenis c / s double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =0; or one of R21and R22has the structure:wherein: ring G is selected from the group consisting of absent, Ce- aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl, wherein Ce-io aryl, C3-11 cycloalkyl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, three, or four R26;Y9and Y11are each independently selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O), and C(S), provided that at least one of Y9and Y11is selected from the group consisting of C(O), C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;Y10is selected from the group consisting of absent, O, NH, and N(CI-6 alkyl);R25, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NO2, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C(O)OH, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6alkyl), and C(S)N(CI-6alkyl)2;R26, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, OH, -CN, halo, NO2, NH2, N(H)(CI-6 alkyl), N(CI-6alkyl)2, C(O)OH, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(0)N(CI-6 alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6alkyl), and C(S)N(CI-6alkyl)2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

51. The method of claim 50, wherein: ring F is selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N and O;R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one or two R23; alternatively, R18and R19, together with the atom to which they are attached, form a ring selected from the group consisting of phenyl and 5- or 6-membered heteroaryl;R20is selected from the group consisting of H, -CN, OH, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or two R24;R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6alkyl, and C(O)NH2;R24, independently at each occurrence, is selected from the group consisting of -CN, OH, halo, and C1-6 alkyl;R21and R22are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCi-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, C(S)N(H)(CI-6alkyl), C(S)N(CI-6alkyl)2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6 alkyl)C(O)H, Ce- aryl, and 5-10 membered heteroaryl, wherein Ce- aryl and 5-10 membered heteroaryl are each optionally substituted with one or two R25, provided that when is cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =0; or one of R21and R22has the structure:wherein: ring G is selected from the group consisting of absent, Ce- aryl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl, wherein Ce- aryl, 5-10 membered heteroaryl, and 3-11 membered heterocycloalkyl are each optionally substituted with one, two, or three R26;Y9and Y11are each independently selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C(O), and C(S), provided that at least one of Y9and Y11is selected from the group consisting of C(O), C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;Y10is selected from the group consisting of absent, O, NH, and N(CI-6 alkyl);R25, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, Ci-6alkoxy, Ci-6haloalkyl, OH, -CN, halo, NO2, NH2, C(O)OH, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6 alkyl), C(O)N(CI-6alkyl)2, C(S)OH, and C(S)NH2;R26, independently at each occurrence, is selected from the group consisting of Ci-6 alkyl, Ci-6 alkoxy, Ci-6haloalkyl, =0, OH, -CN, halo, NO2, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C(O)OH, C(O)Ci-6 alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), C(O)N(CI-6alkyl)2, C(S)OH, and C(S)NH2; and is a single bond, a c / s double bond, a trans double bond, or a mixture of cis and trans double bonds.

52. The method of claim 50 or 51 , wherein: ring F is selected from the group consisting of phenyl and 6-membered heterocycloalkyl, wherein 6-membered heterocycloalkyl contains one or two ring heteroatoms selected from the group consisting of N and O;R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, halo, NH2, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and C2-6 alkenyl, wherein Ci-6 alkyl, Ci-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23; alternatively, R18and R19, together with the atom to which they are attached, form a ring selected from the group consisting of phenyl and 6-membered heteroaryl;R20is selected from the group consisting of H, -CN, OH, and Ci-6 alkyl, wherein Ci-6 alkyl is optionally substituted with one R24;R23is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)Ci-6alkyl, and C(O)NH2;R24, independently at each occurrence, is selected from the group consisting of -CN, OH, and halo;R21and R22are each independently selected from the group consisting of H, Ci-6 alkyl, Ci-6haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCi-6alkyl, C(O)Ci-6alkyl,C(O)NH2, C(0)N(H)(CI-6 alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6alkyl)C(O)H, phenyl, and 5- or 6- membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that whenis cis double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =0; or one of R21and R22has the structure:wherein: ring G is selected from the group consisting of absent, phenyl, 5- or 6-membered heteroaryl, and 5-7 membered heterocycloalkyl, wherein phenyl, 5- or 6-membered heteroaryl, and 5-7 membered heterocycloalkyl are each optionally substituted with one or two R26;Y9and Y11are each independently selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C(0), and C(S), provided that at least one of Y9and Y11is selected from the group consisting of C(0), C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;Y10is selected from the group consisting of absent, O, NH, and N(CI-6 alkyl);R25is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, OH, -CN, halo, N02, NH2, C(O)OH, C(O)CI-6alkyl, and C(O)NH2;R26, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, Ci-6haloalkyl, =0, OH, -CN, halo, N02, NH2, C(O)OH, C(O)Ci-6alkyl, C(O)NH2, C(0)N(H)(CI-6 alkyl), and C(O)N(CI-6alkyl)2; and is a single bond, a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

53. The method of any one of claims 50-52, wherein the compound of formula III is a compound of formula IIIA:(HIA), or a pharmaceutically acceptable salt thereof.

