Anti-parasitic cyclic depsipeptides

Abstract

Provided herein are compounds that exhibit activity against various parasites, and compositions containing such compounds. The present disclosure also provides methods of preventing and / or treating parasitic infections and / or infestations in an animal by administering such compounds or compositions to the animal.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 538,603, filed September 15, 2023, which is incorporated herein by reference in its entirety.

[0003] The scope of this disclosure

[0004] This disclosure relates to compounds, compositions, and methods of use thereof, such as methods of use for the prevention and / or treatment of parasites in relation to human and animal health.

[0005] background

[0006] Parasites that live on or within a host organism can have adverse effects on animals, humans, and plants. Parasites include, for example, protozoa, worms, arthropods, and fungi. Parasites are a significant concern in veterinary medicine, often causing irritation / discomfort in animals, leading to injury if left untreated, and in some cases, death. Parasites can be categorized into endoparasites (living inside the animal's body) (such as whipworms, hookworms, roundworms, and heartworms) and ectoparasites (living on the surface of the animal's body) (such as fleas, ticks, and mites).

[0007] Parasites can have adverse and far-reaching effects on animal health. For example, many parasites are vectors for pathogens that can infect both animals and humans (including, for example, ticks that transmit Lyme disease and Rocky Mountain spotted fever, fleas that transmit tapeworms, and mosquitoes that transmit malaria). As another example of the far-reaching effects of parasites, parasitic infestations in animals can lead to adverse economic impacts on agriculture, such as by interfering with animal digestion and nutrient absorption, and causing tissue and organ damage. Such effects on infected livestock can lead to poor productivity, manifested as little or no weight gain, metabolic disorders, abnormal reproduction, reduced and / or lower quality milk production, and death (all resulting in economic losses for farmers). Some parasites (such as certain worms, arthropods, and fungi) cause damage to plants, threatening food crop production and contaminating fruits and vegetables, leading to further economic losses and public health problems.

[0008] Numerous compounds have been developed as antiparasitic agents targeting one or more parasites. However, some of these compounds suffer from one or more drawbacks, such as insufficient antiparasitic efficacy, slow rate of action, limited duration of action, or high commercial cost. Some such compounds have a low therapeutic index and / or may require extra care in storage and administration to animals. Some antiparasitic agents are becoming ineffective due to parasite resistance. For at least these reasons, there is ongoing interest in the art in developing additional compounds capable of preventing and / or controlling a variety of parasites, which can be used to prevent or treat certain infections, invasions, and / or diseases transmitted by such parasites.

[0009] Brief Overview

[0010] This disclosure relates to compounds, pharmaceutical compositions, and methods for treating and / or preventing parasitic infections and / or invasions in animals and / or humans. The compounds of this disclosure are 24-membered cyclic peptides with activity against endoparasites and / or ectoparasites. In some embodiments, the compounds of this disclosure exhibit anthelmintic activity at the larval stage of parasites, such as against *Filaria canis* (canine filarial worm). Dirofilaria immitis (heartworm) heartworm )), hookworm ( Ancylostoma caninum )(hookworm( hookworm )) and / or Haemaphysema contortus ( Haemonchus contortus The insecticidal activity of Barber's Pole worm.

[0011] In one respect, compounds having the structure according to Formula I or pharmaceutically or veterinarily acceptable salts thereof are provided:

[0012] (I),

[0013] in:

[0014] R1 and R2 are independently selected from H and -CH2-R3, provided that at least one of R1 and R2 is -CH2-R3; and

[0015] R3 is a bridged heterocyclic alkyl group with 5 to 7 carbon atoms that can be optionally substituted, chosen independently for each occurrence.

[0016] In some implementations, R1 is H and R2 is -CH2-R3.

[0017] In some implementations, R1 and R2 are each -CH2-R3.

[0018] In some implementations, R1 and R2 are each -CH2-R3, where each R3 is different.

[0019] In some implementations, R1 and R2 are each -CH2-R3, where each R3 is the same.

[0020] In some implementations, R3 is

[0021] ,

[0022] in:

[0023] n is 1 or 2;

[0024] X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and

[0025] m can be 0, 1, or 2.

[0026] In some implementations, n is 1 or 2; X is (CH2). m And m is 0, 1, or 2.

[0027] In some implementations, R3 is selected from:

[0028] .

[0029] In some implementations, n is 1 or 2; and X is O, NMe, S, or SO2.

[0030] In some implementations, R3 is selected from:

[0031] .

[0032] In some implementations, R3 is selected from:

[0033] .

[0034] In some implementations, R3 is

[0035] ,

[0036] in:

[0037] n is 1 or 2;

[0038] X is selected from (CH2) m,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and

[0039] m can be 0, 1, or 2.

[0040] In some implementations, n is 1 or 2; X is (CH2). m And m is 0, 1, or 2.

[0041] In some implementations, R3 is selected from:

[0042] .

[0043] In some implementations, n is 1 or 2; and X is O, NMe, S, or SO2.

[0044] In some implementations, R3 is selected from:

[0045] .

[0046] In some implementations, R3 is selected from:

[0047] .

[0048] In some implementations, R3 is

[0049] ,

[0050] in:

[0051] n is 1 or 2;

[0052] X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and

[0053] m is 1 or 2.

[0054] In some implementations, n is 1 or 2; X is (CH2).m And m is 1 or 2.

[0055] In some implementations, R3 is selected from:

[0056] .

[0057] In some implementations, n is 1 or 2; and X is O, NMe, S, or SO2.

[0058] In some implementations, R3 is selected from:

[0059] .

[0060] In some implementations, R3 is

[0061] ,

[0062] Where X is C(CH3)OH, CHCO2H, CHCN, CF2, C=NOH, or C=NOCH3.

[0063] In some implementations, R3 is selected from:

[0064] .

[0065] In some implementations, R3 is

[0066]

[0067] in:

[0068] n is 1 or 2;

[0069] X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and

[0070] m is 1 or 2.

[0071] In some implementations, R3 is selected from:

[0072] .

[0073] In some implementations, R3 is

[0074]

[0075] in:

[0076] n is 1 or 2;

[0077] X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and

[0078] m is 1 or 2.

[0079] In some implementations, R3 is

[0080]

[0081] in:

[0082] Q is CH2, NMe, O, S, or SO2; and

[0083] W can be H, CH3, CH2OH, CF3, or CO2H.

[0084] In some implementations, R3 is selected from:

[0085] .

[0086] In some embodiments, the compound is selected from those compounds described in Table 1.

[0087] In another aspect, compositions are provided comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically or veterinary acceptable excipient.

[0088] In another aspect, methods for treating or preventing parasitic infections or invasions in animals are provided, the methods comprising administering to the animal an effective amount of a compound of formula I, a pharmaceutically or veterinarily acceptable salt thereof, or a composition comprising the compound or a salt thereof.

[0089] In some embodiments, the animal is a companion animal. In some embodiments, the companion animal is a dog.

[0090] In some embodiments, the parasitic infection or invasion is caused by species of the genus *Dirofilaria*. In some embodiments, the method treats or prevents canine heartworm.

[0091] In some embodiments, the parasitic infection or invasion is caused by species of the genus *Ancylostoma*. In some embodiments, the method is used to treat or prevent hookworm in dogs or ruminants.

[0092] In some implementations, the parasitic infection or infestation is caused by fleas or ticks.

[0093] These and other features, aspects, and advantages of this disclosure will become apparent from the following detailed description. This disclosure includes any combination of two, three, four, or more features or elements set forth in this disclosure, whether or not such features or elements are explicitly combined in the specific exemplary embodiments described herein or otherwise recorded. This disclosure is intended to be understood holistically such that, unless the context of this disclosure expressly specifies otherwise, any separable feature or element of this disclosure in any aspect and exemplary embodiment shall be considered composable. Therefore, it will be understood that this overview is provided solely for the purpose of outlining some exemplary embodiments to provide a basic understanding of some aspects of this disclosure. Accordingly, it will be understood that the exemplary embodiments described above are merely illustrative and should not be construed as reducing the scope or spirit of this disclosure in any way. Other exemplary embodiments, aspects, and advantages will become apparent from the following detailed description.

[0094] Detailed description

[0095] The present disclosure will now be described more fully below with reference to its example embodiments. Before describing several example embodiments of the technology, it should be understood that the technology is not limited to the details of the construction or method steps set forth in the following description. The technology can have other embodiments and can be practiced or implemented in various ways.

[0096] The following description presents numerous exemplary configurations, methods, parameters, etc., to provide a comprehensive understanding of various implementations of this disclosure. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary implementations.

[0097] This disclosure provides certain compounds, methods for preparing such compounds, compositions comprising such compounds (alone or in combination with one or more other active agents), and methods of use in relation to such compounds and / or compositions. Specifically, this disclosure provides 24-membered cyclic peptides with activity against in vivo and / or ectoparasites, compositions comprising such compounds or pharmaceutically or veterinarily acceptable salts thereof, and methods of treating or preventing certain parasitic infections using such compounds or compositions (optionally in combination with other active agents). In some embodiments, the compounds of this disclosure exhibit anthelmintic activity at the larval stage of parasites, such as against *Heartworm* (canine heartworm), *Hookworm* (canine hookworm), and / or *Haemaphysalis contortus* (canine hookworm). Haemonchus contortus The compounds disclosed herein exhibit insecticidal activity against fleas, ticks, or both.

[0098] It should be noted that the focus of this application is on compounds for animal and human health, but it should be understood that such compounds may have other applications (e.g., including but not limited to uses in an agricultural context).

[0099] definition

[0100] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The following definitions are provided for the terms used in this disclosure. Unless the context in which a term appears requires a different meaning, this application will use the terms as defined below.

[0101] The article “a / an” as used in this disclosure may refer to one or more (i.e., at least one) grammatical object of the article. As an example, “element” may mean one element or more elements.

[0102] As used herein, unless otherwise stated, the term “and / or” as used in this disclosure may mean “and” or “or”.

[0103] Throughout this specification, the term "about" is used to describe and explain small fluctuations. For example, the term "about" may refer to less than or equal to ±10%, less than or equal to ±5%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.2%, less than or equal to ±0.1%, or less than or equal to ±0.05%. Whether explicitly stated or not, all numerical values ​​herein are modified by the term "about." Values ​​modified by the term "about" naturally include specific values. For example, "about 5.0" must include 5.0.

[0104] Unless the context otherwise requires, the terms “comprising,” “containing,” and “including” as used herein throughout this specification and claims are used in their open, non-limiting sense.

[0105] "Alkyl" refers to a straight-chain or branched hydrocarbon chain group composed only of carbon and hydrogen atoms, without unsaturation, and preferably having one to fifteen carbon atoms (i.e., C1-C1). 15 Alkyl groups. In some embodiments, the alkyl group comprises one to thirteen carbon atoms (i.e., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (i.e., C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (i.e., C5-C6 alkyl). 15 Alkyl group. In other embodiments, the alkyl group comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, the alkyl group comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, the alkyl group comprises three to five carbon atoms (i.e., C3-C5 alkyl). In some embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is attached to the rest of the molecule by a single bond.

[0106] When used in conjunction with a chemical motif, such as alkyl, alkenyl, or alkynyl, the term "C" is used. x-y "This refers to groups containing x to y carbons in the chain. For example, the term "C" 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups containing 1 to 6 carbons. Term –C x-y Alkylene – refers to an alkylene chain with x to y carbons, either substituted or unsubstituted. For example, –C 1-6 The alkylene group can be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which may be optionally substituted.

[0107] "Alkoxy" refers to a group bonded by an oxygen atom of the formula –o-alkyl, wherein the alkyl is an alkyl chain as defined above.

[0108] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group composed only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having two to twelve carbon atoms (i.e., C2-C). 12 Alkenyl group. In some embodiments, the alkenyl group comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In some embodiments, the alkenyl group comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, the alkenyl group comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The alkenyl group is connected to the rest of the molecule by a single bond, for example, ethenyl, allyl, butyl, pentyl, pentyl-1,4-dienyl, etc.

[0109] "Alkyne group" refers to a straight-chain or branched hydrocarbon chain group composed only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having two to twelve carbon atoms (i.e., C2-C2). 12 The alkynyl group (C2-C8 alkynyl) is present in some embodiments. In other embodiments, the alkynyl group comprises two to eight carbon atoms (C2-C6 alkynyl). In still other embodiments, the alkynyl group comprises two to four carbon atoms (C2-C4 alkynyl). The alkynyl group is attached to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc.

[0110] Term "C" x-y "Alkenyl" and "C" x-y "Alkyne" refers to a substituted or unsubstituted unsaturated aliphatic group that is similar in length and possible substitutions to the alkyl groups described above, but contains at least one double or triple bond. Term –C x-y An alkenyl group refers to an alkenyl chain with x to y substituted or unsubstituted carbons. For example, –C 2-6 The alkenyl group can be selected from vinylene, propenene, butenene, pentenene, and hexenene, any one of which may be optionally substituted. The alkenyl chain may have one or more double bonds. Terminology – C x-y Amyynyl group refers to a substituted or unsubstituted ynyl chain with x to y carbons. For example, –C 2-6 The alkenyl group can be selected from alkenylene, propynylene, butynylene, pentylyne, and hexynylene, any one of which may be optionally substituted. The alkenylene chain may have one or more triple bonds.

[0111] "alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain that connects the rest of a molecule to a group, consisting only of carbon and hydrogen, without unsaturation, and preferably having one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule and to the group via single bonds. The connection points between the alkylene chain and the rest of the molecule and the group can be any two carbons in the chain. In some embodiments, the alkylene comprises one to ten carbon atoms (i.e., C1-C8 alkylene). In some embodiments, the alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, the alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, the alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, the alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, the alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, the alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, the alkylene comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, the alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, the alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene).

[0112] "Alkenyl" or "alkenyl chain" refers to a straight-chain or branched divalent hydrocarbon chain that connects the rest of a molecule to a group, consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having two to twelve carbon atoms. The alkenyl chain is connected to the rest of the molecule and to the group via single bonds. The connection points between the alkenyl chain and the rest of the molecule and the group can be through any two carbons in the chain. In some embodiments, the alkenyl group contains two to ten carbon atoms (i.e., C2-C2). 10 (Alkenyl group). In some embodiments, the alkenyl group comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In other embodiments, the alkenyl group comprises two to five carbon atoms (i.e., C2-C5 alkenyl). In other embodiments, the alkenyl group comprises two to four carbon atoms (i.e., C2-C4 alkenyl). In other embodiments, the alkenyl group comprises two to three carbon atoms (i.e., C2-C3 alkenyl). In other embodiments, the alkenyl group comprises two carbon atoms (i.e., C2 alkenyl). In other embodiments, the alkenyl group comprises five to eight carbon atoms (i.e., C5-C8 alkenyl). In other embodiments, the alkenyl group comprises three to five carbon atoms (i.e., C3-C5 alkenyl).

[0113] "Imyynyl" or "Imyynyl chain" refers to a straight-chain or branched divalent hydrocarbon chain that connects the rest of a molecule to a group, consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having two to twelve carbon atoms. The ynylyl chain is connected to the rest of the molecule and to the group via single bonds. The connection points between the ynylyl chain and the rest of the molecule and the group can be through any two carbons in the chain. In some embodiments, the ynylyl group contains two to ten carbon atoms (i.e., C2-C2). 10 The ynyl group (C2-C8 ynyl group) comprises two to eight carbon atoms in some embodiments. In other embodiments, the ynyl group comprises two to five carbon atoms (C2-C5 ynyl group). In other embodiments, the ynyl group comprises two to four carbon atoms (C2-C4 ynyl group). In other embodiments, the ynyl group comprises two to three carbon atoms (C2-C3 ynyl group). In other embodiments, the ynyl group comprises two carbon atoms (C2 ynyl group). In other embodiments, the ynyl group comprises five to eight carbon atoms (C5-C8 ynyl group). In other embodiments, the ynyl group comprises three to five carbon atoms (C3-C5 ynyl group).

[0114] "Aryl" refers to a group derived from aromatic monocyclic or polycyclic aromatic hydrocarbon ring systems by removing hydrogen atoms from the ring carbon atoms. Aromatic monocyclic or polycyclic aromatic hydrocarbon ring systems contain only hydrogen and carbon, with five to eighteen carbon atoms. At least one ring in the ring system is aromatic, meaning that, according to Hückel theory, it contains a cyclic, delocalized (4n+2) ring. – Electronic system. The ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indene, indene, tetrahydronaphthalene, and naphthalene.

[0115] "Aryl group" refers to the formula -R c -aryl groups, where R c It is an alkylene chain as defined above, such as methylene, ethylene, etc.

[0116] "Aryl" refers to the formula –R d -aryl groups, where R d This refers to an alkenyl group as defined above. "Arynyl group" refers to the formula -R e -aryl groups, where R e It is an alkyne chain as defined above.

[0117] A "carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocyclic rings can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring in a bicyclic carbocyclic ring can be selected from saturated, unsaturated, or aromatic rings. In some embodiments, the carbocyclic ring is aryl. In some embodiments, the carbocyclic ring is cycloalkyl. In some embodiments, the carbocyclic ring is cycloalkenyl. In an exemplary embodiment, an aromatic ring (e.g., phenyl) can be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, provided the valence allows. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl.

[0118] “Cycloalkyl” refers to a stable, fully saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused or bridged ring systems, and preferably having three to twelve carbon atoms. In some embodiments, the cycloalkyl group contains three to ten carbon atoms. In other embodiments, the cycloalkyl group contains five to seven carbon atoms. The cycloalkyl group can be linked to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc.

