OA19130A

OA19130A - Antimalarial compositions and uses thereof

Info

Publication number: OA19130A
Application number: OA1201800524
Authority: OA
Inventors: Wil Joseph ANDAHAZY; Arnab K. Chatterjee; Case W. MCNAMARA; Federico C. BEASLEY; Anders Mikal ELIASEN; Hank Michael James Petrassi; Jason T. ROLAND; Timothy Wells; Olga Vladimirovna ZATOLOCHNAYA; Fei Zhou; Peter G. Schultz
Original assignee: The Scripps Research Institute
Priority date: 2016-06-20
Filing date: 2017-06-19
Publication date: 2020-01-31

Abstract

Provided herein are compounds, compositions and method of using thereof to treat prevent malaria.

Description

ANTIMALARIAL COMPOSITIONS AND USES THEREOF

CROSS-REFERENCE

[0001] This application daims the benefit of U.S. Application Serial No. 62/352,455 filed June 20, 2016, ail of which is incorporated by reference in its entirety.

BACKGROUND

[0002] Malaria is an infections disease widespread in tropical and sub-tropical régions of Africa, Asia, and the Americas. In 2010 the World Health Organization estimated thatthere were over 219 million documented cases of malaria and between 660,000 and 1.2 million deaths from the disease (Nayyar, Lancet Infections Diseases, 12:488-496, 2012).

[0003] Malaria is a mosquito-borne infections disease of humans and other animais caused by parasitic protozoans (a group of single-celled microorganisms) belonging to the Plasmodium type. Malaria initially manifests with mild to severe symptoms including: chills, fever, fatigue, headache, and nausea. Later symptoms include severe anémia, and blood clotting, which can lead to brain damage and other complications, and death. Although five species of Plasmodium (P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi) can infect humans, the majority of malarial deaths are caused by P. falciparum and P. vivax. Symptoms usually begin ten to fifteen days after being bitten. If not properly treated, people may hâve récurrences of the disease months later. In those who hâve recently survived an infection, reinfection usually causes milder symptoms. This partial résistance disappears over months to years if the person has no continuing exposure to malaria. Five species of the plasmodium parasite can infect humans; the most serions forms of the disease are caused by Plasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae causes milder disease in humans that is not generally fatal. A fifith species, Plasmodium knowlesi, is a zoonosis that causes malaria in macaques but can also infect humans. When a mosquito bites an infected person, a small amount of blood is taken, which contains malaria parasites. These develop within the mosquito, and about one week later, when the mosquito takes its next blood meal, the parasites are injected with the mosquito's saliva into the person being bitten. After a period of between two weeks and several months (occasionally years) spent in the liver, the malaria parasites start to multiply within red blood cells, causing symptoms that include fever, and headache. In severe cases the disease worsens leading to hallucinations, coma, and death.

[0004] A wide variety of antimalarial drugs are available to treat malaria. In the last 5 years, treatment of P. falciparum infections in endemic countries has been transformed by the use of combinations of drugs containing an artemisinin dérivative. Severe malaria is treated with intravenous or intramuscular quinine or, increasingly, the artemisinin dérivative artesunate. Several drugs are also available to prevent malaria in travelers to malaria-endemic countries (prophylaxis). Résistance has developed to several antimalarial drugs, most notably chloroquine.

[0005] Malaria transmission can be reduced by preventing mosquito bites by distribution of inexpensive mosquito nets and insect repellents, or by mosquito-control measures such as spraying insecticides inside houses and draining standing water where mosquitoes lay their eggs.

BR1EF SÜMMARY OF THE INVENTION

[0006] Described herein are compounds of Formula (IV) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

wherein R^{15 * * * * * 21} is optionally substituted C₃-C₃oalkenyl or optionally substituted C₂-C₃oalkynyl.

[0007] In a compound of Formula (IV), R²¹ may be C3-C30alkenyl. In a compound of Formula (IV), R²' may be C6-C30alkenyl. In a compound of Formula (IV), R²¹ may be C6-C₂₅alkenyl. In a compound of Formula (IV), R²¹ may be Cis-Cbsalkenyl. In a compound of Formula (IV), R²¹ may be

[0008] Also described herein is a pharmaceutical composition comprising:

(i) an oil; and (ii) a compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

Formula (III) . wherein:

R¹¹ is a lipophilie moiety.

[0009] In the pharmaceutical composition comprising a compound of Formula (III), R¹' may be optionally substituted Ci-C₃oalkyl, optionally substituted C₂-C₃oalkenyl, or optionally substituted C₂-C₃oalkynyl. In the pharmaceutical composition comprising a compound of Formula (III), R¹¹ may be optionally substituted CiC₂oalkyl, optionally substituted C₂-C₂oalkenyl, or optionally substituted C₂-C₂oalkynyl. In the pharmaceutical composition comprising a compound of Formula (111), R may be Ci-Côalkyl. In the pharmaceutical composition comprising a compound of Formula (III), R¹¹ may be Cv-Csoalkyl. In the pharmaceutical composition comprising a compound of Formula (III), R may be R is is

Me θ . in the pharmaceutical composition comprising a compound of Formula (III), R may be C₂-C3oalkenyl. In the pharmaceutical composition comprising a compound of Formula (III), R may be C3-C₃oalkenyl. In the pharmaceutical composition comprising a compound of Formula (III), R¹¹ may be Cô-Csoalkenyl. In the pharmaceutical composition comprising a compound of Formula (III), R¹¹ may be C6-C₂5alkenyl. In the pharmaceutical composition comprising a compound of Formula (III), R may be Ci5-C₂5alkenyl. In the pharmaceutical composition comprising a compound of

Me

Formula (III), R¹¹ may be R¹¹ is

[0010] In the pharmaceutical composition comprising a compound of Formula (III), the oil may be a vegetable oil. In the pharmaceutical composition comprising a compound of Formula (III), the oil may be selected from corn oil, peanut oil, sesame oil, olive oil, palm oil, safflower oil, soybean oil, cottonseed oil, rapeseed oil, sunflower oil and mixtures thereof. In the pharmaceutical composition comprising a compound of Formula (III), the oil may be sesame oil.

[0011] In the pharmaceutical composition comprising a compound of Formula (III), the concentration of the compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be greater than about 50 mg/mL. In the pharmaceutical composition comprising a compound of Formula (III), the concentration of the compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be greater than about 100 mg/mL. In the pharmaceutical composition comprising a compound of Formula (III), the concentration of the compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be greater than about 200 mg/mL.

[0012] Described herein are methods for the treatment or prévention of malaria in a subject comprising administering to the subject a compound of Formula (IV) or a pharmaceutical composition comprising a compound of Formula (III). In the method for the treatment or prévention of malaria, the pharmaceutical composition may be administered by subcutaneous or intramuscular injection. In the method for the treatment or prévention of malaria, the pharmaceutical composition may be effective for sustained or controlled release. In the method for the treatment or prévention of malaria, the compound of Formula (II) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof, comprised in the pharmaceutical composition may be administered at a dose of about 5 to about 20 mg/day. In the method for the treatment or prévention of malaria, the compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof, comprised in the pharmaceutical composition may be released from the pharmaceutical composition over a period of a minimum of about 30 days after administration. In the method for the treatment or prévention of malaria, the compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof, comprised in the pharmaceutical composition is released from the pharmaceutical composition at a rate providing an average concentration of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthalenedione in the blood plasma ofsaid subject of at least about 1000 nM over about 13 weeks. In the method for the treatment or prévention of malaria, the method may further comprise administering an additional antimalarial

-4Tigent. In the method for the treatment or prévention of malaria, the additional antimalarial agent is selected from artemisinin, artemisinin dérivatives, atovaquone, proguanil, quinine, chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine, pyronaridine, halofantrine, or ELQ-300. [0013] Described herein are methods of killing or inhibiting the growth of a Plasmodium species comprising contacting the species with an effective amount of a compound of Formula (IV). In the method of killing or inhibiting the growth of a Plasmodium species, the Plasmodium species is Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, or Plasmodium knowlesi.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 depicts the exposure of ELQ-300 following PO or IM dosing with Compound 2.

[0015] FIG. 2A depicts the percent protection following a sporozoite challenge at day 14 following IM administration of Compound 2 (3, 10, and 30 mg/kg).

[0016] FIG. 2B depicts the exposure of ELQ-300 in mouse following IM administration of Compound 2 (3, 10, and 30 mg/kg). .

[0017] FIG. 3A depicts the exposure of ELQ-300 in rat following IM administration of Compound 2 (3.72 mg/kg in sesame oil).

[0018] FIG. 3B depicts the plasma exposure of ELQ-300 and Compound 2 in dog following IM administration of Compound 2 (20 mg/mL, 3% TPGS, 1% HPMC E5 suspension).

[0019] FIG. 4A depicts the exposure of ELQ-300 in mouse following IM administration of Compound 2, 4, 8, 9, and 10 (3 mg/kg, 1.5 mg/mL in sesame oil).

[0020] FIG. 4B depicts the exposure of ELQ-300 in mouse following IM administration of Compound 12, 13, 14, 16, 17, and 18 (3 mg/kg, 1.5 mg/mL in sesame oil).

[0021] FIG. 5 depicts the characteristic X-ray diffraction pattern of the crystalline ELQ-300-Form IA.

[0022] FIG. 6 depicts the characteristic X-ray diffraction pattern of the crystalline ELQ-300-Form IB.

[0023] FIG. 7 depicts the characteristic X-ray diffraction pattern of the crystalline ELQ-300-Form II (first préparation).

[0024] FIG. 8 depicts the DSC of the crystalline ELQ-300-Form II (first préparation).

[0025] FIG. 9 depicts the characteristic X-ray diffraction pattern of the scaled up crystalline ELQ-300-Form

II (l^st scale up batch).

[0026] FIG. 10 depicts the characteristic X-ray diffraction pattern of the 2^nd scale up batch of crystalline ELQ-300-Form II (2^nd scale up batch).

[0027] FIG. 11 depicts the DSC of crystalline ELQ-300-Form II (2^d scale up batch).

[0028] FIG. 12 depicts the characteristic X-ray diffraction pattern of the crystalline ELQ-300-Form III.

[0029] FIG. 13A depicts the DSC of crystalline ELQ-300-Form III.

[0030] FIG. 13B depicts the TGA of crystalline ELQ-300-Form III.

[0031] FIG. 14 depicts the characteristic X-ray diffraction pattern of the crystalline ELQ-300-Form IV.

[0032] FIG. 15A depicts the DSC of crystalline ELQ-300-Form IV.

[0033] FIG. 15B depicts the TGA of crystalline ELQ-300-Form IV.

[0034] FIG. 16 depicts the characteristic X-ray diffraction pattern of the crystalline ELQ-300-Form V.

-5FIG. 17A depicts the DSC of crystalline ELQ-300-Form V.

[0036] FIG. 17B depicts the TGA of crystalline ELQ-300-Form V.

[0037] FIG. 18 depicts a comparaison in exposure of ELQ-300 following IM administration of Compound 2 and 13 in sesame oil versus two ELQ-300-Form II suspensions.

[0038] FIG. 19A depicts the exposure of ELQ-300 following IM injection of three ELQ-300-Form II suspensions (100 mg/mL Synperonic).

[0039] FIG. 19B depicts the exposure of ELQ-300 following IM injection of three ELQ-300-Form II suspensions (100 mg/mL 3% TPGS).

[0040] FIG. 20 depicts depicts a comparaison in exposure of ELQ-300 following IM administration of Compound 2 in sesame oil (4 mg/kg) versus two ELQ-300-Form II suspensions (4 mg/kg).

[0041] FIG. 21 depicts depicts the exposure of atovaquone following PO or IM dosing with Compound 27, Compound 28, and atovaquone.

[0042] FIG. 22A depicts the percent protection following a sporozoite challenge at day 15 following IM administration of Compound 27 (16.6, 50, and 150 mg/kg).

[0043] FIG. 22B depicts depicts the exposure of atovaquone in mouse following IM administration of Compound 27 (16.6, 50, and 150 mg/kg).

[0044] FIG. 23 depicts the characteristic X-ray diffraction pattern of the crystalline atovaquone-Form 1.

[0045] FIG. 24A depicts the DSC of crystalline atovaquone-Form I.

[0046] FIG. 24B depicts the TGA of crystalline atovaquone-Form I.

[0047] FIG. 25 depicts the characteristic X-ray diffraction pattern of the crystalline atovaquone-Form II.

[0048] FIG. 26A depicts the DSC of crystalline atovaquone-Form IL

[0049] FIG. 26B depicts the TGA of crystalline atovaquone-Form 11.

[0050] FIG. 27 depicts the exposure of atovaquone following IM injection oftwo atovaquone-Form II suspensions (200 mg/mL Synperonic).

[0051] FIG. 28 depicts the characteristic X-ray diffraction pattern of the crystalline pyronaridine-Form I. [0052] FIG. 29A depicts the DSC of crystalline pyronaridine-FormI.

[0053] FIG. 29B depicts the TGA of crystalline pyronaridine-FormI.

[0054] FIG. 30 depicts the characteristic X-ray diffraction pattern of the crystalline pyronaridine-Form II.

[0055] FIG. 31A depicts the DSC of crystalline pyronaridine-FormII.

[0056] FIG. 31B depicts the TGA of crystalline pyronaridine-FormII.

[0057] FIG. 32 depicts the characteristic X-ray diffraction pattern of the crystalline pyronaridine-Form III.

[0058] FIG. 33A depicts the DSC of crystalline pyronaridine-Form III.

[0059] FIG. 33B depicts the TGA of crystalline pyronaridine-Form III.

[0060] FIG. 34 depicts the characteristic X-ray diffraction pattern of the crystalline pyronaridine-Form IV.

[0061] FIG. 35A depicts the DSC of crystalline pyronaridine-Form IV.

[0062] FIG. 35B depicts the TGA of crystalline pyronaridine-Form IV.

[0063] FIG. 36 depicts the characteristic X-ray diffraction pattern of the crystalline pyronaridine-Form V. [0064] FIG. 37 depicts the DSC of crystalline pyronaridine-Form V.

-6)0065] FIG. 38 depicts the rat exposure of Atovaquone following IM administration of Compound 33 in sesame oil.

[0066] FIG. 39 depicts the rat exposure of ELQ-300 following IM administration of Compound 35.

[0067] FIG. 40 depicts the exposure of ELQ-300 following IM administration of Compound 2 (8 and 24 mg/kg).

[0068] FIG. 41 depicts the characteristic X-ray diffraction pattern of crystalline Compound 2.

[0069] FIG. 42A depicts the DSC of crystalline Compound 2.

[0070] FIG. 42B depicts the TGA of crystalline Compound 2.

DETAILED DESCRIPTION OF THE INVENTION

[0071] Seasonal malaria chemoprevention (SMC) has been an effective strategy to reduce malaria mortality and morbidity rates by up to 75% in chiidren aged 3-59 months. Provided as recurring monthly doses given throughout the season of highest malaria transmission (3-4 months), a single oral or injectable dose would be preferred to ensure continuons coverage throughout the entire season and simplify patient compliance to maximize chemoprevention with a target efficacy goal of >95%. Although many treatments are under development, the challenge of producing a widely available single-dose treatment that provides a high level of protection for a sustained period is still to be met.

[0072] Disclosed herein are new formulations comprising dérivatives of atovaquone, an approved antimalarial compound or comprising dérivatives of ELQ-300. New sustained release formulations, such as depot formulation, comprising these dérivatives are investigated. Disclosed herein are new suspension formulations comprising nanoparticles or microparticles of new crystalline forms of ELQ-300, atovaquone, or pyronaridine. Also disclosed herein are new suspension formulations comprising nanoparticles or microparticles of crystalline dérivatives of atovaquone or comprising crystalline dérivatives of a ELQ-300. Disclosed herein are method of treating or preventing malaria comprising administering one of these new formulations to a subject in need thereof.

Définitions

[0073] As used in the spécification and appended daims, unless specified to the contrary, the following terms hâve the meaning indicated below.

[0074] “Oxo” refers to the =0 substituent.

[0075] “Thioxo” refers to the =S substituent.

[0076] “Alkyl” refers to a linear or branched hydrocarbon chain radical, which is fully saturated, has from one to thirty carbon atoms, and is attached to the rest of the molécule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 30 are included. An alkyl comprising up to 30 carbon atoms is referred to as a C1-C30 alkyl, likewise, for example, an alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, C1-C30 alkyl, C1-C20 alkyl, Ci-Cis alkyl, Cj-Cio alkyl, Ci-Cg alkyl, Ci-Ce alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C₂-C₈ alkyl, C₃-C₈ alkyl, C₄-C₈ alkyl, C5-C12 alkyl, and C7-C20 alkyl. Représentative alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, butyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decanyl, undecanyl, dodecane, tridecane, tetradecane, pentadecane.

-7ffexadecane, heptadecane, octadecane, nonadecane, icosane, and the like. Représentative alkyl groups include, but are not limited to, methyi, ethyl, n-propyl, l-methylethyl (isopropyl), n-butyl, i-butyl, s-butyl, n-pentyl, l,l-dimethylethyl (t-butyl), and the like. Représentative linear alkyl groups include, but are not limited to, methyi, ethyl, n-propyl, n-butyl, n-pentyl and the like. The alkyl may be

wherein each p and q is idependently 0-l 8. Unless stated otherwise specifically in the spécification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, SR^a, -OC(O)-R^a, -N(R^a)2, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)2, -N(R^a)C(O)OR^f, -OC(O)- NR^aR^f, -N(R^a)C(O)R^f, N(R^a)S(O)tR^f (where t is l or 2), -S(O)tOR^a (where t is l or 2), -S(O)tR^f (where t is l or 2) and -S(O)tN(R^a)2 (where t is l or 2) where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl. heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each R^f is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. An alkyl may be optionally substituted with one or more of oxo, halogen, -OR^a, -CN, and -N(R^a)2. An alkyl may be optionally substituted with one or more of oxo, halogen, -OH, -CN, and -NH₂.

[0077] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twenty carbon atoms. An alkenyl comprising up to 30 carbon atoms i s referred to as a C₂-C3o alkenyl, likewise, for example, an alkenyl comprising up to 12 carbon atoms is a C₂-Ci₂ alkenyl. Alkenyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkenyl groups include, but are not limited to C₂-C₃₀ alkenyl, C₂-C₂₀ alkenyl, C2-C15 alkenyl, C2-C10 alkenyl, C₂-C₈ alkenyl, C₂-C₆ alkenyl, C₂C₄ alkenyl, C2-C3 alkenyl, C₂-C₈ alkenyl, C₃-C₈ alkenyl, C₄-C₈ alkenyl, C5-C12 alkenyl, and C7-C20 alkenyl. The alkenyl is attached to the rest of the molécule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. The alkenyl may be ^m or ; wherein each n and m is idependently 0-18. Unless stated otherwise specifically in the spécification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a,

-SR^a, -OC(O)-R^a, -N(R^a)2, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)2, -N(R^a)C(O)OR^f, -OC(O)- NR^aR^f, -N(R^a)C(O)R^f, N(R^a)S(O)_tR^f (where t is l or 2), -S(O),OR^a (where t is l or 2), -S(O)tR^f (where t is l or 2) and -S(O)tN(R^a)₂(where t is l or 2) where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each R^f is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. An alkenyl may be optionally substituted with one or more of oxo, halogen, -OR^a, -CN, and -N(R^a)₂. An alkenyl may be optionally substituted with one or more of oxo, halogen, -OH, -CN, and -NH₂.

- 8 ^0078] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twenty carbon atoms. An alkynyl comprising up to 30 carbon atoms is referred to as a C2-C30 alkynyl, likewise, for example, an alkynyl comprising up to 12 carbon atoms is a C2-C12 alkynyl. Alkynyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkynyl groups include, but are not limited to C2-C30 alkynyl, C₂-C₂o alkynyl, C2-C15 alkynyl, C2-C10 alkynyl, C2-C8 alkynyl, C2-C6 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl, C2-C8 alkynyl, C3-C8 alkynyl, C^-Cg alkynyl, C5-C12 alkynyl, and C7-C20 alkynyl. The alkynyl is attached to the rest of the molécule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the spécification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)2, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)2, -N(R^a)C(O)OR^f, -OC(O)NR^aR^f, -N(R^a)C(O)R^f, -N(R^a)S(O)tR^f (where t is l or 2), -S(O)tOR^a (where t is l or 2), -S(O),R^f (where t is l or 2) and -S(O)_tN(R^a)2 (where t is l or 2) where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each R^fis independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. An alkynyl may be optionally substituted with one or more of oxo, halogen, -OR^a, -CN, and -N(R^a)2. An alkynyl may be optionally substituted with one or more of oxo, halogen, -OH, -CN, and -NH2.

[0079] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molécule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylène, and the like. The alkylene chain is attached to the rest of the molécule through a single bond and to the radical group through a single bond. The points of attachaient of the alkylene chain to the rest of the molécule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. An alkylene may comprise one to eight carbon atoms (e.g., Ci-Cg alkylene). An alkylene may comprise one to five carbon atoms (e.g., C1-C5 alkylene). An alkylene may comprise one to four carbon atoms (e.g., C1-C4 alkylene). An alkylene may comprise one to three carbon atoms (e.g., C1-C3 alkylene). An alkylene may comprise one to two carbon atoms (e.g., C1-C2 alkylene). An alkylene may comprise one carbon atom (e.g., Ci alkylene). An alkylene may comprise five to eight carbon atoms (e.g., Cs-Cs alkylene An alkylene may comprise two to five carbon atoms (e.g., C2-C5 alkylene An alkylene may comprise three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the spécification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, SR^a, -OC(O)-R^a, -N(R^a)2, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)2, -N(R^a)C(O)OR^f, -OC(O)-NR^aR^f, -N(R^a)C(O)R^f, -N (R^a)S(O)tR^f (where t is l or 2), -S(O)tOR^a (where t is l or 2), -S(O)tR^f (where t is l or 2) and -S(O)tN(R^a)₂(where t is l or 2) where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each R^f is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. An alkylene may be optionally substituted with one or

-9^Wnore of oxo, halogen, -OR^a, -CN, and -N(R^a)₂. An alkylene may be optionally substituted with one or more of oxo, halogen, -OH, -CN, and -NH₂.

[0080] “Aminoalkyl” refers to a radical of the formula -R^c-N(R^a)₂ or -R^c-N(R^a)-R^c, where each R^c is independently an alkylene chain as defined above, for example, methylene, ethylene, and the like; and each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0081] “Alkoxy” refers to a radical of the formula -OR^a where R^a is an alkyl radical as defined. Unless stated otherwise specifically in the spécification, an alkoxy group may be optionally substituted as described above for alkyl.

[0082] “Aryl” refers to a radical derived from a hydrocarbon ring System comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring System, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring Systems. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring Systems of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene. phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the spécification, an aryl group is optionally substituted by one or more of the following substituents: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -R^b-OR^a, -R^b-OC(O)-R^a, -R^b-OC(O)-OR^a, -R^b-OC(O)-N(R^a)2, -R^b-N(R^a)2, -R^b-C(O)R^a, -R^b-C(O )OR^a, -R^b-C(O)N(R^a)2, -R^b-O-R^c-C(O)N(R^a)2, -R^b-N(R^a)C(O)OR^a, -R^b-N(R^a)C(O)R^a, -R^b-N(R^a)S(O)tR^a (where t is 1 or 2), -R^b-S(O)tOR^a (where t is 1 or 2), -R^b-S(O)tR^a (where t is 1 or 2), and -R^b-S(O)tN(R^a)2 (where t is 1 or 2), where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl (optionally substituted with one or more alkyl groups), heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, or two R^a attached to the same nitrogen atom are combined to form a heterocycloalkyl, each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. An aryl may be optionally substituted with one or more of halogen, alkyl, -OR^a, -CN, and -N(R^a)₂. An aryl may be optionally substituted with one or more of halogen, methyl, -OH, -CN, and -NH₂.

[0083] “Aryloxy” refers to a radical bonded through an oxygen atom of the formula -O-aryl, where aryl is as defined above.

[0084] “Aralkyl” refers to a radical of the formula -R^c-aryl where R^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0085] “Cycloalkyl” or “carbocycle” refers to a stable, non-aromatic, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring Systems, which is saturated or unsaturated comprising 2 to 20 carbon

- ΙΟ ^^atoms. Cycloalkyls include, but are not limited to C3-C20 cycloalkyl, C3-C15 cycloalkyl, C3-C10 cycloalkyl, C₃-Cs cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, and C3-C4 cycloalkyl, C₂-Cs cycloalkyl, C₃-Cg cycloalkyl, C4-C8 cycloalkyl, C5-C12 cycloalkyl, and C7-C20 cycloalkyl. Monocyclic cycloalkyls or carbocycles include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.l.l]hexane, bicyclo[2.2.l]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.l]heptanyl. Unless otherwise stated specifically in the spécification, the cycloalkyl is optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro,

IO optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-OC(O)-R^a, -R^b-OC(O)-OR^a, -R^b-OC(O)-N(R^a)2, -R^b-N(R^a)2, -R^b-C(O)R^a, -R^b-C(

O)OR^a, -R^b-C(O)N(R^a)2, -R^b-O-R^c-C(O)N(R^a)2, -R^b-N(R^a)C(O)OR^a, -R^b-N(R^a)C(O)R^a, -R^b-N(R^a)S(O)tR^a(where t is l or 2), -R^b-S(O)tOR^a (where t is l or 2), -R^b-S(O)tR^a (where t is l or 2) and -R^b-S(O)tN(R^a)₂ (where t is l or 2), where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. A cycloalkyl may be optionally substituted with one or more of oxo, halogen, alkyl, -OR^a, -CN, and -N(R^a)₂. A cycloalkyl may be optionally substituted with one or more of oxo, halogen, methyl, -OH, -CN, and -NH₂. [0086] “Cycloalkylalkyl” refers to a radical of the formula - IT-cycloalkyl where R^c is an alkylene chain as defïned above. The alkylene chain and the cycloalkyl radical are optionally substituted as defïned above.

[0087] “Fused” refers to any ring structure described herein which is fused to an existing ring structure.

When the fused ring is a heretocycloalkyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heretocycloalkyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.

[0088] “Heteroalkyl” refers to a straight or branched hydrocarbon chain alkyl radical containing no unsaturation, having from one to fifteen carbon atoms (e.g., Ci-Cis alkyl) consisting of carbon and hydrogen atoms and one or two heteroatoms selected from O, N, and S, wherein the nitrogen or sulfur atoms may be optionally oxidized and the nitrogen atom may be quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group including between the rest of the heteroalkyl group and the fragment to which it is attached. The heteroalkyl is attached to the rest of the molécule by a single bond. Unless stated otherwise specifically in the spécification, a heteroalkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)2, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)2, -N(R^a)C(O)OR^f, -OC(O)NR^aR^f, -N(R^a)C(O)R^f, -N(R^a)S(O)tR^f (where t is l or 2), -S(O)tOR^a (where t is l or 2), -S(O)tR^f (where t is l or 2) and -S(O)tN(R^a)₂ (where t is l or 2) where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl,

- Il ^^cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each R^fis independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0089] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. Halogen may refer to chloro or fluoro.

Halogen may refer to fluoro.

[0090] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l,2-difluoroethyl, 3-bromo-2-fluoropropyl, l,2-dibromoethyl, and the like. Unless stated otherwise specifically in the spécification, a haloalkyl group may be optionally substituted.

[0091] “Haloalkoxy” similarly refers to a radical of the formula -ORa where Ra is a haloalkyl radical as defined. Unless stated otherwise specifically in the spécification, a haloalkoxy group may be optionally substituted as described below.

[0092] “Heterocycloalkyl” or “heterocycle” refers to a stable 3- to 24-membered non-aromatic ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. Heterocycloalkyls include, but are not limited to C2-C20 heterocycloalkyl, C2C15 heterocycloalkyl, C2-C10 heterocycloalkyl, C2-C8 heterocycloalkyl, C2-C6 heterocycloalkyl, C2-C5 heterocycloalkyl, and C2-C4 heterocycloalkyl, C2-C8 heterocycloalkyl, Cs-Cs heterocycloalkyl, C4-C8 heterocycloalkyl, C5-C12 heterocycloalkyl, and C7-C20 heterocycloalkyl. Unless stated otherwise specifically in the spécification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring

System, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring Systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the heterocycloalkyl radical may be partially or fully saturated. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[ 1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrroiidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, 2-oxo-l,330 dioxol-4-yl, 1,1 -dioxidotetrahydro-2H-thiopyranyl, tetrahydro-2H-thiopyranyl, and tetrahydro-2H-pyranyl. The term heterocycloalkyl also includes ail ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls hâve from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the spécification, a heterocycloalkyl group is optionally substituted by one or more of the following substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl.

- 12 ^^optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-0R^a, -R^b-OC(O)-R^a, -R^b-OC(O)-OR^a, -R^b-OC(O)-N(R^a)2, -R^b-N(R^a)2, -R^b-C(0)R^a, -R^b-C(0 )OR^a, -R^b-C(O)N(R^a)2, -R^b-0-R^c-C(0)N(R^a)2, -R^b-N(R^a)C(O)OR^a, -R^b-N(R^a)C(O)R^a, -R^b-N(R^a)S(O)tR^a (where t 5 is l or 2), -R^b-S(O)tOR^a (where t is l or 2), -R^b-S(O)tR^a (where t is l or 2) and -R^b-S(O)tN(R^a)2 (where t is l or

2), where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. A heterocycloalkyl may be optionally substituted with one or more of oxo, halogen, alkyl, -OR^a, -CN, and -N(R^a)₂. A heterocycloalkyl may be optionally substituted with one or more of oxo, halogen, methyl, -OH, -CN, and -NH₂. [0093] “Heterocycloalkyllalkyl” refers to a radical of the formula -R^c-heterocycloalkyl where R^c is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocycloalkylslkyl radical is optionally substituted as defined above for an alkylene chain. The heterocycloalkyl part of the heterocycloalkylalkyl radical is optionally substituted as defined above for a heterocycloalkyl group.

[0094] “Heterocycloalkylalkoxy” refers to a radical bonded through an oxygen atom of the formula -OR^c-heterocycloalkyl where R^G is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain ofthe heterocycloalkylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocycloalkyl part of the heterocycloalkylalkoxy radical is optionally substituted as defined above for a heterocycloalkyl group.