54. The method of any one of claims 50-52, wherein the compound of formula III is a compound of formula HUB:(IIIB), or a pharmaceutically acceptable salt thereof, wherein:R21and R22are each independently selected from the group consisting of H, C1-6 alkyl, Ci-6haloalkyl, =0, OH, -CN, -NC, NH2, C(O)OH, C(O)OCi-6alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6 alkyl), C(O)N(CI-6alkyl)2, C(S)OH, C(S)Ci-6alkyl, C(S)NH2, N(H)C(O)H, N(H)C(O)OH, N(CI-6alkyl)C(O)OH, N(CI-6alkyl)C(O)H, phenyl, and 5- or 6- membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one R25, provided that whenis a c / s double bond, a trans double bond, or a mixture of cis and trans double bonds, then R21and R22are not =0.

55. The method of any one of claims 50-53, wherein the compound of formula III is a compound of formula IIIA-i:(IHA-i), or a pharmaceutically acceptable salt thereof, wherein: g is 0, 1 , or 2.

56. The method of any one of claims 50-53, wherein the compound of formula III is a compound of formula IIIA-ii:(IIIA-ii), or a pharmaceutically acceptable salt thereof, wherein:Y12is selected from the group consisting of CH2, NH, O, and S;Y13is selected from the group consisting of CH and N, provided that at least one of Y12and Y13is selected from the group consisting of N, NH, O, and S; and g is 0, 1 , or 2.

57. The method of claim any one of claims 50-53, wherein the compound of formula III is a compound of formula IIIA-iii:(IIIA-iii), or a pharmaceutically acceptable salt thereof, wherein:Y14and Y15are each independently selected from the group consisting of CH2, NH, O, S, and SO2, provided that at least one of Y14and Y15are selected from the group consisting of N, NH, O, S, and SO2; and g is 0, 1 , or 2.

58. The method of claim any one of claims 50-53, wherein the compound of formula III is a compound of formula IIIA-iv:(IIIA-iv), or a pharmaceutically acceptable salt thereof.

59. The method of any one of claims 50-52 and 54, wherein the compound of formula III is a compound of formula IIIB-i:(IHB-i), or a pharmaceutically acceptable salt thereof, wherein:Y16is selected from the group consisting of O and S; andR27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2.

60. The method of any one of claims 50-52 and 54, wherein the compound of formula III is a compound of formula IIIB-ii:(IIIB-ii), or a pharmaceutically acceptable salt thereof, wherein:R15, R16, R17, R18, and R19are each independently selected from the group consisting of H, -CN, OH, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C2-6 alkenyl, wherein C1-6 alkyl, C1-6 alkoxy, and C2-6 alkenyl are each optionally substituted with one R23.

61. The method of any one of claims 50-52 and 54, wherein the compound of formula III is a compound of formula IIIB-iii:(IIIB-iii), or a pharmaceutically acceptable salt thereof, wherein:Y16is selected from the group consisting of O and S;Y17and Y18are each independently selected from the group consisting of CH and N, provided that at least one of Y17and Y18is CH; andR27is selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), and N(CI-6 alkyl)2.

62. The method of any one of claims 50-52 and 54, wherein the compound of formula III is a compound of formula IIIB-iv:(IIIB-iv), or a pharmaceutically acceptable salt thereof, wherein:Y19and Y20are each independently selected from the group consisting of O and S; andR28and R29are each independently selected from the group consisting of OH, NH2, N(H)(CI-6 alkyl), N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 alkoxy.

63. The method of any one of claims 50-60 and 62, wherein at least two of R15, R16, R17, R18, and R19are selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy.

64. The method of any one of claims 50-60, 62, and 63, wherein at least three of R15, R16, R17, R18, and R19are selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy.

65. The method of any one of claims 50-59 and 62, wherein at least one of R15, R16, R17, R18, and R19is selected from the group consisting of H, OH, and halo.

66. The method of any one of claims 50-60 and 62, wherein at least one of R15, R16, R17, R18, and R19is selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are each optionally substituted with C(O)OH or C(O)NH2.

67. The method of any one of claims 50-66, wherein R20is selected from the group consisting of H and C1-6 alkyl.

68. The method of any one of claims 50-59, 61 , and 63-67, wherein R21is selected from the group consisting of =0, OH, -CN, -NC, NH2, and phenyl optionally substituted with R25.

