Anthelmintic benzodiazepines

Abstract

The present disclosure provides compounds, pharmaceutical compositions, and methods useful for treating parasitic worms. The compound is a benzodiazepine type structure substituted at C3 according to Formula I, Formula II, Formula III, Formula IV, or Formula V. In various aspects, the presently described treatment can advantageously provide anthelmintic effects with reduced sedative qualities.

Description

ANTHELMINTIC BENZODIAZEPINESCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 623,631, filed Jan 22, 2024, the disclosure of which is incorporated herein in its entirety by reference.ACKNOWLEDGEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under grant no. NIH R21 Al 146540-02 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] The impact of parasitic flatworms on human health is profound and widespread. These pathogens are responsible for causing various diseases such as schistosomiasis, which infects more than 200 million people each year. Parasitic flatworms also cause disease in livestock and companion animals, which require regular deworming. Treatment of such pathogens is largely addressed by a single drug, praziquantel, resulting in pervasive monotherapy. Reliance on such monotherapy is concerning given recent reports of praziquantel treatment failure, for example, in household dog tapeworm infections (Am J Trop Med Hyg. 2018 Nov;99(5): 1201-1205. PMID: 30226153). Meclonazepam was identified as a potential antiparasitic by Roche in the 1970s, but was not successfully pursued due to dose-limiting sedation in human clinical trials (S. Afr. Med J. 1979 Apr14;55(16):617-8, PMID: 380021). Diethylcarbamazine (DEC) has been used for control of filariasis caused by nematode parasites since the 1940s.

[0004] There remains a need for new anthelmintic treatments.SUMMARY OF THE INVENTION

[0005] The present disclosure provides a method of treating a parasitic worm infection in a patient. The method involves administering a therapeutically effective amount of a compound according to Formula I, or a salt thereof to the patient in need thereofFormula I whereinR1is H, C2-C6alkyl, C2-C6haloalkyl, C3-C6cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3, or haloalkyl;R2and R4 are each independently H, F, Cl, Br, I, methyl, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, -NH2, -NHR, -NRR, CN, or -OR, wherein at least one of R2and R4 is other than H;W is C-R3, C-NO2, C-CH3, C-F, or C-Y;R3is H, alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl;L is pyridyl, phenyl, cyclohexyl,, each of which may be optionally substituted by one, two, or more R5;X is each independently C- R5or N;R5is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or -CO2H;G is C-Y or N;Y is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, -CCR, -OR, pyridinyl, phenyl, or R6;R7is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, or N;T is N or CH;J is O, Z, NH, or NR, or J and the double bond to the carbon to which it is attached are replaced with Ji and J2, wherein Ji and J2 are each independently H, R, OR, SR, NHR, or NR2, or J together with the carbon to which it is attached forms a triazole or imidazole together with Rl and the nitrogen to which it is attached;R9is H, alkyl, cycloalkyl, fluoroalkyl, F, Cl, Br, I, alkyl, or CF3;Z is O or S; each instance of R is independently H, alkyl, or acyl; and wherein the compound is other than meclonazepam.

[0006] The present disclosure also provides a method of treating a parasitic worm infection in a patient by administering a therapeutically effective amount of a compound according to Formula II, or a salt thereof to the patient in need thereof: whereinR1is H, C2-C6alkyl, C2-C6haloalkyl, C3-C6cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3, or haloalkyl;R2and R4 are each independently H, F, Cl, Br, I, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, and -OR, wherein at least one of R2and R4 is other than H;R3is H alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl;X is C-R5or N;R5is H, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or - CO2H;G is C-Y or N;Y is H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, -OR, pyridinyl, phenyl, or R6;R7is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, orN;R9is H, alkyl, cycloalkyl, fluoroalkyl, F, Cl, Br, I, alkyl, or CF3; Z is O or S; and each instance of R is independently H, alkyl, or acyl.

[0007] The present disclosure also provides a method of treating a parasitic worm infection in a patient by administering a therapeutically effective amount of a compound according to Formula III, IV, or V, or a salt thereof to the patient in need thereofFormula V whereinR2and R4 are each independently H, F, Cl, Br, I, CF3, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, and -OR, wherein at least one of R2and R4 is other than H; R3is alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl; and U is CH2, CRH, CR2, or CO.

[0008] The present disclosure also provides an anthelmintic compound having a structure according to Formula I-V, or a salt thereof.

[0009] After substantial effort and experimentation, the inventors of the present disclosure found that modification of various positions of a benzodiazepine core provides compounds with anthelmintic effects. For example, modification of the C3 position of meclonazepam resulted in molecules that retains anti -parasitic effects (e.g., causing parasite contractile paralysis in vitro, clearing worm burden in vivo) with activity comparable to meclonazepam but without imparting the characteristic sedative effects of meclonazepam. Such modification eliminates the main problematic side effect of the meclonazepam drug class that had previously prevented the clinical development of meclonazepam. Modification at C3 position of the benzodiazepine system would not have been expected to provide a fruitful path for developing an anthelmintic compound. Additionally, advantageous results can be achieved with respect to imparting anthelmintic effects without unacceptable host sedation via use of a modified meclonazepam core, but with one, two, three, four, five, or more of the following modifications: (1) modification of C3, (2) modification of the carbonyl, (3) shifting the N4 to become N5 and shifting C5 to become C4 together with moving its pendant halogenated cyclic group, (4) replacing the N4 nitrogen with carbon, (5), moving the nitro group at C7 to C8, (6) adding a methyl group to C6, C7, or C8, or adding two or more methyl groups to a combination of C6, C7, or C8, (7) adding a fluorine group to C6, C7, or C8, or adding two or more fluorine groups to a combination of C6, C7, or C8, (8) halogenated both ortho positions (e.g., with chlorine, iodine, or bromine) of the pendant cyclic group at C5 (i.e., the C ring), (9) shifting the halogen from the ortho position to the meta position or the para position of the pendant cyclic group at C5 (i.e., the C ring), and / or (10) removing aromaticity of the pendant cyclic group at C5 (i.e., the C ring). In various aspects, such advantageous results can be achieved while maintaining utilizing one or more of the aforementioned modifications to meclonazepam while retaining one, two, or more of the following: (1) maintaining the presence of a nitro group at C7 of the A ring of meclonazepam, (2) maintaining the unsubstituted NH group of the B ring of meclonazepam, and / or (3) maintaining the orthohalogenated (e.g., chlorinated) phenyl group at the C ring of meclonazepam. In variousaspects, advantageous can be achieved by use of a compound that targets Smp_33365079 or can be computationally modeled to docket with Smp_33365079.

[0010] Helminth infection can cause hepatosplenomegaly, liver fibrosis, bladder cancer, and gynecological lesions that may increase HIV transmission or cause infertility. Infection with filarial worms residing in the lymphatic system can cause lymphedema, which in advanced stages results in elephantiasis. Accordingly, anthelmintic activity can be advantageous for treating one or more such indications in a patient suffering from parasitic worms.

[0011] The present compounds also represent a promising alternative to Praziquantel, which is the primary treatment of parasitic worms globally. Moreover, these compounds also advantageously show activity against juvenile worms, which represents an advantage over the current Praziquantel -based therapies.BRIEF DESCRIPTION OF FIGURES

[0012] FIG. 1 A shows the structure of MCLZ and provides data illustrating the in vitro effects of MCLZ analogs on adult S. mansoni FIG. IB and FIG. 1C provides additional in vitro data.

[0013] FIG. 2A, FIG. 2B, FIG. 2C, and FIG. 2D provide data illustrating the in vivo effects of MCLZ analogs on S. mansoni.

[0014] FIG. 3A, FIG. 3B, and FIG. 3C provide data illustrating the anti schistosomal activity of (R) and (S)-MYM-V-56 enantiomers.

[0015] FIG. 4A and FIG. 4B provide data illustrating the anti schistosomal activity of (R) and (S)-MYM-III-IO enantiomers.

[0016] FIG. 5 provides data illustrating the sedating activity of some anti schistosomal benzodiazepines by way of a rotarod test.

[0017] FIG. 6A, FIG. 6B, and FIG. 6C provide data illustrating effect of anti schistosomal benzodiazepines on mammalian CNS targets.

[0018] FIG. 7A and FIG. 7B provide data illustrating docking of anti schistosomal benzodiazepines in GABAA and the VSLD cavity of a schistosome TRP.

[0019] FIG. 8 provides structure activity relationships for functional groups on anti schistosomal benzodiazepines with respect to human GABAA and schistosome TRP.

[0020] FIG. 9A, FIG. 9B, and FIG. 9C, provide data illustrating how anti schistosomal activity and sedative activity can be decoupled.DETAILED DESCRIPTION OF THE INVENTION

[0021] The present disclosure provides compounds, pharmaceutical compositions, and methods useful for inactivating parasitic worms and treating parasitic worm infections in patients, which includes human and non-human patients.

[0022] Reference will now be made in detail to certain aspects of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.General Definitions

[0023] Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0024] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

[0025] In the methods described herein, the acts can be carried out in any order without departing from the principles of the disclosure, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0026] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

[0027] The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%.Chemical Definitions

[0028] The term “organic group” as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)O- 2N(R)C(O)R, (CH2)O-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(0R)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (Ci-Cioo)hydrocarbyl, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted.

[0029] The term “independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase “XI, X2, and X3 are independently selected from noble gases” would include the scenario where, for example, XI, X2, and X3 are all thesame, where XI, X2, and X3 are all different, where XI and X2 are the same but X3 is different, and other analogous permutations.

[0030] The term “substituted” as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term “functional group” or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)O- 2N(R)C(O)R, (CH2)O-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (Ci- Cioo)hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. It is envisaged that suitable compounds of the present disclosure can in various examples include the presently described compounds as well as those with additional substitutions. In some contexts, can be useful to refer to various moieties as “optionally substituted” which is intended to encompass unsubstituted moiety, substituted derivatives thereof, and both.

[0031] The term “alkyl” as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some aspects, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0032] The term “alkenyl” as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some aspects from 2 to 8 carbon atoms Examples include, but are not limited to vinylcyclohexenyl, cyclopentenyl, cyclohexadienyl,butadienyl, pentadienyl, and hexadienyl, among others.

[0033] The term “alkynyl” as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some aspects, from 2 to 8 carbon atoms. Examples include, but are not limited to -among others.

[0034] The term “acyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a “formyl” group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3 -carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a “haloacyl” group. An example is a trifluoroacetyl group.

[0035] The term “cycloalkyl” as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some aspects, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other aspects the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbomyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or in combination denotes a cyclic alkenyl group.

[0036] The term “haloalkyl” group, as used herein, includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1 -di chloroethyl, 1,2-di chloroethyl, l,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like. “Haloalkyl” groups include groups having a chiral center, such as -CHFC1, and thus includes (R), (S), and racemic forms of such groups.

[0037] As use herein, the terms “halo,” “halogen,” or “halide” group by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0038] The term “aryl” as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some aspects, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof. The term “aralkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

[0039] The term “heterocyclyl” as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. The term “heteroaryl” as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. The term “heterocyclylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. The term “heteroarylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.

[0040] The term “alkoxy” as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.

[0041] The structures disclosed herein, in all of their aspects are intended to include only "chemically feasible" structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein. By "chemically feasible" is meant a bonding arrangement or acompound where the generally understood rules of organic structure are not violated; for example, a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim.

[0042] All chiral, diastereomeric, racemic forms of a structure are intended, unless a particular stereochemistry or isomeric form is specifically indicated. Compounds described in the present disclosure can include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the disclosure.

[0043] As used herein, the term "purified" and like terms relate to an enrichment of a molecule or compound relative to other components normally associated with the molecule or compound in a native environment. The term "purified" does not necessarily indicate that complete purity of the particular molecule has been achieved during the process. A "highly purified" compound as used herein refers to a compound that is greater than 90% pure.

[0044] A "compound," as used herein, refers to any type of substance or agent that is commonly considered a drug, or a candidate for use as a drug, as well as combinations and mixtures of the above. When referring to a compound of the disclosure, and unless otherwise specified, the term "compound" is intended to encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs or equivalents, including, but not limited to, salts, polymorphs, esters, amides, prodrugs, adducts, conjugates, active metabolites, and the like, where such modifications to the molecular entity are appropriate.

[0045] As used herein, the term “salts” and “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like. Pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In some instances, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric (or larger) amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; for example, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the disclosure of which is hereby incorporated by reference. The term “solvate” means a compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.Anthelmintic Benzodiazepines

[0046] The present disclosure provides a compound having a structure according to Formula I, II, III, IV, or V, and uses thereof.

[0047] For example, the present disclosure provides a compound having a structure according to Formula I, or a salt thereof: whereinR1is H, C2-C6alkyl, C2-C6haloalkyl, C3-C6cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3, or haloalkyl;R2and R4 are each independently H, F, Cl, Br, I, methyl, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, -NH2, -NHR, -NRR, CN, or -OR, wherein at least one of R2and R4 is other than H;W is C-R3, C-NO2, C-CH3, C-F, or C-Y; R3is H, alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl;, each of which may be optionally substituted by one, two, or more Rs;X is each independently C-R5or N;R5is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or -CO2H;G is C-Y or N;Y is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, -CCR, -OR, pyridinyl, phenyl, or R6;R7 is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, or N;T is N or CH;J is O, Z, NH, or NR, or J and the double bond to the carbon to which it is attached are replaced with JI and J2, wherein JI and J2 are each independently H, R, OR, SR, NHR, or NR2, or J together with the carbon to which it is attached forms a triazole or imidazole together with R1and the nitrogen to which it is attached;R9 is H, alkyl, cycloalkyl, fluoroalkyl, F, Cl, Br, I, alkyl, or CF3;Z is O or S; each instance of R is independently H, alkyl, or acyl; and wherein the compound is other than meclonazepam.