[0119] "Cycloalkenyl" refers to a stable, unsaturated, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having three to twelve carbon atoms and containing at least one double bond. In some embodiments, the cycloalkenyl group contains three to ten carbon atoms. In other embodiments, the cycloalkenyl group contains five to seven carbon atoms. The cycloalkenyl group can be linked to the rest of the molecule via a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0120] “Cycloalkylalkyl” refers to the formula –R c -cycloalkyl groups, wherein R c It is an alkylene chain as described above.

[0121] "Cycloalkylalkoxy" refers to the formula – OR c - A cycloalkyl group bonded by an oxygen atom, wherein R c It is an alkylene chain as described above.

[0122] "Halogen" or "halogenated" refers to halogenated substituents such as bromine, chlorine, fluorine, and iodine substituents.

[0123] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above, substituted with one or more halogen groups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group may optionally be further substituted. Examples of halogen-substituted alkanes (“haloalkanes”) include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-halomethanes and tri-halomethanes (e.g., chloroform, tribromomethane, trifluoromethane, triiodomethane), 1-haloethanes, 2-haloethanes, 1,2-dihaloethanes, 1-halopropanes, 2-halopropanes, 3-halopropanes, 1,2-dihalopropanes, 1,3-dihalopropanes, 2,3-dihalopropanes, 1,2,3-trihalopropanes, and any other suitable combination of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When the alkyl group is substituted by more than one halogen group, each halogen can be chosen independently, for example, 1-chloro,2-fluoroethane.

[0124] "Fluoroalkyl" refers to an alkyl group as defined above that is substituted with one or more fluorine groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc.

[0125] "Heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring in a bicyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle is a heteroaryl group. In some embodiments, the heterocycle is a heterocyclic alkyl group. "Heterocyclene" refers to a divalent heterocycle that connects the rest of the molecule to a group.

[0126] "Heterocyclic alkyl" refers to a stable 3- to 12-membered non-aromatic cyclic group containing two to twelve carbon atoms and at least one heteroatom, wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. Heterocyclic alkyl groups may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatom in the heterocyclic alkyl group is optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocyclic alkyl group is partially or fully saturated. Where valence permits, the heterocyclic alkyl group is attached to the remainder of the molecule by any atom of the heterocyclic alkyl group (such as any carbon or nitrogen atom of the heterocyclic alkyl group). Examples of heterocyclic alkyl groups include, but are not limited to, dioxolanecycloyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, thiazoalkyl, tetrahydrofurfuryl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.

[0127] "Heterocyclic alkyl alkyl" refers to the formula –R c - Heterocyclic alkyl groups, wherein R c This refers to an alkylene chain as defined above. If the heterocyclic alkyl group is a nitrogen-containing heterocyclic alkyl group, the heterocyclic alkyl group is optionally attached to the alkylene chain at the nitrogen atom.

[0128] "Heteroaryl" or "aromatic heterocyclic" refers to a group derived from a 3- to 12-membered aromatic ring group, containing one to eleven carbon atoms and at least one heteroatom, where each heteroatom can be selected from N, O, and S. The heteroaryl rings used in this paper can be selected from monocyclic, bicyclic, and fused or bridged ring systems, wherein at least one ring in the ring system is aromatic, i.e., according to Hückel's theory, it contains a cyclic, delocalized (4n+2) ring. – Electronic system. One or more heteroatoms in the heteroaryl group may optionally be oxidized. One or more nitrogen atoms (if present) may optionally be quaternized. Where valence permits, the heteroaryl group may be attached to the remainder of the molecule by any atom of the heteroaryl group (such as a carbon or nitrogen atom). Examples of heteroaryl groups include, but are not limited to, aziridine, acridine, benzimidazolyl, benzoindolyl, 1,3-benzodioxacyclopentadienyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[ b [1,4]dioxane-heptenyl (benzo[ b [1,4]dioxepinyl), benzo[ b[1,4]oxazinyl, 1,4-benzodioxyl, benzonaphthofuranyl, benzooxazolyl, benzodioxanedienyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl / benzothiophenyl, benzothieno[3,2-d]pyrimidinyl, benzotri... Azolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenyl, cyclopentadieno[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentadieno[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cenyl, 6,7-dihydro-5H-benzo[6,7]arylhept[1,2-c [Pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, furano[3,2-c]pyridyl, 5,6,7,8,9,10-hexahydroarocto[d]pyrimidinyl, 5,6,7,8,9,10-hexahydroarocto[d]pyridazinyl, 5,6,7,8,9,10-hexahydroarocto[d]pyridyl, isothiazolyl, imidazolyl, indazole, indoleyl, Indazole, isoindolyl, dihydroindolyl, isodihydroindolyl, isoquinolinyl, indoleazinyl, isoxazolyl, 5,8-methylene-5,6,7,8-tetrahydroquinazolinyl, naphridyl, 1,6-naphridinoneyl, oxadiazolyl, 2-oxoazapyryl, oxazolyl, ethylene oxide, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1 H -pyrrole, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purine, pyrrole, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyrrole, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thiophene [2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-arylheptano[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyridano[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl / thienyl. "X-membered heteroaryl" refers to the number of inner ring atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 inner ring atoms, such as triazoles, oxazoles, thiophenes, etc.

[0129] "Heteroarylalkyl" refers to the formula –R c - A heteroaryl group, wherein Rc An alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, it is optionally attached to the alkylene chain at the nitrogen atom.

[0130] As used herein, the term “bridging” refers to a bicyclic ring system (e.g., cycloalkyl or heterocyclic) in which two bridgehead atoms are separated by a bridge atom and the two rings share three or more atoms (the bridgehead atoms and the bridge atom).

[0131] The term "amino" as used in this article refers to –NH2.

[0132] The term "hydroxyl" refers to –OH.

[0133] As used in this article, the term "oxo" refers to the "=O" group. It can also be abbreviated as C(O) or C=O.

[0134] The term "substituted" refers to a portion having substituents that replace hydrogen atoms on one or more carbons or substituted heteroatoms (e.g., NH) in the structure. It will be understood that "substitution" or "replacement with..." implies the following premise: such substitution conforms to the permissible valence of the substituted atom and the substituent, and the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo transformations (e.g., by rearrangement, cyclization, elimination, etc.). In some embodiments, "substituted" refers to a portion having substituents that replace two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon atom with an oxo, imino, or thio group. As used herein, the term "substituted" is considered to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents may be one or more, and may be the same or different. For the purposes of this disclosure, heteroatoms (such as nitrogen) may have hydrogen substituents and / or any permitted substituents of the organic compounds described herein, said substituents satisfying the valence of the heteroatoms.

[0135] In some embodiments, the substituents may include any substituents described herein, such as: halogen, hydroxyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -Rb -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 -OR 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) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, arylenyl, arynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of these substituents may optionally be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -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)ORa -R b -C(O)N(R a )2、-R b -OR 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) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) replace; where each R a Independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R a If the oxidation state allows, it may be optionally converted to alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -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 -OR 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) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) replace; and where each R b Independently selected from direct-chain or straight-chain or branched alkylene, alkenyl, or ynylene chains, and each R c It is a straight-chain or branched alkylene, alkenyl, or ynylene chain.

[0136] As used herein, the term "unsubstituted" means that the specified group, apart from the portion described, does not contain any substituents (e.g., where the valence is satisfied by hydrogen).

[0137] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of their atoms. "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term "(±)" is used to designate racemic mixtures. "Diadiamers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is defined according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Resolved compounds with unknown absolute configurations can be designated as (+) or (-) based on the direction (dextrorotatory or levorotatory) in which they rotate plane-polarized light at the sodium D line wavelength. Some of the compounds described herein contain one or more asymmetric centers and are therefore capable of producing enantiomers, diastereomers, and other stereoisomers, the asymmetric centers of which, in absolute stereochemistry, can be defined as (R)- or (S)-. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and mixtures of intermediates. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical rotation of the compounds can be analyzed by any suitable method, including but not limited to chiral chromatography and optical rotation determination, and the degree of dominance of one stereoisomer relative to another can be determined.

[0138] In some embodiments, the compounds of this disclosure may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. The term "stereoisomer" can refer to a group of compounds having the same number and type of atoms and the same bond connections between those atoms, but with different three-dimensional structures. The term "stereoisomer" can refer to any member of that group of compounds. For example, a stereoisomer can be an enantiomer or a diastereomer. The compounds of this disclosure intended for all stereoisomeric forms, and mixtures thereof (including racemic mixtures), form part of this disclosure.

[0139] When stereochemistry is not specified, certain molecules described herein include isomers such as enantiomers and diastereomers, mixtures of enantiomers (including racemates), mixtures of diastereomers, and other mixtures thereof (to the extent that they can be prepared by those skilled in the art through routine experiments). In some embodiments, a single enantiomer or diastereomer (i.e., the optically active form) can be obtained by asymmetric synthesis or by resolution of a mixture of racemates or diastereomers. If possible, the resolution of a mixture of racemates or diastereomers can be achieved, for example, by conventional methods such as crystallization in the presence of a resolving agent or by chromatography using, for example, a chiral high-performance liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two enantiomers can be purified by recrystallization and / or grinding to provide a further optically enriched form of the major enantiomer.

[0140] In some embodiments, the chiral center of the compound of this disclosure may have an S or R configuration as defined in IUPAC 1974 Recommendations.

[0141] As used herein, the term "group of a compound" refers to a structure derived from a parent compound by removing one or more atoms (e.g., hydrogen atoms). In some embodiments, "group of a compound" is a monovalent group derived from a parent compound by removing a hydrogen atom.

[0142] It should be understood that, depending on the context, certain group naming conventions may include monoradical or diradical groups. For example, when a substituent needs to be attached to two connection points on the rest of the molecule, the substituent should be understood as diradical. For example, substituents of alkyl groups that are identified as requiring two connection points include diradicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other group naming conventions explicitly indicate that the group is diradical, such as "alkylene", "alkenyl", "arylene", etc.

[0143] Where a substituent is described as a bigroup (i.e., having two connection points attached to the rest of the molecule), it should be understood that the substituent may be connected in any configuration orientation unless otherwise stated.

[0144] A "tautomer" is a molecule in which the migration of a proton from one atom of the molecule to another atom of the same molecule is possible. In some embodiments, the compounds presented herein exist as tautomers. In cases where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact proportions of tautomers depend on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

[0145]

[0146] "Stable compound" and "stable structure" can refer to a compound that is robust enough to withstand separation from the reaction mixture to a useful purity and formulation into an effective therapeutic agent.

[0147] The phrase “parenteral administration / administered parenterally” as used in this article refers to administration methods other than enteral and local administration, usually by injection, including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, spinal, and intrasternal injections and infusions.

[0148] The phrase “pharmaceutically acceptable” as used in this article refers to compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for use in human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0149] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein refers to pharmaceutically acceptable materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be “acceptable” in the sense of compatibility with other components of the formulation and harmlessness to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc (powder); (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, and corn oil. Rice oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0150] As used in this disclosure, the term "carrier" may encompass carriers, excipients, and diluents, and may refer to materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that participate in carrying or delivering pharmaceutical agents of this disclosure, such as one or more compounds, or their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers (e.g., stereoisomers), and tautomers, from one organ or body site to another organ or body site of a subject. The carrier should be selected based on the compatibility and release characteristics of the desired dosage form. Exemplary carrier materials may include, for example, excipients, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, etc. See, for example, Hoover, John E., Remington's Pharmaceutical Sciences Mack Publishing Co., Easton, Pa. 1975. Exemplary carrier materials may also include, but are not limited to, any adjuvants, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonants, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for acceptable use in humans or domestic animals.

[0151] The terms “pharmaceutical acceptable” or “pharmacologically acceptable” can refer to a material that is not biologically or otherwise undesirable—that can be administered to an individual without causing any substantially undesirable biological effects or interacting in a harmful manner with any component of a composition in which it is contained.

[0152] "Pharmaceutical composition" can refer to a formulation of the compound of this disclosure with a generally accepted medium in the art for delivering the biologically active compound to a subject (e.g., a mammal or a human). Such a medium can include all pharmaceutically acceptable carriers used herein.

[0153] The terms “subject,” “individual,” and “patient” are used interchangeably and refer to non-human mammals (e.g., non-human primates, canines, equines, felines, suidae, bovids, ungulates, lagomorphs, etc.).

[0154] As used herein, the phrase “subjects in need” refers to subjects who have or are at risk of developing a certain lesion, as described below, which is to be treated preventively or therapeutically with the compounds or salts described herein.

[0155] The term "administer" is defined as the delivery of a composition to a subject via a route known in the art, including but not limited to intravenous, intra-arterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, mucosal, or intraperitoneal administration. In some embodiments, an oral route of administration of the composition may also be used.

[0156] The term "effective amount" or "therapeutic effective amount" refers to the amount of the compound or salt described herein that is sufficient to be effective for the intended application (including, but not limited to, the treatment of a disease as defined below). Therapeutic effective amounts can vary depending on the intended application (in vitro or in vivo) or the subject and the condition of the disease being treated, such as the subject's weight and age, the severity of the disease, the method of administration, etc., and can be readily determined by those skilled in the art. The term can also be applied to doses that can induce specific responses in target cells (e.g., reduced proliferation or downregulation of target protein activity). Specific doses can vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system carrying it.

[0157] As used herein, "treatment" refers to a method for achieving a beneficial or desired outcome (including, but not limited to, therapeutic and / or preventative benefits) for a disease, disorder, or medical condition. In some embodiments, treatment involves administering to a subject a compound or composition disclosed herein. In some embodiments, therapeutic benefits may include relieving, reducing, or improving symptoms of a disease or condition; preventing additional symptoms; improving or preventing the underlying cause of symptoms; inhibiting a disease or condition, such as preventing its progression; alleviating a disease or condition; causing the remission of a disease or condition; reducing the condition caused by a disease or condition; or preventing and / or therapeutically ending the symptoms of a disease or condition.

[0158] In some embodiments, the therapeutic benefit includes eliminating or improving the underlying barrier being treated. In some embodiments, the therapeutic benefit includes eliminating or improving one or more physiological symptoms associated with the underlying barrier, such as observed improvement in the subject, although the subject may still be suffering from the underlying barrier. In some embodiments, the compound or composition is administered to a subject at risk of developing a specific disease or to a subject exhibiting one or more physiological symptoms of a disease (even if a diagnosis of the disease may not have been made) for preventative benefits. Treatment may include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or condition, or it may include reducing the frequency with which a patient experiences symptoms of a disease, defect, impairment, or adverse condition. Treatment may be used herein to refer to a method of producing a level of treatment or improvement for a disease or condition, and a range of outcomes for that purpose may be considered, including but not limited to complete prevention of the condition.

[0159] In some implementations, the term "preventing" in relation to a disease or disorder can refer to, in a statistical sample, a compound reducing the incidence of the disorder or condition in a treated sample relative to an untreated control sample, or a compound delaying the onset of one or more symptoms of the disorder or condition or reducing their severity relative to an untreated control sample. In some implementations, prevention includes delaying or preventing the onset, recurrence, or spread (whole or part) of a disorder, disease, or condition; preventing a subject from developing a disorder, disease, or condition; or reducing the risk of a subject developing a disorder, disease, or condition.

[0160] In some implementations, the terms “disease” and “symptom” may be used interchangeably or may be different in that a particular disease or symptom may not have a known pathogen (making the cause unclear) and therefore it is not yet considered a disease, but rather an undesirable symptom or syndrome in which a clinician has identified a more or less specific set of symptoms.

[0161] The compounds disclosed herein

[0162] This disclosure provides compounds having biological activity against parasites. Therefore, in some embodiments, compounds of the formula(s) disclosed herein may be referred to as “parasitic compounds(s)” of the corresponding formula.

[0163] Specifically, this disclosure provides compounds having a structure according to Formula I or a pharmaceutically or veterinary-acceptable salt thereof:

[0164] (I),

[0165] in:

[0166] R1 and R2 are independently selected from H and -CH2-R3, provided that at least one of R1 and R2 is -CH2-R3; and

[0167] R3 is a bridged heterocyclic alkyl group with 5 to 7 carbon atoms that can be optionally substituted, chosen independently for each occurrence.

[0168] In some implementations, R1 is H and R2 is -CH2-R3.

[0169] In some implementations, R1 and R2 are each -CH2-R3.

[0170] In some implementations, R1 and R2 are each -CH2-R3, where each R3 is different.

[0171] In some implementations, R1 and R2 are each -CH2-R3, where each R3 is the same.

[0172] In some implementations, R3 is

[0173] ,

[0174] in:

[0175] n is 1 or 2;

[0176] X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and

[0177] m can be 0, 1, or 2.

[0178] In some implementations, n is 1 or 2; X is (CH2). m And m is 0, 1, or 2.

[0179] In some implementations, R3 is selected from:

[0180] .

[0181] In some embodiments, n is 1 or 2; and X is O, NMe, S, or SO2. In some embodiments, X is O. In some embodiments, X is NMe. In some embodiments, X is S. In some embodiments, X is sulfone (SO2).

[0182] In some implementations, R3 is selected from:

[0183] .

[0184] In some implementations, X is a carbonyl or oxime group.

[0185] In some implementations, R3 is selected from:

[0186] .

[0187] In some implementations, R3 is

[0188] ,

[0189] in:

[0190] n is 1 or 2;

[0191] X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and

[0192] m can be 0, 1, or 2.

[0193] In some implementations, n is 1 or 2; X is (CH2). m And m is 0, 1, or 2.

[0194] In some implementations, R3 is selected from:

[0195] .

[0196] In some embodiments, n is 1 or 2; and X is O, NMe, S, or SO2. In some embodiments, X is O. In some embodiments, X is NMe. In some embodiments, X is S. In some embodiments, X is sulfone (SO2).

[0197] In some implementations, R3 is selected from:

[0198] .

[0199] In some embodiments, X is CHOH, CHF, CF2, carbonyl, oxime, or acetamino group.

[0200] In some implementations, R3 is selected from:

[0201] .