[0095] “Heteroaryl” refers to a 5- to 14-membered ring System radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring. The heteroaryl may be is a 5-membered heteroaryl. The heteroaryl may be a 6-membered heteroaryl. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring System, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring

Systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l ,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl,

- I3 ^^yrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the spécification, a heteroaryl group is optionally substituted by one or more of the following substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted araikyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-OC(O)-R^a, -R^b-OC(O)-OR^a, -R^b-OC(O)-N(R^a)2, -R^b-N(R^a)2, -R^b-C(O)R^a, -R^b-C(O )OR^a, -R^b-C(O)N(R^a)2, -R^b-0-R°-C(0)N(R^a)2, -R^b-N(R^a)C(O)OR^a, -R^b-N(R^a)C(O)R^a, -R^b-N(R^a)S(O)tR^a (where t is l or 2), -R^b-S(O)tOR^a (where t is l or 2), -R^b-S(O)tR^a (where t is l or 2) and -R^b-S(O)tN(R^a)₂ (where t is l or 2), where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, araikyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. A heteroaryl may be optionally substituted with one or more of halogen, alkyl, -OR^a, -CN, and -N(R^a)₂. A heteroaryl may be optionally substituted with one or more of halogen, methyl, -OH, -CN, and -NH₂.

[0096] “A-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molécule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0097] “C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molécule is through a carbon atom in the heteroaryl radical. A Cheteroaryl radical is optionally substituted as described above for heteroaryl radicals.

10098] “Heteroaryloxy” refers to radical bonded through an oxygen atom of the formula -O-heteroaryl, where heteroaryl is as defined above.

[0099] “Heteroarylalkyl” refers to a radical of the formula -R^c-heteroaryl, where R^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[00100] “Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula -OR^c-heteroaryl, where R^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group. [00101] A “tautomer” refers to a molécule wherein a proton shifit from one atom of a molécule to another atom of the same molecüle is possible. The compounds presented herein may exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact

- 14Tatio of the tautomers dépends on several factors, including physical state, température, solvent, and pH. Some examples of tautomeric equilibrium include:

[00102] “Optional” or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution. “Optionally substituted” and “substituted or unsubstituted” and “unsubstituted or substituted” are used interchangeably herein.

[00103] “Pharmaceutically acceptable sait” includes both acid and base addition salts. A pharmaceutically acceptable sait of any one of the compounds described herein is intended to encompass any and ail pharmaceutically suitable sait forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. [00104] “Pharmaceutically acceptable acid addition sait” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are fornied with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy aikanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acétates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of

- 15 ^^amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66: l -19 ( 1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the sait.

[00105] “Pharmaceutically acceptable base addition sait” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. The pharmaceutically acceptable base addition salts may be fonned with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnésium, iron, zinc, copper, manganèse, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, AX-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,

A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[00106] As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictâtes otherwise. Thus, for example, référencé to “an agent” includes a plurality of such agents, and référencé to “the cell” includes référencé to one or more cells (or to a plurality of 20 cells) and équivalents thereof.

[00107] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, ail combinations and subcombinations of ranges and spécifie embodiments therein are intended to be included.

[00108] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range varies between 1% and 10% of the stated number or numerical range.

[00109] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that which in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of ’ the described features.

[00110] The term “subject” or “patient” encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animais such as cattle, horses, sheep, goats, swine;

domestic animais such as rabbits, dogs, and cats; laboratory animais including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[00111] The term nanoparticles refers to particles in the nanometer range. The size of the particles should be below a maximum size above which administration by subeutaneous or intramuscular injection becomes

- 16impaired or even no longer is possible. Said maximum size dépends for example on the limitations imposed by the needle diameter or by adverse reactions of the body to large particles, or both.

[00112] The term microparticles refers to particles in the micrometer range. The size ofthe particles should be below a maximum size above which administration by subcutaneous or intramuscular injection becomes impaired or even no longer is possible. Said maximum size dépends for example on the limitations imposed by the needle diameter or by adverse reactions of the body to large particles, or both.

[00113] As used herein, to treat a condition or treatment of the condition (e.g., malaria) is an approach for obtaining bénéficiai or desired results, such as clinical results. Bénéficiai or desired resuits can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition (e.g., preventing the spread of Plasmodium infection beyond the liver, preventing systemic disease, preventing the symptomatic stage of malaria, and/or preventing establishment of Plasmodium infection); delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether détectable or undetectable. Palliating a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.

[00114] As used herein, preventing includes preventing the initiation of malaria and/or reducing the severity or intensity of malaria.

Compounds

[00115] Described herein are compounds of Formula (F) or a pharmaceutically acceptable sait, solvaté, polymorphs, or stereoisomer thereof:

Formula (F) wherein:

R is ^CH₂OC(=O)R‘, -R², -C(=O)OR³, or -C(=O)R⁴;

R¹ is optionally substituted Ci-C₂oalkyl, optionally substituted C₂-C₂₀alkenyl, optionally substituted C₂C₂₀alkynyl, optionally substituted C₃-C₈cycloalkyl, or optionally substituted C₂-C₈heterocycloalkyl;

R² is optionally substituted (Ci-C₆alkylene)aryl, optionally substituted (Ci-C₆alkylene)heteroaryl, optionally substituted (Ci-C6alkylene)C₃-C₈cycloalkyl, or optionally substituted (Ci-C6alkylene)C₂Csheterocycloalkyl;

R³ is optionally substituted Ci-C₂₀alkyl, optionally substituted C₂-C₂₀alkenyl, or optionally substituted C₂-C₂oalkynyl; provided that R·’ is not ethyl; and

R⁴ is optionally substituted Ci-C₂₀alkyl, optionally substituted C₂-C₂alkenyl, or optionally substituted C₂-C₂₀alkynyl.

[00116] Described herein are compounds of Formula (I) or a pharmaceutically acceptable sait, solvaté, polymorphs, or stereoisomer thereof:

wherein:

R is -C(R^la)₂OC(=O)R', -R², -C(=O)OR³, or -C(=O)R⁴;

R¹ is optionally substituted Ci-C₃oalkyl, optionally substituted C₂-C3oalkenyl, optionally substituted C₂5 Csoalkynyl, optionally substituted Cs-Cscycloalkyl, or optionally substituted C₂-Csheterocycloalkyl;

each R^ia is independently hydrogen, halogen, or optionally substituted Ci-Ccalkyl;

or two R^la are taken together with the carbon atom to which they are attached to form an optionally substituted C₃-Cscycloalkyl;

R² is optionally substituted (Ci-Côalkylene)aryl, optionally substituted (Ci-C6alkylene)heteroaryl, optionally substituted (Ci-CôalkylenejCs-Cgcycloalkyl, or optionally substituted (Ci-Côalkylene)C₂Csheterocy c 1 oal ky 1 ;

R³ is optionally substituted Cs-Cwalkyl, optionally substituted C^Csoalkenyl, or optionally substituted C₂-C₃oalkynyl; and

R⁴ is optionally substituted Cs-Csoalkyl, optionally substituted C₂-C₃oalkenyl, or optionally substituted

C₂-C₃oalkynyl.

[00117] In a compound of Formula (I), R may be -C(R^la)2OC(=O)R^l, -C(=O)OR³, or -C(=O)R⁴. In a compound of Formula (1), R may be -C(R^la)2OC(=O)R’ or C(=O)C)R³. In a compound of Formula (I), R may be -C(R^la)2OC(=O)R' or -C(=O)R⁴. In a compound of Formula (I), R may be -C(=O)OR³ or -C(=O)R⁴. [00118] In a compound of Formula (I), R may be -C(R^la)2OC(=O)R’. In a compound of Formula (I), R may be -C(R^la)2OC(=O)R' and R^la may each be hydrogen. In a compound of Formula (I), R may be C(R^la)2OC(=O)R' and R^la may each be Ci-CôalkyL In a compound of Formula (I), R may be C(R^la)2OC(=O)R' and one R^la may be Ci-Cealkyi and one R^Ia may be hydrogen. In a compound of Formula (I), R may be -C(R^la)2OC(=O)R’ and one R^la may be halogen and one R^la may be hydrogen. In a compound of Formula (I), R may be -CH2OC(=O)R’. In a compound of Formula (I), R may be -CH2OC(=O)R¹ and R¹ may be optionally substituted Ci-C?oalkyl, optionally substituted C₂-C₂oalkenyl, or optionally substituted C₂C₂₀alkynyl. In a compound of Formula (I), R may be -CH₂OC(=O)R' and R¹ may be optionally substituted CiC2oalkyl or optionally substituted C2-C2oalkenyl. In a compound of Formula (I), R may be -CH2OC(=O)R’ and R¹ may be optionally substituted Ci-C20alkyl or optionally substituted C₂-C₃oalkenyl. In a compound of Formula (I), R may be -CH₂OC(=O)R¹ and R¹ may be Ci-C₂c>alkyl or C₂-C₂oalkenyl. In a compound of Formula (I), R may be -CH₂OC(=O)R' and R¹ may be Ci-C2oalkyl or C2-C3oalkenyl. In a compound of Formula (I), R may be -CH2OC(=O)R' and R¹ may be Ci-C3oalkyl. In a compound of Formula (I), R may be -CH2OC(=O)R' and R¹may be Ci-C2salkyl. In a compound of Formula (I), R may be -CH2OC(=O)R’ and R¹ may be Ci-C2oalkyl. In a compound of Formula (I), R may be -CH₂OC(=O)R' and R¹ may be Ci-C15alkyl. In a compound of Formula (I), R may be -CH2OC(=O)R’ and R¹ may be Ci-Csalkyl. In a compound of Formula (I), R may be 35 CH2OC(=O)R' and R¹ may be Ci-C7alkyl. In a compound of Formula (I), R may be -CH2OC(=O)R‘ and R¹may be C7-C₂oalkyl. In a compound of Formula (I), R may be -CH₂OC(=O)R’ and R¹ may be substituted Ci19130

- 18^FC₂oalkyl or substituted C2-C₂oalkenyl. In a compound of Formula (I), R may be -CH2OC(=O)R' and R' may be substituted Ci-C2oalkyl or substituted C₂-C3oalkenyl. In a compound of Formula (I), R may be -CH₂OC(=O)R‘ and R* may be substituted Ci-C₃oalkyl. In a compound of Formula (I), R may be -CH₂OC(=O)R' and R' may be substituted Ci-C₂5alkyl. In a compound of Formula (I), R may be -CH₂OC(=O)R’ and R¹ may be substituted Ci-C2oalkyl. In a compound of Formula (I), R may be -CH2OC(=O)R' and R¹ may be substituted Ci-Cisalkyl. In a compound of Formula (I), R may be -CH2OC(=O)R¹ and R¹ may be substituted Ci-CôalkyL In a compound of Formula (I), R may be -CH2OC(=O)R' and R¹ may be substituted Ci-C7alkyl. In a compound of Formula (I), R may be -CH2OC(=O)R' and R¹ may be substituted C7-C2oalkyl. In a compound of Formula (I), R may be CH2OC(=O)R' and R¹ may be or

In a compound of Formula (I), R may be -CH₂OC(=O)R' and R¹ may be

In a compound of Formula (I), R may be -CH₂OC(O)R' and R¹ may be C₂-C3oalkenyl. In a compound of Formula (I), R may be -CH₂OC(=O)R‘ and R¹ may be C₂-Cealkenyl. In a compound of Formula (I), R may be -CH2OC(=O)R' and R¹ may be C-z-Csoalkenyl. In a compound of Formula (I), R may be CH2OC(=O)R’ and R¹ may be C|5-C2oalkenyl. In a compound of Formula (I), R may be -CH2OC(=O)R' and R¹may be C|5-C₃oalkenyl. In a compound of Formula (I), R may be -CH₂OC(=O)R' and R¹ may be C2oCsoalkenyl. In a compound of Formula (I), R may be -CH2OC(=O)R' and R¹ may be substituted C2-C3oalkenyl. In a compound of Formula (I), R may be -CH₂OC(=O)R¹ and R¹ may be substituted OCealkenyl. In a compound of Formula (I), R may be -CH2OC(=O)R‘ and R¹ may be substituted C7-C₃oalkenyl. In a compound of Formula (I), R may be -CH₂OC(=O)R‘ and R¹ may be substituted Ci5-C20alkenyl. In a compound of Formula (I), R may be -CH2OC(=O)R' and R¹ may be substituted C|5-C₃oalkenyl. In a compound of Formula (I), R may be -CH₂OC(=O)R' and R¹ may be substituted C_2O-C₃oalkenyl. In a compound of Formula (I), R may be -

CH₂OC(=O)R' and R¹ may be

T⁵ ^m wherein R⁵ is H or methyl; n is 0-18; and m is 0-18; provided that n+m is less than 18 when R⁵ is H or n+m is less than 17 when R⁵ is methyl. In a compound of Formula (I), n may be 0. In a compound of Formula (I), n may be 1. In a compound of Formula (I), n may be 2. In a compound of Formula (I), n may be 3. In a compound of Formula (I), n may be 4. In a compound of Formula (I), n may be 5. In a compound of Formula (I), n may be 6. In a compound of Formula (I), n may be 7. In a compound of Formula (I), n may be 8. In a compound of Formula (I), n may be 9. In a compound of Formula (I), n may be 10. In a compound of Formula (I), n may be 11. In a compound of Formula (I), n may be 12. In a compound of Formula (I), n may be 13. In a compound of Formula (I), n may be 14. In a compound of Formula (I), n may be 15. In a compound of Formula (1), n may be 16. In a compound of Formula (I), n may be 17. In a compound of Formula (1), n may be 18. In a compound of Formula (1), m may be 0. In a compound of Formula (I), m may be 1. In a compound of Formula (1), m may be 2. In a compound of Formula (I), m may be 3. In a compound of Formula (I), m may be 4. In a compound of Formula (I), m may be 5. In a compound of Formula (I), m may be 6. In a compound of Formula (I), m may be 7. In a compound of Formula (I), m may be 8. In a

- 19compound of Formula (I), m may be 9. In a compound of Formula (I), m may be 10. In a compound of Formula (I), m may be 11. In a compound of Formula (I), m may be 12. In a compound of Formula (I), m may be 13. In a compound of Formula (I), m may be 14. In a compound of Formula (I), m may be 15. In a compound of Formula (I), m may be 16. In a compound of Formula (I), m may be 17. In a compound of Formula (I), m may be 18.

[00119] In a compound of Formula (I), R may be -CH2OC(=O)R' and R^{1 *} may be

[00120] In a compound of Formula (1), R may be -C(=O)OR^{3 * *}. In a compound of Formula (I), R may be C(=O)OR³ and R³ may be optionally substituted Cs-C2oalkyl, optionally substituted C4-C2oalkenyl, or optionally substituted C2-C2oalkynyl. In a compound of Formula (I), R may be -C(=O)OR³ and R³ may be optionally substituted C5-C2oalkyl or optionally substituted C₄-C₂oalkenyl. In a compound of Formula (I), R may be C(=O)OR³ and R³ may be Cs-Csoalkyl. In a compound of Formula (I), R may be -C(=O)OR³ and R³ may be CsC2oalkyl. In a compound of Formula (I), R may be -C(=O)OR³ and R^J may be Cs-Cioalkyl. In a compound of Formula (I), R may be -C(=O)OR³ and R³ may be Cn-Csoalkyl. In a compound of Formula (I), R may be C(=O)OR³ and R³ may be Cs-Cisalkyl. In a compound of Formula (I), R may be -C(=O)OR³ and R’ may be CôCiôalkyl. In a compound of Formula (I), R may be -C(=O)OR³ and R³ may be substituted Cs-Cjoalkyl. In a compound of Formula (I), R may be -C(=O)OR³ and R³ may be substituted Cs-C2oalkyl. In a compound of Formula (I), R may be -C(=O)OR³ and R³ may be substituted Cs-Cioalkyl. In a compound of Formula (I), R may be -C(=O)OR³ and R³ may be substituted Cn-Caoalkyl. In a compound of Formula (I), R may be C(=O)OR³ and R³ may be substituted Cs-Cisalkyl. In a compound of Formula (1), R may be -C(=O)OR³ and R^Jmay be substituted Cé-Ciealkyl. In a compound of Formula (I), R may be ~C(=O)OR³ and R³ may be

I q wherein R⁶ is H or methyl; p is 0 to 18; and q is 0 to 18; provided that p+q is less than 18 when R⁶ is H or p+q is less than 17 when R⁶ is methyl; and provided that R³ is not ethyl. In a compound of Formula (I), p may be 0. In a compound of Formula (I), p may be 1. In a compound of Formula (I), p may be 2. In a compound of Formula (I), p may be 3. In a compound of Formula (I), p may be 4. In a compound of Formula (I), p may be 5. In a compound of Formula (I), p may be 6. In a compound of Formula (I), p may be 7. In a compound of Formula (I), p may be 8. In a compound of Formula (I), p may be 9. In a compound of Formula (I), p may be 10. In a compound of Formula (I), p may be 11. In a compound of Formula (I), p may be

12. In a compound of Formula (I), p may be 13. In a compound of Formula (I), p may be 14. In a compound of Formula (I), p may be 15. In a compound of Formula (I), p may be 16. In a compound of Formula (I), p may be

17. In a compound of Formula (1), p may be 18. In a compound of Formula (I), q may be 0. In a compound of Formula (I), q may be 1. In a compound of Formula (I), q may be 2. In a compound of Formula (I), q may be 3. In a compound of Formula (I), q may be 4. In a compound of Formula (I), q may be 5. In a compound of Formula (I), q may be 6. In a compound of Formula (I), q may be 7. In a compound of Formula (I), q may be 8.

In a compound of Formula (I), q may be 9. In a compound of Formula (1), q may be 10. In a compound of

Formula (I), q may be 11. In a compound of Formula (I), q may be 12. In a compound of Formula (I), q may be

13. In a compound of Formula (I), q may be 14. In a compound of Formula (1), q may be 15. In a compound of

ormula (I), q may be 16. In a compound of Formula (I), q may be 17. In a compound of Formula (I), q may be

18. In a compound of Formula (I), R may be -C(-O)OR³ and R^J may be

[00121] In a compound of Formula (I), R may be -C(=O)R⁴.

[00122] In a compound of Formula (I), R may be -C(=O)R⁴ and R⁴ may be Cs-Cjoalkyl. In a compound of

Formula (I), R may be -C(=O)R⁴ and R⁴ may be optionaily substituted C5-C20alkyl, optionally substituted C2C20alkenyl, or optionally substituted C2-C20alkynyl. In a compound of Formula (I), R may be -C(=O)R⁴ and R⁴may be optionally substituted Cs-C2oalkyl or optionally substituted C₂-C₂oalkenyl. In a compound of Formula (I), R may be -C(=O)R⁴ and R⁴ may be C₅-C₃₀alkyl. In a compound of Formula (I), R may be -C(=O)R⁴ and R⁴ may be C5-C₂oalkyl. In a compound of Formula (I), R may be -C(=O)R⁴ and R⁴ may be Cs-Cioalkyl. In a compound of Formula (I), R may be -C(=O)R⁴ and R⁴ may be Cn-Csoalkyl. In a compound of Formula (I), R may be -C(=O)R⁴ and R⁴ may be C5-Ci5alkyl. In a compound of Formula (I), R may be -C(=O)R⁴ and R⁴ may be Cis-Csoalkyl. In a compound of Formula (I), R may be C(=O)R’ and R⁴ may be Ci5-C25alkyl. In a compound of Formula (I), R may be -C(=O)R⁴ and R⁴ may be substituted C₅-C₃₀alkyl. In a compound of

Formula (I), R may be -C(=O)R⁴ and R⁴ may be substituted C5-C2oalkyl. In a compound of Formula (I), R may be C(=O)R⁴ and R⁴ may be substituted C5-Ci_Oalkyl. In a compound of Formula (I), R may be -C(=O)R⁴ and R⁴may be substituted Cn-C3oalkyl. In a compound of Formula (I), R may be C(=O)R⁴ and R⁴ may be substituted C5-Ci₅alkyl. In a compound of Formula (I), R may be -C(=O)R⁴ and R⁴ may be substituted Ci5-C3Oalkyl. In a compound of Formula (I), R may be —C(=O)R⁴ and R⁴ may be substituted Ci5-C25alkyl.

[00123] Described herein are compounds of Formula (1Γ) or a pharmaceutically acceptable sait, solvaté, polymorphs, or stereoisomer thereof:

Formula (ΙΓ) wherein:

R’ is -CH₂OC(=O)R⁷, -R⁸, -C(=O)OR⁹, or-C(=O)R¹⁰;

R⁷ is optionally substituted Ci-C₂₀alkyl, optionally substituted C₂-C₂₀alkenyl, optionally substituted C₂C₂₀alkynyl, optionally substituted C₃-C₈cycloalkyl, or optionally substituted C₂-C₈heterocycloalkyl;

R⁸ is optionally substituted (Ci-C₆alkylene)aryl, optionally substituted (Ci-C6alkylene)heteroaryl, optionally substituted (Ci-C₆alkylene)C₃-C₈cycloalkyl, or optionally substituted (Ci-C₆alkylene)C₂Cgheterocycloalkyl;

R⁹ is optionally substituted CrC^alkyl, optionally substituted C₂-C₂₀alkenyl, or optionally substituted

C₂-C₂oalkynyl; and

R¹⁰ is optionally substituted Ci-C₂oalkyl, optionally substituted C₂-C₂oalkenyl, or optionally substituted C₂-C₂oalkynyl.

-2l [00124] Described herein are compounds of Formula (II) or a pharmaceutically acceptable sait, solvaté, polymorphs, or stereoisomer thereof:

H₃CC

Cl

N CH₃ ocf₃

Formula (II) wherein:

R’ is -C(R^7a)₂OC(=O)R⁷, -R⁸, -C(=O)OR⁹, or -C(=O)R¹⁰;

R⁷ is optionally substituted Ci-C₃oalkyl, optionally substituted C₂-C3oalkenyl, optionally substituted C₂Cjoalkynyl, optionally substituted C₃-Cscycloalkyl, or optionally substituted C2-Csheterocycloalkyl; each R^7a is independently hydrogen, halogen, or optionally substituted Ci-Cealkyl;

or two R^7a are taken together with the carbon atom to which they are attached to form an optionally substituted Ca-Cscycloalkyl;

R⁸ is optionally substituted (Ci-C₆alkylene)aryl, optionally substituted (Ci-C₆alkylene)heteroaryl, optionally substituted (Ci-C₆alkylene)C3-C₈cycloalkyl, or optionally substituted (Ci-C₆alkylene)C2Cgheterocycloalkyl;

R⁹ is optionally substituted Ci-C₃oalkyl, optionally substituted C₂-C₃oalkenyl, or optionally substituted C₂-C₃oalkynyl; and

R'° is optionally substituted Ci-C₃₀alkyl, optionally substituted C₂-C₃₀alkenyl, or optionally substituted C2-C₃oalkynyl.

[00125] In a compound of Formula (II), R’ may be -C(R^7a)2OC(=O)R⁷, -C(=O)OR⁹, or -C(=O)R¹⁰. In a compound of Formula (I), R’ may be -C(R^7a)2OC(=O)R⁷ or -C(=O)OR⁹. In a compound of Formula (II), R’ may be -C(R^7a)₂OC(=O)R⁷ or -C(=O)R¹⁰. In a compound of Formula (II), R’ may be -C(=O)OR⁹ or C(=O)R¹⁰.

[00126] In a compound of Formula (II), R’ may be -C(R^7a)2OC(=O)R⁷. In a compound of Formula (II), R’ may be -C(R^7a)2OC(=O)R⁷ and R^7a may each be hydrogen. In a compound of Formula (II), R’ may be C(R^7a)2OC(=O)R⁷ and R^7a may each be Ci-C6alkyl. In a compound of Formula (II), R’ may beC(R^7a)2OC(=O)R⁷ and one R^7a may be Ci-C6alkyl and one R^7a may be hydrogen. In a compound of Formula (II), R’ may be -C(R^7a)2OC(=O)R⁷ and one R^7a may be halogen and one R^7a may be hydrogen. In a compound of Formula (II), R’ may be CI12OC(=O)R⁷. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷may be optionally substituted Ci-C20alkyl, optionally substituted C₂-C₂₀alkenyl, or optionally substituted C₂C₂oalkynyl. In a compound of Formula (II), R’ may be —CH₂OC(=O)R⁷ and R⁷ may be optionally substituted Ci-C20alkyl or optionally substituted C2-C3oalkenyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷and R⁷ may be optionally substituted Ci-C2oalkyl or optionally substituted C₂-C₂oalkenyl. In a compound of Formula (II), R’ may be -CH₂OC(=O)R⁷ and R⁷ may be Ci-C20alky! or C2-C30alkenyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be Ci-C2oalkyl or C₂-C₂₀alkenyl. In a compound of Formula (II), R’ may be -CH₂OC(=O)R⁷ and R⁷ may be C1-C3oalkyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be Ci-C25alkyl. In a compound of Formula (II), R’ may be -CH₂OC(=O)R⁷ and R⁷may be Ci-Ci5alkyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be Ci-C2oalkyl. In

-22 compound of Formula (II), R’ may be -CH?OC(=O)R⁷ and R⁷ may be Ci-Côalkyl. In a compound of Formula (II), R’ may be -CH₂OC(=O)R⁷ and R⁷ may be Ci-C?alkyl. In a compound of Formula (II), R’ may be CH2OC(=O)R⁷ and R⁷ may be C7-C2oalkyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷may be substituted Ci-Csoalkyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be substituted Ci-C25alkyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be substituted Ci-C2oalkyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be substituted Ci-Cisalkyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be substituted Ci-Côalkyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be substituted Ci-Cyalkyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be substituted C7-C2oalkyl. In a compound of Formula (II), R’ may be -CH₂OC(=O)R⁷ and R⁷ may be or

In a compound of Formula (II), R’ may be -CH₂OC(-O)R⁷ and

R⁷ may be

In a compound of Formula (II), R’ may be -CH₂OC(=O)R⁷ and R⁷ may be C2Csoalkenyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be C2-C6alkenyl. In a compound of Formula (II), R’ may be -CH₂OC(=O)R⁷ and R⁷ may be C7-C3oalkenyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be Ci5-C₂₀alkenyl. In a compound of Formula (II), R’ may be -CH₂OC(=O)R⁷ and R⁷ may be Ci5-C3oalkenyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷and R⁷ may be C2o-C3oalkenyl. In a compound of Formula (II), R’ may be -CH₂OC(=O)R⁷ and R⁷ may be substituted C2-C3oalkenyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be substituted C2-Côalkenyl. In a compound of Formula (II), R’ may be -CH₂OC(=O)R⁷ and R⁷ may be substituted C7-C3oalkenyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be substituted CisC2oalkenyl. In a compound of Formula (II), R’ may be —CH₂OC(=O)R⁷ and R⁷ may be substituted C15Csoalkenyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be substituted C20Caoalkenyl. In a compound of Formula (II), R’ may be -CH2OC(=O)R⁷ and R⁷ may be ^m wherein R⁵ is H or methyl; n is 0-18; and m is O-l8; provided that n+m is less than 18 when R⁵ is H or n+m is less than 17 when R⁵ is methyl. In a compound of Formula (II), n may be 0. In a compound of Formula (II), n may be l. In a compound of Formula (II), n may be 2. In a compound of Formula (II), n may be 3. In a compound of Formula (II), n may be 4. In a compound of Formula (II), n may be 5. In a compound of Formula (II), n may be 6. In a compound of Formula (II), n may be 7. In a compound of Formula (II), n may be 8. In a compound of Formula (II), n may be 9. In a compound of Formula (II), n may be 10. In a compound of Formula (II), n may be 11. In a compound of Formula (II), n may be 12. In a compound of Formula (II), n may be 13. In a compound of Formula (II), n may be 14. In a compound of Formula (II), n may be 15. In a compound of Formula (II), n may be 16. In a compound of Formula (II), n may be 17. In a compound of Formula (II), n may be 18. In a compound of Formula (II), m may be 0. In a compound of Formula (II), m may be l. In a compound of Formula (II), m may be 2. In a compound of Formula (II), m may be 3. In a compound of Formula (II), m

-23 Tnay be 4. In a compound of Formula (II), m may be 5. In a compound of Formula (II), m may be 6. In a compound of Formula (II), m may be 7. In a compound of Formula (II), m may be 8. In a compound of Formula (II), m may be 9. In a compound of Formula (II), m may be 10. In a compound of Formula (II), m may be 11. In a compound of Formula (II), m may be 12. In a compound of Formula (II), m may be 13. In a compound of Formula (II), m may be 14. In a compound of Formula (II), m may be 15. In a compound of Formula (11), m may be 16. In a compound of Formula (II), m may be 17. Inacompound of Formula (II), m may be 18.

[00127] In a compound of Formula (II), R’ may be -CH₂OC(=O)R⁷ and R⁷ may be

[00128] In a compound of Formula (II), R’ may be -C(=O)OR⁹.

[00129] In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be optionally substituted CiC20alkyl, optionally substituted C2-C2oalkenyl, or optionally substituted C2-C20alkynyl. In a compound of Formula (H), R’ may be -C(=O)OR⁹ and R⁹ may be optionally substituted Ci-C2oalkyl or optionally substituted C₂-C₂oalkenyl. In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be C5-C3oalkyl. In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be C5-C₂₀alkyl. In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be C5-CiOalkyl. In a compound of Formula (11), R’ may be -C(=O)OR⁹ and R⁹ may be Cn-Csoalkyl. In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be C5-C|5alkyl. In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be Ce-Ciealkyl. In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be substituted C5-C3oalkyl. In a compound of Formula (II), R’ may be C(=O)OR⁹ and R⁹ may be substituted C5-C₂₀alkyl. In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be substituted Cs-Cioalkyl. In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be substituted Cn-C₃oalkyl. In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be substituted CsCisalkyl. In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be substituted Cô-Ciealkyl. . In a

P compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be I ^M wherein R is H or methyl; p is 0 to 18; and q is 0 to 18; provided that p+q is less than 18 when R⁶ is H or p+q is less than 17 when R⁶ is methyl. In a compound of Formula (II), p may be 0. In a compound of Formula (II), p may be 1. In a compound of Formula (II), p may be 2. In a compound of Formula (II), p may be 3. In a compound of Formula (II), p may be 4. In a compound of Formula (II), p may be 5. In a compound of Formula (II), p may be 6. In a compound of Formula (II), p may be 7. In a compound of Formula (II), p may be 8. In a compound of Formula (TI), p may be 9. In a compound of Formula (II), p may be 10. In a compound of Formula (II), p may be 11. In a compound of Formula (II), p may be 12. In a compound of Formula (II), p may be 13. In a compound of Formula (II), p may be 14. In a compound of Formula (II), p may be 15. In a compound of Formula (II), p may be 16. In a compound of Formula (II), p may be 17. In a compound of Formula (II), p may be 18. In a compound of Formula (II), q may be 0. In a compound of Formula (II), q may be 1. In a compound of Formula (II), q may be 2. In a compound of Formula (II), q may be 3. In a compound of Formula (II), q may be 4. In a compound of Formula (II), q may be 5. In a compound of Formula (II), q may be 6. In a compound of Formula (II), q may be 7. In a compound of Formula (II), q may be 8. In a compound of Formula (II), q may be 9. In a compound of

-24 Formula (II), q may be 10. In a compound of Formula (II), q may be 11. In a compound of Formula (II), q may be 12. In a compound of Formula (II), q may be 13. In a compound of Formula (II), q may be 14. In a compound of Formula (II), q may be 15. In a compound of Formula (II), q may be 16. In a compound of

Formula (II), q may be 17. In a compound of Formula (II), q may be 18. In a compound of Formula (II), R’ may be -C(=O)OR⁹ and R⁹ may be

[00130] In a compound of Formula (II), R’ may be -C(=O)Rⁱ⁰.

