Methods and compositions relating to ELQ compounds

Abstract

The present invention provides Endochin-like compounds (ELQs) for the treatment of malaria, toxoplasmosis, and babesiosis, as well as useful in preventing or reducing incidence of said maladies by mosquitos upon application to solid surfaces. The present invention also concerns new Endochin-like compounds (ELQs) of Formula (I), below, that are useful in preventing or reducing transmission of malaria parasites to mosquitos upon application to solid surfaces, such as those of bed netting, fabrics, screens, and traps.

Description

Attorney Docket No: 002806-000159WOPT METHODS AND COMPOSITIONS RELATING TO ELQ COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under 35 U.S.C. § 119 of U.S. Provisional Application Nos.63 / 651,852 filed May 24, 2024 and 63 / 651,776 filed May 24, 2024, the contents of which are incorporated herein by reference in their entireties. GOVERNMENT SUPPORT

[0002] This invention was made with government support under AI148646, AI100569, and AI141412 awarded by National Institutes of Health (NIH) and under W81XWH-19-2-0031 awarded by Defense Health Agency, Medical Research and Development Branch (DHA / MRDB). The government has certain rights in this invention. TECHNICAL FIELD

[0003] The present invention concerns new Endochin-like compounds (ELQs) that are useful in preventing or reducing transmission of malaria parasites to mosquitos upon application to solid surfaces, such as those of bed netting, fabrics, screens, and traps. BACKGROUND

[0004] After a consistent decline in cases and deaths in the initial years of this century, the malaria burden has worryingly plateaued in recent years, resulting in an estimated 249 million cases and 608,000 deaths in 2022 (By-Nc-Sa C. World malaria report 2023). The World Health Organization estimates that 241 million clinical cases of malaria occurred in 2020 and more than 600,000 died from malaria, most of them children in Africa.

[0005] Vector control targeting the anopheline mosquitoes that transmit malaria has played a major role in this decline in cases, especially due to the use of long-lasting insecticidal nets (LLINs), that were estimated to account for up to 68% of the reduction in malaria prevalence in sub-Saharan Africa from 2000–2015 (Bhatt et al., Nature.2015;526(7572):207-210E). However, widespread levels of insecticide resistance jeopardize the continued efficacy of our mainstay control tools (By-Nc-Sa C. World malaria report 2023; Global report on insecticide resistance in malaria vectors: 2010–2016. :72; Kumala et al., Parasites & Vectors.2022;15(1):220. doi:10.1186 / s13071-022-05299-3; and Toe et al., Emerg Infect Dis.2014;20(10):1691-1696. doi:10.3201 / eid2010.140619), and novel approaches that capitalize on the benefits of vector-targeted prevention while circumventing insecticide resistance are urgently needed.

[0006] Interventions that directly target parasites within the mosquito represent a promising tool in our arsenal of strategies to disrupt Plasmodium transmission and reduce malaria burden (Burrows et al., Am J Trop Med Hyg.2019;101(4):734-735. doi:10.4269 / ajtmh.19-0318; Smith et al., Mem Inst Oswaldo Cruz.2014;109(5):644-661. doi:10.1590 / 0074-0276130597; and Yu et al., Frontiers in Cellular and Infection Microbiology.2022;12. Accessed January 17, 2024. frontiersin.org / articles 1 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT / 10.3389 / fcimb.2022.820650). We previously reported that the antimalarial drug atovaquone could be used in just such a way to directly target Plasmodium falciparum parasites within their anopheline vector (Paton et al., Nature.2019;567(7747):239-243. doi:10.1038 / s41586-019-0973-1). Mosquitoes that were allowed to briefly land on an atovaquone-coated surface—in a manner analogous to mosquito contact exposure to insecticides—before taking an infectious bloodmeal did not develop any parasites. To assess the predicted epidemiological impact of such transmission blocking effects, we generated a mathematical model using bed net availability, malaria prevalence and insecticide resistance data across a range of transmission settings and found that the incorporation of a similarly potent antimalarial to existing LLINs would cause a significant reduction in malaria prevalence across sub-Saharan Africa (Paton et al., Nature.2019, supra). In support of this model, we experimentally demonstrated that atovaquone contact strongly inhibited the establishment of infection in field-derived insecticide resistant mosquitoes and with parasite isolates circulating in West African children (Paton et al., PLOS Pathogens.2022;18(6):e1010609. doi:10.1371 / journal.ppat.1010609).

[0007] Endochin-like compounds useful in the treatment of malaria are taught in the art, including US 2012 / 0010237 A1 (Riscoe et al.), which includes the compound 5,7-difluoro-3-heptyl-2- methylquinolin-4(3H)-one (CAS 1228283-36-0 – ELQ-121) and Cross et al. teach the compound 6- chloro-3-heptyl-7-methoxy-2-methylquinolin-4(3H)-one (CAS 1248347-05-8 – ELQ-432) in their article titled Endochin Optimization: Structure-Activity and Structure-Property Relationship Studies of 3-Substituted 2-Methyl-4(1H)-quinolones with Antimalarial Activity, J. Med. Chem., Vol.53, Issue 19, pp.7076-7094, 2010. Inclusion of alkoxy carbonate prodrugs on ELQ compounds can be seen in US 2017 / 0022164 A1 (Riscoe et al.) and US 2020 / 00369616 (Riscoe et al.).

[0008] US Patent Publication 2021 / 0330585 (Catterucia et al.) teaches the application of antimalarial agents to a surface, including Endochin-like compound 6-Chloro-7-methoxy-2-methyl-3- {4-[4-(trifluoromethoxy) phenoxy]phenyl}quinolin-4(1H)-one (ELQ-300).

[0009] There remains a need for effective compounds to reduce the spread of malaria and other mosquito-borne illnesses, including those effectively applied to mosquitoes from surfaces on which they land. There also remains a need for effective compounds to reduce the spread of malaria and other mosquito-borne illnesses, including for pharmaceutical administrations and compositions that effectively apply to mosquitoes from surfaces on which they land. SUMMARY

[0010] Described herein are ELQ compounds that can inhibit Plasmodium falciparum infection in Anopheles mosquitoes and / or humans. It is demonstrated herein that the ELQ compounds can be topically provided to mosquitoes, e.g., on bed nets.

[0011] One embodiment provides a coating compositions comprising a medium and an effective amount of a compound of Formula (I): 2 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein: R1is selected from the group of H, halogen, and -OCH3; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0012] Other embodiments provide, respectively, compositions for treating surfaces, treated surfaces, and methods for inhibiting the mosquito life cycle, each comprising an effective amount of one or more of the compounds above, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0013] One embodiment provides a compound of the formula:wherein: R1is selected from the group of H, halogen, and -OCH3; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R5is C1-C10alkyl; and R4is selected from the group of C4-C12alkyl and the 4-trifluoromethyl phenoxy phenyl moiety of the formulathe wavy line () represents a bond through which the 4-trifluoromethyl phenoxy phenylmoiety, when present, is bound to the 3-position carbon of the quinoline ring; with the proviso that R4may only be the 4-trifluoromethyl phenoxy phenyl moiety when R1is halogen, R2is H, and R3is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 3 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0014] Other embodiments provide, respectively, pharmaceutical compositions and compositions for treating surfaces, each comprising an effective amount of one or more of the compounds above, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0015] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (I):wherein: R1is selected from the group of H, halogen, and -OCH3; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0016] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (II):wherein each of R1, R2, R3, R4, and R5is as defined above herein; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0017] In one aspect of any of the embodiments, described herein is a composition comprising at least one compound of Formula (I):4 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT wherein: R1is selected from the group of H, halogen, and -OCH3; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R4is selected from the group of C4-C12alkyl and the 4-trifluoromethyl phenoxy phenyl moiety of the formulathe wavy line () represents a bond through which the 4-trifluoromethyl phenoxy phenylmoiety, when present, is bound to the 3-position carbon of the quinoline ring; with the proviso that R4 may only be the 4-trifluoromethyl phenoxy phenyl moiety when R1is halogen, R2is H, and R3is halogen; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0018] In some embodiments of any of the aspects, the at least one compound is of Formula (II):wherein each of R1, R2, R3, R4, and R5is as defined above herein; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0019] In some embodiments of any of the aspects, at least one variable selected from the group of R1, R2, and R3is hydrogen, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, two variables selected from the group of R1, R2, and R3are hydrogen and the remaining variable selected from the group of R1, R2, and R3is not hydrogen, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0020] In some embodiments of any of the aspects: R1is selected from the group of F, Cl, and - OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H, F, and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 5 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0021] In some embodiments of any of the aspects, R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H, F, and Cl; R4is C5- C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0022] In some embodiments of any of the aspects, R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H and F; R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0023] In some embodiments of any of the aspects, R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H and F; R4is heptyl; and R5is C1-C4alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0024] In some embodiments of any of the aspects, the at least one compound is of Formula (III):wherein: R2is halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0025] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (III):6 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT wherein: R2is halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0026] In some embodiments of any of the aspects, R1is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R2is F; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R2is Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0027] In some embodiments of any of the aspects, the at least one compound is of Formula (IV):wherein, R1is selected from the group of -OCH3and halogen; R3is halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0028] In some embodiments of any of the aspects, R1is selected from the group of -OCH3, F, and Cl; R3is selected from the group of F and Cl; R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0029] In some embodiments of any of the aspects, R1is -OCH3; R3is selected from the group of F and Cl; R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0030] In some embodiments of any of the aspects, R1is selected from the group of F and Cl; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 7 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0031] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (IV):wherein, R1is selected from the group of -OCH3and halogen; R3is halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0032] In some embodiments of any of the aspects, R1is selected from the group of -OCH3, F, and Cl; R3 is selected from the group of F and Cl; R4 is C4-C10 alkyl; and R5 is C1-C10 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0033] In some embodiments of any of the aspects, R1is -OCH3; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0034] In some embodiments of any of the aspects, R1is selected from the group of F and Cl; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0035] In some embodiments of any of the aspects, the at least one compound is of Formula (V):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0036] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (V): 8 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0037] In some embodiments of any of the aspects, the at least one compound is of Formula (VI):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0038] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (VI):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0039] In some embodiments of any of the aspects, the at least one compound is of Formula (VII): 9 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0040] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (VII):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0041] In some embodiments of any of the aspects, the at least one compound is of Formula (VIII):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0042] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (VIII): 10 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0043] In some embodiments of any of the aspects, the at least one compound is of Formula (IX):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0044] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (IX):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0045] In some embodiments of any of the aspects, the at least one compound is of Formula (X): 11 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0046] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (X):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0047] In some embodiments of any of the aspects, the at least one compound is of Formula (XI):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0048] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (XI): 12 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0049] In some embodiments of any of the aspects, the at least one compound is of Formula (XII):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0050] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (XII):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0051] In some embodiments of any of the aspects, the at least one compound is of Formula (XIII): 13 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0052] In one aspect of any of the embodiments, described herein is a coating composition comprising a coating medium and an effective amount of at least one compound of Formula (XIII):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0053] In some embodiments of any of the aspects, the at least one compound is of Formula (XIV):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0054] In one aspect of any of the embodiments, described herein is a composition comprising a coating medium and an effective amount of at least one compound of Formula (XIV): 14 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0055] In some embodiments of any of the aspects, R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is C5-C9alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is C6-C8alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is heptyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is C7 alkyl; and R5 is C1-C10 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or 15 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT polymorph thereof. In some embodiments of any of the aspects, R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0056] In some embodiments of any of the aspects, the coating composition or composition comprises:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0057] In some embodiments of any of the aspects, the coating composition or composition comprises:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0058] In some embodiments of any of the aspects, the coating composition or composition comprises: 16 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTpharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0059] In some embodiments of any of the aspects, the coating composition or composition comprises:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0060] In some embodiments of any of the aspects, the coating composition or composition comprises:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof

[0061] In some embodiments of any of the aspects, the coating composition or composition comprises:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof

[0062] In some embodiments of any of the aspects, the coating composition or composition comprises: 17 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTpharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0063] In some embodiments of any of the aspects, the coating composition or composition comprises:pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0064] In some embodiments of any of the aspects, the coating composition or composition comprises:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0065] In some embodiments of any of the aspects, the coating composition or composition comprises: 18 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTpharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0066] In some embodiments of any of the aspects, the coating composition or composition comprises:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0067] In some embodiments of any of the aspects, the coating composition or composition comprises:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0068] In some embodiments of any of the aspects, the coating composition or composition comprises a first compound of: 19 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein: R1is a halogen; R2is H; R3is a halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; and a second compound selected from:wherein: R1is -OCH3; R2is a halogen; R3is H; R4is C4-C10alkyl; and R5is C1-C10alkyl.

[0069] In some embodiments of any of the aspects, the medium comprises a saturated or unsaturated fatty acid, or an alkyl ester thereof, having from about 10 to about 26 carbon atoms in the fatty acid chain. In some embodiments of any of the aspects, the medium comprises one or more materials selected from the group of lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, lignoceric acid, oleic acid, linoleic acid, arachidonic acid, linolenic acid, eicosapentaenoic acid, docosahexanoic acid, stearidonic acid, and cervonic acid, or an alkyl ester thereof. In some embodiments of any of the aspects, the medium comprises a methyl ester of a fatty acid selected from the group of lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, lignoceric acid, oleic acid, linoleic acid, arachidonic acid, linolenic acid, eicosapentaenoic acid, docosahexanoic acid, stearidonic acid, and cervonic acid. In some embodiments of any of the aspects, the medium is palmitic acid methyl ester. In some embodiments of any of the aspects, the medium is α-linolenic acid methyl ester. In some embodiments of any of the aspects, the medium is rapeseed methyl esters.

[0070] In some embodiments of any of the aspects, the coating composition or composition further comprises an effective amount of an insecticide agent. In some embodiments of any of the aspects, the insecticide agent is selected from the group of an antibiotic insecticide, a macrocyclic lactone insecticide, an arsenical insecticide, a botanical insecticide, a carbamate insecticide, a diamide insecticide, a desiccant insecticide, a dinitrophenol insecticide, a fluorine insecticide, a formamidine insecticide, a fumigant insecticides, an inorganic insecticides, an insect growth regulator, an nereistoxin analogue insecticide, a nicotinoid insecticide, an organochlorine insecticide, an organophosphorus insecticide, an oxadiazine insecticide, an oxadiazolone insecticide, a phthalimide insecticide, a pyrazole insecticide, a pyrethroid insecticide, a pyrimidinamine insecticide, a pyrrole 20 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT insecticide, a tetramic acid insecticide, a tetronic acid insecticide, a thiazole insecticide, a thiazolidine insecticide, athiourea insecticide, and a urea insecticide. In some embodiments of any of the aspects, the insecticide agent is selected from the group of 1,2- dichloropropane, 1,3-dichloropropene, abamectin, acephate, acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile, alanycarb, aldicarb, aldoxycarb, aldrin, allethrin, allosamidin, allyxycarb, alpha-cypermethrin, alpha-endosulfan, amidithion, aminocarb, amiton, amitraz, anabasine, athidathion, azadirachtin, azamethiphos, azinphos-ethyl, azinphos-methyl, azothoate, barium hexafluorosilicate, barthrin, bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin, bifenthrin, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, bistrifluoron, borax, boric acid, boric acid, bromfenvinfos, bromocyclen, bromo-DDT, bromophos, bromophos-ethyl, bufencarb, buprofezin, butacarb, butathiofos, butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate, calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, cartap, chlorantraniliprole, chlorbicyclen, chlordane, chlordecone, chlordimeform, chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chloroform, chloropicrin, chlorphoxim, chlorprazophos, chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, cinerin I, cinerin cismethrin, cloethocarb, closantel, clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate, copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos, crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O- methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos, diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos, dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor, dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos, dimetilan, dinex, dinoprop, dinosam, dinotefuran, diofenolan, dioxabenzofos, dioxacarb, dioxathion, disulfoton, dithicrofos, d-limonene, DNOC, doramectin, ecdysterone, emamectin, EMPC, empenthrin, endosulfan, endothion, endrin, EPN, epofenonane, eprinomectin, esfenvalerate, etaphos, ethiofencarb, ethion, ethiprole, ethoate-methyl, ethoprophos, ethyl formate, ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide, etofenprox, etrimfos, EXD, famphur, fenamiphos, fenazaflor, fenchlorphos, fenethacarb, fenfluthrin, fenitrothion, fenobucarb, fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion, fenthion, fenthion- ethyl, fenvalerate, fipronil, flonicamid, flubendiamide, flucofuron, flucycloxuron, flucythrinate, flufenerim, flufenoxuron, flufenprpx, fluvalinate, fonofos, formetanate, formothion, formparanate, fosmethilan, fospirate, fosthietan, furathiocarb, furethrin, gamma- cyhalothrin, gamma-HCH, halfenprox, HCH, HEOD, heptachlor, heptenophos, heterophos, hexaflumuron, HHDN, hydramethylnon, hydrogen cyanide, hydroprene, hyquincarb, imidacloprid, imiprothrin, indoxacarb, iodomethane, IPSP, isazofos, isobenzan, isocarbophos, isodrin, isofenphos, isoprocarb, isoprothiolane, 21 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT isothioate, isoxathion, ivermectin, jasmolin I, jasmolin II, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kelevan, kinoprene, lambda-cyhalothrin, lead arsenate, lepimectin, leptophos, lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben, mazidox, mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride, mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion, methiocarb, methocrotophos, methomyl, methoprene, methoxychlor, methyl bromide, methylchloroform, methylene chloride, metofluthrin, metolcarb, metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime, mipafox, mirex, monocrotophos, morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine, nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron, noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos, oxydisulfoton, para- dichlorobenzene, parathion, parathion-methyl, penfluoron, pentachlorophenol, permethrin, phenkapton, phenothrin, phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor, phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite, potassium thiocyanate, pp'-DDT, prallethrin, precocene I, precocene II, precocene III, primidophos, profenofos, profluthrin, promacyl, promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos, prothoate, protrifenbute, pyraclofos, pyrafluprole, pyrazophos, pyresmethrin, pyrethrin I, pyrethrin II, pyridaben, pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimitate, pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl, quinothion, rafoxanide, resmethrin, rotenone, ryania, sabadilla, schradan, selamectin, silafluofen, silica gel, sodium arsenite, sodium fluoride, sodium hexafluorosilicate, sodium thiocyanate, sophamide, spinetoram, spinosad, spiromesifen, spirotetramat, sulcofuron, sulfoxaflor, sulfluramid, sulfotep, sulfuryl fluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos, TEPP, terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos, tetramethrin, theta-cypermethrin, thiacloprid, thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiodicarb, thiofanox, thiometon, thiosultap, thuringiensin, tolfenpyrad, tralomethrin, transfluthrin, transpermethrin, triarathene, triazamate, triazophos, trichlorfon, trichlormetaphos-3, trichloronat, trifenofos, triflumuron, trimethacarb, triprene, vamidothion, vaniliprole, XMC, xylylcarb, zeta-cypermethrin, zolaprofos, and a- ecdysone.

[0071] In one aspect of any of the embodiments, described herein is a method of preparing a solid surface to facilitate transmission of a compound from a coating composition as described herein, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, to a female mosquito, the method comprising applying an effective amount of the coating composition to the solid surface.

[0072] In one aspect of any of the embodiments, described herein is a surface, wherein the surface comprises an effective amount of at least one coating composition described herein. 22 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0073] In one aspect of any of the embodiments, described herein is a surface coating, wherein the surface coating comprises an effective amount of at least one coating composition described herein, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, the surface coating is present on the surface at a concentration of 10 μmol / m2-1 mmol / m2. In some embodiments of any of the aspects, the surface coating is present on the surface at a concentration selected from the group of 10 μmol / m2-20 μmol / m2, 10 μmol / m2-30 μmol / m2, 10 μmol / m2-40 μmol / m2, 10 μmol / m2-50 μmol / m2, 10 μmol / m2-60 μmol / m2, 10 μmol / m2-70 μmol / m2, 10 μmol / m2-80 μmol / m2, 10 μmol / m2-90 μmol / m2, 10 μmol / m2- 100 μmol / m2, 20 μmol / m2-100 μmol / m2, 30 μmol / m2-100 μmol / m2, 40 μmol / m2-100 μmol / m2, 50 μmol / m2-100 μmol / m2, 60 μmol / m2-100 μmol / m2, 70 μmol / m2-100 μmol / m2, 80 μmol / m2-100 μmol / m2, 90 μmol / m2-100 μmol / m2, 100 μmol / m2-200 μmol / m2, 100 μmol / m2-300 μmol / m2, 100 μmol / m2-400 μmol / m2, 100 μmol / m2-500 μmol / m2, 100 μmol / m2-600 μmol / m2, 100 μmol / m2-700 μmol / m2, 100 μmol / m2-800 μmol / m2, 100 μmol / m2-900 μmol / m2, 100 μmol / m2-1 mmol / m2, 100 μmol / m2-1 mmol / m2, 200 μmol / m2-1 mmol / m2, 300 μmol / m2-1 mmol / m2, 400 μmol / m2-1 mmol / m2, 500 μmol / m2-1 mmol / m2, 600 μmol / m2-1 mmol / m2, 700 μmol / m2-1 mmol / m2, 800 μmol / m2-1 mmol / m2, or 900 μmol / m2-1 mmol / m2. In some embodiments of any of the aspects, the surface coating is present on the surface at a concentration lower than 10 μmol / m2. In some embodiments of any of the aspects, the surface coating is present on the surface at a concentration higher than 1 mmol / m2.

[0074] In one aspect of any of the embodiments, described herein is a method of preparing a solid surface to facilitate transmission of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined herein, to a female mosquito, the method comprising applying an effective amount of a coating composition comprising an effective amount of the compound to the solid surface.

[0075] In one aspect of any of the embodiments, described herein is a surface comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined herein.

[0076] In one aspect of any of the embodiments, described herein is a surface coating comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined herein.

[0077] In one aspect of any of the embodiments, described herein is a method for reducing transmission of Plasmodium parasites to a female mosquito, the method comprising contacting the 23 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined herein.

[0078] In some embodiments of any of the aspects, the female mosquito is an Anopheles mosquito.

[0079] In one aspect of any of the embodiments, described herein is a method for a substantially reducing Plasmodium and / or oocyst development in an adult female mosquito, the method comprising contacting the female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined herein.

[0080] In one aspect of any of the embodiments, described herein is a method of substantially reducing mating success of an adult female mosquito, the method comprising contacting the adult female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined described herein.

[0081] In one aspect of any of the embodiments, described herein is a method of substantially abolishing egg development in an adult female mosquito after blood feeding, the method comprising contacting the adult female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined herein.

[0082] In one aspect of any of the embodiments, described herein is a method of substantially reducing the mean survival rate of adult female mosquitoes, the method comprising contacting the adult female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined herein.

[0083] In some embodiments of any of the aspects, the adult female mosquito is selected from the group of Anopheles spp (e.g., An. arabiensis, An. Funestus, An. Stephensi, An. sinensis, An. yatsushiroensis, and An. lesteri), Aedes spp (including Aedes vexans) and Culex spp (including Culex pipiens, Cx. orientalis, Cx. perexiguus, Cx. quinquefasciatus, and Cx. modestus).

[0084] In one aspect of any of the embodiments, described herein is a pharmaceutical composition comprising a pharmaceutically effective amount of a composition described herien, or a 24 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, and a pharmaceutically acceptable carrier or excipient.