[0202] In some implementations, R3 is

[0203] ,

[0204] in:

[0205] n is 1 or 2;

[0206] X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and

[0207] m is 1 or 2.

[0208] In some implementations, n is 1 or 2; X is (CH2). m And m is 1 or 2.

[0209] In some implementations, R3 is selected from:

[0210] .

[0211] In some embodiments, n is 1 or 2; and X is O, NMe, S, or SO2. In some embodiments, X is O. In some embodiments, X is NMe. In some embodiments, X is S. In some embodiments, X is sulfone (SO2).

[0212] In some implementations, R3 is selected from:

[0213] .

[0214] In some implementations, X is CHF, C=O, C=CH2, oxime, CH(C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, or acetamino.

[0215] In some implementations, R3 is selected from:

[0216] .

[0217] In some implementations, R3 is

[0218] ,

[0219] Where X is C(CH3)OH, CHCO2H, CHCN, CF2, C=NOH, or C=NOCH3.

[0220] In some implementations, R3 is

[0221] ,

[0222] in:

[0223] n is 1 or 2;

[0224] X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and

[0225] m is 1 or 2.

[0226] In some implementations, R3 is selected from:

[0227] .

[0228] In some implementations, R3 is

[0229] ,

[0230] in:

[0231] n is 1 or 2;

[0232] X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and

[0233] m is 1 or 2.

[0234] In some implementations, R3 is

[0235] ,

[0236] in:

[0237] Q is CH2, NMe, O, S, or SO2; and

[0238] W can be H, CH3, CH2OH, CF3, or CO2H.

[0239] In some implementations, Q is CH2. In some implementations, Q is O.

[0240] In some embodiments, W is H. In some embodiments, W is CH3 or CF3. In some embodiments, W is CH2OH or CO2H.

[0241] In some implementations, R3 is selected from:

[0242] .

[0243] In some embodiments, the compounds of Formula I are selected from the compounds described in Table 1.

[0244] Isomers

[0245] In some embodiments, the compounds of this disclosure may be enriched to primarily provide one enantiomer of the compounds described herein. The enantiomer enrichment mixture may contain, for example, at least 60 mol% of one enantiomer, or at least 75 mol%, at least 80 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, at least 96 mol%, at least 97 mol%, at least 98 mol%, at least 99 mol%, at least 99.5 mol%, or even 100 mol%. In some embodiments, the compounds described herein enriched with one enantiomer may be substantially free of the other enantiomer, where substantially free may mean, for example, that in the compound mixture, the other enantiomer accounts for less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% compared to the amount of the target enantiomer. For example, if a mixture of compounds contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, it will be said to contain 98 mol% of the first enantiomer and only 2 mol% of the second enantiomer.

[0246] In some embodiments, the compounds of this disclosure may be enriched to primarily provide one diastereomer of the compounds disclosed herein. The diastereomer enrichment mixture may contain, for example, at least 60 mol% of one diastereomer, or at least 75 mol%, at least 80 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, at least 96 mol%, at least 97 mol%, at least 98 mol%, at least 99 mol%, at least 99.5 mol%, or even 100 mol%. In some embodiments, the compounds described herein enriched with one diastereomer may be substantially free of other diastereomers, where substantially free may mean, for example, that in the compound mixture, other diastereomers account for less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% relative to the amount of the target diastereomer.

[0247] Based on their physicochemical differences, diastereomer mixtures can be separated into their individual diastereomers using methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or Mosher's acid chloride) to convert the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their respective pure enantiomers. Enantiomers can also be separated using a chiral HPLC column. Furthermore, some compounds in this disclosure may be transisomers or rotational isomers and are considered part of this disclosure.

[0248] In some embodiments, the compounds of this disclosure are regioisomers of Formula I. For example, as further described below, during the preparation of compounds of Formula I, ortho and / or meta isomers (with respect to the R1 and R2 substituents) have been observed in addition to the predominant para-substituted compounds shown in Formula I. Therefore, in some embodiments, compounds having structures according to one or more of Formulas II, III, IV, V, VI, VII, VIII, and IX are provided:

[0249] (II)

[0250] (III);

[0251] (IV);

[0252] (V);

[0253] (VI);

[0254] (VII);

[0255] (VIII); and

[0256] (IX),

[0257] where each of R1, R2, and R3 is as defined above for formula I.

[0258] Isotopes and isotopically labeled compounds

[0259] The compounds described herein may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched with a particular isotope that has the same atomic number but a different atomic mass or mass number than the atomic mass or mass number predominantly found in nature. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. Accordingly, reference to an element is intended to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes its isotopes. For example, hydrogen has three naturally occurring isotopes, designated as 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment of deuterium can provide certain therapeutic advantages such as increased in vivo half-life and / or exposure, or can provide compounds that can be used to study the in vivo pathways of drug elimination and metabolism. Isotopically enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0260] The compounds described herein further include all pharmaceutically acceptable isotopically labeled compounds. An "isotope" or "radioisotopically labeled" compound can be a compound in which one or more atoms are replaced or substituted with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (i.e., naturally occurring). For example, in some embodiments, a hydrogen atom in a compound described herein is replaced or substituted with one or more deuterium or tritium.

[0261] Certain isotopically labeled compounds of the present disclosure, such as those incorporating a radioactive isotope, can be used for drug and / or substrate tissue distribution studies. Given their ease of incorporation and convenient methods of detection, the radioactive isotopes tritium, i.e., ³ H and carbon 14, i.e., ¹4C can be particularly useful for this purpose. Substitution with a heavier isotope (such as deuterium, i.e., ²H) can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirement, and is therefore preferred in some cases. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced or substituted with deuterium. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Suitable isotopes that can be introduced into the compounds described herein include, but are not limited to, those that are not included in the present invention. 2 H (also written as D, representing deuterium) 3 H (also written as T, representing tritium) 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 18 F, 35 S, 36 Cl、 82 Br、 75 Br、 76 Br、 77 Br、 123 I, 124 I, 125 I, and 131 I. Using positron emission of isotopes (e.g.) 11 C 18 F, 15 O, and 13 N) can be used as a substitute for positron emission tomography (PET) studies.

[0262] Isotopically labeled versions of the compounds disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with appropriate isotopically labeled reagents through a series of steps similar to those disclosed in the schemes and / or examples herein.

[0263] Metabolites

[0264] This disclosure is also intended to cover in vivo metabolites of the disclosed compounds. Such products can originate from, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Therefore, this disclosure may include compounds produced by methods comprising administering the compound of this disclosure to a subject (e.g., a mammal) for a duration sufficient to generate its metabolites. Such products are typically identified by the following steps: administering a radiolabeled compound of this disclosure to a subject such as a rat, mouse, guinea pig, monkey, or human at a detectable dose, allowing sufficient time for metabolism to occur, and isolating its metabolites from urine, blood, or other biological samples.

[0265] Salts and solvates

[0266] This disclosure further provides pharmaceutically or veterinarily acceptable salts, solvates (e.g., hydrates), and combinations thereof of any of the compounds disclosed herein. The terms “salt,” “hydrate,” “solvent,” etc., are intended to equally apply to salts, hydrates, or solvates of enantiomers, diastereomers, isomers, stereoisomers, rotational isomers, tautomers, positional isomers, or racemates of the disclosed compounds.

[0267] The term "salt," or "pharmaceutically acceptable salt," or "veterinary acceptable salt," refers to a salt derived from a variety of organic and inorganic counterions well known in the art. Salts can form pharmaceutically or veterinarily acceptable acid addition salts with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic 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, and salicylic acid. Salts can form pharmaceutically or veterinarily acceptable base addition salts with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases that can derive salts include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the base addition salt is selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. In some implementations, pharmaceutically or veterinarily acceptable salts may include, for example, water-soluble and water-insoluble salts such as acetates, aniline (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium salt, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, ethanedisulfonate, estolate, ethanesulfonate, fiunarate, glucono-p-hydroxylate, gluconate, glutamate, glycolyllarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, and hydrobromic acid. Salts, hydrochlorides, hydroxynaphthylcarboxylate, iodides, hydroxyethyl sulfonate, lactates, lactobionates, laurates, magnesium salts, malates, maleates, mandelates, methanesulfonates, methyl bromide, methyl nitrates, methyl sulfates, mucilages, naphthalene sulfonates, nitrates, N-methylglucosamine ammonium salts, 3-hydroxy-2-naphthylcarboxylate, oleates, oxalates, palmitates, dihydroxynaphthylcarboxylate, 1,1-methylene-bis-2-hydroxy-3-naphthylcarboxylate, einbonate, pantothenate, phosphates / bisphosphonates, picrates, polygalacturonic acid esters, propionates, p-toluenesulfonate, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicylates, suramates, tannates, tartrates, teoclates, toluenesulfonate, triethyl iodide, and valerates.

[0268] Suitable anionic salt forms include, but are not limited to, acetates, benzyl sulfonates, benzoates, benzyl compounds, bicarbonates, tartrates, bromides, calcium edetate, camphor sulfonate, carbonates, chlorides, citrates, dihydrochlorides, edetates, ethanedisulfonates, estolates, ethanesulfonates, fumarates, glucono-p-aminophenylarsethanoate, gluconate, glutamate, glycolyl-p-aminophenylarsethanoate, hexylresorcinol salts, hydrabamine, hydrobromide, and hydrochloride salts. Hydroxynaphthalene, iodides, hydroxyethyl sulfonates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, methyl bromides, methyl nitrates, methyl sulfates, mucilages, naphthalene sulfonates, nitrates, bis(hydroxynaphthalene) salts, pantothenates, phosphates and diphosphates, polygalacturonic acids, salicylates and disalicylates, stearates, basic acetates, succinates, sulfates, tannates, tartrates, teoclates, toluenesulfonates, triethyl iodide, valerates, etc.

[0269] Suitable cation salt forms include, but are not limited to, aluminum, benzylamine, calcium, ethylenediamine, lysine, magnesium, meglumine, potassium, procaine, sodium, tromethamine, zinc, etc.

[0270] In some embodiments, the salt is selected from acetate, ascorbate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, hydrogen sulfate / sulfate, borate, camphorsulfonate, citrate, ethanedisulfonate, etoglutarate, ethanesulfonate, formate, fumarate, gluconate, gluconate, glucuronate, glycerophosphate, hexafluorophosphate, 2-(4-hydroxybenzoyl)benzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethylsulfonate, lactate, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthyl salt, phosphate / hydrogen phosphate / dihydrogen phosphate, glycosyl salt, stearate, succinate, tartrate, toluenesulfonate, and trifluoroacetate.

[0271] The compounds disclosed herein also include those compounds, pharmaceutically acceptable salts of such compounds having the same type of activity, and crystalline and amorphous forms of active metabolites, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolventized polymorphs (including anhydrous polymorphs), conformational polymorphs, and amorphous forms such as spray-dried dispersions, and mixtures thereof.

[0272] The compounds of this disclosure, including their stereoisomers and tautomers, and any salts thereof, may exist as solvates. Typically, crystallization produces solvates of the compounds of this disclosure. As used herein, the term "solvate" can refer to an aggregate of one or more molecules of a compound comprising this disclosure with one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds and salts of this disclosure may exist as hydrates (including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc.) and corresponding solvates. The compounds of this disclosure may be true solvates, while in other cases, the compounds of this disclosure may contain only external water, or a mixture of water and some external solvent.

[0273] Preparation of the compounds disclosed herein

[0274] The compounds of this disclosure can be prepared by synthetic methods known in the field of organic synthesis, as partially illustrated in conjunction with the synthetic schemes described below and in the examples, and the guidance provided herein. In the schemes described below and provided in the figures, it should be understood that, where necessary, protecting groups targeting sensitive or reactive groups may be employed according to general principles or chemistry, and in accordance with the guidance provided herein. Protecting groups can be operated according to standard methods of organic synthesis (TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis,” 3rd edition, Wiley, New York 1999). Based on the detailed teachings provided herein, these groups can be removed at a convenient stage of compound synthesis using methods obvious to those skilled in the art. The choice of methods, reaction conditions, and their sequence of execution should be consistent with this disclosure.

[0275] Typically, methods for preparing the compounds of this disclosure involve combinations of reactions and conditions. By way of example and not limitation, certain compounds can be prepared as outlined in the schemes shown below and the examples set forth herein. It should be noted that those skilled in the art will understand how to modify the schemes and steps set forth in the examples to obtain the desired product.

[0276] General Scheme 1 describes a representative, non-limiting strategy for preparing compounds according to Formula I of this disclosure. Referring to Scheme 1, in some embodiments, bromomethylated cyclic condensate A, dibromomethylated cyclic condensate B, or mixtures thereof are permitted to react with a bridged bicyclic amine to form the corresponding monoamine or diamine product (C or D, respectively). Bromomethylated cyclic condensates A and B can be readily prepared by alkylation of the known cyclic condensate PF1022A with a bromomethyl methyl ether under Friedel-Crafts conditions. Suitable steps are disclosed, for example, in International Patent Application Publication No. WO2019 / 108591 (incorporated herein by reference in its entirety).

[0277] Option 1

[0278]

[0279] Suitable bridged bicyclic amines are commercially available or readily synthesized using known methods. The reaction of bridged bicyclic amines with bromomethylated cyclic peptides is typically carried out in a solvent in the presence of a suitable base. Suitable solvents include, but are not limited to, dichloromethane, acetonitrile, and dimethylformamide. Suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, etc.

[0280] In some embodiments, the bridged bicyclic amine has one of the following structures:

[0281] ,

[0282] in:

[0283] n is 1 or 2;

[0284] X is (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,C H(C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2;

[0285] Q is CH2, NMe, O, S, or SO2;

[0286] W can be H, CH3, CH2OH, CF3, or CO2H; and

[0287] m can be 0, 1, or 2.

[0288] In some embodiments, the bridged bicyclic amine has the structure described in Table 1.

[0289] After the N-alkylation reaction is completed, the crude product is purified (e.g., by chromatographic methods such as HPLC) to provide monoamined or diamined products (as described above with reference to Scheme 1, C and D). In some embodiments, additional regiomeric compounds can be isolated from such reactions. For example, when the bromomethylation intermediate is prepared by Friedel-Crafts alkylation, although the para-isomer is dominant, other isomers are present, such as ortho- or meta-bromomethylation compounds and various mixtures thereof, including those described above as in Formulas II to IX. Therefore, the corresponding amination regiomeric isomer, if present in crude intermediates A and / or B, may also be present in the crude reaction product mixture and can be separated and isolated during purification, and any such isomers or combinations thereof are considered herein.

[0290] Composition

[0291] Although the compounds of Formula I provided herein can be used alone (e.g., by application), they are generally more advantageously provided in compositions for animal health, human health, or agriculture. Typically, such compositions comprise a therapeutically or agriculturally effective amount of one or more compounds and at least one carrier, such as a veterinary-acceptable carrier, a pharmaceutically acceptable carrier, and / or an agriculturally acceptable carrier. The term "carrier" is used herein to describe any component (e.g., excipients, diluents, etc.) other than the compounds of this disclosure or any other optional active agents (e.g., additional antiparasitic agents, as mentioned below) introduced into the composition. The compositions of this disclosure can be prepared, for example, by combining one or more compounds of this disclosure (or one or more of their salts, solvates, stereoisomers, or tautomers) with a suitable carrier, and can be formulated as preparations in solid, semi-solid, liquid, or gaseous form.

[0292] The compounds disclosed herein, as well as their salts, solvates, isomers, etc., can be administered to a subject alone or in a composition thereof mixed with one or more biologically suitable and pharmaceutically / veterinary acceptable carriers or excipients. The compositions can be in various forms, including but not limited to oral formulations, injectable formulations, suppositories, and topical, skin, or subcutaneous formulations. The selection of an appropriate formulation of the compounds provided herein can be based, for example, on the physicochemical properties of the compound (and any other optional active agent to be administered), the type of animal being treated, the condition of the animal being treated, and cost.

[0293] The composition may contain at least the compounds or salts described herein and one or more carriers, diluents, excipients, stabilizers, dispersants, suspending agents, and / or thickeners. Specific components and their relative amounts will vary depending on, for example, the intended route of administration. The composition may be formulated to contain a single daily dose or a convenient fraction of a daily dose in dosage units (e.g., a single tablet, a single capsule, a convenient volume of liquid / ointment, etc.). The amount of compounds of the formulas provided above contained in a given composition for use in animal and human health can vary widely. Compounds are typically included in the composition in amounts that are likely to induce the desired effect. Compositions to be administered to a subject or patient are typically in the form of one or more dosage units, wherein, for example, tablets may be single dosage units, and containers of one or more compounds of this disclosure, or their acceptable salts, solvates, stereoisomers, or tautomers, in aerosol form may contain multiple dosage units.

[0294] Compositions for the purposes described in this disclosure can be formulated in a conventional manner using one or more acceptable carriers comprising excipients and adjuvants that facilitate the processing of the active compound into a preparation usable pharmaceutically or veterinarily. Suitable formulations depend on the chosen route of administration. Acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in this disclosure. Such excipients and carriers are described, for example, in “Remington’s Pharmaceutical Sciences,” Mack Publishing Co., New Jersey (1991). Generally, compositions of the disclosed compounds can be prepared in ways known per se, such as by means of conventional methods of mixing, dissolving, granulating, forming sugar-coated pellets, grinding, emulsifying, encapsulating, embedding, or lyophilizing. Techniques for formulation can be found in references well known to those skilled in the art, such as “Remington’s Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, latest edition.

[0295] oral dosage form

[0296] The compositions described herein can be formulated for oral administration. When intended for oral administration, the pharmaceutical compositions of this disclosure are generally in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms may also be included in forms considered solid or liquid herein.