[00131] In a compound of Formula (II), R’ may be -C(=O)R¹⁰ and R'° may be optionally substituted CiC2oalkyl, optionally substituted C2-C?oalkenyl, or optionally substituted C2-C2oalkynyl. In a compound of

Formula (11), R’ may be -C(=O)Rⁱ⁰ and R¹⁰ may be optionally substituted Ci-C2oalkyl or optionally substituted C2-C2oalkenyl. In a compound of Formula (II), R’ may be -C(=O)R¹⁰ and R¹⁰ may be Cs-C3oalkyl. In a compound of Formula (II), R’ may be —C(=O)R¹⁰ and R¹⁰ may be Cs-C2oalkyl. In a compound of Formula (II), R’ may be -C(=O)R¹⁰ and R¹⁰ may be C5-CiOalkyl. In a compound of Formula (II), R’ may be -C(=O)R¹⁰ and R¹⁰ may be Cu-C3oalkyl. In a compound of Formula (II), R’ may be -C(=O)R'° and R¹⁰ may be Cs-Cisalkyl. In a compound of Formula (II), R’ may be -C(=O)R'° and R¹⁰ may be C15-C30alkyl. In a compound of Formula (II), R’ may be -C(=O)R'° and R¹⁰ may be Ci5-C25alkyl. In a compound of Formula (II), R’ may be -C(=O)R¹⁰and R¹⁰ may be substituted Cs-Csoalkyl. In a compound of Formula (II), R’ may be -C(=O)R¹⁰ and R¹⁰ may be substituted Cs-Czoalkyl. In a compound of Formula (II), R’ may be -C(=O)R’° and R¹⁰ may be substituted C₅Cioalkyl. In a compound of Formula (II), R’ may be -C(=O)R¹⁰ and R¹⁰ may be substituted Cu-Cjoalkyl. In a compound of Formula (II), R’ may be —C(=O)R¹⁰ and R¹⁰ may be substituted Cs-Cisalkyl. In a compound of Formula (II), R’ may be -C(=O)R¹⁰ and R¹⁰ may be substituted Ci5-C30alkyl. In a compound of Formula (II), R’ may be -C(=O)R'° and R¹⁰ may be substituted Ci5-C25alkyl.

[00132] Described herein are crystalline compounds of Formula (II) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

Formula (II) wherein:

R’ is -C(R^7a)₂OC(=O)R⁷, -R⁸, -C(=O)OR⁹, or -C(=O)R'°;

R⁷ is optionally substituted Ci-C₃₀alkyl, optionally substituted C₂-C₃oalkenyl, optionally substituted C₂C₃₀alkynyl, optionally substituted C₃-C₈cycloalkyl, or optionally substituted C₂-C₈heterocycloalkyl;

each R^7a is independently hydrogen, halogen, or optionally substituted Ci-Cealkyl;

or two R^7a are taken together with the carbon atom to which they are attached to form an optionally substituted C₃-Cscycloalkyl;

ri

-25 R⁸ is optionally substituted (Ci-C6alkylene)aryl, optionally substituted (Ci-Côalkylene)heteroaryl, optionally substituted (Ci-CealkylenejCs-Cscycloalkyl, or optionally substituted (Ci-Côalkylene)C₂Cgheterocycloalkyl;

R⁹ is optionally substituted Ci-C₃oalkyl, optionally substituted Cî-Csoalkenyl, or optionally substituted Ca-Cjoalkynyl; and

R’° is optionally substituted Ci-C₃oalkyl, optionally substituted C₂-C3oalkenyl, or optionally substituted C₂-C₃oalkynyl.

[00133] The crystalline compound of Formula (II) may be crystalline ((6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methyl butyrate or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof.

[00134] The crystalline form of ((6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methyl butyrate may hâve at least one of the following properties:

(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 41; or (b) an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 14.4+0.1° 20, about 15.1+0.1° 20, about 17.7+0.1° 20, about 18.1+0.1° 20, about 22.3+0.1° 20, and about 22.6+0.1° 20; or (c) a DSC thermogram substantially the same to the one set forth in FIG. 42A; or (d) a DSC thermogram with an endotherm having a peak at about 99.5 °C.

[00135] The crystalline form of ((6-chloro-7-methoxy-2-methy 1-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methyl butyrate may hâve an X-ray powder diffraction (XRPD) pattern further comprising characteristic peaks at about 19.0°±0.1° 20, about 20.3°±0.1° 20, about 21.2°±0.1 ° 20, about 26.7°±0.1 ° 20, and about 29.2°±0.1 ° 20.

[00136] Described herein are compounds of Formula (III) or a pharmaceutically acceptable sait, solvaté, polymorphs, or stereoisomer thereof:

•CI

Formula (III) wherein:

R is a lipophilie moiety.

[00137] In a compound of Formula (III), R¹¹ may be optionally substituted Ci-Csoalkyl, optionally substituted C2-C30alkenyl, or optionally substituted C2-C30alkynyl. In a compound of Formula (III), R¹' may be optionally substituted Ci-C2oalkyl, optionally substituted C₂-C₂oalkenyl, or optionally substituted C₂-C₂oalkynyl.

[00138] In a compound of Formula (III), R may be Ci-C₂₀alkyl. In a compound of Formula (III), R may be Ci-C₃₀alkyl. In a compound of Formula (III), R¹¹ may be CrCealkyl. In a compound of Formula (III), R¹¹ may

-26 CvCsoalkyl. In a compound of Formula (III), R^H may be Cv-Csoalkyl. In a compound of Formula (III), R¹¹ may be substituted Ci-C₂oalkyl. In a compound of Formula (III), R may be substituted Ci-Csoalkyl. In a compound of Formula (III), R¹¹ may be substituted Ci-Côalkyl. In a compound of Formula (III), R may be substituted Cv-Csoalkyl. In a compound of Formula (III), R may be substituted Cv-Csoalkyl. In a compound of

[00139] In a compound of Formula (III), R may be C₂-C₃oalkenyl. In a compound of Formula (III), R may be Cj-Csoalkenyl. In a compound of Formula (III), R may be Cô-Csoalkenyl. In a compound of Formula (III), R¹¹ may be Ce-Cssalkenyl. In a compound of Formula (III), R¹¹ may be Ci5-C2salkenyl. In a compound of Formula (III), R¹¹ may be C2-C₂₅alkenyl. In a compound of Formula (III), R” may be C₂-C₂₀alkenyl. In a compound of Formula (III), R¹¹ may be C2-Cisalkenyl. In a compound of Formula (III), R may be C2Cioalkenyl. In a compound of Formula (111), R may be C2-C6alkenyl. In a compound of Formula (III), R may be Cé-Csoalkenyl. In a compound of Formula (III), R may be C6-C25alkenyl. In a compound of Formula (III), R¹¹ may be substituted C2-C₃oalkenyl. In a compound of Formula (III), R may be substituted C₃-C₃oalkenyl. In a compound of Formula (III), R¹¹ may be substituted Cû-Csoalkenyl. In a compound of Formula (III), R may be substituted Cô-C25alkenyl. In a compound of Formula (III), R¹¹ may be substituted Ci5-C2salkenyl. In a compound of Formula (III), R¹¹ may be substituted C2-C25alkenyl. In a compound of Formula (III), R¹¹ may be substituted C2-C₂oalkenyl. In a compound of Formula (III), R may be substituted C₂-Ci5alkenyl. In a compound of Formula (III), R¹’ may be substituted C2-Ci0alkenyl. In a compound of Formula (III), R¹¹ may be substituted Cv-Cealkenyl. In a compound of Formula (III), R may be substituted Ce-Csoalkenyl. In a compound of Formula (III), R may be substituted C6-C₂₅alkenyl. In a compound of Formula (III), R may be

. In a compound of Formula (III), R²¹ may comprise between 1 and double bonds. In a compound of Formula (III), R²¹ may comprise between 1 and 6 double bonds. In a compound of Formula (III), R²¹ may comprise between 4 and 8 double bonds. In a compound of Formula (III), R²¹ may comprise between 4 and 6 double bonds. In a compound of Formula (III), R²¹ may comprise between 2 and 8 double bonds. In a compound of Formula (III), R²¹ may comprise between 2 and 6 double bonds. In a compound of Formula (III), R²¹ may comprise more than 1 double bond. In a compound of Formula (III), R²¹may comprise more than 2 double bonds. In a compound of Formula (III), R²ⁱ may comprise more than 3 double bonds. In a compound of Formula (III), R²¹ may comprise more than 4 double bonds. In a compound of Formula (III), R²¹ may comprise more than 5 double bonds. In a compound of Formula (III), R²¹ may comprise 1 double bond. In a compound of Formula (III), R²¹ may comprise 2 double bonds. In a compound of Formula (III), R²¹ may comprise 3 double bonds. In a compound of Formula (III), R²¹ may comprise 4 double bonds. In a

-27 ompound of Formula (III), R²¹ may comprise 5 double bonds. In a compound of Formula (III), R²¹ may comprise 6 double bonds.

[00140] Described herein are compounds of Formula (IV) or a pharmaceutically acceptable sait, solvaté, polymorphs, or stereoisomer thereof:

Formula (IV) wherein R²' is optionally substituted C₃-C₃oalkenyl or optionally substituted C2-C₃oalkynyl.

[00141] In a compound of Formula (IV), R²¹ may be C3-C3oalkenyl or C2-C3oalkynyl. In a compound of Formula (IV), R²¹ may be C3-C₃oalkenyl. In a compound of Formula (IV), R²¹ may be Cô-Csoalkenyl. In a compound of Formula (IV), R²¹ may be C6-C25alkenyl. In a compound of Formula (IV), R²¹ may be CisC25alkenyl. In a compound of Formula (IV), R²¹ may be substituted C₃-C₃₀alkenyl. In a compound of Formula (IV), R²¹ may be substituted C6-C3oalkenyl. In a compound of Formula (IV), R²¹ may be substituted CeC25alkenyl. In a compound of Formula (IV), R²¹ may be substituted Ci5-C₂₅alkenyl. In a compound of Formula ^Me (IV), R²¹ may be _ j_{n a} compound of Formula (IV), R²¹ may comprise between 1 and 10 double bonds. In a compound of Formula (IV), R²¹ may comprise between 1 and 6 double bonds. In a compound of Formula (IV), R²¹ may comprise between 4 and 8 double bonds. In a compound of Formula (IV), R²¹ may comprise between 4 and 6 double bonds. In a compound of Formula (IV), R²¹ may comprise between 2 and 8 double bonds. In a compound of Formula (IV), R²¹ may comprise between 2 and 6 double bonds. In a compound of Formula (IV), R²¹ may comprise more than 1 double bond. In a compound of Formula (IV), R²¹ may comprise more than 2 double bonds. In a compound of Formula (IV), R²¹may comprise more than 3 double bonds. In a compound of Formula (IV), R²¹ may comprise more than 4 double bonds. In a compound of Formula (IV), R²¹ may comprise more than 5 double bonds. In a compound of Formula (IV), R²¹ may comprise 1 double bond. In a compound of Formula (IV), R²¹ may comprise 2 double bonds. In a compound of Formula (IV), R²¹ may comprise 3 double bonds. In a compound of Formula (IV), R²¹may comprise 4 double bonds. In a compound of Formula (IV), R²¹ may comprise 5 double bonds. In a compound of Formula (IV), R²¹ may comprise 6 double bonds.

[00142] Described herein are crystalline compounds of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

•Cl

Formula (III) wherein:

R¹¹ is a lipophilie moiety.

[00143] Described herein are crystalline forms of ELQ-300 or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

Cl

HoCO^^^N^CHo

H ELQ-300 (6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one). The crystalline form of ELQ-300, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be ELQ-300-Form IA. The crystalline form of ELQ-300, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be ELQ-300Form IB. The crystalline form of ELQ-300, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be ELQ-300-Form IL The crystalline form of ELQ-300, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be ELQ-300-Form III. The crystalline form of ELQ-300, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be ELQ-300-Form IV. The crystalline form of ELQ-300, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be ELQ-300Form V.

[00144] Described herein are crystalline forms of atovaquone or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

CI atovaquone (trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4naphthalenedione).

[00145] The crystalline form of atovaquone, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be atovaquone -Form 1. The crystalline form of atovaquone, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be atovaquone -Form II.

[00146] Described herein are crystalline forms of pyronaridine or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

pyronaridine (4-[(7-chloro-2-methoxy-pyrido[3,2-b]quinolin-10-yl)amino]2,6-bis(pyrrolidin-l-ylmethyl)phenol).

[00147] The crystalline form of pyronaridine may be obtained from a pyronaridine sait. The pyronaridine sait may be pyronaridine pamoate, pyronaridine benzenesulfonate, pyronaridine palmitate, pyronaridine naphthalate, pyronaridine benzoate, pyronaridine edetate, pyronaridine edisylate, pyronaridine estolate, pyronaridine napsylate, pyronaridine mesylate, pyronaridine stéarate, or pyronaridine valerate. The pyronaridine sait may be pyronaridine pamoate.

[00148] The crystalline form of pyronaridine, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be pyronaridine-Form L The crystalline form of pyronaridine, or a pharmaceutically acceptable 10 sait, solvaté, or stereoisomer thereof may be pyronaridine-Form II. The crystalline form of pyronaridine, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be pyronaridine-Form III. The crystalline form of pyronaridine, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be pyronaridine-Form V. The crystalline form of pyronaridine, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof may be pyronaridine-Form V.

[00149] In some embodiments, the compound disclosed herein has the structure provided in Table 1.

TABLE 1

Comp.	Name	Structure
1	(6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yloxy)methyl acetate	O ' o o η η HjCO^^^N^CHa
2	(6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yloxy)methyl butyrate	O Jk x-v ? ïC ^-₃ h₃co^x^''^î^n^îx:h3
3	(6-chloro-7-methoxy-2-methy 1 -3 -(4-(4(trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yloxy)methyl isobutyrate	0 Ήγό H3CO-^X^^<N^CH3
4	(6-chloro-7-methoxy-2-methy 1-3-(4-(4(trifl uoromethoxy)phenoxy)pheny l)qui nolin-4-yloxy)methyl hexanoate	0 <A_0CF3 ν,Η₃

'Comp.	Name	Structure
5	(6-chloro-7-methoxy-2-methyl-3-(4-(4- (trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yloxy)methyl cyclohexanecarboxylate	O-'O 0 fl h₃co''^Xx;^n^ch₃
6	4-((6-chloro-7-methoxy-2-methyl-3-(4(4- (trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yloxy)methyl)phenyl acetate	O Me-^O HsCO'^^N^CHj
7	(6-chloro-7-methoxy-2-methyl-3-(4-(4- (trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yloxy)methyl 2propylpentanoate	Γ ° c'yyUAJJ GA_ocf>
8	(6-chloro-7-methoxy-2-methyl-3-(4-(4- (trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yloxy)methyl decanoate	0 JL /V. C9H19 0 0 J] ^1x^^Îocf₃ Η₃ΟΟ^χΑχΐί?^Ν^<ί^ΟΗ₃
9	(6-chloro-7-methoxy-2-methyl-3-(4-(4- (trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yloxy)methyi tetradecanoate	0 ^^ocf3 HaCO'^^^'N'^CHa
ΙΟ	(6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yloxy)methyl palmitate	0 C15H31 O 0 \|\| \|\| \| ^0Ι'ν^Υ^Ζ1^^Ϊ:^ ^OCFa H₃CO'^Xx<:?:A^N^<<'GH₃
H	(E)-(6-chloro-7-methoxy-2-methyl-3- (4-(4- (trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yloxy)methyl octadec-9-enoate	O L Α χ-'-. 'cro p n ]\| η ^^OCFs
12	6-chloro-7-methoxy-2-methyl-3-(4-(4(trifl uoromethoxy)phenoxy)pheny l)qui nolin-4-yl methyl carbonate	O MeO^O f^:Î>A⁰Jf^^îl HjCO^^^N^CHa

Comp.	Name	Structure
13	6-chloro-7-methoxy-2-methyl-3-(4-(4- (trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yl ethyl carbonate	O ⁰ î ιϊYi HsCO^^^N^CHa
14	6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yl propyl carbonate	O Xs A AK =χ<3 o n q H₃CO''^K''^:^N^î:XH3
15	6-chloro-7-methoxy-2-methyl-3-(4-(4(tri fl uoromethoxy )phenoxy )pheny 1 )qui nolin-4-yl isopropyl carbonate	1 ⁰ A JL ° î /Ύh ^ciYYjl ^UocC3
16	6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yl hexyl carbonate	O χ^χ^χ^ο^ο ^c’YY5l ^^0CF3 H₃CO'^>x^^S'N^<Î^CH₃
17	6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yl decyl carbonate	L. JL \χ^>χ^ο o η ^ciYyV^ ^^OCF3
18	6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)qui noiin-4-yl hexadecyl carbonate	_o L^x^x^XX^x^o^O [^ίίί>Υ'^ΟχϊΓ^^ΐ] HjCO^^^N^CHa
19	6-chloro-7-methoxy-2-methyl-3-(4-(4- (trifluoromethoxy)phenoxy)phenyl)qui nolin-4-yl decan-2-yl carbonate	^CIYYY^ ^^OCF’
35	((6-chloro-7-methoxy-2-methyl-3-(4(4- (trifluoromethoxy)phenoxy)phenyl)qui nol in-4-yl)oxy)methy 1 (4Z,7Z, 1OZ, 13Z, 16Z, 19Z)-docosa- 4,7.10,13,16,19-hexaenoate	Me r''^] o L Λ l A ο ^ειγγψ^ ^^ocFaMeO'^AYx''N^Me

[00150] In some embodiments, the compound disclosed herein has the structure provided in Table 2. TABLE 2

Comp.

Name

Structure

Comp.	Name	Structure
20	3-((lr,4r)-4-(4chlorophenyl)cyclohexyl)-1,4dioxo-1,4-dihydronaphthalen- 2-yl acetate	i^T^cl 0 xk O^Me
2l	3-((lr,4r)-4-(4chlorophenyl)cyclohexyl)-1,4dioxo-1,4-dihydronaphthalen- 2-yl propionate	xÿ^z-CI ° x'^xk.^'k^^x ° O^CH₂CH₃
22	3_((lr,4r)-4-(4chlorophenyl)cyclohexyl)-1,4dioxo-1,4-dihydronaphthalen- 2-yl butyrate	_o o O^/^(CH₂)₂CH₃
23	3_(( k,4r)-4-(4chlorophenyl)cyclohexyl)-1,4dioxo-1,4-dihydronaphthalen- 2-yl pivalate	_o o ⁰ \
24	3-((1 r ,4r)-4-(4chlorophenyl)cyclohexy 1)-1,4dioxo-1,4-dihydronaphthalen- 2-yl isobutyrate	o A-/ ° \
25	3-((1 r,4r)-4-(4chloropheny l)cyclohexyl)-1,4dioxo-1,4-dihydronaphthalen- 2-yl hexanoate	>J^X^CI O xk O-^(CH₂)₄CH₃
26	3-((11-,40-4-(4chlorophenyl)cyclohexyl)-1,4dioxo-l,4-dihydronaphthalen- 2-y 1 pentahoate	xi'sx⁰¹o Χ^^γΧ^Χ.^'^^χ¹ ⁰ 0^{CH₂)₃CH₃

Comp.	Name	Structure
27	3_((lr,4r)-4-(4- chlorophenyl)cyclohexyl)-l,4- dioxo-1,4-dihydronaphthalen- 2-yl decanoate	fHr⁰¹ 0 o xL O^(CH₂)₈CH₃
²⁸	3-(( l r,4r)-4-(4- chloropheny l)cyclohexyl)-1,4dioxo-1,4-dihydronaphthalen2-yl dodecanoate	° ° O^CHJmCHs
29	3_((lr,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4dioxo-1,4-dihydronaphthalen- 2-yl palmitate	rr^c' ⁰ ° O^<^(CH₂)₁₄CH₃
30	3-((lr,4r)-4-(4chloropheny l)cyclohexyl)-1,4dioxo-1,4-dihydronaphthalen2-yl 2-propylpentanoate	rr^cl Q °oA^ Me._____J Me
31	3_(( l _r,4r)-4-(4- chlorophenyl)cyclohexyl)-l,4dioxo-1,4-dihydronaphthalen2-yl butyrate	f^y^cl CCjC' ° O'^^s'(CH₂)₂CH₃
32	3-(( l r,4r)-4-(4- chlorophenyl)cyclohexyl)-l,4dioxo-1,4-dihydronaphthalen2-yl nonanoate	_fÎÎ^?X^^CI _o ° O^(CH₂)₇CH₃
33	3-((lr,4r)-4-(4- chlorophenyl)cyclohexyl)-l,4dioxo-1,4-dihydronaphthalen- 2-yl (4Z,7Z,lOZ,l3Z,l6Z,l9Z)docosa-4,7,10,13,16,19hexaenoate	ο 0 M W M

Comp.	Name	Structure
34	2-(( 1 r,4r)-4-(4chlorophenyl)cyclohexyl)-3((((4Z,7Z, 10Z, 13Z, 16Z, 19Z)docosa-4,7,10,13,16,19hexaen-1- yl)oxy)methoxy)naphthalene1,4-dione	XJ O ________' (f Ύ J _ ° M M U

Preparation of the Compounds

[00151] The compounds used in the reactions described herein are made according to known organic synthesis techniques, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, CA), Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN

Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc.

(Rockville, MD), and WuXi (Shanghai, China).

[00152] Suitable reference books and treatises that detail the synthesis of reactants useful in the préparation of compounds described herein, or provide references to articles that describe the préparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Préparations,” 2nd Ed., Academie Press, New York, 1983; H. O. House, “Modem Synthetic Reactions”, 2nd

Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the préparation of compounds described herein, or provide references to articles that describe the préparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,

Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-52729074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN ΟΙ 9-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Préparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J.

(editor) “Modem Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. •Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C.,

-35 ^Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[00153] Spécifie and analogous reactants are also identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many ofthe standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the préparation and sélection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Further Forms of Compounds Disclosed Herein

Isomers

[00154] Furthermore, the compounds described herein may exist as géométrie isomers. The compounds described herein may possess one or more double bonds. The compounds presented herein include ail cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include ail possible tautomers within the formulas described herein.

[00155] In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein may possess three chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein may possess four chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein may include ail diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single préparative step, combination, or interconversion are useful for the applications described herein. The compounds described herein may be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. Dissociable complexes may be preferred (e.g., crystalline diastereomeric salts). The diastereomers may hâve distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. The diastereomers may be separated by chiral chromatography, or preferably, by separation/resolution techniques based upon différences in solubility. The optically pure enantiomer may then be recovered, along with the resolving agent, by any practical means that would not resuit in racemization.

Labeled compounds

[00156] The compounds described herein may exist in their isotopically-labeled forms. The methods disclosed herein may include methods of treating diseases by administering such isotopically-labeled compounds. The

-36^^nethods disclosed herein may include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, the compounds disclosed herein may include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, suifur, fluorine and chloride, such as ²H, Ή, ^l3C, ^l4C, ^l5N, ^l8O, ^l70,^3IP, ³²P, ³⁵S, ^l8F, and ³⁶Cl, respectively. Compounds described herein, and pharmaceutically acceptable salts, esters, solvaté, hydrates or dérivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ³H and ^l4C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., ³H and carbon-14, i. e., ⁱ⁴C, isotopes are particularly preferred fortheir ease of préparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., ²H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. The isotopically labeled compounds, pharmaceutically acceptable sait, ester, solvaté, hydrate or dérivative thereof may be prepared by any suitable method.

[00157] The compounds described herein may be labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts

[00158] The compounds described herein may exist as their pharmaceutically acceptable salts. The methods disclosed herein may include methods of treating diseases by administering such pharmaceutically acceptable salts. The methods disclosed herein may include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[00159] The compounds described herein may possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable sait. These salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the sait thus formed.

Solvatés

[00160] The compounds described herein may exist as solvatés. The invention provides for methods of treating diseases by administering such solvatés. The invention further provides for methods of treating diseases by administering such solvatés as pharmaceutical compositions.

[00161] Solvatés contain either stoichiometric or non-stoichiometric amounts of a solvent, and, may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, éthanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvatés ofthe compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein exist in

-37^^unsolvated as well as solvated forms. In general, the solvated forms are considered équivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Polymorphs

[00162] The compounds described herein, may be in crystalline forms, also known as polymorphs.

Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually hâve different X-ray diffraction patterns, melting points, density, hardness, crystal shape, optical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage température may cause a single crystal form to dominate.

[00163] The crystalline form may be ELQ-300-Form IA. The crystalline form may be ELQ-300-Form IB. The crystalline form may be ELQ-300-Form II. The crystalline form may be ELQ-300-Form III. The crystalline form may be ELQ-300-Form IV. The crystalline form may be ELQ-300-Form V.

[00164] The crystalline form may be a crystalline compound of Formula (II). The crystalline form may be crystalline 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl propionate. The crystalline form may be crystalline 6-chloro-7-methoxy-2-methyl-3-(4-(415 (trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl ethyl carbonate. The crystalline form may be crystalline (6chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methyl butyrate. [00165] The crystalline form may be atovaquone-Fonn L The crystalline form may be atovaquone-Form II. [00166] The crystalline form may be a crystalline compound of Formula (III). The crystalline form may be crystalline crystalline 3-((1 r,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4-dioxo-l,4-dihydronaphthalen-2-yl decanoate.

[00167] The crystalline form may be pyronaridine-Form I. The crystalline form may be pyronaridine-Form

II. The crystalline form may be pyronaridine-Form III. The crystalline form may be pyronaridine-Form IV. The crystalline form may be pyronaridine-Form V.

Pharmaceutical compositions

[00168] The compounds described herein may be formulated into pharmaceutical compositions.

Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingrédients that facilitate processing of the active compounds into préparations that are used pharmaceutically. Proper formulation is dépendent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, twentyfirst Ed (Lippincott Williams & Wilkins 2012); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[00169] The compounds described herein may be administered in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration ofthe compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. The compounds disclosed herein, such as compounds of Formula (II) or Formula (III) may be formulated as a depot formulation for administration via intramuscular or subcutaneous injection. The

-38^^ompounds disclosed herein, such as crystalline ELQ-300 (ELQ-300-Form IA, ELQ-300-Form IB, ELQ-300Form II, ELQ-300-Form III, ELQ-300-Form IV, or ELQ-300-Form V), crystalline compounds of Formula (II), crystalline atovaquone (atovaquone-Form I or atovaquone-Form II), crystalline compounds of Formula (III), or crystalline pyronaridine (pyronaridine-Form I, pyronaridine-Form II, pyronaridine-Form III, pyronaridine-Form 5 IV, or pyronaridine-Form V) may be formulated as suspension for administration via intramuscular or subcutaneous injection.

Depot Formulation

[00170] Depot formulations are efficient, well-tolerated, sustained or delayed release compositions of the active ingrédient that are therapeutically effective for a number of weeks, such as at least about one week, at 10 least about two weeks, at least about three weeks, at least about four weeks, at least about fïve weeks, at least about six weeks, at least about seven weeks, at least about eight weeks, at least about nine weeks, at least ten about weeks, at least about eleven weeks, at least about twelve weeks or more. Depot formulations are efficient, well-tolerated, sustained or delayed release compositions of the active ingrédient that are therapeutically effective for a number of days, such as at least about 5 days, at least about 10 days, at least about 15 days, at 15 least about 20 days, at least about 25 days, at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 55 days, at least about 60 days, at least about 65 days, at least about 70 days, at least about 75 days, at least about 80 days, at least about 85 days, at least about 90 days, at least about 95 days, at least about 100 days, at least about 105 days, at least about 110 days, at least about 115 days, at least about 120 days or more.

[00171] In -ddition to the active agent describe herein, additional ingrédients may be used in the depot formulations of the présent invention including surfactants, solubilizers, emulsifiers, preservatives, isotonicity agents, dispersing agents, wetting agents, fiilers, solvents, buffers, stabilizers, lubricants, thickening agents, suspending agents, and combination thereof.

[00172] The depot formulation may comprise a compound disclosed herein and a suitable hydrophobie materials. The suitable hydrophobie material may be a monoglyceride, diglyceride, or a triglycéride. The suitable hydrophobie material may be an oil. The oil may be a biocompatible oil. The oil may be minerai oil.

The oil may be castor oil. The oil may be vegetable oil. The vegetable oil may be selected from corn oil, peanut oil, sesame oil, olive oil, palm oil, safflower oil, soybean oil, cottonseed oil, rapeseed oil, suntlower oil and mixtures thereof. The oil may be sesame oil. The oil may be a semi-synthetic vegetable oil obtained by total 30 estérification and/or hydrolysis and/or fractionation of a naturel vegetable oil, for instance fatty acid triglycérides derived from vegetable oils, such as triglycérides of capryiic, capric, linoleic or succinic acids (sold under the trade names Miglyol(TM) 810, 812, 818, 820, 829), esters of propylene glycol and of a fatty acid, derived from vegetable oil, such as esters of propylene glycol and of capryiic and capric acids (sold under the trade name Miglyol(TM) 840), and also mixtures thereof.