[0085] In one aspect of any of the embodiments, described herein is a pharmaceutical composition comprising a pharmaceutically or therapeutically effective amount of a composition described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0086] In one aspect of any of the embodiments, described herein is a method for treating malaria in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a composition described herein, or a pharmaceutically acceptable salt thereof. In one aspect of any of the embodiments, described herein is a method for inhibiting malaria in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a composition described herein, or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments of any of the aspects, the malaria is an infection of at least one parasite selected from the group of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. In some embodiments of any of the aspects, the malaria is a drug-resistant malaria. In some embodiments of any of the aspects, the malaria is resistant to treatment with at least one agent selected from the group of chloroquine, sulphadoxine-pyrimethamine, quinine, piperaquine, mefloquine, artemisinin-based combination therapy (ACT, including artemether-lumefantrine (COARTEM®) and artesunate-mefloquine), pyrimethamine, dapsone, atovaquone, and a P. falciparum DHOD inhibitor. In some embodiments of any of the aspects, the malaria is a multidrug- resistant malaria resistant to treatment with at least two agents selected from the group of chloroquine, sulphadoxine-pyrimethamine, quinine, piperaquine, mefloquine, artemisinin-based combination therapy (ACT, including artemether-lumefantrine (COARTEM®) and artesunate-mefloquine), pyrimethamine, dapsone, atovaquone, and a P. falciparum DHOD inhibitor. In some embodiments of any of the aspects, the malaria is a latent malaria infection.

[0088] In some embodiments of any of the aspects, the method further comprises administering to the human in need thereof a pharmaceutically effective amount of one or more compounds selected from the group of quinine, chloroquine, atovaquone, proguanil, primaquine, amodiaquine, mefloquine, piperaquine, artemisinin, artesunate, methylene blue, pyrimethamine, sulfadoxine, artemether-lumefantrine, dapsone-chlorproguanil, artesunate, quinidine, clopidol, and dihydroartemisinin, or a pharmaceutically acceptable salt thereof.

[0089] In one aspect of any of the embodiments, described herein is a method for treating toxoplasmosis in a human subject, the method comprising administering to the human in need thereof 25 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT a pharmaceutically effective amount of a composition described herein, or a pharmaceutically acceptable salt thereof.

[0090] In one aspect of any of the embodiments, described herein is a method for treating babesiosis in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a composition described herein, or a pharmaceutically acceptable salt thereof.

[0091] In one aspect of any of the embodiments, described herein is a method for treating babesiosis in a non-human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a composition described herein, or a pharmaceutically acceptable salt thereof.

[0092] In one aspect of any of the embodiments, described herein is a method for treating babesiosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of a composition described herein, or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments of any of the aspects, the non-human subject is a bovine subject. In some embodiments of any of the aspects, the babesiosis is caused by a Babesia bovis infection or a Babesia bigemina infection.

[0094] In some embodiments of any of the aspects, the non-human subject is an equine subject. In some embodiments of any of the aspects, the babesiosis is caused by a Babesia caballi infection or a Theileria equi infection.

[0095] In one aspect of any of the embodiments, described herein is a method for treating coccidiosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of a composition described herein, or a pharmaceutically acceptable salt thereof.

[0096] In one aspect of any of the embodiments, described herein is a method for treating theileriosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of a composition described herein, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects, the theileriosis is caused by a Theileria equi infection.

[0097] In one aspect of any of the embodiments, described herein is a method for treating neosporosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of a composition described herein, or a pharmaceutically acceptable salt thereof.

[0098] In one aspect of any of the embodiments, described herein is a method of treatment of a Besnoitia besnoti infection in a non-human subject, the method comprising administering to the 26 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT subject in need thereof a pharmaceutically or therapeutically effective amount of a composition described herein, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0099] In some embodiments of any of the aspects, the non-human subject is equine. In some embodiments of any of the aspects, the non-human subject is bovine. In some embodiments of any of the aspects, the non-human subject is canine. BRIEF DESCRIPTION OF THE DRAWINGS

[0100] Figs.1A-1J depict an in vivo topical application screen for mosquito-stage antiplasmodial efficacy. Fig.1A depicts a schematic of the screen. Figs.1B-1J depict the results of the screen for the indicated compounds.

[0101] Figs.2A-2C depict tarsal contact assays. Fig.2A) Tarsal contact schematic. Mosquitoes land on a surface coated with 1 mmol / m2compound of interest or a vehicle control for up to six minutes. One hour later, exposed mosquitoes are provided with an infectious blood meal and 7 dpi mosquito midguts are dissected. Fig.2B) Of the representative topically active compounds tested, only ELQ-456 demonstrated antiparasitic activity by tarsal contact assay. The odds ratio of compound treated versus vehicle control infection prevalence bounded by its 95% confidence interval is plotted (Baptista-Pike method). An upper confidence bound below 1 signifies reduced P. falciparum prevalence. For any compound that reduced oocyst prevalence relative to the DMSO control, tarsal contact assays were repeated for a minimum of two biological replicates to confirm activity. Fig.2C) ELQ-456 tarsal contact causes a significant reduction in the prevalence (pie charts, two-tailed Fisher’s exact test) and intensity (two-tailed Mann-Whitney test) of infection. n = number of mosquitoes dissected, median lines and values indicated. *** indicates p-value ≤ 0.001, **** indicates p-value ≤ 0.0001.

[0102] Figs.3A-3E demonstrate that modifications in ELQ structures enhance tarsal inhibition. Fig.3A depicts a compound scheme. Fig.3B depicts a table of compounds. Figs.3C-3E depict the activity of the indicated compounds in preventing P. falciparum infection in topical (Fig.3C) and tarsal (Figs.3D-3E) assay.

[0103] Figs. 4A-4E demonstrate that a combination of Qo and Qi inhibitors improves potency andis highly active in bed net-like materials. Fig.4A depicts a dose-response curve. Fig.4B depicts a scheme of the experiment. Figs.4C-4E depict the activity of the indicated compounds in polyethylene LDPE films.

[0104] Figs.5A-5D demonstrate that Qomutants are susceptible to Qiinhibitors and vice versa, and are unable to complete sporogonic development in the mosquito. Fig.5A depicts the experimental 27 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT scheme and exemplary results. Fig.5B depicts the specificity of the indicated mutations. Figs.5C and 5D depict the results of the indicated mutations.

[0105] Figs.6A-6C depict an in vivo screen of 81 antiplasmodial compounds identifies seven P. falciparum targets essential during development in the Anopheles female. A total of 2 mM of each antimalarial was solubilized in acetone and 2% DMSO and 0.5 µl was pipetted onto the dorsal thorax of female An. gambiae mosquitoes. Mosquitoes were then provided a P. falciparum infectious blood meal and maintained until midgut dissections at 7 days post-infection (dpi) to detect oocysts. For any compound that reduced oocyst prevalence relative to the DMSO control, topical applications were repeated for a minimum of two biological replicates to confirm activity. Fig.6A) A total of 81 antiplasmodial compounds (spanning 28 modes of action) were screened (top 50 shown) and 22 compounds with seven distinct targets significantly reduced P. falciparum prevalence. The odds ratio of compound treated versus DMSO control infection prevalence bounded by its 95% confidence interval is plotted (Baptista-Pike method). Compounds where the upper confidence bound is below 1 significantly reduced P. falciparum prevalence and are shown in shading. Fig.6B) Infection data from the most active compound within each hit target class that caused a significant reduction in parasite prevalence (prevalence shown in pie charts, minimum of two biological replicates, n = number of mosquitoes dissected, median lines and values indicated, two-tailed Fisher’s exact test). Fig.6C) 22 hpi immunofluorescence assays showing that the ATP4 inhibitor cipargamin and the EF2 inhibitor M5717 disrupt parasite development during the zygote to ookinete transition (ordinal logistic regression model). Five biological replicates, n = number of total parasites counted. * indicates p- value < 0.05, ** indicates p-value ≤ 0.01, *** indicates p-value ≤ 0.001, **** indicates p-384 value ≤ 0.0001.

[0106] Figs.7A-7E demonstrate that modifications in ELQ structures vastly enhance tarsal inhibition. Fig.7A) Endochin like quinolone (ELQ) core scaffold indicating all residues discussed in the text. Alkoxy carbonate ester promoiety at C4 is rapidly converted to its active form in vivo by parasite and / or host esterases Fig.7B) The panel of Qo- and Qi-site prodrug inhibitors synthesized to investigate the role of structural alterations in tarsal contact activity. The prodrug is listed and its respective active form is noted in parentheses. Tarsal prevalence reduction (percent change in prevalence relative to control) is calculated for prodrugs only. Figs.7C, 7D) Topical application of c) Qo-site and d) Qi-site inhibitors uniformly inhibited P. falciparum prevalence (pie charts) of infection, while tarsal contact demonstrated variable activity associated with structural variation. The difference in ELQ-456 tarsal contact activity between Fig.2C and this figure is within the observed variability for partially active compounds. Fig.7E) Liquid chromatography-mass spectrometry quantification of ELQ prodrugs and active forms (indicated in parentheses) in mosquito midguts at different time points following tarsal contact exposure. Hpe: hours post exposure. Each time point represents the average of two biological replicates with two technical replicates each consisting of five pooled 28 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT midguts. For Fig.7C) and Fig.7D), two biological replicates were performed, n = number of mosquitoes dissected, median lines and values indicated, and prevalence significance was calculated by two-tailed Fisher’s exact test with post hoc Bonferroni multiple test correction. Letters indicate significant differences in prevalence (pie charts) between groups (p-value < 0.05).

[0107] Figs.8A-8F demonstrate that a combination of Qoand Qi inhibitors improves potency and is highly active in bed net-like materials. Fig.8A) Tarsal contact dose response curves were generated for ELQ-453 (Qo-site) and ELQ-613 (Qi-site) alone or in combination, as well as for atovaquone, ranging from 1 mmol / m2to 0.01 µmol / m2. Each point represents the infection prevalence relative to a vehicle control. Every dose was tested for a minimum of two biological replicates. The half-maximal effective concentrations (EC50s) were calculated from interpolated nonlinear regression dose response curves. Fig.8B) Scheme of mosquito exposure to low density polyethylene (LDPE) thin films impregnated with ELQ compounds. Tarsal contact exposures were performed as described in Fig.2. c) ELQ-613 and ELQ-453 used alone at 5% w / w and 1% w / w in LDPE, and in combination at 1% w / w (0.5% each ELQ) and 0.4% (0.2% each ELQ) completely inhibited parasite infection. Fig. 8D) Time course tarsal contact exposure to 1% w / w ELQ combination LDPE film. Four- day pre- infection exposures were performed in a separate experiment. Fig.8E) Dipped net tarsal contact schematic. Polyester nets were soaked in solutions of ELQ-453 and ELQ-613 in acetone. Acetone was allowed to evaporate overnight, and then tarsal contact experiments were performed with the dried nets. Fig.8F) Tarsal contact with ELQ-613+ELQ-453 dipped nets completed inhibited parasite infection at concentrations as low as 50 mg / m2(25 mg / m2each ELQ) and remarkably reduced parasite burden at 10 mg / m2, with effects still significant at concentrations as low as 1 mg / m2. In Fig.8C, 8D, and 8F, two biological replicates were performed, n = number of mosquitoes dissected, median lines and values indicated, prevalence significance calculated via two tailed Fisher’s exact test. In Fig.8D) intensity was calculated via two-tailed Mann-Whitney and in Fig.8F) intensity was calculated via Kruskal-Wallis test with Dunn’s post hoc multiple comparisons correction. * indicates p-value < 0.05, ** indicates p-value ≤ 0.01, **** indicates p-value ≤ 0.0001.

[0108] Figs.9A-9D demonstrate that Qo-site mutants are susceptible to Qi-site inhibitors and are unable to complete sporogonic development in the mosquito. Fig.9A) Drug selection schematic of ELQ-121 (active form of ELQ-453). Fig.9B) Fold-change asexual blood stage EC50 for Cyt Bmutants relative to WT NF54. Resistant parasites with mutations in their Qo-site retainedsusceptibility to Qi-site inhibitors, and vice versa, in asexual blood stages. The clinical isolate TM90- C2B has a >13,000 foldEC50shift to atovaquone, and thus was log-transformed and plotted separately for clarity. Figs.9C, 9D) The Qo-site resistant V259L parasites Fig.9C) showed severe defects in their ability to produce oocysts (five biological replicates, n = number of mosquitoes dissected, median lines and values indicated, prevalence significance calculated via two tailed Fisher’s exact test and intensity calculated via two-tailed Mann-Whitney) and Fig.9D) had no sporozoites (three 29 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT biological replicates, n = number of mosquitoes dissected, median lines and values indicated, prevalence significance calculated via two tailed Fisher’s exact test and intensity calculated via two- tailed Mann-Whitney.) **** indicates p-value ≤ 0.0001.

[0109] Fig.10 depicts a correlation plot for GA-MLR QSAR model. Comparison of predicted (x-axis) and observed (y-axis) topical application activity. Predicted values were generated with a genetic algorithm-multiple linear regression (GA-MLR) model, which produced a 0.70 R2 (coefficient of determination) between observed and predicted topical application activity. White dots represent compounds used in the model training set and grey dots represent compounds used in the model test set. Goodness-of-fitness for each set is represented by the R2values.

[0110] Fig.11 depicts ELQ-613 stage specificity. Immunofluorescence assays performed at 22 hours post infection demonstrated that the Cyt B Qo-site inhibitor ELQ-613 disrupts parasite development during the zygote to ookinete transition (ordinal logistic regression model). Five biological replicates, n = number of total parasites counted. **** indicates p-value ≤ 0.0001.

[0111] Figs.12A-12E depict post infection ELQ exposure. Fig.12A) Tarsal contact schematic. Assays were performed as previously described but at 3 days post-infection rather than prior to an infectious blood meal. Fig.12B) Post-infection tarsal contact with ELQ-453 and ELQ-613 alone or in combination did not significantly alter the prevalence or intensity of parasites, but Fig.12C) caused a significant reduction in oocyst size in the ELQ-453 and combination groups. Oocyst cross-sectional area significance calculated via Kruskal-Wallis test with Dunn’s post hoc multiple comparisons correction. Fig.12D) Lower prevalence of sporozoite infection (6.3%) was detected in the same two groups at 11 dpi, an early time point when instead 40% of control females were carrying sporozoites. Fig.12E) At 14 dpi, the prevalence of sporozoites in the combination exposed group had a 28.6% reduction in sporozoite prevalence relative to controls. For Figs.12B, 12D, and 12E median lines and values indicated, and for Fig.12C average line and values indicated. For Figs.12B-12E, n = number of mosquitoes dissected, two biological replicates were performed, prevalence significance was calculated via two tailed Fisher’s exact test. ns indicates non-significant, * indicates p-value < 0.05, ** indicates p-value ≤ 0.01, **** indicates p-value ≤ 0.0001.

[0112] Figs.13A-13C depicts polymer film longevity, activity against insecticide resistant mosquitoes, and extrusion testing. Fig.13A) Low density polyethylene (LDPE) ELQ thin films were generated as described in Example 2.5%, 1%, and 1% combination w / w ELQ-613 and ELQ-453 films retained complete inhibitory activity over one year after they were first generated after being stored at ambient room temperature (~21 °C) with regular day-night light exposure. Fig.12B) Tarsal contact exposures were performed using insecticide resistant An. gambiae (RES line). Contact with 1% w / w combination ELQ films completely inhibited infection in both insecticide resistant (RES) and susceptible (G3) An. gambiae. Fig.13C) Tarsal contact with high density polyethylene films incorporated with 1% w / w ELQ (0.5% ELQ-453, 0.5% ELQ-613), extruded into a polymer, and 30 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT flattened into a film completely inhibited parasite infection. In Fig.13A) and Fig.13C) two biological replicates were performed and in Fig.13B) three biological replicates were performed. n = number of mosquitoes dissected, median lines and values indicated, prevalence significance was calculated via two tailed Fisher’s exact test. **** indicates p-value ≤ 0.0001.

[0113] Fig.14 demonstrates that V284L mutants show low oocyst intensity and prevalence of infection. Parasites with the Cyt B Qo-site mutation V284L have a significant decline in oocyst intensity and prevalence relative to controls at 7 dpi. Four biological replicates, median lines and values indicated, n = number of mosquitoes dissected, prevalence significance calculated via two tailed Fisher’s exact test and intensity calculated via two-tailed Mann-Whitney. **** indicates p-value ≤ 0.0001.

[0114] Fig.15 depicts a table of topical application screening compounds. Compounds used for topical application screening are listed in order of activity, where their number corresponds to their order number in Fig.1B and 6A. Known molecular targets or known resistance mechanisms are listed, as well as any alternative names / identifiers. The odds ratio of compound treated versus DMSO control infection prevalence is given, with its 95% confidence interval noted in parentheses. Odds ratios and 95% confidence intervals were calculated by the Baptista-Pike method and compounds with an upper bound confidence interval below 1 significantly reduced infection prevalence relative to control. Where available, the compound Simplified Molecular Input Line Entry System (SMILES) is provided.

[0115] Fig.16 depicts a table of endochin-like quinolone activity in asexual blood stages and topical application. ELQ compound activity against WT P. falciparum NF54 in asexual blood stages (ABS) and mosquito stages. ABS half maximal effective concentrations (EC50) were calculated from 72 hour drug susceptibility assays via nonlinear regression. Average EC50s from three biological replicates are shown with standard deviations reported in parentheses. Topical application odds ratios of compound treated versus DMSO control infection prevalence are given, with 95% confidence intervals noted in parentheses. Odds ratios and 95% confidence intervals were calculated by the Baptista-Pike method and compounds with an upper bound confidence interval below 1 significantly reduced infection prevalence relative to control.

[0116] Fig.17 depicts a table of Cyt B mutant resistance and transmissibility. P. falciparum CytB mutants were generated in asexual blood stages (ABS) via selection with Qo-site inhibitors ELQ-121, ELQ-400, ELQ-437, and atovaquone, and Qi-site inhibitors ELQ-300. Previously established Cyt B mutant lines were also used: the I22L Qi-site mutant in a non-transmissible P. falciparum Dd2 background and the Y268S Qo-site mutant clinical P. falciparum isolate. ABS half maximal effective concentrations (EC50) were calculated from 72 hour drug susceptibility assays and the fold-change inEC50of each mutant line relative to WT P. falciparum NF54 is reported. Mosquito transmission experiments were performed with the V259L, V284L, and M133I lines. Oocyst prevalence at 7 days 31 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT post-infection (dpi) and sporozoite prevalence 14 dpi are reported with median parasite intensities in parentheses. Percent change of mutant oocyst and sporozoite prevalence and intensity relative to WT is reported. DETAILED DESCRIPTION

[0117] The technology described herein is directed to compounds which exhibit surprising activity in inhibiting Plasmodium falciparum infection or development in Anopheles mosquitoes and mammals. The inventors found that transfer from a surface into the mosquito was possible and provided effective activity. The compounds are surprisingly shown to inhibit and / or entirely prevent Plasmodium falciparum infection in the previously uninfected mosquitoes. Further disclosed herein are combinations of compounds that exhibit synergistic activity. Accordingly, provided herein are compositions comprising such compounds and method of using them.

[0118] Another embodiment provides the use in the compositions and other applications herein of a compound of Formula (II):wherein each of R1, R2, R3, R4, and R5is as defined above for Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments,R1 is selected from the group of H, halogen, and -OCH3 ; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R4 is C4-C10 alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments, R1is selected from the group of H, halogen, and -OCH3; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R5is C1-C10alkyl; and R4is 32 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT selected from the group of C4-C12alkyl and the 4-trifluoromethyl phenoxy phenyl moiety of the formulathe wavy line ( ) represents a bond through which the 4-trifluoromethyl phenoxy phenylmoiety, when present, is bound to the 3-position carbon of the quinoline ring; with the proviso that R4may only be the 4-trifluoromethyl phenoxy phenyl moiety when R1is halogen, R2is H, and R3is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments, R1is selected from the group of H, halogen, and -OCH3; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments, R1is selected from the group of H, halogen, and -OCH3; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R5is C1-C10alkyl; and R4is selected from the group of C4-C12alkyl.

[0119] Another embodiment provides the use in the compositions and other applications herein of a compound of Formula (II), wherein each of R1, R2, R3, R4, and R5is as defined for Formulas (I) and (II), above, with the proviso that at least one variable selected from the group of R1, R2, and R3is hydrogen, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0120] Another embodiment provides the use in the compositions and other applications herein of a compound of Formula (II), wherein each of R1, R2, R3, R4, and R5is as defined for Formulas (I) and (II), above, with the proviso that two variables selected from the group of R1, R2, and R3are hydrogen and the remaining variable selected from the group of R1, R2, and R3is not hydrogen, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0121] Another embodiment provides the use in the compositions and other applications herein of a compound of Formula (II), wherein: R1is selected from the group of F, Cl, and -OCH3; R2is selected from the group of H, F, and Cl; 33 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT R3is selected from the group of H, F, and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0122] Another embodiment provides the use in the compositions and other applications herein of a compound of Formula (II), wherein: R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H, F, and Cl; R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0123] A further embodiment provides the use in the compositions and other applications herein of a compound of Formula (II), wherein: R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H and F; R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0124] A further embodiment provides the use in the compositions and other applications herein of a compound of Formula (II), wherein: R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H and F; R4is heptyl; and R5 is C1-C4 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0125] An additional embodiment provides the use in the compositions and other applications herein of a compound of Formula (III): 34 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein: R2is halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0126] Another embodiment provides the use in the compositions and other applications herein of a compound of Formula (III), wherein R1is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0127] A further embodiment provides the use in the compositions and other applications herein of a compound of Formula (III), wherein R2is F; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0128] Another separate embodiment provides the use in the compositions and other applications herein of a compound of Formula (III), wherein R2is Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0129] A separate embodiment provides the use in the compositions and other applications herein of a compound of Formula (III), above, wherein R2is selected from the group of F and Cl; R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0130] Another separate embodiment provides the use in the compositions and other applications herein of a compound of Formula (III), above, wherein R2is selected from the group of F and Cl; R4is C6-C8alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 35 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0131] An additional embodiment provides the use in the compositions and other applications herein of a compound of Formula (III), above, wherein R2is F; R4is C6-C8alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0132] An additional embodiment provides the use in the compositions and other applications herein of a compound of Formula (III), above, wherein R2is Cl; R4is C6-C8alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0133] An additional embodiment provides the use in the compositions and other applications herein of a compound of Formula (III), above, wherein R2is Cl; R4is heptyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0134] An additional embodiment provides the use in the compositions and other applications herein of a compound of Formula (III), above, wherein R2is F; R4is heptyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0135] One embodiment provides the use in the compositions and other applications herein of the compound ((6-chloro-3-heptyl-7-methoxy-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate, also referred to as ELQ-613, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0136] A different embodiment provides the use in the compositions and other applications herein of a compound of Formula (IV):wherein, R1is selected from the group of -OCH3and halogen; 36 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT R3is halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0137] An additional embodiment provides the use in the compositions and other applications herein of a compound of Formula (IV), wherein, R1is selected from the group of -OCH3, F, and Cl; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0138] An additional embodiment provides the use in the compositions and other applications herein of a compound of Formula (IV), wherein, R1is selected from the group of -OCH3, F, and Cl; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0139] An additional embodiment provides the use in the compositions and other applications herein of a compound of Formula (IV), wherein, R1is -OCH3; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0140] An additional embodiment provides the use in the compositions and other applications herein of a compound of Formula (IV), wherein, R1is selected from the group of F and Cl; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and 37 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0141] Some embodiments herein comprise the use, respectively, of a compound of each of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula (XIV):38 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, in each embodiment, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0142] Additional separate embodiments provide, respectively, the use in the compositions and other applications herein of a compound of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula (XIV), wherein in each embodiment, R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0143] Additional separate embodiments provide, respectively, the use in the compositions and other applications herein of a compound of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula(XIV),, wherein in each embodiment, R4 is C6-C8 alkyl; and R5 is C1-C3 alkyl; or a pharmaceuticallyacceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0144] Additional separate embodiments provide, respectively, the use in the compositions and other applications herein of a compound of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula (XIV), wherein in each embodiment, R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0145] Additional separate embodiments provide, respectively, the use in the compositions and other applications herein of a compound of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula (XIV), wherein in each embodiment, R4is C6-C8alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0146] Additional separate embodiments provide, respectively, the use in the compositions and other applications herein of a compound of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula (XIV), 39 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT wherein in each embodiment, R4is heptyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0147] Some embodiments herein comprise the use of the compound ((5,7-difluoro-3-heptyl-2- methylquinolin-4-yl)oxy)methyl ethyl carbonate, also referred to as ELQ-453, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0148] Some embodiments herein comprise the use of the compound ethyl (((5-fluoro-3-heptyl- 7-methoxy-2-methylquinolin-4-yl)oxy)methyl) carbonate, also referred to as ELQ-621, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0149] Some embodiments herein comprise the use of the compound ethyl (((6-fluoro-3-heptyl- 2-methylquinolin-4-yl)oxy)methyl) carbonate, also referred to as ELQ-403, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0150] Some embodiments herein comprise the use of the compound ethyl (((3-heptyl-7- methoxy-2-methylquinolin-4-yl)oxy)methyl) carbonate, also referred to as ELQ-701, having the structure: 40 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTpharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0151] Some embodiments herein comprise the use of the compound ethyl (((6-fluoro-3-heptyl- 7-methoxy-2-methylquinolin-4-yl)oxy)methyl) carbonate, also referred to as ELQ-465, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0152] Some embodiments herein comprise the use of the compound ((7-chloro-5-fluoro-3- heptyl-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate, also referred to as ELQ-617, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0153] An additional embodiment provides a coating composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, and an effective medium. Additional embodiments are understood that provide coating compositions, separately comprising a compound of each formula and each specific compound described herein, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, and an effective medium.