[0048] As further examples, the present disclosure provides a compound having a structure according to one or more of the following, or a salt thereof:whereinR1is H, C2-C6alkyl, C2-C6haloalkyl, C3-C6cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3, or haloalkyl;R2and R4 are each independently H, F, Cl, Br, I, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, -NH2, -NHR, -NRR, CN, or -OR, wherein at least one of R2and R4 is other than H;W is C-R3, C-NO2, C-CH3, C-F, or C-Y; R3is H alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl;X is each independently C-R5or N;R5is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or -CO2H;G is C-Y or N;Y is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, -OR, pyridinyl, phenyl, or R6;R7 is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, or N;T is N or CH;J is O, S, NH, or NR, or J and the double bond to the carbon to which it is attached are replaced with JI and J2, wherein JI and J2 are each independently H, R, OR, SR, NHR, or NR2;R9 is H, alkyl, cycloalkyl, fluoroalkyl, F, Cl, Br, I, alkyl, or CF3;Z is O or S; and each instance of R is independently H, alkyl, or acyl.

[0049] As another example, the present disclosure provides a compound having a structure according to Formula II, or a salt thereof:Formula II whereinR1is H, C2-C6alkyl, C2-C6haloalkyl, C3-C6cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3, or haloalkyl;R2and R4 are each independently H, F, Cl, Br, I, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, and -OR, wherein at least one of R2and R4 is other than H; R3is H alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl;X is C-R5or N;R5is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or -CO2H;G is C-Y or N;Y is H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, -OR, pyridinyl, phenyl, or R6;R? is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, or N;R9 is H, alkyl, cycloalkyl, fluoroalkyl, F, Cl, Br, I, alkyl, or CF3;Z is O or S; and each instance of R is independently H, alkyl, or acyl.

[0050] The present disclosure provides a compound having a structure according to Formula III, or a salt thereof:whereinR2and R4 are each independently H, F, Cl, Br, I, CF3, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, and -OR, wherein at least one of R2and R4 is other than H.

[0051] The present disclosure provides a compound having a structure according to Formula IV, or a salt thereof:whereinR2and R4 are each independently H, F, Cl, Br, I, CF3, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, and -OR, wherein at least one of R2and R4 is other than H; R3is alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl; and U is CH2, CRH, CR2, or CO.

[0052] The present disclosure provides a compound having a structure according to Formula V, or a salt thereof:Formula V whereinR2and R4 are each independently H, F, Cl, Br, I, CF3, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)s, and -OR, wherein at least one of R2and R4 is other than H, and R3is alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl.

[0053] The compound can be an enantiomer. In various aspects, R2and R4 taken together with the carbon to which they are attached provide an S-stereocenter. In other aspects, R2and R4 taken together with the carbon to which they are attached provide an R-stereocenter. The compound can be in an enantiomerically purified form. The enantiomerically purified form can demonstrate an enantiomeric excess of at least or about 50% ee, 55% ee, 60% ee, 65% ee, 70% ee, 75% ee, 80% ee, 85% ee, 90% ee, 95% ee, 97% ee, 99% ee, 99.9% ee, or about 100% ee. In various other aspects, the compound can be in racemic form.

[0054] In various aspects, R1is H, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, CD3, (S)-CDFH, (R)-CDFH, (S)-CH3CHCF3, or (R)-CH3CHCF3. In various aspects, R1is H.

[0055] In various aspects, R2is F, Cl, Br, I, trifluoromethyl, CF2H, CH2F, trichloromethyl, methyl, ethyl, OH, or OAc. In further aspects, R2is H or methyl. In yet further aspects, R2is H.

[0056] In various aspects, R4 is F, Cl, Br, I, trifluoromethyl, CF2H, CH2F, trichloromethyl, ethyl, OH, or OAc. In further aspects, R4 is OH, OAc, F, or ethyl. In various further aspects, one of R2and R4 is F.

[0057] In various aspects, X is C-R5and R5is F, Br, Cl, I, cyano, nitro, methyl, or -CO2H. In further aspects, R5is F or Cl.

[0058] In various aspects, G is C-Y and Y is nitro, -CO2H, chloro, bromo, trifluoromethyl, cyano, methoxy, hydroxy, cyclopropyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, or R6.

[0059] In various aspects,whereinR7 if present is methyl, cyano, trifluoromethyl, hydroxy or methoxy, and R8if present is methyl, cyano, trifluoromethyl, hydroxy or methoxy.

[0060] In various aspects, Y is nitro. In various aspects, Y is -CO2H.

[0061] In various aspects, R is H, methyl, or acetyl.

[0062] In various aspects, Z is O.

[0063] In various aspects, Q is CH.

[0064] In various aspects, one of R2and R4 is other than H, alkyl, and OR. In various aspects, one of R2and R4 is a halogen. In various aspects, one of R2and R4 is F. In various aspects, R5can be other than Cl.

[0065] In various aspects, when one of R2and R4 is halogen, then at least one of Rs is other than halogen and H. In further aspects, when one of R2and R4 is halogen, then at least one of Y is other than halogen, H, and NO2.

[0066] In various aspects, R1is H, is HR,3X is C-Rs, G is C-Y, Q is C-H, and Z is O.

[0067] In various aspects, R1is H, is HR,3X is C-Rs, G is C-Y, Q is C-H, Z is O, and Rs is Cl.

[0068] In various aspects, R1is H, is HR,3X is C-Rs, G is C-Y, Q is C-H, Z is O, and Y is nitro or -CO2H. In various aspects, R1is H, is H, XR3is C-Rs, G is C-Y, Q is C-H, Z is O, Rs is Cl, and Y is nitro or -CO2H. In various aspects, is H, XR is3C-Rs, G is C-Y, Q is C-H, Z is O, R5is Cl, Y is nitro or -CO2H, one of R2and R4 is halogen, and one of R2and R4 is a halogen. In various aspects, R1is H, is H,R X3is C-Rs, G is C-Y, Q is C-H, Z is O, R5is Cl, Y is nitro or -CO2H, one of R2and R4 is halogen, and one of R2and R4 is F.

[0069] The disclosure also provides a compound having the following structure, or a salt thereof:

[0070] The disclosure also provides a compound having the following structure, or a salt thereof:

[0071] The disclosure also provides a compound having the following structure, or a salt thereof:

[0072] The disclosure also provides a compound having the following structure, or a salt thereof:

[0073] The disclosure also provides a compound having the following structure, or a salt thereof:enantiopurified form.

[0074] The disclosure also provides a compound having the following structure, or a salt thereof:

[0075] The disclosure also provides a compound having the following structure, or a salt thereof:

[0076] The disclosure also provides a compound having a structure according to FormulaI, or a salt thereof:whereinR1is H, C2-C6alkyl, C2-C6haloalkyl, C3-C6cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3, or haloalkyl;R2and R4 are each independently H, F, Cl, Br, I, methyl, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, -NH2, -NHR, -NRR, CN, or -OR, wherein at least one of R2and R4 is other than H;W is C-R3, C-NO2, C-CH3, C-F, or C-Y; R3is H, alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl;L is pyridyl, phenyl, cyclohexyl,, each of which may be optionally substituted by one, two, or more Rs;X is each independently C-R5or N;R5is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or -CO2H;G is C-Y or N;Y is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, -CCR, -OR, pyridinyl, phenyl, or R6;R7 is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, or N;T is N or CH;J is O, Z, NH, or NR, or J and the double bond to the carbon to which it is attached are replaced with JI and J2, wherein JI and J2 are each independently H, R, OR, SR, NHR, or NR2, or J together with the carbon to which it is attached forms a triazole or imidazole together with R1and the nitrogen to which it is attached;R9 is H, alkyl, cycloalkyl, fluoroalkyl, F, Cl, Br, I, alkyl, or CF3;Z is O or S; each instance of R is independently H, alkyl, or acyl; and wherein the compound is other than meclonazepam.

[0077] The disclosure also provides a compound having a structure according to FormulaII, or a salt thereof:Formula II wherein R1is H, alkyl, cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3or haloalkyl, ;R2and R4 are each independently H, Cl, Br, F, I, C2-C6haloalkyl, C2-C6alkyl, and - OR, wherein at least one of R2and R4 is other than H; R3is H, F, Cl, Br, I, or alkyl;X is C-R5or N;R5is Cl, Br, F, I, cyano, nitro, alkyl, or -CO2H;G is C-Y or N;Y is H, nitro, -CO2H, Cl, Br, F, I, cyano, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, cycloalkylalkyl, cyclopropyl alkyl, isopropyl alkyl, t-butylalkyl, -OR, pyridinyl, phenyl, or R6;R7 is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, or N;R9 is alkyl, cycloalkyl, fluoroalkyl, or haloalkyl;Z is O or S; each instance of R is independently H, alkyl, or acyl,when R2or R4 is -OR, then Y if present is other than F, Cl, Br, NO2, and OCF3, X is C-Rs, and R5if present is other than H and halogen, and when R2or R4 is -F or Cl, then Y if present is other than F, Cl, Br, and NO2, X is C- Rs, and R5if present is other than H and halogen.

[0078] The disclosure also provides a compound having a structure according to FormulaII, or a salt thereof:Formula II

[0079] wherein R1is H, alkyl, cycloalkyl, or haloalkyl; R2and R4 are each independently H, Cl, Br, F, I, C2-C6haloalkyl, C2-C6alkyl, and -OR, wherein at least one of R2and R4 is other than H; R is3H or alkyl; X is C-R5or N; R5is Cl, Br, F, I, cyano, nitro, alkyl, or - CO2H; G is C-Y or N; Y is nitro, -CO2H, Cl, Br, F, I, cyano, alkyl, cycloalkyl, fluoroalkyl, -OR, pyridinyl, phenyl, or R6;

[0080]

[0081] R7 is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR; R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR; Q is C-H or N; Z is O or S; each instance of R is independently H, alkyl, or acyl, when R2or R4 is -OR, then Y if present is other than F, Cl, Br, NO2, and OCF3, X is C-Rs, and R5if present is other than H and halogen, and when R2or R4 is -F or Cl, then Y if present is other than F, Cl, Br, and NO2, X is C-Rs, and R5if present is other than H and halogen.

[0082] A compound having a structure according to Formula I-V, or a salt thereof, wherein the compound exhibits reduced affinity for Gamma-aminobutyric acid receptor subunit alpha-1 relative to meclonazepam. Example compounds of Formula I-V are provided in Table 1.Table 1. Structures of MCLZ-type Benzodiazepine Derivatives

[0083] The benzodiazepine meclonazepam (MCLZ) has proven anti-parasitic efficacy in vivo and its mechanism differs from the present broad-spectrum monotherapy, praziquantel, currently used global to treat schistosomiasis. Unlike praziquantel, MCLZ is directly schistocidal and can cure immature (juvenile) parasite infections. Development of MCLZ stalled in the 1980’s due to dose-limiting sedation in human trials. However, we now know that Schistosoma genomes lack GABAARS. Without limiting to theory, MCLZ and MCLZ- type compounds may sedation via this target. Notably, the receptor or mechanistic underpinnings for schistocidal activity is not known. Gene loss is common with the evolution of parasitism, and MCLZ is inactive against the channels most similar to GABAARS retained in these worms (Glutamate-Gated Cl- Channels). The schistosome target of MCLZ is distinct from GABAARS, thus offering the possibility of identifying a selective compound having schistocidal activity without sedative effects.

[0084] Previous drug discovery efforts related to MCLZ relied on superficial, subjective readouts such as inhibition of movement that are frequently not reproducible between labs. (See, Panic, G., Vargas, M., Scandale, I. & Keiser, J. Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni. PLoS Negl Trop Dis 9, e0003962, doi: 10.1371 / journal.pntd.0003962 (2015). ). The present disclosure provides new vitro assays for screening schistocidal compounds. After in vivo drug exposure, parasites are swept from the mesenteric vasculature to the liver where they are cleared from the host. This acute ‘hepatic shift’ can be quantified within hours after drug treatment, or animals can be tracked longer term (1 wk) and assayed for reduction in parasite burden. Pairing these outcomes with measurements of MCLZ binding to GABAARS have now allowed structure-activity screen to identify suitable modifications to the benzodiazepine core that increase parasite selectivity.

[0085] Various compounds presently described offer schistocidal activity against parasitic worms without dose-limiting sedation in the parasite host. In various further aspects, various compounds described herein can inactivate a parasitic worm with minimal affinity for mammalian gamma-aminobutyric acid receptors, such as Gamma-aminobutyric acid receptor subunit alpha- 1. In yet further aspects, various compounds described herein can inactivate a parasitic worm with minimal effect on sedating receptors within the brain or central nervous system.

[0086] Non-sedative MCLZ-type compounds represent a promising approach to schistosomiasis therapy because such compounds can be both (i) directly schistocidal and (ii) efficacious against immature and mature parasites. Not only is this profile superior topraziquantel, but it may indicate a distinct mechanism of action, which is desirable should praziquantel resistant parasites emerge. Various compounds of the present disclosure also have the potential to be efficacious against a range of flatworms. Praziquantel is the frontline drug to treat the tapeworm and liver fluke infections that comprise l / 5th of all WHO classified neglected tropical diseases (taeniasis, echinococcosis and food-borne trematode infections), and various of the present compounds may be reasonably expected to address such parasites. Additionally, human schistosomiasis is often co-endemic with zoonotic infections, resulting in increased transmission and hybrids with increased fecundity. Developing veterinary drugs for improved control of these parasite reservoirs will provide advantages to animals but also aid in human schistosomiasis elimination.Synthesis of Anthelmintic Benzodiazepines

[0087] The present disclosure provides a method of synthesizing various compounds of Formula I-V. Those of ordinary skill in the art in view of the present disclosure will readily understand how to apply their knowledge of organic synthesis to prepare compounds of the present disclosure as well as variations and analogs thereof.

[0088] In one example approach, the starting amino benzophenone can be prepared from commercially available anilines with desired substituents as a Friedel-Crafts acylation with the desirably substituted benzoyl chloride using copper tritiate. Chiral C3 (R)- or (S)-analogs can be prepared coupling D or L alanine, respectively, with amino benzophenone. Other substitution of functional groups at C3 such as hydroxyl or esters at the benzodiazepine C3 position can be readily achieved via alpha-functionalized of appropriate l,3-dihydro-2H- benzo[e] [ 1 ,4]diazepin-2-ones.