[0297] Solid dosage forms for oral administration include capsules, tablets, pills, powders, chewable tablets (e.g., flavored formulations), and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicate; b) binders such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants such as glycerin; d) disintegrants such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; and e) solution retarding agents. The dosage forms may contain: f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; i) lubricants, such as talc (powder), calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and j) flavoring agents. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer. When the pharmaceutical composition is in the form of capsules (e.g., gelatin capsules), it may also contain a liquid carrier, such as polyethylene glycol or oil, in addition to the materials disclosed herein.

[0298] Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose / milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells (such as enteric coatings and other coatings well known in the field of pharmaceutical formulation). They may optionally contain light-blocking agents and may have compositions that release (one or more) active ingredients only or preferably in a delayed manner at certain sites in the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes. In some embodiments, capsules (hard or soft capsules) containing compounds of the formula described herein are provided, such as gelatin capsules. In some embodiments, hard gelatin capsules may contain compounds of the formula described herein, mixed with an inert solid diluent such as starch, powdered cellulose (e.g., crystalline cellulose or microcrystalline cellulose), sugar (e.g., fructose, mannitol, or sucrose), cereal flour, calcium carbonate, calcium phosphate, and / or kaolin, which are encapsulated within the capsule. In some embodiments, soft gelatin capsules or liquid gelatin capsules may contain a compound of the formula described herein, which is mixed with water or solvents such as propylene glycol, polyethylene glycol (PEG), and / or ethanol, or with an oily medium such as peanut oil, liquid paraffin, or olive oil, and is encapsulated within the capsule. In some embodiments, such capsules are microcapsules.

[0299] In some embodiments, compositions in tablet form are provided comprising a compound of the formula described herein in combination with one or more pharmaceutically acceptable excipients. Tablets are typically prepared by direct compression (e.g., wet or dry granulation of the ingredients). Excipients suitable for tablet preparation are generally known and include, for example, inert diluents (e.g., starch, lactose, mannitol, powdered sugar, powdered cellulose derivatives, kaolin, calcium carbonate, sodium carbonate, lactose, calcium phosphate, calcium sulfate, sodium phosphate, and / or inorganic salts such as sodium chloride); granulating and disintegrants (e.g., starches such as corn starch or potato starch, clay, cellulose, methylcellulose, carboxymethylcellulose, alginate and / or alginic acid, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, guar gum, citrus pomace, and / or sodium lauryl sulfate); binders (e.g., starch, gelatin, sugars (e.g., lactose, fructose, glucose, etc.), natural or synthetic gums such as gum arabic, alginate, methylcellulose, polyvinylpyrrolidine, etc.), polyethylene glycol, ethylcellulose, and / or waxes; and lubricants (e.g., magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, and / or talc (powder)). Tablets may be uncoated or coated using known techniques (which can be used to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time). For example, in some embodiments, delay-release materials such as glyceryl monostearate or glyceryl distearate may be used. Tablets may also be optionally coated using techniques described in U.S. Patent No. 4,256,108 to Theeuwes; U.S. Patent No. 4,166,452 to Generales Jr.; and U.S. Patent No. 4,265,874 to Bonsen et al., the portions of these patents relating to the preparation of osmotic therapeutic tablets for controlled release are incorporated herein by reference in their entirety. Lozenges are examples of tablets and are typically formulated as small, hard tablets that dissolve slowly when placed under the tongue. Tablets may optionally be coated, for example, with sugar as a flavoring agent and sealant, or with film-forming protectants to modify the dissolution properties of the tablet.

[0300] The compositions of this disclosure may be in liquid form, such as elixirs, syrups, solutions, emulsions, or suspensions. As two examples, the liquids may be intended for oral administration or for delivery by injection. When intended for oral administration, in addition to one or more compounds of this disclosure or their acceptable salts, solvates, stereoisomers, or tautomers, the compositions of this disclosure typically also contain one or more sweeteners, preservatives, dyes / colorants, and flavor enhancers.

[0301] In some embodiments, compositions comprising compounds according to Formula I as described herein are provided in the form of emulsions, such as oil-in-water or water-in-oil emulsions. The oil phase of the emulsion may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture of any such oils. In some embodiments, the oil phase is formed from unsaturated polysaccharide-based glycerides, triglycerides (e.g., medium-chain triglycerides, such as C8-C10 caprylic / capric triglycerides), or combinations thereof. The aqueous phase may comprise water or glycol derivatives (e.g., propylene glycol, glycol ethers, polyethylene glycol, or glycerol). Specific examples include, but are not limited to, propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, and mixtures thereof. Suitable emulsifiers may include, for example, naturally occurring phospholipids (e.g., soybean, lecithin), and esters or metaesters derived from fatty acids and hexitanhydrides (e.g., sorbitan monooleate), and condensation products of the aforementioned metaesters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may optionally contain sweeteners, bittering agents, flavoring agents, and / or preservatives. In one embodiment, the emulsion is in the form of a microemulsion (consisting of a stable dispersion of aqueous droplets in an oil phase or a stable dispersion of oil droplets in an aqueous phase). Microemulsions are quaternary systems comprising an aqueous phase, an oil phase, a surfactant, and a co-surfactant. They are translucent and isotropic liquids. The size of these droplets is less than 200 nm (in contrast to droplets with sizes from about 1000 nm to 100,000 nm used in emulsions). In some embodiments, the oil phase will comprise the microemulsion in the range of % v / v selected from: about 2 to about 15%, about 7 to about 10%, and about 8 to about 9% v / v. Typically, the aqueous phase will comprise the microemulsion in the proportion of about 1 to about 4% v / v. The interfacial film consists of alternating surfactant (SA) and co-surfactant (Co-SA) molecules, which allows the microemulsion to form spontaneously by reducing interfacial tension. Surfactants used in microemulsions include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolyzed C8-C10 glycerides, or polyglycerol-6 dioleate. In addition to these surfactants, co-surfactants include short-chain alcohols such as ethanol and propanol. Some compounds are common to the three components discussed above: the aqueous phase, the surfactant, and the co-surfactant. However, using different compounds for each component in the same formulation is entirely within the skill level of a practitioner. In one embodiment, the ratio of co-surfactant to surfactant will be from about 1 / 7 to about 1 / 2. In another embodiment, the microemulsion will contain about 25% to about 75% v / v of surfactant and about 10% to about 55% v / v of co-surfactant.

[0302] In some embodiments, compositions comprising compounds according to Formula I as described herein are provided as suspensions, said suspensions typically comprising said compound dispersed in a liquid (optionally together with other ingredients). The compounds are typically in the form of dispersible powders or granules; dispersible powders and granules suitable for preparing suspensions typically provide an active ingredient mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified as mentioned above. Additional excipients, such as sweeteners, bittering agents, flavoring agents, and coloring agents, may also be present. The liquid may be oily or aqueous. Oily suspensions can be formulated by suspending said compound in vegetable oils (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (e.g., liquid paraffin). Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as sucrose, saccharin, or aspartame), bittering agents, and flavoring agents can be added to provide palatable oral formulations. These compositions can be preserved by adding antioxidants such as ascorbic acid or other known preservatives. Aqueous suspensions contain compounds mixed with excipients suitable for preparing aqueous suspensions. For example, such aqueous suspensions may contain excipients that act as suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents may be naturally occurring phospholipids (e.g., lecithin), or condensation products of ethylene oxide and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxycetyl alcohol), or condensation products of ethylene oxide and esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide and esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene dehydrated sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (e.g., ethylparaben or n-propylparaben), one or more colorants, one or more flavoring agents, and one or more sweeteners and / or bittering agents, as described above. Aqueous suspensions may contain, for example, juice (such as apple juice or orange juice).

[0303] In some embodiments, compositions comprising compounds according to Formula I as described herein are provided in the form of syrups or elixirs. Syrups and elixirs may be formulated with sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose. Such formulations may also contain modifiers, preservatives, one or more flavoring agents, and / or one or more coloring agents.

[0304] In some embodiments, compositions comprising compounds of formula I as described herein are in paste form. Examples of embodiments in paste form include, but are not limited to, those described in U.S. Patent No. 6,787,342 to Chen; U.S. Patent No. 7,001,889 to Freehauf et al.; and U.S. Patent No. 7,563,773 to Freehauf, each of which is incorporated herein by reference in its entirety. In addition to the compounds(s) disclosed herein, the paste may also contain components including, for example, vapor-deposited silica; viscosity modifiers (e.g., selected from PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene (20) sorbitan monooleate (polysorbate 80 or Tween 80), and polyoxamer (e.g., Pluronic L 81)); carriers (e.g., hydrophilic carriers selected from triacetin, monoglycerides, diglycerides, and triglycerides); optionally, absorbents (e.g., selected from magnesium carbonate, calcium carbonate, starch, and cellulose and their derivatives); and optionally, colorants (e.g., selected from iron oxide and FD&C Blue #1 aluminum lake), stabilizers, surfactants, and / or preservatives.

[0305] Sustained-release formulations can also be prepared. Examples of sustained-release formulations may include semi-permeable matrices of solid hydrophobic polymers, which may contain compounds or salts, and these matrices may be in the form of molded articles (e.g., membranes or microcapsules). Examples of sustained-release matrices may include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide, copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid esters, non-degradable ethylene-vinyl acetate, and degradable lactic acid-glycolic acid copolymers such as LUPRON DEPO. TM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0306] injectable form

[0307] The compositions described herein can be formulated as injections for administration. Compositions intended for injection may include one or more of surfactants, preservatives, wetting agents, dispersants, suspending agents, buffers, stabilizers, and isotoners. Non-limiting examples of formulations for injection may include sterile suspensions, solutions, or emulsions in oily or aqueous media. Suitable oily media may include, but are not limited to, lipophilic solvents or media such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. Suspensions may also contain suitable stabilizers. Injections may be formulated for bolus injection or continuous infusion. Alternatively, the compositions described herein may be lyophilized or in powder form for reconstitution with a suitable media such as sterile, pyrogen-free water prior to use.

[0308] For parenteral administration, compounds or salts can be formulated in combination with pharmaceutically acceptable parenteral mediators in a unit-dose injectable form (e.g., use letter solutions, suspensions, emulsions). Such mediators can be inherently non-toxic and non-therapeutic. Mediators can be water, saline, Ringer's solution, dextran solution, and 5% human serum albumin. Non-aqueous mediators such as triacetin, butyl diethylene glycol, miglyol, N-methylpyrollidinone, benzyl benzoate, glyceryl formaldehyde, dipropylene glycol monomethyl ether, tetraethylene glycol, non-volatile oils, and ethyl oleate can also be used. Liposomes can be used as carriers. Mediators may contain trace amounts of additives, such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0309] The liquid compositions of this disclosure, whether solutions, suspensions, or other similar forms, may contain one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, physiological saline, Ringer's solution, isotonic sodium chloride, non-volatile oils such as synthetic monoglycerides or diglycerides (which may act as solvents or suspension media), polyethylene glycol, glycerol, propylene glycol, or other solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and tonic agents such as sodium chloride or dextran. Parenteral preparations may be sealed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. In some embodiments, the adjuvant is physiological saline. In some embodiments, the injectable pharmaceutical composition is sterile.

[0310] Another consideration is injectable sustained-release compositions. For example, in some embodiments, the composition comprises biodegradable microparticles having a compound of formula I as described herein distributed among or on a plurality of polymeric microparticles. Suitable biodegradable polymers include, but are not limited to, polylactic acid, polylactide (PLA), poly(lactic-co-glycolic acid), poly(lactide-co-glycolic acid) (PLGA), polyphosphazine, polyimide carbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acids, and combinations thereof. Particle size may vary, but is generally in the range of about 10 to about 200 micrometers, such as particles having an average particle size of about 40 to about 150 micrometers. Methods for preparing such microparticles are generally known in the art. An example of a suitable method for preparing biodegradable polymeric microparticles is described in U.S. Patent Application Publication No. 2024 / 0238204, which is incorporated herein by reference in its entirety.

[0311] Other dosage forms

[0312] The compositions disclosed herein are intended for topical application, in which case the carrier may suitably comprise a solution, emulsion, ointment, or gel matrix. For example, the matrix may comprise one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents (such as water and alcohol), and emulsifiers and stabilizers. Thickeners may be present in the pharmaceutical compositions for topical application.

[0313] In some embodiments, compositions are provided comprising compounds of formula I as described herein, suitable for topical, dermal, and / or subcutaneous formulations. Topical, dermal, and subcutaneous formulations may include, for example, emulsions, creams, ointments, gels, pastes, powders, patches, shampoos, pour-on formulations, ready-to-use formulations, spray formulations, and spot-on formulations. Such formulations may be, for example, concentrated solutions, suspensions, microemulsions, or emulsions. In some embodiments, topical application may allow distribution of one or more active compounds via the animal's glands (e.g., sebaceous glands), and / or allow one or more active compounds to achieve a systemic effect (plasma concentration), and / or allow distribution throughout the haircoat. Certain suitable formulations for topical, dermal, and / or subcutaneous applications include, but are not limited to, those disclosed in U.S. Patent No. 6,395,765 to Etchegaray, which is incorporated herein by reference in its entirety.

[0314] Spotting compositions are typically applied to localized areas, meaning areas other than the whole animal. Spotting compositions are usually applied by applying the composition at a specific location on the animal (e.g., between the shoulders). Another embodiment of a localized area is a strip, for example, a strip from the animal's head to its tail. Such compositions can be applied, for example, using a pipette, squeezer, or drop-on.

[0315] The carrier may be a liquid carrier medium as described in U.S. Patent No. 6,426,333, which is incorporated herein by reference in its entirety. For example, in one embodiment, the dot application formulation comprises a solvent and a co-solvent, wherein the solvent is selected from acetone, acetonitrile, benzyl alcohol, butyl diethylene glycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycol, propylene glycol, 2-pyrrolidone (e.g., N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate fatty acid esters such as diethyl phthalate or diisobutyl adipate, and mixtures of at least two of these solvents, and the co-solvent is selected from anhydrous ethanol, isopropanol, or methanol. The liquid carrier medium may optionally contain a crystallization inhibitor selected from anionic surfactants, cationic surfactants, nonionic surfactants, amine salts, amphoteric surfactants, or copolymers of polyvinylpyrrolidone, polyvinyl alcohol, vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylene sorbitan ester; lecithin, sodium carboxymethyl cellulose and acrylic derivatives, or mixtures of these crystallization inhibitors.

[0316] Pouring compositions are typically applied by pouring the composition along the animal's dorsal line (e.g., from the neck to the tail). Pouring formulations are advantageously oily and typically contain a diluent or medium, and if the active ingredient is insoluble in the diluent, also contain a solvent (e.g., an organic solvent) for the active ingredient. Certain non-limiting pouring compositions are disclosed, for example, in U.S. Patent No. 6,010,710 to Etchegaray and U.S. Patent No. 8,097,266 to Gogolewski et al., which are incorporated herein by reference in their entirety.

[0317] Spray compositions are typically used by spraying the composition along the animal's back line (e.g., from the neck to the tail). Each of these compositions may involve applications such as concentrated solutions, suspensions, microemulsions, or emulsions.

[0318] Such topical compositions (e.g., dotting, spraying, and pouring compositions) may typically contain compounds as provided herein in combination with one or more diluents / media and / or one or more solvents. Diluents / media include, but are not limited to: vegetable oils (e.g., soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grapeseed oil, sunflower oil, etc.); mineral oils (e.g., petrolatum, paraffin, silicone, etc.); aliphatic or cyclic hydrocarbons; medium-chain (e.g., C8 to C12) triglycerides, and combinations thereof. In some embodiments, solvents (e.g., organic solvents) that may be added include, but are not limited to, acetyl tributyl citrate, fatty acid esters such as dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diethylene glycol, dimethyl acetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethyl acetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycol, propylene glycol, 2-pyrrolidone (e.g., N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol, and diethyl phthalate, and mixtures of two or more of these. In some embodiments, the composition includes a softener and / or a spreader and / or a film-forming agent. Softeners and / or spreaders and / or film-forming agents may be selected, for example, from: polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerin, sorbitol, polyoxyethylene sorbitan ester; lecithin, sodium carboxymethyl cellulose, silicone oil, polydiorganosiloxane oil (such as polydimethylsiloxane (PDMS) oil), such as those containing silanol functional groups, or 45V2 oil; anionic surfactants such as basic stearates, sodium stearate, potassium stearate, or ammonium stearate; calcium stearate, triethanolamine stearate; sodium rosinate; alkyl sulfates (such as sodium lauryl sulfate and sodium cetyl sulfate); sodium dodecylbenzene sulfonate, sodium dioctyl sulfosuccinate; fatty acids (such as those derived from coconut oil); cationic surfactants such as water-soluble quaternary ammonium salts of the formula N+R′R″R′″R″″, Y-. The following are possible formulations: wherein the group R is optionally a hydroxylated hydrocarbon group, and Y- is an anion of a strong acid, such as a halide, sulfate, or sulfonate anion; cetyltrimethylammonium bromide is one of the cationic surfactants that can be used; an amine salt of the formula N+R′R″R′″, wherein the group R is optionally a hydroxylated hydrocarbon group (e.g., octadecylamine hydrochloride); a nonionic surfactant such as sorbitan ester, which is optionally polyoxyethyleneized (e.g., polysorbate 80); a polyoxyethyleneized alkyl ether; a polyoxypropylene-styrene alcohol, such as polyoxypropylene-styrene ether; polyethylene glycol stearate, a polyoxyethyleneized derivative of castor oil, a polyglycerol ester; a polyoxyethyleneized fatty alcohol; a polyoxyethyleneized fatty acid, a copolymer of ethylene oxide and propylene oxide; an amphoteric surfactant such as a substituted lauryl betaine compound; and a mixture of at least two of these agents.