69. The method of any one of claims 50-53, 55-58, and 63-67, wherein Y9and Y11are each independently selected from the group consisting of absent, C1-6 alkyl, C1-6 alkoxy, and C(O), provided that at least one of Y9and Y11is selected from the group consisting of C(O), C1-6 alkyl, and C1-6 alkoxy.

70. The method of any one of claims 50-53, 55-58, 63-67, and 69, wherein Y10is selected from the group consisting of NH and N(CI-6 alkyl).

71. The method of any one of claims 50-59, 61 , and 63-70, wherein R25is selected from the group consisting of OH, -CN, halo, NO2, and NH2.

72. The method of any one of claims 50-53, 55-57, and 63-71 , wherein R26, independently at each occurrence, is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, =0, halo, and NO2.

73. The method of any one of claims 50-72, wherein the compound is selected from the group consisting of a compound in Table 7, or a pharmaceutically acceptable salt thereof.

74. A method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound of formula IV, or a pharmaceutically acceptable salt thereof:(IV), wherein: ring H and ring I are each independently selected from the group consisting of Ce- aryl, 5-11 membered heteroaryl, C3-11 cycloalkyl, and 5-11 membered heterocycloalkyl, wherein 5-11 membered heteroaryl, and 5-11 membered heterocycloalkyl each contain one or two ring heteroatoms selected from the group consisting of N, O, and S;Y21is selected from the group consisting of CH2, C(H)(CI-6 alkyl), C(Ci-6 alkyl)2, 0, and S;R30, independently at each occurrence, is selected from the group consisting of =0, - CN, OH, halo, N02, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C1-6 alkyl, Ci-6alkylthio, Ci-6haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Ce- aryl, 5-11 membered heteroaryl, C3-11 cycloalkyl, and 5-11 membered heterocycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ce- aryl, 5-11 membered heteroaryl, C3-11 cycloalkyl, and 5-11 membered heterocycloalkyl are each optionally substituted with one, two, or three R34, and wherein 5-11 membered heteroaryl and 5-11 membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S; alternatively, two adjacent R30, together the atom to which they are attached, form a ring selected from the group consisting of phenyl and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one, two, or three R35, and wherein 5- or 6-membered heteroaryl contains one or two ring heteroatoms selected from the group consisting of N, O, and S;R31is selected from the group consisting of H, -CN, OH, halo, NH2, N(H)(CI-6 alkyl), N(CI-6 alkyl)2, C1-6 alkyl, C1.6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(0)0Ci-6 alkyl, C(O)Ci-6alkyl, C(O)NH2, C(O)N(H)(CI-6alkyl), and C(O)N(CI-6alkyl)2;R32is selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;R33, independently at each occurrence, is selected from the group consisting of =0, - CN, OH, halo, N02, NH2, N(H)(CI-6alkyl), N(CI-6alkyl)2, C1-6 alkyl, Ci-6haloalkyl, Ci-6alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Ce- aryl, 5-11 membered heteroaryl, C3-11 cycloalkyl, and 5-11 membered heterocycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ce- aryl, 5-11 membered heteroaryl, C3-11 cycloalkyl, and 5-11 membered heterocycloalkyl are each optionally substituted with one, two, or three R36’, andwherein 5-11 membered heteroaryl and 5-11 membered heterocycloalkyl each contain one or two ring heteroatoms selected from the group consisting of N, O, and S;R34, R35, and R36, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, N(H)(CI-6 alkyl), N(CI-6 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl; h and i are each independently 0, 1 , 2, 3, or 4; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

75. The method of claim 74, wherein: ring H and ring I are each independently selected from the group consisting of Ce- aryl, 5-7 membered heteroaryl, C3-6 cycloalkyl, and 5-7 membered heterocycloalkyl, wherein 5-7 membered heteroaryl, and 5-7 membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S;Y21is selected from the group consisting of CH2, C(H)(CI-6 alkyl), C(Ci-6 alkyl)2, 0, and S;R30, independently at each occurrence, is selected from the group consisting of =0, - CN, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, Ce- aryl, and C3-11 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, Ce- aryl, and C3-11 cycloalkyl are each optionally substituted with one or two R34; alternatively, two adjacent R30, together the atom to which they are attached, form a ring selected from the group consisting of phenyl and 5- or 6-membered heteroaryl, wherein phenyl and 5- or 6-membered heteroaryl are each optionally substituted with one, two, or three R35, and wherein 5- or 6-membered heteroaryl contains one or two ring heteroatoms selected from the group consisting of N and O;R31is selected from the group consisting of H, -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C(O)OH, C(O)OCi-6 alkyl, C(O)Ci-6 alkyl, and C(O)NH2;R32is selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;R33, independently at each occurrence, is selected from the group consisting of =0, - CN, OH, halo, NO2, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, Ce- aryl, 5-11 membered heteroaryl, and C3-11 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, Ce- 10 aryl, 5-11 membered heteroaryl, and C3-11 cycloalkyl are each optionally substituted with one or two R36;R34, R35, and R36, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl;h and i are each independently 0, 1 , 2, 3, or 4; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