[0089] Additional example approaches to functionalizing various positions of the benzodiazepines core are provided in Scheme 1 and Scheme 2 as follows.Scheme 1. Example Synthetic Approach (C-3 modified analogs)Scheme 2. Example Synthetic Approach (C-7 modified analogs)

[0090] Preparation of derivatives modified at other positions can be achieved by using advanced analogs or de novo. Synthesis of benzodiazepines and their analogs are widely described in the literature. The aforementioned synthetic routes are merely examples of the many possible approaches to compounds described herein. Those skilled in the art will readily ascertain alternative paths to such compounds as well as how to access various modifications and variations of such compounds based on the present disclosure. Synthetic transformations suitable for preparing the presently described compounds and derivatives thereof are described in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. Author(s): Michael B. Smith, Jerry March, First published: 18 May 2006, which is herein incorporated by reference. Benzodiazepines can also be accessed as described inMian et al. (2024). Development of non-sedating benzodiazepines with in vivo anti schistosomal activity.Pharmaceutical Compositions

[0091] The present disclosure also provides a pharmaceutical composition comprising one or more of the presently described compounds together with a pharmaceutically acceptable carrier.

[0092] Various aspects of the present disclosure also contemplate pharmaceutical compositions comprising one or more compounds of the present disclosure and one or more pharmaceutically acceptable excipients. A “pharmaceutical composition” refers to a chemical or biological composition suitable for administration to a subject (e.g., mammal). Such compositions can be specifically formulated for administration via one or more of a number of routes, including but not limited to buccal, cutaneous, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. In addition, administration can by means of capsule, drops, foams, gel, gum, injection, liquid, patch, pill, porous pouch, powder, tablet, or other suitable means of administration.

[0093] A “pharmaceutical excipient” or a “pharmaceutically acceptable excipient” is a carrier, sometimes a liquid, in which an active therapeutic agent is formulated. The excipient generally does not provide any pharmacological activity to the formulation, though it can provide chemical and / or biological stability, and release characteristics. Examples of suitable formulations can be found, for example, in Remington, The Science And Practice of Pharmacy, 20th Edition, (Gennaro, A. R., Chief Editor), Philadelphia College of Pharmacy and Science, 2000, which is incorporated by reference in its entirety.

[0094] As used herein “pharmaceutically acceptable carrier” or “excipient” includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are physiologically compatible. In one aspect, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual, or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0095] Pharmaceutical compositions can be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the desired particle size in the case of dispersion and by the use of surfactants.

[0096] In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, the compounds described herein can be formulated in a time release formulation, for example in a composition that includes a slow-release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art.

[0097] Oral forms of administration are also contemplated herein. The pharmaceutical compositions of the present disclosure can be orally administered as a capsule (hard or soft), tablet (film coated, enteric coated or uncoated), powder or granules (coated or uncoated) or liquid (solution or suspension). The formulations can be conveniently prepared by any of the methods well-known in the art. The pharmaceutical compositions of the present disclosure can include one or more suitable production aids or excipients including fillers, binders, disintegrants, lubricants, diluents, flow agents, buffering agents, moistening agents, preservatives, colorants, sweeteners, flavors, and pharmaceutically compatible carriers.

[0098] For each of the recited aspects, the compounds can be administered by a variety of dosage forms as known in the art. Any biologically- acceptable dosage form known to persons of ordinary skill in the art, and combinations thereof, are contemplated. Examples of such dosage forms include, without limitation, chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, gum, granules, particles, microparticles, dispersible granules, cachets, douches, suppositories, creams, topicals, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, ingestibles, injectables (including subcutaneous, intramuscular, intravenous, and intradermal), infusions, and combinations thereof.

[0099] Other compounds which can be included by admixture are, for example, medically inert ingredients (e.g., solid and liquid diluent), such as lactose, dextrosesaccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; gelling agents such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin, polysorbates or laurylsulphates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations.

[0100] Liquid dispersions for oral administration can be syrups, emulsions, solutions, or suspensions. The syrups can contain as a carrier, for example, saccharose or saccharose with glycerol and / or mannitol and / or sorbitol. The suspensions and the emulsions can contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[0101] The amount of active compound in a therapeutic composition according to various aspects of the present disclosure can vary according to factors such as the infection state, age, gender, weight, patient history, risk factors, predisposition to infection, administration route, pre-existing treatment regime (e.g., possible interactions with other medications), and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response.For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of therapeutic situation.

[0102] The pharmaceutical composition can be in a dosage unit form suitable for treating a parasitic worm infection in a human or veterinary subject. A “dosage unit form,” as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on the characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects. In therapeutic use for treatment of parasites in mammals (e.g., humans) for which the compounds of the present disclosure or an appropriate pharmaceutical composition thereof are effective, the compounds of the present disclosure can be administered in an effective amount. The dosages as suitable can be a composition, a pharmaceutical composition or any other compositions described herein.

[0103] The compositions described herein can be administered in any of the following routes: buccal, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. In various aspects, the route of administration is oral. The administration can be local, where the composition is administered directly, close to, in the locality, near, at, about, or in the vicinity of, the site(s) of the parasite, wherein the composition is given to the patient and passes through the body widely, thereby reaching the site(s) of the parasite. Local administration can be administration to, for example, tissue, organ, and / or organ system, which encompasses and / or is affected by the parasite, and / or where the parasite is active or are likely to occur.

[0104] The disclosure also provides a pharmaceutical composition comprising a compound according to Formula I-V formulated for use as an anthelmintic agent. Such formulation can be at an amount effective to inactivate a parasitic worm, treat a parasitic worm infection, or treat schistosomiasis.

[0105] In various aspects, the disclosure provides a pharmaceutical composition comprising a compound according to Formula I-V in an amount below the amount effectiveto induce sedative effects, hypnotic effects, CNS effects, GAB Anergic effects, anxiolytic effects, nervous system effects, brain effects, antiseizure effects, muscle relaxant effects. For example, the pharmaceutical composition can be formulated to exploit the therapeutic window between anthelmintic effects and sedative effects. Thus, in various examples, the pharmaceutical composition can be formulated in an amount effective to inactivate a parasitic worm, treat a parasitic worm infection, and / or treat schistosomiasis, but not at an amount effective to induce sedative effects, hypnotic effects, CNS effects, GAB Anergic effects, anxiolytic effects, nervous system effects, brain effects, antiseizure effects, muscle relaxant effects.Treatment of Parasitic Worms

[0106] The present disclosure provides a method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound according to Formula I, Formula III, Formula IV, or Formula V, or a salt thereof, to the patient in need thereof. The present disclosure also provides a method of treating schistosomiasis in a patient, comprising administering a therapeutically effective amount of a compound according to Formula I, Formula III, Formula IV, or Formula V, or a salt thereof, to the patient in need thereof. The present disclosure further provides a method of inactivating a parasitic worm, comprising contacting the parasitic worm with a compound according to Formula I, Formula III, Formula IV, or Formula V, or a salt thereof to the patient in need thereof. The present disclosure yet further provides a method of treating a disease or condition arising from a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound according to Formula I, Formula III, Formula IV, or Formula V, or a salt thereof, to the patient in need thereof.

[0107] In various aspects, the parasitic worm is an intestinal parasite. For example, the parasitic worm can be a flatworm. The parasitic worm can be a bloodworm. In various aspects, the parasitic worm is Schistosoma mansoni. In various other aspects, the parasitic worm is Schistosoma haematobium. The parasitic worm can be a juvenile worm, or a mixture of adult and juvenile worms. In various aspects, the parasitic worm or parasitic worm infection is praziquantel-resistant.

[0108] The term “therapeutically effective amount” as used herein, refers to that amount of one or more compounds of the various examples of the present disclosure that elicits a biological or medicinal effect in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor or other clinician, which effects include inactivatinga parasite, treating a parasitic worm infection, or alleviating one or more symptoms of a parasitic worm infection. In some examples, the therapeutically effective amount is that which can treat or alleviate the parasitic worm infection at a reasonable benefit / risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the compounds and compositions described herein can be decided by a physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the condition being treated and the severity of the condition; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician. It is also appreciated that the therapeutically effective amount can be selected with reference to any toxicity, or other undesirable side effect, which might occur during administration of one or more of the compounds described herein. In various aspects, the therapeutically effective amount is an amount effective for treatment of a parasitic worm infection or a disease or symptom arising therefrom. In various aspects, the therapeutically effective amount is less than the amount sufficient to impart, minimizes, or does not impart, a GABA-related effect in the patient. For example, the therapeutically effective amount can be an amount sufficient to treat a parasitic worm infection or a disease or symptom arising therefrom, but less than the amount that imparts one or more sedative effects, hypnotic effects, CNS effects, GAB Anergic effects, anxiolytic effects, nervous system effects, brain effects, antiseizure effects, muscle relaxant effects, and other GABA-imparted effects in a patient.

[0109] The term "inactivate," as used herein, refers to the ability of a compound of the disclosure to reduce or impede normal functioning of a given target, such as a parasitic worm. For example, inactivation of a parasitic worm can include reducing or impeding growth, reproduction, motility, infectiousness, survival, and the like of the parasitic worm. Inactivating can include killing and destroying.

[0110] As used herein, the terms "administering" a compound should be understood to mean providing a compound of the present disclosure to a subject in need of treatment.

[0111] In various aspects, the patient is a human. In various other aspects, the patient is a non-human animal. As used herein, a "subject" or “patient” refers to a human or non-humananimal being treated or otherwise being administered the presently described compound, e.g., for experimental, diagnostic, prophylactic and / or therapeutic purposes. Subject and patient can include non-human animals, for example companion animals, non-human mammals, veterinary animals, livestock, zoo animals, domesticated animals, exotic animals, wild animals, and non-domesticated animals being treated. A “veterinary subject” refers to a non- human animal. It is understood and herein contemplated that “mammal” includes but is not limited to humans, non-human primates, cows, horses, dogs, cats, mice, rats, rabbits, and guinea pigs.EXAMPLES

[0112] Various aspects of the present disclosure can be better understood by reference to the following Examples which are offered by way of illustration. The invention is not limited to the Examples given herein.Materials & Methods

[0113] Chemical Materials. Meclonazepam was purchased from Anant Pharmaceuticals and verified as greater than 99% pure by HPLC. For HPLC experiments, a meclonazepam reference standard was purchased from Sigma Aldrich (catalog number M-197-1ML) (St. Louis, MO). The reactions were performed in round-bottom flasks with magnetic stir bars under an argon atmosphere or air condition. Organic solvents were purified, when appropriate, by standard methods or purchased from Sigma-Aldrich Chemicals. Reagents and other chemicals were purchased from either Sigma-Aldrich (St. Louis, MO), Oakwood Chemical (West Columbia, SC), Alfa Aesar (Ward Hill, MA), Matrix Scientific (Elgin, SC), Admiral Chemical Company (Milwaukee, WI), or Acros Organic (Antwerp, Belgium). The progress of reactions was visualized with TLC plates from Dynamic Adsorbents, Inc.(Norcross, GA), under a UV light. LCMS 2020 was used to monitor some reactions. Flash column chromatography was done for purification of some analogs on silica gel (230-400 mesh, Dynamic Adsorbents). A normal phase Agilent HPLC was used to determine the ratio of optically active enantiomers as well as to determine %ee. The 1H NMR and 13C NMR spectra were obtained on Bruker Spectrospin 500 MHz instrument in CDC13 and chemical shifts were reported in 5 (ppm). Multiplicities are represented as follows: singlet (s), broad signal (br), doublet (d), triplet (t), quartet (q), dd (doublet of doublets), and multiplet (m). The technique employed for HRMS was carried out on a LCMS-IT-TOF at the MilwaukeeInstitute for Drug Discovery in the Shimadzu Laboratory for Advanced and Applied Analytical Chemistry.

[0114] Purification of enantiomers. MYM-III-10 and MYM-V-56 enantiomers were purified by preparative HPLC. The (R) and (S) enantiomers of MYM-III-10 were separated by using an isocratic mixture of 88% n-hexane and 12% ethanol as the mobile phase in an HPLC system consisting of a quaternary pump, auto sampler and a DAD detector. The method time was set for 55 min. A chiral preparative HPLC column, Reflect I cellulose C 5 pm, 25 cm x 21.1 mm was used for separating the enantiomers. The first fraction (R isomer) for MYM-III-10 was collected from 35.2 to 40.2 min and the second fraction was collected from 45.5 to 50 min. Approximately, 15 mL of sample was collected for each fraction after each injection. The fractions were evaporated separately just after collection and dried. Compounds were then analyzed by NMR. The DAD wavelength range was set at 200-400 nm. A 254 nm wavelength was used for relative % area determination. The flow rate was set at 21 mL / min. The (R) and (S) enantiomers of MYM-V-56 were separated using the same method, but set for 25 min. The first fraction (R isomer) for MYM-V-56 was collected from 19.5 min to 21.2 min and the second fraction was collected from 22.4 min to 23.4 min. Approximately, 15 mL of sample was collected for each fraction after each injection. The fractions were evaporated separately just after collection, dried, and analyzed by NMR. To confirm the absolute configuration of MYM-V-56, the X-ray crystal structure of the first fraction was determined and it turned out to be the (R) configuration, indicating the other enantiomer is (S)-configuration. A clear colorless chunk crystal of dimensions 0.236 x 0.185 x 0.080 mm was mounted on a MiteGen MicroMesh using a small amount of Cargille Immersion Oil. Data were collected on a Bruker three-circle platform diffractometer equipped with a PHOTON II CP AD detector. The crystals were irradiated using a Ips microfocus CuKasource (1 = 1.54178) with Montel optics. Data was collected at room temperature (20°C) and the unit cell was initially refined using APEX3 [v2015.5-2]. Data Reduction was performed using SAINT [v8.34A] axAXPREP [v2014 / 2] (Bruker AXS Inc.). Corrections were applied for Lorentz, polarization, and absorption effects using SADABS [v2014 / 2] and the structure was solved and refined with the aid of SHELXL-2014 / 7 (Bruker AXS Inc.). The full-matrix least-squares refinement on F2included atomic coordinates and anisotropic thermal parameters for all non-H atoms. Hydrogen atoms were located from the difference electron-density maps and added using a riding model.