[0154] A still further embodiment provides a method of preparing a solid surface to facilitate transmission of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, 41 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, to a female mosquito, the method comprising applying an effective amount of a coating composition comprising an effective amount of the compound to the solid surface.

[0155] Another embodiment provides a surface, wherein the surface comprises an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0156] Another embodiment provides a surface coating, wherein the surface coating comprises an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0157] Exemplary surfaces include, but are not limited to, an interior wall of a building; an exterior wall of a building; a bed net; an indoor fabric (draperies, furniture, carpets, bedding, etc.); an outdoor fabric (tarps, umbrellas, tents, backpacks, furniture, etc.); clothing; an inside surface of a trap; and an outside surface of a trap. In one embodiment, the trap is a bait trap. In one embodiment, the composition is present on the surface at an effective concentration of 10 μmol / m2-1 mmol / m2.

[0158] One embodiment provides a polymer fiber coated or treated with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments, the polymer fiber comprises one or more of high-density polyethylene (HDPE), low density polyethylene (LDPE), mixtures of HDPE and LDPE, polyamide, polypropylene and polyester. In some embodiments, the coated or treated polymer fiber comprises a mixture of HDPE and LDPE materials. In some embodiments, the coated or treated polymer fiber comprises a mixture of HDPE and LDPE materials and a wax.

[0159] In other embodiments, the polymer fiber(s) used is one or more thermoplastic polymers selected from the group of polypropylene, polyethylene, polypropylene co-polymer, polyethylene co- polymer, polyethylene terephthalate, polybutylene terephthalate, polylactic acid, polyhydroxyalkanoates, polyamide-6, polyamide-6,6, and combinations thereof.

[0160] Other embodiments provide, respectively, a thread, a string, a yarn, a fabric, a screen, and a mesh formed from the polymer fiber(s) in question (and, optionally, a wax).

[0161] In some embodiments, the wax utilized in the products and methods herein is selected from the group of a polyethylene wax and a polypropylene wax.

[0162] In other embodiments, the wax is a lipid, mineral wax, or combination thereof, wherein the lipid, mineral wax, or combination thereof has a melting point of greater than 25° C. More preferred is a melting point above 35° C., still more preferred above 45° C. and most preferred above 42 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT 50° C. The wax can have a melting point that is lower than the melting temperature of the thermoplastic polymer in the composition. The terms “wax” and “oil” are differentiated by crystallinity of the component at or near 25° C. In all cases, the “wax” will have a maximum melting temperature less than the thermoplastic polymer, preferably less than 100° C. and most preferably less than 80° C. The wax can be a lipid. The lipid can be a monoglyceride, diglyceride, triglyceride, fatty acid, fatty alcohol, esterified fatty acid, epoxidized lipid, maleated lipid, hydrogenated lipid, alkyd resin derived from a lipid, sucrose polyester, or combinations thereof. The mineral wax can be a linear alkane, a branched alkane, or combinations thereof. The waxes can be partially or fully hydrogenated materials, or combinations and mixtures thereof, that were formally liquids at room temperature in their unmodified forms. When the temperature is above the melting temperature of the wax, it is a liquid oil. When in the molten state, the wax can be referred to as an “oil”. The terms “wax” and “oil” only have meaning when measured at 25° C. The wax will be a solid at 25° C., while an oil is not a solid at 25° C. Otherwise they are used interchangeably above 25° C.

[0163] The wax can be present in the composition in an amount of about 1 wt % to about 20 wt %, about 2 wt % to about 15 wt %, or about 3 wt % to about 10 wt % based upon the total weight of the composition. The wax can comprise a lipid, which can be selected from the group consisting of a monoglyceride, diglyceride, triglyceride, fatty acid, fatty alcohol, esterified fatty acid, epoxidized lipid, maleated lipid, hydrogenated lipid, alkyd resin derived from a lipid, sucrose polyester, or combinations thereof. The wax can comprise a mineral wax, such as a linear alkane, a branched alkane, or combinations thereof. Specific examples of mineral wax are paraffin and petrolatum. The wax can be selected from the group consisting of hydrogenated soy bean oil, partially hydrogenated soy bean oil, epoxidized soy bean oil, maleated soy bean oil, tristearin, tripalmitin, 1,2-dipalmitoolein, 1,3-dipalmitoolein, 1-palmito-3-stearo-2-olein, 1-palmito-2-stearo-3-olein, 2-palmito-1-stearo-3-olein, 1,2-dipalmitolinolein, 1,2-distearo-olein, 1,3-distearo-olein, trimyristin, trilaurin, capric acid, caproic acid, caprylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, and combinations thereof. The wax can be selected from the group consisting of a hydrogenated plant oil, a partially hydrogenated plant oil, an epoxidized plant oil, a maleated plant oil. Specific examples of such plant oils include soybean oil, corn oil, canola oil, and palm kernel oil.

[0164] In some embodiments, the effective amount of the compound of Formula (I), or the salt or other forms thereof, may be contained within the wax prior to application / treatment of the polymer fiber(s) in question.

[0165] Another embodiment provides a textile product comprising a first yarn product and a second yarn product, wherein the first yarn product is treated or coated with an effective concentration of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, and the second yarn product is untreated. In an embodiment, the first yarn 43 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT comprises a mixture of polyethylene polymers and the second yarn comprises a polymer composition selected from the group of high-density polyethylene (HDPE), low-density polyethylene (LDPE), mixtures of HDPE and LDPE, polyamide, polypropylene, and polyester.

[0166] In another embodiment, both the first yarn and second yarn are treated with the same compound of Formula (I), or the salt or other forms described herein. In other embodiments, the first yarn is treated or coated with the effective amount of the compound of Formula (I) and the second yarn is treated or coated with an effective amount of an additional compound of Formula (I), or a salt or other form thereof. In still other embodiments, the first yarn is treated or coated with the effective amount of the compound of Formula (I) and the second yarn is treated or coated with an effective amount of an additional antimalarial or insecticide agent described herein.

[0167] The compounds herein may be applied to or coated onto a surface by any means practicable, including spraying (such as aerosol, non-aerosol, and electrostatic spraying techniques), brushing, spreading, rolling, or wiping desired compositions onto the surface or dipping the surface or material of interest into a volume of a composition comprising the one or more compounds of Formula (I), or a salt or other form thereof.

[0168] In other embodiments, respectively, the composition is present on the surface at an effective concentration selected from the group of 10 μmol / m2-20 μmol / m2, 10 μmol / m2-30 μmol / m2, 10 μmol / m2-40 μmol / m2, 10 μmol / m2-50 μmol / m2, 10 μmol / m2-60 μmol / m2, 10 μmol / m2-70 μmol / m2, 10 μmol / m2-80 μmol / m2, 10 μmol / m2-90 μmol / m2, 10 μmol / m2-100 μmol / m2, 20 μmol / m2-100 μmol / m2, 30 μmol / m2-100 μmol / m2, 40 μmol / m2-100 μmol / m2, 50 μmol / m2-100 μmol / m2, 60 μmol / m2-100 μmol / m2, 70 μmol / m2-100 μmol / m2, 80 μmol / m2-100 μmol / m2, 90 μmol / m2-100 μmol / m2, 100 μmol / m2-200 μmol / m2, 100 μmol / m2-300 μmol / m2, 100 μmol / m2-400 μmol / m2, 100 μmol / m2-500 μmol / m2, 100 μmol / m2-600 μmol / m2, 100 μmol / m2-700 μmol / m2, 100 μmol / m2-800 μmol / m2, 100 μmol / m2-900 μmol / m2, 100 μmol / m2-1 mmol / m2, 100 μmol / m2-1 mmol / m2, 200 μmol / m2-1 mmol / m2, 300 μmol / m2-1 mmol / m2, 400 μmol / m2-1 mmol / m2, 500 μmol / m2-1 mmol / m2, 600 μmol / m2-1 mmol / m2, 700 μmol / m2-1 mmol / m2, 800 μmol / m2-1 mmol / m2, or 900 μmol / m2-1 mmol / m2. In one embodiment, the composition is present on the surface at a concentration lower than 10 μmol / m2. In one embodiment, the composition is present on the surface at a concentration higher than 1 mmol / m2.

[0169] Coating compositions for applying one or more active compounds described herein may utilize any components known in the art for such purposes. Non-limiting examples include saturated and unsaturated fatty acid and alkyl esters thereof having from about 10 to about 26 carbon atoms in their fatty acid chain (C10-C26fatty acid chains), including, but not limited to, lauric, myristic, palmitic, stearic, behenic, lignoceric, oleic, linoleic, arachidonic, linolenic, eicosapentaenoic, docosahexanoic, stearidonic, and cervonic fatty acids. Useful fatty acid alkyl esters include methyl esters such as palmitic acid methyl ester and α-linolenic acid methyl ester, as well as combinations 44 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT found in rapeseed methyl ester. In some embodiments, the combination of methyl esters comprising combined rapeseed methyl esters is oleic acid methyl ester (about 55-65%), linoleic acid methyl ester (about 18-25% linolenic acid methyl ester (about 5-11%) and palmitic acid methyl ester (about 5-8%).

[0170] Useful plant oils include corn, safflower, sunflower, soybean, cottonseed, grapeseed, and canola oils. Also useful are the essential oils used in perfumes and cosmetics, such as terpenes (α- pinene and β-pinene) and terpenoids (such as camphor and menthol).

[0171] Useful organic solvents include alkanols, such as ethanol and isopropanol. Useful aromatics, include xylenes. Useful ketones include acetone and methyl isobutyl ketone.

[0172] Some coating compositions may include mediums known in the art including, but not limited to, sustained release compositions, such as the aqueous dispersions described by Sun et al. in US Patent Publication 2016 / 0330954, and insecticidal paints, such as those described in US Patent Publication 2014 / 0302240 (Horley et al.), the contents of both publications are incorporated herein in their entirety.

[0173] Some compositions may further comprise one or more insecticide agents. Non-limiting examples of useful insecticide agents include antibiotic insecticides, macrocyclic lactone insecticides (e.g., avermectin insecticides, milbemycin insecticides, and spinosyn insecticides), arsenical insecticides, botanical insecticides, carbamate insecticides (e.g., benzofuranyl methylcarbamate, dimethylcarbamate insecticides, oxime carbamate insecticides, and phenyl methylcarbamate insecticides), diamide insecticides, desiccant insecticides, dinitrophenol insecticides, fluorine insecticides, formamidine insecticides, fumigant insecticides, inorganic insecticides, insect growth regulators (e.g., chitin synthesis inhibitors, juvenile hormone mimics (e.g., hydroprene, fenoxycarb and pyriproxyfen), juvenile hormones, moulting hormone agonists, moulting hormones, moulting inhibitors, precocenes, and other unclassified insect growth regulators), nereistoxin analogue insecticides, nicotinoid insecticides (e.g., nitroguanidine insecticides, nitromethylene insecticides, and pyridylmethylamine insecticides), organochlorine insecticides, organophosphorus insecticides, oxadiazine insecticides, oxadiazolone insecticides, phthalimide insecticides, pyrazole insecticides, pyrethroid insecticides (e.g., permethrin, deltamethrin, cypermethrin, cyphenothrin, etofenprox, fenvalerate, and cyfluthrin), pyrimidinamine insecticides, pyrrole insecticides, tetramic acid insecticides, tetronic acid insecticides, thiazole insecticides, thiazolidine insecticides, thiourea insecticides, urea insecticides, as well as, other unclassified insecticides.

[0174] Additional non-limiting useful insecticide agents include 1,2- dichloropropane, 1,3- dichloropropene, abamectin, acephate, acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile, alanycarb, aldicarb, aldoxycarb, aldrin, allethrin, allosamidin, allyxycarb, alpha-cypermethrin, alpha- endosulfan, amidithion, aminocarb, amiton, amitraz, anabasine, athidathion, azadirachtin, azamethiphos, azinphos-ethyl, azinphos-methyl, azothoate, barium hexafluorosilicate, barthrin, bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin, bifenthrin, bioallethrin, 45 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT bioethanomethrin, biopermethrin, bioresmethrin, bistrifluoron, borax, boric acid, boric acid, bromfenvinfos, bromocyclen, bromo-DDT, bromophos, bromophos-ethyl, bufencarb, buprofezin, butacarb, butathiofos, butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate, calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, cartap, chlorantraniliprole, chlorbicyclen, chlordane, chlordecone, chlordimeform, chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chloroform, chloropicrin, chlorphoxim, chlorprazophos, chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, cinerin I, cinerin cismethrin, cloethocarb, closantel, clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate, copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos, crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O- methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos, diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos, dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor, dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos, dimetilan, dinex, dinoprop, dinosam, dinotefuran, diofenolan, dioxabenzofos, dioxacarb, dioxathion, disulfoton, dithicrofos, d-limonene, DNOC, doramectin, ecdysterone, emamectin, EMPC, empenthrin, endosulfan, endothion, endrin, EPN, epofenonane, eprinomectin, esfenvalerate, etaphos, ethiofencarb, ethion, ethiprole, ethoate-methyl, ethoprophos, ethyl formate, ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide, etofenprox, etrimfos, EXD, famphur, fenamiphos, fenazaflor, fenchlorphos, fenethacarb, fenfluthrin, fenitrothion, fenobucarb, fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion, fenthion, fenthion- ethyl, fenvalerate, fipronil, flonicamid, flubendiamide, flucofuron, flucycloxuron, flucythrinate, flufenerim, flufenoxuron, flufenprpx, fluvalinate, fonofos, formetanate, formothion, formparanate, fosmethilan, fospirate, fosthietan, furathiocarb, furethrin, gamma- cyhalothrin, gamma-HCH, halfenprox, HCH, HEOD, heptachlor, heptenophos, heterophos, hexaflumuron, HHDN, hydramethylnon, hydrogen cyanide, hydroprene, hyquincarb, imidacloprid, imiprothrin, indoxacarb, iodomethane, IPSP, isazofos, isobenzan, isocarbophos, isodrin, isofenphos, isoprocarb, isoprothiolane, isothioate, isoxathion, ivermectin, jasmolin I, jasmolin II, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kelevan, kinoprene, lambda-cyhalothrin, lead arsenate, lepimectin, leptophos, lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben, mazidox, mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride, mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion, methiocarb, methocrotophos, methomyl, methoprene, methoxychlor, methyl bromide, methylchloroform, methylene chloride, metofluthrin, metolcarb, metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime, mipafox, mirex, monocrotophos, morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine, nifluridide, nitenpyram, nithiazine, 46 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT nitrilacarb, novaluron, noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos, oxydisulfoton, para- dichlorobenzene, parathion, parathion-methyl, penfluoron, pentachlorophenol, permethrin, phenkapton, phenothrin, phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor, phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite, potassium thiocyanate, pp'-DDT, prallethrin, precocene I, precocene II, precocene III, primidophos, profenofos, profluthrin, promacyl, promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos, prothoate, protrifenbute, pyraclofos, pyrafluprole, pyrazophos, pyresmethrin, pyrethrin I, pyrethrin II, pyridaben, pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimitate, pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl, quinothion, rafoxanide, resmethrin, rotenone, ryania, sabadilla, schradan, selamectin, silafluofen, silica gel, sodium arsenite, sodium fluoride, sodium hexafluorosilicate, sodium thiocyanate, sophamide, spinetoram, spinosad, spiromesifen, spirotetramat, sulcofuron, sulfoxaflor, sulfluramid, sulfotep, sulfuryl fluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos, TEPP, terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos, tetramethrin, theta-cypermethrin, thiacloprid, thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiodicarb, thiofanox, thiometon, thiosultap, thuringiensin, tolfenpyrad, tralomethrin, transfluthrin, transpermethrin, triarathene, triazamate, triazophos, trichlorfon, trichlormetaphos-3, trichloronat, trifenofos, triflumuron, trimethacarb, triprene, vamidothion, vaniliprole, XMC, xylylcarb, zeta-cypermethrin, zolaprofos, and α-ecdysone.

[0175] In some embodiments, a surface may be coated with both a compound of Formula (I), as described herein, and a mosquito attracting agent (attractant) known in the art. In one embodiment, the mosquito attracting agent is an agent that mimics the attractant smells of humans or other animals. For instance, agents such as lactic acid, octene alcohol (octanol or R-octenal) , and ammonia or ammonium hydrogencarbonate, or combinations thereof, may be used. In other embodiments, a mechanism for releasing carbon dioxide may be utilized near or through a coated surface.

[0176] In some embodiments, light is used to attract mosquitoes to the surface in question. In respective embodiments, the light utilized is a) 495-570 nm (green); b) 450–495 nm (blue); c) 380– 450 nm (violet); and d) 395 nm (commercial UV LEDs). In separate embodiments, a light source emitting light waves of a) 365 nm; b) 520 nm; and c) 470 nm may be used. In some embodiments, the light may be emitted in a pulsatile fashion. In some embodiments a frequency of from about 400 Hz to about 600 Hz may be used. In some embodiments, the frequency is about 500 Hz.

[0177] A further embodiment provides a method for reducing transmission of Plasmodium parasites to a female mosquito, the method comprising contacting the female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments 47 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT the composition comprises a coating composition as described herein. In other embodiments, the composition comprises a surface coating as described herein. In some embodiments, the female mosquito in the methods herein is an Anopheles mosquito.

[0178] Another embodiment provides a method of substantially reducing Plasmodium and / or oocyst development in an adult female mosquito, the method comprising contacting the female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments the composition comprises a coating composition as described herein. In other embodiments, the composition comprises a surface coating as described herein.

[0179] Another embodiment provides a method for substantially reducing mating success of an adult female mosquito, the method comprising contacting the adult female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments the composition comprises a coating composition as described herein. In other embodiments, the composition comprises a surface coating as described herein.

[0180] Another embodiment provides a method for substantially abolishing egg development in an adult female mosquito after blood feeding, the method comprising contacting the adult female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments the composition comprises a coating composition as described herein. In other embodiments, the composition comprises a surface coating as described herein.

[0181] The term "substantially abolishing egg development after blood feeding" generally refers to reducing egg development in adult, female mosquitoes by about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 99%, about 100% or from about 50% to about 100% (e.g., from about 60% to about 90%, about 70% to about 99%, about 80% to about 100% or about 90% to about 100%)) relative to a control. An "effective amount of at least one compound of Formula (I),” or one of the pharmaceutically acceptable forms thereof described herein, is one that achieves these reductions. An effective amount may be accomplished using the coating concentrations described herein, which may also be referred to as an effective coating concentration, an effective surface coating, or an effective concentration.

[0182] As used herein, the term "substantially reducing the mean survival rate" generally refers to reducing the survival rate of adult, female mosquitoes after 14 days by about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 48 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT 97%, about 99%, about 100%) or from about 50% to about 100% (e.g., from about 60% to about 90%, about 70% to about 99%, about 80% to about 100% or about 90% to about 100%)) relative to a control (e.g., no DBH relative to DBH). An "effective amount of one or more non-steroidal ecdysone agonists" is one that achieves these reductions.

[0183] Another embodiment provides a method for substantially reducing the mean survival rate of adult female mosquitoes, the method comprising contacting the adult female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0184] Species of mosquitos that may be targeted in embodiments herein include Anopheles spp (e.g., An. arabiensis, An. Funestus, An. Stephensi, An. sinensis, An. yatsushiroensis, and An. lesteri), Aedes spp (including Aedes vexans) or Culex spp (including Culex pipiens, Cx. orientalis, Cx. perexiguus, Cx. quinquefasciatus, and Cx. modestus).

[0185] In one embodiment, the composition described herein reduces transmission of Plasmodium species, which includes the species of Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. As used herein, “reduces transmission of Plasmodium” refers to the inhibition of zygote / ookinete transition of Plasmodium development. In one embodiment, the zygote / ookinete transition is inhibited by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, as compared to an appropriate control.100% inhibition of the zygote / ookinete transition is referred to here as complete inhibition of the zygote / ookinete transition. Immunofluorescence techniques that visual the presence of ookinetes, as described herein in the Examples, can be used to determine if the zygote / ookinete transition has been inhibited. As used herein, an appropriate control refers to a mosquito that has not been contacted by the composition.

[0186] In one embodiment, the composition described herein reduces transmission of Plasmodium. As used herein, “reduces transmission of Plasmodium” refers to the inhibition of Plasmodium ookinete development. In one embodiment, the Plasmodium ookinete development is inhibited by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, as compared to an appropriate control.100% inhibition of the Plasmodium ookinete development is referred to here as complete inhibition of Plasmodium ookinete development. Immunofluorescence techniques that visual the stage of development for ookinetes present in the mosquito, as described herein in the Examples, can be used to determine if the zygote / ookinete transition has been inhibited. As used herein, an appropriate control refers to a mosquito that has not been contacted by the composition.

[0187] Also provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or 49 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT other mixtures thereof), tautomer, isotope, or polymorph thereof, in the preparation of a coating composition.