[00173] The depot formulation may comprise a compound of Formula (II), or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof and an oil. The concentration of the compound of Formula (II), or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof in the oil may be between about 20 mg/mL and about 500 mg/mL, between about 20 mg/mL and about 400 mg/mL, between about 20 mg/mL and about 300 mg/mL, between about 20 mg/mL and about 200 mg/mL, between about 20 mg/mL and about 100 mg/mL,

-39•or between about 50 mg/mL and about 100 mg/mL. The concentration may be at least about 20 mg/mL, at least about 30 mg/mL, at least about 40 mg/mL, at least about 50 mg/mL, at least about 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL. The concentration may be less than about 20 mg/mL, less than about 30 mg/mL, less than about 40 mg/mL, less than about 50 mg/mL, less than about 60 mg/mL, less than about 70 mg/mL, less than about 80 mg/mL, less than about 90 mg/mL, or less than about 100 mg/mL. The concentration may be more than about 20 mg/mL, more than about 30 mg/mL, more than about 40 mg/mL, more than about 50 mg/mL, more than about 60 mg/mL, more than about 70 mg/mL, more than about 80 mg/mL, more than about 90 mg/mL, more than about 100 mg/mL, more than about 150 mg/mL, or more than about 200 mg/mL.

[00174] The compound of Formula (II) may be released from the depot formulation at a rate providing an average plasma concentration of 6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one (ELQ-300) of at least about 1 μΜ over a period of about 12 weeks. The average plasma concentration of 6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one may be at least about 900 nM, at least about 800 nM, at least about 700 nM, at least about 600 nM, at least about 500 nM, at least about 400 nM, at least about 300 nM, at least about 200 nM, at least about 100 nM, at least about 95 nM, at least about 90 nM, at least about 85 nM, at least about 80 nM, at least about 75 nM, at least about 70 nM, at least about 65 nM, at least about 60 nM, at least about 55 nM, at least about 50 nM, at least about 45 nM, at least about 40 nM, at least about 35 nM, at least about 30 nM, at least about 25 nM, or at least about 20 nM over a period of about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, or about 1 week. The average plasma concentration of 6-chloro-7methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one may be at least about 100 nM over a period of about 4 weeks upon administration of a compound of Formula (II).

[00175] The depot formulation may comprise a compound of Formula (III), or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof and an oil. The concentration of the compound of Formula (III), or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof in the oil may be between about 20 mg/mL and about 500 mg/mL, between about 20 mg/mL and about 400 mg/mL, between about 20 mg/mL and about 300 mg/mL, between about 20 mg/mL and about 200 mg/mL, between about 20 mg/mL and about 100 mg/mL, or between about 50 mg/mL and about 100 mg/mL. The concentration may at least about 20 mg/mL, at least about 30 mg/mL, at least about 40 mg/mL, at least about 50 mg/mL, at least about 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL. The concentration may be less than about 20 mg/mL, less than about 30 mg/mL, less than about 40 mg/mL, less than about 50 mg/mL, less than about 60 mg/mL, less than about 70 mg/mL, less than about 80 mg/mL, less than about 90 mg/mL, or less than about 100 mg/mL. The concentration may be more than about 20 mg/mL, more than about 30 mg/mL, more than about 40 mg/mL, more than about 50 mg/mL, more than about 60 mg/mL, more than about 70 mg/mL, more than about 80 mg/mL, more than about 90 mg/mL, more than about 100 mg/mL, more than about 150 mg/mL, or more than about 200 mg/mL.

[00176] The compound of Formula (III) may be released from the depot formulation at a rate providing an average plasma concentration of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthalenedione

-40 ^atovaquone) of at least about 5 μΜ over a period of about 13 weeks. The average plasma concentration of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthalenedione may be at least about 5 μΜ, at least about 4.5 μΜ, at least about 4 μΜ, at least about 3.5 μΜ, at least about 3 μΜ, at least about 2.5 μΜ, at least about 2 μΜ, at least about l .5 μΜ, at least about l μΜ, at least about 900 nM, at least about 800 nM, at least about 700 nM, at least about 600 nM, at least about 500 nM, at least about 400 nM, at least about 300 nM, at least about 200 nM, at least about 100 nM, at least about 95 nM, at least about 90 nM, at least about 85 nM, at least about 80 nM, at least about 75 nM, at least about 70 nM, at least about 65 nM, at least about 60 nM, at least about 55 nM, at least about 50 nM, at least about 45 nM, at least about 40 nM, at least about 35 nM, at least about 30 nM, at least about 25 nM, or at least about 20 nM over a period of about 13 weeks, over a period of about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, or about l week. The average plasma concentration of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-!,4-naphthalenedione may be at least about 100 nM over a period of about 4 weeks upon administration of a compound of Formula (III).

[00177] The compound of Formula (III) may be 3-((lr,4r)-4-(4-chlorophenyi)cyclohexyl)-l,4-dioxo-l,4dihydronaphthalen-2-yl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate and may be released from the depot formulation at a rate providing an average plasma concentration oftrans-2-[4-(4chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthalenedione (atovaquone) of at least about 2 μΜ over a period of about 13 weeks. The average plasma concentration of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy1,4-naphthalenedione may be at least about 2 μΜ, about 1.9 μΜ, about 1.8 μΜ, about 1.7 μΜ, about 1.6 μΜ, about 1.5 μΜ, about 1.4 μΜ, about 1.3 μΜ, about 1.2 μΜ, about 1.1 μΜ, about 1 μΜ, at least about 900 nM, at least about 800 nM, at least about 700 nM, at least about 600 nM, at least about 500 nM, at least about 400 nM, at least about 300 nM, at least about 200 nM, at least about 100 nM, at least about 95 nM, at least about 90 nM, at least about 85 nM, at least about 80 nM, at least about 75 nM, at least about 70 nM, at least about 65 nM, at least about 60 nM, at least about 55 nM, at least about 50 nM, at least about 45 nM, at least about 40 nM, at least about 35 nM, at least about 30 nM, at least about 25 nM, or at least about 20 nM over a period of about 13 weeks, about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, or about 1 week. The average plasma concentration of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthalenedione may be at least about 1000 nM over a period of about 13 weeks upon administration of 3-((1 r,4r)-4-(4-chlorophenyl)cyclohexyl)-1,4dioxo-1,4-dihydronaphthalen-2-yl (4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7,10,13,16,19-hexaenoate.

Nanoparticles or microparticle Suspension

[00178] The compounds disclosed herein may be formulated as nanoparticle or microparticle suspensions. The pharmaceutical suspensions described herein comprise nanoparticles or microparticles of a crystalline compound disclosed herein and suitable excipients.

[00179] Nanoparticles are submicroscopic solid particles with size ranging from about 10 nm to about 1000 nm or from about 50 nm to about 1000 nm. The average particle size of the nanoparticles describe herein may be below about 1000 nm, or below about 900 nm, or below about 800 nm, or below about 700 nm, or below about 600 nm, or below about 500 nm, or below about 400 nm, or below about 300 nm, or below about 200 nm,

-4l όγ below about 100 nm. The lower limit of the average particle size may be as low as about 100 nm or as low as about 50 nm. The average particle size may be in the range of about 50 nm to about 1000 nm, or about 50 nm to about 500 nm, or about 50 nm to about 400 nm, or about 50 nm to about 300 nm, or about 50 nm to about 250 nm, or about 100 nm to about 250 nm, or about 150 nm to about 220 nm, or 100 to 200 nm, or about 150 nm to about 200 nm, e.g. about 100 nm, about 130 nm, or about 150 nm.

[00180] Microparticles are solid particles with size ranging from about 1 μιη to about 1000 μιη. The average particle size of the micro particles describe herein may be below about 1000 μιη, or below about 900 μιη, or below about 800 μιη, or below about 700 μιη, or below about 600 μιη, or below about 500 μιη, or below about 400 μιη, or below about 300 μιη, or below about 200 μιη, or below about 100 μιη, or below about 90 μπι, or below about 80 μιη, or below about 70 μιη, or below about 60 μιη, or below about 50 μιη, or below about 40 μιη, or below about 30 μιη, or below about 20 μπι, or below about 10 μιη, or below about 5 μπι, or below about 2 μιη. The lower limit of the average particle size may be as low as about 10 μπι or as low as about 5 μιη. The average particle size may be in the range of about 1 μιη to about 100 μιη, or about 1 μιη to about 50 μιη, or about 1 μιη to about 40 μπι, or about 1 μιη to about 30 μιη, or about 1 μπι to about 20 μιη, or about 1 μπι to about 10 μιη or about 1 μιη to about 5 μιη, e.g. about 1 μιη, about 2 μιη, about 3 μιη, about 4 μιη , or about 5 μιη.The nanoparticle or microparticle suspensions may be sustained or delayed release compositions of the active ingrédient that are therapeutically effective for a number of weeks, such as at least about one week, at least about two weeks, at least about three weeks, at least about four weeks, at least about five weeks, at least about six weeks, at least about seven weeks, at least about eight weeks, at least about nine weeks, at least ten about weeks, at least about eleven weeks, at least about twelve weeks or more. The nanoparticle or microparticle suspensions are efficient, well-tolerated, sustained or delayed release compositions of the active ingrédient that are therapeutically effective for a number of days, such as at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 55 days, at least about 60 days, at least about 65 days, at least about 70 days, at least about 75 days, at least about 80 days, at least about 85 days, at least about 90 days, at least about 95 days, at least about 100 days, at least about 105 days. at least about 110 days, at least about 115 days, at least about 120 days or more.

[00181] In addition to the active agent, additional ingrédients may be used in the nanoparticle or microparticle suspensions of the présent invention including surfactants, solubilizers, emulsifiers, preservatives, isotonicity agents, dispersing agents, wetting agents, fillers, solvents, buffers, stabilizers, lubricants, thickening agents, suspending agents, and combination thereof. The suspension may comprise a suspending agent and a surfactant. Most commonly, surfactants are classified according to polar head group. A non-ionic surfactant has no charged groups in its head. The head of an ionic surfactant carries a net positive, or négative charge. If the charge is négative, the surfactant is more specifically called anionic; if the charge is positive, it is called cationic. If a surfactant contains a head with two oppositely charged groups, it is termed zwitterionic. Anionic surfactants contain anionic functional groups at their head, such as sulfate, sulfonate, phosphate, and carboxylates. Prominent alkyl sulfates include ammonium lauryi sulfate, sodium lauryl sulfate (sodium dodecyl sulfate, SLS, or SDS), and the related alkyl-ether sulfates sodium laureth sulfate (sodium lauryl ether sulfate or SLES), and sodium myreth sulfate. Others include: docusate (dioctyl sodium sulfosuccinate),

-42 ^Lrfluorooctanesulfonate (PFOS), perfluorobutanesulfonate, alkyl-aryl ether phosphates, alkyl ether phosphates. Cationic surfactant include pH-dependent primary, secondary, or tertiary amines such as octenidine dihydrochloride; and permanently charged quaternary ammonium salts such as cetrimonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzéthonium chloride (BZT), dimethyldioctadecylammonium chloride, and dioctadecyldimethylammonium bromide (DODAB). Zwitterionic (amphoteric) surfactants hâve both cationic and anionic centers attached to the same molécule. The cationic part is based on primary, secondary, or tertiary amines or quaternary ammonium cations. The anionic part can be more variable and include sulfonates, as in the sultaines CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-lpropanesulfonate) and cocamidopropyl hydroxysultaine. Betaines such as cocamidopropyl betaine hâve a carboxylate with the ammonium. The most common biological zwitterionic surfactants hâve a phosphate anion with an amine or ammonium, such as the phospholipids phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and sphingomyelins. Nonionic surfactants include fatty alcohols, cetyl alcohol, stearyl alcohol, and cetostearyl alcohol, and oleyl alcohol. Also used as nonionic surfactants are polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, octyl glucoside), polyethylene glycol octylphenyl ethers (such as Triton X-lOO), polyethylene glycol alkylphenyl ethers (such as nonoxynol-9), glycerol alkyl esters (such as glyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (such as polysorbate, i.e., polysorbate 20 and polysorbate 80), sorbitan alkyl esters (such as Spans), cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, triblock copolymer comprising blocks of polyethylene glycol and blocks of polypropylene glycol such as poly(ethylene glycol)-Moc£-poly(propylene glycol)-Woc£-poly(ethylene glycol) (such as poloxamers), and polyethoxylated tallow amine (POEA). The suspension may comprise between about 0.1 wt% and about 10 wt% of a surfactant. The suspension may comprise between about 0.5 wt% and about 5 wt% of a surfactant. The suspension may comprise between about l wt% and about 4 wt % of a surfactant. The suspension may comprise between about 2 wt% and about 4 wt% of a surfactant. The suspension may comprise between about 3 wt% of a surfactant. The suspension may comprise a nonionic surfactant. The nonionic surfactant may comprise polyethylene glycol. The nonionic surfactant may be a triblock copolymer comprising blocks of polyethylene glycol and blocks of polypropylene glycol such as poly(ethylene glycol)-WocÂ-poly(propylene glycol)-Woc£-poly(ethylene glycol). The non-ionic surfactant may be Synperonic® Fl08. The non-ionic surfactant may be Pluronic . The nonionic surfactant may be a vitamin dérivative, such as vitamin E dérivative. The nonionic surfactant may be an estérification product of vitamin E succinate with polyethylene glycol. The nonionic surfactant may be an estérification product of vitamin E succinate with polyethylene glycol 1000. The non-ionic surfactant may be D-α -tocopheryl polyethylene glycol succinate. The non-ionic surfactant may be D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS). The suspension may comprise an anionic surfactant.The anionic surfactant may be dodecyl sodium sulfate (SES). The suspension may comprise a suspending agent. The suspension may comprise between about 0.1 wt% and about 10 wt% of a suspending agent. The suspension may comprise between about 0.5 wt% and about 5 wt% of a suspending agent. The suspension may comprise between about 0.5 wt% and about 2 wt% of a suspending agent. The suspension may comprise between about 0.5 wt% and about l .5 wt% of a suspending agent. The suspension may comprise about l wt% of a suspending agent. The suspending agent

-43 ^^nay be selected from acacia, agar, alginic acid, bentonite, calcium stéarate, carbomers, cellulose or cellulose dérivatives (such as carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), methylcellulose), carrageenan, ceratonia, colloïdal silicon dioxide, dextrin, gelatin, guar gum, kaolin, magnésium aluminum silicate, maltitol, medium-chain triglycérides, microcrystalline cellulose, microcrystalline cellulose and carboxymethylcellulose sodium, polycarbophil, polyethylene glycol, potassium alginate, povidone, propylene glycol alginate, sesame oil, sodium alginate, sodium starch glycolate, sorbitan esters, sucrose, tragacanth, and xanthan gum. The suspending agent may be a cellulose dérivative. The suspension may comprise hydroxypropyl methylcellulose (HPMC). The suspension may comprise one or more of Synperonic®

Fl08, dodecyl sodium sulfate (SLS), or D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS). The suspension may comprise one or more of Synperonic® Fl08, dodecyl sodium sulfate (SLS), D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), or hydroxypropyl methylcellulose (HPMC). The suspension may comprise D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) and hydroxypropyl methylcellulose (HPMC).

[00182] The nanoparticles or microparticle described herein may be prepared by means of micronization/particle size reduction/nanonization by mechanical means. The nanoparticles or microparticle may be prepared by dry milling. The nanoparticles or microparticle may be prepared by wet milling. [00183] The pharmaceutical suspension may comprise crystalline 6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof (such as ELQ-300-Form IA, ELQ-300-Form IB, ELQ-300-Form II, ELQ-300-Form III, ELQ-300-Form IV, or ELQ-300-Form V). The pharmaceutical suspension may comprise ELQ-300-Form II.The concentration of crystalline 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin4(lH)-one, or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof in the suspension may be between about 20 mg/mL and about 500 mg/mL, between about 20 mg/mL and about 400 mg/mL, between about 20 mg/mL and about 300 mg/mL, between about 20 mg/mL and about 200 mg/mL, between about 20 mg/mL and about 100 mg/mL, or between about 50 mg/mL and about 100 mg/mL. The concentration may be at least about 20 mg/mL, at least about 30 mg/mL, at least about 40 mg/mL, at least about 50 mg/mL, at least about 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL. The concentration may be less than about 20 mg/mL, less than about 30 mg/mL, less than about 40 mg/mL, less than about 50 mg/mL, less than about 60 mg/mL, less than about 70 mg/mL, less than about 80 mg/mL, less than about 90 mg/mL, or less than about 100 mg/mL.

[00184] In some aspects, 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin4(1 H)-one is released from the suspension at a rate providing an average plasma concentration of 6-chloro-7methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(l H)-one (ELQ-300) of at least about

3 μΜ over a period of about 12 weeks. The average plasma concentration of 6-chloro-7-methoxy-2-methyl-3(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(l H)-one may be at least about 3 μΜ, at least about 2.5 μΜ, at least about 2 μΜ, at least about 1.5 μΜ, at least about 1 μΜ, at least about 900 nM, at least about 800 nM, at least about 700 nM, at least about 600 nM, at least about 500 nM, at least about 400 nM, at least about 300 nM, at least about 200 nM, at least about 100 nM, at least about 95 nM, at least about 90 nM, at least about 85 nM,

-44Wt least about 80 nM, at least about 75 nM, at least about 70 nM, at least about 65 nM, at least about 60 nM, at least about 55 nM, at least about 50 nM, at least about 45 nM, at least about 40 nM, at least about 35 nM, at least about 30 nM, at least about 25 nM, or at least about 20 nM over a period of about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, or about l week. The average plasma concentration of 6-chloro-7methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one may be at least about 500 nM over a period of about 4 weeks.

[00185] The pharmaceutical suspension may comprise crystalline trans-2-[4-(4-chlorophenyl)cyclohexyl]-3hydroxy-l,4-naphthalenedione, or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof (such as atovaquone-Form I or atovaquone-Form II). The pharmaceutical suspension may comprise atovaquone-Form II. The concentration of crystalline trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthalenedione, or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof in the suspension may be between about 20 mg/mL and about 500 mg/mL, between about 20 mg/mL and about 400 mg/mL, between about 20 mg/mL and about 300 mg/mL, between about 20 mg/mL and about 200 mg/mL, between about 20 mg/mL and about 100 mg/mL, or between about 50 mg/mL and about 100 mg/mL. The concentration may be at least about 20 mg/mL, at least about 30 mg/mL, at least about 40 mg/mL, at least about 50 mg/mL, at least about 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL. The concentration may be less than about 20 mg/mL, less than about 30 mg/mL, less than about 40 mg/mL, less than about 50 mg/mL, less than about 60 mg/mL, less than about 70 mg/mL, less than about 80 mg/mL, less than about 90 mg/mL, or less than about 100 mg/mL.

[00186] In some aspects, trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione is released from the suspension at a rate providing an average plasma concentration of trans-2-[4-(4chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthalenedione (atovaquone) of at least about 5 μΜ over a period of about 12 weeks. The average plasma concentration of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy25 1.4-naphthalenedione may be at least about 5 μΜ, at least about 4.5 μΜ, at least about 4 μΜ, at least about 3.5 μΜ, at least about 3 μΜ, at least about 2.5 μΜ, at least about 2 μΜ, at least about 1.5 μΜ, at least about 1 μΜ, at least about 900 nM, at least about 800 nM, at least about 700 nM, at least about 600 nM, at least about 500 nM, at least about 400 nM, at least about 300 nM, at least about 200 nM, at least about 100 nM, at least about 95 nM, at least about 90 nM, at least about 85 nM, at least about 80 nM, at least about 75 nM, at least about 70 nM, at least about 65 nM, at least about 60 nM, at least about 55 nM, at least about 50 nM, at least about 45 nM, at least about 40 nM, at least about 35 nM, at least about 30 nM, at least about 25 nM, or at least about 20 nM over a period of about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, or about 1 week. The average plasma concentration of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthalenedione may be at least about 3 μΜ over a period of about 4 weeks.

[00187] The pharmaceutical suspension may comprise crystalline (6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methyl butyrate (compound 2), or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof. The concentration of crystalline (6-chloro-7-rnethoxy-2methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methyl butyrate, or pharmaceutically

-45 feceptable sait, solvaté, or stereoisomer thereof in the suspension may be between about 20 mg/mL and about 500 mg/mL, between about 20 mg/mL and about 400 mg/mL, between about 20 mg/mL and about 300 mg/mL, between about 20 mg/mL and about 200 mg/mL, between about 20 mg/mL and about 100 mg/mL, or between about 50 mg/mL and about 100 mg/mL. The concentration may be at least about 20 mg/mL, at least about 30 mg/mL, at least about 40 mg/mL, at least about 50 mg/mL, at least about 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL. The concentration may be less than about 20 mg/mL, less than about 30 mg/mL, less than about 40 mg/mL, less than about 50 mg/mL, less than about 60 mg/mL, less than about 70 mg/mL, less than about 80 mg/mL, less than about 90 mg/mL, or less than about 100 mg/mL.

[00188] In some aspects, (6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin4-yloxy)methyl butyrate is released from the suspension at a rate providing an average plasma concentration of 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one (ELQ-300) of at least about 3 μΜ over a period of about 12 weeks. The average plasma concentration of 6-chloro-7-methoxy-2methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one may be at least about 3 μΜ, at least about 2.5 μΜ, at least about 2 μΜ, at least about 1.5 μΜ, at least about 1 μΜ, at least about 900 nM. at least about 800 nM, at least about 700 nM, at least about 600 nM, at least about 500 nM, at least about 400 nM, at least about 300 nM, at least about 200 nM, at least about 100 nM, at least about 95 nM, at least about 90 nM, at least about 85 nM, at least about 80 nM, at least about 75 nM, at least about 70 nM, at least about 65 nM, at least about 60 nM, at least about 55 nM, at least about 50 nM, at least about 45 nM, at least about 40 nM, at least about 35 nM, at least about 30 nM, at least about 25 nM, or at least about 20 nM over a period of about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, or about 1 week.

[00189] The pharmaceutical suspension may comprise crystalline compounds of Formula (II), or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof. The concentration of crystalline compounds of Formula (II), or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof in the suspension may be between about 20 mg/mL and about 500 mg/mL, between about 20 mg/mL and about 400 mg/mL, between about 20 mg/mL and about 300 mg/mL, between about 20 mg/mL and about 200 mg/mL, between about 20 mg/mL and about 100 mg/mL, or between about 50 mg/mL and about 100 mg/mL. The concentration may be at least about 20 mg/mL, at least about 30 mg/mL, at least about 40 mg/mL, at least about 50 mg/mL, at least about 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL. The concentration may be less than about 20 mg/mL, less than about 30 mg/mL, less than about 40 mg/mL, less than about 50 mg/mL, less than about 60 mg/mL, less than about 70 mg/mL, less than about 80 mg/mL, less than about 90 mg/mL, or less than about 100 mg/mL.

[00190] In some aspects, the crystalline compound of Formula (II), or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is released from the suspension at a rate providing an average plasma concentration of 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one (ELQ-300) of at least about 3 μΜ over a period of about 12 weeks. The average plasma concentration of 6chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one may be at least about 3 μΜ, at least about 2.5 μΜ, at least about 2 μΜ, at least about 1.5 μΜ, at least about 1 μΜ, at least about

-46*00 nM, at least about 800 nM, at least about 700 nM, at least about 600 nM, at least about 500 nM, at least about 400 nM, at least about 300 nM, at least about 200 nM, at least about 100 nM, at least about 95 nM, at least about 90 nM, at least about 85 nM, at least about 80 nM, at least about 75 nM, at least about 70 nM, at least about 65 nM, at least about 60 nM, at least about 55 nM, at least about 50 nM, at least about 45 nM, at least about 40 nM, at least about 35 nM, at least about 30 nM, at least about 25 nM, or at least about 20 nM over a period of about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, or about l week.

[00191] The pharmaceutical suspension may comprise crystalline compounds of Formula (III), or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof. The concentration of crystalline compounds of Formula (III), or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof in the suspension may be between about 20 mg/mL and about 500 mg/mL, between about 20 mg/mL and about 400 mg/mL, between about 20 mg/mL and about 300 mg/mL, between about 20 mg/mL and about 200 mg/mL, between about 20 mg/mL and about 100 mg/mL, or between about 50 mg/mL and about 100 mg/mL. The concentration may be at least about 20 mg/mL, at least about 30 mg/mL, at least about 40 mg/mL, at least about 50 mg/mL, at least about 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL. The concentration may be less than about 20 mg/mL, less than about 30 mg/mL, less than about 40 mg/mL, less than about 50 mg/mL, less than about 60 mg/mL, less than about 70 mg/mL, less than about 80 mg/mL, less than about 90 mg/mL, or less than about 100 mg/mL.

[00192] In some aspects, the crystalline compound of Formula (III), or pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is released from the suspension at a rate providing an average plasma concentration of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthalenedione (atovaquone) of at least about 5 μΜ over a period of about 12 weeks. The average plasma concentration oftrans-2-[4-(4chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthalenedione may be at least about 5 μΜ, at least about 4.5 μΜ, at least about 4 μΜ, at least about 3.5 μΜ, at least about 3 μΜ, at least about 2.5 μΜ, at least about 2 μΜ, at least about 1.5 μΜ, at least about 1 μΜ, at least about 900 nM, at least about 800 nM, at least about 700 nM, at least about 600 nM, at least about 500 nM, at least about 400 nM, at least about 300 nM, at least about 200 nM, at least about 100 nM, at least about 95 nM, at least about 90 nM, at least about 85 nM, at least about 80 nM, at least about 75 nM. at least about 70 nM, at least about 65 nM, at least about 60 nM, at least about 55 nM, at least about 50 nM, at least about 45 nM, at least about 40 nM, at least about 35 nM, at least about 30 nM, at least about 25 nM, or at least about 20 nM over a period of about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, or about 1 week.

Methods of Treatment and Treatment Régiments

[00193] Described herein are methods for the treatment or prévention of malaria.

[00194] Described herein are methods for the treatment or prévention of malaria, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof to a subject in need thereof.

-47^^[00195] Described herein are methods for the treatment or prévention of malaria, comprising administering a pharmaceutical composition comprising an oil and a compound of Formula (II), or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof to a subject in need thereof. The compound of Formula (II) may be ((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methyl butyrate.

[00196] Described herein are methods for the treatment or prévention of malaria, comprising administering a pharmaceutical composition comprising an oil and a compound of Formula (III), or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof to a subject in need thereof. The compound of Formula (III) may be 3-(( 1 r,4r)-4-(4-chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl (4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7,10,13,16,19-hexaenoate.

[00197] Described herein are methods for the treatment or prévention of malaria, comprising administering a pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline form of 6-chloro-7methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4( 1 H)-one, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof to a subject in need thereof. The crystalline form of 6-chloro-715 methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one may be ELQ-300-Form IA.

The crystalline form of 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin4(lH)-one may be ELQ-300-Form IB. The crystalline form of 6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one may be ELQ-300-Form II. The crystalline form of 6chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(l H)-one may be ELQ-30020 Form III. The crystalline form of 6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one may be ELQ-300-Form IV. The crystalline form of 6chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4( 1 H)-one may be ELQ-300Form V.

[00198] Described herein are methods for the treatment or prévention of malaria, comprising administering a 25 pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline compound of Formula (II), or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof to a subject in need thereof. The crystalline compound of Formula (11) may be crystalline 6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl propionate. The crystalline compound of Formula (II) may be 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl ethyl carbonate. The crystalline compound of Formula (II) may be (6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methyl butyrate.

[00199] Described herein are methods for the treatment or prévention of malaria, comprising administering a pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline form oftrans-2-[4-(4chloropheny!)cyclohexyl]-3-hydroxy-l,4-naphthalenedione, or a pharmaceutically acceptable sait, solvaté, or 35 stereoisomer thereof to a subject in need thereof. The crystalline form of trans-2-[4-(4chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthalenedione may be atovaquone-Form I. The crystalline form of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthalenedione may be atovaquone-Form II.

[00200] Described herein are methods for the treatment or prévention of malaria, comprising administering a pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline compound of Formula

-48^), or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof to a subject in need thereof. The crystalline compound of Formula (III) may be crystalline 3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4-dioxol ,4-dihydronaphthalen-2-yl decanoate.

{00201] Described herein are methods for the treatment or prévention of malaria, comprising administering a pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline form of 4-(7-chloro-2methoxybenzo[b][l,5]naphthyridin-10-ylamino)-2,6-bis(pyrrolidin-l-ylmethyl)phenol, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof to a subject in need thereof. The crystalline form of4-(7-chloro2-methoxybenzo[b][l,5]naphthyridin-10-ylamino)-2,6-bis(pyrrolidin-l-ylmethyl)phenol may be pyronaridineForm I. The crystalline form of 4-(7-chloro-2-methoxybenzo[b][l,5]naphthyridin-10-ylamino)-2,610 bis(pyrrolidin-l-ylmethyl)phenol may be pyronaridine-Form IL The crystalline form of4-(7-chloro-2methoxybenzo[b][l,5]naphthyridin-10-ylamino)-2,6-bis(pyrrolidin-l-ylmethyl)phenol may be pyronaridineForm III. The crystalline form of 4-(7-chloro-2-methoxybenzo[b][l,5]naphthyridin-10-ylamino)-2,6bis(pyrrolidin-l-ylmethyl)phenol may be pyronaridine-Form IV. The crystalline form of4-(7-chloro-2methoxybenzo[b][l,5]naphthyridin-10-ylamino)-2,6-bis(pyrrolidin-l-ylmethyl)phenol may be pyronaridine15 Form V.

[00202] In some embodiments of any of the foregoing methods, the malaria is drug résistant (e.g., the malaria is résistant to chloroquine, quinine, pyrimethamine, sulfadoxine, mefloquine, artemether, lumefantrine, artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil, doxycycline, clindamycin, artemisinin, atovaquone, or any combination thereof). The malaria may be liver stage.

[00203] The compounds described herein may be useful in any of the foregoing methods and, while not bound by theory, are believed to exert their désirable effects through their ability to inhibit the growth of or kili the parasitic protozoan which causes malaria (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, P. knowlesi). The treatment of malaria may includes causative prophylaxis, such as preventing the spread of plasmodium infection beyond the liver, preventing systemic disease, preventing the symptomatic stage of malaria, and/or preventing the establishment ofthe infection. The treatment of malaria may refers to treatment intended to achieve cure (e.g., of P. vivax or P. malariae), e.g., treatment for radical cure (i.e., clearing hypnozoites from the liver). The methods may include preventing spread of infection of a malaria-causing parasite as described herein from the liver.

[00204] The pharmaceutical compositions and the pharmaceutical suspension containing the compound(s) described herein may be administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the pharmaceutical compositions and pharmaceutical suspensions are administered to a patient aiready suffering from malaria, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of malaria. Amounts effective for this use dépend on the severity and course ofthe disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeuticaliy effective amounts are optionally determined by methods including, but not limited to, a dose escaiation and/or dose ranging clinical trial.