[0115] In vitro antischistosomal activity assays. Female Swiss Webster mice infected with NMRI strain S. mansoni were provided by the NIH-NIAID Schistosomiasis Resource Center and euthanized by CO2 asphyxiation and cervical dislocation 6-7 weeks postinfection. Adult schistosomes were harvested from the mesenteric vasculature and placed in culture media consisting of high -glucose DMEM supplemented with 5% fetal calf serum, penicillin-streptomycin (100 units / mL), HEPES (25 mM) and sodium pyruvate (1 mM) and cultured at 37°C / 5% CO2. Worms were treated with either DMSO control or test compounds for 14 hours at 37°C / 5% CO2 prior to observing phenotypes. Worms were visually observed on a Zeiss Stemi 305 Stereo Microscope to assess changes in morphology and images were captured on an Axiocam 208 color camera. For motility experiments, serotonin (5-HT) was added at 250 pM to increase worm movement at least 1 hour prior to imaging on an ImageXpress Nano (Molecular Devices). Time lapse recordings were acquired for each well (15 second videos at a rate of 4 frames / second) using a 2X objective.Movement was analyzed using the wrmXpress package.

[0116] All animal work was carried out with the oversight and approval of UW -Madison Research Animal Resources and Compliance (RARC), adhering to the humane standards for the health and welfare of animals used for biomedical purposes defined by the Animal Welfare Act and the Health Research Extension Act.

[0117] In vivo antischistosomal activity assays. For hepatic shift assays, mice harboring seven week old S. mansoni infections were administered either DMSO control, MCLZ or test compound solubilized in vegetable oil (0.25 mL) by oral gavage and then euthanized as outlined above (CO2 asphyxiation followed by cervical dislocation) three hours later. Worms were dissected from the liver and mesenteries, and the percentage of worms in each location was calculated. For longer term assays measuring curative activity of drugs, compounds were administered orally to mice harboring six week old S. mansoni infections. Mice were euthanized one week later, and the total parasite burden for each mouse was counted. To assess the curative effects of compounds on juvenile, liver stage parasites mice harboring four week old S. mansoni infections were dosed orally with test compound and euthanized at seven weeks to count parasite burden.

[0118] Rotarod assay for sedation. Six week old female Swiss Webster mice were chosen for study since this matches the strain used in the parasite assays. Uninfected mice were ordered from Taconic or Charles River and trained to perform the rotarod test using a IITC Life Science rotarod device with the following settings: 20 RPM max speed, 20 rampspeed, and 300 second duration test. Mice were run five at a time and used for drug assays if they were capable of completing the training and able to run on the device for 300 seconds. Mice were then dosed with test compounds by oral gavage and tested on the rotarod device after 5 minutes.

[0119] Detection of MCLZ and MYM-III-10 from brain and serum. Six week old female Swiss Webster mice were dosed with MCLZ or MYM-III-10 (100 mg / kg) as described in the anti schistosomal assays and then euthanized after 10 minutes by CO2 asphyxiation. Whole blood samples were collected from each mouse and allowed to clot at room temperature for 15 minutes. Serum was separated by centrifugation at 2,000 x g for 10 minutes. The skull was opened with scissors and all brain tissue was removed. Both samples were frozen at -80°C until ready for analysis by HPLC. To prepare samples for HPLC brain tissue homogenized with BeadBug microtube homogenizer and the solid phase extraction procedure was carried out on Hypersep Cl 8 cartridges. Separations were obtained on Shimadzu HPLC System with Waters Symmetry C18 column (150x3.9 mm id, 5 pm) kept at 30°C. The mobile phase was composed of a mixture of MeOH (65% v / v) + 0.1% Formic acid and ultrapure water (35% v / v) + 0.1% Formic acid. The flow rate was set at 0.5 mL / min. Detection was carried out on a Shimadzu Diode Array Detector SPD-M20A at 254 nm. Spiked in meclonazepam used as an internal standard for MYM-III-10 treated samples, and vice versa.

[0120] Binding and functional assays. MYM-V-56 binding was assessed by two panels of assays. The Safety Screen 44 Panel was performed by Eurofins Pharma Discovery. Per vendor recommendations, each assay was performed using 10 pM of MYM-V-56 in technical duplicates. MYM-V-56 (10 pM) binding to receptors in the NIMH Psychoactive Drug Screening Program (PDSP) in technical quadruplicate per SOPs in the PDSP assay protocol book found at pdsp.unc.edu / pdspweb / .

[0121] Additional analysis of worm (TRP) and human (GABAAR) binding. The human GABAAR cryo-EM derived structure (6HUP)89and S. mansoni TRP channel Smp_333650 AlphaFold model (AF-A0A5K4FCC0-F1 -model) are prepared for docking using ChimeraX vl.7 DockPrep utility. Benzodiazepine libraries are prepared using OpenEye OMEGA. Visual inspection of binding poses and scoring functions from docking output are used to prioritize compounds for synthesis. Affinity of test compounds for mammalian GABAARS are further measured by displacement of flunitrazepam from rat brain membrane homogenate. Membranes (200pg, Novus Biologicals) in Tris-HCl (50 mM, pH 7.7) plus[3H]-flunitrazepam (0.4nM, Perkin Elmer) and either DMSO or test ligand (10 nM - 10 pM) are added to 96 well filter plates (Millipore Multi Screenirrs) and incubated 60 min, 4°C. Nonspecific binding is assessed with diazepam (3 pM). Following vacuum filtration, radioactivity is measured by liquid scintillation counting. Adult schistosomes are harvested from infected mice cultured overnight in drug; DMSO (negative control), meclonazepam (positive control) or test compound (0.1 - 30 pM, 8 worms per concentration). Motility is measured using wrmXpress, per Wheeler et al. (2022) “wrmXpress: A modular package for high-throughput image analysis of parasitic and free-living worms.” PLOS Neglected Tropical Diseases 16(11): e0010937). Compounds will be considered active if they are at least as potent as meclonazepam, 1 - 5 pM. A murine mouse model of schistosomiasis can be used to analyze anti schistosomal efficacy and sedation to confirm results of in silico and in vitro studies.Experimental Examples

[0122] Synthesis of MCLZ-type Benzodiazepine Derivatives. In order to identify antiparasitic benzodiazepines with decreased sedative potential, MCLZ derivatives were synthesized with modifications at various positions to determine whether the compounds retained antischistosomal activity. Seventeen derivatives were synthesized with modifications to the Nl, C3, N4, C7 and C2’ positions of a meclonazepam-type benzodiazepine ring system. The structures of the seventeen derivatives are summarized in Table 2. See, also, FIG. 1.

[0123] These compounds were synthesized as follows and according to the approaches illustrated in Scheme 1 and 2. A divergent synthetic approach permits functionalization at several positions on the MCLZ-type skeleton. For example, modifications at C3 can be furnished after formation of the diazepine ring core via alpha-functionalization of the carbonyl functional position. With C3 functionalization in place, further steps can be utilized to introduce or exchange other functional groups, offering C3 -modified derivatives that have a OH, Br, F, or Cl at C3. Latent functional handles at Y can be carried through to provide an option further embellishment via Suzuki coupling to larger side chains or via nitration to provide the desirable C7 nitro group. Similar, latent functional handles at Z can be carried through the synthesis to provide an option for 2’C1 at the ortho-position of the pendant phenyl group. In each case, chiral components can be resolved by using prep LC. Below, synthesis and characterization details are provided for compounds of Table 2 as well as additional examples.Table 2. Test Benzodiazepine Derivatives

[0124] (S)-5-(2-chlorophenyl)-l,3-dimethyl-7-nitro-l,3-dihydro-2H- benzo[e][l,4]diazepin-2-one (2, MYM-II-53). An oven dried 3 neck round bottom flask was charged with meclonazepam 15 (80 mg, 0.243 mmol) (Anant Pharmaceuticals Pvt. Ltd., India), anhydrous -di methyl formamide (5 ml) and methyl iodide (0.02 ml, 0.32 mmol).The mixture was stirred for 10 min until homogeneous and cooled to -30 °C. Then potassium / c / Vbutoxide (27 mg, 0.254 mmol) was added to the reaction mixture. The solution was stirred at 25 °C for 2 hours. The reaction was monitored by TLC. After completion, the reaction was quenched by adding ice cold water and then extracted with ethyl acetate (3 ^ 10 mL). The combined organic layer was washed with 25% aq. ammonium chloride (1 x 10 mL), brine (3x 10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the solid obtained was purified by flash chromatography (neutral alumina, EtOAc: hexane, 3:2) to afford pure methylated meclonazepam 2 as yellow solid (75 mg, 91%). 'H NMR (500 MHz, CDC13) 5 8.38 (dd, J= 9.1, 2.7 Hz, 1H, Ar), 7.96 (d, J= 2.6 Hz, 1H, Ar), 7.71 - 7.65 (m, 1H, Ar), 7.50 (d, J= 9.1 Hz, 1H, Ar), 7.47 - 7.43 (m, 2H, Ar), 7.39 - 7.35 (m, 1H, Ar), 3.80 (d, J= 6.5 Hz, 1H, CH), 3.55 (s, 3H, N-CH3), 1.78 (d, J= 6.5 Hz, 3H, CH3). 13C NMR (126 MHz, CDC13) 5 170.31, 166.62, 147.78, 143.12, 137.22, 133.00, 131.59, 131.27, 130.78, 130.29, 127.47, 126.09, 124.16, 122.06, 59.09, 35.33, 17.28. HRMS (ESI / ITTOF) m / z: [M + H]+ Calcd for C17H14N3O3C1 344.0796; found 344.0792.

[0125] 2-Bromo-N-(4-bromo-2-(2-chlorobenzoyl)phenyl)acetamide (4, MYM-II-81).A round bottom flask was charged with (2-amino-5-nitrophenyl)(2-chlorophenyl)methanone ( 30 g, 108 mmol) and anhydrous DCM (300 mL) and stir to make a homogenous solution. The sodium bi-carbonate (18.15 g, 216 mmol, solid) was added once to the reaction mixture. Bromoacetyl bromide (19.6 mL, 224.4 mmol) was added dropwise to the mixture at rt over a period of 30 min. The mixture was the stirred for additional 3 hours after complete addition of bromoacetyl bromide. The completion of the reaction was confirmed by silica gel TLC (30% EtOAc-hexane). The reaction mixture was quenched slowly by adding water (100 mL) over a 10 min as carbon dioxide gas evolved. The biphasic mixture, which resulted, was allowed to stand for 5 min and the layers were separated. The organic layer was separated and the aq layer was extracted with dichloromethane (2x100 mL).The combined organic layers were washed with 5% aq sodium bicarbonate solution (lx 250 mL), 10% aq sodium chloride solution (2x 250 mL) and dried (Na2SO4). The residue was slurried in ethanol (150 mL) and stirred for 20 minutes at 50°C. Upon cooling to rt, the residue was filtered, washed with cold ethanol (2x20 mL), and dried under vacuum at 40 °C to afford the product 4 as an off-white powder (42 g, 97.5%).1H NMR (500 MHz, CDCl3) δ 12.35 (s, 1H), 8.99 (d, J= 9.3 Hz, 1H), 8.45 (dd, J= 9.3, 2.7 Hz, 1H), 8.29 (d, J= 2.7 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.49 - 7.46 (m, 1H), 7.42 (dd, J= 7.6, 1.4 Hz, 1H), 4.12 (s, 2H);13C NMR (126 MHz, CDCl3) δ 197.76 (s), 166.00 (s), 145.52 (s), 142.28 (s), 137.03 (s), 132.48 (s), 131.09 (s), 130.58 (s), 130.13 (s), 129.50 (s), 129.09 (s), 127.34 (s), 121.92 (s), 121.10 (s), 29.26 (s). HRMS (ESI / IT-TOF) m / z: [M -H]- Calcd for C15H10N2O4CI 394.9440 found 394.9428.

[0126] 2-Bromo-N-(4-bromo-2-(2-fluorobenzoyl)phenyl)acetamide (5, MYM-III-50). Bromoacetyl bromide (3.3 mL, 27 mmol) was added dropwise to the mixture of (2-amino-5- nitrophenyl)(2-fluorophenyl)methanone (7 g, 27 mmol), solid sodium bicarbonate (3.4 g,40.5 mmol), and anhydrous di chloromethane (70 mL) at OoC. The mixture was the stirred for 4 hour after complete addition of bromoacetyl bromide. The completion of the reaction was confirmed by silica gel TLC (EtOAc: hexane = 3:7). The reaction mixture was quenched slowly by adding water (50 mL) over a 10 min as carbon dioxide gas evolved. The biphasic mixture, which resulted, was allowed to stand for 5 min and the layers were separated. The organic layer was separated and the aq layer was extracted with dichloromethane (2x50 mL) and the combined organic layers were washed with 5% aq sodium bicarbonate solution (lx 50 mL), 10% aq sodium chloride solution (2x 50 mL) and dried (Na2SO4). The residue was slurried in EtOH (40 mL) and stirred for 20 min at 50°C. Upon cooling to rt and holding for 2 h, the residue was filtered, washed with EtOH (2x10 mL), and dried under vacuum at 40 °C to afford the product 5 as an off-white powder (9.5 g, 92.5%). 'H NMR (500 MHz, CDCl3) δ 12.17 (s, 1H), 8.97 (d, J= 9.9 Hz, 1H), 8.47 (dd, J= 5.4, 2.4 Hz, 2H), 7.70 - 7.64 (m, 1H), 7.62 - 7.58 (m, 1H), 7.38 (t, J= 7.6 Hz, 1H), 7.26 (t, J = 9.2 Hz, 1H), 4.11 (s, 2H).13C NMR (126 MHz, CDCl3) δ 195.30 (s), 165.84 (s), 159.64 (d, J= 253.4 Hz), 144.97 (s), 142.38 (s), 134.69 (d, J= 8.5 Hz), 130.63 (d, J= 1.9 Hz), 129.78 (s), 129.11 (d, J= 2.9 Hz), 125.92 (d, J = 14.0 Hz), 125.02 (d, .7= 3.6 Hz), 122.97 (s), 121.17 (s), 116.81 (d, J= 21.5 Hz), 29.18 (s). HRMS (ESI / IT-TOF) m / z: [M +H]+ Calcd for C15H10N2O4F 380.98807 found 380.98852.