[0319] The compositions disclosed herein are intended for rectal administration, for example in the form of suppositories, which will dissolve and release the drug in the rectum. Compositions for rectal administration may contain an oily matrix as a suitable, non-irritating excipient. Such a matrix may include, but is not limited to, lanolin, cocoa butter, and polyethylene glycol.

[0320] The compositions of this disclosure can comprise a variety of materials in physical form that modify solid or liquid dosage units. For example, the composition can comprise a material that forms a coating around the active ingredient. The material forming the coating is typically inert and can be selected from, for example, sugars, shellac, and other enteric coating agents. Alternatively, the active ingredient can be encapsulated in gelatin capsules.

[0321] The activity of the compound

[0322] The compounds and compositions provided herein may be active against one or more different parasites. For example, in some embodiments, certain compounds and compositions comprising such compounds are effective against a single species or genus of parasite. In some embodiments, certain compounds and compositions comprising such compounds are effective against a broad spectrum of parasites.

[0323] In some embodiments, the compounds of this disclosure exhibit anthelmintic activity. In some embodiments, the compounds of this disclosure exhibit selective anthelmintic activity at the larval stage of the parasite. For example, in some embodiments, the compounds of this disclosure exhibit anthelmintic activity against L1 stage *Heartworm* (canine heartworm). In some embodiments, the compounds of this disclosure have selective activity against L3 / L4 stage *Heartworm* (canine heartworm). In some embodiments, the compounds of this disclosure exhibit activity against L3 stage *Haemaphysalis contortus* (*Haemaphysalis twistutus*). Haemonchus contortus Selective insecticidal activity against *Barber's Pole worm*. In some embodiments, the compounds of this disclosure exhibit selective insecticidal activity against the genus *Barber's Pole worm*. Ancylostoma ) species, genus *Platycodon* ( Necator ) species, genus *Yangkou* ( Bunostomum The compounds of this disclosure exhibit anthelmintic activity against hookworm species or combinations thereof (the cause of hookworm infection in humans and / or animal hosts). In some embodiments, the compounds of this disclosure exhibit anthelmintic activity against canine hookworm. Therefore, in some embodiments, the compounds of this disclosure can be used for the prevention or treatment of hookworm infection, for example, in dogs.

[0324] As described below, the activity (i.e., potency) against parasites, including but not limited to heartworm and Haemaphysalis contortus, can vary. In some embodiments, the compounds of this disclosure may be described as having a degree of potency at a specific time point after application, or having potency that persists for a period of time after application, and / or having potency over a period of time and specifically against a particular life stage of the parasite. In some embodiments, potency is measured in terms of the minimum effective concentration for eliminating larval motility. Determination of potency is known in the art and includes, but is not limited to, in vitro assays, such as those described in Examples 10-12 and 14 of this disclosure.

[0325] Not wishing to be bound by any particular theory, it is believed that the anthelmintic activity of the compounds disclosed herein is a result of the activation of SLO-1 ion channels in the parasite. This activity has been observed in *C. elegans* (…). C. elegans Two similar types of calcium-activated potassium channels (SLO-1 and SLO-2) were identified in the study. Although these channels share some similar motif sequences, they differ significantly in their regulation by intracellular ions. For example, SLO-2 is regulated by intracellular Na+ and Cl-, while SLO-1 is primarily regulated by intracellular Ca2+. 2+ Regulation of SLO-1 K channels. SLO-1 K channels have large (~200 pS) conductance and are sometimes referred to as “large” potassium (BK) channels, maxi-K channels, or SLO family channels. The proposed function of SLO-1 K channels is that they regulate the resting membrane potential of electroexcitable cells and modulate excitability levels (up- or down-regulation), thereby affecting responses to other inputs. Again, it is not intended to be theoretically correct, but it is believed that in some embodiments, the compounds of this disclosure selectively activate nematode SLO-1 channels. Assays to determine SLO-1 activity are known in the art and include, but are not limited to, in vitro assays, such as those described in Example 13 of this disclosure.

[0326] Methods for treating and / or preventing parasitic infections

[0327] This disclosure provides methods for preventing, treating, and / or controlling parasitic intrusions and / or infections or parasitic diseases, such as in animals. Parasitic intrusions or infections can be caused by ectoparasites or endoparasites. In some embodiments, the methods are methods for treating parasitic diseases (i.e., diseases caused by one or more of the parasites described herein). The methods include administering an effective amount of a compound or veterinary / pharmaceutical composition as described herein to the animal. It is noted that pharmaceuticals and veterinary compositions are generally provided in dose units; according to the disclosed methods, one or more such dose units may be administered to the animal.

[0328] application

[0329] The route of administration may depend on, for example, the type and extent of the infection, invasion, or disease being treated, and / or the type of animal. In some embodiments, those skilled in the art will be able to select a suitable composition as described above for the desired route of administration. Thus, one or more of the compounds or compositions described herein may be administered to a subject enterically (e.g., orally or rectally), topically, or parenterally (e.g., intravenously, intramuscularly, or subcutaneously).

[0330] The amount of compound or composition administered to animals requiring prevention or treatment can vary considerably. The amount of compound administered can depend on factors such as: the potency of the compound, the type of animal being treated, the animal's weight, the animal's age, the desired effect, and the type and severity of the invasion / infection to be prevented or treated.

[0331] Therefore, the amount of compound or composition administered to a subject requiring treatment can vary considerably. The amount of compound administered can depend on factors such as: the potency of the compound, the type of subject being treated, the subject's weight, the subject's age, the desired effect, and the nature and severity of the disease. It should be understood that the dosage can vary depending on each subject's needs and the severity of the disorder or disease being treated. Those skilled in the art will be able to determine the specific effective dosage. Generally, a therapeutically effective dosage is an amount of compound or composition sufficient to provide a beneficial effect to the subject administering the compound or composition or to otherwise reduce harmful non-beneficial events. A therapeutically effective dosage can be a dosage that produces one or more desired or desirable (e.g., beneficial) effects as intended by administering that dosage, and such administration occurs once or multiple times over a given period of time. Furthermore, it should be understood that an initial, higher dose (i.e., one or more loading doses) can be administered to rapidly achieve the desired plasma concentration. On the other hand, the initial dose may be less than the optimal dose, and the daily dose may be gradually increased during the treatment process (i.e., dose adjustment) depending on the specific circumstances.

[0332] The administration of the compounds or compositions provided herein can vary in duration of treatment. For example, administration can be intermittent and can be performed daily, weekly, bi-weekly, monthly, bi-monthly, quarterly, or even longer durations. In some embodiments, the desired dose may be administered as a single dose or as separate doses administered at appropriate intervals, such as two, three, four, or more sub-dose daily. The sub-dose itself can be further subdivided, for example, into a number of discrete, loosely spaced administrations, such as multiple oral dosage forms. In some embodiments, administration is performed daily for at least one, two, three, one, or two weeks, or for a period of six months, one year, or many years, including the lifetime of the subject. The duration of treatment can depend on factors such as the parasite(s) being treated, the degree of invasion, the type of animal being treated, and the environment in which the animal inhabits. Those skilled in the art will be able to develop specific administration regimens for particular situations.

[0333] In some embodiments, the compounds or compositions provided herein are administered as a once-daily dose over a period of time, said period ranging from one day to several days, weeks, months, or years. In some embodiments, the compounds or compositions provided herein are administered two, three, four, or more times daily. In some embodiments, the compounds or compositions provided herein are administered as a single dose monthly, every three months, every six months, or annually.

[0334] Those skilled in the art will understand that the optimal amount and interval of a single dose of a compound as described herein, or a composition comprising a compound as described herein, will depend on the characteristics and extent of the condition being treated, the form, route, and site of administration, and the age and condition of the specific subject being treated, and the physician or veterinarian will ultimately determine the appropriate dose, frequency, and duration of treatment to be used. The selected dose may be repeated as appropriate. If side effects occur, the amount and / or frequency of the dose may be modified or reduced according to routine clinical practice. Those skilled in the art will be able to develop specific administration regimens for particular situations.

[0335] animal

[0336] The animal to which the disclosed compound and / or composition is administered according to the disclosed method can be any type of animal, such as mammals, birds, and fish. The animal can be at any developmental stage, including embryonic and fetal stages. The animal can be of any age; in some embodiments, the method relates to the treatment of adult animals. In some embodiments, the method relates to the treatment of juvenile animals. In some embodiments, the method relates to the treatment of mammals. In some embodiments, these methods relate to the treatment of companion animals (e.g., dogs, cats, llamas, and horses). In some embodiments, the method relates to the treatment of livestock (e.g., pigs, camels, rabbits, goats, sheep, deer, moose, cattle, and bison). Certain animals that can be effectively treated include, but are not limited to: humans, cattle, bison, pigs, sheep, deer, moose, horses, pigs, chickens, and dogs, as well as horses, zebras, goats, llamas, alpacas, camels, yaks, buffalo, donkeys, mules, fallow deer, reindeer, cats, rabbits, rodents, fur-bearing animals (such as mink, chinchillas, raccoons), birds (such as hens, chickens, geese, turkeys, quails, ostriches, and ducks), and fish (such as those belonging to the classes Chondrichthyes (e.g., sharks and rays) and Osteichthyes (bone fish), including but not limited to sharks, salmon, trout, whitefish, catfish, tilapia, sea bass, tuna, halibut, turbot, flatfish, sole, striped bass, eels, yellowtail, grouper, etc.). In some embodiments, the animal being treated is a human, and in other embodiments, the animal being treated is a non-human animal. In a specific embodiment, the animal is a companion animal, such as a dog or a cat. In a specific embodiment, the animal is a dog.

[0337] Pests and parasites

[0338] Parasitic infestations and / or infections treated according to the methods provided herein can originate from various types of pests. Animal pests can be, for example, ectoparasites. In some embodiments, the pests are ectoparasites selected from insects, arachnids, fleas, ticks, mites, mosquitoes, flies, lice, and / or blowflies. In some embodiments, the pests are endoparasites, such as those selected from helminths (e.g., filarial worms), including cestodes, roundworms, and trematodes (flatworms or flukes). In some embodiments, the compounds and compositions provided herein are active against both ectoparasites and endoparasites.

[0339] In some implementations, the pests are ectoparasites from the following genera: Anoplura, such as *Haematopinus* spp., *Linognathus* spp., *Solenoptes* spp., *Pediculus* spp., and *Pthirus* spp.; Mallophaga, such as *Trimenopons* spp., *Menopon* spp., *Eomenacanthus* spp., *Menacanthus* spp., *Trichodectes* spp., *Felicola* spp., *Damalinea* spp., and *Bovicola* spp.; and Brachycera, Diptera, such as *Chrysops* spp. and *Tabanus* spp. spp.), Musca spp., Hydrotaea spp., Muscina spp., Haematobosca spp., Haematobia spp., Stomoxys spp., Fannia spp., Glossina spp., Luculida spp., Calliphora spp., Auchmeromyia spp., Cordylobia spp., Cochliomyia spp., Chrysomyia spp., Sarcophagas spp., Wohlfahrtia spp., Gasterophilus spp., Oedemagena spp., genus *Hypoderma* spp., genus *Oestrus* spp., genus *Rhinoestrus* spp., genus *Melophagus* spp., genus *Hippobosca* spp.; from the suborder Nematocera of Diptera, such as genus *Culex* spp., genus *Aedes* spp., genus *Anopheles* spp., genus *Culicoides* spp., genus *Phlebotomus* spp., genus *Simulium* spp.From the order Siphonaptera, such as *Ctenocephalides* spp., *Echidnophaga* spp., *Ceratophyllus* spp., and *Pulex* spp.; from the suborder Metastigmata, such as *Hyalomma* spp., *Rhipicephalus* spp., *Boophilus* spp., *Amblyomma* spp., *Haemaphysalis* spp., *Dermacentor* spp., *Ixodes* spp., *Argas* spp., and *Otobius* spp.; from the order Mesostigmata, such as *Dermanyssus* *Ornithonyssus* spp., *Pneumonyssus* spp.; from the order Prostigmata, such as *Cheyletiella* spp., *Psorergates* spp., *Myobia* spp., *Demodex* spp., *Neotrombicula* spp.; from the order Astigmata, such as *Acarus* spp., *Myocoptes* spp., *Psoroptes* spp., *Chorioptes* spp., *Otodectes* spp., *Sarcoptes* spp., *Notoedres* spp., *Knemidocoptes* spp. *Laminosioptes* spp., *Neoknemidocoptes* spp., *Cytodites* spp., and fleas (Siphonaptera, such as *Ctenophora*, *Corydalis*, *Lepidoptes*, and *Tectus*), ticks (*Hypertricis*, *Tectus*, *Tectus*, *Tectus*, *Tectus*, *Tectus*, and *Tectus*).

[0340] In some implementations, the parasite is an animal parasite (i.e., a parasite that causes infection in animals such as mammals). The disclosed compounds and compositions are effective against specific, non-restricted animal parasites, including but not limited to cat and dog fleas (Ctenocephalides felis, Ctenocephalides, etc.), ticks (Amblyoma, Amblyoma, Amblyoma, Amblyoma, etc.), mites (Dmodex, Sarcoptes (e.g., Sarcoptes scabici), Octodectes, Psoroptes (e.g., Psoroptesovis), lice (Hypertricis, Amblycium, Lignonoathus, etc.)), mosquitoes (Aedes, Culex, Anopheles, etc.), and flies (Hornflies (e.g., Haematobia irritans)). *Fly* species include *Musca domestica*, *Stomoxys calcitrans / stable fly*, *Dematobia spp.*, and *Cochliomyia hominivorax*. Other non-restrictive parasites include parasites of the genus *Ixodes* (e.g., parasites of *Ixodes microticus*, *Ixodes leucopus*, and *Ixodes annularis*); parasites causing myiasis, such as *Dermatobia hominis* and *Cochliomyia hominivorax*; parasites causing myiasis in sheep, such as *Lucilia sericata* and *Lucilia cuprina*; and migrating dipteran larvae.

[0341] In some implementations, the animal pests are endoparasitic pests, including but not limited to *Anaplocephala*, *Anecator* (e.g., *Ancylostoma duodenale*), *Anecator*, *Ascaris*, *Capillaria*, *Caenorhabditis*, *Cooperia*, *Dipylidium*, *Dipyllidinum*, and *Filaria* (e.g., *Filaria canis*). D. immitis), creeping filarial worms (D. repens), D. ursi, D. tenuis, D. spectans, D. lutrae, etc.), genus Echinococcus, genus Enterobius, genus Fasciola, genus Haemaphysalis (e.g., Haemaphysalis contortus), genus Oesophagostumum, genus Ostertagia, genus Parascaris, genus Toxocara, genus Strongyloides, genus Toxascaris, genus Trichinella, genus Trichuris (e.g., Trichuris trichiura), and genus Trichostrongylus. Other non-limiting examples of pests are filamentous nematodes in the family Onchoceridae, including, for example, genera such as *Brugia*, *Wucheria*, *Dipetalonoma* (e.g., *D. reconditum*, *D. repens*), *Necator americanus* (e.g., *Necator americanus*), *Onchocerca*, *Elaeophora* (e.g., *E. Bohmi*, *E. elaphi*, *E. poeli*, *E. sagitta*, *E. schneideri*), *Mansonella* (e.g., *M. ozzardi*, *M. perstans*), and *Loa* (e.g., *L. loa*).

[0342] In some embodiments, the compounds or compositions provided herein are used to treat or prevent diseases caused by worm infections (e.g., filariasis). In some embodiments, the compounds or compositions provided herein are used to treat diseases caused by parasitic infections (including, but not limited to, heartworm disease, ascariasis, whipworm disease, schistosomiasis, schistosomiasis, onchocerciasis, and lymphatic filariasis).

[0343] Parasitic diseases can be associated with any of the parasites disclosed herein (e.g., worms, including nematodes, tapeworms, and trematodes; insects, arachnids, or arthropods, including lice, fleas, flies, ticks, etc.). In some embodiments, the parasitic disease is selected from: enterobiasis, oxyuriasis, ascariasis, hookworm disease, tetanus, dracunculiasis, elephantiasis, filariasis (e.g., lymphatic filariasis, Bancroftian filariasis, hypofilariasis, or serious cavityfilariasis), and haemocercariasis (e.g., in sheep and goats, haemocercariasis caused by *Haemocercaria contorta*). ) ), onchocerciasis, schistosomiasis (e.g., urinary schistosomiasis, visceral schistosomiasis, acute schistosomiasis, or intestinal schistosomiasis, such as Asian intestinal schistosomiasis), or whipworm disease.

[0344] In some implementations, the parasite is a fish parasite (i.e., an infecting marine or freshwater fish). Like animals, fish can be infected by parasites, and these parasites can be internal or external. Fish parasites include, but are not limited to, tapeworms (e.g., *Schizothorax spp.*). Schistocephalus solidus ), salmonid trigenella ( Gyrodactylus salaris ) 、 Ichthyophthirius multifiliis (Ichthyophthirius multifiliis) Ichthyophthirius multifiliis Cryptocaryon ( cryptocaryon ), velvet disease, Brook's protozoan ( Brooklynella hostilis Hole in the head, and *Glechomae* (a type of parasite). Glugea ), Ceratomyxa shasta Kudau worm ( Kudoa thyrsite ), mossy salmon tetracystis ( Tetracapsuloides bryosalmonae ), and the shrunken-headed fish louse ( Cymothoa exigua ), leeches, nematodes, flukes, and lice, such as carp lice and salmon lice. In some implementations, the parasites are sea lice, such as those in the genus *Ophiopogon* (fish lice). Caligus ) or scabies lice ( Lepeophtheirus Sea lice. Sea lice are ectoparasites that feed on mucus, blood, and skin, and migrate and attach to the skin of fish such as salmon (farmed or wild) during their free-swimming, planktonic nauplius, or copepod larval stages. In some embodiments, the compounds of this disclosure are effective against parasites of the genus *Ichthyophthirius* or *Ichthyophthirius* in their larval stages. Therefore, in one aspect, a method for treating or preventing sea lice infection in fish is provided, the method comprising administering to the fish an effective amount of a compound of formula I, a salt thereof, or a composition containing said compound or salt. In some embodiments, the fish is salmon.