76. The method of claim 74 or 75, wherein: ring H and ring I are each independently selected from the group consisting of phenyl, 5- or 6-membered heteroaryl, C3-5 cycloalkyl, and 5- or 6-membered heterocycloalkyl, wherein 5- or 6-membered heteroaryl and 5- or 6-membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S;Y21is selected from the group consisting of CH2, O, and S;R30, independently at each occurrence, is selected from the group consisting of =0, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, and C3-6 cycloalkyl are each optionally substituted with one R34; alternatively, two adjacent R30, together the atom to which they are attached, form a ring selected from the group consisting of phenyl and 6-membered heteroaryl, wherein phenyl and 6-membered heteroaryl are each optionally substituted with one or two R35, and wherein 6-membered heteroaryl contains one ring heteroatom selected from the group consisting of N and O;R31is selected from the group consisting of H, -CN, OH, halo, NH2, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl;R32is selected from the group consisting of H, C1-6 alkyl, and C1-6 alkoxy;R33, independently at each occurrence, is selected from the group consisting of =0, halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, phenyl, 5- or e- membered heteroaryl, and C3-6 cycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, phenyl, 5- or e- membered heteroaryl, and C3-6 cycloalkyl are each optionally substituted with one R36;R34, R35, and R36, independently at each occurrence, are selected from the group consisting of -CN, OH, halo, NH2, and C1-6 alkyl; h and i are each independently 0, 1 , 2, 3, or 4; and is a cis double bond, a trans double bond, or a mixture of cis and trans double bonds.

77. The method of any one of claims 74-76, wherein: ring H is selected from the group consisting of phenyl, 5-membered heteroaryl, C3-5 cycloalkyl, and 5-membered heterocycloalkyl, wherein 5-membered heteroaryl and 5-membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S; and ring I is selected from the group consisting of phenyl, 5-membered heteroaryl, and 5- membered heterocycloalkyl, wherein 5-membered heteroaryl and 5-membered heterocycloalkyl each contain one, two, or three ring heteroatoms selected from the group consisting of N, O, and S.

78. The method of any one of claims 74-77, wherein the compound of formula (IV) is a compound of formula (IVA):(IVA), or a pharmaceutically acceptable salt thereof.

79. The method of any one of claims 74-77, wherein the compound of formula (IV) is a compound of formula (IVB):(IVB), or a pharmaceutically acceptable salt thereof, wherein:Y22is selected from the group consisting of CH2, NH, O, and S;Y23is selected from the group consisting of CH and N, provided that at least one of Y22and Y23is selected from the group consisting of N, NH, O, and S; h is 0, 1 , 2, or 3; and i is 0, 1 , 2, 3, or 4.

80. The method of any one of claims 74-77, wherein the compound of formula (IV) is a compound of formula (IVC):(IVC), or a pharmaceutically acceptable salt thereof, wherein:Y22is selected from the group consisting of CH2, NH, O, and S;Y23is selected from the group consisting of CH and N;Y24are each independently selected from the group consisting of CH2, NH, O, and S;Y25and Y26are each independently selected from the group consisting of CH and N, provided that at least one of Y24, Y25, and Y26is selected from the group consisting of N, NH, O, and S; h is 0, 1 , 2, or 3; and i is 0 or 1.

81. The method of any one of claims 74-77, wherein the compound of formula (IV) is a compound of formula (IVD):(IVD), or a pharmaceutically acceptable salt thereof, wherein: h is 0, 1 , or 2; and i is 0, 1 , 2, 3, or 4.

82. The method of any one of claims 74-77, wherein the compound of formula (IV) is a compound of formula (IVE):(IVE), or a pharmaceutically acceptable salt thereof, wherein:Y27and Y28are each independently selected from the group consisting of CH2, NH, O, and S, provided that at least one of Y27and Y28is selected from the group consisting of NH, O, and S; h is 0, 1 , 2, 3, or 4;i is 0 or 1 ; and is a single bond or a double bond.