[0127] 7-Nitro-5-(2-chlorophenyl)-l,3-dihydro-2H-benzo[e] [l,4]diazepin-2-one (6, MYM-II-82). A round bottom flask was charged with 2-bromo-N-(4-nitro-2-(2- chlorobenzoyl) phenyl)acetamide (57, 70 g, 177 mmol), IPA (400 mL), HMTM (54.58 g, 390 mmol), ammonium acetate (30.07 g, 390 mmol) and the mixture was refluxed for 4 h at 82°C at which point the reaction was deemed to complete on TLC analysis (silica gel, EtOAc: Hexane=l : 1). The reaction mixture was then cooled to -10 to -5°C and hold for 2 hrs. The residue was filtered, washed cold IPA (100 mL), and water (4x200 mL). The solid was dried under vacuum at 40°C for 6 h to afford pure 6 as an off white (44.4 g, 80%). 'H NMR (500 MHz, DMSO) 5 11.31 (s, 1H), 8.37 (dd, J= 9.0, 2.7 Hz, 1H), 7.75 (d, J= 2.6 Hz, 1H), 7.65 (dt, J= 7.7, 3.5 Hz, 1H), 7.55 - 7.52 (m, 1H), 7.51 - 7.48 (m, 1H), 7.45 (dd, J= 9.0, 3.4 Hz, 1H), 4.32 (s, 2H).13C NMR (126 MHz, DMSO) 5 169.77 (s), 168.36 (s), 144.78 (s), 142.07 (s), 138.45 (s), 132.27 (s), 132.00 (s), 131.93 (s), 130.28 (s), 128.00 (s), 127.41 (s), 126.91 (s), 125.36 (s), 122.62 (s), 57.55 (s). HRMS (LCMS-IT-TOF) Calc, for C15H10N3O3CI (M - H)- 314.0338, found 314.0316.

[0128] 7-Nitro-5-(2-fluorophenyl)-l,3-dihydro-2H-benzo[e] [l,4]diazepin-2-one (7, MYM-III-55). Compound 7 (7.6 g, 80%) was synthesized from 2-bromo-N-(4-nitro-2-(2-fluorobenzoyl) phenyl) acetamide (5, 9.5 g, 23 mmol), IPA (100 mL), HMTM (7.09 g, 50.3 mmol), and ammonium acetate (3.87 g, 50.3 mmol) according to the procedure described for the synthesis of compound 7. 'HNMR (500 MHz, DMSO) 5 11.27 (s, 1H), 8.37 (d, J= 8.9 Hz, 1H), 7.90 (d, J= 2.0 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.45 (d, J= 9.0 Hz, 1H), 7.35 (t, J= 7.4 Hz, 1H), 7.24 (t, J= 9.3 Hz, 1H), 4.30 (s, 2H).13C NMR (126 MHz, DMSO) 5 169.91 (s), 165.64 (s), 160.16 (d, J = 249.0 Hz), 144.30 (s), 142.21 (s), 133.22 (d, J= 8.2 Hz), 132.11 (s), 127.68 (s), 127.16 (d, J= 12.2 Hz), 126.87 (s), 125.68 (s), 125.26 (s), 122.71 (s), 116.55 (d, J= 21.4 Hz), 57.63 (s). HRMS (LCMS-IT-TOF) Calc, for C15H10N3O3F (M + H)+300.0779, found 300.0782.

[0129] 7-Nitro-5-(2-chlorophenyl)-2-oxo-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl acetate (8, MYM-II-83). A round bottom flask was charged with potassium acetate (13.05 g, 133 mmol), iodine (8.44, 33 mmol), 7-nitro-5-(2-chlorophenyl)-l,3-dihydro-2H- benzo[e][l,4]diazepin-2-one (61, 21 g, 66.5mmol), glacial acetic acid (200 mL) and the mixture was then allowed to heat at 65°C. Then potassium persulfate (35.96 g, 133 mmol) was added to the reaction mixture at several portions. The reaction mixture was stirred at 65- 70°C for additional 5 h. At that point the reaction was deemed to complete on TLC analysis (silica gel, 50% EtOAc-hexane). The acetic acid and iodine were evaporated which resulted a purple color gummy mass. A solution of sodium thiosulfate (40 g) in water (150 mL) was added to the gummy mass and the mixture was at 70°C for 2 h. Upon cooling to 10°C, the residue was filtered, washed with hot water (2x100 mL), and dried under vacuum at 50°C for 4 h. The orange-colored crude products, which resulted was then dissolved in hot DMF (70- 80°C, 100 mL) and filtered to remove any inorganic materials. Then IPA (150 mL) was added dropwise very slowly to the clear DMF solution at 70°C and stirred for 30 minutes. The mixture was cooled to rt and kept in the refrigerator (-20°C) for 3 h. The fluffy materials, which resulted was filtered, washed with IPA (2x30 mL), and dried under vacuum at 40°C for 3 h to afford 8 as a white powder (20.4, 82%).1H NMR (500 MHz, DMSO) 5 11.77 (s, 1H), 8.44 (dd, J= 9.0, 2.6 Hz, 1H), 7.78 (d, J= 2.6 Hz, 1H), 7.70 (dd, 1H), 7.62 - 7.55 (m, 2H), 7.55 - 7.49 (m, 2H), 5.96 (s, 1H), 2.23 (s, 3H).13C NMR (126 MHz, DMSO) 5 170.00 (s), 165.01 (s), 164.66 (s), 143.47 (s), 142.56 (s), 137.33 (s), 132.52 (s), 132.31 (s), 132.04 (s), 130.43 (s), 128.15 (s), 127.65 (s), 127.38 (s), 125.16 (s), 123.10 (s), 85.36 (s), 21.14 (s). HRMS (LCMS-IT-TOF) Calc, for C17H12N3O5CI (M + H)+374.0538, found 374.0562.

[0130] 5-(2-Chlorophenyl)-3-hydroxy-7-nitro-l,3-dihydro-2H-benzo[e][l,4]diazepin- 2-one (10, MYM-III-10). A solution of NaOH (4.28 g, 107 mmol) in water (30 mL) wasadded dropwise to the stirred solution of 7-nitro-5-(2-chlorophenyl)-2-oxo-2,3-dihydro-lH- benzo[e][l,4]diazepin-3-yl acetate (65, 20 g, 53.5 mmol) in ethanol (200 mL) over a period of 30 min. The reaction mixture was then stirred for Ih at +5 to 10°C at which point the reaction was deemed to complete on TLC analysis (silica gel, 100% EtOAc). Glacial acetic acid (10 mL) was then added dropwise to the reaction mixture. The mixture was cooled to 0 to 5°C. The residue was filtered, washed with water (3x 30 mL), and dried under vacuum. The crude products were then slurried in ethanol and refluxed for 20 min. The mixture was cooled to 0 to 5°C and hold for 1 h. The residue was filtered, washed with cold ethanol (2x20 mL), and dried under vacuum for 2 h at 40°C to afford pure 10 as an off-white powder (14.7 g, 83%). ‘HNMR (500 MHz, DMSO) 5 11.44 (s, IH), 8.39 (dd, J= 9.0, 2.6 Hz, IH), 7.77 (d, J= 2.6 Hz, IH), 7.70 (dd, J= 5.8, 3.4 Hz, IH), 7.58 - 7.54 (m, 2H), 7.52 - 7.49 (m, IH), 7.44 (d, J= 9.1 Hz, IH), 6.63 (d, J= 7.1 Hz, IH), 4.96 (s, IH).13C NMR (126 MHz, DMSO) 5 169.62 (s), 144.06 (s), 142.16 (s), 137.93 (s), 132.27 (s), 132.07 (s), 131.96 (s), 130.32 (s), 128.05 (s), 127.49 (s), 127.10 (s), 124.88 (s), 122.69 (s), 83.59 (s), 56.49 (s), 19.03 (s). HRMS (LCMS-IT-TOF) Calc, for C15H10N3O4CI (M - H)- 330.0287, found 330.0266.

[0131] 5-(2-Fluorophenyl)-3-hydroxy-7-nitro-l,3-dihydro-2H-benzo[e][l,4]diazepin- 2-one (11, MYM-V-58). A round bottom flask was charged with 5-(2-fluorophenyl)-7-nitro- 2-oxo-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl acetate (66, 0.5 g, 1.34 mmol), ethanol (10 mL) and stirred to make a suspension. A solution of NaOH (0.13 g, 3.21 mmol) in water (2 mL) was added dropwise to the reaction mixture. The reaction mixture was then stirred for 30 min at +5 to 10°C at which point the reaction was deemed to complete on TLC analysis (silica gel, 100% EtOAc). Glacial acetic acid (1 mL) was then added dropwise to the reaction mixture. The mixture was cooled to 0 to 5°C. The residue was filtered, washed with water (2x 5 mL), and dried under vacuum. The crude products was purified by a flash chromatography (silica gel, EtOAc) to afford pure 11 as a yellow colored powder (308 mg, 70%). 'H NMR (500 MHz, DMSO) 5 11.40 (s, IH), 8.40 (dd, J= 9.0, 2.6 Hz,lH), 7.92 (d, J= 2.3 Hz, IH), 7.69 - 7.57 (m, 2H), 7.45 (d, J= 9.0 Hz, H), 7.39 (t, J= 7.4 Hz, IH), 7.27 (dd, J= 10.3, 8.8 Hz, IH), 6.65 (d, J= 8.7 Hz, IH), 4.93 (d, J= 8.4 Hz, IH). HRMS (LCMS-IT-TOF) Calc, for C15H10N3O4F (M + H)+316.07281, found 316.0727..

[0132] 5-(2-Chlorophenyl)-7-nitro-lH-benzo[e][l,4]diazepine-2, 3-dione (12, MYM-V- 50). Bis(trifluoroacetoxy)iodobenzene (0.25 g, 0.60 mmol) was added to the stirred solution of 5 -(2-chlorophenyl)-3 -hy droxy-7-nitro- 1 , 3 -dihy dro-2H-benzo[e] [ 1 ,4] diazepin-2-one (10, 0.1 g, 0.3 mmol) in anhydrous acetonitrile (10 mL). The mixture was stirred for 5 h at whichpoint the reaction was deemed to complete on TLC analysis (silica gel, 50% EtOAc-hexane, Rf=0.4; Rf=0.3 for 10). The reaction was then quenched with water (10 mL) and the aq. layer was extracted with DCM (2x10 mL). The combined organic layer was washed with brine (2x10 mL), and dried (Na2SO4). The solvents were evaporated under reduced pressure and the residue was purified by a flash chromatography (silica gel, 40% EtOAc-hexane) to afford 12 as white solid (60.8 mg, 61%). *H NMR (500 MHz, DMSO) 5 8.82 (ddd, J= 9.6, 7.2, 2.5 Hz, 1H), 8.52 (dd, .7= 16.4, 9.3 Hz, 1H), 8.42 - 8.36 (m, 1H), 7.81 (d, J= 8.1 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.67 (dd, J= 10.6, 4.0 Hz, 1H).13C NMR (126 MHz, CDCl3) δ 171.13 (s), 170.96 (s), 163.77 (s), 154.71 (s), 152.65 (s), 134.17 (s), 132.38 (s), 132.12 (s), 132.07 (s), 131.24 (s), 131.21 (s), 130.44 (s), 128.17 (s), 127.60 (s), 123.85 (s). HRMS (LCMS-IT-TOF) found for C15H9N3O4CI (M - H)- 329.0287.

[0133] 5-(2-Chlorophenyl)-3-fluoro-7-nitro-l,3-dihydro-2H-benzo[e][l,4]diazepin-2- one(13, MYM-V-56). 5-(2-chlorophenyl)-3-hydroxy-7-nitro-l,3-dihydro-2H- benzo[e][l,4]diazepin-2-one (10, 0.6 g, 1.83 mmol) was dissolved in anhydrous DCM (15 mL) and the mixture was cooled to -70°C using an acetone / dry ice bath. Then diethyl amino sulfur trifluoride (DAST, 0.8 mL, 6.1 mmol) was added dropwise to the reaction mixture over 5 min period while maintaining the temperature -70°C to -65°C. The mixture was then allowed to warm slowly to -20 to -10°C and stirred for 30 min at that temperature. The temperature of the reaction should be less than -10°C; otherwise N1H will be replaced by fluorine atom. The consumption of starting material was monitored by TLC (silica gel, 70% EtOAc-hexane; Rf of 13 =0.5; Rf of 10 =0.35). The reaction was quenched with water and the aq layer was extracted with chloroform (30 mL). The organic layer was washed with brine (2x10 mL) and dried (Na2SO4). The solvents were removed under reduced pressure and the residue was slurried in ethanol (8 mL). The mixture was stirred for 15 min at 80°C. Upon cooling to rt, the mixture was kept at -20°C freezer for 2 h. The residue was filtered, washed with cold ethanol (2x3 mL), and dried under vacuum at 45°C for 2h to afford pure MYM-V- 56 as white colored powder.1H NMR (500 MHz, DMSO) 5 11.74 (s, 1H), 8.43 (dd, J= 9.0, 2.5 Hz, 1H), 7.77 (d, J= 2.4 Hz, 1H), 7.75 - 7.72 (m, 1H), 7.63 - 7.57 (m, 2H), 7.56 - 7.53 (m, 1H), 7.49 (d, J= 9.0 Hz, 1H), 6.00 (d, J= 55.4 Hz, 1H).13C NMR (126 MHz, DMSO) 5 165.72 (d, = 28.7 Hz), 162.64 (d, J= 22.4 Hz), 143.56 (s), 142.45 (s), 137.12 (s), 132.59 (s), 132.30 (s), 132.08 (s), 130.47 (s), 128.21 (s), 127.62 (s), 127.41 (s), 125.04 (s), 123.31 (s), 97.24 (d, J= 180.5 Hz). HRMS LCMS-IT-TOF) Calc, for C15H9N3O3FCI (M + H)+ 334.0389, found 334.0393.