[0188] Preparation

[0189] Synthesis of 2-Methyl-3-(n-heptyl)-5.7-difluorquinolone (ELQ-121)

[0190] Ethyl 2-n-heptylacetoacetate (10.0 g, 43.9 rnmol), 3.5-difiuoroaniline (5.67 g, 43.9 rnmol), 200 ml benzene and 0.20 g p-toluenesulfonic acid monohydrate are heated in a flask fitted with a water separator for 20 hours; more acid (0.30 g) is added and water removal continued for 3 more days. Solvent is removed (rotary evaporator) and the residue dropped quickly into 15 ml of boiling Dowtherm A, kept at boiling temperature for 5 minutes and allowed to cool. The product crystallizes out upon cooling. After one and one-half hours the mass is broken up and transferred to a suction funnel; soluble components are washed out with a total of about 50 ml of hexane. Re- crystallization from about 100 ml of dimethylformamide leaves 6.43 g of pure product as shiny flakes (50.0%). M.p.294-296° C.1 H - I m x spectum (400 MHz, (CD3)2SO, Si(CH3)4=O): bCH3(pos 2)=2.33 ppm, s, 3H; C7-Chain:8 ^ ^ , = 2.41 , dist. t, 21¾ 8 > =1.2-1.4, indistinct features, 10H; Sci73=O.87, t, J=6.8 Hz, 3H.86=6.95, d-d-d, J56=12, J67=IO, J68=2.5; 88=7.0, d-d-d, J58 =I.35 (not resolved in19F-Spectrum), J68=2.5, J78=10.0, H(6)+H(8) =2H; Sjsay=I 1.4, s(br.), 0.85H.19F- n.m.r. spectrum (400 MHz, (CD3)2SO, CCl3F=O): S5=-108.6, t, J=12.7 Hz, IF; 87 =-106.3, quartett, J=10.6 Hz, IF. Mass spectrum: M+=293, 18%; (M-C6H13)+=208, 100%.

[0191] The synthesis of 6-Chloro-3-heptyl-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-432) was described as Compound 54 by Cross et al., in their article Endochin Optimization: Structure- Activity and Structure-Property Relationship Studies of 3-Substituted 2-Methyl-4(1H)-quinolones with Antimalarial Activity, J. Med. Chem., Vol.53, Issue 19, pp.7076-7094, 2010; and the compound was characterized as: Yield: 30%, mp=238-239 _C.1HNMR(400 MHz, DMSO) δ 11.34 (s, 1H), 7.95 (s, 1H), 6.98 (s, 1H), 3.92 (s, 3H), 2.46-2.40 (m, 2H), 2.34 (s, 3H), 1.25 (d, J=10.4 Hz, 10H), 0.84 (d, J=7.0 Hz, 3H).13CNMR(101 MHz,DMSO)δ 174.16, 156.23, 145.52, 139.31, 125.92, 119.08, 117.86, 117.47, 99.16, 56.25, 31.31, 29.23, 28.68, 28.56, 24.70, 22.10, 17.45, 13.94. HRMS calcd for C18H24ClNO2 [M þ H] þ: 322.15683. Found: 322.15720.

[0192] Alkoxycarbonate prodrug chains may be added to ELQ compounds in methods known in the art, including those of US 2020 / 0369616 (Riscoe et al.), which is incorporated herein byreference in its entirety. In general, an appropriate starting alcohol (R5OH) can be reacted withchloromethyl chloroformate in the presence of 2 equivalents of triethylamine in dry tetrahydrofuran at -78°C to produce the corresponding chloromethyl alkyl carbonate, RO-C(=O)-O-CH2Cl, which then can be reacted with the ELQ compound of interest in dimethylformamide (DMF) in the presence of tetrabutylammonium iodide and potassium carbonate to produce the desired alkoxycarbonate prodrug. 50 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0193] Another embodiment provides a compound of Formula (I), wherein: R1is selected from the group of H, halogen, and -OCH3; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0194] Another embodiment provides a compound of Formula (II),wherein each of R1, R2, R3, R4, and R5is as defined above for Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0196] Another embodiment provides a compound of Formula (II), wherein each of R1, R2, R3,R4, and R5is as defined for Formulas (I) and (II), above, with the proviso that at least one variable selected from the group of R1, R2, and R3is hydrogen, or a pharmaceutically acceptable salt, co- 51 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0197] Another embodiment provides a compound of Formula (II), wherein each of R1, R2, R3, R4, and R5is as defined for Formulas (I) and (II), above, with the proviso that two variables selected from the group of R1, R2, and R3are hydrogen and the remaining variable selected from the group of R1, R2, and R3is not hydrogen, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0198] Another embodiment provides a compound of Formula (II), wherein: R1is selected from the group of F, Cl, and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H, F, and Cl; R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0199] Another embodiment provides a compound of Formula (II), wherein: R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H, F, and Cl; R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0200] A further embodiment provides a compound of Formula (II), wherein: R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H and F; R4is C5-C9alkyl; and R5 is C1-C5 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0201] A further embodiment provides a compound of Formula (II), wherein: R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H and F; 52 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT R4is heptyl; and R5is C1-C4alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0202] An additional embodiment provides a compound of Formula (III):

[0203] wherein: R2is halogen; R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0204] Another embodiment provides a compound of Formula (III), wherein R2is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0205] A further embodiment provides a compound of Formula (III), wherein R2is F; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0206] Another separate embodiment provides a compound of Formula (III), wherein R2is Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0207] A separate embodiment provides a compound of Formula (III), above, wherein R2is selected from the group of F and Cl; R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0208] Another separate embodiment provides a compound of Formula (III), above, wherein R2is selected from the group of F and Cl; R4 is C6-C8 alkyl; and R5 is C1-C3 alkyl; or a pharmaceutically 53 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0209] An additional embodiment provides a compound of Formula (III), above, wherein R2is F; R4is C6-C8alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0210] An additional embodiment provides a compound of Formula (III), above, wherein R2is Cl; R4is C6-C8alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0211] An additional embodiment provides a compound of Formula (III), above, wherein R2is Cl; R4is heptyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0212] An additional embodiment provides a compound of Formula (III), above, wherein R2is F; R4is heptyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0213] One embodiment provides the compound ((6-chloro-3-heptyl-7-methoxy-2- methylquinolin-4-yl)oxy)methyl ethyl carbonate, also referred to as ELQ-613, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0214] An embodiment provides the compound ((5,7-difluoro-3-heptyl-2-methylquinolin-4- yl)oxy)methyl ethyl carbonate, also referred to as ELQ-453, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 54 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0215] Some embodiments herein comprise the use of the compound ethyl (((5-fluoro-3-heptyl- 7-methoxy-2-methylquinolin-4-yl)oxy)methyl) carbonate, also referred to as ELQ-621, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0216] Some embodiments herein comprise the use of the compound ethyl (((6-fluoro-3-heptyl- 2-methylquinolin-4-yl)oxy)methyl) carbonate, also referred to as ELQ-403, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0217] Some embodiments herein comprise the use of the compound ethyl (((3-heptyl-7- methoxy-2-methylquinolin-4-yl)oxy)methyl) carbonate, also referred to as ELQ-701, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0218] Some embodiments herein comprise the use of the compound ethyl (((6-fluoro-3-heptyl- 7-methoxy-2-methylquinolin-4-yl)oxy)methyl) carbonate, also referred to as ELQ-465, having the structure: 55 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTpharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0219] Some embodiments herein comprise the use of the compound ((7-chloro-5-fluoro-3- heptyl-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate, also referred to as ELQ-617, having the structure:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0220] Another embodiment provides the base compound of ELQ-617, tautomers 7-chloro-5- fluoro-3-heptyl-2-methylquinolin-4-ol and 7-chloro-5-fluoro-3-heptyl-2-methylquinolin-4(3H)-one:acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0221] Another embodiment provides the base compound of ELQ-621, tautomers 5-fluoro-3- heptyl-7-methoxy-2-methylquinolin-4-ol and 5-fluoro-3-heptyl-7-methoxy-2-methylquinolin-4(3H)- one:acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0222] A different embodiment provides a compound of Formula (IV): 56 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R1is selected from the group of -OCH3and halogen; R3is halogen; R4is C4-C12alkyl; and R5 is C1-C10 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0223] An additional embodiment provides a compound of Formula (IV), wherein, R1is selected from the group of -OCH3, F, and Cl; R3is selected from the group of F and Cl; R4is C4-C12alkyl; and R5is C1-C12alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0224] An additional embodiment provides a compound of Formula (IV), wherein, R1is selected from the group of -OCH3, F, and Cl; R3is selected from the group of F and Cl; R4is C4-C12alkyl; and R5is C1-C12alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0225] An additional embodiment provides a compound of Formula (IV), wherein, R1is -OCH3; R3is selected from the group of F and Cl; R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0226] An additional embodiment provides a compound of Formula (IV), wherein, R1is selected from the group of F and Cl; 57 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C12alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0227] For the sake of brevity, it is understood that reference to a compound of a formula or a specific compound, or a pharmaceutically acceptable salt thereof, also includes reference to or a pharmaceutically acceptable co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0228] Additional separate embodiments provide, respectively, a compound of each of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula (XIV):58 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, in each embodiment, R4 is C4-C12 alkyl; and R5 is C1-C10 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0229] Additional separate embodiments provide, respectively, a compound of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula (XIV), wherein in each embodiment, R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0230] Additional separate embodiments provide, respectively, a compound of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula (XIV),, wherein in each embodiment, R4is C6-C8alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0231] Additional separate embodiments provide, respectively, a compound of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula (XIV), wherein in each embodiment, R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0232] Additional separate embodiments provide, respectively, a compound of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula 59 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT (XII), Formula (XIII), and Formula (XIV), wherein in each embodiment, R4is C6-C8alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0233] Additional separate embodiments provide, respectively, a compound of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula (XIV), wherein in each embodiment, R4is heptyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0234] An additional embodiment provides a pharmaceutical composition comprising a pharmaceutically or therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, and a pharmaceutically acceptable carrier or excipient. Additional embodiments are understood that provide pharmaceutical compositions, separately comprising a compound of each formula and each specific compound described herein, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, and a pharmaceutically acceptable carrier or excipient.

[0235] Additional embodiments comprise different pharmaceutical compositions comprising, respectively, a pharmaceutically effective amount of a compound of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), and Formula (XIV), as well as each of the subgeneric groups describing subsets of those formulas, and the individual ELQ compounds described herein.

[0236] In some embodiments of any of the aspects, described herein is a compound wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (I) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (III) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IV) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer 60 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (V) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VI) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VII) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VIII) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IX) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (X) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XI) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XII) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIII) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIV) wherein R4is C7-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0237] In some embodiments of any of the aspects, described herein is a compound wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, 61 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (I) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (III) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IV) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (V) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VI) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VII) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VIII) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IX) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (X) wherein R4is C7or C11alkyl; and R5 is C2 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XI) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XII) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a 62 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIII) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIV) wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0238] In some embodiments of any of the aspects, described herein is a compound wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (I) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (III) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IV) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (V) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VI) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of theaspects, described herein is a compound of Formula (VII) wherein R4 is C1-C7 alkyl; and R5 is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VIII) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of 63 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT Formula (IX) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (X) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XI) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XII) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIII) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIV) wherein R4is C1-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0239] In some embodiments of any of the aspects, described herein is a compound wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (I) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (III) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodimentsof any of the aspects, described herein is a compound of Formula (IV) wherein R4 is C7 alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (V) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of 64 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT Formula (VI) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VII) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VIII) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IX) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (X) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XI) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XII) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIII) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIV) wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0240] In some embodiments of any of the aspects, described herein is a compound wherein R4 isC1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (I) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, 65 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT described herein is a compound of Formula (III) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IV) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (V) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VI) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VII) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VIII) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IX) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (X) wherein R4is C1- C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XI) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XII) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIII) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or 66 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIV) wherein R4is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0241] In some embodiments of any of the aspects, described herein is a compound wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (I) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (III) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IV) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (V) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VI) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VII) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VIII) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IX) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (X) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, 67 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XI) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XII) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIII) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIV) wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0242] In some embodiments of any of the aspects, described herein is a compound wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (I) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (III) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IV) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (V) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VI) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VII) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer 68 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VIII) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IX) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (X) wherein R4is C5- C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XI) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XII) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIII) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIV) wherein R4is C5-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0243] In some embodiments of any of the aspects, described herein is a compound wherein R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound ofFormula (I) wherein R4 is C5-C11 alkyl; and R5 is C2 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (III) wherein R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IV) wherein R4is C5-C11alkyl; and 69 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT R5is C12alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (V) wherein R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VI) wherein R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VII) wherein R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VIII) wherein R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IX) wherein R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (X) wherein R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XI) wherein R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XII) wherein R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is acompound of Formula (XIII) wherein R4 is C5-C11 alkyl; and R5 is C2 alkyl; or a pharmaceuticallyacceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIV) wherein R4is C5-C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 70 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0244] In some embodiments of any of the aspects, described herein is a compound wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (I) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (III) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IV) wherein R4is C5-C7alkyl; and R5is C12alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (V) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VI) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VII) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VIII) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IX) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (X) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XI) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph 71 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XII) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIII) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIV) wherein R4is C5-C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0245] In some embodiments of any of the aspects, described herein is a compound wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (I) wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (III) wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IV) wherein R4is C5- C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (V) wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VI) wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VII) wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (VIII) wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures 72 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (IX) wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (X) wherein R4is C5- C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XI) wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XII) wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIII) wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments of any of the aspects, described herein is a compound of Formula (XIV) wherein R4is C5-C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

[0246] In some embodiments of any of the aspects, described herein is a coating composition or composition of comprising a first compound of Formula (II):R1is a halogen; R2is H; R3is a halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; and a second compound of Formula (II): 73 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTR1is -OCH3; R2is a halogen; R3is H; R4is C4-C10alkyl; and R5is C1-C10alkyl.

[0247] Also provided herein is a method for treating malaria in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0248] Also provided herein is a method for inhibiting malaria in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0249] Methods for treating or inhibiting malaria in a human subject include the treatment or inhibition of infections caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.

[0250] Also provided herein is a method for treating multidrug-resistant malaria in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Multidrug-resistant malaria infections that may be treated using the compounds and methods herein include malaria resistant to treatment with one or more agents selected from the group of chloroquine, sulphadoxine-pyrimethamine, quinine, piperaquine, mefloquine, artemisinin-based combination therapy (ACT, including artemether-lumefantrine (COARTEM®) and artesunate-mefloquine), pyrimethamine, dapsone, atovaquone, and a P. falciparum dihydroorotate dehydrogenase (DHOD inhibitor or PfDHOD inhibitor). DHOD inhibitors include, but are not limited to DSM265 (Coteron J M et al, J Med Chem 54, 5540-5561 (2011)

[0251] Also provided herein is a method for treating chloroquine-resistant malaria in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0252] Also provided herein is a method for treating a latent malaria infection in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. 74 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0253] The methods for treating malarial infections described herein may also further comprise co-administering with the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the human in need thereof a therapeutically effective amount of one or more compounds selected from the group of quinine, chloroquine, atovaquone, proguanil, primaquine, amodiaquine, mefloquine, piperaquine, artemisinin, artesunate, methylene blue, pyrimethamine, sulfadoxine, artemether- lumefantrine, dapsone-chlorproguanil, artesunate, quinidine, clopidol, and ihydroartemisinin, or a pharmaceutically acceptable salt thereof.

[0254] Also provided herein is a method for treating toxoplasmosis (Toxoplasma gondii infection) in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided is a method for treating toxoplasmosis (Toxoplasma gondii infection) in a non-human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In different embodiments, the non-human subjects to be treated are selected from the group of cats, dogs, chickens, ducks, sheep, goats, pigs, cattle, and horses.

[0255] Also provided herein is a method for treating babesiosis in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Methods of treatment for babesiosis in a human subject includes that for infections by Babesia microti.

[0256] Also provided herein is a method for treating babesiosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Such methods include bovine babesiosis, including infections caused by Babesia bovis and B. bigemina, and equine babesiosis, including infections caused by B. caballi and Theileria equi.

[0257] Also provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, in the preparation of a medicament. Additional embodiments provide the use of each such compound for use in the preparation of a medicament for use in treating each of the diseases and conditions referenced herein.

[0258] Preparation

[0259] Synthesis of 2-Methyl-3-(n-heptyl)-5.7-difluorquinolone (ELQ-121)

[0260] Ethyl 2-n-heptylacetoacetate (10.0 g, 43.9 rnmol), 3.5-difiuoroaniline (5.67 g, 43.9 rnmol), 200 ml benzene and 0.20 g p-toluenesulfonic acid monohydrate are heated in a flask fitted with a water separator for 20 hours; more acid (0.30 g) is added and water removal continued for 3 more days. Solvent is removed (rotary evaporator) and the residue dropped quickly into 15 ml of boiling Dowtherm A, kept at boiling temperature for 5 minutes and allowed to cool. The product 75 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT crystallizes out upon cooling. After one and one-half hours the mass is broken up and transferred to a suction funnel; soluble components are washed out with a total of about 50 ml of hexane. Re- crystallization from about 100 ml of dimethylformamide leaves 6.43 g of pure product as shiny flakes (50.0%). M.p.294-296° C.1 H - I m x spectum (400 MHz, (CD3)2SO, Si(CH3)4=O): bCH3(pos 2)=2.33 ppm, s, 3H; C7-Chain:8 ^ ^ , = 2.41 , dist. t, 21¾ 8 > =1.2-1.4, indistinct features, 10H; Sci73=O.87, t, J=6.8 Hz, 3H.86=6.95, d-d-d, J56=12, J67=IO, J68=2.5; 88=7.0, d-d-d, J58 =I.35 (not resolved in19F-Spectrum), J68=2.5, J78=10.0, H(6)+H(8) =2H; Sjsay=I 1.4, s(br.), 0.85H.19F- n.m.r. spectrum (400 MHz, (CD3)2SO, CCl3F=O): S5=-108.6, t, J=12.7 Hz, IF; 87 =-106.3, quartett, J=10.6 Hz, IF. Mass spectrum: M+=293, 18%; (M-C6H13)+=208, 100%.

[0261] The synthesis of 6-Chloro-3-heptyl-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-432) was described as Compound 54 by Cross et al., in their article Endochin Optimization: Structure- Activity and Structure-Property Relationship Studies of 3-Substituted 2-Methyl-4(1H)-quinolones with Antimalarial Activity, J. Med. Chem., Vol.53, Issue 19, pp.7076-7094, 2010; and the compound was characterized as: Yield: 30%, mp=238-239 _C.1HNMR(400 MHz, DMSO) δ 11.34 (s, 1H), 7.95 (s, 1H), 6.98 (s, 1H), 3.92 (s, 3H), 2.46-2.40 (m, 2H), 2.34 (s, 3H), 1.25 (d, J=10.4 Hz, 10H), 0.84 (d, J=7.0 Hz, 3H).13CNMR(101 MHz,DMSO)δ 174.16, 156.23, 145.52, 139.31, 125.92, 119.08, 117.86, 117.47, 99.16, 56.25, 31.31, 29.23, 28.68, 28.56, 24.70, 22.10, 17.45, 13.94. HRMS calcd for C18H24ClNO2 [M þ H] þ: 322.15683. Found: 322.15720.

[0262] Alkoxycarbonate prodrug chains may be added to ELQ compounds in methods known in the art, including those of US 2020 / 0369616 (Riscoe et al.), which is incorporated herein by reference in its entirety. In general, an appropriate starting alcohol (R5OH) can be reacted with chloromethyl chloroformate in the presence of 2 equivalents of triethylamine in dry tetrahydrofuran at -78°C to produce the corresponding chloromethyl alkyl carbonate, RO-C(=O)-O-CH2Cl, which then can be reacted with the ELQ compound of interest in dimethylformamide (DMF) in the presence of tetrabutylammonium iodide and potassium carbonate to produce the desired alkoxycarbonate prodrug. 76 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0263] The compounds and pharmaceutical compositions disclosed herein can be used for inhibiting or preventing parasitic diseases. For example, human or animal (non-human) parasitic diseases include malaria, toxoplasmosis, theileriosis, amebiasis, giardiasis, leishmaniasis, trypanosomiasis, neosporosis (Neospora cranium infection), Besnoitia besnoiti infections, and coccidiosis, caused by organisms such as Toxoplasma sp. (such as Toxoplasma gondii), Eimeria sp. (Eimeriosis), Babesia bovis (babesiosis), Theileria sp. (Theileria annulata – tropical theileriosis and Theileria parva – East Coast fever), and also includes infections by helminths, such as ascaris, schistosomes and filarial worms.

[0264] Provided is a method for treating coccidiosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the non- human subject is a poultry subject, including chickens, ducks, and turkeys. In some embodiments, the chickens in need of such treatment are infected with a pathogen selected from the group of Eimeria tenella, E. maxima, E. mitis, E. acervulina, E. brunetti, E. praecox, and E. necatrix.

[0265] In some embodiments, the non-human subject is a ruminant subject, including cattle (bovine), bison, sheep (ovine), and goats (caprine or hircine). In some embodiments, the coccidiosis in the ruminant concerns and infection of a pathogen selected from the group of Eimeria bovis, E. zuernii, E. auburnensis, E. alabamensis,

[0266] In goats, the coccidiosis may be associated with infection of a pathogen selected from the group of E. christenseni, E. arloingi, E. caprina, and E. ninakohlyakimovae. 77 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0267] The compounds and compositions described herein are also effective in the inhibition of fungal pathogens including Pneumocystis carinii, Aspergillus fumigatus, and others.

[0268] In particular embodiments, the parasitic diseases may be caused by parasites that cause malaria. Particular species of parasites that are included within this group include all species that are capable of causing human or animal infection. Illustrative species include Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium knowlesi, and Plasmodium malariae. The compounds and compositions disclosed herein are particularly useful for inhibiting drug-resistant malaria such as chloroquine-resistant malaria or multidrug-resistant malaria that is caused by organisms harboring resistance to chloroquine, quinine, mefloquine, pyrimethamine, dapsone, and / or atovaquone.

[0269] Toxoplasmosis is caused by a sporozoan parasite of the Apicomplexa called Toxoplasma gondii. It a common tissue parasite of humans and animals. Most of the infections appear to be asymptomatic (90%), however toxoplasmosis poses a serious health risk for immuno-compromised individuals, such as organ transplant recipients, cancer and AIDS patients, and the unborn children of infected mothers. The compounds disclosed herein may be used alone to treat toxoplasmosis or they may be co-administered with “antifolates” such as sulfonamides, pyrimethamine, tirmethoprim, biguanides and / or atovaquone.

[0270] In further embodiments, the compounds disclosed herein may be co-administered with another pharmaceutically active compound. For example, the compounds may be co-administered with quinine, chloroquine, atovaquone, proguanil, primaquine, amodiaquine, mefloquine, piperaquine, artemisinin, methylene blue, pyrimethamine, sulfadoxine, artemether-lumefantrine (COARTEM®), dapsone-chlorproguanil (LAPDAP®), artesunate, quinidine, clopidol, pyridine / pyridinol analogs, 4(1H)-quinolone analogs, dihydroartemisinin, a mixture of atovaquone and proguanil, an endoperoxide, an acridone as disclosed in WO 2008 / 064011 (which is incorporated herein by reference in its entirety), a pharmachin as disclosed in U.S. Provisional Patent Application titled “Compounds for Treating Parasitic Disease” filed Nov.18, 2008 (which is incorporated herein by reference in its entirety), or any combination of these.

[0271] The use of ELQ compounds in the treatment of Neospora caninum infections is discussed in the article Endochin-like quinolones (ELQs) and bumped kinase inhibitors (BKIs): Synergistic and additive effects of combined treatments against Neospora caninum infection in vitro and in vivo, Anghel et al., International Journal for Parasitology: Drugs and Drug Resistance, Vol.17, Dec.2021, pages 92-96.

[0272] Another embodiment provides a method of treatment of neosporosis infections in a subject, the method comprising administering to the subject in need thereof a pharmaceutically or therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures 78 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT thereof), tautomer, isotope, or polymorph thereof. In some embodiments, the neosporosis infection is caused by or associated with a Neospora caninum infection. In some embodiments, in the Neospora caninum infections, the subject to be treated is a non-human subject. In some embodiments, the non- human subject to be treated is bovine. In other embodiments, the non-human subject to be treated is canine. In further embodiments, the non-human subject is equine. Additional separate embodiments concern, respectively, a Neospora caninum infection, and the treatment thereof, in sheep, goats, and chickens.