[00205] In prophylactic applications, pharmaceutical compositions and pharmaceutical suspensions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of developing malaria. Such an amount is defined to be a -‘prophylactically effective amount or dose.” In this use,

-49lie précisé amounts also dépend on the patient’s state of health, weight, and the like. When used in patients, effective amounts for this use will dépend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable sait thereof, in order to prevent a return of the symptoms of the disease or condition.

[00206] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discrétion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[00207] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (z.e., a “drug holiday”). In spécifie embodiments, the length of the drug holiday is between 2 days and l year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose réduction during a drug holiday is, by way of example only, by !0%-l00%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[00208] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in spécifie embodiments, the dosage or the frequency of administration, or both, is reduced. as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any récurrence of symptoms.

[00209] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the spécifie agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[00210] In general, however, doses employed for adult human treatment are typically in the range of 0.1 mg100 mg per day. In one aspect, doses employed for adult human treatment are from about 0.5 mg to about 10 mg per day. The pharmaceutical composition or pharmaceutical suspension may be formulated to deliver from about 0.5 mg to about 10 mg per day for about 90 days. Thepharmaceutical composition or pharmaceutical suspension may be formulated to deliver about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5

-50g, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 10 mg per day for about 90 days, about 80 days, about 70 days, about 60 days, about 50 days, about 40 days, about 30 days, about 20 days, or about 10 days. The pharmaceutical composition or pharmaceutical suspension may be formulated to deliver from about 0.5 mg to about 10 mg per day for about 120 days. The pharmaceutical composition or pharmaceutical suspension may be formulated to deliver from about 0.5 mg to about 10 mg per day for about 120 days, about 115 days, about 110 days, about 105 days, about 100 days, about 95 days, about 90 days, about 85 days, about 80 days, about 75 days, about 70 days, about 65 days, about 60 days, about 55 days, about 50 days, about 45 days, about 40 days, about 35 days, about 30 days, about 25 days, about 20 days, about 15 days, or about 10 days.

[00211] In one embodiment, the dosages appropriate for the compound described herein, or a pharmaceutically acceptable sait thereof, are from about 0.01 to about 100 mg/kg per body weight. In one aspect, the dosage is from about 5 to about 50 mg/kg, or about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg.

[00212] The daily dosage or the amount of active in the dosage form may be lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment régime. In varions embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[00213] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animais, including, but not limited to, the détermination ofthe LD₅₀ and the ED₅o- The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LDso and EDso. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. The daily dosage amount of the compounds described herein may lie within a range of circulating concentrations that include the EDso with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[00214] In one embodiment, thé therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (z.e., by itseif the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, the

- 51 wnefit experienced by a patient may be increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit. The other agent may be an additional antimalarial agent. The additional antimalarial agent may be artemisinin, artemisinin dérivatives, atovaquone, proguanil, quinine, chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine, pyronaridine, halofantrine, or ELQ-300.

[00215] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may be additive of the two therapeutic agents or the patient may expérience a synergistic benefit.

[00216] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease, disorder or condition from which the subject suffers; the âge, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, deviates from the dosage regimens set forth herein. [00217] For combination thérapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the spécifie drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.

[00218] The compounds described herein, or a pharmaceutically acceptable sait thereof, as well as combination thérapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophyiactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In spécifie embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. The length required for treatment may vary, and the treatment length is adjusted to suit the spécifie needs of each subject. For example, in spécifie embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.

EXAMPLES

[00219] The following examples are provided for illustrative purposes only and not to limit the scope of the daims provided herein.

Example 1: General procedure for the préparation of Compounds 1-5, 7-11, and 35.

[00220] 6-Chloro-7-methoxy-2-methy 1-3-(4-(4-( trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one (1 equiv), Cs₂CO₃ (3 equiv), and anhydrous DMF (0.1 M) were added to a vial followed by the appropriate chloromethylester (3 equiv). The mixture was allowed to stir at 80 °C ovemight. After that, the reaction was quenched with saturated aqueous NH4CI solution, extracted with EtOAc, and washed with brine. The organic layers were combined, dried under Na₂SO4, filtered, and concentrated under reduced pressure. The crude

-52nnaterial was submitted to silica gel column chromatography to afford the desired products (eluent hexanes hexanes:EtOAc = 4:l) as white solids.

Example 2: General procedure for the préparation of Compounds 12-19.

[00221] A suspension of 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin4(lH)-one (1 equiv) and NaH (2 equiv) in anhydrous THF (0.1 M) was stirred at 80 °C for 1 h. After cooling the reaction mixture to ambient température the appropriate chloroformate were added (2 equiv). The reaction mixture was then stirred at 80 °C for 2 h. After that, the reaction was quenched with saturated aqueous NH₄C1 solution, extracted with EtOAc, and washed with brine. The organic layers were combined, dried under Na₂SO₄, filtered, and concentrated under reduced pressure. The crude material was submitted to silica gel column chromatography to afford the desired products (eluent hexanes hexanes:EtOAc = 4:1) as white solids.

Example 3: General procedure for the préparation of Compounds 20-33.

[00222] To a suspension of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione ( 1 equiv) and K₂CO₃ (2 equiv) in anhydrous CH₃CN (0.1 M) was added the appropriate acid chloride (3.5 equiv). The reaction mixture stirred for 10 hours at 80 °C. Upon completion, the reaction was cooled to ambient température and quenched with water, extracted with EtOAc, and washed with brine. The organic layers were combined, dried under Na₂SO₄, filtered, and concentrated under reduced pressure. The crude material was submitted to silica gel column chromatography to afford the desired products (eluent hexanes -* hexanes:EtOAc = 19:1) as yellow solids.

[00223] Analytical data are presented in table 3.

TABLE 3

Cmpd.	Characterization Data (NMR and LCMS)
2	Ή NMR (400 MHz, CDC1₃) δ 8.06 (s, 1H), 7.47 (s, 1H), 7.41 - 7.36 (m, 2H), 7.26 (d, mz, 2H), 7.17-7.10 (m, 4H), 5.31 (s, 2H), 4.06 (s, 3H), 2.54 (s, 3H), 2.17 (t, J = 7.4 Hz, 2H), 1.54 (sex, J= 7.4 Hz, 2H), 0.85 (t, J= 7.4 Hz, 3H). ¹⁹F NMR (376 MHz, CDC1₃) δ -58.24 (s, 3F). MS-ES1: m/z 576.14 observed (M+H)⁺
3	'H NMR (400 MHz, CDC1₃) δ 8.07 (s, 1H), 7.52 (s, 1H), 7.42 - 7.36 (m, 2H), 7.27 (m, 2H), 7.18 - 7.09 (m, 4H), 5.30 (s, 2H), 4.07 (s, 3H), 2.56 (s, 3H), 2.43 (sept, J= 7.0 Hz, 1 H), 1.06 (d, J = 7.0 Hz, 6H). ^I9F NMR (376 MHz, CDC1₃) δ -58.23. MS-ESI: m/z 576.15 observed (M+H)⁺
4	Ή NMR (400 MHz, CDC1₃) δ 8.06 (s, 1H), 7.49 (s, 1H), 7.40 - 7.36 (m, 2H), 7.28 - 7.24 (m, 2H), 7.18-7.10 (m, 4H), 5.31 (s, 2H), 4.06 (s, 3H), 2.54 (s, 3H), 2.17 (t. J= 7.6 Hz, 2H), 1.48 (p, J= 7.5 Hz, 2H), 1.28 - 1.1 (m, 4H), 0.84 (t, J= 7.2 Hz, 3H). ¹⁹F NMR (376 MHz, CDC1₃) δ -58.24 (s, 3F). MS-ESI: m/z 604.16 observed (M+H)⁺
8	Ή NMR (400 MHz, CDC1₃) δ 8.06 (s, 1 H), 7.48 (s, 1 H), 7.41 - 7.35 (m, 2H), 7.30 - 7.23 (m, 2H), 7.18-7.07 (m, 4H), 5.31 (s, 2H), 4.07 (s, 3H), 2.55 (s, 3H), 2.18 (t, J= 7.6 Hz, 2H), 1.54 - 1.43 (m, 2H), 1.33 - 1.12 (m, 12H), 0.89 (t, 7.0 Hz, 3H). ¹⁹F NMR (376 MHz, CDC1₃) δ -58.24 (s, 3F). MS-ESI: m/z 659.83 observed (M+H)⁺___________________
9	Ή NMR (400 MHz, CDC1₃) δ 8.06 (s, 1H), 7.48 (s, 1H), 7.41 - 7.26 (m, 2H), 7.31 - 7.23 (m, 2H), 7.19-7.09 (m, 4H), 5.31 (s, 2H), 4.07 (s, 3H), 2.55 (s, 3H), 2.18 (t, 7.5 Hz, 2H), 1.53 - 1.40 (m, 2H), 1.36 - 1.12 (m, 20H), 0.89 (t, J= 6.7 Hz, 3H). MS-ESI: m/z 716.29 observed (M+H)⁺
10	Ή NMR (400 MHz, CDCb) δ 8.06 (s, 1H), 7.47 (s, 1H), 7.41 - 7.35 (m, 2H), 7.30 - 7.23 (m, 2H), 7.17 - 7.10 (m, 4H), 5.31 (s, 2H), 4.06 (s, 3H), 2.55 (s, 3H), 2.18 (t, J= 7.5 Hz, 2H), 1.54 - 1.44 (m, 2H), 1.34 - 1.13 (m, 24H), 0.89 (t, J= 6.8 Hz, 4H). ¹⁹F NMR (376 MHz, CDCI₃) δ -58.24 (s, 3F). MS-ESI: m/z 745.30 observed (M+H)⁺

Cmpd.	Characterization Data (NMR and LCMS)
12	Ή NMR (400 MHz, CDCh) δ 7.89 (s, 1H), 7.53 (s, 1H), 7.32 - 7.22 (m, 4H), 7.15 - 7.06 (m, 4H), 4.07 (s, 3H), 3.77 (s, 3H), 2.55 (s, 3H). MS-ESI: m/z 534.04 observed (M+H)⁺
13	Ή NMR (400 MHz, CDCh) δ 7.91 (s, 1H), 7.55 (s, IH), 7.35 - 7.18 (m, 4H), 7.15 - 7.07 (m, 4H), 4.18 (q, J = 7.1 Hz, 2H), 4.08 (s, 3H), 2.57 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3H). ^I9F NMR (376 MHz, CDCh) δ -58.25 (s, 3F). MS-ESI: m/z 548.10 observed (M+H)⁺
14	Ή NMR (400 MHz, CDCh) δ 7.91 (s, 1H), 7.55 (s, 1H), 7.34 - 7.22 (m, 4H), 7.15- 7.05 (m, 4H), 4.12 - 4.05 (m, 5H), 2.57 (s, 3H), 1.62 (sex, J = 7.2, 2H), 0.90 (t, J = 7.4 Hz, 4H). ^I9F NMR (376 MHz, CDCh) δ -58.25 (s, 3F). MS-ESI: m/z 562.11 observed (M+H)⁺
15	’HNMR(400 MHz, CDCh) δ 7.91 (s, 1H), 7.51 (s, 1H), 7.34 -7.29 (m, 2H), 7.26 - 7.20 (m, 2H), 7.13-7.05 (m, 4H), 4.80 (sept, J = 6.3 Hz, 1H), 4.07 (s, 3H), 2.55 (s, 3H), 1.22 (d, J= 6.2 Hz, 6H). ^I9F NMR (376 MHz, CDCh) δ -58.25 (s, 3F). MS-ESI: m/z 562.11 observed (M+H)⁺
16	Ή NMR (400 MHz, CDCh) δ 7.90 (s, 1H), 7.52 (s, 1H), 7.36 - 7.21 (m, 4H), 7.18 - 7.04 (m, 4H), 4.12 (t, J = 6.7 Hz, 2H), 4.08 (s, 3H), 1.58 (p, J = 6.7 Hz, 3H), 1.38 - 1.22 (m, 6H). 0.91 (t, J= 6.9 Hz, 3H). MS-ESI: m/z 604.16 observed (M+H)⁺
17	Ή NMR (400 MHz, CDCh) δ 7.89 (s, 1H), 7.50 (s, IH), 7.34 - 7.27 (m, 2H), 7.26 - 7.22 (m, 2H), 7.14 - 7.05 (m, 4H), 4.10 (t, J= 6.7 Hz, 2H), 4.06 (s, 3H), 2.55 (s, 3H), 1.62 1.51 (m, 2H), 1.34 - 1.22 (m, 14H), 0.92 - 0.89 (t, J= 7.0 Hz, 3H). ^I9F NMR (376 MHz, CDCh) δ -58.27 (s, 3F). MS-ESI: m/z 659.89 observed (M+H)⁺
18	Ή NMR (400 MHz, CDCh) δ 7.88 (s, IH), 7.49 (s, IH), 7.34 - 7.17 (m, 4H), 7.15 - 7.04 (m, 4H), 4.10 (t, J= 6.7 Hz, 2H), 4.06 (s, 3H), 2.55 (s, 3H), 1.57 (s, 2H), 1.34 - 1.22 (m, 26H), 0.88 (t, J= 7.0 Hz, 3H). ^I9F NMR (376 MHz, CDCh) δ -58.26 (s, 3F). MS-ESI: m/z 743.98 observed (M+H)⁺
20	Ή NMR (400 MHz, CDCh,) δ 8.16 - 8.10 (m, 1 H), 8.10 - 8.06 (m, 1 H), 7.79 - 7.69 (m, 2H), 7.31 - 7.26 (m, 2H), 7.21 - 7.14 (m, 2H), 3.08 (tt, J= 12.3, 3.5 Hz, IH), 2.60 (tt, J = 12.3,3.3 Hz, IH), 2.46 (s, 3H), 2.07- 1.93 (m, 4H), 1.88- 1.78 (m, 2H), 1.61 - 1.48 (m, 2H).
21	‘H NMR (400 MHz, Chloroform-i/) δ 8.19 - 8.13 (m, IH), 8.10 (dd, J= 7.2, 1.8 Hz, IH), 7.83 - 7.71 (m, 2H), 7.30 (d, J= 8.8 Hz, 3H), 7.24 - 7.17 (m, 2H), 3.27 - 3.01 (m, IH), 2.80 (q, .7=7.5 Hz, 2H), 2.62 (t, J= 12.1 Hz, IH), 2.04 (dd, J= 15.4, 11.7 Hz, 5H), 1.91 1.78 (m, 2H), 1.39 (t, J= 7.5 Hz, 3H).
22	Ή NMR (400 MHz, CDCh) δ 8.14 - 8.10 (m, IH), 8.10 - 8.06 (m, IH), 7.78 - 7.69 (m, 2H), 7.27 (d, J= 8.5 Hz, 2H), 7.20 - 7.13 (m, 2H), 3.13 - 3.03 (m, 1 H), 2.71 (t, J= 7.4 Hz. 2H), 2.59 (t, J= 12.3 Hz, 1 H), 2.08- 1.94 (m, 5H), 1.92- 1.77 (m, 4H), 1.53 (d, J = 3.5 Hz, IH), 1.13 (t,J= 7.4 Hz, 3H).
23	Ή NMR (400 MHz, Chloroform-<7) δ 8.23 - 8.12 (m, IH), 8.12 - 8.04 (m, IH), 7.83 7.70 (m, 2H), 7.30 (d, J= 6.4 Hz, 2H), 7.24 - 7.15 (m, 2H), 3.12 (d, J = 12.3 Hz, IH), 2.59(0 12.2 Hz, IH), 2.02 (d, J= 13.3 Hz, 3H), 1.85 (d, J= 12.1 Hz, 2H), 1.64-1.52 (m, 2H), 1.50 (s, 9H).
24	Ή NMR (400 MHz, Chloroform-<7) δ 8.18 - 8.12 (m, IH), 8.12 - 8.06 (m, 1H), 7.81 7.71 (m, 2H), 7.30 (d, J= 8.4 Hz, 2H), 7.23 - 7.15 (m, 2H), 3.13 (d, J = 12.2 Hz, IH), 2.60 (t, J= 12.3 Hz, IH), 2.02 (d, J = 12.3 Hz, 5H), 1.85 (d, J= 11.4 Hz, 2H), 1.57 (m, 2H), 1.46 (d, J =7.0 Hz, 6H).
25	Ή NMR (400 MHz, Chloroform-<7) δ 8.18 - 8.13 (m, IH), 8.10 (dd, J= 7.3, 1.7 Hz, IH), 7.82 - 7.72 (m, 2H), 7.30 (d, J= 9.5 Hz, 2H), 7.19 (d, J= 8.4 Hz, 2H), 3.10 (s, IH), 2.75 (t, J= 7.5 Hz, 2H), 2.62 (s, IH), 2.02 (s, 4H), 1.87 (q, J= 7.9 Hz, 4H), 1.56 - 1.52 (m, 6H), 0.99 (t, J = 7.1 Hz, 3H).
26	’H NMR (400 MHz, Chloroform-J) δ 8.20 - 8.12 (m, IH), 8.10 (dd, J= 7.3, 1.7 Hz, IH), 7.83 - 7.70 (m, 2H), 7.30 (d, J= 8.6 Hz, 2H), 7.20 (td, J= 6.3, 5.9, 2.3 Hz, 2H), 3.14 — 3.04 (m, IH), 2.75 (t, .7=7.5 Hz, 2H), 2.68-2.56 (m, IH), 2.02 (dd, J= 13.3, 7.7 Hz, 4H), 1.92 - 1.79 (m, 4H), 1.69 - 1.47 (m, 4H), 1.05 (t, J = 7.3 Hz, 3H)._____________________
27	Ή NMR (400 MHz, CDCh) δ 8.17 - 8.08 (m, 2H), 7.81 - 7.70 (m, 2H), 7.32 - /.2/ (m,

Cmpd.	Characterization Data (NMR and LCMS)
	2H), 7.22 - 7.17 (m, 2H), 3.18 — 3.03 (m, IH), 2.78 -2.72 (m, 2H), 2.67 -2.57 (m, IH), 2.H - l.96(m, 4H), 1.93- l.80(m, 4H), 1.66- l.22(m, 15H), 0.96 - 0.86 (m, 3H).
28	Ή NMR (400 MHz, CDClj) δ 8.20 - 8.05 (m, 2H), 7.85 - 7.68 (m, 2H), 7.36 - 7.23 (m, 2H), 7.23 - 7.09 (m, 2H), 3.18 - 3.00 (m, IH), 2.75 (t, 7 = 7.4 Hz, 2H), 2.68 - 2.52 (m, IH), 2.12- 1.92 (m, 4H), 1.92- 1.75 (m, 4H), 1.64- 1.45 (m, 5H), 1.45 - 1.18 (m, 13H), 0.90 (t, 7= 6.7 Hz, 3H).
29	’H NMR (400 MHz, Chloroform-<7) δ 8.17 - 8.12 (m, IH), 8.12 - 8.07 (m, IH), 7.81 7.67 (m, 2H), 7.31 (m, 2H), 7.23 - 7.16 (m, 2H), 3.09 (d, 7= 12.0 Hz, IH), 2.74 (t, J= 7.5 Hz, 2H), 2.62 (t, 7= 12.4 Hz, IH), 2.01 (d, 7= 12.3 Hz, 4H), L86 (q, 7= 7.4 Hz, 4H), l .67 (q,7=7.2 Hz, l H), l .62 - l .46 (m, 6H), l .28 (m, 19H), 0.96 - 0.82 (m, 3H).
30	Ή NMR (400 MHz, Chloroform-7) δ 8.16 - 8.12 (m, l H), 8.12 - 8.09 (m, l H), 7.80 7.72 (m, 2H), 7.29 (m, 2H), 7.20 - 7.14 (m, 2H), 3.20 - 2.95 (m, lH), 2.86 - 2.71 (m, IH), 2.72-2.55 (m, lH), 2.22 - 2.06 (m, 2H), 2.01 (d,7= H.5 Hz, IH), l.97 — l.76 (m, 4H), l .74 - l .43 (m, 9H), l .06 (t, 7 = 7.1 Hz, 6H).
31	Ή NMR (400 MHz, Chloroform-7) δ 8.18 - 8.12 (m, IH), 8.12 - 8.07 (m, IH), 7.81 7.71 (m, 2H), 7.30 (d, 7= 8.5 Hz, 2H), 7.23 - 7.16 (m, 2H), 3.22 - 2.97 (m, IH), 2.73 (t, J = 7.4 Hz, 2H), 2.62 (t, 7= 12.3 Hz, l H), 2.06 - l .96 (m, 5H), l .96 - l .80 (m, 4H), l. 15 (t, 7=7.4 Hz, 3H).
32	Ή NMR (400 MHz, Chloroform-7) δ 8.18 - 8.12 (m, IH), 8.12 - 8.07 (m, IH), 7.81 7.71 (m, 2H), 7.28 (m, 2H), 7.22 - 7.16 (m, 2H), 3.10 (m, IH), 2.75 (t, 7= 7.4 Hz, 2H), 2.66-2.54(m, IH), 2.02 (s, 4H), l.86 (q, 7= 7.2, 6.7 Hz, 4H), l .38 (d, 7= 46.6 Hz, 12H), 0.97-0.83 (m, 3H).
33	Ή NMR (400 MHz, CDCh) δ 8.14 - 8.12 (m, IH), 8.10 - 8.08 (m, IH), 7.78 - 7.71 (m, 2H), 7.27 (d, 7= 8.5 Hz, 2H), 7.20 - 7.13 (m, 2H), 5.60 - 5.51 (m, 2H), 5.47 - 5.31 (m, 10H), 3.16 - 3.08 (m, l H), 2.96 - 2.82 (m, 12H), 2.67 - 2.59 (m, 3H), 2.13 - l .99 (m, 6H) 1.88 - 1.84 (m, 2H), 1.63- l.52(m, 2H), 0.99 (t,7=8.0 Hz, 3H).
34	Ή NMR (400 MHz, CDCl₃) δ 8.11 - 8.08 (m, IH), 8.07 - 8.04 (m, IH), 7.76 - 7.69 (m, 2H), 7.27 (d, 7= 8.5 Hz, 2H), 7.20 - 7.13 (m, 2H), 5.52 (s, 2H), 5.45 - 5.29 (m, 12H), 3.82 (t, 7= 8.0 Hz, 2H), 3.31 - 3.23 (m, IH), 2.87 - 2.79 (m, 10H), 2.72 - 2.64 (m, IH), 2.29 (qd, 7 = 12.0, 4.0 Hz, 2H), 2.22 - 2.16 (m, 2H), 2.13 - 2.05 (m, 2H), 2.04 - l .99 (m, 2H), l .80 - l .70 (m, 4H),l .61 - l .50 (m, 2H), 0.99 (t, 7= 8.0 Hz, 3H).
35	Ή NMR (400 MHz, CDCl₃) δ 8.04 (s, IH), 7.45 (s, IH), 7.37 - 7.35 (m, 2H), 7.26 - 7.23 (m, 2H), 7.14 - 7.09 (m, 4H), 5.41 - 5.30 (m, l IH), 5.29 (s, 2H), 5.23 - 5.18 (m, IH), 4.04 (s, 3H), 2.84 - 2.73 (m, 10H), 2.52 (s, 3H), 2.27 - 2.21 (m, 4H), 2.10 - 2.02 (m, 2H), 0.95 (t, 7 = 7.2 Hz, 3H); ^l9F NMR (376 MHz, CDCl₃) δ -58.24 (s, 3F). MS-ESI: m/z 816.10 observed (M+H)

Example 5: Sesame Oil Formulation

[00224] Sesame oil (10 gL) was dispensée! into compound (10 mg). The mixture was vortexed, sonicated and warmed (using heat gun) to aid dissolution. The solubility of the compound was judged after the sesame oil mixture cooled to room température. If the compound was not completely dissolved, additional sesame oil was 5 added in low-volume incréments.

Example 6: General methods and materiais for solid state characterization

Polarized light microscope (PLM)

[00225] Nikon LV100 PLM (Nikon Instruments Inc., USA) was used to examine the presence of big crystals (typically size larger than 5 μηι) in the milled crystalline compounds suspensions. One drop of the test 0 suspension was smeared on a microscope slide and covered by a cover slip for examination under crossed polarizers.

-Ray Powder Diffraction (XRPD)

[00226] The X-ray powder diffraction patterns of ail crystalline forms of the compounds were obtained on Bruker D8 advance X-ray powder diffractometer. Test materials were placed on monocrystalline silicon XRPD pan for analysis. The instrument spécification and settings are as follows:

Tube: Cu: K- Alpha (λ= l .54179Â).

Generator: Voltage: 40 kV; Current: 40 mA.

Scan Scope: 4 to 40 deg.

Sample rotation speed: 15 rpm.

Scanning rate: 10 deg./min.

Differential Scanning Calorimetrv (PSC)

[00227] DSC data were acquired using a TA Q2000 DSC. A sample weighted between 0.5 and l mg was sealed into an aluminum pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The heating program was set to heat the sample from 30°C to 300°C at a rate of l0°C/min. When the run is completed, the data were analyzed using TA Universal Analysis.

Thermal Gravimétrie Analysis (TGA)

[00228] TGA data were acquired using a TA Q5000 TGA. A sample weighted between 2 and 5 mg was placed in an open platinum pan and heated from 25°C to 300°C at a rate of l0°C/min. When the run is completed, the data were analyzed using TA Universal Analysis.

Size distribution measurement

[00229] Size distribution of milled crystalline compound suspensions was measured by Nicomp Zêta Potential & Particle Sizer 380 (Particle Sizing Systems Inc., USA). One drop of a test suspension was diluted with deionized water to a desired light scattering intensity (typically 300-700 kHz) and added into the sample cell to l/3 - 2/3 of the cell volume. The sample cell was left in the cell pedestal for 5 min to allow température équilibration. The settings of instrument parameters are as follows:

Intensity setpoint: 300 kHz.

Fixed angle: 90°.

Température: 23°C.

Liquid viscosity: 0.933CP.

Liquid index of refraction: 1.333.

HPLC method

[00230] Concentrations of the crystalline compound in suspensions were determined using Agilent HPLC

1200 and 1260 and the HPLC condition is as follows:

Column	Ascentis Express Cl8, 100 x 4.6 mm, 2.7μιη
Mobile Phase	A = 0.l%H₃PO4/H₂O B = ACN
Gradient	A:B Initial: 90:10 6min: 5:95 8min: 5:95

Flow rate	1. 8mL/min
Gradient Time	8 min (+ 2 min re-equilibration)
Température	40°C
Injection volume	10 pL
Wavelength	210 nm

Example 7: Synthesis of ELQ-300 crystalline forms

[00231] ELQ-300 crystalline forms were prepared and characterized via DSC, XRPD and TGA. Two distinct crystalline forms of the raw material were identified, designated as form IA and form IB. Four new crystalline forms of ELQ-300 were identified and designated as Form II, Form III, Form IV and Form V. FIG. 5 shows the 5 characteristic X-ray diffraction pattern of the crystalline ELQ-300-Form IA. FIG. 6 shows the characteristic Xray diffraction pattern of the crystalline ELQ-300-Form IB.

[00232] Table 4 shows the characteristic reflections and the corresponding d-spacings for crystalline ELQ300-Form IA.

TABLE 4

No.	2-Theta (°)	d-spacing (À)	No.	2-Theta (°)	d-spacing (À)
I	7.65	11.55	17	22.44	3.96
2	8.63	10.24	18	23.02	3.86
3	11.46	7.71	19	24.18	3.68
4	11.96	7.39	20	24.73	3.60
5	12.74	6.94	21	25.89	3.44
6	15.79	5.61	22	27.27	3.27
*7 !	16.07	5.51	23	28.26	3.16
8	16.45	5.38	24	28.95	3.08
9	16.96	5.22	25	29.15	3.06
10	17.34	5.11	26	29.86	2.99
11	18.67	4.75	27	30.27	2.95
12	19.09	4.65	28	32.31	2.77
13	19.72	4.50	29	32.74	2.73
14	20.16	4.40	30	36.21	2.48
15	20.45	4.34	31	37.77	2.38
16	20.93	4.24

[00233] Table 5 shows the characteristic reflections and the corresponding d-spacings for crystalline ELQ300-Form IB.

TABLES

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	5.23	16.87	16	23.16	3.84
2	7.77	11.36	17	24.32	3.66
3	8.90	9.93	18	24.83	3.58
4	12.90	6.86	19	26.04	3.42
5	15.95	5.55	20	27.40	3.25

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
6	16.26	5.45	21	28.37	3.14
7	17.00	5.21	22	29.14	3.06
8	17.43	5.08	23	30.17	2.96
9	18.09	4.90	24	31.20	2.86
10	18.77	4.72	25	32.52	2.75
11	19.23	4.61	26	33.68	2.66
12	19.84	4.47	27	34.35	2.61
13	20.33	4.36	28	36.37	2.47
14	20.63	4.30	29	37.85	2.38
15	22.56	3.94	30	38.91	2.31

First préparation of crystalline ELQ-300-Form II and characterization

[00234] Ail operations were carried ont at room température, at 18-23° C unless specifically stated. 37 mg of ELQ-300-Form IA was completely dissolved in 5 mL of DCM-MeOH mixture (1:1). The solution was stirred at 200 rpm and 15 mL of hexane was added to the solution over about 0.5 min. Précipitâtes were observed after addition of hexane and the suspension was kept stirring at 200 rpm for 3 hours. The sample was centrifuged at 14,000 rpm for 10 min and the précipitâtes were dried overnight in a vacuum oven at 40°C. Obtained product was characterized by XRPD and DSC and shown to be a new crystalline form, which was designated ELQ-300Form IL FIG. 7 shows the characteristic X-ray diffraction pattern of the crystalline ELQ-300-Form II.

Characteristic reflections and the corresponding d-spacings for crystalline Form II are shown inTable 6. FIG. 8 10 shows the DSC of the crystalline ELQ-300-Form II.