[0134] 5-(2-chlorophenyl)-3-hydroxy-l-methyl-7-nitro-l,3-dihydro-2H-benzo[e][l,4] diazepin-2-one (14, MYM-V-51). 5-(2-chlorophenyl)-3-hydroxy-7-nitro-l,3-dihydro-2H- benzo[e][l,4]diazepin-2-one (10, 0.1 g, 0.3 mmol) was dissolved in anhydrous acetonitrile (3 mL) and 2 drops of concentrated H2SO4 was added. The mixture was stirred for 5 min and anhydrous methanol (10 mL) was added. The mixture was stirred for 10 min at 50-60°C. The all the solvents were evaporated under reduced pressure. Water (10 mL) and DCM (20 mL) were added and the mixture was allowed to stand to separate layers. The organic layer was separated, washed (brine, 2x 10 mL), and dried (Na2SO4). The solvents were removed under reduced pressure and the residue was purified by a flash chromatography (silica gel, 50% EtOAc-hexane) to afford 14 as white solid (67 mg, 65%). ’H NMR (500 MHz, CDCI3) 5 8.71 (dd, J= 9.2, 2.5 Hz, 1H), 8.61 (d, J= 2.4 Hz, 1H), 8.42 (d, J= 9.2 Hz, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.54 (d, J= 4.2 Hz, 2H), 5.75 (s, 1H), 3.61 (s, 3H).13C NMR (126 MHz, CDCl3) δ 170.24 (s), 163.92 (s), 152.84 (s), 146.37 (s), 134.59 (s), 132.75 (s), 131.72 (s), 131.44 (s), 131.12 (s), 130.42 (s), 127.57 (s), 127.41 (s), 123.81 (s), 122.21 (s), 103.90 (s), 54.60 (s). HRMS (LCMS-IT-TOF) Calc, for C16H12N3O4CI (M + H)+ 346.05891, found 346.0589.

[0135] (S)-5-(2-chlorophenyl)-3-ethyl-l,3-dihydro-2H-benzo[e][l,4]diazepin-2-one (26, MYM-V-19). (2-Amino-5-nitrophenyl)(2-chlorophenyl)methanone ( 0.3 g, 1.0 mmol) was dissolved in anhydrous toluene (10 mL) and trifluoro acetic acid (0.2 mL, 2 mmol) was added. The mixture was heated to 50°C. At that point, (S)-4-ethyloxazolidine-2, 5-dione (NCA, 0.24 g, 2.5 mmol) was added once. The mixture was then stirred for an hour at 50°C at which point the starting material was deemed to consume (TLC, silica gel, 50% EtOAc- hexane) to form the TFA-salt of amide intermediate. Then, tri ethylamine (0.4 mL, 2.8 mmol) added dropwise and a white fume was observed during the addition. Upon completion of addition, the mixture was stirred for additional one hour. The consumption of starting material was confirmed by TLC (silica gel, 50% EtOAchexane). The solvents were evaporated and the residue was dissolved in dichlormethane. Water (20 mL) was added to dilute the mixture. The layers were separated and the aq. layer was extracted with DCM (2x10 mL). The organic layer was washed with water (2x10 mL) and dried (Na2SO4). The solvents were removed under reduced pressure and the residue was purified by neutral alumina column chromatograpy to afford pure 23 as a white colored powder (67 mg, 18%). 1H NMR (500 MHz, CDC13) 5 9.60 (s, 1H), 8.35 (dd, J= 8.9, 2.5 Hz, 1H), 8.02 (d, J= 2.5 Hz, 1H), 7.59 (dd, J= 5.6, 2.4 Hz, 1H), 7.46 - 7.43 (m, 2H), 7.41 - 7.38 (m, 1H), 7.33 (d, J=8.9 Hz, 1H), 3.55 (t, .7= 7.1 Hz, 1H), 2.37 - 2.25 (m, 2H), 1.14 (td, J = 7.4, 4.7 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 171.18 (s), 167.49 (s), 143.10 (s), 142.59 (s), 137.68 (s), 133.18 (s), 131.52 (s), 131.37 (s), 130.37 (s), 128.32 (s), 127.33 (s), 126.51 (s), 125.65 (s), 121.73 (s), 65.15 (s), 24.20 (s), 10.61 (s). HRMS (LCMS-ITTOF) Calc, for C17H14N3O3CI (M + H)+344.0796; found 344.0792.

[0136] ( (S)-5-(2-chlorophenyl)-3-methyl-l,3-dihydro-2H-benzo[e][l,4]diazepin-2-one(29, MYM-V-03). Anhydrous trifluoroacetic acid was added (0.5 mL, 8.6 mmol) to the stirred solution (2-aminophenyl)(2-chlorophenyl)methanone (1 g, 4.3 mmol) and the reaction mixture was heated to 50°C. N-carboxy alanine anhydride (NCA, 0.65 g, 5.6 mmol) was added one portions .The mixture was stirred for an hour at 50°C until the starting material was fully consumed, as confirmed by TLC analysis. Following this, triethylamine (1.2 mL, 8.6 mmol) was added dropwise, resulting in the formation of white fumes. After one more hour of stirring, TLC analysis again confirmed the complete consumption of the starting material. The solvents were then evaporated under reduced pressure, and the residue was dissolved in dichloromethane. The addition of water (20 mL) facilitated the separation of the layers, and the aqueous layer was extracted with di chloromethane (2x10 mL). The organic layer was washed with water (2x10 mL) and dried using sodium sulfate (Na2SO4). After removing the solvents under reduced pressure, the remaining residue was purified by washing with a 10% ethyl acetate (EtOAc) and hexane mixture followed by drying under vacuum at 50°C to afford compound 27 (0.6 g, 78%) as a white-colored powder. 'H NMR (500 MHz, CDCI3) 5 8.98 (s, 1H), 7.53 (s, 1H), 7.50 (td,1H), 7.37 (d, J = 3.0 Hz, 3H), 7.17 (t, J = 7.6 Hz, 1H), 7.12 (dd, 2H), 3.86 (q, J = 6.5 Hz, 1H), 1.79 (d, J = 6.5 Hz, 3H).13C NMR (126 MHz, CDCI3) 5 168.52 (s), 138.99 (s), 137.64 (s), 133.37 (s), 131.77 (s), 131.13 (s), 130.54 (s), 130.02 (s), 129.68 (s), 128.32 (s), 128.19 (s), 126.86 (s), 123.76 (s), 120.90 (s), 58.63 (s), 16.96 (s). HRMS (ESI / ITTOF) m / z: [M + H]+ Calcd for C16H13N2OCI 285.0789; found 285.0767.

[0137] (S)-5-(2-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[e][l,4]diazepine-7-carbonitrile (30, MYM-IV-12). A round bottom flask was charged with (S)-7-bromo-5-(2-chlorophenyl)-3-methyl-l,3-dihydro-2Hbenzo[e][l,4]diazepin-2-one (1 g, 2.75 mmol), z-PrOH (0.5 ml, 4.8 vol%), Na2CO3 (0.32 g, 3.02 mmol), Pd(OAc)2 (0.0037 g, .0167 mmol), and NMP (10 mL) under argon atmosphere. The mixture was heated to 140°C. At that point, K4Fe(CN)e.3H2O (0.46 g, 1.1 mmol) was added to the mixture at once. The mixture was heated for 4 h under sealedcondition while maintaining temperature 140-150°C. The completion of reaction was monitored by TLC (silica gel, 40% EtOAc-hexane). Upon cooling, the mixture was diluted with water (10 mL) and ethyl acetate (10 mL). The layers were separated and the aq. layer was extracted with ethyl acetate (2x10 mL). The combined organic layer was washed with water (5x 10 mL), brine (2x10 mL), and dried (Na2SO4). The solvents were evaporated, and the residue was purified by column chromatography (silica gel, 20% EtOAc-hexane to 40% EtOAc-hexane). The appropriate fractions were pooled and the solvents were removed under reduced pressure. The residue was dried under vacuum for 1 h to afford pure 28 as white powder (450 mg, 53%). Rf = 0.3 (silica TLC, 40% EtOAc-hexane, Rf of 47=0.5). *HNMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 7.71 (dd, J= 8.5, 1.7 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.44 - 7.41 (m, 1H), 7.39 (dd, J= 7.0, 2.3 Hz, 3H), 7.35 (d, J= 8.5 Hz, 1H), 3.80 (q, J= 6.5 Hz, 1H), 1.76 (d, J= 6.5 Hz, 3H). HRMS (ESI / IT-TOF) m / z: [M + H]+Calcd for C17H12N3OCI 310.07417; found 310.07403.

[0138] (( )-5-(2-chlorophenyl)-3-methyl-7-(4-(trifluoromethyl)phenyl)-l,3-dihydro- 2H-benzo[e][l,4]diazepin-2-one (31, MYM-IV-02). To a mixture of Pd(OAc)2 (0.044 g, 0.189 mmol), tri-(O-tolyl) phosphine (0.119 g, 0. 378 mmol) in toluene (10 mL), the benzodiazepine, (S)-7-bromo-5-(2-chlorophenyl)-3-methyl-l,3-dihydro-2H- benzo[e][l,4]diazepin-2-one 25 (0.1 g, 2.7 mmol), 4-trifluoromethyl phenyl boronic acid ( 2 g, 10 mmol), tri-basic potassium phosphate (2.5 g, 12.1 mmol), water (0.4 mL, 12.1 mmol) were added sequentially under argon. The reaction mixture was then stirred at 100°C for 6 h. LCMS 2020 (single quadrupole mass analyzer), and TLC (silica gel, 50% EtOAchexane) confirmed the consumption of starting material. The reaction mixture was cooled and opened to air once all the starting material consumed. The reaction mixture was passed through a pad of celite bead to remove any palladium salts. The filtrate was diluted with water (20 mL) and ethyl acetate (20 mL). The biphasic mixture, which resulted, was allowed to stand to separate. The organic layer was collected, and the aqueous layer was extracted (2x10 mL). The combined organic layer was washed with 10% aq. NaCl (3x10 mL) and dried (Na2SO4). The solvents were removed under reduced pressure. The orange-colored residue, which resulted, was purified a flash chromatography (silica gel 100g, 40% EtOAc-hexane). The desired fractions were pooled, and the solvents were removed. The solid residue was dried under vacuum for 2 h to afford a yellow-colored powder of 29 (0.94 g, 80%). 'H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H), 7.84 (s, 1H), 7.67 (d, J= 8.2 Hz, 2H), 7.57 (dd, J= 5.6, 3.4 Hz, 2H), 7.43 (dd, J= 16.5, 7.9 Hz, 2H), 7.33 (dd, J= 5.4, 3.2 Hz, 1H), 7.11 (s, 2H), 6.88 (d, J= 7.7Hz, 1H), 3.80 (q, J= 6.3 Hz, 1H), 1.79 (d, J= 5.0 Hz, 2H);13C NMR (126 MHz, CDC13) 5 172.14 (s), 170.09 (s), 144.62 (s), 142.95 (s), 140.82 (s), 139.03 (s), 137.63 (s), 134.72 (s), 130.90 (s), 130.18 (d, J= 9.4 Hz), 129.87 (s), 129.12 (s), 128.39 (s), 128.13 (s), 127.06 (s), 125.94 (q, J= 3.1 Hz), 125.18 (d, J= 5.4 Hz), 124.54 (q, J= 3.5 Hz), 123.02 (d, J= 5.4 Hz)

[0139] (S)-5-(2-chlorophenyl)-7-(4-methoxyphenyl)-3-methyl-l,3-dihydro-2H- benzo[e][l,4] diazepin-2-one (32, MYM-IV-30). Pd(OAc)2 (0.025 g, 0.115 mmol), tri-(O- tolyl) phosphine (0.07 g, 0. 23 mmol) were dissolved in toluene (lOmL) and the mixture was stirred for 10 min under argon atmosphere to generate the Pd(OAc)2-p-O -(tol)3-phosphine catalyst in-situ. Then benzodiazepine, (S)-7-bromo-5-(2-chlorophenyl)-3-methyl-l,3-dihydro- 2Hbenzo[e][l,4]diazepin-2-one 25 (0.6 g, 1.65 mmol), 4-methoxy phenyl boronic acid ( 0.51 g, 3.3 mmol), tri-basic potassium phosphate (1.57 g, 7.42 mmol), water (0.2 mL, 7.42 mmol) were added sequentially to the previous reaction mixture under argon. The reaction mixture was then stirred at lOOoC for 6 h. LCMS 2020 (single quadrupole mass analyzer), and TLC (silica gel, 50% EtOAc-hexane) confirmed the consumption of starting material. The reaction mixture was cooled and opened to air once all the starting material consumed. The reaction mixture was passed through a pad of celite bead to remove any palladium salts. The filtrate was diluted with water (20 mL) and ethyl acetate (20 mL). The biphasic mixture, which resulted, was allowed to stand to separate. The organic layer was collected, and the aqueous layer was extracted (2x10 mL). The combined organic layer was washed with 10% aq. NaCl (3x10 mL) and dried (Na2SO4). The solvents were removed under reduced pressure. The orange-colored residue, which resulted, was purified a flash chromatography (silica gel 100 g, 40% EtOAc-hexane). The desired fractions were pooled, and the solvents were removed under reduced pressure. The solid residue was dried under vacuum for 2 h to afford a yellow- colored powder of 30 (0.55 g, 79%). 'H NMR (500 MHz, CDCI3) 5 9.23 (s, 1H), 7.68 (dd, J = 8.4, 2.1 Hz, 1H), 7.57 (dd, J= 8.3, 3.6 Hz, 1H), 7.40 - 7.36 (m, 5H), 7.25 (d, J= 2.0 Hz, 1H), 7.23 (d, J= 4.1 Hz, 1H), 6.96 - 6.92 (m, 2H), 3.93 (q, J= 6.5 Hz, 1H), 3.83 (s, 3H), 1.82 (d, J= 6.5 Hz, 3H).13C NMR (126 MHz, CDCI3) 5 172.22 (s), 168.55 (s), 159.44 (s), 138.89 (s), 136.50 (s), 136.39 (s), 133.36 (s), 131.94 (s), 131.16 (s), 130.59 (s), 130.14 (s), 130.11 (s), 128.66 (s), 128.04 (s), 127.38 (s), 126.92 (s), 121.40 (s), 114.35 (s), 58.75 (s), 55.38 (s), 16.99 (s). HRMS (ES I / IT-TOF) m / z: [M + H]+Calcd for C23H19N2O2CI 391.1207; found 391.1206.