[0345] In some implementations, the parasitic disease is haemoceriasis, which can be caused by infection with, for example, Haemocera contorta (…). Haemonchus contortus Caused by *Haemaphysalis contortus*, a common and highly pathogenic nematode. The most common hosts are ruminants such as sheep, cattle, and goats. Haemaphysalis infection leads to anemia, edema, depression, and gastrointestinal disturbances, often resulting in host death. Adult female worms are 18–30 mm long and exhibit a distinctive "barber pole" coloration due to their white ovaries coiled around a red, blood-filled intestine. Adult males are smaller (10–20 mm) and display a well-developed copulatory umbrella containing an asymmetrical dorsal lobe and a Y-shaped dorsal rib. Infection is prevalent in tropical and subtropical regions and warm temperate and summer-rainy areas compared to cold temperate and arid regions. The current challenge in treating and preventing haemaphysalis infection is the development of multi-drug resistant strains of *Haemaphysalis contortus*. Haemonchus The widespread presence of strains makes infection control difficult, affects ruminants, and causes anemia, edema, morbidity, weight loss and death in infected animals (such as sheep and goats).

[0346] In the life cycle of *Haemaphysalis contortus*, infected female adults release a large number of eggs in the animal's feces. These eggs then develop into L1 (rod-like) and L2 larval stages, feeding on bacteria in the feces. The L2 rod-like larva sheds its exoskeleton and develops into the L3 infective filamentous larva. Sheep, goats, and other ruminants become infected when they graze and ingest the L3 larvae. The larvae pass through the first three gastric chambers to reach the abomasum, where they shed their exoskeleton and burrow into the inner lining of the abomasum. Once inside, the larvae develop into pre-adult larvae (L4). The L4 larvae then molt and develop into the adult form (L5), at which point they feed on the blood in the abomasum. Male and female larvae mate there and produce fertilized eggs, continuing the life cycle.

[0347] In some embodiments, the cyclic peptides of this disclosure have been found to be highly effective against Haemonchus contortus. Therefore, in one aspect, a method for treating or preventing Haemonchus contortus infection in ruminants is provided, the method comprising administering to the ruminant an effective amount of a compound of formula I, a salt thereof, or a composition comprising said compound or salt.

[0348] In some implementations, the parasitic disease is difilariasis (i.e., heartworm, such as canine heartworm), which can be caused by, for example, *Dicirius canis*, *Dicirius creepingus*, etc. Dirofilaria repens ), Hong Kong filariasis ( Dirofilaria honkongensis It is caused by [the virus]. The most common hosts are dogs and cats, but other mammals such as ferrets and raccoons can also be infected.

[0349] Heartworm infection is a serious and life-threatening disease. Before heartworms become adults that infect the pulmonary arteries of host mammals (especially dogs), they undergo several life stages. The worm requires a mosquito as an intermediate host to complete its life cycle. The period between the initial infection of the host mammal (e.g., a dog) by a mosquito bite and the worm's maturation into an adult living in the heart and pulmonary arteries in dogs is six to seven months and is known as the "latent period." In the life cycle of *Filaria canis*, after feeding on the blood of an infected host (e.g., a dog), the mosquito ingests the microfilariae (first-stage larvae, L1). The L1 larvae develop into second-stage larvae (L2) in the mosquito's Malpighian tubules, followed by the development of third-stage larvae (L3) that enter the mosquito's body cavity. The development from L1 to L3 takes 15–16 days. L3 larvae migrate to the tip of the mosquito's mouth (lip) during the mosquito's blood-feeding process, leave the mosquito, and deposit on the skin of a host mammal (such as a dog), where they then migrate into the host through the bite wound. Most L3 larvae molt into fourth-stage larvae (L4) in the definitive host 0–14 days post-infection. L4 larvae migrate to the subcutaneous membrane and subcutaneous tissue and remain dormant. They then migrate to the muscles of the thorax and abdomen and molt into fifth-stage larvae (L5, immature adults) 45–60 days post-infection. 75–120 days post-infection, these immature heartworms then enter the bloodstream and are transported through the heart, residing in the pulmonary artery. L5 larvae mature into adults, which further migrate to the right ventricle or pulmonary artery 85–120 days post-infection. Adults reach maturity over the next two months, sexually reproduce in the pulmonary artery and right ventricle, and release microfilariae into the bloodstream, repeating this cycle. The male adult is about 15 cm long and the female adult is about 25 cm long, and their normal lifespan as adults is calculated to be about 5 years.

[0350] Treatment of mature heartworm infection with adult-killing drugs (such as melazomin dihydrochloride) is expensive and can cause serious side effects. Therefore, prevention by monthly administration of drugs that interrupt larval development is widely used. Commercially available canine heartworm prophylaxis aims to prevent the parasite from developing into adult heartworms by interrupting the post-infection life cycle of the *Dermatofilaria* genus. Macrolides (MLs; such as ivermectin, irinotecan, milbemex, moxicillin, and silachlor) are the most commonly used chemopreventive agents and have been effective against both infective L3 larvae (L3) and mature L4 larvae of *Dermatofilaria canis*. However, recently, selective resistance to heartworm prophylaxis has been reported in some populations of *Dermatofilaria canis* (“Heartworm Preventive Resistance. Is it Possible?”, Bulletin of the American Heartworm Society, 2010, Vol. 37, p. 5).

[0351] Cyclic peptides with antiparasitic activity are also known. PF-1022a, a 24-membered cyclic octapeptide isolated from the fungus *Mycelia sterilia* by Sasaki et al. (J. Antibiotics 45: 692-697 (1992)), has been found to exhibit broad-spectrum anthelmintic activity against a variety of endoparasites in vivo with low toxicity. These compounds are described, for example, in U.S. Patent Nos. 5,514,773; 5,747,448; 5,646,244; and 5,874,530, which are incorporated herein by reference. emodepside is a semi-synthetic analog of PF-1022a containing a morpholino group at the para-position of the aromatic ring of the phenyl lactate group. emodepside is a potent anthelmintic used in combination with praziquantel in the product PROFENDER® for the treatment of parasites in cats and dogs. However, the antiparasitic activity of PF-1022a and Amedes has not been satisfactory in establishing their use for the treatment of certain parasites, particularly for the control of *Filaria canis* in mammals to prevent heartworm disease. Therefore, there is a need in the art for more effective antiparasitic agents for the treatment and protection of animals against *Filaria canis* and other internal parasites.

[0352] In some embodiments, the cyclic peptides of this disclosure have been found to be highly effective against *Heartworm of Canis Majoris*. Therefore, in one aspect, a method for treating or preventing heartworm in a companion animal is provided, the method comprising administering to the animal an effective amount of a compound of formula I, a salt thereof, or a composition comprising said compound or salt. For the avoidance of doubt, as stated above, references to compounds of formula I encompass regioisomers, such as compounds of formulas II-IX.

[0353] In some implementations, the parasitic disease is a helmintic disease caused by infection with various types of roundworms. In some implementations, the roundworm is a hookworm. Hookworms are intestinal, blood-sucking, parasitic roundworms. The worm's head is curved relative to the rest of its body, forming a hook at the anterior end. Hookworms have a well-developed mouth, with two pairs of teeth or a pair of cutting plates within the buccal capsule, depending on the species. Hookworms are approximately 5 to 10 mm × 0.5 mm in size, with females typically being longer and thicker than males. At least 68 species of hookworms have been described in wild mammals. In humans, hookworm infection is caused by two main groups of species belonging to the genera *Hexata* and *Isodon*. Domestic cats are commonly infected with *Ahrenia brasiliensis* (Brazilian hookworm). Ancylostoma braziliense ) and hookmouth nematode ( Ancylostoma tubaeforme Dogs are usually infected with hookworm, and cattle are usually infected with bovine hookworm. Bunostomum phlebotomum ).

[0354] Hookworm infection is found in many parts of the world and is common in areas where clean water, sanitation, and personal hygiene are difficult to access. Hookworms thrive in areas with sufficient rainfall to keep the soil moist and high temperatures, making rural and coastal areas ideal for parasite reproduction. The host (human or animal) is infected by the larvae, not the eggs, usually through the skin. The first-stage larvae (L1) are non-infectious; once they hatch in deposited feces, they feed on fecal matter and soil microorganisms until they molt into the second-stage larvae (L2). The first and second-stage larvae are in the rod-like stage. After feeding for about seven days, they molt into the third-stage larvae (L3), also known as the filamentous stage, which is non-feeding and infectious. Filamentous larvae can survive for up to two weeks and are highly motile. Once the L3 larvae have entered the host, they reach the lungs in the circulatory system, where they enter the alveoli, then travel up the trachea, are coughed up, swallowed, and eventually reach the small intestine. In the small intestine, the larvae molt into stage four (L4; adult), and it takes five to nine weeks from skin penetration to maturity in the intestine. Adults mate inside the host, and the females lay eggs inside the host. The eggs are excreted into the environment in the host's feces, and the cycle begins again.

[0355] The signs and symptoms of hookworm infection vary depending on the host and the hookworm species. In humans, the first signs of infection are itching and a rash. People with mild infections may be asymptomatic, but those with severe infections may experience abdominal pain, diarrhea, loss of appetite, weight loss, fatigue, and anemia. Dogs and cats may experience dermatitis, enteritis, and intestinal bleeding. Dogs may also experience anemia, hemorrhagic diarrhea, anorexia, and dehydration. Cattle may experience skin lesions, anemia, and rapid weight loss.

[0356] In some embodiments, the cyclic peptides of this disclosure have been found to be highly effective against canine hookworms. Therefore, in one aspect, a method for treating or preventing hookworm in mammals is provided, the method comprising administering to the mammal an effective amount of a compound of formula I, a salt thereof, or a composition comprising said compound or salt. For the avoidance of doubt, as stated above, references to compounds of formula I encompass regioisomers, such as compounds of formulas II-IX. In some embodiments, the mammal is a human, dog, cat, or cattle.

[0357] Combination therapy

[0358] In some embodiments, prevention or treatment is achieved by administering the compound as provided herein together with an additional active agent as part of a combination therapy. In the context of combination with an additional active agent or combination therapy, the term "combination" includes the co-administration of the compound of this disclosure with an additional active agent; the administration of the compound of this disclosure followed by the administration of an additional active agent; or the administration of an additional active agent followed by the administration of the compound of this disclosure. Such combinations may include, for example, the administration of a single veterinary / pharmaceutical composition comprising both the compound of this disclosure and an additional active agent, or the administration of two (or more) active agents independently (e.g., as two separate compositions).

[0359] In some embodiments, by providing such combination therapy, the compounds and compositions provided herein can control a variety of pests, or can control certain pests at multiple life stages. In some embodiments, it may be advantageous to apply such compounds or compositions in combination with compounds known to be effective against other parasites or their life stages.

[0360] Various veterinary therapeutic agents that can be used for such combination therapies (either by incorporation into compositions as provided herein or by administration alone) are known in the art. See, for example, Plumb's Veterinary Drug Handbook, 5th edition, edited by Donald C. Plumb, Blackwell Publishing, (2005) and The Merck Veterinary Manual, 9th edition (January 2005), which are incorporated herein by reference in their entirety. Specific examples of suitable alternative active agents include, but are not limited to: acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetylhydroxylamine, acetylcysteine, acitretin, acyclovir, albendazole, salbutamol sulfate, alfentanil, allopurinol, alprazolam, allylprogesterone, amantadine, amikacin sulfate, aminocaproic acid, aminovaleramide bisulfate, aminophylline / theophylline, amiodarone, amitracetamol, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphotericin B deoxycholate, and amphotericin B lipid-based (amphotericin B) Lipid-based drugs, ampicillin, amprofen, antacids (oral), antivenom, apomorphine, ampicillin sulfate, ascorbic acid, asparaginase, aspirin, atenolol, atemetazole, atracurium besylate, atropine sulfate, aurnofin, glucosinolate, chlorpyrifos (e.g., avermectin, dimethicone, doxycycline, emamectin, irinotecan, iramectin, lepimectin, moxicidin, silacycline, etc.), azapirolone, azathioprine, azithromycin, baclofen, barbiturates. ates), benazepril, betamethasone, clobetacholine, bisacodyl, bismuth subsalicylate, bleomycin sulfate, pevidone undecanoate, bromide, bromocriptine mesylate, budesonide, budenoside, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, salmon calcitonin, calcitriol, calcium salts, canbendazole, captopril, benzylindoxime sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, closulon, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, ceftriaxone sodiumSodium), cephalexin, cephalosporins, cefepime, (activated) charcoal, chlorambucil, chloramphenicol, chlorazine, chlorazine + / - cristatin, chlorothiazide, chlorpheniramine, chlorpromazine, chlorpropamide, chlortetracycline, human chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clomastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, dipotassium chlorazine, closulone, cloxacillin, codeine phosphate, colchicine, adrenocorticotropic hormone (ACTH), octadecosyl-2-tetrapeptide adrenocorticotropic hormone, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, actinomycin D (dactinomycin / actinomycin) D) Dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinone ester, deferroamine mesylate, demiditraz, delacoxib, diloxacin acetate, desmopressin acetate, desoxycorticosterone pitavaate, detoximide, dexamethasone, dextropanol, dexraazoxane, dextran, diazepam, diazoxide (oral), dichlorphenamide, diclofenac sodium, dicloxacin, ethamazol, ethamazol citrate, diethylstilbestrol (DES), diflufloxacin, digoxin, dihydrotamethasone (DHT), diltiazem, dimenhydrinate, dimercaprol / BAL, dimethyl sulfoxide, tromethamine dinoprost Diphenylhydramine, disopyramide phosphate, dobutamine, docusate / DSS, dolasetron mesylate, domperidone, dopamine, dolacritin, doxapram, doxepin, doxorubicin, doxycycline, calcium sodium edetate, calcium EDTA, enalapril, enalapril, enoxaparin sodium, enflufloxacin, ephedrine sulfate, adrenaline, recombinant human erythropoietin, elinocritin, estastatin, erythromycin, esmolol, estradiol cyclopentylpropionate, ethacrynic acid / sodium ethacrynic acid, ethanol (alcohol), etidronate sodium, etoposide, etomidate, euthanasia agents containing pentobarbitalw / pentobarbital), famotidine, fatty acids (essential / ω), felbamate, fenbendazole, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil, florfenicol, flubendazole, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, metoprolol (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoids Hormones, Glucosamine / Chondroitin Sulfate, Glutamine, Glibenclamide, Glycerin (oral), Gastrointestinal Pills, Gonaforin, Griseofulvin, Guaifenesin, Halothane, Glutamoglobin-200 (OXYGLOBIN®), Heparin, Hydroxyethyl Starch, Sodium Hyaluronate, Hydralazine, Hydrochlorothiazide, Hydrocodone Bitartrate, Hydrocortisone, Hydromorphone, Ethyltetramethrin, Hydroxyurea, Hydroxyzine, Ifosfamide, Imidacloprid, Midoca Dipropionate, Impenetrable Sodium, Imipramine, Inamrinone Lactate, Insulin, Interferon Alpha-2a (Recombinant Human), Iodides (Sodium / Potassium), Ipecac Syrup, Sodium Iopoise, Iron Dextran, Isoflurane, Isoproterenol, Isotretinoin, Isochlorpheniramine, Itraconazole, Ivermectin, Kaolin / Pectin, Ketamine, Ketoconazole, Ketoprofen, Ketoprofen Tromethamine, Acetaminophen, Lactulose, Leuprolide, Levamisole, Levetiracetam, Levothyroxine Sodium, Lidocaine, Lincomycin, Isothelonine Sodium, Lisinopril, Lomustine (CCNU), Clofenuron, Lysine, Magnesium, Mannitol, Marbofloxacin, Mebendazole, Nitrogen Mustard, Meclofenamic Acid, Metformin, Medium Chain Glycerides Medroxyprogesterone acetate, melatonin, melatonin, meloxicam, meloxicam, melphalan, meridine, mercaptopurine, meropenem, cyfluthrin, metformin, methadone, acetazolamide, urotropine mandelate / urotropine hippurate, methimazole, methionine, mesobarum, sodium mesobital, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidazole, mexiletine, mibolerlone, midazolam, milbeycin derivatives (e.g., mibemycin, milbeycin D) D), Moxicillin and Nymakine), Milbexime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, molentaxel, morphine sulfate, moxicillin, naloxone, mandrolone decanoate, naproxen, narcotic (opioid) agonist analgesics.Analgesic), neomycin sulfate, neostigmine, nicotinamide, nicotinamide, nitrozole, acetamiprid, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, neomycin sodium, nystatin, octadepsipeptide, octreotide acetate, oxalamicin sodium, omeprazole, ondansetron, opioid antidiarrheals, oxadiazine, oxazolidin sodium, oxazepam, oxifenezazole, oxendazole, oxoximidezazole, oxybutynin chloride, pyridaben and Milbemycins (5-oxo and 5-oxime derivatives), hydroxymorphone, oxytetracycline, oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide, paraherquamides (e.g., derquantel), palbendazole, paromomycin sulfate, paroxetine, penicillamine, and general penicillins. Information penicillins), penicillin G, penicillin V potassium, pentazocine, sodium pentobarbital, sodium pentothiosulfate, pentoxifylline, pergolide mesylate, primethrin, phenobarbital, phenylbenzamine, phenylbutazone, norepinephrine, phenylpropanolamine, phenytoin sodium, pheromones, parenteral phosphates, vitamin K-1 (phytonadione / vitamin K-1), pimoxadione, piperazines, piroxim, piroxicam, polysulfated glycosaminoglycans, ponazuril, potassium chloride, pralidoxime, praziquantel, praziquantel, prazosin, prednisolone / prednisolone, primidone, procainamide, procarbazine, prochlorperazine, brombutazone, Propionibacterium MeCNes injection (propionibacterium)MeCNesinjection), propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium oleoresin, pyrethrins, pyridostigmine bromide, mepiracetam maleate, pyridostigmine bromide, pyrimethamine, pyriproxyfen, quinacrine, quinidine, ranitidine, rifampin, S-adenosylmethionine (SAMe), saline / hyperosmolarity laxative, selenophenate, selegiline / 1-deprazole, sertraline, sevelamer, sevoflurane, silymarin / silymarin, sodium bicarbonate, sodium polystyrene sulfonate, sodium antimony gluconate, sodium sulfate, sodium thiosulfate, growth hormone, sotalol, spectinomycin, spironolactone Stanozolol, streptokinase, streptozoline, dimercaptosuccinic acid, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachlordazine sodium, sulfadimentoxine / trimethoprim, sulfamethoxazole / trimethoprim, sulfadimentoxine, sulfadesodium / olomeprine, sulfasalazine, taurine, tepoxaline, terbinafine, terbutaline sulfate, testosterone, tetracycline, tetraimidazole, thiabendazole, thioarsamine sodium, thiamine, thioguanine, thiopental sodium, thiotepa, thyroid-stimulating hormone, thiouracil, ticarcilin disodium Disodium, telazopyram / zoprazepam, tilmocsin, thioproline, tobramycin sulfate, tocamide, torazoline, telfenamic acid, topiramate, tramadol, triclobenzazole, triamcinolone acetonide, triamcinolone, trilosterone, tartratew / prednisolone, tripyridine, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vincristine sulfate, vinblastine sulfate, vitamin E / selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate / zinc sulfate, zonisamide and mixtures thereof.