TABLE 6

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	4.37	20.19	15	20.94	4.24
2	5.12	17.24	16	22.43	3.96
3	7.67	11.52	17	23.01	3.86
4	8.94	9.89	18	24.18	3.68
5	10.23	8.64	19	25.62	3.47
6	12.74	6.94	20	28.20	3.16
7	15.29	5.79	21	30.88	2.89
8	15.76	5.62	22	31.54	2.83
9	17.30	5.12	23	32.28	2.77
10	17.85	4.97	24	32.62	2.74
11	18.63	4.76	25	33.50	2.67
12	19.11	4.64	26	36.11	2.49
13	20.14	4.41	27	38.79	2.32
14	20.43	4.34

l^st Scale up of crystalline ELQ-300-Form II and characterization

[00235] Ail operations were carried out at room température, at 18-23°C unless specifically stated. 188.64 mg of ELQ-300-Form IA was completely dissolved in 15 mL of DCM-MeOH mixture (1:1). The solution was stirred at 200 rpm and 45 mL of hexane was added to the solution over about 1 min. Précipitâtes were observed

-58^Kfter addition ofhexane and the suspension was kept stirring at 200 rpm for 3 hours., The sample was centrifuged at 14,000 rpm for 10 min and the précipitâtes were dried overnight in a vacuum oven at 40°C.

Obtained product was characterized by XRPD to confirm the formation of crystalline Form II and named as l^stscale up batch of crystalline ELQ-300-Form IL FIG. 9 shows the characteristic X-ray diffraction pattern of the 5 scaled up crystalline ELQ-300-Form II (l^st scale up batch). Characteristic reflections and the corrcsponding dspacings for the scaled up crystalline ELQ-300-Form II ( l^st scale up batch) are shown inTable 7.

TABLE 7

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	5.11	17.29	16	22.48	3.95
2	7.65	11.55	17	23.03	3.86
3	8.95	9.87	18	24.19	3.68
4	10.21	8.66	19	25.60	3.48
5	12.74	6.94	20	27.93	3.19
6	15.28	5.79	21	28.22	3.16
7	15.70	5.64	22	29.92	2.98
8	17.30	5.12	23	30.82	2.90
9	17.85	4.97	24	32.18	2.78
10	18.56	4.78	25	32.36	2.76
11	19.05	4.66	26	32.54	2.75
12	19.68	4.51	27	33.47	2.68
13	19.68	4.51	28	36.11	2.49
14	20.12	4.41	29	38.81	2.32
15	20.43	4.34

2^nd Scale up of crystalline ELQ-300-Form II and characterization

[00236] Ail operations were carried out at room température, at 18-23°C unless specifically stated. 1.2 grams of ELQ-300-Form IB was completely dissolved in 100 mL of DCM-MeOH mixture (1:1). The solution was stirred at 200 rpm and 290 mL of hexane was added to the solution over about 3 min. Précipitâtes were observed after addition of hexane and the suspension was kept stirring at 200 rpm for 2 days. The sample was centrifuged at 14,000 rpm for 10 min and the précipitâtes were dried overnight in a vacuum oven at 40°C.

Obtained product was characterized by XRPD and DSC to confirm the formation of crystalline Form II and named as 2^nd scale up batch of crystalline ELQ-300-Form IL FIG. 10 shows the characteristic X-ray diffraction pattern ofthe 2^nd scale up batch of crystalline ELQ-300-Form II. Characteristic reflections and the corresponding d-spacings for the 2^nd scale up batch of crystalline Form II are shown in Table 8. FIG. 11 shows the DSC ofthe 2^nd scale up batch of crystalline ELQ-300-Form II (2^nd scale up batch).

TABLE 8

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	5.16	17.10	20	23.76	3.74
2	7.69	11.48	21	24.22	3.67
3	8.99	9.83	22	24.71	3.60
4	10.21	8.66	23	25.61	3.48
5	12.22	7.24	24	25.88	3.44

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
6	12.75	6.94	25	27.22	3.27
7	15.28	5.79	26	27.96	3.19
8	15.77	5.62	27	28.21	3.16
9	16.40	5.40	28	30.01	2.98
10	17.33	5.11	29	30.74	2.91
11	17.90	4.95	30	32.28	2.77
12	18.65	4.75	31	32.52	2.75
13	19.07	4.65	32	33.43	2.68
14	19.66	4.51	33	34.19	2.62
15	20.14	4.41	34	34.49	2.60
16	20.41	4.35	35	36.13	2.48
17	20.98	4.23	36	37.86	2.37
18	22.43	3.96	37	38.83	2.32
19	22.98	3.87

Crystalline ELQ-300-Form III and ELQ-300-Form IV

[00237] Crystalline ELQ-300-Form III was prepared by slurry method using THF as the solvent and it was shown to be a solvaté by DSC. After heating at 1OO°C for 5 min, the crystalline ELQ-300-Form III transferred to a new crystalline form, which was designated crystalline ELQ-300-Form IV.

Préparation and characterization of crystalline ELQ-300-Form III

[00238] About 30 mg of crystalline ELQ-300-Form IA was suspended in 0.3 mL of THF in an l .5 mL sealed glass vial. The vial was placed in an Eppendorf Thermomixer and shaked at 50°C, 700 rpm for 72 h. The vial was centrifuged to collect solids. XRPD showed that the isolated solids hâve a new XRPD pattern. Thus, the wet solids were dried overnight in a vacuum oven at 40°C and the resulting dried product was characterized by

XRPD and DSC to confirm the formation of a new crystalline Form, which was designated as ELQ-300-Form

III. FIG. 12 shows the characteristic X-ray diffraction pattern of the crystalline ELQ-300-Form III.

Characteristic reflections and the corresponding d-spacings for crystalline ELQ-300-Form III are shown inTable 9. DSC and TGA of crystalline ELQ-300-Form III are shown in FIG. 13A and FIG. 13B respectively.

TABLE 9

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	5.09	17.34	23	25.10	3.55
2	7.65	11.55	24	25.60	3.48
3	11.45	7.72	25	25.81	3.45
4	12.74	6.94	26	27.18	3.28
5	15.31	5.78	27	27.86	3.20
6	15.72	5.63	28	28.20	3.16
7	15.98	5.54	29	29.05	3.07
8	16.33	5.42	30	29.25	3.05
9	16.97	5.22	31	29.76	3.00
10	17.30	5.12	32	32.28	2.77
11	17.85	4.96	33	32.62	2.74
12	18.58	4.77	34	33.09	2.71

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
13	19.03	4.66	35	33.49	2.67
14	19.62	4.52	36	33.68	2.66
15	20.10	4.41	37	34.20	2.62
16	20.43	4.34	38	34.51	2.60
17	20.91	4.25	39	35.58	2.52
18	22.38	3.97	40	36.12	2.49
19	23.00	3.86	41	36.62	2.45
20	23.65	3.76	42	37.14	2.42
21	24.16	3.68	43	37.66	2.39
22	24.62	3.61	44	38.79	2.32

Preparation and characterization of crystalline ELQ-300-Form IV

[00239] The crystalline ELQ-300-Form III obtained from slurry in THF was heated to l00°C and maintained the température for 5 min. the obtained product was characterized by XRPD, DSC and TGA and shown to be a new crystalline Form, which was designated crystalline ELQ-300-Form IV. FIG. 14 shows the characteristic X5 ray diffraction pattern of the crystalline ELQ-300-Form IV. Characteristic réfactions and the corresponding dspacings for crystalline ELQ-300-Form IV are shown inTable 10. DSC and TGA of crystalline ELQ-300-Form IV are shown in FIG. 15A and FIG. 15B respectively.

TABLE 10

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	7.65	11.55	14	23.17	3.84
2	8.91	9.92	15	24.33	3.66
3	12.97	6.82	16	24.83	3.58
4	15.88	5.58	17	25.95	3.43
5	17.45	5.08	18	27.32	3.26
6	18.04	4.91	19	28.32	3.15
7	18.81	4.71	20	29.92	2.98
8	19.19	4.62	21	30.07	2.97
9	19.77	4.49	22	32.46	2.76
10	20.29	4.37	23	32.72	2.74
11	20.64	4.30	24	33.70	2.66
12	21.08	4.21	25	36.23	2.48
13	22.48	3.95	26	36.41	2.47

Préparation and characterization of crystalline ELQ-300-Form V

[00240] Crystalline Form V was prepared by slurry method using NMP as the solvent. About 48 mg of crystalline ELQ-300-Form IA was suspended in 0.2 mL of NMP in an 1.5 mL sealed glass vial. The vial was placed in an Eppendorf Thermomixer and shaked at 37°C, 700 rpm for 24 h. The vial was centrifuged to collect the solids. XRPD showed that the isolated solids hâve a new XRPD pattern. Thus, 0.5 mL of éthanol was added to the wet solids for removing NMP. The sample was centrifuged at 14,000 rpm for 10 min and the supernatant was removed. The precipitated solids were dried overnight in a vacuum oven at 30°C and analyzed by XRPD,

-6l -

SC and TGA. The obtained product was shown to be a new crystalline Form, which was designated ELQ300-Form V.

FIG. 16 shows the characteristic X-ray diffraction pattern of the crystalline ELQ-300-Form V. Characteristic reflections and the corresponding d-spacings for crystalline Form V are shown in Table 11. DSC and TGA of 5 crystalline ELQ-300-Form V are shown in FIG. 17A and FIG. 17B respectively.

TABLE H

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	7.61	11.60	22	25.89	3.44
2	12.72	6.96	23	27.26	3.27
3	15.28	5.79	24	27.95	3.19
4	15.79	5.61	25	28.20	3.16
5	16.09	5.51	26	28.87	3.09
6	16.40	5.40	27	29.11	3.07
7	16.88	5.25	28	30.01	2.98
8	17.37	5.10	29	30.29	2.95
9	17.92	4.94	30	30.84	2.90
10	18.66	4.75	31	31.79	2.81
11	19.09	4.65	32	32.26	2.77
12	19.68	4.51	33	32.56	2.75
13	20.14	4.41	34	33.48	2.67
14	20.41	4.35	35	33.68	2.66
15	20.98	4.23	36	34.22	2.62
16	22.44	3.96	37	34.44	2.60
17	23.01	3.86	38	34.93	2.57
18	23.71	3.75	39	36.09	2.49
19	24.22	3.67	40	37.77	2.38
20	24.69	3.60	41	38.77	2.32
21	25.60	3.48

Example 8: Préparation and characterization of ELQ-300 crystalline form suspension

[00241] Wet-milling method was used to préparé the suspensions. Crystalline ELQ-300-Form II was selected as the raw material for milling and suspensions in two formulations were prepared:

(a) 1% (w/v) Synperonic® F108 (Flake) - 0.2% (w/v) dodecyl sodium sulfate (SLS, Richjoint Chemicals);

and (b) 3% (w/v) D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS, Sigma Aldrich).

[00242] ELQ-300-Form II suspensions were prepared at two concentrations, 15 mg/mL and 100 mg/mL, respectively.

Préparation of 15 mg/mL ELQ-300-Form II suspension

[00243] The l^st scale up batch of crystalline ELQ-300-Form II was used to préparé 15 mg/mL ELQ-300-Form II suspensions. About 30 mg of the obtained crystalline ELQ-300-Form II was weighted in a 30 mL highdensity polyethylene bottle. 1.2 mL of suspension vehicle, i.e., 1% (w/v) Synperonic® F108 - 0.2% (w/v) SLS or 3% (w/v) TPGS, was added. 2.4 mL of zirconium beads with a diameter of 0.8 mm (YTZ® Grinding Media,

-62Tlikkato Co., Japan) were added using a measuring cylinder. The bottles were placed on a US Stoneware Roller Mixer and the rolling speed was set at 220 rpm.

[00244] The milling duration was 2 days and one drop of milled suspension was diluted with deionized water to for size distribution measurement by Nicomp Zêta Potential & Particle Sizer 380. The suspensions were also examined under PLM to see if the obtained products contained particles bigger than 5pm. If a majority of the particles were smaller than 5pm, the suspensions were collected using a ImL pipette. Concentrations of ELQ300-Form II in the suspensions were détermination by HPLC. The suspensions were further diluted with their corresponding formulation vehicles to a final concentration of 15 mg/mL and stored in sealed glass vials at room température before PK study. Visual inspection of the suspensions showed that the products were homogeneous, syringeable and easily resuspendable following short-time vortex or water-bath sonication, suitable for preclinical PK study via intramuscular injection. The suspensions were characterized on dosing day by particle sizer and HPLC to ensure that the samples remained stable after storage at room température in terms of particle size and API concentration.

Préparation of 100 mg/mL ELQ-300-Form II suspension

[00245] The 2^nd sealed up batch of crystalline ELQ-300-Form II was used for preparing aqueous ELQ-300Form II suspension at 100 mg/mL. Initially, the targeted concentration of ELQ-300-Form II suspensions was set at 200 mg/mL. About 250 mg of the crystalline ELQ-300-Form II was weighted in a 30 mL high-density polyethylene bottle. I mL of suspension vehicle, i.e., l% (w/v) Synperonic®Fl08 - 0.2% (w/v) SLS or 3% (w/v) TPGS, was added. 2 mL of zirconium beads with a diameter of 0.8 mm (YTZ® Grinding Media, Nikkato Co., Japan) were added using a measuring cylinder. The bottles were placed on a US Stoneware Roller Mixer and the rolling speed was set at 220 rpm. After 2 days of milling, the crystals suspended in both milling vehicles formed a solid paste. Thus, extra milling medium (approximately l mL) was added to each sample for getting a liquid form for continued milling. The samples were milled for 72 h and the products were characterized by Nicomp Zêta Potential & Particle Sizer 380, PLM and HPLC as described above. The suspensions were further diluted with their corresponding formulation vehicles to a final concentration of 100 mg/mL for PK study. Visual inspection of the suspensions showed that the products were homogeneous, syringeable and easily resuspendable following short-time vortex or water-bath sonication, suitable for preclinical PK study via intramuscular injection. The suspensions were characterized on dosing day by particle sizer and HPLC to ensure that the samples remained stable after storage at room température in terms of particle size and API concentration.

Example 9: Synthesis of atovaquone crystalline forms

[00246] Polymorph screening of atovaquone identified two stable forms. The raw form is characterized by large crystals of varying shape with lengths as large as 5 mm (atovaquone-form I). A second polymorph was identified by évaporation of the raw API from acetone : l,4-dioxane (l : l). This crystalline form, named atovaquone-form II, was characterized by PLM and found to be small needles.

Characterization of the crystalline atovaquone-Form I

The crystalline atovaquone-Form I was characterized by XRPD and DSC. FIG. 23 shows the characteristic Xray diffraction pattern of the crystalline atovaquone-Form I. Characteristic reflections and the corresponding d

-63 Çpacings for crystalline atovaquone-Form I are shown inTable 12. FIG. 24A shows DSC of the crystalline atovaquone-Form I. FIG. 24B shows TGA of the crystalline atovaquone-Form I.

TABLE 12

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	7.26	12.17	21	25.31	3.52
2	7.44	11.87	22	26.36	3.38
3	9.88	8.95	23	26.79	3.33
4	10.90	8.11	24	27.66	3.22
5	11.21	7.89	25	28.59	3.12
6	11.92	7.42	26	28.81	3.10
7	14.66	6.04	27	29.30	3.05
8	15.61	5.67	28	29.87	2.99
9	16.29	5.44	29	30.14	2.96
10	16.94	5.23	30	30.84	2.90
11	17.54	5.05	31	32.23	2.78
12	18.11	4.90	32	32.91	2.72
13	19.43	4.57	33	33.63	2.66
14	20.12	4.41	34	34.36	2.61
15	21.42	4.14	35	35.56	2.52
16	22.25	3.99	36	36.02	2.49
17	22.98	3.87	37	36.69	2.45
18	23.73	3.75	38	38.21	2.35
19	24.86	3.58	39	39.63	2.27
20	25.07	3.55

Préparation and characterization of the crystalline atovaquone-Form II

Crystalline atovaquone-Form II was prepared by solvent évaporation method. Ail operations were carried out at room température, at 18-23° C unless specifically stated. 300 mg of atovaquone-Form I was weighted in a 40 mL glass vial and 9 mL of a mixture of acetone and 1,4-dioxane (volume ratio: 1:1) was added. Short time of vortex or sonication (around 5 to 10 s) was also used and atovaquone-Form I completely dissolved easily. The vial was covered with a piece of aluminium foil with pinholes for overnight solvent évaporation in a fume cupboard at room température. The obtained solids were further dried overnight in a vacuum oven at 30°C and then characterized by XRPD, DSC and TGA. The product was shown to be a new crystalline Form, which was designated crystalline atovaquone-Form IL FIG. 25 shows the characteristic X-ray diffraction pattern of the crystalline atovaquone-Form IL Characteristic reflections and the corresponding d-spacings for crystalline atovaquone-Form II are shown in Table 13. FIG. 26A shows the DSC of the crystalline atovaquone-Form IL

FIG. 26B shows the DSC of the crystalline atovaquone-Form IL

TABLE 13

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	7.02	12.57	19	25.35	3.51
2	9.29	9.51	20	25.66	3.47_______
3	9.71	9.10	21	26.38	3.38

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
4	12.77	6.93	22	26.97	3.30
5	14.29	6.19	23	27.29	3.27
6	14.86	5.96	24	27.78	3.21
7	15.25	5.80	25	28.59	3.12
8	17.14	5.17	26	28.88	3.09
9	18.62	4.76	27	30.66	2.91
10	19.29	4.60	28	32.77	2.73
11	20.13	4.41	29	33.60	2.67
12	20.53	4.32	30	35.27	2.54
13	20.73	4.28	31	37.72	2.38
14	21.92	4.05	32	38.04	2.36
15	22.17	4.01	33	38.46	2.34
16	22.78	3.90	34	38.72	2.32
17	23.36	3.81	35	39.66	2.27
18	24.38	3.65

Example ΙΟ: Préparation and characterization of atovaquone crystalline form suspension

[00247] Wet-milling method was used to préparé crystalline atovaquone suspensions. Both crystalline atovaquone-Form I and atovaquone-Form II were used as the raw material for milling and suspensions using l% (w/v) Synperonic® F108 (Flake) - 0.2% (w/v) dodecyl sodium sulfate (SLS, Richjoint Chemicals), targeted concentration of 200 mg/mL. However, crystalline atovaquone-Form I was not suitable for the suspension préparation, as big rod-shaped crystals around 5 mm in length were observed in collected suspension, which may be explained by the Ostwald ripening theory. In contrast, a nanosuspension of crystalline atovaquone Form II at 200 mg/mL was successfully prepared and used in the PK studies.

Préparation of 200 mg/mL nanosuspensions using crystalline atovaquone-Form II

[00248] Crystalline atovaquone-Form II was used to préparé 200 mg/mL nanosuspension. About 200 mg of the obtained crystalline atovaquone-Form II was weighted in a 30 mL high-density polyethylene bottle. 0.8 mL of suspension vehicle, i.e., l% (w/v) Synperonic® Fl08 - 0.2% (w/v) SLS, was added. 1.6 mL of zirconium beads with a diameter of 0.8 mm (YTZ® Grinding Media, Nikkato Co„ Japan) were added using a measuring cylinder. The bottles were placed on a US Stoneware Roller Mixer and the rolling speed was set at 220 rpm.

The milling duration was 3 days and one drop of milled suspension was diluted with deionized water for size distribution measurement by Nicomp Zêta Potential & Particle Sizer 380. The suspension was also examined under PLM to see if the obtained product contained particles bigger than 5 pm. If a majority ofthe particles were smaller than 5 μιη, the suspension was collected using an ImL pipette. Concentration of atovaquone-Form II in the suspension was determined by HPLC. The suspension was further diluted with l% (w/v) Synperonic®

Fl08 - 0.2% (w/v) SLS to a final concentration of 200 mg/mL. The final product was stored in an l .5 mL sealed glass vial at room température and protected from light before PK study. Visual inspection ofthe suspensions showed that the products were homogeneous, syringeable and easily resuspendable following short-time vortex or water-bath sonication, suitable for preclinical PK study via intramuscular injection. The suspensions were characterized on dosing day by particle sizer and HPLC to ensure that the samples remained stable after storage at room température in tenus of particle size and API concentration.

-65 Example 11: Synthesis of Pyronaridine crystalline forms

[00249] Four new crystalline forms of pyronaridine are summarized inTable 14 and designated as Form II,

Form III, Form IV and Form V.

TABLE 14

Crystalline Form No.	Préparation method	Solvent used and conditions
Form II	Slurry method	EtOH	40°C,48hr
Form III	Slurry method	IPA	40°C,48hr
acetone
THF
1,4-Dioxane
Form IV	Slurry method	MeOH:H2O (v:v, 3:1)	40°C,48hr
EtOH:H2O (v:v, 3:1)
Acetone:H2O (v:v, 1:2)
IPA:H2O (v:v, 1:1)
Form V	Heating method	No solvents used, heated to 120°C for 5 min

Characterization ofthe crystalline pyronaridine-Form I

[00250] Crystalline pyronaridine-Form I was characterized by XRPD, DSC and TGA. FIG. 28 shows the characteristic X-ray diffraction pattern of the crystalline pyronaridine-Form I. Characteristic reflections and the corresponding d-spacings for crystalline pyronaridine-Form I are shown in Table 15. FIG. 29A shows DSC of the crystalline pyronaridine-Form I. FIG. 29B shows TGA of the crystalline pyronaridine-Form I.

TABLE 15

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	7.44	11.88	18	21.12	4.20
2	9.65	9.16	19	21.89	4.06
3	11.29	7.83	20	22.58	3.93
4	12.65	6.99	21	23.56	3.77
5	13.41	6.60	22	23.83	3.73
6	14.19	6.24	23	24.30	3.66
7	14.74	6.00	24	25.57	3.48
8	15.51	5.71	25	25.86	3.44
9	15.85	5.59	26	26.22	3.40
10	16.38	5.41	27	26.75	3.33
11	16.72	5.30	28	27.13	3.28
12	17.23	5.14	29	28.47	3.13
13	17.88	4.96	30	28.96	3.08
14	18.18	4.88	31	30.03	2.97
15	18.60	4.77	32	31.89	2.80

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
16	20.06	4.42	33	32.65	2.74
17	20.51	4.33	34	36.31	2.47

Preparation of crystalline pyronaridine-Form II, pyronaridine-Form III and pyronaridine-Form IV and characterization results

[00251] Crystalline Form II, Form III and Form IV of pyronaridine were prepared by slurry method using different solvents (details summarized in Table 14). About 30 mg of crystalline pyronaridine-Form I was suspended in 0.2 mL of each solvent in a 1.5 mL sealed glass vial. The vial was placed in an Eppendorf Thermomixer and shaken at 40°C, 700 rpm for 48 h. The API solids were collected by centrifugation and shown to be new crystalline forms. Thus, the wet solids were dried overnight in a vacuum oven at 30°C and the resulting dried products were characterized by XRPD, DSC and TGA.

[00252] The new crystalline form obtained from slurry in éthanol was designated pyronaridine-Form IL FIG.

30 shows the characteristic X-ray diffraction pattern of the crystalline pyronaridine-Form IL Characteristic reflections and the corresponding d-spacings for crystalline pyronaridine-Form II are shown in Table 16. FIG.

31A shows the DSC of the crystalline pyronaridine-Form II. FIG. 3 IB shows the TGA ofthe crystalline pyronaridine-Form II.

TABLE 16

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (À)
1	6.76	13.06	22	22.27	3.99
2	7.40	11.94	23	22.46	3.95
3	8.45	10.46	24	23.65	3.76
4	9.08	9.73	25	24.32	3.66
5	10.62	8.33	26	24.56	3.62
6	12.93	6.84	27	25.94	3.43
7	13.48	6.56	28	27.17	3.28
8	14.84	5.96	29	29.61	3.01
9	15.23	5.81	30	30.19	2.96
10	15.67	5.65	31	30.52	2.93
11	16.68	5.31	32	31.59	2.83
12	16.92	5.24	33	32.20	2.78
13	17.43	5.08	34	32.76	2.73
14	18.20	4.87	35	33.31	2.69
15	18.57	4.77	36	33.92	2.64
16	18.91	4.69	37	34.69	2.58
17	19.90	4.46	38	35.70	2.51
18	20.49	4.33	39	36.71	2.45
19	20.93	4.24	40	37.18	2.42
20	21.08	4.21	41	37.60	2.39
21	21.97	4.04	42	39.08	2.30

[00253] After slurry in IPA, acetone, THF and 1,4-Dioxane, the crystalline pyronaridine-Form I transferred to another new crystalline form, which was designated pyronaridine-Form III. FIG. 32 shows the characteristic X

-67Tay diffraction pattern of the crystalline pyronaridine-Form III. Characteristic reflections and the corresponding d-spacings for crystalline Form III are shown in Table 17. FIG. 33A shows the DSC of the crystalline pyronaridine-Form III. FIG. 33B shows the TGA of the crystalline pyronaridine-Form III.

TABLE 17

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	5.68	15.55	25	24.50	3.63
2	6.71	13.17	26	24.80	3.59
3	7.91	11.16	27	25.08	3.55
4	9.37	9.43	28	25.63	3.47
5	9.98	8.86	29	26.31	3.38
6	11.05	8.00	30	26.50	3.36
7	12.04	7.35	31	27.05	3.29
8	13.46	6.57	32	28.02	3.18
9	14.49	6.11	33	28.36	3.14
10	15.77	5.61	34	29.23	3.05
11	16.17	5.48	35	29.60	3.02
12	17.13	5.17	36	29.79	3.00
13	17.98	4.93	37	30.51	2.93
14	18.84	4.71	38	30.76	2.90
15	19.03	4.66	39	31.62	2.83
16	19.44	4.56	40	31.89	2.80
17	20.10	4.41	41	32.25	2.77
18	20.77	4.27	42	32.93	2.72
19	21.46	4.14	43	33.75	2.65
20	21.65	4.10	44	34.69	2.58
21	22.38	3.97	45	36.57	2.46
22	22.94	3.87	46	37.49	2.40
23	23.17	3.84	47	38.37	2.34
24	23.83	3.73	48	38.97	2.31

[00254] The dried crystals obtained after slurry in MeOH:H₂O (v.v, 3:1), EtOH:H₂O (v:v, 3:1), acetone:H₂O (v:v, 1:2) and IPA:H₂O (v:v, 1:1) showed a different crystalline form from Form I, Il and III of pyronaridine and it was designated crystalline pyronaridine-Form IV. FIG. 34 shows the characteristic X-ray diffraction pattern of the crystalline pyronaridine-Form IV. Characteristic reflections and the corresponding d-spacings for crystalline Form IV are shown in Table 18. FIG. 35A shows the DSC of the crystalline pyronaridine-Form IV.

FIG. 35B shows the TGA of the crystalline pyronaridine-Form IV.

TABLE 18

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
1	8.36	10.57	17	22.80	3.90
2	9.35	9.45	18	23.41	3.80
3	10.93	8.09	19	24.58	3.62
4	14.27	6.20	20	24.91	3.57
5	14.55	6.08	21	25.33	3.51

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (Â)
6	15.46	5.73	22	25.88	3.44
7	16.48	5.38	23	27.54	3.24
8	17.84	4.97	24	28.01	3.18
9	18.04	4.91	25	28.35	3.15
10	18.40	4.82	26	28.86	3.09
11	19.03	4.66	27	29.26	3.05
12	19.45	4.56	28	29.93	2.98
13	20.37	4.36	29	31.57	2.83
14	20.65	4.30	30	32.73	2.73
15	21.32	4.16	31	33.43	2.68
16	21.97	4.04

Préparation of crystalline pyronaridine-Form V and characterization results

[00255] Crystalline pyronaridine-Form V was prepared from crystalline pyronaridine-Form I by heating and cooling method. About 10 mg of crystalline pyronaridine-Form I was placed in an open platinum pan and heated by TA Q5000 TGA. The heating process was set to heat the sample from 25°C to 12O°C at a rate of lO°C/min and maintained 12O°C for 5 min. After this, the powder was allowed to cool down to room température. The obtained solids were characterized by XRPD and DSC and showed to be a new crystalline form, which was designated crystalline pyronaridine-Form V. FIG. 36 shows the characteristic X-ray diffraction pattern ofthe crystalline pyronaridine-Form V. Characteristic reflections and the corresponding d-spacings for crystalline pyronaridine-Form V are shown inTable 19. FIG. 37 shows the DSC ofthe crystalline pyronaridine10 Form V.

TABLE 19

No.	2-Theta (°)	d-spacing (Â)	No.	2-Theta (°)	d-spacing (A)
1	6.77	13.05	19	19.44	4.56
2	9.36	9.44	20	19.80	4.48
3	9.93	8.90	21	20.33	4.36
4	11.01	8.03	22	20.69	4.29
5	12.11	7.30	23	21.01	4.22
6	13.46	6.57	24	22.95	3.87
7	13.85	6.39	25	23.48	3.79
8	14.07	6.29	26	24.20	3.67
9	14.61	6.06	27	24.87	3.58
10	15.34	5.77	28	25.49	3.49
11	16.15	5.48	29	26.04	3.42
12	16.36	5.41	30	26.59	3.35
13	16.74	5.29	31	27.03	3.30
14	17.31	5.12	32	29.64	3.01
15	17.57	5.04	33	29.89	2.99
16	17.87	4.96	34	32.56	2.75
17	18.35	4.83	35	32.59	2.75
18	19.07	4.65

-69^fcxample 12: Pharmacokinetic studies

PO

1. Animais

[00256] Animais (Male CD-1 mice, 7-9 weeks) were obtained from an approved vendor (SLAC Laboratory

Animal Co. Ltd., Shanghai, China; or SIPPR-B&K Laboratory Animal Co. Ltd., Shanghai, China).

[00257] Acclimation/Ouarantine: Following arrivai animais were assessed as to their general health by a member of the veterinary staff or other authorized personnel. Animais were acclimated for at least 3 days before being placed on study.

[00258] Animal Husbandry: Animais were group housed during acclimation and individually housed during the study. The animal room environment was controlled (target conditions: température 18 to 26°C, relative humidity 30 to 70%, 12 hours artificial light and 12 hours dark). Température and relative humidity was monitored daily.

[00259] Animais were fasted at least 12 hours prior to the administration. AH animais had access to Certified Rodent Diet (Catalog # MOI-F, SLAC Laboratory Animal Cl. Ltd., Shanghai, China) ad libitum 4 hours post dosing.

[00260] Water was autoclaved before provided to the animais ad libitum. Periodic analyses of the water was performed.

2. Formulation

PO Formulation

[00261] Appropriate amount of test compound was accurately weighed and mixed with appropriate volume of vehicle to get a clear solution or a uniform suspension, vortexing or sonication in water bath was sometimes needed. The formulations were prepared on the day of dosing. Animais were dosed within four hours after the formulation was prepared. Two 20 pL aliquots of each formulation were removed from each ofthe formulation solutions, transferred into 1.5 mL of polypropylene microcentrifuge tubes and run dose validation by LC/UV or 25 LC-MS/MS.