[0273] Also provided is a method of treatment of a Besnoitia besnoti infection in a non-human subject, the method comprising administering to the subject in need thereof a pharmaceutically or therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. In some embodiments, the non-human subject to be treated for the B. besnoti infection is bovine.

[0274] The compounds disclosed herein may be included in pharmaceutical compositions (including therapeutic and prophylactic formulations), typically combined together with one or more pharmaceutically acceptable vehicles or carriers and, optionally, other therapeutic ingredients (for example, antibiotics, anti-inflammatories, or drugs that are used to reduce pruritus such as an antihistamine). The compositions disclosed herein may be advantageously combined and / or used in combination with other antimalarial agents as described above.

[0275] Such pharmaceutical compositions can be administered to subjects by a variety of mucosal administration modes, including by oral, rectal, intranasal, intrapulmonary, or transdermal delivery, or by topical delivery to other surfaces. Optionally, the compositions can be administered by non-mucosal routes, including by intramuscular, subcutaneous, intravenous, intra-arterial, intra- articular, intraperitoneal, intrathecal, intracerebroventricular, or parenteral routes. In other alternative embodiments, the compound can be administered ex vivo by direct exposure to cells, tissues or organs originating from a subject.

[0276] In some embodiments, the antimalarial agent or combination of antimalarial agents, including the compounds described herein, or a pharmaceutically acceptable salt thereof, may be administered to animals, such as chickens, as an additive to their prepared feed or grain.

[0277] In some embodiments, a pharmaceutically effective amount of a compound herein (including those of Formula (I) and all other formulas and individual compounds described herein), or a pharmaceutically acceptable salt thereof, may be administered to a human in need thereof by injection. In some embodiments, the injection may be subcutaneous. In other embodiments, the injection is intramuscular.

[0278] The forms in which the compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, may be incorporated for administration by injection include aqueous or oil 79 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline may also conventionally be used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0279] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, may be administered using a formulation comprising sesame oil, preferably pharmaceutical grade sesame oil. Components of an injectable formulation may include additional polar compounds, such as those selected from the group of monoglycerides, diglycerides, free fatty acids, plant sterols, sesamin, and sesamolin. Some injectable formulations further comprise ethanol. In some embodiments, the injectable formulation comprises from about 5 weight % to about 10 weight% ethanol. In other embodiments, the injectable formulation comprises from about 7 weight % to about 8 weight% ethanol. In other embodiments, the injectable formulation comprises from about 7.25 weight % to about 7.75 weight% ethanol. In other embodiments, the injectable formulation comprises about 7.5 weight % ethanol.

[0280] Additional components that may be used for intramuscular injections include vegetable oils, such as peanut oil, almond oil, olive oil, castor oil, and soybean oil. Also suitable are synthetic oils, such as polyethylene glycol, triglycerides of higher saturated fatty acids, monoesters of higher fatty acids, etc.

[0281] The injectable composition may also comprise one or more excipients, such as benzyl alcohol or benzoic acid compounds, including benzyl benzoate or sodium benzoate. Other useful excipients include methyl cholate, hydrophobic colloidal anhydrous silica, colloidal silicon dioxide, cholesteryl fatty acid ester like cholesteryl oleate, cholesteryl nonanoate, cholesteryl stearate, polyoxyethylen(5)sorbitan monooleate, polyoxyethylen(6) stearate, polyvalent metal salts of fatty acids e.g. aluminium stearate, fatty acid ester of carbohydrates like Rheopearl®, sorbitan fatty acid esters like sorbitan monolaurate, sorbitan sesquioleate, and sorbitan monostearate, and glycerol fatty acid ester like glycerol monostearate.

[0282] Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of 80 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. In some embodiments, for parenteral administration, sterile injectable solutions are prepared containing a therapeutically effective amount, e.g., 0.1 to 1000 mg, of the compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.

[0283] To formulate the pharmaceutical compositions, the compound can be combined with various pharmaceutically acceptable additives, as well as a base or vehicle for dispersion of the compound. Desired additives include, but are not limited to, pH control agents, such as arginine, sodium hydroxide, glycine, hydrochloric acid, citric acid, and the like. In addition, local anesthetics (for example, benzyl alcohol), isotonizing agents (for example, sodium chloride, mannitol, sorbitol), adsorption inhibitors (for example, Tween 80 or Miglyol 812), solubility enhancing agents (for example, cyclodextrins and derivatives thereof), stabilizers (for example, serum albumin), and reducing agents (for example, glutathione) can be included. Adjuvants, such as aluminum hydroxide (for example, Amphogel, Wyeth Laboratories, Madison, N.J.), Freund's adjuvant, MPL™ (3-O- deacylated monophosphoryl lipid A; Corixa, Hamilton, Ind.) and IL-12 (Genetics Institute, Cambridge, Mass.), among many other suitable adjuvants well known in the art, can be included in the compositions. When the composition is a liquid, the tonicity of the formulation, as measured with reference to the tonicity of 0.9% (w / v) physiological saline solution taken as unity, is typically adjusted to a value at which no substantial, irreversible tissue damage will be induced at the site of administration. Generally, the tonicity of the solution is adjusted to a value of about 0.3 to about 3.0, such as about 0.5 to about 2.0, or about 0.8 to about 1.7.

[0284] The compound can be dispersed in a base or vehicle, which can include a hydrophilic compound having a capacity to disperse the compound, and any desired additives. The base can be selected from a wide range of suitable compounds, including but not limited to, copolymers of polycarboxylic acids or salts thereof, carboxylic anhydrides (for example, maleic anhydride) with other monomers (for example, methyl (meth)acrylate, acrylic acid and the like), hydrophilic vinyl polymers, such as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives, such as hydroxymethylcellulose, hydroxypropylcellulose and the like, and natural polymers, such as chitosan, collagen, sodium alginate, gelatin, hyaluronic acid, and nontoxic metal salts thereof. Often, a biodegradable polymer is selected as a base or vehicle, for example, polylactic acid, poly(lactic acid- glycolic acid) copolymer, polyhydroxybutyric acid, poly(hydroxybutyric acid-glycolic acid) 81 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT copolymer and mixtures thereof. Alternatively or additionally, synthetic fatty acid esters such as polyglycerin fatty acid esters, sucrose fatty acid esters and the like can be employed as vehicles. Hydrophilic polymers and other vehicles can be used alone or in combination, and enhanced structural integrity can be imparted to the vehicle by partial crystallization, ionic bonding, cross-linking and the like. The vehicle can be provided in a variety of forms, including fluid or viscous solutions, gels, pastes, powders, microspheres and films for direct application to a mucosal surface.

[0285] The compound can be combined with the base or vehicle according to a variety of methods, and release of the compound can be by diffusion, disintegration of the vehicle, or associated formation of water channels. In some circumstances, the compound is dispersed in microcapsules (microspheres) or nanocapsules (nanospheres) prepared from a suitable polymer, for example, isobutyl 2-cyanoacrylate (see, for example, Michael et al., J. Pharmacy Pharmacol.43:1-5, 1991), and dispersed in a biocompatible dispersing medium, which yields sustained delivery and biological activity over a protracted time.

[0286] The compositions of the disclosure can alternatively contain as pharmaceutically acceptable vehicles substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate. For solid compositions, conventional nontoxic pharmaceutically acceptable vehicles can be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.

[0287] Pharmaceutical compositions for administering the compound can also be formulated as a solution, microemulsion, or other ordered structure suitable for high concentration of active ingredients. The vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity for solutions can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of a desired particle size in the case of dispersible formulations, and by the use of surfactants. In many cases, it will be desirable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol and sorbitol, or sodium chloride in the composition. Prolonged absorption of the compound can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.

[0288] In certain embodiments, the compound can be administered in a time release formulation, for example in a composition which includes a slow release polymer. These compositions can be prepared with vehicles that will protect against rapid release, for example a controlled release vehicle such as a polymer, microencapsulated delivery system or bioadhesive gel. Prolonged delivery in various compositions of the disclosure can be brought about by including in the composition agents 82 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT that delay absorption, for example, aluminum monostearate hydrogels and gelatin. When controlled release formulations are desired, controlled release binders suitable for use in accordance with the disclosure include any biocompatible controlled release material which is inert to the active agent and which is capable of incorporating the compound and / or other biologically active agent. Numerous such materials are known in the art. Useful controlled-release binders are materials that are metabolized slowly under physiological conditions following their delivery (for example, at a mucosal surface, or in the presence of bodily fluids). Appropriate binders include, but are not limited to, biocompatible polymers and copolymers well known in the art for use in sustained release formulations. Such biocompatible compounds are non-toxic and inert to surrounding tissues, and do not trigger significant adverse side effects, such as nasal irritation, immune response, inflammation, or the like. They are metabolized into metabolic products that are also biocompatible and easily eliminated from the body.

[0289] Exemplary polymeric materials for use in the present disclosure include, but are not limited to, polymeric matrices derived from copolymeric and homopolymeric polyesters having hydrolyzable ester linkages. A number of these are known in the art to be biodegradable and to lead to degradation products having no or low toxicity. Exemplary polymers include polyglycolic acids and polylactic acids, poly(DL-lactic acid-co-glycolic acid), poly(D-lactic acid-co-glycolic acid), and poly(L-lactic acid-co-glycolic acid). Other useful biodegradable or bioerodable polymers include, but are not limited to, such polymers as poly(epsilon-caprolactone), poly(epsilon-aprolactone-CO-lactic acid), poly(epsilon.-aprolactone-CO-glycolic acid), poly(beta-hydroxy butyric acid), poly(alkyl-2- cyanoacrilate), hydrogels, such as poly(hydroxyethyl methacrylate), polyamides, poly(amino acids) (for example, L-leucine, glutamic acid, L-aspartic acid and the like), poly(ester urea), poly(2- hydroxyethyl DL-aspartamide), polyacetal polymers, polyorthoesters, polycarbonate, polymaleamides, polysaccharides, and copolymers thereof. Many methods for preparing such formulations are well known to those skilled in the art (see, for example, Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978). Other useful formulations include controlled-release microcapsules (U.S. Pat. Nos.4,652,441 and 4,917,893), lactic acid-glycolic acid copolymers useful in making microcapsules and other formulations (U.S. Pat. Nos.4,677,191 and 4,728,721) and sustained-release compositions for water- soluble peptides (U.S. Pat. No.4,675,189).

[0290] The pharmaceutical compositions of the disclosure typically are sterile and stable under conditions of manufacture, storage and use. Sterile solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the compound and / or other biologically active agent into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein. 83 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT In the case of sterile powders, methods of preparation include vacuum drying and freeze-drying which yields a powder of the compound plus any additional desired ingredient from a previously sterile- filtered solution thereof. The prevention of the action of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0291] In some embodiments, the method of delivering a pharmaceutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, may be administered to a subject in need thereof through a medical implant, particularly an implant designed to provide a continuous release, sustained release, or timed release of the active compound. In some embodiments, the implant comprises an amount of the desired compound and an ethylene vinyl acetate (EVA) copolymer, such as the copolymer designs described in U.S. Patent Nos.7,736,665 (Patel et al.), 8,852,623 (Patel et al.), 9,278,163 (Patel et al.), 10,111,830 (Patel et al.), and 10,123,971 (Patel et al.), each granted to Titan Pharmaceuticals, Inc.

[0292] In some embodiments, an implant may comprise dimensions of from 0.5 to about 7 mm in diameter. In some embodiments the devices are about 0.5 to 10 cm in length. In one embodiment, the device is from about 1 to about 3 cm in length. In one embodiment, the device is about 2 cm to about 3 cm in length. In another embodiment, the device is about 2.6 cm in length. In one embodiment, the device is about 1 to about 3 mm in diameter. In another embodiment, the device is about 2 to about 3 mm in diameter. In one embodiment, the device is about 2.4 mm in diameter. In some embodiments in which devices comprises dimensions of about 2.4 mm in total diameter and about 2.6 cm in total length, the devices each release 1 mg of pharmaceutical substance per day.

[0293] In some embodiments the implantable devices comprise from about 10% by weight to about 85% by weight a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the remainder of the implant comprises an ethylene vinyl acetate (EVA) copolymer. In some embodiments, the implant comprises about 75% active drug (a compound of Formula I, or a pharmaceutically acceptable salt thereof) and about 25% EVA. In other separate embodiments the implant comprises, respectively about 10% active drug / about 90% EVA, about 20% active drug / about 80% EVA, about 30% active drug / about 70% EVA, about 40% active drug / about 60% EVA, about 50% active drug / about 50% EVA, about 60% active drug / about 40% EVA, about 70% active drug / about 30% EVA, and about 80% active drug / about 20% EVA.

[0294] Additional embodiments comprise methods in which the active drug described herein (a compound of Formula I, or a pharmaceutically acceptable salt thereof) is administered to a subject in need thereof in a continuous release, sustained release, or timed release gel formulation, such as a hydrogel formulation. Gel carriers useful for delivering a pharmaceutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, include thermally responsive hydrogel carriers, including, but not limited to injectable block copolymer-based thermally 84 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT responsive hydrogels; carbapol (poly-acrylic acid) gels; chitosan gels, such as chitosan thermogels; nanoparticle-containing / nanocomposite hydrogels; modified poly(ethylene glycol) gels; carrageenan gels; and water-in-sorbitan-monostearate gels. Examples of useful gel carriers include those described in Sarah Gordon’s chapter Gels as Vaccine Delivery Systems at pages 203-220 in Subunit Vaccine Delivery, Springer New York 2015 (Print ISBN: 1-4939-1416-2), US Pat. No.10,272,140 (Yu et al.), US Pat. No.9,526,787 (Ko et al.), and Bobbala et al., AAPS J.2016 Jan, 18(1), pp.261- 269.

[0295] Oral gel, gel-bead, or gel droplet formulations may also be used for delivering effective amounts of the compounds herein, or pharmaceutically acceptable salts thereof, to animals, such as poultry. Examples of gel formulations that may be used with the active drugs described herein include those described in U.S. Pat. No.10,155,034 (Lee) and U.S. Pat. No.8,858,959 (Jenkins et al.).

[0296] In accordance with the various treatment methods of the disclosure, the compound can be delivered to a subject in a manner consistent with conventional methodologies associated with management of the disorder for which treatment or prevention is sought. In accordance with the disclosure herein, a prophylactically or therapeutically effective amount of the compound and / or other biologically active agent is administered to a subject in need of such treatment for a time and under conditions sufficient to prevent, inhibit, and / or ameliorate a selected disease or condition or one or more symptom(s) thereof.

[0297] Typical subjects intended for treatment with the compositions and methods of the present disclosure include humans, as well as non-human primates and other animals. To identify subjects for prophylaxis or treatment according to the methods of the disclosure, accepted screening methods are employed to determine risk factors associated with a parasitic infection to determine the status of an existing disease or condition in a subject. These screening methods include, for example, preparation of a blood smear from an individual suspected of having malaria. The blood smear is then fixed in methanol and stained with Giemsa and examined microscopically for the presence of Plasmodium infected red blood cells. These and other routine methods allow the clinician to select patients in need of therapy using the methods and pharmaceutical compositions of the disclosure.

[0298] The administration of the compound of the disclosure can be for either prophylactic or therapeutic purpose. When provided prophylactically, the compound is provided in advance of any symptom. The prophylactic administration of the compound serves to prevent or ameliorate any subsequent disease process. When provided therapeutically, the compound is provided at (or shortly after) the onset of a symptom of disease or infection.

[0299] For prophylactic and therapeutic purposes, the compound can be administered to the subject by the oral route or in a single bolus delivery, via continuous delivery (for example, continuous transdermal, mucosal or intravenous delivery) over an extended time period, or in a repeated administration protocol (for example, by an hourly, daily or weekly, repeated administration 85 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT protocol). The therapeutically effective dosage of the compound can be provided as repeated doses within a prolonged prophylaxis or treatment regimen that will yield clinically significant results to alleviate one or more symptoms or detectable conditions associated with a targeted disease or condition as set forth herein. Determination of effective dosages in this context is typically based on animal model studies followed up by human clinical trials and is guided by administration protocols that significantly reduce the occurrence or severity of targeted disease symptoms or conditions in the subject. Suitable models in this regard include, for example, murine, rat, avian, porcine, feline, non- human primate, and other accepted animal model subjects known in the art. Alternatively, effective dosages can be determined using in vitro models (for example, whole cell assays that monitor the effect of various drugs on parasite growth rate). Using such models, only ordinary calculations and adjustments are required to determine an appropriate concentration and dose to administer a therapeutically effective amount of the compound (for example, amounts that are effective to elicit a desired immune response or alleviate one or more symptoms of a targeted disease). In alternative embodiments, an effective amount or effective dose of the compound may simply inhibit or enhance one or more selected biological activities correlated with a disease or condition, as set forth herein, for either therapeutic or diagnostic purposes.

[0300] The actual dosage of the compound will vary according to factors such as the disease indication and particular status of the subject (for example, the subject's age, size, fitness, extent of symptoms, susceptibility factors, and the like), time and route of administration, other drugs or treatments being administered concurrently, as well as the specific pharmacology of the compound for eliciting the desired activity or biological response in the subject. Dosage regimens can be adjusted to provide an optimum prophylactic or therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental side effects of the compound and / or other biologically active agent is outweighed in clinical terms by therapeutically beneficial effects. A non-limiting range for a therapeutically effective amount of a compound and / or other biologically active agent within the methods and formulations of the disclosure is about 0.01 mg / kg body weight to about 20 mg / kg body weight, such as about 0.05 mg / kg to about 5 mg / kg body weight, or about 0.2 mg / kg to about 2 mg / kg body weight.

[0301] Dosage can be varied by the attending clinician to maintain a desired concentration at a target site (for example, the lungs or systemic circulation). Higher or lower concentrations can be selected based on the mode of delivery, for example, trans-epidermal, rectal, oral, pulmonary, or intranasal delivery versus intravenous or subcutaneous delivery. Dosage can also be adjusted based on the release rate of the administered formulation, for example, of an intrapulmonary spray versus powder, sustained release oral versus injected particulate or transdermal delivery formulations, and so forth. 86 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0302] The instant disclosure also includes kits, packages and multi-container units containing the herein described pharmaceutical compositions, active ingredients, and / or means for administering the same for use in the prevention and treatment of diseases and other conditions in mammalian subjects. Kits for diagnostic use are also provided. In one embodiment, these kits include a container or formulation that contains one or more of the conjugates described herein. In one example, this component is formulated in a pharmaceutical preparation for delivery to a subject. The conjugate is optionally contained in a bulk dispensing container or unit or multi-unit dosage form. Optional dispensing means can be provided, for example a pulmonary or intranasal spray applicator. Packaging materials optionally include a label or instruction indicating for what treatment purposes and / or in what manner the pharmaceutical agent packaged therewith can be used.

[0303] The compounds and pharmaceutical compositions herein may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.

[0304] In some embodiments, a human daily dose may be from about 0.1 mg to about 1,000 mg. In other embodiments, a human daily dose may be from about 0.1 mg to about 500 mg. In other embodiments, the human daily dose may be from about 1 mg to about 250 mg. In still other embodiments, the human daily dose may be from about 1 mg to about 200 mg. In further embodiments, the human daily dose may be from the group of ranges of from a) about 1 mg to about 150 mg; b) about 1 mg to about 100 mg; c) about 1 mg to about 75 mg; d) about 1 mg to about 50 mg; e) about 5 mg to about 50 mg; f) about 5 mg to about 40 mg; g) about 1 mg to about 25 mg; and about 1 mg to about 20 mg.

[0305] In other embodiments, the doses listed above for daily use may be administered as once- weekly or twice-weekly (semi-weekly) doses. In some embodiments, the compound may be delivered bi-weekly (every other week) as a prophylaxis for the disease states described herein. Non-limiting examples of once weekly, twice weekly, or bi-weekly doses include 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and 200 mg doses.

[0306] In each dosage range, the pharmaceutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, may comprise a single daily administration or divided over two, three, or four administrations per day.

[0307] Synthetic Methods: 87 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT15 3 7 15Scheme 1: (a) ethylacetoacetate, sodium ethoxide, 1-bromoheptane, ethanol, reflux, 24 hours; (b) 1. aniline, cat. HCl, benzene, reflux, 24-48 hours, 2. Dowtherm A, boiling, 10 minutes; (c) chloromethyl ethyl carbonate, tetrabutyl ammonium iodide, potassium carbonate and DMF, 60°C, 24 h.Scheme 2: (a) chloromethyl ethyl carbonate, tetrabutyl ammonium iodide, potassium carbonate and DMF, 60°C, 24 h.

[0308] General Chemistry. Unless otherwise stated all chemicals and reagents were from Sigma- Aldrich Chemical Company in St. Louis, MO (USA), Combi-Blocks, San Diego (CA), or TCI America, Portland (OR) and were used as received.4(1H)-Quinolone 1 and 4,4,5,5-tetramethyl-2-(4- (4-(trifluoromethoxy)phenoxy)phenyl)-1,3,2-dioxaborolane (15k) were obtained as previously reported12. Melting points were obtained in the Optimelt Automated Melting point system from Stanford Research Systems, Sunnyvale, CA (USA). Analytical TLC utilized Merck 60F-254250 micron precoated silica gel plates and spots were visualized under 254 nm UV light. GC-MS was obtained using an Agilent Technologies 7890B gas chromatograph (30 m, DBS column set at either 100°C or 200°C for 2 min, then at 30°C / min to 300°C with inlet temperature set at 250°C) with an Agilent Technologies 5977A mass-selective detector operating at 70 eV. Flash chromatography over 88 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT silica gel column was performed using an Isolera One flash chromatography system from Biotage, Uppsala, Sweden.1H-NMR spectra were obtained using a Bruker 400 MHz Avance NEO NanoBay NMR spectrometer operating at 400.14 MHz. The NMR raw data were analyzed using the iNMR Spectrum Analyst software.1H chemical shifts are reported in parts per million (ppm) relative to internal tetramethylsilane (TMS) standard or residual solvent peak. Coupling constant values (J) are reported in hertz (Hz). Decoupled19F operating at 376 MHz was also obtained for compounds containing fluorine (data not shown). HPLC analyses were performed using an Agilent 1260 Infinity instrument with detection at 254 nm and a Phenomenex, Luna® 5 µm C8(2) 100 Å reverse phase LC column 150 x 4.6 mm at 40°C, and eluted with a gradient of A / B at 25% : 75% to A / B at 10% : 90% (A:0.05% formic acid in milliQ water, B: 0.05% formic acid in methanol). All compounds were at least >95% pure for in vitro testing and >98% pure for in vivo testing as determined by GC-MS,1H- NMR and HPLC.

[0309] Ethyl 2-n-heptylacetoacetate (1). A solution of ethyl acetoacetate (0.04 mol), sodium ethoxide (1 equivalent) and 1-bromoheptane (1 equivalent) in alcohol was refluxed for 24 hours. The solvent was removed in vacuo, and the resulting residue was stirred with 150 ml of hexanes and filtered. The resulting filtrate was concentrated in vacuo to give crude 1, which was used without further purification.

[0310] Ethyl 2-n-alkylacetoacetates with n-alkyl = n-butyl, n-pentyl, n-hexyl, n-octyl, n-nonyl-, n-decyl, n-undecyl and n-dodecyl were obtained by a method analogous with that for the preparation of ethyl 2-n-heptylacetoacetate. The end of the reaction was determined by checking the pH of the reaction mixture: when a pH-paper strip moistened with the reaction solution indicated a pH < 7, the reaction was ended. In each case, the crude product was used in the subsequent condensation with an aniline.