[0361] Some additional active agents that can be applied in publicly available combination therapies are insect growth regulators (IGRs), which interfere with the development or growth of pests. Compounds belonging to this group are known to those skilled in the art and represent a broad range of chemicals. Some IGRs mimic or regulate juvenile hormone levels in insects, and include, but are not limited to, azadirachtin, benzyl ether, phenoxycarb, tebufenozide, tebufenozide, pyriproxyfenozide, tetrahydroazadirachtin, and 4-chloro-2-(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridinylmethoxy)pyridazin-3(2H)one. Some IGRs are chitin synthesis inhibitors, including but not limited to chlorofluazuron, cyromazine, diflubenzuron, pyridaben, flucyclobenzuron, formamidines (such as amitraz), flufenoxuron, flufenoxuron, lufenuron, fluazinam, pyrethroids, tebufenozide, flufenoxuron, triflumoron, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea), 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea, and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

[0362] Some of the additional active agents that can be used in publicly available combination therapies are adult insecticides and acaricides. Such compounds include, for example, pyrethrins (including cinnamyl arvense I, cinnamyl arvense II, jatropha arvense I, jatropha arvense II, pyrethrin I, pyrethrin II and mixtures thereof) and pyrethroids, arylpyrazoles (e.g., fipronil, sisapronil) and carbamates (e.g., benomyl, methomyl, carbaryl, carbofuran, methiocarb, fenpropathrin, propoxyr, aldicarb, methyl ethyl ketone, chlorpyrifos, fenpropathrin, and chlorpyrifos).

[0363] Certain additional active agents that can be used in publicly available combination therapies are anticline agents. Suitable anticline agents include, but are not limited to, benzimidazoles, imidazothiazoles, tetrahydropyrimidines, and organophosphate compounds. Specific, non-limiting examples of anticline agents include thiabendazole, canbendazole, pabendazole, ocbendazole, mebendazole, flubendazole, fenbendazole, oxifendazole, albendazole, cyclobendazole, febantel, thiourea ester and its O,O-dimethyl analogues, tetraimidazole, levamisole, butamidazole, pyrantel, octocel, molotovateil, coumarin, trichlorfon, haloctone ketone, naphthiophos and dichlorvos, heptenphos, methamidophos, tebufenozide, TE dichlorvos, etc. PP, stirophos, phenothiazine, piperazine in neutral compound form and in various salt forms, ethylamine, phenols such as diiodonitrophenol, arsenic agents such as thioarsine, ethanolamines such as benzylphenol, silylbenzenesulfonate, and metilidine; cyanine blue dyes, including pyrethrum chloride, embopyrethrum, and iododithionine; isothiocyanates (salts), including dithiocyanobenzene, sulamine sodium, phthalylhexylenide, and various natural products, including but not limited to hygromycin B, α-sandonian, and erythrine.

[0364] Certain additional active agents that can be used in publicly available combination therapies are anti-nematicides. Suitable anti-nematicides include, but are not limited to: miracils, such as miracil D and mirasan; praziquantel, clonazepam and its 3-methyl derivatives, otepralatre, thioanthrone, henone, oxaniquine, niridazol, nitroisocyanate, niridazol, nitroisocyanone, various bisphenol compounds known in the art, including hexachlorophenol, thiochlorophenol, thiobisphenol sulfoxide and binitrochlorophenol; various salicylaniline compounds, including tribromosalamine, hydroxychlorozadamide, clonisocyanate, rafenib, nitroisocyanone, brotinib, brosanthide and chlorsenoyl; trichlorobenzazole, difenitol, closulon, trichlorobenzylpropionylazine and emetine. Anti-tapeworm compounds can also be advantageously used in certain compositions provided herein, including but not limited to arecoline, bufenamidin, niclosamide, nitrothiocyanate, paromomycin, paromomycin II, praziquantel, and esitainil in various salt forms.

[0365] Some of the additional active agents that can be used in publicly available combination therapies are compounds that are effective against arthropod parasites. Such surfactants include, but are not limited to: bromoxynil, chlordane, DDT, endosulfan, lindane, methoxydichlorophenate, toxaphene, bromothion, ethyl bromoxynil, carbothion, chlorpyrifos, methamidophos, methamidophos, diazinon, dichlorvos, cyclophosphamide, dimethoate, dioxin, ethion, fenpropathrin, phosmet, malathion, dibromophos, fenpropathrin, phosmet, oxammonium phosphate, fenpropathrin, fenpropathrin, stiotronidazole, allethrin, deltamethrin, cypermethrin, deltamethrin, fenpropathrin, permethrin, permethrin, pyrethrin, benzyl benzoate, carbon disulfide, cromamidophos, difluorourea, diphenylamine, disulfiram, isobornyl thiocyanate. Acetate), methoxyprone, sulphurine, pirenonylbutoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, dimethyl phthalate, and compounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofuranaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methylene-1H-isoindole-1,3(2H)dione (MGK-264), dipropyl 2,5-pyridinedicarboxylate (MGK-326) and 2-(octylthio)ethanol (MGK-874).

[0366] Certain additional active agents that may be administered in publicly available combination therapies are biologically active peptides or proteins, including but not limited to pentapeptides (e.g., including but not limited to amedas), which act at the neuromuscular junction by mimicking presynaptic receptors belonging to the secretin receptor family, leading to paralysis / death of the parasite.

[0367] Some other active agents that can be used in publicly available combination therapies are neonicotinoid antiparasitic agents that bind to and inhibit insect-specific nicotinic acetylcholine receptors. Non-limiting examples of such antiparasitic agents include substituted pyridylmethyl derivative compounds, such as imidacloprid and acetamiprid. Some other active agents are urea derivatives, such as cyfluthrin. Some other active agents are isoxazoline compounds known in the art, such as fluralaner, which are particularly effective against ectoparasites. Some other active agents are nodulisporic acid and its derivatives (a class of known acaricides, anthelmintics, antiparasitics, and insecticides) used to treat or prevent infections in humans and animals.

[0368] Some other active agents that can be used in publicly available combination therapies are anthelmintic compounds in the aminoacetonitrile (AAD) class, such as monepantel (ZOLVIX®). Some other active agents are aryloazol-2-ylcyanoethylamino compounds and their thioamide derivatives. Some other active agents are paraclump-like penicillinamide compounds (containing a spirodioxane-heptene and indole core active against certain parasites) and their derivatives (e.g., detrifente), as well as structurally related marcfortine compounds, such as marcfortine AC. Some other active agents are spinosyns or semi-synthetic spinosoid active agents produced by the soil actinomycete *Saccharopolyspora spinosa* (e.g., including but not limited to spinosine A, spinosine D, spinosamycin, spintoram, or combinations thereof).

[0369] Although the technology has been described herein with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the technology. It will be apparent to those skilled in the art that various modifications and variations can be made to the methods and apparatus of the technology without departing from the spirit and scope of the technology. Therefore, modifications and variations intended to include the technology within the scope of the appended claims and their equivalents are intended to be applicable. Thus, this disclosure is not limited except for the appended claims.

[0370] Throughout this specification, references to "an embodiment" or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of this disclosure. Therefore, the appearance of the phrase "in one embodiment" or "in one embodiment" throughout this specification does not necessarily refer to all of the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in one or more embodiments in any suitable manner. Any scope referenced herein is inclusive.

[0371] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be used to practice the invention. The scope of the invention is intended to be defined by the following claims, and the methods and structures within the scope of these claims, and their equivalents, are covered therein.

[0372] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is expressly and individually indicated to be incorporated by reference.

[0373] The following embodiments illustrate aspects of the present technology more fully. Before describing several exemplary embodiments of the present technology, it should be understood that the present technology is not limited to the details of the construction or method steps set forth in the following description. The present technology can have other embodiments and can be practiced or implemented in various ways. The following embodiments are set forth to illustrate certain aspects of the present technology and should not be construed as limiting it. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to them. It should also be understood that, by using appropriate starting materials and modifying the synthetic route as needed, those skilled in the art will be able to prepare additional compounds within the scope of this disclosure in a manner similar to that described below. Typically, starting materials and reagents are available from commercial suppliers or synthesized from sources known to those skilled in the art, or prepared as described herein.

[0374] The reagent / reactant names given are as indicated on the commercial bottle or according to IUPAC rules, ChemDraw 19.0 (CAMBRIDGESOFT). ® Compounds designated as salts (e.g., hydrochlorides, acetates, sulfates) may contain more than one molar equivalent of acid.

[0375] Example

[0376] The aspects of this disclosure are illustrated more fully by way of the following embodiments, which are set forth to illustrate certain aspects of the invention and should not be construed as limiting thereto.

[0377] Example 1. (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(bromomethyl)benzyl)-3,9, 15,21-Tetraisobutyl-4,10,12,16,22,24-Hexamethyl-1,7,13,19-Tetraoxa-4,10,16,22-Tetraazacyclodi Tetradecane-2,5,8,11,14,17,20,23-octaketone (intermediate 1A) and (3S,6R,9S,12R,15S,18R,21S,24R)-6- Benzyl-18-(4-(bromomethyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13, Synthesis of 19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,5,8,11,14,17,20,23-octaone (intermediate 1B) become.

[0378]

[0379] The title compound was prepared from PF1022A, bromomethyl methyl ether, and aluminum chloride according to the steps described in International Patent Application Publication No. WO2019 / 108591. The title compound was obtained as an inseparable mixture of several products—primarily 1.0 g of the bis-bromomethyl (1A) and mono-bromomethyl (1B) intermediates—together with small amounts of other regioisomers (e.g., ortho- and / or meta-mono-bromomethylated and di-bromomethylated isomers). The mixture of products was used directly in subsequent synthesis. For intermediate (1A), [M+H] = 1133 and for intermediate (1B), [M+H] = 1041.

[0380] Example 2. General Synthesis Method 1 (S1)

[0381]

[0382] In general synthetic method 1 (S1), bridged amine and diisopropylethylamine (DIEA) are added to a mixture of mono-bromomethyl and di-bromomethyl intermediates 1A and 1B in a suitable solvent (Example 1), and the mixture is stirred at room temperature until the reaction is complete. The reaction mixture is subjected to an aqueous post-treatment and several column types (Luna) are used. TM C18 (Phenomonex TM , Torrance, CA, USA); Sunfire C18 OBD (Waters TM , Milford, MA, USA); XBridge Prep C18 (Waters TM The crude substance was purified by HPLC from a compound prepared by a method from Milford, MA, USA. Table 1 below provides the HPLC conditions, structure, and analytical data for each compound prepared by this method.

[0383] In a representative embodiment according to method S1, compounds 1 and 2 were prepared. 2-azabicyclo[2.2.1]heptane (58.20 mg, 0.6 mmol) and diisopropylethylamine (DIEA; 116.00 mg, 0.90 mmol) were added to a solution of crude bromomethyl intermediates 1A and 1B (Example 1; 330.00 mg, 0.30 mmol) in CH2Cl2 (5 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (EtOAc; 10 mL), washed with water (10 mL) and brine, dried (Na2SO4), and concentrated under vacuum. The crude substance was purified using preparative HPLC to provide a monoamine (compound 2; (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((2-azabicyclo[2.2.1]hept-2-yl)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,5,8,11,14,17, 20,23-octaone) and diamine (compound 1; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-azabicyclo[2.2.1]hept-2-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,5,8,11,14,17,20,23-octaone).

[0384] Example 3. General Synthesis Method 2 (S2)

[0385] In general synthetic method 2 (S2), a mixture of mono-bromomethyl and di-bromomethyl intermediates 1A and 1B (Example 1) was added to a bridged amine and DIEA in a suitable solvent, and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was subjected to an aqueous post-treatment and several column types (Luna) were used. TM C18 (Phenomonex TM , Torrance, CA, USA); Sunfire C18 OBD (Waters TM , Milford, MA, USA); XBridge Prep C18 (Waters TM The crude substance was purified by HPLC from a compound prepared by a method from Milford, MA, USA. Table 1 below provides the HPLC conditions, structure, and analytical data for each compound prepared by this method.

[0386] In a representative embodiment according to method S2, compounds 45, 46, 47, and 48 were prepared. DIEA (300 mg, 2.32 mmol) was added to a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (153 mg, 1.02 mmol) in CH₂Cl₂ (6 mL), and a solution of crude bromomethyl intermediates A and B (330 mg, 0.29 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with water (10 mL) and brine, dried (Na₂SO₄), and concentrated under vacuum. The crude substances were purified using preparative HPLC to provide compounds 45, 46, 47, and 48.

[0387] Example 4. General Synthesis Method 3 (S3)

[0388]

[0389] In general synthetic method 3 (S3), bridged amine and diisopropylethylamine (DIEA) are added to bis-bromomethyl intermediate 1A in a suitable solvent, and the mixture is stirred at room temperature until the reaction is complete. The reaction mixture is then subjected to an aqueous post-treatment and several column types (Luna) are used. TM C18 (Phenomonex TM , Torrance, CA, USA); Sunfire C18 OBD (Waters TM , Milford, MA, USA); XBridge Prep C18 (Waters TM The crude substance was purified by HPLC from a compound prepared by a method from Milford, MA, USA. Table 1 below provides the HPLC conditions, structure, and analytical data for each compound prepared by this method.

[0390] In a representative embodiment according to method S3, compounds 61 and 62 were prepared. 2-Thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide (HCl salt) (72.74 mg, 0.40 mmol) and DIEA (82.56 mg, 0.64 mmol) were added to a solution of crude bromomethyl intermediate 1A (180 mg, 0.16 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with water (10 mL) and brine, dried (Na₂SO₄), and concentrated under vacuum. The crude substance was purified using preparative HPLC to provide compounds 61 and 62.

[0391] Example 5. General Synthesis Method 4 (S4)

[0392] In general synthetic method 4 (S4), bridged amine and diisopropylethylamine (DIEA) are added to mono-bromomethyl intermediate 1B in a suitable solvent and stirred at room temperature until the reaction is complete. The reaction mixture is then subjected to an aqueous post-treatment and several column types (Luna) are used. TM C18 (Phenomonex TM , Torrance, CA, USA); Sunfire C18 OBD (Waters TM , Milford, MA, USA); XBridge Prep C18 (Waters TM The crude substance was purified by HPLC from a compound prepared by a method from Milford, MA, USA. Table 1 below provides the HPLC conditions, structure, and analytical data for each compound prepared by this method.

[0393] In a representative embodiment according to method S4, compound 145 was prepared. 2-Thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide (HCl salt) (44.78 mg, 0.24 mmol) and DIEA (63.13 mg, 0.49 mmol) were added to a solution of crude bromomethyl intermediate 1B (170 mg, 0.16 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with water (10 mL) and brine, dried (Na₂SO₄), and concentrated under vacuum. The crude substance was purified using preparative HPLC to provide compound 145.

[0394] Example 6. General Synthesis Method 5 (S5)

[0395]

[0396] In general synthetic method 5 (S5), bis-bromomethyl intermediate 1A is added to the bridged amine and DIEA in a suitable solvent, and the mixture is stirred at room temperature until the reaction is complete. The reaction mixture is then subjected to an aqueous post-treatment and several column types (Luna) are used. TM C18 (Phenomonex TM , Torrance, CA, USA); Sunfire C18 OBD (Waters TM , Milford, MA, USA); XBridge Prep C18 (Waters TMThe crude substance was purified by HPLC from a compound prepared by a method from Milford, MA, USA. Table 1 below provides the HPLC conditions, structure, and analytical data for each compound prepared by this method.

[0397] In a representative embodiment according to method S5, compounds 183 and 184 were prepared. Bromomethyl intermediate 1A (210.0 mg, 0.19 mmol) was added to a solution of 2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (105.0 mg, 0.57 mmol) and DIEA (245.0 mg, 1.90 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to produce a residue, which was purified using preparative HPLC to provide compounds 183 and 184.