3. Dose Administration

[00262] The PO dose formulation was administered via oral gavage following facility SOPs.

4. Sample Collection

[00263] For PO group, Approximately 30 pL blood was collected from saphenous vein at each time point. Ail blood samples were transferred into microcentrifuge tubes containing 2pL of K^EDTA (0.5M) as anti-coagulant and placed on wet ice until processed for plasma.

5. Blood/Plasma processing

[00264] Blood samples were processed for plasma by centrifugation at approximately 4°C, 3000 g 15 min within half an hour of collection. Plasma samples were stored in polypropylene tubes, quick frozen over dry ice 35 and kept at —70± 10 °C until LC/MS/MS analysis.

6. Sample Analysis

Dose formulation concentration vérification

Aliquots ofthe formulations were collected in the middle position of each dose formulation in dupiicate.

The concentrations of the test compound in dose formulation samples were determined by the LC/UV or LC/MS/MS method.

Bioanalytical method and sample analysis

LC-MS/MS methods for the quantitative détermination of test compound in corresponding biological matrix was developed under non-GLP compliance.

A calibration curve with 8 non-zero calibration standards was applied for the method including LLOQ.

A set of QC samples consisting of low, middle, and high concentration was applied for the method.

The study sample analysis was performed concurrently with a set of calibration standards and two sets of QC samples using the LC-MS/MS method(If sample numbers are more than 48, then two calibration curves with 2 sets of QC samples will be applied).

Acceptance criteria:

Linearity: a minimum of 6 calibration standards was back calculated to within ±20% of their nominal values in plasma

Accuracy: A minimum of 4 out of 6 QC samples was back calculated to within ±20% of their nominal values in plasma.

Specificity: The mean calculated concentration in the single blank matrix should be 0.5 times the LLOQ.

Sensitivity: LLOQ target: l~3 ng/mL.

Carryover: the mean calculated carry-over concentration in the single blank matrix immediately after the highest standard injection should be <LLOQ. If the carryover couldn’t meet the criteria, then the percent of carryover should be estimated following in-house bioanalytical SOP.

7. Data Analysis

[00265] Plasma concentration versus time data was analyzed by non-compartmental approaches using the Phoenix WinNonlin 6.3 software program. C max, Tmax? T'/₂, AUC(o-t), AUC(o-inf), MRT(o-t), MRT(o-inf), %F and graphs of plasma concentration versus time profile will be reported.

IM/SC

1. Animal

Rats (Sprague-Dawley, Male, 7-9 weeks) were obtained from an approved vendor (SLAC Laboratory Animal Co. Ltd., Shanghai, China or SIPPR/BK Laboratory Animal Co. Ltd., Shanghai, China

[00266] Acclimation/Quarantine: Following arrivai animais were assessed as to their general health by a member of the veterinary staff or other authorized personnel. Animais were acclimated for at least 3 days before being placed on study.

[00267] Animal Husbandry: Animais were group housed during acclimation and individually housed during the study. The animal room environment was controlled (target conditions: température 18 to 26°C, relative humidity 30 to 70%, 12. hours artificial light and 12 hours dark). Température and relative humidity was monitored daily.

[00268] Animais were fasted at least 12 hours prior to the administration. Ail animais had access to Certified Rodent Diet (Catalog # MOI-F, SLAC Laboratory Animal CL Ltd., Shanghai, China) ad libitum 4 hours post

- 71 ^osing. Water was autoclaved before provided to the animais ad libitum. Periodic analyses of the water was performed.

2. Dose Formulation

[00269] Formulation will be picked up directly from PDS.

[00270] Two 20 liL aliquots of each formulation will be removed from each of the formulation solutions, transferred into 1.5 mL of polypropylene microcentrifuge tubes and run dose validation by LC/UV or LCMS/MS.

3. Dose Administration

[00271] For IM/SC dosing, the dose formulation were administered via intramuscular/subcutaneous injection following facility SOPs.

4. Sample Collection

[00272] Approximately 200 pL blood were collected from saphenous vein at each time point. Ail blood samples were transferred into microcentrifuge tubes containing 4pL of K?EDTA (0.5M) as anti-coagulant and placed on wet ice until processed for plasma.

5. Blood/Plasma processing

[00273] Blood samples were processed for plasma by centrifugation at approximately 4°C, 3000 g 15 min within half an hour of collection. Plasma samples will be stored in polypropylene tubes, quick frozen over dry ice and kept at -70±10 °C until LC/MS/MS analysis.

6. Sample Analysis

Dose fonnuiation concentration vérification

For the clear solution, 1 sample were collected in the middle of each dose formulation; for the suspension, 3 samples were collected from top, middle, button of each dose solution.

« A LC/UV method was developed and 1 standard solution was prepared.

The peak area of test article in dose formulation solution and in standard solution samples was determined by the LC/UV method » Acceptance criteria: the peak area of formulation solution sample was within 80%~120% of that in standard solution.

Bioanalytical method and sample analysis ^a LC-MS/MS methods for the quantitative détermination of test compound in corresponding biological matrix was developed under non-GLP compliance.

» A calibration curve with 8 non-zero calibration standards was applied for the method including LLOQ.

° A set of QC samples consisting of low, middle, and high concentration was applied for the method.

» The study sample analysis was performed concurrently with a set of calibration standards and two sets of QC samples using the LC-MS/MS method(lf sample numbers are more than 48, then two calibration curves with 2 sets of QC samples will be applied).

Acceptance criteria:

- 72 Accuracy: A minimum of 4 out of 6 QC samples was back calculated to within ±20% of their nominal values in plasma.

Specificity: The mean calculated concentration in the single blank matrix should be 0.5 times the

LLOQ.

Sensitivity: LLOQ target: l~3 ng/mL.

Carryover: the mean calculated carry-over concentration in the single blank matrix immediately after the highest standard injection should be <DLLOQ. If the carryover couldn’t meet the criteria, then the percent of carryover should be estimated following in-house bioanalytical SOP.

7. Data Analysis

[00274] Plasma concentration versus time data will be analyzed by non-compartmental approaches using the

Phoenix WinNonlin 6.3 software program. C_max, T_max, T/₂, AUC₍o-t), AUC(o-inf), MRT₍o-t), MRT(o-inf), %F and graphs of plasma concentration versus time profile will be reported.

[00275] Table 20 shows the PK data for Compound 2 following PO and IM administration. Graph is shown in

FIG. L

TABLE 20

	Compound 2 (PO)	Compound 2 (IM)
mpk	0.03	0.1	0.3	0.03	0.1	0.3
Cmax (nM)	45.2	173.4	554.8	ND	5.6	18.7
T_max(h)	3.67	3.0	4.67	ND	96	112
Ti_/2(h)	24.9	23.7	22.5	ND	-	418
AUCo._last (nMh)	1450	4936	16524	ND	797	2801
AUCo-inf (nM-h)	1555	5044	16764	ND	2972	4823
CL/F (mL/min/kg)	0.576	0.599	0.520	ND	0.586	0.864

[00276] Table 21 shows the average plasma concentration of ELQ-300 following IM administration of Compound 2 at 3 doses (3, 10. and 30 mg/kg). Table 22 shows the ELQ-300 plasma concentration in ail animais at day 14 (prior to the sporozoites challenge). The exposure is not highly variable between animais m a given group. The C_trough is about 83 ± 32 nM for animais that are protected from infection. The graphs are shown in FIG. 2A and FIG. 2B.

TABLE 21

Time	ELQ-300 (nM)
3.33 mg/kg	10 mg/kg	30 mg/kg
1 d	723 ± 144	2942 ±633	10959 ±2029
7d	36+ 16	112 ±66	257 ± 70
14 d	27 ± 14	68 ±40	214 ± 54
21 d	28 ± 17	88 ± 61	155 ±38

Time	ELQ-300 (nM)
3.33 mg/kg	10 mg/kg	30 mg/kg
28 d	21 ±32	69 ±37	181 ±59

TABLE 22

3 mg/kg	10 mg/kg	30 mg/kg
5	43 nM	9	56 nM	13	137 nM
6	15 nM	10	73 nM	14	219 nM
7	35 nM	11	119nM	15	246 nM
8	15 nM	12	23 nM	16	256 nM

[00277] Table 23 shows rat PK data for compound 2 (3.72 mg/kg in 100% sesame oil) injected intramuscularly. Table 24 shows the average plasma concentration of ELQ-300 following IM administration of Compound 2. Rat IM PK of Compound 2 demonstrated a slow release for the first month with ELQ-300 plasma 5 level around 70 nM week two through four an significant burst in day l and significant drop in concentration between week one and two. The graph is shown in FIG. 3A.

TABLE 23

mpk	3.72
Czmax (nM)	399.3 ± 340
T_max (h)	49.7 ±38.7
T_1/2(h)	359 ±25.5
AUCo-iast (nM.h)	68060 ± 3966
AUCo-inf (nM.h)	103311± 9144
CL/F (mL/min/kg)	1.05 ±0.09

TABLE 24

Time	ELQ-300 (nM)	Time	ELQ-300 (nM)
1 h	151 ±209	6d	169 ±22
8h	235 ±281	13 d	73 ± 17
1 d	151 ±209	20 d	75 ± 19
3 d	157 ± 80	27 d	68 ± 5

[00278] Table 24A shows dog PK data for crystalline compound 2 (20 mg/mL, 3% TPGS, l% HPMC E5 suspension) injected intramuscularly. Compound 2 was dosed in dog at 10 mg/kg (Injection volume: 0.5 mL/kg). The material was formulated as a 20 mg/mL suspension in 3% TPGS and l% HPMC E5. Compound 2 plasma exposure was low but détectable throughout the duration of the study. Plasma concentrations of ELQ300 remained several orders of magnitude higher than that of Compound 2. Half-life of ELQ-300 was about

-74wice as long as that of compound 2 (205 and 124 respectively). Additionally, clearance of ELQ-300 remained very low (0.23 mL/min/kg). The graph is shown in FIG. 3B.

TABLE 24A

	Compound 2	ELQ-300
Tmax(h)	3(2)	48 (0)
T_l/2(h)	124(34)	205 (39)
Cmax (nM)	730(149)	4639 (832)
Clast (mM)	4.5 (4.7)	482 (123)
AUCo-iast (nM.h)	16427 (3738)	1140080(100116)
AUCo-mf (nM.h)	18054 (3387)	1287335 (95176)
CL/F (mL/min/kg)	14.4 (3.3)	0.23 (0.02)

[00279] Table 25 shows the ELQ-300 plasma concentration following administration of compounds 2, 8, 9,

10, 12, 16, 17, and 18 (3 mg/kg, 1.5 mg/mL in 100% sesame oil). Graphs are shown in FIG. 4A and FIG. 4B.

TABLE 25

Time	ELQ-300 (nM)
2	8	9	10	12	16	17	18
8h	175 + 82	27 ±22	38 ±6	12± 11	948 ± 609	272 ± 393	50 ± 3	17 ± 7
1 d	142 + 42	23 ± 16	24 ±4	15 ± 17	406± 165	137 ±97	28 ± 5	10 ± 4
6d	85 ±40	31 ±9	32± 15	34 ±7	156 ±45	18 ± 5	12 ± 3	3.0 ± 5
13 d	46 ± 8	28 ±9	33 ± 10	38 ±2	83 ±30	20 ±20	5± 1	1.6± 1.4
27 d	27 ± 16	32 ± 11	36 ±7	33 ±5			6±3	2.5 ± 0.4

[00280] Table 26 shows the average plasma concentration of ELQ-300 following IM administration of suspensions of ELQ-300-Form II in two different formulations (15 mg/mL, 30 mg/kg) as compared to the average plasma concentration of ELQ-300 following IM administration of Compound 2 and Compound 13 in 100% sesame oil (1.5 mg/mL, 3 mg/kg). The graph is shown in FIG. 18.

TABLE 26

Time	ELQ-300 (μΜ)	ELQ-300 (nM)
3% TPG S	1% Synperonic® F 108- 0.2% SLS	Comp. 2	Comp. 13
8 h	1.7 ±0.3	1.7 ± 0.1	175 ±82	382 ±48
1 d	2.1 ±0.4	2.5 ± 0.9	142 ±42	410 ± 83
6d	1.3 ±0.2	2.4 ±0.3	123 ±85	313 ± 89
13 d	0.8 ±0.1	1.1 ± 0.2	46 ± 8	110 ± 7
20 d	0.64 ± 0.99	0.94 ±0.03	32 ± 16	79 ±6
27 d	0.48 ± 0.04	0.78 ± 0.24	27 ± 16	80 ±7

N'

-75 •[00281] Table 27 shows the mouse PK data following IM administration of 6 different ELQ-300-Form II suspensions (100 mg/mL). IMl = Synperonic® 4 mg/kg, IM2 = Synperonic® 12 mg/kg, IM3 = Synperonic® 36 mg/kg. IM4 = TPGS 4 mg/kg, IM5 = TPGS 12 mg/kg, IM6 = TPGS 36 mg/kg. Doese proportionality (up to 13 days) is observed in the 2 different vehicles. Graphs are shown in FIG. 19A and FIG. 19B.

TABLE 27

	IMl	IM2	IM3	IM4	IM5	1M6
Nominal Dose (mg/kg)	4	12	36	4	12	36
Concentration (mg/mL)	100	100	100	100	100	100
Dose Volume (uL)	10	30	90	10	30	90
tm (h)	242 (34)	250(36)	250 (38)	381 (182)	227 (41)	320 (83)
Cmax (nM)	333 (l18)	820(128)	1813 (255)	263 (17)	605 (342)	855 (33)
Clast (nM)	37(2)	109 (25)	277(13)	31 (4)	49 (4)	190 (12)
AUC (o-oc)	87091	235908	566904	70864	123766	342465
(nM.h/mL)	(22497)	(37505)	(27951)	(5521)	(16564)	(40399)
CL/F (mL/h/kg)	1.7 (0.4)	1.8(0.3)	2.2 (0.1)	2.0 (0.2)	3.4 (0.5)	3.7 (0.4)

[00282] Table 28 shows the mouse PK data following IM administration of 2 different ELQ-300-Form II suspensions (at 4mg/kg) as compared with IM administration of Compound 2 (at 4mg/kg) in sesame oil. The graph is shown in FIG. 20.

ΙΟ

TABLE 28

	ELQ-300-Form II (Synperonic®)	ELQ-300-Form II (TPGS)	Compound 2 (sesame oil)
Nominal Dose (mg/kg)	4	4	5
Concentration (mg/mL)	100	100	12.5
Dose Volume (uL)	10	10	100
tl/2 (h)	242 (34)	381 (182)	359 (26)
Cmax (ΠΜ)	333 (118)	263 (17)	399 (54)
Clast (nM)	37(2)	31 (4)	68 (4)
AUC_u.(nM⁴h/mL)	87091 (22497)	70864 (5521)	103321 (9160)
CL/F (mL/h/kg)	1.7(0.4)	2.0 (0.2)	1.0 (0.1)

[00283] Table 29 shows the average atovaquone plasma concentration following IM and PO administration of Compound 27 (in sesame oil) as compared to PO administration of atovaquone. The graph is shown in FIG. 21.

TABLE 29

Time

Atovaquone from Compound 27 (μΜ)

	IM	PO
8 h	4.6 + 2.7	19 ± 3
1 d	4.9 + 1.6	27 ±9
7d	3.8 ±2.1 ^L	15 ± 11
14 d	2.8 ±0.9	0.3 ± 0.3
28 d	3.3 ±0.9	BQL

[00284] Table 30 shows the average atovaquone plasma and liver concentration following IM administration of Compound 27 at three different doses (16.7, 50, and 150 mg/kg). Table 31 shows the plasma concentration by animal in the 16.7 mg/kg group. Graphs are shown in FIG. 22A and - Figure 22B

TABLE 30

Time	Atovaquone (nM)
16.7 mg/kg	50 mg/kg	150 mg/kg
1 d	1445 + 550	6371 +3619	8035 ± 3452
14 d	55 + 25	295 ± 280	1279 + 752
28 d	35 + 31*	180 + 68	1170 + 644
49 d	33+11*	75 + 38	294 ± 85
49 d (liver)		36.7 + 0.2	138 + 28
*For surviving animais

TABLE 31

Time	Atovaquone (nM)
Animal 5	Animal 6	Animal 7	Animal 8
1 d	1761	660	1477	1884
7d	78	148	152	102
14 d	30	61	88	40
21 d	47	49	78	55
28 d	-	19	56	65
49 d	-	-	40	25

[00285] Table 32 shows the average Atovaquone concentration following IM rat administration of Compound at two different doses (20 and 60 mg/kg) formulated in sesame oil. Table 33 shows the liver and brain exposures at week 13. The Graph is shown in FIG. 38.

TABLE 32

	Compound 33	Compound 33
Dose of ATO (mg/kg)	20	60
Concentration of ATO	295 mg/mL (650	295 mg/mL (650

	Compound 33	Compound 33
(max concentration)	mg/mL)	mg/mL)
Injection Volume (uL)	2xl0	2x30
Formulation	Sesame oil solution	Sesame oil solution
Gmax (nM)	13813 (4909)	35349 (5413)
C_last (nM)	2256 (935)	5379 (886)
A UCu (η M * h/m L)	8172753 (466892)	23869258(1387755)
CL/F (mL/min/kg)	0.06 (0.02)	0.06 (0.03)

TABLE 33

	Compound 33	Compound 33
Dose of ΑΤΟ (mg/kg)	20	60
Liver Exposure (nM)	2793 (944)	3717 (351)
Brain Exposure (nM)	37.9(13.8)	64.0(10.3)

[00286] Table 34 shows the average ELQ-300 concentration following IM rat administration of Compound 35 5 at two different doses (10.5 and 30 mg/kg) formulated in sesame oil. The Graph is shown in FIG. 39.

TABLE 34

	Compound 35	Compound 35
Dose of ELQ-300 (mg/kg)	10.5	30
Concentration of ELQ-300 (max concentration)	291 mg/mL (580 mg/mL)	291 mg/mL (580 mg/mL)
Injection Volume (uL)	10	30
Cmax (nM)	2265 (512)	2431 (1105)
Clast (nM)	51 (10)	145(11)
A U Co-x. (η M * h/m L)	410174(22195)	1024416(225651
CL/F (mL/min/kg)	0.8(0.1)	0.9 (0.2)

[00287] Table 35 shows the average ELQ-300 concentration following IM rat administration of crystalline

Compound 2 at two different doses (8 and 24 mg/kg). Table 36 shows key in vitro ADME for Compound 2. 10 The Graph is shown in FIG. 40.

TABLE 35

	Compound 2	Compound 2
Dose of ELQ-300 (mg/kg)	8	24
Formulation	34 mg/mL in 3% TPGS and 1% HPMC E5
Injection Volume (uL)	59	177
Cmax (nM)	474 (70)	1201 (114)

	Compound 2	Compound 2
c_last (nM)	90(10)	232 (28)
AUCo^(nM*h/mL)	108338(5183)	332595 (47709)
CL/F (mL/min/kg)	1.37 (0.22)	1.57 (0.19)

TABLE 36

	Plasma	Liver S9	Hépatocyte T1/2
% remaining after 2 hours
Mouse	0%
Rat	0%
Dog	83%	47%	22 min
Monkey	85%
Human	82%	35%	77 min

Example 13: Solid state characterization of (6-chloro-7-methoxy-2-methyl-3-(4-(45 (trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methyl butyrate (Compound 2)

[00288] FIG. 41 shows the characteristic X-ray diffraction pattern of the Compound 2. Characteristic reflections and the corresponding d-spacings for crystalline Compound 2 are shown in Table 37. FIG. 42A shows the DSC of the crystalline compound 2 and FIG. 42B shows the TGA of the crystalline compound 2.

TABLE 37

No.	2-Theta (°)	d-spacing (Â)	Height	1%
1	8.90	9.93	503	6.3
2	12.31	7.19	474	5.9
3	13.04	6.78	337	4.2
4	13.93	6.35	749	9.4
5	14.44	6.13	6919	86.5
6	14.96	5.92	540	6.8
7	15.15	5.84	3178	39.7
8	16.30	5.44	251	3.1
9	16.50	5.37	745	9.3
10	16.89	5.25	317	4
11	17.03	5.20	224	2.8
12	17.68	5.01	2694	33.7
13	18.11	4.89	2475	30.9
14	18.54	4.78	295	3.7
15	19.06	4.65	1048	13.1
16	20.30	4.37	973	12.2

17	20.52	4.33	383	4.8
18	20.80	4.27	721	9
19	21.21	4.19	1018	12.7
20	21.66	4.10	1910	23.9
21	21.94	4.05	946	11.8
22	22.32	3.98	2300	28.8
23	22.59	3.93	8000	100
24	22.99	3.87	566	7.1
25	23.44	3.79	332	4.2
26	23.62	3.76	646	8.1
27	24.09	3.69	783	9.8
28	24.62	3.61	430	5.4
29	25.75	3.46	1597	20
30	26.66	3.34	840	10.5
31	27.09	3.29	503	6.3
32	28.06	3.18	424	5.3
33	28.93	3.08	364	4.6
34	29.21	3.06	1023	12.8
35	29.93	2.98	486	6.1
36	31.36	2.85	614	7.7
37	31.85	2.81	220	2.8
38	31.99	2.80	177	2.2
39	32.80	2.73	277	3.5
40	33.19	2.70	162	2
41	33.41	2.68	345	4.3
42	33.65	2.66	244	3
43	35.64	2.52	178	2.2
44	35.90	2.50	416	5.2
45	36.23	2.48	63	0.8
46	37.02	2.43	96	1.2
47	37.32	2.41	110	1.4
48	37.75	2.38	130	1.6
49	39.03	2.31	195	2.4
50	39.39	2.29	183	2.3

[00289] Crystaline Compound 2 was also charaecterized by PLM which showed particle size range of l-50 μιη.

Example 14. Préparation and characterization of Compound 2 microsuspensions [00290] Two Compound 2 microsuspensions were prepared.

- 80 T. Préparation and characterization of 167.27 mg/mL Compound 2 microsuspension

[00291] A Compound 2 microsuspension was prepared by wet-milling method. About 240 mg of Compound was added to 1 mL of 3%(w/v) TPGS-l%(w/v) HPMC E5 in a millingjar. 2 mL of zirconium beads with a diameter of 0.8 mm (YTZ® Grinding Media, Nikkato Co., Japan) were added using a measuring cylinder. The millingjar was placed in a planetaty miller. The milling was conducted at a rotating speed of 800 rpm for 1 hour in each cycle and the suspension was collected after 3 milling cycles.

[00292] The collected suspension was about 0.1-0.2 mL. Large volume loss was due to sample residual on the milling beads. PLM showed most particles were below 5 pm in size. Concentration of Compound 2 in the suspension determined by HPLC was 167.27mg/mL. The final product was stored in a 1.5 mL sealed glass vial at room température and protected from light before PK study. Visual inspection of the suspensions showed that the product was homogeneous, syringeable and easily resuspendable following short-time vortex or water-bath sonication, suitable for intramuscular injection.

2. Préparation and characterization of 259.62 mg/mL Compound 2 microsuspension

[00293] A Compound 2 microsuspension was prepared by wet-milling method. About 1.6 g of Compound 2 was added to 4 mL of 3%(w/v) TPGS-l%(w/v) HPMC E5 in a millingjar. 4 mL of zirconium beads with a diameter of 0.8 mm (YTZ® Grinding Media, Nikkato Co., Japan) were added using a measuring cylinder. The millingjar was placed in a planetaty miller. The milling was conducted at a rotating speed of 800 rpm for 1 hour in each cycle and the suspension was collected after 3 milling cycles.

[00294] The collected suspension was About 2.8 mL and most particles were between 1 pm and 5 pm in size. Concentration of Compound 2 in the suspension determined by HPLC was 259.62 mg/mL. The collected microsuspension was stored in a 1.5 mL sealed glass vial at room température and protected from light before PK study. Visual inspection of the suspension showed that the product was homogeneous, syringeable and easily resuspendable following short-time vortex or water-bath sonication, suitable for preclinical PK study via intramuscular injection.

[00295] While preferred aspects of the présent invention hâve been shown and described herein, it will be obvious to those skilled in the art that such aspects are provided by way of example only. Numerous variations, changes, and substitutions will now occurto those skilled in the art without departing from the invention. It should be understood that various alternatives to the aspects of the invention described herein may be employed in practicing the invention. It is intended that the following daims define the scope of the invention and that methods and structures within the scope of these daims and their équivalents be covered thereby.

Embodiments directed to a pharmaceutical suspension comprising crystalline Formula (III)

[00296] Embodiment 1 : A pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline compound of Formula (III), or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

CI

Formula (III)

wherein:

R is a lipophilie moiety.

[00297] Embodiment 2: The pharmaceutical composition of Embodiment l, wherein R^u is optionally substituted Ci-C₃₀alkyl, optionally substituted C2-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl.

[00298] Embodiment 3: The pharmaceutical composition of Embodiment l or 2, wherein R¹¹ is optionally substituted Ci-C2oalkyl, optionally substituted C2-C2oalkenyl, or optionally substituted C2-C2oalkynyl.

[00299] Embodiment 4: The pharmaceutical composition of Embodiment 1 or 2, wherein R'¹ is Ci-C2oalkyl.

[00300] Embodiment 5: The pharmaceutical composition of Embodiment 1 or 2, wherein R¹¹ is Ci-C₃oalkyl.

[00301] Embodiment 6: The pharmaceutical composition of Embodiment 1 or 2, wherein R” is Ci-Cealkyl.

[00302] Embodiment 7: The pharmaceutical composition of Embodiment 1 or 2, wherein R¹¹ is C₇-C₃oalkyl.

[00303]

Embodiment 8: The pharmaceutical composition of Embodiment 1 or 2, wherein R is C?-C2oalkyl.

[00304]

Embodiment 9: The pharmaceutical composition of any one Embodiments 1-8, wherein R is

[00305] Embodiment 10: The pharmaceutical composition of Embodiment 1 or 2, wherein R¹¹ is C₂C₃oalkenyl.

[00306] Embodiment 11 : The pharmaceutical composition of Embodiment 10, wherein R¹¹ is

[00307] Embodiment 12: The pharmaceutical suspension of Embodiment 1, wherein the compound of formula (III) is:

or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof.

[00308] Embodiment 13: The pharmaceutical suspension of Embodiment 1, wherein the compound of formula (III) is:

stereoisomer thereof.

or a pharmaceutically acceptable sait, solvaté, or

- 82 ^^[00309] Embodiment 14: The pharmaceutical suspension of any one of Embodiments l -13, wherein the size of the nanoparticles is between about 50 nm and about 1000 nm.

[00310] Embodiment 15: The pharmaceutical suspension of any one of Embodiments 1-14, wherein the size of the nanoparticles is about 100 nm.

[00311] Embodiment 16: The pharmaceutical suspension of any one of Embodiments 1-13, wherein the size of the microparticles is between about 1 μιτι and about 10 μιτι.

[00312] Embodiment 17: The pharmaceutical suspension of any one of Embodiments 1-13, wherein the size of the microparticles is between about 1 pm and about 5 μιη.

[00313] Embodiment 18: The pharmaceutical suspension of any one of Embodiments 1-17, further comprising a pharmaceutically acceptable excipient selected from surfactants, solubilizers, emulsifiers, preservatives, isotonicity agents, dispersing agents, wetting agents, fillers, solvents, buffers, stabilizers, lubricants, thickening agents, suspending agents, and any combinations thereof.

[00314] Embodiment 19: The pharmaceutical suspension of any one of Embodiments 1-18, further comprising a surfactant.

[00315] Embodiment 20: The pharmaceutical suspension of any one of Embodiments 1-19, further comprising a suspending agent.

[00316] Embodiment 21 : The pharmaceutical suspension of any one of Embodiments 1-20, further comprising Synperonic® F108, dodecyl sodium sulfate (SLS), D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropyl methylcellulose (HPMC), and any combinations thereof.

[00317] Embodiment 22: The pharmaceutical suspension of any one of Embodiments 1-21, further comprising D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) and hydroxypropyl methylcellulose (HPMC).

[00318] Embodiment 23: The pharmaceutical composition of any one of Embodiments 1-22, wherein the concentration of the crystalline compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is between about 10 mg/mL and about 50 mg/mL.

[00319] Embodiment 24: The pharmaceutical suspension of any one of Embodiments 1-23, wherein the concentration of the crystalline compound of Formula (III) is greater than about 50 mg/mL.

[00320] Embodiment 25: A method for the treatment or prévention of malaria in a subject comprising administering to the subject a pharmaceutical suspension of any one of Embodiments 1-24.

[00321] Embodiment 26: The method of Embodiment 25, wherein the pharmaceutical suspension is administered by subcutaneous or intramuscular injection.

[00322] Embodiment 27: The method of Embodiment 25, wherein the pharmaceutical suspension is effective for sustained or controlled release.

[00323] Embodiment 28: The method of any one of Embodiments 25-27, further comprising administering an additional antimalarial agent.

[00324] Embodiment 29: The method of Embodiment 28, wherein the additional antimalarial agent is selected from artemisinin, artemisinin dérivatives, atovaquone, proguanil, quinine, chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine, pyronaridine, halofantrine, or ELQ-300.

- 83 Embodiments directed to a pharmaceutical suspension comprising crystalline atovaquone

[00325] Embodiment l : A pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline form of atovaquone, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof.

[00326] Embodiment 2: The pharmaceutical suspension of Embodiment l, wherein the crystalline form of atovaquone, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is atovaquone-Form I or atovaquone-Form II.

[00327] Embodiment 3: The pharmaceutical suspension of Embodiment 2, wherein the crystalline form of atovaquone, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof, is atovaquone-Form II wherein the crystalline form has at least one of the following properties:

(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 25; or (b) an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 7.0±0.1⁰ 20, about 9.3+0.1° 20, about 14.3+0.1° 20, about 14.9+0.1° 20, about 18.6+0.1° 20, about 19.3+0.1° 20, about 20.1+0.1° 20, 22.8+0.1° 20, 23.4+0.1° 20, and 24.4+0.1° 20; or

[00328] Embodiment 4: The pharmaceutical suspension of Embodiment 3, wherein the crystalline form of atovaquone-Form II has at least one of the following properties:

(a) a DSC thermogram substantially the same to the one set forth in FIG. 26A; or (b) a DSC thermogram with an endotherm having a peak at about 219.9 °C.

[00329] Embodiment 5: The pharmaceutical suspension of any one of Embodiments 1-4, wherein the size of the nanoparticles is between about 50 nm and about 1000 nm.