83. The method of any one of claims 74-77, wherein the compound of formula (IV) is a compound of formula (IVF):(IVF), or a pharmaceutically acceptable salt thereof, wherein:Y29is selected from the group consisting of CH2, C(H)(R30), NH, NR30, O, and S;Y30is selected from the group consisting of CH, CR30, and N, provided that at least one of Y29and Y30is selected from the group consisting of N, NH, NR30, O, and S; i is 0, 1 , 2, 3, or 4; and j is 0, 1 , or 2.

84. The method of any one of claims 77-78, wherein the compound of formula (IV) is a compound of formula (IVA-i):(IVA-i), or a pharmaceutically acceptable salt thereof, wherein:Y31and Y32are each independently selected from the group consisting of CH and N, provided that at least one of Y31and Y32is N; andR36is selected from the group consisting of -CN, OH, halo, NH2, and C1-6 alkyl.

85. The method of any one of claims 74-77 and 79, wherein the compound of formula (IV) is a compound of formula (IVB-ii):(IVB-ii), or a pharmaceutically acceptable salt thereof, wherein:Y22is selected from the group consisting of CH2, NH, O, and S;Y23is selected from the group consisting of CH and N; h is 0, 1 , or 2; and i is 0, 1 , 2, 3, or 4.

86. The method of any one of claims 74-77 and 82, wherein the compound of formula (IV) is a compound of formula (IVE-i):(IVE-i), or a pharmaceutically acceptable salt thereof, wherein:Y28is selected from the group consisting of CH2, C(H)(R33), C(R33)2, NH, NR33, O, and S; h is 0, 1 , 2, 3, or 4; i is 0 or 1 ; and is a single bond, a c / s double bond, a trans double bond, or a mixture of cis and trans double bonds.

87. The method of any one of claims 74-86, wherein Y21is selected from the group consisting of O and S.

88. The method of any one of claims 74-82 and 85-87, wherein R30, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and phenyl.

89. The method of any one of claims 74-88, wherein R31is selected from the group consisting of H, -CN, OH, and C2-6 alkynyl.

90. The method of any one of claims 74-89, wherein R32is selected from the group consisting of H and C1-6 alkyl.

91. The method of any one of claims 74-90, wherein R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, and phenyl.

92. The method of any one of claims 74-91 , wherein R33, independently at each occurrence, is selected from the group consisting of halo, NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, and phenyl.

93. The method of any one of claims 79, 80, 85, and 87-91 , wherein Y22is selected from the group consisting of NH, O, and S.

94. The method of any one of claims 79, 80, 85, and 87-93, wherein Y23is selected from the group consisting of CH and N.

95. The method of any one of claims 80 and 87-94, wherein Y24is selected from the group consisting of O and S.

96. The method of any one of claims 80 and 87-95, wherein Y25and Y26are N.

97. The method of any one of claims 82, 86, and 87-91 , wherein Y28is selected from the group consisting of NH and NR33.

98. The method of any one of claims 83 and 87-91 , wherein Y29is selected from the group consisting of O and S.

99. The method of any one of claims 83, 87-91 , and 98, wherein Y30is selected from the group consisting of CR30and N.

100. The method of any one of claims 74-80, 82, and 86-99, wherein h is 0, 1 , or 2.

101. The method of any one of claims 74-81 and 85-100, wherein h is 0 or 1.

102. The method of any one of claims 74-79, 81 , 83, 85, and 87-101 , wherein i is 0, 1, 2, or 3.

103. The method of any one of claims 74-79, 81, 83, 85, and 87-102, wherein i is 0, 1, or 2.

104. The method of any one of claims 83 and 87-103, wherein j is 0 or 1.

105. The method of any one of claims 74-104, wherein the compound is selected from the group consisting of a compound in Table 9, or a pharmaceutically acceptable salt thereof.

106. A method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound of Table 1, Table 2, Table 5, Table 6, Table 7, Table 8, Table 9, or Table 11, or a pharmaceutically acceptable salt thereof.

107. A method of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 30-48, or the pharmaceutical composition of claim 49.

108. The method of any one of claims 1-29 and 50-107, wherein the parasitic infection is a parasitic worm infection.

109. The method of claim 108, wherein the parasitic worm infection is selected from the group consisting of roundworm infection, whipworm infection, hookworm infection, flatworm infection, tapeworm infection, fluke infection, and pinworm (threadworm) infection.

110. The method of claim 108 or 109, wherein the parasitic worm infection is selected from the group consisting of whipworm infection, hookworm infection, flatworm infection, tapeworm infection, fluke infection, and pinworm (threadworm) infection.

111. The method of any one of claims 108-110, wherein the parasitic worm is resistant to one or more anthelmintic treatment.

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