[0398] Example 7. General Synthesis Method 6 (S6)

[0399] In general synthetic method 6 (S6), mono-bromomethyl intermediate 1B is added to the bridged amine and DIEA in a suitable solvent, and the mixture is stirred at room temperature until the reaction is complete. The reaction mixture is then subjected to an aqueous post-treatment and several column types (Luna) are used. TM C18 (Phenomonex TM , Torrance, CA, USA); Sunfire C18 OBD (Waters TM , Milford, MA, USA); XBridge Prep C18 (Waters TM The crude substance was purified by HPLC from a compound prepared by a method from Milford, MA, USA. Table 1 below provides the HPLC conditions, structure, and analytical data for each compound prepared by this method.

[0400] In a representative embodiment according to method S6, compound 206 was prepared. A bromomethyl intermediate (260.0 mg, 0.25 mmol) was added to a solution of 2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (93.0 mg, 0.50 mmol) and DIEA (194.0 mg, 1.5 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to produce a residue, which was purified using preparative HPLC to provide compound 206.

[0401] Example 8. General Synthesis Method 7 (S7)

[0402] In general synthetic method 7 (S7), DIEA is added to a solution of bis-bromomethyl intermediate 1A and bridged amine in a suitable solvent, and the mixture is stirred at room temperature until the reaction is complete. The reaction mixture is subjected to an aqueous post-treatment and several column types (Luna) are used. TM C18 (Phenomonex TM , Torrance, CA, USA); Sunfire C18 OBD (Waters TM , Milford, MA, USA); XBridge Prep C18 (Waters TM The crude substance was purified by HPLC from a compound prepared by a method from Milford, MA, USA. Table 1 below provides the HPLC conditions, structure, and analytical data for each compound prepared by this method.

[0403] In a representative embodiment according to method S7, compounds 219 and 220 were prepared. Sodium acetate (81.16 mg, 0.99 mmol) was added to a solution of 2-azabicyclo[2.2.1]hepta-5-one (55.00 mg, 0.49 mmol) and O-methylhydroxylamine hydrochloride (41.33 mg, 0.49 mmol) in H2O (5 mL) under nitrogen atmosphere at 10 °C. The reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated under pressure at 50 °C to yield (E)-2-azabicyclo[2.2.1]hepta-5-one oxime (80.00 mg) as a white solid (80% purity, 92.24% yield). LCMS: [M+H] + =127.1.

[0404] DIEA (122.93 mg, 0.95 mmol) was added to a solution of bis-bromomethyl intermediate 1A and (E)-2-azabicyclo[2.2.1]hepta-5-one oxime (60 mg, 0.48 mmol) in DCM (10 mL) stirred at 10 °C under nitrogen. The reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated under pressure at 50 °C. The reaction mixture was diluted with EtOAc (10 mL), washed with water (10 mL) and brine, dried (Na2SO4), and concentrated under vacuum. The crude substances were purified by preparative HPLC to provide compounds 219 and 220.

[0405] Example 9. General Synthesis Method 8 (S8)

[0406] In general synthetic method 8 (S8), DIEA is added to a solution of mono-bromomethyl intermediate 1B and bridged amine in a suitable solvent, and the mixture is stirred at room temperature until the reaction is complete. The reaction mixture is subjected to an aqueous post-treatment and several column types (Luna) are used. TM C18 (Phenomonex TM , Torrance, CA, USA); Sunfire C18 OBD (Waters TM , Milford, MA, USA); XBridge Prep C18 (Waters TM The crude substance was purified by HPLC from a compound prepared by a method from Milford, MA, USA. Table 1 below provides the HPLC conditions, structure, and analytical data for each compound prepared by this method.

[0407] In a representative embodiment according to method S8, compound 227 was prepared. DIEA (78.71 mg, 0.61 mmol) was added to a solution of mono-bromomethyl intermediate 1B (126.93 mg, 0.12 mmol) in DCM (10 mL) stirred at 15 °C under nitrogen. The reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated under pressure at 50 °C. The reaction mixture was diluted with DCM (20 mL), washed with water (10 mL) and brine, dried (Na₂SO₄), and concentrated under vacuum. The crude substance was purified using preparative HPLC to provide compound 227.

[0408] Table 1. Structure, preparation method, and analytical data of the compounds disclosed herein.

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487] Represents the meta-isomer of R2

[0488] # Represents the ortho isomer of R2

[0489] Example 10. Screening for compounds targeting the microfilariae of *Filaria canis*

[0490] To evaluate the efficacy of the compounds of this disclosure against *Filaria canis*, L1 stage larvae were exposed to multiple concentrations of the compounds to determine larval survival or paralysis. Results were reported as the minimum effective dose (MED) (defined as the concentration required to eliminate motility).

[0491] To perform this assay, microfilariae of *Filaria canis* were added to the wells of a microtiter plate containing buffer and the test compound in DMSO. Microfilariae exposed to DMSO alone served as a control. Evaluation was performed at 24 hours to determine microfilariae survival. The results are provided in Table 2, showing the minimum effective dose (“MED”) range from less than 0.3 mM to 31 mM. For comparison, *Eimedes* showed a MED of 0.02 μM in this assay.

[0492] Table 2. Minimum Effective Dose (MED) of the compounds of this disclosure screened against L1 larvae of *Filaria canis*.

[0493]

[0494]

[0495]

[0496]

[0497]

[0498] Example 11. Screening for compounds targeting L3 / L4 larvae of *Filaria canis*.

[0499] To evaluate the efficacy of the compounds of this disclosure against L3 stage larvae of *Filaria canis*, L3 larvae were exposed to multiple concentrations of the compounds to determine motility, viability, and development toward stage L4.

[0500] The Berkeley isolate of *Heartworm* was used for this assay. The isolate was obtained as follows: In April 2014, a dog from Berkeley County, South Carolina, USA, tested positive for *Heartworm*. The duration of the heartworm infection was unknown. Blood was collected from the dog on April 7, 2014, and sent to the laboratory. Mosquitoes were infected with this blood on April 8, 2014. The Berkeley heartworm isolate was confirmed in December 2014 by microfilariae detection, antigen detection, and worm recovery.

[0501] To conduct this measurement, approximately 5... L3s*Filarial canis* was added to each of the three individual wells of a 24-well plate and incubated with growth medium and either a test compound or a positive control. Development to the L4 stage and viability were assessed after 7 days. A negative control (DMSO, three wells, 5 L3s per well) was also included in each larval development assessment cycle. In this assay, stock solutions of each test compound and control were prepared in DMSO at 100x the desired final concentration. Each well was filled with 890 μL of in vitro medium, 100 μL of in vitro medium containing approximately 5 infective L3 *Filarial canis* larvae, and 10 μL of the test compound stock solution to produce the appropriate final concentration in a total volume of 1 mL and 1% DMSO. Any unwanted precipitation in the individual wells of the 24-well plate was recorded. The plate was incubated at 37°C and 5% CO2 with saturated humidity. On day 7 (±2 hours), the number of stage 4 larvae (L4) was counted, and viability and / or motility were described. When L4s were not observed, the viability and / or motility of L3s were described. Larval motility was qualitatively scored as dead, quiescent, sluggish, or active. Data for L3 (failed to molt / survive) and L4 stages are reported in Table 3, respectively.

[0502] Table 3. L3 / L4 Mobility and Survival

[0503]

[0504] Example 12. Screening for compounds targeting Haemonchus contortus.

[0505] To evaluate the efficacy of the compounds of this disclosure against Haemonchus contortus, L4 stage larvae were exposed to multiple concentrations of the compounds of this disclosure to determine larval survival or paralysis. Results were reported as the minimum effective dose (MED) (defined as the concentration required to eliminate motility).

[0506] To perform this assay, approximately 100 eggs of *Haemaphysalis contortus* were mixed with food (*Escherichia coli*). E. coli The test compound and DMSO were placed together in individual wells of a 384-well plate. The plate was incubated at 25°C for 48 h to allow the nematodes to develop to the L4- stage. Larvae exposed to DMSO alone served as controls. Assessments were performed at 48 h to determine larval survival or paralysis (motor activity; MTA) and migration activity (LDA). Results are provided in Table 4, showing a minimum effective dose range from 1 mM to above 100 mM. For comparison, Emedes showed an LDA MED of 2.5 μM in this assay.

[0507] Table 4. Minimum effective doses of the compounds of this disclosure screened against L4 larvae of Haemonchus contortus. (MED)

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515] Example 13. Screening compounds for activity against SLO-1 calcium-gated potassium channels

[0516] This protocol allows for the pharmacological characterization of the compounds disclosed herein for the SLO-1 calcium-gated potassium ion channel. To perform this assay, compounds derived from the nematode *C. elegans* (…) C. elegans The SLO-1 channel of Xenopus laevis was expressed in Xenopus oocytes. The membrane potential was clamped to a fixed value, and voltage steps were applied at fixed intervals. 。 Compound 3 was evaluated in this assay and showed an enhanced current indicating SLO-1 activity. EC was calculated. 50 The maximum enhancement is approximately 2.2 mM at 10 mM and approximately 200%.

[0517] Example 14. Screening for canine hookworm ( A. Caninum ) compounds

[0518] The activity of the compounds of this disclosure against hookworm larvae was evaluated. L3 stage hookworm larvae were placed in multi-well plates, treated with the compounds of this disclosure in DMSO solution, and incubated for 144 hours. The effect of the compounds was quantified as a decrease in motility using an automated data acquisition system, with efficacy expressed as a % reduction compared to the negative control. Data are provided in Table 5, showing a minimum effective dose range of approximately 10 μmol to greater than 30 μmol.

[0519] Table 5. Minimum Effective Dose (MED) of the compounds of this disclosure screened against canine hookworm.

[0520]

[0521]

[0522]

[0523]

[0524] Example 15. Screening of the liver microsomal stability of compounds

[0525] The stability of the compounds disclosed herein in liver microsome formulations (mice or rats) was evaluated. The test compound was diluted with DMSO to provide a 1 mM stock solution. Aliquots (10 µL) of the stock solution were mixed with 40 µL of acetonitrile to provide a working solution of the test compound containing 20% ​​DMSO. Liver microsomes were freshly thawed in a 37 °C water bath and diluted with phosphate-buffered saline to 0.629 mg / mL (mice) or 1.258 mg / mL (humans). A fresh solution of 5 mM NADPH in phosphate-buffered saline was prepared. Terfenadine and tolbutamide were used as control compounds and prepared in stock solutions at 1 mg / mL in DMSO. These compounds were also used as internal standards for LC / MS analysis. Internal standard solutions were prepared by diluting the two stock solutions with acetonitrile. The concentration of terfenadine was 5 ng / mL, and the concentration of tolbutamide was 10 ng / mL. For microsome studies, 1.5 µL of the control / test compound working solution was added to 238.5 µL of liver microsome working solution in a 1.1 mL microtube and gently mixed. The samples were pre-incubated in a 37°C water bath shaker for 5 min. The reaction was initiated by adding 60 µL of NADPH working solution. The reaction was mixed by pipetting. After incubation for 0, 5, 15, 30, and 60 min, 30 µL of each reaction mixture was transferred to 300 µL of quenching solution and thoroughly mixed by pipetting. All samples were vortexed vigorously for 1 min and centrifuged at 4000 rpm for 15 min at 4°C. The supernatant (100 µL) was mixed with 100 µL of distilled water, and the diluted supernatant solution was used for LC-MS / MS analysis. The liver microsome stability results are reported in Table 6.

[0526] Table 6. Microparticle Stability

[0527]

[0528] Example 16. Pharmacokinetic assay in mice

[0529] The half-life and C64 of the compounds disclosed herein were evaluated in mice. max And AUC.

[0530] Male BALB / c mice weighing 20–30 grams were socially housed and allowed free access to food and water. The study was conducted in multiple groups of mice, with three animals in each group. All groups were administered the test compound dissolved in 100% DMSO to the desired concentration and volume. Mice received the oral dose via gavage. Serial blood samples were collected from the saphenous vein of each animal 24 hours after administration. Plasma was separated by centrifugation and frozen for storage until analysis.

[0531] For bioanalysis of plasma samples, standards and quality control samples (QCs) were first prepared in blank male Balb / c mouse plasma (EDTA potassium anticoagulant). The resulting plasma standard curve ranged from 1 to 1000 ng / mL. The QC concentration levels in mouse plasma were 2,200 and 800 ng / mL. To prepare samples for LC-MS / MS bioanalysis, 10 μL of plasma (standard, QC, blank control, or unknown sample) was added to 200 μL of internal standard (5 ng / mL terfenadine) in methanol / acetonitrile (1:1, v / v). For double-blank samples, 200 μL of blank methanol / acetonitrile (1:1, v / v) was added to the blank matrix. The samples were mixed for 1 min and centrifuged at 4000 rpm for 15 min at 4°C. The supernatant was transferred and diluted 5-fold with methanol / water (1:1 v / v) containing 0.1% FA for injection into the LC / MS instrument. Pharmacokinetic parameters after oral administration were calculated using a non-compartmental method with WinNonlin (Certara USA Inc., St. Louis, MO). The results are reported as the average of three replicates in Table 7.

[0532] Table 7. In vivo pharmacokinetic data

[0533]

[0534] Many modifications and other embodiments of the invention will arise for those skilled in the art from the teachings provided in the foregoing description. Therefore, it should be understood that the invention is not limited to the specific embodiments disclosed, and that the modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terminology is used herein, it is used only in a superlative and descriptive sense and not for purposes of limitation.

Claims

1. A compound having a structure according to Formula I or a pharmaceutically or veterinarily acceptable salt thereof: (I)， in: R1 and R2 are independently selected from H and -CH2-R3, provided that at least one of R1 and R2 is -CH2-R3; and R3 is a bridged heterocyclic alkyl group of 5 to 8 carbon atoms that may be optionally substituted, chosen independently for each occurrence.

2. The compound according to claim 1, wherein: R1 is H; and R2 is CH2-R3.

3. The compound according to claim 1, wherein R1 and R2 are each CH2-R3.

4. The compound according to claim 3, wherein each R3 is identical.

5. The compound according to any one of claims 1-4, wherein R3 is ， in: n is 1 or 2; X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and m can be 0, 1, or 2.

6. The compound according to claim 5, wherein X is (CH2). m , O, NMe, S, or SO2.

7. The compound according to claim 5, wherein X is (CH2). m m is 0, 1, or 2; and n is 1 or 2.

8. The compound according to claim 7, wherein R3 is selected from: 。 9. The compound according to claim 5, wherein n is 1 or 2; and X is O, NMe, S, or SO2.

10. The compound according to claim 9, wherein R3 is selected from: 。 11. The compound according to claim 5, wherein R3 is selected from... 。 12. The compound according to any one of claims 1-4, wherein R3 is ， in: n is 1 or 2; X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and m can be 0, 1, or 2.

13. The compound according to claim 12, wherein X is (CH2). m O, NMe, S, or SO2; and n is 1 or 2.

14. The compound according to claim 12, wherein X is (CH2). m m is 0, 1, or 2; and n is 1 or 2.

15. The compound according to claim 14, wherein R3 is selected from: 。 16. The compound according to claim 12, wherein X is O, NMe, S, or SO2; and n is 1 or 2.

17. The compound according to claim 16, wherein R3 is selected from: 。 18. The compound according to claim 12, wherein R3 is selected from... 。 19. The compound according to any one of claims 1-4, wherein R3 is ， in: n is 1 or 2; X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and m is 1 or 2.

20. The compound according to claim 19, wherein X is (CH2). m m is 1 or 2; and n is 1 or 2.

21. The compound according to claim 20, wherein R3 is selected from: 。 22. The compound according to claim 19, wherein X is O, NMe, S, or SO2; and n is 1 or 2.

23. The compound according to claim 22, wherein R3 is selected from: 。 24. The compound according to claim 19, wherein R3 is ,and Where X is C(CH3)OH, CHCO2H, CHCN, CF2, C=NOH, or C=NOCH3.

25. The compound according to claim 19, wherein R3 is selected from... 。 26. The compound according to any one of claims 1-4, wherein R3 is in: n is 1 or 2; X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and m is 1 or 2.

27. The compound according to claim 27, wherein R3 is selected from... 。 28. The compound according to any one of claims 1-4, wherein R3 is in: n is 1 or 2; X is selected from (CH2) m ,CHOH,C(CH3)OH,C(CF3)OH,CHF,CF2,CHCN,CHCO2H,C=O,C=NOH,C=NOCH3,C=NOCH2CF3,C=CH2,CH (C=O)CH3, CH(C=NOH)CH3, CH(C=NOCH3)CH3, CH(C=NOCH2CF3)CH3, NH, NMe, N(C=O)CH3, O, S, SO2; and m is 1 or 2.

29. The compound according to any one of claims 1-4, wherein R3 is in: Q is CH2, NMe, O, S, or SO2; and W can be H, CH3, CH2OH, CF3, or CO2H.

30. The compound according to claim 29, wherein R3 is selected from... 。 31. The compound according to claim 1, wherein the compound is selected from those compounds described in Table 1.

32. A composition comprising any one of the compounds of claims 1-31 or a pharmaceutically or veterinary acceptable salt thereof, and a pharmaceutically or veterinary acceptable excipient.

33. A method for treating or preventing parasitic infection or invasion in an animal, the method comprising administering to the animal an effective amount of any one of claims 1-31, or the composition of claim 32.

34. The method of claim 33, wherein the animal is a companion animal.

35. The method of claim 34, wherein the companion animal is a dog.

36. The method according to any one of claims 33-35, wherein the parasitic infection or invasion is caused by a species of the genus *Dysfilaria*.

37. The method according to any one of claims 33-36, wherein the method treats or prevents canine heartworm.

38. The method according to any one of claims 33-35, wherein the parasitic infection or invasion is caused by a species of the genus *Hippophae*.

39. The method of claim 38, wherein the method treats or prevents hookworm in dogs or ruminants.

Images