[00330] Embodiment 6: The pharmaceutical suspension of any one of Embodiments 1-5, wherein the size of the nanoparticles is about 100 nm.

[00331] Embodiment 7: The pharmaceutical suspension of any one of Embodiments 1-4, wherein the size of the microparticles is between about 1 qm and about 10 qm.

[00332] Embodiment 8: The pharmaceutical suspension of any one of Embodiments 1-4, wherein the size of the microparticles is between about 1 qm and about 5 qm.

[00333] Embodiment 9: The pharmaceutical suspension of any one of Embodiments 1 -8, further comprising a pharmaceutically acceptable excipient selected from surfactants, solubilizers, emulsifiers, preservatives, isotonicity agents, dispersing agents, wetting agents, fillers, solvents, buffers, stabilizers, lubricants, thickening agents, suspending agents, and any combinations thereof.

[00334] Embodiment 10: The pharmaceutical suspension of any one of Embodiments 1-9, further comprising a surfactant.

[00335] Embodiment 11 : The pharmaceutical suspension of any one of Embodiments 1-10, further comprising a suspending agent.

[00336] Embodiment 12: The pharmaceutical suspension of any one of Embodiments 1-11, further comprising Synperonic® F108, dodecyl sodium sulfate (SLS), D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropyl methylcellulose (HPMC), and any combinations thereof.

[00337] Embodiment 13: The pharmaceutical suspension of any one of Embodiments 1-12, further comprising D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) and hydroxypropyl methylcellulose (HPMC).

-8400338] Embodiment 14: The pharmaceutical composition of any one of Embodiments 1-13, wherein the concentration of the crystalline atovaquone or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is between about 10 mg/mL and about 50 mg/mL.

[00339] Embodiment 15: The pharmaceutical suspension of any one of Embodiments l-13, wherein the concentration of the crystalline atovaquone is greater than about 50 mg/mL.

[00340] Embodiment 16: A method for the treatment or prévention of malaria in a subject comprising administering to the subject a pharmaceutical suspension of any one of Embodiments l-15.

[00341] Embodiment 17: The method of Embodiment 16, wherein the pharmaceutical suspension is administered by subcutaneous or intramuscular injection.

[00342] Embodiment 18: The method of Embodiment 17, wherein the pharmaceutical suspension is effective for sustained or controlled release.

[00343] Embodiment 19: The method of any one of Embodiments 10-18, further comprising administering an additional antimalarial agent.

[00344] Embodiment 20: The method of Embodiment 19, wherein the additional antimalarial agent is selected from artemisinin, artemisinin dérivatives, atovaquone, proguanil, quinine, chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine, pyronaridine, halofantrine, or ELQ-300.

Embodiments directed to a pharmaceutical suspension comprising crystalline pyronaridine

[00345] Embodiment 1 : A pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline form of pyronaridine, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof.

[00346] Embodiment 2: The pharmaceutical suspension of Embodiment 1, wherein the pharmaceutical acceptable sait of pyronaridine is pyronaridine pamoate, pyronaridine benzenesulfonate, pyronaridine palmitate, or pyronaridine naphthalate.

[00347] Embodiment 3: The pharmaceutical suspension of Embodiment 1 or 2, wherein the crystalline form of pyronaridine, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is pyronaridine-Form I, pyronaridine-Form II, pyronaridine-Form III, pyronaridine-Form IV, or pyronaridine-Form V.

[00348] Embodiment 4: The pharmaceutical suspension of any one of Embodiment 1-3, wherein the size of the nanoparticles is between about 50 nm and about 1000 nm.

[00349] Embodiment 5: The pharmaceutical suspension of any one of Embodiment 1-4, wherein the size of the nanoparticles is about 100 nm.

[00350] Embodiment 6: The pharmaceutical suspension of any one of Embodiments 1-3, wherein the size of the microparticles is between about 1 pm and about 10 pm.

[00351] Embodiment 7: The pharmaceutical suspension of any one of Embodiments 1-3, wherein the size of the microparticles is between about 1 pm and about 5 pm.

[00352] Embodiment 8: The pharmaceutical suspension of any one of Embodiments 1-7, further comprising a pharmaceutically acceptable excipient selected from surfactants, solubilizers, emulsifiers, preservatives, isotonicity agents, dispersing agents, wetting agents, fillers, solvents, buffers, stabilizers, lubricants, thickening agents, suspending agents, and any combinations thereof.

- 85 00353] Embodiment 9: The pharmaceutical suspension of any one of Embodiments l-8, further comprising a surfactant.

[00354] Embodiment 10: The pharmaceutical suspension of any one of Embodiments l-9, further comprising a suspending agent.

[00355] Embodiment 11 : The pharmaceutical suspension of any one of Embodiments l-ΊΟ, further comprising Synperonic® Fl08, dodecyl sodium sulfate (SLS), D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropyl methylcellulose (HPMC), and any combinations thereof.

[00356] Embodiment 12: The pharmaceutical suspension of any one of Embodiments l-l l, further comprising D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) and hydroxypropyl methylcellulose (HPMC).

[00357] Embodiment 13: The pharmaceutical composition of any one of Embodiments 1-12, wherein the concentration of the crystalline pyronaridine or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is between about 10 mg/mL and about 50 mg/mL.

[00358] Embodiment 14: The pharmaceutical suspension of any one of Embodiments 1-13, wherein the concentration of the crystalline pyronaridine is greater than about 50 mg/mL.

[00359] Embodiment 15: A method for the treatment or prévention of malaria in a subject comprising administering to the subject a pharmaceutical suspension of any one of Embodiments l-l4.

[00360] Embodiment 16: The method of Embodiment 15, wherein the pharmaceutical suspension is administered by subcutaneous or intramuscular injection.

[00361] Embodiment 17: The method of Embodiment 15, wherein the pharmaceutical suspension is effective for sustained or controlled release.

[00362] Embodiment 18: The method of any one of Embodiments 15-17, further comprising administering an additional antimalarial agent.

[00363] Embodiment 19: The method of Embodiment 18, wherein the additional antimalarial agent is selected from artemisinin, artemisinin dérivatives, atovaquone, proguanil, quinine, chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine, pyronaridine, halofantrine, or ELQ-300.

Embodiments directed to a pharmaceutical composition comprising a crystalline ELQ-300

[00364] Embodiment 1 : A pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline form of ELQ-300, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof.

[00365] Embodiment 2: The pharmaceutical suspension of Embodiment 1, wherein the crystalline form of ELQ-300, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is ELQ-300-Form IA, ELQ300-Form IB, ELQ-300-Form II, ELQ-300-Form III, ELQ-300-Form IV, or ELQ-300-Form V.

[00366] Embodiment 3: The pharmaceutical suspension of Embodiment 2, wherein the crystalline form of ELQ-300, or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof, is ELQ-300-Form II wherein the crystalline form has at least one of the following properties:

(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 9; or (b) an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 7.6+0.1° 20, about 12.7+0.1° 2Θ, about 20.4+0.1° 2Θ, about 23.0+0.1° 2Θ, about 25.6+0.1° 20, about 28.2+0.1° 20, about 30.8+0.1° 20, about 33.5+0.1° 20, about 36.1° 20, and about 38.8+0.1° 20.

- 86 [00367] Embodiment 4: The pharmaceutical suspension of Embodiment 3, wherein the crystalline form of

ELQ-300-Form II has at least one of the following properties:

(a) a DSC thermogram substantially the same to the one set forth in FIG. 11 ; or (b) a DSC thermogram with an endotherm having a peak at about 297.5 °C.

[00368] Embodiment 5: The pharmaceutical suspension of any one of Embodiments l-4, wherein the size of the nanoparticles is between about 50 nm and about 1000 nm.

[00369] Embodiment 6: The pharmaceutical suspension of any one of Embodiments I-5, wherein the size of the nanoparticles is about 100 nm.

[00370] Embodiment 7: The pharmaceutical suspension of any one of Embodiments l-4, wherein the size of 10 the microparticles is between about l μιη and about 10 μιη.

[00371] Embodiment 8: The pharmaceutical suspension of any one of Embodiments 1-4, wherein the size of the microparticles is between about 1 μιη and about 5 μιη.

[00372] Embodiment 9: The pharmaceutical suspension of any one of Embodiments 1-8, further comprising a pharmaceutically acceptable excipient selected from surfactants, solubilizers, emulsifiers, preservatives, isotonicity agents, dispersing agents, wetting agents, fillers, solvents, buffers, stabilizers, lubricants, thickening agents, suspending agents, and any combinations thereof.

[00373] Embodiment 10: The pharmaceutical suspension of any one of Embodiments 1-9, further comprising a surfactant.

[00374] Embodiment 11: The pharmaceutical suspension of any one of Embodiments 1-10, further comprising a suspending agent.

[00375] Embodiment 12: The pharmaceutical suspension of any one of Embodiments 1-11, further comprising Synperonic® F108, dodecyl sodium sulfate (SLS), D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropyl methylcellulose (HPMC), and any combinations thereof.

[00376] Embodiment 13: The pharmaceutical suspension of any one of Embodiments 1-12, further comprising D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) and hydroxypropyl methylcellulose (HPMC).

[00377] Embodiment 14: The pharmaceutical suspension of any one of Embodiments 1-12, further comprising D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS).

[00378] Embodiment 15: The pharmaceutical suspension ofany one of Embodiments 1-12, further comprising Synperonic® F108.

[00379] Embodiment 16: The pharmaceutical composition of any one of Embodiments 1-15, wherein the concentration of the crystalline ELQ-300 or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is between about 10 mg/mL and about 50 mg/mL.

[00380] Embodiment 17: The pharmaceutical suspension of any one of Embodiments 1-15, wherein the concentration of the crystalline ELQ-300 is greater than about 50 mg/mL.

[00381] Embodiment 18: A method for the treatment or prévention of malaria in a subject comprising administering to the subject a pharmaceutical suspension of any one of Embodiments 1-17.

- 87 J00382] Embodiment 19: The method of Embodiment 18, wherein the pharmaceutical suspension is administered by subcutaneous or intramuscular injection.

[00383] Embodiment 20: The method of Embodiment 19, wherein the pharmaceutical suspension is effective for sustained or controlled release.

[00384] Embodiment 21 : The method of any one of Embodiments 18-20, further comprising administering an additional antimalarial agent.

[00385] Embodiment 22: The method of Embodiment 21, wherein the additional antimalarial agent is selected from artemisinin, artemisinin dérivatives, atovaquone, proguanil, quinine, chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine, pyronaridine, halofantrine, or ELQ-300. Embodiments directed to a compound of Formula (I)

[00386] Embodiment l : A compound of Formula (I) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

Formula (I) wherein:

R is -C(R^la)₂OC(=O)R', -R², -C(=O)OR³, or-C(=O)R⁴;

R¹ is optionally substituted Ci-C₃oalkyl, optionally substituted C₂-C₃oalkenyl, optionally substituted C₂C₃₀alkynyl, optionally substituted C₃-C₈cycloalkyl, or optionally substituted C₂-C₈heterocycloalkyl;

each R^la is independently hydrogen, halogen, or optionally substituted Ci-Cealkyl;

or two R^la are taken together with the carbon atom to which they are attached to form an optionally substituted Cs-Cscycloalkyl;

R² is optionally substituted (Ci-C₆alkylene)aryl, optionally substituted (Ci-C₆alkylene)heteroaryl, optionally substituted (Ci-C6alkylene)C₃-C₈cycloalkyl, or optionally substituted (Ci-C₆alkylene)C₂Csheterocycloalkyl;

R³ is optionally substituted Cs-Csoalkyl, optionally substituted C4-C₃oalkenyl, or optionally substituted C₂-C₃oalkynyl; and

R⁴ is optionally substituted Cs-C₃oalkyl, optionally substituted C₂-C₃oalkenyl, or optionally substituted C₂-C₃oalkynyl.

[00387] Embodiment 2: The compound of Embodiment 1, wherein R is -C(R^la)₂OC(=O)R¹. [00388] Embodiment 3: The compound of Embodiment 1 or 2, wherein each R^la is hydrogen.

[00389] Embodiment 4: The compound of any one of Embodiments 1-3, wherein R' is optionally substituted Ci-C₂oalkyl or optionally substituted C₂-C₃oalkenyl.

[00390] Embodiment 5: The compound of any one of Embodiments 1-4, wherein R' is Ci-C₆alkyl. [00391] Embodiment 6: The compound of any one of Embodiments 1-4, wherein R¹ is C₇-C₂oalkyl.

- 88 10

15·

[00392] Embodiment 7: The compound of any one of Embodiments l-4, wherein R¹ i

or

[00393]

[00394]

[00395]

[00396]

[00397]

Embodiment 8: The compound of any one of Embodiments 1-4, wherein R i

Embodiment 9: The compound of any one of Embodiments 1-3, wherein R¹ is C2-C3oalkenyl.

Embodiment 10: The compound of Embodiment 9, wherein R¹ is Cz-CealkenyL

Embodiment 11: The compound of Embodiment 9, wherein R¹ is Cv-Csoalkenyl.

Embodiment 12: The compound of Embodiment 9, wherein R¹ is

Me

[00398]

[00399]

[00400]

[00401]

[00402] or

Embodiment 13: The compound of Embodiment 1, wherein R is -C(=O)ORT Embodiment 14: The compound of Embodiment 13, wherein R³ is C5-C2oalkyl. Embodiment 15: The compound of Embodiment 14, wherein R³ is Cs-Cioalkyl.

Embodiment 16: The compound of Embodiment 14, wherein R³ is Cn-C2oalkyl.

Embodiment 17: The compound of Embodiment 14, wherein R³ is

, or '

Embodiment 18: The compound of Embodiment 1, wherein R is-C(=O)R⁴.

Embodiment 19: The compound of Embodiment 18, wherein R⁴ is Cs-C2oalkyl. Embodiment 20: The compound of Embodiment 18, wherein R⁴ is Cs-Cioalkyl. Embodiment 21: The compound of Embodiment 18, wherein R⁴ is Cn-C2oalkyl.

[00403]

[00404]

[00405]

[00406]

Embodiments directed to crystalline form of ((6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methyl butyrate

[00407] Embodiment 1 : A crystalline form of ((6-chloro-7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methyl butyrate:

or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof.

[00408] Embodiment 2: The crystalline form of Embodiment 1, wherein the crystalline form of ((6-chloro-7methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methyl butyrate has at least one of the foilowing properties:

(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 41 ; or (b) an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about l4.4±0.l°

2Θ, about 15.1+0.1° 2Θ, about 17.7±6.1°26, about 18.1±O.1°20, about 22.3±0.1° 26, and about

22.6+0.1° 20; or (c) a DSC thermogram substantially the same to the one set forth in FIG. 42A; or (d) a DSC thermogram with an endotherm having a peak at about 99.5 °C.

Embodiment 3: The crystalline form of Embodiment 2, wherein the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 19.1 °±0.1 ° 20, about 20.3°±0.1 ° 26, about 21,2°±0.1 ° 26, about 26.7°±0.1° 26, and about 29.21°±6.1° 26.

Embodiments directed to a pharmaceutical composition comprising a compound of Formula (II)

[00409] Embodiment 1: A pharmaceutical composition comprising:

(i) an oil; and (ii) a compound of Formula (11) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

Formula (II) wherein:

R’ is-C(R^7a)₂OC(=O)R⁷, -R⁸, -C(=O)OR⁹, or-C(=0)R¹⁰;

R⁷ is optionally substituted Ci-C₃₀alkyl, optionally substituted C₂-C₃oalkenyl, optionally substituted C₂Csoalkynyl, optionally substituted Cs-Cscycloalkyl, or optionally substituted C₂-C₈heterocycloalkyl;

R⁸ is optionally substituted (Ci-C₆alkylene)aryl, optionally substituted (CrCealkylenejheteroaryl, optionally substituted (Ci-C6alkylene)C₃-C₈cycloalkyl, or optionally substituted (Ci-C₆alkylene)C₂Csheterocycloalkyl;

R¹⁰ is optionally substituted Ci-C₃oalkyl, optionally substituted C₂-C?,oalkenyl, or optionally substituted C₂-C₃₀alkynyl.

[00410] Embodiment 2: The pharmaceutical composition of Embodiment 1, wherein R’ is C(R^7a)₂OC(=O)R⁷.

[00411] Embodiment 3: The pharmaceutical composition of Embodiment 1 or 2, wherein each R^7a is hydrogen.

[00412] Embodiment 4: The pharmaceutical composition of any one of Embodiment 1-3, wherein R⁷ is optionally substituted Ci-C₂oalkyl or optionally substituted C₂-C₃₀alkenyl.

-90Embodiment 5: The pharmaceutical composition of any one of Embodiments l-4, wherein R⁷ is CiCôalkyl.

[00414]

C₂oalkyl.

Embodiment 6: The pharmaceutical composition of any one of Embodiments 1-4, wherein R⁷ is C₇[00415]

Embodiment 7: The pharmaceutical composition of any one of Embodiments 1-4, wherein R⁷ is

[00416] Embodiment 8: The pharmaceutical composition of any one of Embodiments 1-4, wherein R⁷ is

[00417] Embodiment 9: The pharmaceutical composition of any one of Embodiment 1-4, wherein R⁷ is C₂Csoalkenyl.

[00418] Embodiment 10: The pharmaceutical composition of Embodiment 9, wherein R⁷ is C₂-C6alkenyl.

[00419] Embodiment 11 : The pharmaceutical composition of Embodiment 9, wherein R⁷ is C₇-C₃oalkenyl.

[00420] Embodiment 12: The pharmaceutical composition of Embodiment 9 or 11, wherein R⁷ is

[00421] Embodiment 13: The pharmaceutical composition of Embodiment 1, wherein R’ is -C(=O)OR⁹. [00422] Embodiment 14: The pharmaceutical composition of Embodiment 13, wherein R⁹ is optionally substituted C₅-C₃oalkyl, optionally substituted C₄-C₃oalkenyl, or optionally substituted C₂-C₃₀alkynyl.

[00423]

[00424]

[00425]

[00426]

[00427]

Embodiment 15: The pharmaceutical composition of Embodiment 13, wherein R⁹ is Ci-C₆alkyl.

Embodiment 16: The pharmaceutical composition of Embodiment 13, wherein R⁹ is C₇-C_2Oalkyl.

Embodiment 17: The pharmaceutical composition of Embodiment 13, wherein R⁹ is C₅-C₂oalkyl.

Embodiment 18: The pharmaceutical composition of Embodiment 13, wherein R⁹ is Cs-Cioalkyl.

Embodiment 19: The pharmaceutical composition of Embodiment 13, wherein R⁹ is Cn-C₂oalkyl.

[00428]

Embodiment 20: The pharmaceutical composition of Embodiment 13, wherein R⁹ is

, or

[00429] Embodiment 21 : The pharmaceutical composition of Embodiment 1, wherein R’ is -C(=O)R'°. [00430] Embodiment 22: The pharmaceutical composition of Embodiment 21, wherein R¹⁰ is optionally substituted C5-C30alkyl, optionally substituted C2-C30alkenyl, or optionally substituted C2-C3oalkynyl. [00431] Embodiment 23: The pharmaceutical composition of Embodiment 21, wherein R¹⁰ is Ci-Côalkyl. [00432] Embodiment 24: The pharmaceutical composition of Embodiment 21, wherein R¹⁰ is C7-C₂oalkyl.

-9l •[00433]

Embodiment 25: The pharmaceutical composition of Embodiment 21, wherein R¹⁰ is C5-C2oalkyl.

[00434] Embodiment 26: The pharmaceutical composition of Embodiment 21, wherein R ⁰ is C₅-Cioalkyl. [00435] Embodiment 27: The pharmaceutical composition of Embodiment 21, wherein R¹⁰ is Cn-Czoalkyl.

[00436] Embodiment 28: The pharmaceutical composition of any one of Embodiments 1-27, wherein the oil is a vegetable oil.

[00437] Embodiment 29: The pharmaceutical composition of any one of Embodiments 1-28, wherein the oil is selected from corn oil, peanut oil, sesame oil, olive oil, palm oil, safflower oil, soybean oil, cottonseed oil, rapeseed oil, sunflower oil and mixtures thereof.

[00438] Embodiment 30: The pharmaceutical composition of Embodiments 1-29, wherein the oil is sesame oil.

[00439] Embodiment 31 : The pharmaceutical composition of any one of Embodiments 1 -30, wherein the concentration of the compound of Formula (II) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is greater than about 50 mg/mL.

Embodiments directed to a pharmaceutical suspension comprising crystalline Formula (II) [00440] Embodiment 1 : A pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline compound of Formula (II), or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

wherein:

R’ is -C(R^7a)₂OC(=O)R⁷, -R⁸, -C(=O)OR⁹, or -C(=O)R¹⁰;

R⁷ is optionally substituted Ci-C₃oalkyl, optionally substituted C2-C₃oalkenyl, optionally substituted C₂C₃₀alkynyl, optionally substituted C₃-C₈cycloalkyl, or optionally substituted C₂-C₈heterocycloalkyl;

or two R^7a are taken together with the carbon atom to which they are attached to form an optionally substituted C₃-C₈cycloalkyl;

R⁸ is optionally substituted (Ci-C₆alkylene)aryl, optionally substituted (Ci-C₆alkylene)heteroaryl, optionally substituted (Ci-C6alkylene)C₃-C₈cycloalkyl, or optionally substituted (Ci-C6alkylene)C₂Csheterocycloalkyl;

R⁹ is optionally substituted Ci-C₂₀alkyl, optionally substituted C₂-C₂₀alkenyl, or optionally substituted C₂-C₂oalkynyl; and

R¹⁰ is optionally substituted Ci-C₂₀alkyl, optionally substituted C₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl.

[00441] Embodiment 2: The pharmaceutical suspension of Embodiment 1, wherein R’ is -C(R^7a)2OC(=O)R⁷. [00442] Embodiment 3: The pharmaceutical suspension of Embodiment 1 or 2, wherein each R^7a is hydrogen. [00443] Embodiment 4: The pharmaceutical suspension of any one of Embodiment 1-3, wherein R⁷ is optionally substituted Cl-C₂oalkyl or optionally substituted C₂-C₃₀alkenyl.

-92^0444]

Côalkyl.

[00445]

C₂oalkyl.

Embodiment 5: The pharmaceutical suspension of any one of Embodiments l-3, wherein R⁷ is CiEmbodiment 6: The pharmaceutical suspension of any one of Embodiments l-3, wherein R⁷ is C₇[00446]

Embodiment 7: The pharmaceutical suspension of any one of Embodiments l-3, wherein R⁷ is

[00447] Embodiment 8: The pharmaceutical suspension of any one of Embodiments l-3, wherein R⁷ is

[00448] Embodiment 9: The pharmaceutical suspension of any one of Embodiment l-3, wherein R⁷ is C₂Csoalkenyl.

[00449] Embodiment 10: The pharmaceutical suspension of Embodiment 9, wherein R⁷ is C₂-C6alkenyl.

[00450] Embodiment 11: The pharmaceutical suspension of Embodiment 9, wherein R⁷ is C₇-C₃oalkenyl.

[00451] Embodiment 12: The pharmaceutical suspension of any one of Embodiments 9, wherein R⁷ is

[00452] Embodiment 13: The pharmaceutical suspension of Embodiment 1, wherein R’ is -C(=O)OR⁹. [00453] Embodiment 14: The pharmaceutical suspension of Embodiment 13, wherein R⁹ is optionally substituted Cs-Csoalkyl, optionally substituted C4-C3oalkenyl, or optionally substituted C₂-C3oalkynyl. [00454] Embodiment 15: The pharmaceutical suspension of Embodiment 13, wherein R⁹ is Ci-Céalkyl.

[00455] Embodiment 16: The pharmaceutical suspension of Embodiment 13, wherein R⁹ is C₇-C₂oalkyl.

[00456] Embodiment 17: The pharmaceutical suspension of Embodiment 13, wherein R⁹ is C5-C₂oalkyl.

[00457] Embodiment 18: The pharmaceutical suspension of Embodiment 13, wherein R⁹ is C₅-Ci₀alkyl.

[00458] Embodiment 19: The pharmaceutical suspension of Embodiment 13, wherein R⁹ is Cn-C₂oalkyl.

[00459] Embodiment 20: The pharmaceutical suspension of Embodiment 13, wherein R⁹ is

[00460] Embodiment 21 : The pharmaceutical suspension of Embodiment 1, wherein R’ is -C(=O)Rⁱ⁰.

[00461] Embodiment 22: The pharmaceutical suspension of Embodiment 21, wherein R¹⁰ is optionally substituted C₅-C₃₀alkyl, optionally substituted C₂-C₃oalkenyl, or optionally substituted C₂-C₃₀alkynyl. [00462] Embodiment 23: The pharmaceutical suspension of Embodiment 21, wherein R¹⁰ is Ci-C₆alkyl.

[00463] Embodiment 24: The pharmaceutical suspension of Embodiment 21, wherein R¹⁰ is C₇-C₂₀alkyl.

-93 •[00464] Embodiment 25: The pharmaceutical suspension of Embodiment 21, wherein R'° is Cs-C^oalkyl.

[00465] Embodiment 26: The pharmaceutical suspension of Embodiment 21, wherein R¹⁰ is Cs-Cioalkyl.

[00466] Embodiment 27: The pharmaceutical suspension of Embodiment 21, wherein R¹⁰ is Cii-Csoalkyl.

[00467] Embodiment 28: The pharmaceutical suspension of Embodiment 21, wherein the compound of formula (II) is ((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4yl)oxy)methyl butyrate or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof.

[00468] Embodiment 29: The pharmaceutical suspension of Embodiment 28, wherein the crystalline ((6chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyI)quinolin-4-yl)oxy)methyl butyrate has at least one of the following properties:

(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 41 ; or (b) an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 14.4+0.1 20, about 15.1+0.1° 20, about 17.7+0.1° 20, about 18.1+0.1° 20, about 22.3+0.1° 20, and about 22.6+0.1° 20; or (c) a DSC thermogram substantially the same to the one set forth in FIG. 42A; or (d) a DSC thermogram with an endotherm having a peak at about 99.5 °C.

[00469] Embodiment 30: The pharmaceutical suspension of Embodiment 29, wherein the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 19.1 °±0.1 ° 20, about 20.3°±0.1 ° 20, about 21,2°±0.1 ° 2Θ, about 26.7°±0.1 ° 20, and about 29.2°±0.1 ° 20.

[00470] Embodiment 31 : The pharmaceutical suspension of any one of Embodiments 1-30, wherein the size 20 of the microparticles is between about 1 μιη and about 10 gm.

[00471] Embodiment 32: The pharmaceutical suspension of any one of Embodiments 1-31, wherein the size of the microparticles is between about 1 gm and about 5 gm.

[00472] Embodiment 33: The pharmaceutical suspension of any one of Embodiments 1-32, further comprising a pharmaceutically acceptable excipient selected from surfactants, solubilizers, emulsifiers, preservatives, isotonicity agents, dispersing agents, wetting agents, fil 1ers, solvents, buffers, stabilizers, lubricants, thickening agents, suspending agents, and any combinations thereof.

[00473] Embodiment 34: The pharmaceutical suspension of any one of Embodiments 1-33, further comprising a surfactant.

[00474] Embodiment 35: The pharmaceutical suspension of any one of Embodiments 1-34, further comprising a suspending agent.

[00475] Embodiment 36: The pharmaceutical suspension of any one of Embodiments 1-35, further comprising Synperonic® F108, dodecyl sodium sulfate (SLS), D-α -tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropyl methylcellulose (HPMC), and any combinations thereof.

[00476] Embodiment 37: The pharmaceutical suspension of any one of Embodiments 1-36, further comprising D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) and hydroxypropyl methylcellulose (HPMC).

[00477] Embodiment 38: The pharmaceutical composition of any one of Embodiments 1-37, wherein the concentration of the crystalline compound of Formula (II) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is between about 10 mg/mL and about 50 mg/mL.

-94^00478] Embodiment 39: The pharmaceutical suspension of any one of Embodiments l-38, wherein the concentration of the crystalline compound of Formula (II) is greater than about 50 mg/mL.

Claims

We claim:

l. A pharmaceutical composition comprising:

(i) an oil;

(ii) a compound of Formula (111) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof:

wherein:

Formula (III)

R¹¹ is Ci-Cô alkyl.
2. The pharmaceutical composition of claim 1, wherein R¹¹ is Ce alkyl.

The pharmaceutical composition of claim 1, wherein R¹¹ is
5. The pharmaceutical composition of any one of daims 1-4, wherein the oil is a vegetable oil.
6. The pharmaceutical composition of any one of daims 1-5, wherein the oil is seiected from corn oil, peanut oil, sesame oil, olive oil, palm oil, safflower oil, soybean oil, cottonseed oil, rapeseed oil, sunflower oil and mixtures thereof.
7. The pharmaceutical composition of any one of daims 1-6, wherein the oil is sesame oil.
8. The pharmaceutical composition of any one of daims l-7, wherein the concentration of the compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is greater than about 50 mg/mL.
9. The pharmaceutical composition of any one of daims l -8, wherein the concentration of the compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is greater than about 100 mg/mL.
10. The pharmaceutical composition of any one of daims l -9, wherein the concentration of the compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is greater than about 200 mg/mL.
11. A pharmaceutical composition according to any one of daims l - l 0 for use in the treatment or prévention of malaria.
12. A pharmaceutical composition for use according to daim 11, wherein the pharmaceutical composition is for administration by subcutaneous or intramuscular injection.
13. A pharmaceutical composition for use according to claim 11 or 12, wherein the pharmaceutical composition is effective for sustained or controlled release.
14. A pharmaceutical composition for use according to daim 11, wherein the compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is for administration at a dose of about 5 to about 20 mg/day.
15. A pharmaceutical composition for use according to any one of daims 11-14, wherein the compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is released from the pharmaceutical composition over a period of a minimum of about 30 days after administration.
16. A pharmaceutical composition for use according to any one of daims l l-l 5, wherein the compound of Formula (111) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is released from the pharmaceutical composition at a rate providing an average concentration of trans2-[4-(4-chlorophenyl)cyciohexyl]-3-hydroxy-l,4-naphthalenedione in the blood plasma of said subject of at least about 1000 nM over about 13 weeks.
17. A pharmaceutical composition for use according to any one of daims 11-16, wherein the compound of Formula (III) or a pharmaceutically acceptable sait, solvaté, or stereoisomer thereof is for administration with an additional antimalarial agent, in particular selected from artemisinin, artemisinin dérivatives, atovaquone, proguanil, quinine, chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine, pyronaridine, halofantrine, or ELQ-300.