[0140] (S)-4-(5-(2-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[e][l,4]diazepin-7-yl)benzonitrile (33, MYM-IV-01). Pd(OAc)2 (0.025 g, 0.115mmol), tri-(O-tolyl) phosphine (0.07 g, 0. 23 mmol) were dissolved in toluene (10 mL) and the mixture was stirred for 10 min under argon atmosphere to generate the Pd(OAc)2-p-O- (tol)3-phosphine catalyst in-situ. Then the benzodiazepine, (S)-7-bromo-5-(2-chlorophenyl)- 3-methyl-l,3-dihydro-2H-benzo[e][l,4]diazepin-2-one 25 (0.6 g, 1.65 mmol), 4-cyano phenyl boronic acid ( 0.5 g, 3.3 mmol), tri-basic potassium phosphate (1.57 g, 7.42 mmol), water (0.2 mL, 7.42 mmol) were added sequentially to the previous reaction mixture under argon. The reaction mixture was then stirred at 100°C for 6 h. LCMS 2020 (single quadrupole mass analyzer), and TLC (silica gel, 50% EtOAc-hexane) confirmed the consumption of starting material. The reaction mixture was cooled and opened to air once all the starting material consumed. The reaction mixture was passed through a pad of celite bead to remove any palladium salts. The filtrate was diluted with water (20 mL) and ethyl acetate (20 mL). The biphasic mixture, which resulted, was allowed to stand to separate. The organic layer was collected and the aqueous layer was extracted (2x10 mL). The combined organic layer was washed with 10% aq. NaCl (3x10 mL) and dried (Na2SO4). The solvents were removed under reduced pressure. The orange colored residue, which resulted, was purified a flash chromatography (silica gel 100g, 40% EtOAc-hexane). The desired fraction were pooled and the solvents were removed. The solid residue was dried under vacuum for 2 h to afford an yellow colored powder of 31 (0.42 g, 69%).1H NMR (500 MHz, CDCl3) δ 9.27 (s, 1H), 7.74 - 7.67 (m, 3H), 7.59 (s, 1H), 7.53 (d, J= 8.1 Hz, 2H), 7.39 (dd, J= 8.4, 5.0 Hz, 3H), 7.30 (dd, J= 12.7, 8.9 Hz, 2H), 3.92 (q, J= 6.3 Hz, 1H), 1.82 (d, J= 6.4 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 172.11 (s), 168.16 (s), 143.79 (s), 138.56 (s), 138.01 (s), 134.69 (s), 133.31 (s), 132.73 (s), 131.24 (s), 130.89 (s), 130.44 (s), 130.19 (s), 128.86 (s), 128.66 (s), 128.20 (s), 127.56 (s), 127.36 (s), 127.08 (s), 121.82 (s), 118.66 (s), 111.33 (s), 58.87 (s), 16.95 (s). HRMS (ESEIT-TOF) m / z: [M + H] Calcd for C23H16N3OCI 386.10547; found 386.10550

[0141] ( )-7-(3,3-dimethylbut-l-yn-l-yl)-5-(2-fluorophenyl)-3-methyl-l,3-dihydro- 2H-benzo[e][l,4]diazepin-2-one (34, MYM-II-72). Tri-(O-tolyl) phosphine (0.15 g, 0.518 mmol), Pd(OAc)2 (0.058 g, 0.259 mmol) were dissolved in ACN (5 mL) and the mixture was stirred for 10 min under argon atmosphere to generate the Pd catalyst in-situ. Then, the benzodiazepine 26 (1.5 g, 4.32 mmol), triethylamine (1.5 mL, 12.9 mmol), t-butyl acetylene (0.6 mL, 4.7 mmol) and additional acetonitrile (10 mL) were added sequentially to the previous reaction mixture under argon. The reaction mixture was then refluxed for 4 h and the consumption of starting material was confirmed by TLC (silica gel; 60% ethyl acetate-hexane). The mixture was then cooled to rt and silica gel (5g) was added to the flask and the mixture was stirred for 15 min. The contents were filtered through a pad of celite and the residue was washed with DCM (2x50 mL). The solvents were removed under reduced pressure. DCM (20 mL) and water (10 mL) was added to the resulting black oily mass to dissolve the contents. The mixture was stirred for 5 minutes and allowed to stand to separate layers for 5 min. The layers were separated, and the aqueous layer was extracted with DCM (2x10 mL). The combined organic layers were washed with 10% aq. NaCl (2x10 mL) and dried (Na2SO4). The DCM was removed under reduced pressure. The residue was purified by silica gel (50 g) flash chromatography using 40% EtOAc-hexane. The desired fractions were collected, and the solvents were removed under reduced pressure. The yellow colored solid, which resulted was then dried under vacuum for Ihr to afford pure 32 (1.13 g, 75%) as yellow powder. Rf = 0.6 (silica gel, 60% EtOAc-hexane). 'H NMR (500 MHz, CDCl3) δ 9.41 (s, 1H), 7.60 (td, J= 7.5, 1.7 Hz, 1H), 7.49 (dd, J= 8.4, 1.9 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.26 (dd, J= 7.5, 1.0 Hz, 1H), 7.24 (d, J= 1.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 7.08 - 7.04 (m, 1H), 3.77 (q, J= 6.5 Hz, 1H), 1.78 (d, J= 6.5 Hz, 3H), 1.28 (s, 9H);13C NMR (126 MHz, CDCl3) δ 172.37 (s), 165.26 (s), 160.52 (d, J= 252.0 Hz), 136.37 (s), 134.87 (s), 132.26 (s), 131.83 (d, J= 8.3 Hz), 131.60 (d, J= 2.3 Hz), 128.45 (s), 127.62 (d, J= 12.5 Hz), 124.30 (d, J= 3.5 Hz), 121.11 (s), 119.79 (s), 116.26 (d, J= 21.5 Hz), 99.14 (s), 77.72 (s), 58.83 (s), 30.90 (s), 27.92 (s), 16.97 (s); HRMS (ESI / IT-TOF) m / z: [M + H]+ Calcd for C23H23N2OF 363.1867; found 363.1858.

[0142] (S)-5-(2-chlorophenyl)-7-cyclopropyl-3-methyl-l,3-dihydro-2H- benzo[e][l,4]diazepin-2-one (35, MYM-IV-63) Pd(OAc)2 (0.013 g, 0.075 mmol), tri-(O- tolyl) phosphine (0.04 g, 0. 12 mmol) were dissolved in toluene (10 mL) and the mixture was stirred for 10 min under argon atmosphere to generate the Pd(OAc)2-p-O-(tol)3-phosphine catalyst in-situ. Then the benzodiazepine, (S)-7-bromo-5-(2-chlorophenyl)-3-methyl-l,3- dihydro2H-benzo[e][l,4]diazepin-2-one 26 (0.3 g, 0.83 mmol), 4-cyclopropyl boronic acid ( 0.2 g, 1.6 mmol), tri-basic potassium phosphate (0.75 g, 3.8 mmol), water (0.1 mL, 3.8 mmol) were added sequentially to the previous reaction mixture under argon. The reaction mixture was then stirred at 100° C for 6 h. LCMS 2020 (single quadrupole mass analyzer), and TLC (silica gel, 50% EtOAc-hexane) confirmed the consumption of starting material. The reaction mixture was cooled and opened to air once all the starting material consumed. The reaction mixture was passed through a pad of celite bead to remove any palladium salts. The filtrate was diluted with water (20 mL) and ethyl acetate (20 mL). The biphasic mixture,which resulted, was allowed to stand to separate. The organic layer was collected and the aqueous layer was extracted (2x10 mL). The combined organic layer was washed with 10% aq. NaCl (3x10 mL) and dried (Na2SO4). The solvents were removed under reduced pressure. The orange colored residue, which resulted, was purified by chromatography (longer bed of alumina 100 g, 2% EtOAc-hexane to 30% EtOAc-hexane). The desired fraction were pooled and the solvents were removed. The solid residue was dried under vacuum for 2 h to afford an yellow-colored powder of 35 (0.015 g, 5.7%).1HNMR (500 MHz, CDCl3) δ 9.26 (s, 1H), 7.49 (t, J = 11.4 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.24 (dt, J = 11.4, 2.9 Hz, 1H), 7.15 - 7.10 (m, 1H), 7.08 (dd, J = 8.3, 2.1 Hz, 1H), 6.84 (dd, J = 23.9, 1.5 Hz, 1H), 3.85 - 3.80 (m, 1H), 1.77 (d, J = 9.7 Hz, 3H), 1.28 (t, J = 7.1 Hz, 1H), 0.89 (dd, J = 17.6, 10.7 Hz, 3H), 0.55 - 0.48 (m, 2H).13C NMR (126 MHz, CDCl3) δ 170.91 (s), 168.43 (s), 141.58 (s), 140.80 (s), 138.97 (s), 133.33 (s), 131.13 (s), 130.43 (s), 129.99 (s), 129.56 (s), 129.37 (s), 128.80 (s), 128.57 (s), 126.80 (s), 60.41 (s), 16.95 (s), 14.85 (s), 9.19 (s), 7.16 (s).

[0143] l-(4-(2-chlorophenyl)-6-nitro-2-oxo-l,2-dihydroquinolin-3-yl)pyridin-l-ium chloride (15, MYM-V-48). A round bottom flask was charged with 2-bromo-N-(4-nitro-2- (2-chlorobenzoyl) phenyl) acetamide (4, 1 g, 2.52 mmol), pyridine (10 mL) and the mixture was refluxed for 2 h at 115° C. The reaction mixture was then cooled to rt and hold for 1 h. The solid residue, which resulted, was filtered and washed with anhydrous DCM (2x10 mL). The residue was then dried under vacuum for 2 h to afford 14 as an off-white powder (1.02 g, 98%).1H NMR (500 MHz, DMSO) 5 13.67 (s, 1H), 9.23 (d, J = 6.2 Hz, 1H), 9.15 (d, J = 6.2 Hz, 1H), 8.91 - 8.88 (m, 1H), 8.76 (tt, J = 7.9, 1.4 Hz, 1H), 8.61 (dd, J = 9.2, 2.5 Hz, 1H), 8.29 (dt, J = 12.5, 6.6 Hz, 2H), 7.82 (d, J = 9.2 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.65 (dd, J = 8.0, 1.1 Hz, 1H), 7.60 (td, J = 7.5, 1.8 Hz, 1H), 7.56 (dd, J = 7.9, 1.9 Hz, 1H), 7.52 (td, J = 7.5, 1.2 Hz, 1H).13C NMR (126 MHz, DMSO) 5 169.62 (s), 162.37 (s), 144.05 (s), 142.16 (s), 137.93 (s), 132.27 (s), 132.07 (s), 131.96 (s), 130.32 (s), 128.05 (s), 127.48 (s), 127.10 (s), 124.87 (s), 122.68 (s), 83.59 (s), 56.49 (s), 19.03 (s). HRMS (LCMS-IT-TOF) Calc, for C20H12N3O3CI (M + H)+378.0640, found 378.0645.

[0144] Analysis of Anthelmintic Benzodiazepine Derivatives. The synthesized compounds were screened against adult S. mansoni in vitro (30 pM for 14 hours) to triage compounds based on activity. Compounds showing activity caused contractile paralysis in the worms, while worms incubated with inactive compounds remained motile with no visible impact on worm movement or morphology. See, FIG. 1. The result data showed that several positions on MCLZ were not particularly amenable to substitution. Analogs withmodifications at Nl (MYM-II-53), N4 (MYM-V-48, MYM-V-49) and C7 (MYM-V-03, MYM-IV-01, MYM-IV-02, MYM-IV-03, MYM-IV-12, MYM-IV-63, MYM-IL72) lacked activity in this initial assay. However, modification of the C3 position showed effects on structure activity. While some compounds modified at C3 were inactive (MYM-II-53, MYM- 11-74, MYM-V-50), other modifications retained activity (MYM-V-19, MYM-II-83, MYM- V-56, MYM-III-10, MYM-V-58).

[0145] Activity compounds from this initial screen were subsequently assayed at a series of decreasing concentrations to explore their structure-activity relationship. Adult S. mansoni were incubated in compound (0.1 - 30 pM for 14 hours) and motility was measured using a high content imaging system and the wrmXpress pipeline to quantify worm movement. Most of these compounds were less active than MCLZ, but two compounds (MYM-V-56 and MYM-III-10) with substitutions at the C3 position retained anti schistosomal activity at potency near the parent molecule MCLZ. See, FIG. 1. The effects of these compounds on motility (FIG. IB) and morphology (FIG. 1C) were observed to be slightly less potent than MCLZ. However, MYM-V-56 and MYM-III-10 were initially screened as racemic mixtures, while MCLZ is the purified (S) enantiomer of 3-methyl clonazepam because the (R)- enantiomer of MCLZ has been reported to be inactive on parasites.