[0311] General Procedure A for the synthesis of quinolone ELQ: A mixture of crude 1, aniline (1 equivalent, calculated from ethyl acetoacetate used to prepare 1), benzene (0.45 molar) and catalytic concentrated p-toluenesulfonic acid was refluxed for 24-48 hours using a Dean-Stark trap to azeotropically remove the water formed during the condensation reaction. The reaction was complete when starting material was consumed (monitored by GC-MS). The reaction was concentrated in vacuo, and the resulting residue was added to 65 ml of boiling Dowtherm A (0.62 molar) over 4 minutes and boiled for another 10 minutes. After cooling, the product ELQ was isolated by filtration, washed with hexanes and recrystallized from aqueous alcohol.

[0312] General Procedure B for the synthesis of the alkoxy carbonate pro-drug: A stirred mixture of 4-(1H)-quinolone ELQ (1 eq), tetrabutylammonium iodide (2 eq), chloromethyl ethylcarbonate (2 eq) and dry potassium carbonate (2 eq) in DMF was heated at 60°C until TLC showed no more starting material remained, usually over 24 hrs. The mixture was cooled to room temperature, filtered and the filtrate concentrated to dryness to give of an oil. The resulting residue was stirred with ethyl 89 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT acetate for 30 minutes and the insoluble tetra-butyl ammonium iodide filtered and wash with ethyl acetate. The filtrate was concentrated to dryness and purified by flash chromatography using a gradient of ethyl acetate / hexane as eluent to give the desired prodrug. If the resulting prodrugs were not pure enough by TLC, GM-MS and NMR they can be obtained in pure form by recrystallization from hexane / ethyl acetate.3-n-Heptyl-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-100, Endochin). General Procedure A.1H- NMR (400 MHz; DMSO-d6): δ 11.16 (s, 1H), 7.94-7.92 (m, 1H), 6.86-6.81 (m, 2H), 3.83 (s, 3H), 2.44 (t, J = 7.5 Hz, 2H), 2.33 (s, 3H), 1.38-1.25 (m, 10H), 0.86 (t, J = 6.9 Hz, 3H).3-n-Hexyl-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-108): General procedure A.1H-NMR (400 MHz; DMSO-d6): δ 11.16 (s, 1H), 7.94-7.92 (m, 1H), 6.87-6.80 (m, 2H), 3.83 (s, 3H), 2.44 (t, J = 7.4 Hz, 2H), 2.33 (s, 3H), 1.37-1.28 (m, 8H), 0.86 (t, J = 6.6 Hz, 3H).7-methoxy-2-methyl-3-n-pentylquinolin-4(1H)-one (ELQ-114): General procedure A.1H-NMR (400 MHz; DMSO-d6): δ 11.19 (s, 1H), 7.94-7.92 (m, 1H), 6.86-6.80 (m, 2H), 3.83 (s, 3H), 2.44 (t, J = 7.6 Hz, 2H), 2.34 (s, 3H), 1.39-1.27 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H).3-n-Butyl-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-115): General procedure A:1H-NMR (400 MHz; DMSO-d6): δ 11.16 (s, 1H), 7.94-7.92 (m, 1H), 6.85-6.80 (m, 2H), 3.83 (s, 3H), 2.45 (t, J = 7.4 Hz, 2H), 2.34 (s, 3H), 1.36-1.31 (m, 4H), 0.90 (t, J = 7.1 Hz, 3H). 90 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT5,7-Difluoro-3-n-heptyl-2-methylquinolin-4(1H)-one (ELQ-121). General Procedure A.1H-nmr spectrum (400 MHz, (CD3)2SO, Si(CH3)4=0): δCH3(pos.2)=2.33 ppm, s, 3H; C7-chain: δCH2(pos.3)=2.41, dist. t, 2H; δ(CH2)5(middle)= 1.2-1.4, indistinct features, 10H; δ CH3= 0.87, t, J = 6.8 Hz, 3H. δ6= 6.95, d-d-d, J56=12, J67≈ 10, J68≈ 2.5; δ8 ≈ 7.0, d-d-d, J58=1.35 (not resolved in 19Fspectrum), J68=2.5, J78=10.0, H(6) + H(8) = 2H; δNH= 11.4, s(br.), 0.85H.19F-nmr spectrum (400 MHz, (CD3)2SO, CCl3F=0): δ5= −108,6, t, J = 12.7 Hz,1F; δ7= −106,3, quartett, J=10.6 Hz, 1F.6-Fluoro-3-n-heptyl-2-methylquinolin-4(1H)-one (ELQ-131). General Procedure A.1H-NMR (400 MHz; DMSO-d6): δ 11.54 (s, 1H), 7.67 (dd, J = 9.5, 2.9 Hz, 1H), 7.56-7.46 (m, 2H), 2.47 (t, J = 7.6 Hz, 2H), 2.39 (s, 3H), 1.38-1.24 (m, 10H), 0.87-0.84 (m, 3H).19F-NMR (376 MHz; DMSO): δ -119.3 (m).7-methoxy-2-methyl-3-n-undecylquinolin-4(1H)-one (ELQ-145): General procedure A.1H-NMR (400 MHz; DMSO-d6): δ 11.16 (s, 1H), 7.94-7.92 (m, 1H), 6.86-6.80 (m, 2H), 3.83 (s, 3H), 2.47-2.39 (m, 2H), 2.33 (s, 3H), 1.36-1.24 (m, 18H), 0.89-0.81 (m, 3H).7-Chloro-5-fluoro-3-n-heptyl-2-methylquinolin-4(1H)-one (ELQ-212). General Procedure A.1H- NMR (400 MHz; DMSO-d6): δ 11.44 (s, 1H), 7.28 (dd, J = 1.8, 1.3 Hz, 1H), 7.07 (dd, J = 11.6, 2.0 91 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT Hz, 1H), 2.40 (t, J = 7.4 Hz, 2H), 2.33 (s, 3H), 1.37-1.25 (m, 10H), 0.86 (t, J = 6.9 Hz, 3H).19F-NMR (376 MHz; DMSO): δ -111.2 (m).92 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT ((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-331). Synthesized using a published procedure (Frueh et al. ACS Infect Dis 2017).5,7-difluoro-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)-phenyl)quinolin- 4(1H)-one (ELQ-400). Synthesized using a published procedure (Stickles et al. Am J Trop Med Hyg 2015).Ethyl (((6-fluoro-3-heptyl-2-methylquinolin-4-yl)oxy)methyl) carbonate (ELQ-403). Following the general Procedure B using ELQ-131 (2.75 g, 10 mmol, 1eq), tetrabutylammonium iodide (7.38 g, 20 mmol, 2 eq), chloromethyl ethylcarbonate (2.78 g, 20 mmol, 2 eq) and dry potassium carbonate (2.76g, 20 mmol, 2 eq) in DMF (150 ml) was heated at 60°C for 72 hours. The residue was treated with ethyl acetate (50 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane 4 / 6 to give pure ELQ-403 (1.55 g, 41 %) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.97 (dd, J = 9.2, 5.3 Hz, 1H), 7.54 (dd, J = 9.5, 2.8 Hz, 1H), 7.39 (ddd, J = 9.2, 8.3, 2.8 Hz, 1H), 5.77 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 2.82-2.78 (m, 2H), 2.73 (s, 3H), 1.57-1.28 (m, 13H), 0.89 (t, J = 6.96-Chloro-3-n-heptyl-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-432, WR-109,878). General Procedure A. The crude product was boiled with methanol, filtered and subsequently re-crystallized 93 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT from d.m.f.1H-NMR (400 MHz; DMSO-d6): δ 11.35 (s, 1H), 7.96 (s, 1H), 6.99 (s, 1H), 3.93 (s, 3H), 2.44 (t, J = 7.5 Hz, 2H), 2.34 (s, 3H), 1.38-1.22 (m, 10H), 0.86 (t, J = 6.9 Hz, 3H).6-Fluoro-3-n-heptyl-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-433). General Procedure A. δ 11.34 (s, 1H), 7.65 (d, J = 11.9 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H), 3.92 (s, 3H), 2.44 (t, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.36−1.25 (m, 9H), 0.85 (t, J = 6.3 Hz, 3H).5,7-Difluoro-2-methyl-3-undecylquinolin-4(1H)-one (ELQ-437). General Procedure A. δ 7.01 (ddd, J = 12.0, 9.0, 3.0 Hz, 1H), (ddd,J = 1.6, 9.6, 3 Hz, 1H), 2.74 (s, 3H), 2.93 (m, 2H), 1.2−1.6(m, 18H), 0.88 (t, J = 7 Hz, 3H).((5,7-Difluoro-3-heptyl-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-453). Following the general Procedure B using ELQ-121 (2.93 g, 10 mmol, 1eq), tetrabutylammonium iodide (7.38 g, 20 mmol, 2 eq), chloromethyl ethylcarbonate (2.78 g, 20 mmol, 2 eq) and dry potassium carbonate (2.76g, 20 mmol, 2 eq) in DMF (50 ml) was heated at 60°C for 24 hours. The residue was treated with ethyl acetate (50 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane 1 / 9 to give pure ELQ-453 (3.38 g, 86 %) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.49 (ddd, J = 9.7, 2.5, 1.4 Hz, 1H), 6.99 (ddd, J = 12.2, 8.9, 2.5 Hz, 1H), 5.78 (d, J = 1.9 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.82-2.78 (m, 2H), 2.73 (s, 3H), 1.59-1.28 (m, 13H), 0.91 (t, J = 6.9 Hz, 3H). 94 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT((5,7-difluoro-2-methyl-3-undecylquinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-456): Following the general Procedure B using ELQ-437 (3.49 g, 10.0 mmol, 1eq), tetrabutylammonium iodide (7.38 g, 20.0 mmol, 2 eq), chloromethyl ethylcarbonate (2.78 g, 20.0 mmol, 2 eq) and dry potassium carbonate (2.76 g, 20.0 mmol, 2 eq) in DMF ( 150 ml) was heated at 60°C for 18 hours. The residue was treated with ethyl acetate (100 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane to give pure ELQ-456 (4.0 g, 89 %) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.46 (ddd, J = 9.7, 2.5, 1.4 Hz, 1H), 6.97 (ddd, J = 12.2, 8.9, 2.5 Hz, 1H), 5.75 (d, J = 1.9 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 2.79-2.75 (m, 2H), 2.71 (s, 3H), 1.58-1.50 (m, 2H), 1.42-1.23 (m, 19H), 0.88((5,7-difluoro-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-458): Following the general Procedure B using ELQ-400 (10.6 g, 23.7 mmol, 1eq), tetrabutylammonium iodide (17.5 g, 47.4 mmol, 2 eq), chloromethyl ethylcarbonate (6.5 g, 47.4 mmol, 2 eq) and dry potassium carbonate (6.5 g, 47.4 mmol, 2 eq) in DMF ( 200 ml) was heated at 60°C for 24 hours. The residue was treated with ethyl acetate (250 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane to give ELQ-458 (10.74 g). The product was further crystallized in ethyl acetate / hexane to give pure ELQ-458 (9.31 g) as a white solid. The mother liquor yielded an additional 766 mg for a total ELQ-458 (10.08 g 77 %).1H-NMR (400 MHz; CDCl3): δ 7.53 (ddd, J = 9.7, 2.5, 1.4 Hz, 1H), 7.35-7.32 (m, 2H), 7.26-7.23 (m, 2H), 7.13-7.09 (m, 4H), 7.01 (ddd, J = 11.8, 9.0, 2.7 Hz, 1H), 5.41 (d, J = 1.2 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 2.53 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 95 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTEthyl (((6-fluoro-3-heptyl-7-methoxy-2-methylquinolin-4-yl)oxy)methyl) carbonate (ELQ-465). Following the general Procedure B using ELQ-433 (1.22 g, 4.0 mmol, 1eq), tetrabutylammonium iodide (2.95 g, 8.0 mmol, 2 eq), chloromethyl ethylcarbonate (1.11 g, 8.0 mmol, 2 eq) and dry potassium carbonate (1.10 g, 8.0 mmol, 2 eq) in DMF (50 ml) was heated at 60°C for 24 hours. The residue was treated with ethyl acetate (50 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane 5 / 5. Second purification by flash chromatography using a gradient of ethyl acetate / hexane 3 / 7 to give pure ELQ-465 (1.0 g, 61 %) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.54 (d, J = 11.9 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 5.75 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 2.76 (t, J = 7.8 Hz, 2H), 2.70 (s, 3H), 1.58-1.25 (m, 13H), 0.89 (t, J = 5.9 Hz, 3H).((6-Chloro-3-heptyl-7-methoxy-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-613). Following the general Procedure B using ELQ-432 (644 mg, 2.0 mmol, 1eq), tetrabutylammonium iodide (1.48 g, 4.0 mmol, 2 eq), chloromethyl ethylcarbonate (556 mg, 4.0 mmol, 2 eq) and dry potassium carbonate (556 mg, 4.0 mmol, 2 eq) in DMF (25 ml) was heated at 60°C for 24 hours. The residue was treated with ethyl acetate (25 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane 3 / 7 to give pure ELQ-613 (510 mg, 60%) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.94 (s, 1H), 7.41 (s, 1H), 5.78 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 2.80- 2.76 (m, 2H), 2.73 (s, 3H), 1.61-1.28 (m, 13H), 0.91 (t, J = 6.9 Hz, 3H).96 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT ((3-butyl-6-fluoro-7-methoxy-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-614): Following the general Procedure B using ELQ-250 (526 mg, 2.0 mmol, 1eq), tetrabutylammonium iodide (1.48 g, 4.0 mmol, 2 eq), chloromethyl ethylcarbonate (556 mg, 4.0 mmol, 2 eq) and dry potassium carbonate (556 mg, 4.0 mmol, 2 eq) in DMF ( 25 ml) was heated at 60°C for 24 hours. The residue was treated with ethyl acetate (50 ml) and purified by flash chromatography twice using a gradient of ethyl acetate / hexane to give pure ELQ-614(237 mg, 32%) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.54 (d, J = 11.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 5.75 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 2.79-2.75 (m, 2H), 2.70 (s, 3H), 1.57-1.51 (m, 2H), 1.47-1.41 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H).((7-Chloro-5-fluoro-3-heptyl-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-617). Following the general Procedure B using ELQ-212 (310 mg, 1.0 mmol, 1eq), tetrabutylammonium iodide (740 mg, 2.0 mmol, 2 eq), chloromethyl ethylcarbonate (278 mg, 2.0 mmol, 2 eq) and dry potassium carbonate (278 mg, 2.0 mmol, 2 eq) in DMF (25 ml) was heated at 60°C for 24 hours. The residue was treated with ethyl acetate (25 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane 3 / 7 to give pure ELQ-617 (266 mg, 65%) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.83 (dd, J = 1.9, 1.2 Hz, 1H), 7.16 (dd, J = 11.9, 2.0 Hz, 1H), 5.77 (d, J = 1.9 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.81-2.77 (m, 2H), 2.73 (s, 3H), 1.58-1.30 (m, 13H), 0.91 (t, J = 6.9 Hz, 3H).((3-butyl-6-chloro-7-methoxy-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-618): Following the general Procedure B using ELQ-285 (560 mg, 2.0 mmol, 1eq), tetrabutylammonium iodide (1.48 g, 4.0 mmol, 2 eq), chloromethyl ethylcarbonate (556 mg, 4.0 mmol, 2 eq) and dry potassium carbonate (556 mg, 4.0 mmol, 2 eq) in DMF ( 25 ml) was heated at 60°C for 24 hours. The residue was treated with ethyl acetate (50 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane to give pure ELQ-618 (90 mg, 12%) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.92 (s, 1H), 7.39 (s, 1H), 5.76 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.01 (s, 3H), 2.79-2.75 97 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT (m, 2H), 2.69 (t, J = 1.6 Hz, 3H), 1.57-1.51 (m, 2H), 1.48-1.41 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H).Ethyl (((5-fluoro-3-heptyl-7-methoxy-2-methylquinolin-4-yl)oxy)methyl) carbonate (ELQ-621). Following the general Procedure B using ELQ-622 (610 mg, 2.0 mmol, 1eq), tetrabutylammonium iodide (1.48 g, 4.0 mmol, 2 eq), chloromethyl ethylcarbonate (556 mg, 4.0 mmol, 2 eq) and dry potassium carbonate (556 mg, 4.0 mmol, 2 eq) in DMF (25 ml) was heated at 60°C for 24 hours. The residue was treated with ethyl acetate (25 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane 3 / 7 to give pure ELQ-621 (539 mg, 66%) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.19 (d, J = 2.3 Hz, 1H), 6.83 (dd, J = 13.7, 2.4 Hz, 1H), 5.77 (d, J = 1.8 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 2.79-2.75 (m, 2H), 2.71 (s, 3H), 1.59-1.26 (m, 13H), 0.91 (t, J = 6.8 Hz, 3H).5-Fluoro-3-n-heptyl-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-622). General Procedure A. The isomeric 5-methoxy compound was produced in only trace amounts and was removed from the crude product bt crystallization.1H-NMR (400 MHz; DMSO-d6): δ 11.18 (s, 1H), 6.67 (s, 1H), 6.57 (d, JF= 13.3 Hz, 1H), 3.82 (s, 3H), 2.38 (t, J = 7.2 Hz, 2H), 2.30 (s, 3H), 1.34-1.26 (m, 10H), 0.86 (t, J = 6.2 Hz, 3H).19F NMR (376 MHz; DMSO): δ -112.2 (d, JH= 13.6 Hz)7-methoxy-2-methyl-3-n-octylquinolin-4(1H)-one (ELQ-684): General procedure A.1H-NMR (400 MHz; DMSO-d6): δ 11.16 (s, 1H), 7.94-7.92 (m, 1H), 6.85-6.81 (m, 2H), 3.83 (s, 3H), 2.47-2.40 (m, 2H), 2.33 (s, 3H), 1.38-1.25 (m, 12H), 0.89-0.81 (m, 3H). 98 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTEthyl (((3-heptyl-7-methoxy-2-methylquinolin-4-yl)oxy)methyl) carbonate (ELQ-701). Following the general Procedure B using ELQ-100 (574 mg, 2.0 mmol, 1eq), tetrabutylammonium iodide (1.48 g, 4.0 mmol, 2 eq), chloromethyl ethylcarbonate (556 mg, 4.0 mmol, 2 eq) and dry potassium carbonate (556 mg, 4.0 mmol, 2 eq) in DMF (25 ml) was heated at 60°C for 24 hours. The residue was treated with ethyl acetate (25 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane 3 / 7 to give pure ELQ-621 (359 mg, 46%) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.83 (d, J = 9.1 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 9.1, 2.5 Hz, 1H), 5.79 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 2.80-2.76 (m, 2H), 2.73 (s, 3H), 1.60-1.27 (m, 13H), 0.90 (t, J = 6.9 Hz, 3H).7-methoxy-2-methyl-3-n-nonylquinolin-4(1H)-one (ELQ-705): General procedure A.1H-NMR (400 MHz; DMSO-d6): δ 11.17 (s, 1H), 7.94-7.92 (m, 1H), 6.86-6.80 (m, 2H), 3.83 (s, 3H), 2.47-2.40 (m, 2H), 2.33 (s, 3H), 1.37-1.24 (m, 14H), 0.89-0.81 (m, 3H).3-n-decyl-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-706): General procedure A.1H-NMR (400 MHz; DMSO-d6): δ 11.17-11.15 (m, 1H), 7.94-7.92 (m, 1H), 6.86-6.81 (m, 2H), 3.83 (s, 3H), 2.47- 2.39 (m, 2H), 2.33 (s, 3H), 1.38-1.24 (m, 16H), 0.89-0.81 (m, 3H).3-n-dodecyl-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-719): General procedure A.1H-NMR (400 MHz; DMSO-d6): δ 11.18 (s, 1H), 7.94-7.92 (m, 1H), 6.85-6.82 (m, 2H), 3.83 (s, 3H), 2.48-2.38 (m, 2H), 2.33 (s, 3H), 1.38-1.23 (m, 20H), 0.89-0.81 (m, 3H). 99 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTScheme 3: (a) chloromethyl acetate, tetrabutyl ammonium iodide, potassium carbonate and DMF, 60°C, 24 h. (b) chloromethyl pivalate, tetrabutyl ammonium iodide, potassium carbonate and DMF, 60°C, 24 h. (c) sodium hydride 60% dispersion in paraffin liquid, pivaloyl chloride and dry THF, 60oC, 1-5 h.

[0313] General Procedure A for the synthesis of the pivaloyl ester pro-drug : To a stirred mixture of (1H)-quinolone ELQ (1 eq) in dry THF was slowly (5-10 minutes) portion wise sodium hydride 60% dispersion in paraffin liquid (2 eq). The mixture was heated to 60°C for 30 minutes. Then pivaloyl chloride (2 eq) was added and heated at 60°C until TLC and / or HPLC showed no more starting material remained, usually over 1-5 h. The mixture was cooled to room temperature and water was added. The organic layer was separated and concentrated under vacuum to give an aqueous suspension. Ethyl acetate was added and the organic layer was separated, dried over Mg2SO4, filtered, concentrated under vacuum to dryness and purified by flash chromatography using a gradient of ethyl acetate / hexane as eluent to give the desired prodrug. If the resulting prodrugs were not pure enough by TLC, GM-MS and NMR they can be obtained in pure form by recrystallization from hexane / ethyl acetate.

[0314] General Procedure B for the synthesis of the alkoxy ester pro-drug: A stirred mixture of 4-(1H)-quinolone ELQ (1 eq), tetrabutylammonium iodide (2 eq), chloromethyl ester (2 eq) and dry potassium carbonate (2 eq) in DMF was heated at 60°C until TLC and / or HPLC showed no more 100 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT starting material remained, usually over 24 hrs. The mixture was cooled to room temperature, filtered and the filtrate concentrated to dryness to give of an oil. The resulting residue was stirred with ethyl acetate for 30 minutes and the insoluble tetra-butyl ammonium iodide filtered and wash with ethyl acetate. The filtrate was concentrated to dryness and purified by flash chromatography using a gradient of ethyl acetate / hexane as eluent to give the desired prodrug. If the resulting prodrugs were not pure enough by TLC, GM-MS and NMR they can be obtained in pure form by recrystallization from hexane / ethyl acetate.5,7-difluoro-3-heptyl-2-methylquinolin-4-yl pivalate (ELQ-849): Following the general procedure A using ELQ-121 (2.93 g, 10 mmol, 1 eq), 60 % sodium hydride (800 mg, 20 mmol, 2 eq) and pivaloyl chloride (2.42 g, 20 mmol, 2 eq) in dry THF (100 ml) was heated at 60oC for 1h. Water (10 ml) and ethyl acetate (100 ml) were used in the work up of the reaction to give a yellow oil (4.69 g) and purified by flash chromatography using a gradient of ethyl acetate / hexane to give pure ELQ-849 (2.62 g, 69 %) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.47 (ddd, J = 9.7, 2.3, 1.4 Hz, 1H), 6.92 (ddd, J = 11.9, 9.1, 2.6 Hz, 1H), 2.73 (s, 3H), 2.72-2.67 (m, 1H), 2.58-2.50 (m, 1H), 1.60-1.51 (m, 2H), 1.45 (d, J = 0.9 Hz, 9H), .6-chloro-3-heptyl-7-methoxy-2-methylquinolin-4-yl pivalate (ELQ-850): Following the general procedure A using ELQ-285 (3.22 g, 10 mmol, 1 eq), 60 % sodium hydride (800 mg, 20 mmol, 2 eq) and pivaloyl chloride (2.42 g, 20 mmol, 2 eq) in dry THF (100 ml) was heated at 60oC for 5 h. Water (10 ml) and ethyl acetate (100 ml) were used in the work up of the reaction to give a yellow oil (5.9 g) and purified by flash chromatography using a gradient of ethyl acetate / hexane to give pure ELQ-850 (2.78 g, 68 %) as a white solid. 101 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT((5,7-difluoro-3-heptyl-2-methylquinolin-4-yl)oxy)methyl acetate (ELQ-851): Following the general procedure B using ELQ-121 (2.93 g, 10 mmol, 1 eq), tetrabutylammonium iodide (7.38 g, 20 mmol, 2 eq), chloromethyl acetate (2.17 g, 20 mmol, 2 eq) and dry potassium carbonate (2.76 g, 20 mmol, 2 eq) in DMF (75 ml) was heated at 60°C for 7 days. No more progression of the reaction was observed after 96 hours as monitored by HPLC. The residue was treated with ethyl acetate (50 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane to give pure ELQ-851 (528 mg, 14%) as a white solid.1H-NMR (400 MHz; CDCl3): δ 7.49-7.47 (m, 1H), 6.98 (ddd, J = 12.1, 8.9, 2.6 Hz, 1H), 5.74 (d, J = 1.8 Hz, 2H), 2.80-2.76 (m, 2H), 2.72 (s, 3H), 2.09 (s, 3H), 1.58-1.51 (m, 2H), 1.44-1.23 (m, 8H), 0.89 (t, J = 6.9 Hz, 3H).((6-chloro-3-heptyl-7-methoxy-2-methylquinolin-4-yl)oxy)methyl acetate (ELQ-852)((5,7-difluoro-3-heptyl-2-methylquinolin-4-yl)oxy)methyl pivalate (ELQ-853): Following the general procedure B using ELQ-121 (2.93 g, 10 mmol, 1 eq), tetrabutylammonium iodide (7.38 g, 20 mmol, 2 eq), chloromethyl pivalate (3.02 g, 20 mmol, 2 eq) and dry potassium carbonate (2.76 g, 20 mmol, 2 eq) in DMF (75 ml) was heated at 60°C for 24 hours. The residue was treated with ethyl acetate (50 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane to give pure ELQ- 853 (3.36 g, 83%) a viscous white oil.1H-NMR (400 MHz; CDCl3): δ 7.49-7.47 (m, 1H), 6.97 (ddd, J = 11.9, 9.0, 2.7 Hz, 1H), 5.76 (d, J = 1.8 Hz, 2H), 2.81-2.77 (m, 2H), 2.71 (s, 3H), 1.57-1.49 (m, 2H), 1.42-1.26 (m, 8H), 1.18 (s, 9H), 0.89 (t, J = 6.9 Hz, 3H). 102 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT((6-chloro-3-heptyl-7-methoxy-2-methylquinolin-4-yl)oxy)methyl pivalate (ELQ-854): Following the general procedure B using ELQ-285 (3.22 g, 10 mmol, 1 eq), tetrabutylammonium iodide (7.38 g, 20 mmol, 2 eq), chloromethyl pivalate (3.02 g, 20 mmol, 2 eq) and dry potassium carbonate (2.76 g, 20 mmol, 2 eq) in DMF (75 ml) was heated at 60°C for 4 days. No more progression of the reaction was observed after 48 hours as monitored by HPLC. The residue was treated with ethyl acetate (50 ml) and purified by flash chromatography using a gradient of ethyl acetate / hexane to give pure ELQ-854 (2.29 g) as a white viscous oil. The overlap fractions were combined and purified by purified by flash chromatography using a gradient of ethyl acetate / hexane to an additional give pure ELQ-854 (0.748 g) with a total ELQ-854 (3.04g, 70%).1H-NMR (400 MHz; CDCl3): δ 8.01 (s, 1H), 7.39 (s, 1H), 5.76 (s, 2H), 4.01 (s, 3H), 2.79-2.75 (m, 2H), 2.71 (s, 3H), 1.58-1.52 (m, 2H), 1.43-1.26 (m, 8H), 1.18 (s, 9H), 0.89 (t, J = 6.9 Hz, 3H).

[0315] In some embodiments, the technology described herein relates to a pharmaceutical composition comprising at least one compound as described herein, and optionally a pharmaceutically acceptable carrier. In some embodiments, the active ingredients of the pharmaceutical composition comprise at least one compound as described herein. In some embodiments, the active ingredients of the pharmaceutical composition consist essentially of at least one compound as described herein. In some embodiments, the active ingredients of the pharmaceutical composition consist of at least one compound as described herein. In some embodiments, the active ingredients of the pharmaceutical composition comprise a compound as described herein. In some embodiments, the active ingredients of the pharmaceutical composition consist essentially of a compound as described herein. In some embodiments, the active ingredients of the pharmaceutical composition consist of a compound as described herein. In some embodiments, the active ingredients of the pharmaceutical composition comprise a plurality of compounds as described herein. In some embodiments, the active ingredients of the pharmaceutical composition consist essentially of a plurality of compounds as described herein. In some embodiments, the active ingredients of the pharmaceutical composition consist of a plurality of compounds as described herein.

[0316] In some embodiments, the technology described herein relates to a coating composition comprising at least one compound as described herein, and optionally a coating medium. In some embodiments, the active ingredients of the coating composition comprise at least one compound as described herein. In some embodiments, the active ingredients of the coating composition consist essentially of at least one compound as described herein. In some embodiments, the active 103 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT ingredients of the coating composition consist of at least one compound as described herein. In some embodiments, the active ingredients of the coating composition comprise a compound as described herein. In some embodiments, the active ingredients of the coating composition consist essentially of a compound as described herein. In some embodiments, the active ingredients of the coating composition consist of a compound as described herein. In some embodiments, the active ingredients of the coating composition comprise a plurality of compounds as described herein. In some embodiments, the active ingredients of the coating composition consist essentially of a plurality of compounds as described herein. In some embodiments, the active ingredients of the coating composition consist of a plurality of compounds as described herein.

[0317] In one respect, the present invention relates to the herein described compositions, methods, and respective component(s) thereof, as essential to the technology, yet open to the inclusion of unspecified elements, essential or not ("comprising). In some embodiments of any of the aspects, other elements to be included in the description of the composition, method or respective component thereof are limited to those that do not materially affect the basic and novel characteristic(s) of the technology (e.g., the composition, method, or respective component thereof “consists essentially of” the elements described herein). This applies equally to steps within a described method as well as compositions and components therein. In other embodiments of any of the aspects, the compositions, methods, and respective components thereof, described herein are intended to be exclusive of any element not deemed an essential element to the component, composition or method (e.g., the composition, method, or respective component thereof “consists of” the elements described herein). This applies equally to steps within a described method as well as compositions and components therein.

[0318] Definitions

[0319] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification shall prevail.

[0320] The term "alkyl" refers to a straight or branched hydrocarbon. Nonlimiting examples include alkyl groups having 1 to 12 carbon atoms (i.e, C1-C12alkyl), 1 to 10 carbon atoms (i.e, C1-C10alkyl), 1 to 8 carbon atoms (i.e., C1-C8alkyl), 1 to 6 carbon atoms (i.e., C1-C6alkyl), 5 to 9 carbon atoms (i.e, C5-C9alkyl), 4 to 12 carbon atoms (i.e, C4-C12alkyl), 4 to 10 carbon atoms (i.e, C4-C10104 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT alkyl), 1 to 4 carbon atoms (i.e, C1-C14alkyl), and 6 to 8 carbon atoms (i.e, C6-C8alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, --CH3), ethyl (Et, -CH2CH3), 1- propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, - CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, --CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, - CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, - CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2- butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (- C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (- CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (- CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (- CH(CH3)C(CH3)3, hexyl (-(CH2)5CH3), heptyl (-(CH2)6CH3), (octyl (-(CH2)7CH3), nonyl (- (CH2)8CH3), and decyl (-(CH2)9CH3). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, --CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -- CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, - C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (- CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3- methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (- CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (- CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (- CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (- C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (- C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, hexyl (-(CH2)5CH3), heptyl (- (CH2)6CH3), (octyl (-(CH2)7CH3), nonyl (-(CH2)8CH3), decyl (-(CH2)9CH3), undecyl (-(CH2)10CH3), and dodecyl (-(CH2)11CH3).

[0321] The term "halogen" or "halo" refers and element or substituent selected from the group of F, Cl, Br, and I.

[0322] The term “coating composition” refers to a composition comprising one or more of the ELQ compounds described herein, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, and an effective medium that allows application to a surface to form a stable surface coating that allows an insect, such as a mosquito, particularly a female mosquito, upon landing or settling on such surface coating, to contact an effective amount of the ELQ compound(s) associated with the surface coating. The coating composition may be in any form that allows 105 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT application to a desired surface to form the desired coating, including, but not limited to, solutions, dispersions, suspensions, emulsions, pastes, slurries, paints, polymerizable materials, resins, foams, particulates (including hydrophobic solid particles), granules, colloids, gels, hydrogels, films, powder coatings (water-dispersible or other medium-dispersible powders), oils, fatty acids, wax (including animal-based waxes, plant-based waxes, mineral waxes, synthetic waxes, or a waxes containing organic acids and / or esters), dispersible and / or modified starch, surfactants, gums, and other media useful in creating such surface coatings. In some embodiments, the coating composition may be applied as a liquid or other fluid or spreadable material and allowed to dry to the final surface coating. In other embodiments, the coating composition may be applied, followed by hardening through thermal or ultraviolet light treatment.

[0323] The terms “contacting” and “contact” and the like refer to situations in which a mosquito comes into physical contact with a compound of Formula (I) or any of the other ELQ compounds described herein, including 5,7-difluoro-3-heptyl-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-453) and 6-chloro-3-heptyl-7-methoxy-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-613). Such contact may occur upon a mosquito landing on or otherwise touching with any portion of its body a surface or coating onto or into which an ELQ compound or an ELQ compound- comprising composition described herein has been applied. In some embodiments, this contact may be a topical contact, such as a “tarsal contact” in which the tarsus of one or more of a mosquito’s legs contacts a composition or surface coating described herein and an effective amount of a compound of Formula (I), as described herein, is transferred to the mosquito. In some embodiments, the tarsal contact results in a tarsal absorption of the compound of Formula (I), or salt or other form thereof.

[0324] The term “trap” refers to any device, structure, or arrangement that has one or more means for attracting a mosquito and a surface or coating onto or into which an ELQ compound or an ELQ compound-comprising composition described herein has been applied, wherein the means for attracting a mosquito (chemical attractant, light, etc.) is structured or arranged to draw the mosquito to land on or otherwise contact the surface or coating, thus contacting one or more active ELQ agents described herein, alone or in combination with other agents of interest in combating mosquitos and their life cycle. Traps may include walls, screens, strips or other structures or arrangements to contain the mosquito within the trap. Traps may also be open arrangements, such as a flat or curved surface that allow the mosquito to leave the trap, preferably after contacting the surface or coating comprising the ELQ compound or the ELQ-compound-comprising composition in question. Non-limiting examples of trap designs with which the compounds and coating compositions described may be used include those of US 2013 / 0067795 (Wesson et al.), US Pat. No.9,775,335 (Kohler et al.), US Pat. No. 9,554,567 (Kohler et al.), US Pat. No.10,954,358 (Larsen et al.), and US Pat. No.8,800,198 (Frisch). In some embodiments, the trap or surface of interest may be an artificial resting site prepared to attract mosquitos, particularly female mosquitos. 106 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0325] The term "substantially reducing Plasmodium and / or oocyst development" generally refers to reducing the number of oocysts per midgut of adult female mosquitoes by about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 99%, about 100% or from about 50% to about 100% (e.g., from about 60% to about 90%, about 70% to about 99%, about 80% to about 100% or about 90% to about 100%) relative to a control. An “effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof" is an amount that achieves these reductions.

[0326] As used herein, the term "substantially reducing mating success" generally refers to reducing the ratio of the percentages of "mated" to "not mated" adult, female mosquitoes from about 7 to about 0.1 (e.g., about 7 to about 0.4, about 6 to about 0.5, about 5 to about 0.4 or about 4 to about 0.4) relative to control (e.g., no DBH relative to DBH). An "effective amount of effective amount of at least one compound of Formula (I)” or one of the pharmaceutically acceptable forms thereof described herein, is one that achieves these reductions. As used herein, the term "mated" includes females that become inseminated during mating and females that, for one reason or another, (e.g., females exposed to DBH treatment) do not become inseminated, even though they have mated.

[0327] In some embodiments, the substantially reducing mating success comprises a substantial reduction in number of eggs produced by the adult, female mosquitoes or a substantial reduction in the success of insemination of the adult, female mosquitoes.

[0328] The terms “decrease”, “reduced”, “reduction”, or “inhibit” are all used herein to mean a decrease by a statistically significant amount. In some embodiments, “reduce,” “reduction" or “decrease" or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment or agent) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more. As used herein, “reduction” or “inhibition” does not encompass a complete inhibition or reduction as compared to a reference level. “Complete inhibition” is a 100% inhibition as compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.

[0329] The terms “increased”, “increase”, “enhance”, or “activate” are all used herein to mean an increase by a statistically significant amount. In some embodiments, the terms “increased”, “increase”, “enhance”, or “activate” can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at 107 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. In the context of a marker or symptom, an “increase” is a statistically significant increase in such level.

[0330] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). In some embodiments the term “about” refers to the amount indicated, plus or minus 10%. In some embodiments the term “about” refers to the amount indicated, plus or minus 5%.

[0331] As used herein, the singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Also, as used herein, the term "comprises" means "includes." Hence "comprising A or B" means including A, B, or A and B.

[0332] The terms “embodiment” and “aspect” used herein each refer to an example, an instance, or an illustration of the present disclosure and may be used interchangeably. In some instances, as described, one may further define, limit, or serve as a subset, subgeneric description, or specific example of the other. In other instances, one embodiment or aspect may provide a comparison to another or a distinction from the other.

[0333] The term "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount or dose that is sufficient to effect treatment, as defined below, when administered to a subject (e.g., a mammal, such as a human) in need of such treatment. The therapeutically or pharmaceutically effective amount will vary depending upon the subject and disease condition being treated, such as malaria, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. For example, a "therapeutically effective amount" or a "pharmaceutically effective amount" of a compound of Formula I, or a pharmaceutically acceptable salt, co-crystal, or other form thereof, is an amount sufficient to modulate a Plasmodium infection, and thereby treat a subject (e.g., a human) suffering an indication, or to ameliorate or alleviate the existing symptoms of the indication. For example, a therapeutically or pharmaceutically effective amount may be an amount sufficient to decrease a symptom of malaria.

[0334] In some embodiments, each dosage unit contains from 0.1 mg to 1 g, 0.1 mg to 500 mg, or 0.1 mg to 100 mg of a compound of Formula I, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. In some 108 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT embodiments, a therapeutically effective amount or a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises from about 0.1 mg to about 500 mg per dose, given once or twice daily. In some embodiments, the individual dose is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, and 500 mg per dose.

[0335] As used herein, "pharmaceutically acceptable excipient" is a pharmaceutically acceptable vehicle that includes, without limitation, any and all carriers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0336] The term " pharmaceutically acceptable carrier" refers to an excipient or vehicle that includes without limitation diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, and the like with which the compound is administered. Carriers are generally described herein and also in "Remington's Pharmaceutical Sciences" by E. W. Martin. Examples of carriers include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, carboxymethylcellulose sodium, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyoctacosanyl hydroxystearate, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, povidone, silicon dioxide, colloidal silicon dioxide, silicone, silicone adhesive 4102, and silicone emulsion. It should be understood, however, that the carriers selected for the pharmaceutical compositions, and the amounts of such carriers in the composition, may vary depending on the method of formulation (e.g., dry granulation formulation, solid dispersion formulation).

[0337] The terms “pharmaceutically acceptable salt(s)” or “pharmacologically acceptable salt(s)” refer to salts prepared by conventional means that include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. A “pharmaceutically acceptable salt” of the presently disclosed compounds also include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, 109 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base. Any chemical compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof. “Pharmaceutically acceptable salts” are also inclusive of the free acid, base, and zwitterionic forms. Descriptions of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). When compounds disclosed herein include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. Such salts are known to those of skill in the art. For additional examples of “pharmacologically acceptable salts,” see Berge et al., J. Pharm. Sci.66:1 (1977).

[0338] It is understood that substituents and substitution patterns of the compounds described herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art and further by the methods set forth in this disclosure.

[0339] The terms "treatment" or "treating" refer to an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: (i) inhibiting the disease or condition, such as a malaria infection (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); (ii) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or (iii) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival).

[0340] The terms “inhibiting” or "inhibition" indicate a decrease, such as a significant decrease, in the baseline activity of a biological activity or process. For instance, “inhibition" of a malaria, babesiosis, or toxoplasmosis infection refers to a decrease in symptoms or progress of such an infection as a direct or indirect response to the presence of a compound of Formula (I), or a pharmaceutically acceptable salt or co-crystal thereof, relative to symptoms or progress of such an infection in the absence of such compound or a pharmaceutically acceptable salt or co-crystal thereof.

[0341] The terms "subject" or “patient” refer to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in both human therapy and veterinary applications. In some embodiments, the subject is a 110 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT mammal; in some embodiments the subject is human; and in some embodiments the subject is chosen from cats and dogs. "Subject in need thereof" or "human in need thereof" refers to a subject, such as a human, who may have or is suspected to have diseases or conditions that would benefit from certain treatment; for example, treatment with a compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, as described herein. This includes a subject who may be determined to be at risk of or susceptible to such diseases or conditions, such that treatment would prevent the disease or condition from developing.

[0342] “Multidrug-resistant” or “drug-resistant” refers to malaria, or the parasites causing malaria, that have developed resistance to treatment by at least one therapeutic agent historically administered to treat malaria. For example, there are multidrug-resistant strains of Plasmodium falciparum that harbor high-level resistance to chloroquine, quinine, mefloquine, pyrimethamine, sulfadoxine and atovaquone.

[0343] All ranges disclosed and / or claimed herein are inclusive of the recited endpoint and independently combinable. For example, the ranges of "from 2 to 10," “2 through 10,” and “2-10” are inclusive of the endpoints, 2 and 10, and all the intermediate values between in context of the units considered. For instance, reference to “Claims 2-10” or “C2-C10alkyl” includes units 2, 3, 4, 5, 6, 7, 8, 9, and 10, as claims and atoms are numbered in sequential numbers without fractions or decimal points, unless described in the context of an average number. The context of “pH of from 5-9” or “a temperature of from 5˚C to 9˚C”, on the other hand, includes whole numbers 5, 6, 7, 8, and 9, as well as all fractional or decimal units in between, such as 6.5 and 8.24.

[0344] As used herein, the term "administering," refers to the placement of a compound as disclosed herein into a subject by a method or route which results in at least partial delivery of the agent at a desired site. Pharmaceutical compositions comprising the compounds disclosed herein can be administered by any appropriate route which results in an effective treatment in the subject. In some embodiments, administration comprises physical human activity, e.g., an injection, act of ingestion, an act of application, and / or manipulation of a delivery device or machine. Such activity can be performed, e.g., by a medical professional and / or the subject being treated.

[0345] As used herein, the term “comprising” means that other elements can also be present in addition to the defined elements presented. The use of “comprising” indicates inclusion rather than limitation.

[0346] The term "consisting of" refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.

[0347] As used herein the term "consisting essentially of" refers to those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the invention. 111 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT

[0348] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The abbreviation, "e.g." is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation "e.g." is synonymous with the term "for example."

[0349] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0350] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Definitions of common terms in immunology and molecular biology can be found in The Merck Manual of Diagnosis and Therapy, 20th Edition, published by Merck Sharp & Dohme Corp., 2018 (ISBN 0911910190, 978-0911910421); Bruce Alberts et al., Molecular Biology of the Cell, published by W.W. Norton & Company, 2022 (ISBN 0393884821, 978-0393884821); John M. Lackie eat al. (eds.), The Dictionary of Cell and Molecular Biology, 5thEdition, published by Academic Press, 2013 (ISBN 0123849314, 978-0123849311); Nalini Chandar et al., Lippincott Illustrated Reviews: Cell and Molecular Biology, 3rdEdition, published by LWW, 2023 (ISBN 1975180895, 978-1975180898); Teresa Atwood et al., Oxford Dictionary of Biochemistry and Molecular Biology, 2ndEdition, published by Oxford University Press, 2006; Robert S. Porter et al. (eds.), The Encyclopedia of Molecular Cell Biology and Molecular Medicine, published by Blackwell Science Ltd., 1999-2012(ISBN 9783527600908); Johnathan Law et al., (eds.), A Dictionary of Chemistry, 8thEdition,published by Oxford University Press, 2020 (ISBN 9780198841227, 9780191876783); Robert C. King et al. (eds.), A Dictionary of Genetics, 8thEdition, published by Oxford University Press, 2013 (ISBN 9780199766444, 9780199376865); Richard Cammack et al. (eds.), Oxford Dictionary of Biochemistry and Molecular Biology, 2ndEdition, published by Oxford University Press, 2006 (ISBN 9780198529170, 9780191727641); John Lackie et al. (eds.), A Dictionary of Biomedicine, 2ndEdition, published by Oxford University Press, 2019 (ISBN 9780191829116); Lodish et al., 112 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT Molecular Cell Biology, 8thEdition, published by W.H. Freeman, 2016 (ISBN 1464183392, 978- 1464183393); Abul K. Abbas et al., Cellular and Molecular Immunology, 10thEdition, published by Elsevier, 2021 (ISBN 0323757480, 978-0323757485); Kenneth M. Murphy et al., Janeway's Immunobiology, 10thEdition, published by W. W. Norton & Company, 2022 (ISBN 0393884899, 978-0393884890); Lewin's Genes XI, published by Jones & Bartlett Publishers, 2014 (ISBN- 1449659055); Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (2012) (ISBN 1936113414); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (2012) (ISBN 0444569464); Laboratory Methods in Enzymology: DNA, Jon Lorsch (ed.) Elsevier, 2013 (ISBN 0124199542); Frederick M. Ausubel (ed.), Current Protocols in Molecular Biology (CPMB), John Wiley and Sons, 1987-2010 (ISBN 047150338X, 9780471503385); Current Protocols in Protein Science (CPPS), John E. Coligan (ed.), John Wiley and Sons, Inc., 2005; and Current Protocols in Immunology (CPI) (John E. Coligan, ADA M Kruisbeek, David H Margulies, Ethan M Shevach, Warren Strobe, (eds.) John Wiley and Sons, Inc., 2003 (ISBN 0471142735, 9780471142737), the contents of which are all incorporated by reference herein in their entireties.

[0351] Other terms are defined herein within the description of the various aspects of the invention.

[0352] All patents and other publications; including literature references, issued patents, published patent applications, and co-pending patent applications; cited throughout this application are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

[0353] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, 113 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT functions and concepts of the above references and application to provide yet further embodiments of the disclosure. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[0354] Specific elements of any of the foregoing embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure.

[0355] In some embodiments, the present technology may be defined in any of the following numbered paragraphs: 1. A coating composition comprising a coating medium and an effective amount of a compound of Formula (I):wherein: R1is selected from the group of H, halogen, and -OCH3; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 2. A coating composition comprising a coating medium and an effective amount of a compound of Formula (II):114 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT wherein each of R1, R2, R3, R4, and R5is as defined in Paragraph 1; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 3. The coating composition of any of Paragraphs 1 and 2, further with the proviso that at least one variable selected from the group of R1, R2, and R3is hydrogen, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 4. The coating composition of any of Paragraphs 1 and 2, with the proviso that two variables selected from the group of R1, R2, and R3are hydrogen and the remaining variable selected from the group of R1, R2, and R3is not hydrogen, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 5. The coating composition of any of Paragraphs 1, 2, 3, and 4, wherein: R1is selected from the group of F, Cl, and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H, F, and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 6. The coating composition of any of Paragraphs 1, 2, 3, and 4, wherein: R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H, F, and Cl; R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 7. The coating composition of any of Paragraphs 1, 2, 3, and 4, wherein: R1 is selected from the group of F and -OCH3 ;R2is selected from the group of H, F, and Cl; R3is selected from the group of H and F; R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 115 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT 8. The coating composition of any of Paragraphs 1, 2, 3, and 4, wherein: R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H and F; R4is heptyl; and R5is C1-C4alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 9. A coating composition comprising a coating medium and an effective amount of a compound of Formula (III):wherein: R2is halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 10. The coating composition of Paragraph 9, wherein R1is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 11. The coating composition of any of Paragraphs 9 and 10, wherein R2is F; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 12. The coating composition of any of Paragraphs 9 and 10, wherein R2is Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 13. A coating composition comprising a coating medium and an effective amount of a compound of Formula (IV): 116 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R1is selected from the group of -OCH3and halogen; R3is halogen; R4is C4-C10alkyl; and R5 is C1-C10 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 14. The coating composition of Paragraph 13, wherein, R1is selected from the group of -OCH3, F, and Cl; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 15. The coating composition of Paragraph 13, wherein, R1is -OCH3; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 16. The coating composition of Paragraph 13, wherein, R1is selected from the group of F and Cl; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 17. A coating composition comprising a coating medium and an effective amount of a compound of Formula (V): 117 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 18. A coating composition comprising a coating medium and an effective amount of a compound of Formula (VI):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 19. A coating composition comprising a coating medium and an effective amount of a compound of Formula (VII):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 20. A coating composition comprising a coating medium and an effective amount of a compound of Formula (VIII): 118 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 21. A coating composition comprising a coating medium and an effective amount of a compound of Formula (IX):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 22. A coating composition comprising a coating medium and an effective amount of a compound of Formula (X):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 23. A coating composition comprising a coating medium and an effective amount of a compound of Formula (XI): 119 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 24. A coating composition comprising a coating medium and an effective amount of a compound of Formula (XII):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 25. A coating composition comprising a coating medium and an effective amount of a compound of Formula (XIII):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 26. A coating composition comp...

Claims

Attorney Docket No: 002806-000159WOPT What is claimed herein is:

1. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (I):wherein: R1is selected from the group of H, halogen, and -OCH3; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

2. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (II):wherein each of R1, R2, R3, R4, and R5is as defined in Claim 1; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

3. A composition comprising at least one compound of Formula (I): 200 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein: R1is selected from the group of H, halogen, and -OCH3; R2is selected from the group of H and halogen; R3is selected from the group of H and halogen; R4 is selected from the group of C4-C12 alkyl and the 4-trifluoromethyl phenoxy phenyl moiety of the formulathe wavy line () represents a bond through which the 4-trifluoromethyl phenoxyphenyl moiety, when present, is bound to the 3-position carbon of the quinoline ring; with the proviso that R4may only be the 4-trifluoromethyl phenoxy phenyl moiety when R1is halogen, R2is H, and R3is halogen; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

4. The composition of Claim 3 wherein the at least one compound is of Formula (II):wherein each of R1, R2, R3, R4, and R5is as defined in Claim 3; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

5. The coating composition or composition of any one of the preceding claims, further with the proviso that at least one variable selected from the group of R1, R2, and R3is hydrogen, or a 201 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

6. The coating composition or composition of any one of the preceding claims, with the proviso that two variables selected from the group of R1, R2, and R3are hydrogen and the remaining variable selected from the group of R1, R2, and R3is not hydrogen, or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

7. The coating composition or composition of any one of the preceding claims, wherein: R1is selected from the group of F, Cl, and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H, F, and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

8. The coating composition or composition of any one of the preceding claims, wherein: R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H, F, and Cl; R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

9. The coating composition or composition of any one of the preceding claims, wherein: R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H and F; R4is C5-C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

10. The coating composition of any of Claims 1, 2, 3, and 4, wherein: R1is selected from the group of F and -OCH3; R2is selected from the group of H, F, and Cl; R3is selected from the group of H and F; R4is heptyl; and 202 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT R5is C1-C4alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

11. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (III):wherein: R2is halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

12. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (III):wherein: R2is halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

13. The coating composition or composition of any one of the preceding claims, wherein R1is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 203 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT 14. The coating composition or composition of any one of the preceding claims, wherein R2is F; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

15. The coating composition or composition of any one of the preceding claims, wherein R2is Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

16. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (IV):wherein, R1is selected from the group of -OCH3and halogen; R3is halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

17. The coating composition or composition of Claim 16, wherein R1is selected from the group of -OCH3, F, and Cl; R3is selected from the group of F and Cl; R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

18. The coating composition or composition of Claim 16, wherein R1is -OCH3; R3is selected from the group of F and Cl; R4is C4-C12alkyl; and 204 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

19. The coating composition or composition of Claim 16, wherein R1is selected from the group of F and Cl; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

20. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (IV):wherein, R1is selected from the group of -OCH3and halogen; R3is halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

21. The coating composition of claim 20, wherein R1is selected from the group of -OCH3, F, and Cl; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

22. The coating composition of claim 20, wherein R1is -OCH3; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and 205 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

23. The coating composition of claim 20, wherein R1is selected from the group of F and Cl; R3is selected from the group of F and Cl; R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

25. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (V):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

26. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (V):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

27. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (VI): 206 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

28. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (VI):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

29. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (VII):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

30. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (VII): 207 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

31. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (VIII):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

32. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (VIII):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

31. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (IX): 208 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

32. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (IX):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

33. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (X):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

34. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (X): 209 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

35. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (XI):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

36. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (XI):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

37. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (XII): 210 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

38. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (XII):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

39. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (XIII):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

40. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (XIII): 211 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

41. The coating composition or composition of any one of the preceding claims, wherein the at least one compound is of Formula (XIV):wherein, R4is C4-C12alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

42. A coating composition comprising a coating medium and an effective amount of at least one compound of Formula (XIV):wherein, R4is C4-C10alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

43. The coating composition or composition of any one of the preceding claims, wherein R4is C5- C9alkyl; and R5is C1-C5alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 212 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT 44. The coating composition or composition of any one of the preceding claims, wherein R4is C5- C9alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

45. The coating composition or composition of any one of the preceding claims, wherein R4is C6- C8alkyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

46. The coating composition or composition of any one of the preceding claims, wherein R4is heptyl; and R5is C1-C3alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

47. The coating composition or composition of any one of the preceding claims, wherein R4is C7- C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

48. The coating composition or composition of any one of the preceding claims, wherein R4is C7or C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

49. The coating composition or composition of any one of the preceding claims, wherein R4is C1- C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

50. The coating composition or composition of any one of the preceding claims, wherein R4is C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

51. The coating composition or composition of any one of the preceding claims, wherein R4 is C1-C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

52. The coating composition or composition of any one of the preceding claims, wherein R4is C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, 213 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

53. The coating composition or composition of any one of the preceding claims, wherein R4is C5- C7alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

54. The coating composition or composition of any one of the preceding claims, wherein R4is C5- C7alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

55. The coating composition or composition of any one of the preceding claims, wherein R4is C5- C11alkyl; and R5is C2alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

56. The coating composition or composition of any one of the preceding claims, wherein R4is C5- C11alkyl; and R5is C1-C10alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

57. The coating composition or composition of any one of the preceding claims, comprising the compound:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

58. The coating composition or composition of any one of the preceding claims, comprising the compound: 214 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTpharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

59. The coating composition or composition of any one of the preceding claims, comprising the compound:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

60. The coating composition or composition of any one of the preceding claims, comprising the compound:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

61. The coating composition or composition of any one of the preceding claims, comprising the compound:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof 62. The coating composition or composition of any one of the preceding claims, comprising the compound: 215 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTpharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof 63. The coating composition or composition of any one of the preceding claims, comprising the compound:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

64. The coating composition or composition of any one of the preceding claims, comprising the compound:pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

65. The coating composition or composition of any one of the preceding claims, comprising the compound:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof. 216 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT 66. The coating composition or composition of any one of the preceding claims, comprising the compound:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

67. The coating composition or composition of any one of the preceding claims, comprising the compound:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

68. The coating composition or composition of any one of the preceding claims, comprising the compound:pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

69. The coating composition or composition of any one of the preceding claims, comprising a first compound of any one of the preceding claims of: 217 4935-9168-8742.2Attorney Docket No: 002806-000159WOPTwherein: R1is a halogen; R2is H; R3is a halogen; R4is C4-C10alkyl; and R5is C1-C10alkyl; and a second compound of any one of the preceding claims selected from:R1is -OCH3; R2is a halogen; R3is H; R4is C4-C10alkyl; and R5is C1-C10alkyl.

70. The coating composition of any one of the preceding claims, wherein the medium comprises a saturated or unsaturated fatty acid, or an alkyl ester thereof, having from about 10 to about 26 carbon atoms in the fatty acid chain.

71. The coating composition of Claim 70, wherein the medium comprises one or more materials selected from the group of lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, lignoceric acid, oleic acid, linoleic acid, arachidonic acid, linolenic acid, eicosapentaenoic acid, docosahexanoic acid, stearidonic acid, and cervonic acid, or an alkyl ester thereof.

72. The coating composition of any one of Claims 70 and 71, wherein the medium comprises a methyl ester of a fatty acid selected from the group of lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, lignoceric acid, oleic acid, linoleic acid, arachidonic acid, linolenic acid, eicosapentaenoic acid, docosahexanoic acid, stearidonic acid, and cervonic acid.

73. The coating composition of any one of Claims 70-72, wherein the medium is palmitic acid methyl ester. 218 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT 74. The coating composition of any one of Claims 70-72, wherein the medium is α-linolenic acid methyl ester.

75. The coating composition of any one of Claims 70-72, wherein the medium is rapeseed methyl esters.

76. The coating composition of any one of the preceding claims, further comprising an effective amount of an insecticide agent.

77. The coating composition of Claim 76, wherein the insecticide agent is selected from the group of an antibiotic insecticide, a macrocyclic lactone insecticide, an arsenical insecticide, a botanical insecticide, a carbamate insecticide, a diamide insecticide, a desiccant insecticide, a dinitrophenol insecticide, a fluorine insecticide, a formamidine insecticide, a fumigant insecticides, an inorganic insecticides, an insect growth regulator, an nereistoxin analogue insecticide, a nicotinoid insecticide, an organochlorine insecticide, an organophosphorus insecticide, an oxadiazine insecticide, an oxadiazolone insecticide, a phthalimide insecticide, a pyrazole insecticide, a pyrethroid insecticide, a pyrimidinamine insecticide, a pyrrole insecticide, a tetramic acid insecticide, a tetronic acid insecticide, a thiazole insecticide, a thiazolidine insecticide, athiourea insecticide, and a urea insecticide.

78. The coating composition of any one of Claims 76 and 77, wherein the insecticide agent is selected from the group of 1,2- dichloropropane, 1,3-dichloropropene, abamectin, acephate, acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile, alanycarb, aldicarb, aldoxycarb, aldrin, allethrin, allosamidin, allyxycarb, alpha-cypermethrin, alpha-endosulfan, amidithion, aminocarb, amiton, amitraz, anabasine, athidathion, azadirachtin, azamethiphos, azinphos-ethyl, azinphos-methyl, azothoate, barium hexafluorosilicate, barthrin, bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin, bifenthrin, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, bistrifluoron, borax, boric acid, boric acid, bromfenvinfos, bromocyclen, bromo-DDT, bromophos, bromophos-ethyl, bufencarb, buprofezin, butacarb, butathiofos, butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate, calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, cartap, chlorantraniliprole, chlorbicyclen, chlordane, chlordecone, chlordimeform, chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chloroform, chloropicrin, chlorphoxim, chlorprazophos, chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, cinerin I, cinerin cismethrin, cloethocarb, closantel, clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate, copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos, crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O- methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos, diatomaceous earth, diazinon, 219 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT dicapthon, dichlofenthion, dichlorvos, dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor, dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos, dimetilan, dinex, dinoprop, dinosam, dinotefuran, diofenolan, dioxabenzofos, dioxacarb, dioxathion, disulfoton, dithicrofos, d- limonene, DNOC, doramectin, ecdysterone, emamectin, EMPC, empenthrin, endosulfan, endothion, endrin, EPN, epofenonane, eprinomectin, esfenvalerate, etaphos, ethiofencarb, ethion, ethiprole, ethoate-methyl, ethoprophos, ethyl formate, ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide, etofenprox, etrimfos, EXD, famphur, fenamiphos, fenazaflor, fenchlorphos, fenethacarb, fenfluthrin, fenitrothion, fenobucarb, fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion, fenthion, fenthion-ethyl, fenvalerate, fipronil, flonicamid, flubendiamide, flucofuron, flucycloxuron, flucythrinate, flufenerim, flufenoxuron, flufenprpx, fluvalinate, fonofos, formetanate, formothion, formparanate, fosmethilan, fospirate, fosthietan, furathiocarb, furethrin, gamma- cyhalothrin, gamma-HCH, halfenprox, HCH, HEOD, heptachlor, heptenophos, heterophos, hexaflumuron, HHDN, hydramethylnon, hydrogen cyanide, hydroprene, hyquincarb, imidacloprid, imiprothrin, indoxacarb, iodomethane, IPSP, isazofos, isobenzan, isocarbophos, isodrin, isofenphos, isoprocarb, isoprothiolane, isothioate, isoxathion, ivermectin, jasmolin I, jasmolin II, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kelevan, kinoprene, lambda- cyhalothrin, lead arsenate, lepimectin, leptophos, lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben, mazidox, mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride, mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion, methiocarb, methocrotophos, methomyl, methoprene, methoxychlor, methyl bromide, methylchloroform, methylene chloride, metofluthrin, metolcarb, metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime, mipafox, mirex, monocrotophos, morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine, nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron, noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos, oxydisulfoton, para- dichlorobenzene, parathion, parathion-methyl, penfluoron, pentachlorophenol, permethrin, phenkapton, phenothrin, phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor, phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite, potassium thiocyanate, pp'-DDT, prallethrin, precocene I, precocene II, precocene III, primidophos, profenofos, profluthrin, promacyl, promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos, prothoate, protrifenbute, pyraclofos, pyrafluprole, pyrazophos, pyresmethrin, pyrethrin I, pyrethrin II, pyridaben, pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimitate, pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl, quinothion, rafoxanide, resmethrin, rotenone, ryania, sabadilla, schradan, selamectin, silafluofen, silica gel, sodium arsenite, sodium fluoride, sodium hexafluorosilicate, sodium thiocyanate, sophamide, spinetoram, spinosad, spiromesifen, spirotetramat, sulcofuron, sulfoxaflor, sulfluramid, sulfotep, sulfuryl fluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos, 220 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT TEPP, terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos, tetramethrin, theta-cypermethrin, thiacloprid, thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiodicarb, thiofanox, thiometon, thiosultap, thuringiensin, tolfenpyrad, tralomethrin, transfluthrin, transpermethrin, triarathene, triazamate, triazophos, trichlorfon, trichlormetaphos-3, trichloronat, trifenofos, triflumuron, trimethacarb, triprene, vamidothion, vaniliprole, XMC, xylylcarb, zeta-cypermethrin, zolaprofos, and a- ecdysone.

79. A method of preparing a solid surface to facilitate transmission of a compound from a coating composition as described in any one of the preceding claims, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, to a female mosquito, the method comprising applying an effective amount of the coating composition to the solid surface.

80. A surface, wherein the surface comprises an effective amount of at least one coating composition of any one of the preceding claims.

81. A surface coating, wherein the surface coating comprises an effective amount of at least one coating composition of any one of the preceding claims, or a pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

82. The surface coating of Claim 81, which is present on the surface at a concentration of 10 μmol / m2-1 mmol / m2.

83. The surface coating of Claim 81, which is present on the surface at a concentration selected from the group of 10 μmol / m2-20 μmol / m2, 10 μmol / m2-30 μmol / m2, 10 μmol / m2-40 μmol / m2, 10 μmol / m2-50 μmol / m2, 10 μmol / m2-60 μmol / m2, 10 μmol / m2-70 μmol / m2, 10 μmol / m2-80 μmol / m2, 10 μmol / m2-90 μmol / m2, 10 μmol / m2-100 μmol / m2, 20 μmol / m2-100 μmol / m2, 30 μmol / m2-100 μmol / m2, 40 μmol / m2-100 μmol / m2, 50 μmol / m2-100 μmol / m2, 60 μmol / m2-100 μmol / m2, 70 μmol / m2-100 μmol / m2, 80 μmol / m2-100 μmol / m2, 90 μmol / m2-100 μmol / m2, 100 μmol / m2-200 μmol / m2, 100 μmol / m2-300 μmol / m2, 100 μmol / m2-400 μmol / m2, 100 μmol / m2-500 μmol / m2, 100 μmol / m2-600 μmol / m2, 100 μmol / m2-700 μmol / m2, 100 μmol / m2-800 μmol / m2, 100 μmol / m2-900 μmol / m2, 100 μmol / m2-1 mmol / m2, 100 μmol / m2-1 mmol / m2, 200 μmol / m2-1 mmol / m2, 300 μmol / m2-1 mmol / m2, 400 μmol / m2-1 mmol / m2, 500 μmol / m2-1 mmol / m2, 600 μmol / m2-1 mmol / m2, 700 μmol / m2-1 mmol / m2, 800 μmol / m2-1 mmol / m2, or 900 μmol / m2-1 mmol / m2.

84. The surface coating of Claim 81, which is present on the surface at a concentration lower than 10 μmol / m2.

85. The surface coating of Claim 81, which is present on the surface at a concentration higher than 1 mmol / m2.

86. A method of preparing a solid surface to facilitate transmission of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical 221 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined in any one of the preceding claims, to a female mosquito, the method comprising applying an effective amount of a coating composition comprising an effective amount of the compound to the solid surface.

87. A surface comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined in any one of the preceding claims.

88. A surface coating comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined in any one of the preceding claims.

89. A method for reducing transmission of Plasmodium parasites to a female mosquito, the method comprising contacting the female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined in any one of the preceding claims.

90. The method of Claim 89, wherein the female mosquito is an Anopheles mosquito.

91. A method for a substantially reducing Plasmodium and / or oocyst development in an adult female mosquito, the method comprising contacting the female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined in any one of the preceding claims.

92. A method of substantially reducing mating success of an adult female mosquito, the method comprising contacting the adult female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined in any one of the preceding claims.

93. A method of substantially abolishing egg development in an adult female mosquito after blood feeding, the method comprising contacting the adult female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined in any one of the preceding claims. 222 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT 94. A method of substantially reducing the mean survival rate of adult female mosquitoes, the method comprising contacting the adult female mosquito with a composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, as defined in any one of the preceding claims.

95. The method of Claim 94, wherein the adult female mosquito is selected from the group of Anopheles spp (e.g., An. arabiensis, An. Funestus, An. Stephensi, An. sinensis, An. yatsushiroensis, and An. lesteri), Aedes spp (including Aedes vexans) and Culex spp (including Culex pipiens, Cx. orientalis, Cx. perexiguus, Cx. quinquefasciatus, and Cx. modestus).

96. A pharmaceutical composition comprising a pharmaceutically effective amount of a composition of any one of Claims 1 through 69, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof, and a pharmaceutically acceptable carrier or excipient.

97. A pharmaceutical composition comprising a pharmaceutically or therapeutically effective amount of a composition selected from any one of Claims 1-59, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

98. A method for treating malaria in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a composition selected from any one of Claims 1-69, or a pharmaceutically acceptable salt thereof.

99. A method for inhibiting malaria in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a composition selected from any one of Claims 1-69, or a pharmaceutically acceptable salt thereof.

100. The method of any one of Claims 98 and 99, wherein the malaria is an infection of at least one parasite selected from the group of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.

101. The method of any one of Claims 98-100, wherein the malaria is a drug-resistant malaria.

102. The method of Claim 101, wherein the malaria is resistant to treatment with at least one agent selected from the group of chloroquine, sulphadoxine-pyrimethamine, quinine, piperaquine, mefloquine, artemisinin-based combination therapy (ACT, including artemether-lumefantrine (COARTEM®) and artesunate-mefloquine), pyrimethamine, dapsone, atovaquone, and a P. falciparum DHOD inhibitor.

103. The method of any one of Claims 98-102, wherein the malaria is a multidrug-resistant malaria resistant to treatment with at least two agents selected from the group of chloroquine, sulphadoxine- pyrimethamine, quinine, piperaquine, mefloquine, artemisinin-based combination therapy (ACT, including artemether-lumefantrine (COARTEM®) and artesunate-mefloquine), pyrimethamine, dapsone, atovaquone, and a P. falciparum DHOD inhibitor. 223 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT 104. The method of any of Claims 98-103, wherein the malaria is a latent malaria infection.

105. The method of any of Claims 98-104, further comprising administering to the human in need thereof a pharmaceutically effective amount of one or more compounds selected from the group of quinine, chloroquine, atovaquone, proguanil, primaquine, amodiaquine, mefloquine, piperaquine, artemisinin, artesunate, methylene blue, pyrimethamine, sulfadoxine, artemether-lumefantrine, dapsone-chlorproguanil, artesunate, quinidine, clopidol, and dihydroartemisinin, or a pharmaceutically acceptable salt thereof.

106. A method for treating toxoplasmosis in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a composition selected from any one of Claims 1-69, or a pharmaceutically acceptable salt thereof.

107. A method for treating babesiosis in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a composition selected from any one of Claims 1-69, or a pharmaceutically acceptable salt thereof.

108. A method for treating babesiosis in a non-human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a composition selected from any one of Claims 1-69, or a pharmaceutically acceptable salt thereof.

109. A method for treating babesiosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of a composition selected from any one of Claims 1-69, or a pharmaceutically acceptable salt thereof.

110. The method of Claim 109, wherein the non-human subject is a bovine subject.

111. The method of any one of Claims 109 and 110, wherein the babesiosis is caused by a Babesia bovis infection or a Babesia bigemina infection.

112. The method of Claim 109, wherein the non-human subject is an equine subject.

113. The method of any one of Claims 110 and 112, wherein the babesiosis is caused by a Babesia caballi infection or a Theileria equi infection.

114. A method for treating coccidiosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of a composition selected from any one of Claims 1-69, or a pharmaceutically acceptable salt thereof.

115. A method for treating theileriosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of a composition selected from any one of Claims 1-69, or a pharmaceutically acceptable salt thereof.

116. The method of Claims 115, wherein the theileriosis is caused by a Theileria equi infection.

117. A method for treating neosporosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of a composition selected from any one of Claims 1-69, or a pharmaceutically acceptable salt thereof. 224 4935-9168-8742.2Attorney Docket No: 002806-000159WOPT 118. The method of Claim 117, wherein the non-human subject is equine.

119. The method of Claim 117, wherein the non-human subject is bovine.

120. The method of Claim 117, wherein the non-human subject is canine.

121. A method of treatment of a Besnoitia besnoti infection in a non-human subject, the method comprising administering to the subject in need thereof a pharmaceutically or therapeutically effective amount of a composition of any one of Claims 1-69, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, or polymorph thereof.

122. The method of Claim 121, wherein the non-human subject is bovine. 225 4935-9168-8742.2

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