[0146] In order to determine whether hit compounds identified as having in vitro activity at 30 pM displayed in vivo anti schistosomal activity, they were administered to mice infected with S. mansoni and the hepatic shift assay to observe acute anti schistosomal activity. Adult worms normally live within the mesenteric vasculature, but upon exposure to anthelmintic compounds paralyzed worms are swept through the portal vein to the liver. Mice were administered compound by oral gavage at a dose of 100 mg / kg and then euthanized three hours later to observe the portion of worms in the liver versus the mesenteries. See, FIG. 2A. Only 1.8±1.8% of worms were found in the livers of mice treated with vehicle control. Following MCLZ treatment, 100% of worms were found in the liver and no worms were found in the mesenteries of any mice. Following treatment with two example compounds that showed in vitro efficacy, MYM-V-56 and MYM-III-10, 100% of worms were located in the liver and no worms were found in the mesenteries. Generally, compounds that showed weaker potency in vitro were less active in the hepatic shift assay. MYM-V-19 was active at the higher concentration (30 pM) in vitro and caused little hepatic shift (5.0 ± 3.2% of worms found in the liver). MYM-V-58 was similarly weakly active in vitro, but caused a moderate hepatic shift (60.0 ± 23.4% of worms found in the liver). MYM-II-83, which contains anester at the C3 position that is likely hydrolyzed in vivo, was not active in vitro but displayed moderate activity in vivo (81.0 ± 10.6% hepatic shift).

[0147] The three most efficacious compounds, MYM-III-10, MYM-V-56 and MYM-II- 83, were then administered to mice (single oral dose of 100 mg / kg) and euthanized after one week to count the number of surviving worms. Mice treated with vehicle control harbored 39.4 ± 4.0 worm pairs, but no live worms were found in MCLZ, MYM-III-10 or MYM-V-56 treated mice. See, FIG. 2B. Mice treated with MYM-II-83 did not have any reduction in worm burden compared to control (40.0 ± 0.6 worm pairs per mouse), in contrast to the moderate acute activity of this compound in the hepatic shift assay.

[0148] Given that MYM-V-56 and MYM-III-10 exhibited acute in vivo efficacy and cured infections at 100 mg / kg. The potency of these compounds relative to MCLZ was assessed by treating infected mice with a range of doses (10-120 mg / kg) and counting the live worm burden after one week. See. FIG. 2C. MCLZ cured infected mice at a dose of 30 mg / kg, in line with the effective dose between 33-57 mg / kg previously reported. MYM-V-56 and MYM-III-10 displayed curative activity at slightly higher doses of 90-120 mg / kg. This is consistent with the in vitro results where the racemate of these compounds were slightly less potent than MCLZ, which is the purified active (S) isoform. See, FIG. 1.

[0149] Finally, one of the features of MCLZ compared to other anti schistosomal drugs such as PZQ or oxamniquine is that MCLZ is active against juvenile liver stages of worms. Therefore, additional testing was performed to confirm that MYM-V-56 and MYM-III-10 were also capable of clearing these stages of parasites. Infected mice were dosed with both compounds (100 mg / kg) at 4 weeks post infection, which corresponds to the period where PZQ displays the least efficacy. Mice were then euthanized at 7 weeks post infection to count the surviving worms. A single dose of either MYM-V-56 or MYM-III-10 reduced parasite burden by over 90%. See, FIG. 2D.

[0150] These initial experiments on MYM-III-10 and MYM-V-56 were conducted with racemic preparations of compound, given the resources involved in achieving enantiomeric separation of the (A) and (S) isomers at sufficient scale for in vivo mouse studies. In MCLZ, the purified (S) enantiomer is more potent than the (R) enantiomer; however, it was not previously known whether this effect would be seen in the present compounds. The two enantiomers of MYM-III-10 and MYM-V-56 were separated at a small scale by preparative HPLC and adult worms were incubated in each in vitro to measure paralysis. For MYM-V- 56, both the (S) and (R) enantiomer caused contractile paralyzed worms above 5 pM after 14hours incubation. See, FIG. 3 A. While these two compounds initially appear equipotent from these data, the kinetics of drug action were quite different. Worms were incubated in 10 pM of each enantiomer and tracked over time. (S)-MYM-V-56 caused contractile paralysis within minutes, while the (R) enantiomer did not cause this phenotype until after several hours incubation in drug. See, FIG. 3B. It is likely that the (S) enantiomer is more active in vivo, because of the rapid kinetics of the hepatic shift observed with racemic MYM-V-56 treatment. See, FIG. 2A. This was confirmed by dosing mice harboring adult parasites orally with both enantiomers. Mice were euthanized one week after drug administration to assess worm burden and in vivo anti schistosomal activity of each compound. (S)-MYM-V-56 caused a reduction in worm burden of more than 90% at 30 mg / kg (2 ± 3 worm pairs per mouse, compared to 27 ± 3 worm pairs per mouse with vehicle control), while (A)-MYM-V- 56 did not decrease worm burden up to a dose of 90 mg / kg. See, FIG. 3C.

[0151] Worms incubated with various concentrations of both (S) and (A)-MYM-III-l 0 for 14 hours also displayed contractile paralysis, with the (S) enantiomer displaying greater potency than the (R) enantiomer. See, FIG. 4A. Unlike MYM-V-56, both enantiomers displayed in vivo activity, with (S)-MYM-III-IO curing infections at 60 mg / kg while (R)- MYM-III-10 cured infections at 90 mg / kg. See, FIG. 4B. Given the hydroxyl group on the C3 position of this compound, an experiment was run to determine if the compound racemized over time in aqueous solution. Indeed, purified MYM-III-10 enantiomers racemized within one hour. Therefore, the (S) MYM-III-10 enantiomer may still be more active than the (R) isoform, if much of the anti schistosomal activity seen with dosing the (R) enantiomer is in fact due to conversion to the (S) form.

[0152] Given that both MYM-V-56 and MYM-III-10 both retain the anti schistosomal activity of MCLZ, the sedative activity of these compounds was assessed. Mice were trained to perform the rotarod test, running on the rod for 300 seconds at a speed of 20 RPM. Animals not infected with schistosomiasis were chosen for this assay, because the hepatomegaly caused by parasite infection can interfere with mouse mobility. Animals were then dosed orally with increasing amounts of MCLZ or test compound and after 5 minutes were placed on the rotarod device to perform the test. Whenever a mouse fell off of the device, this time point was noted and the test was ended for that animal. For other animals, the test was ended at 300 seconds. Mice dosed with MCLZ displayed impaired performance on the rotarod test, consistent with this assay serving as a measurement of sedation. At the dose of 30 mg / kg (which corresponds to the dose that cures infection) 2 / 14 mice were able tocomplete the test, and the average time they were able to run on the device was 102 ± 26 seconds. See, FIG. 5. Mice treated with MYM-III-10 (30 mg / kg) exhibited less impairment, running on the device for an average of 246 ± 26 seconds, and mice treated with MYM-V-56 (30 mg / kg) ran on the device for an average of 232 ± 30 seconds. The purified (R) and (S) MYM-V-56 enantiomers were also tested and displayed minimal sedation, running for 293 ± 8 seconds and 299 ± 1 seconds, respectively, at the 30 mg / kg dose.

[0153] While it may appear from these results that MYM-V-56 does not impair mouse locomotion / coordination, observing the mice in their cages following treatment indicates that this compound does have psychoactive effects, even if it is not sedating. MYM-V-56 treated mice (100 mg / kg each) appear unusually hyperactive. To record a 20 second video of these mice a plexiglass cover was placed over the cage to keep them from jumping out and escaping. Mice treated with MYM-V-56 were observed that could not complete the rotarod test but did not appear sedated. Instead, they would jump off of the device and attempt to escape during the assay. Therefore, while this compound does not have pronounced sedating activity, it does appear to have other psychoactive effects.

[0154] In order to investigate the action of the two hit compounds, MYM-III-10 and MYM-V-56, on host targets, a series of binding and functional assays were performed. Binding assays revealed that both compounds displace diazepam radioligand from rat brain membrane preparations with similar potency as MCLZ. Therefore, both MYM-III-10 and MYM-V-56 appear to have affinity for host GABAARS (See, FIG. 6A), even if they are bit sedating in vivo. Similarly, both compounds have similar activity in functional assays measuring positive allosteric modulator activity at GABAARS, stimulating peak currents measured from uip2y2 GABAA channels recombinantly expressed in mammalian CHO-K1 cells (See, FIG. 6B).

[0155] However, given the increased polarity of MYM-III-10 (ClogP 1.01) relative to MCLZ (ClogP 2.39), testing was conducted to explore whether the decrease in sedation observed with MYM-III-10 treatment may be due to less compound crossing the blood brain barrier. This was confirmed by measuring levels of drug in serum and brain tissue. Mice were treated orally with either MCLZ or MYM-III-10 as in the anti schistosomal assays and the rotarod assays, then euthanized to harvest whole blood and dissect brains from each animal. Drug levels were measured in each sample, revealing that indeed MCLZ but not MYM-III-10 accumulated in the brain tissue. This was not due to a lack of MYM-III-10 bioavailability since this compound was found at high levels in the serum. See, FIG. 6C.

[0156] An explanation for the lack of MYM-V-56 sedation is less clear. Like MCLZ, it is a relatively nonpolar compound (ClogP 2.42) that would be expected to cross the blood brain barrier. MYM-V-56 was submitted to a panel of 44 different binding and functional assays (Eurofins Safety Screen44 Panel) to profile activity against a range of targets at a concentration of 10 pM, reasoning that activity at receptors other than GABAARS may mediate the psychoactive effects of this compound. These results confirmed that MYM-V-56 binds GABAARS, but no other assay showed significant displacement of radioligand. MYM- V-56 was also submitted to the NIH NIMH Psychoactive Drug Screening Program (PDSP)https: / / paperpile.com / c / iIXCzg / 86Ao. Binding assays were performed against 46 different targets with MYM-V-56 (10 pM), and these data also did not show any displacement of radioligand at any of the targets screened.

[0157] These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index and point to the C3 position of the benzodiazepine ring system for modifying the MCLZ backbone for achieving tolerable antiparasitic activity with reduced sedation effects.

[0158] The data also confirm two example compounds exhibiting in vivo efficacy against S. mansoni while displaying a lack of sedation, or markedly reduced sedation, relative to the parent molecule MCLZ.Structure-Activity Relationship Analysis

[0159] Meclonazepam cures schistosome infection but also has activity at host GABAARS resulting in sedation. Human subjects given high doses of meclonazepam experienced amnesia and had no memory of testing. We have found that meclonazepam can be modified to reduce its sedative side effects in mice. VSLD domains of parasite TRPs retrieved from AlphaFold2 models of each channel can be used to for docking-based virtual screening of compounds and analysis of structure activity relationships. In this example, the VSLD cavity of the S. mansoni TRP Smp_333650 (AlphaFold structure prediction for A0A5K4FCC0) was used, but other VSLD cavities of S. mansoni (flatworm) and B. malayi (nematode) TRPM isoforms can be used.

[0160] FIG. 7A and FIG. 7B illustrate meclonazepam, (S)-MYM-V-56, and (S)-MYM-III- 10 docked into the benzodiazepine binding pocket of the human α1β3γ2L GABAA receptor (cyro-EM structure 6HUP). The same three benzodiazepines docked into the VSLD cavity of the S. mansoni TRP Smp_333650 (AlphaFold structure prediction for A0A5K4FCC0).Structure activity interactions based on this data between ligands and amino acid side chains are listed with respect to each docking site.

[0161] FIG. 8 provides an additional comparison of illustrates the structure-activity relationship (SAR) of benzodiazepines on GABAARS, and specifically the al -containing subtypes which cause sedation. The basis for these data is supported by the cryo-EM structure of diazepam at the interface of the GABAAR al and y2 subunits. Considering the effect of benzodiazepine modifications on GABAAR affinity moving clockwise from the N1 position, N1 alkyl groups are tolerated (e.g., diazepam). The C2 position typically contains a carbonyl group, although the first and second positions can be closed in a ring (e.g., imidazobenzodiazepines). Removing the carbonyl group typically results in a decreased GABAAR affinity (e.g., medazepam). The C3 position typically does not have a substituent, but a small functional group such as a methyl (meclonazepam) or hydroxyl group (lorazepam) is permitted. The stereochemistry of this chiral center can have a SAR effect; (S) enantiomers can exhibit higher GABAAR affinity than (R) isoforms. The N4 position is typically unmodified, and when the N4 is shifted to the fifth position on the ring (1,5 rather than 1,4-benzodiazepines) compounds tend to be less sedating with lower al -GABAAR affinity (e.g., clobazam). The phenyl ring can be unmodified, but ortho halogens (C2’ position) increase GABAAR affinity while para substitutions are not tolerated. Similarly, electron withdrawing groups are commonly found at the C7 position. C6, C8 and C9 positions are typically not modified and moving the C7 group to these locations decreases GABAAR affinity. In summary, many positions on the benzodiazepine ring system can be modified to tune GABAAR affinity and sedation. FIG. 8 also describes antiparasitic effects based on analysis of several hundred compounds. Early studies noted only nitro containing benzodiazepines were active; 3 -methylclonazepam (or meclonazepam) and clonazepam. Removing the C3 substituent results in ~10x less activity. Loss of the ortho halogen at the phenyl ring results in a complete loss of activity (e.g., nitrazepam). The N1 modification eliminates activity. FIG. 8 shows that the antiparasitic effects of benzodiazepines such as meclonazepam are likely due to agonist activity at a schistosome TRPM channel, while sedation is due to binding host GABAARS at the interface of alphal and gamma2 subunits. Sedative and antiparasitic effects can occur at comparable doses. Some criteria for binding are shared between the targets, such as a C7 and C2' electrophilic group and chirality of the C3 position, which favors (S) over (R). Many modifications disrupting GABAAR binding can be observed, which may be undesirable in the context of developing human therapeutics forconventional benzodiazepine targets and indications, but are promising routes for the development of anti schistosomal compounds. These data also show that modification away from meclonazepam can provide an active therapeutic agent having increased affinity for parasite TRPM target and decreased affinity for host GABAARS. Such agents will lead to a higher therapeutic index when treating humans infected with parasitic worms.

[0162] FIG. 9A, FIG. 9B, and FIG. 9C together provide: (A) a photogram showing worm paralysis and GABAARS binding, and illustrating the technical result of disconnecting TRPM activity from host GABA activity, thus improving therapeutic index of treatment; (B) graphs reporting sedative effect against worm burden of host; and (C) structure activity relationships with respect to antiparasitic activity, such that one or more of the C7 nitro group, the C’2 chloro group, and unsubstituted N1 are associated with antiparasitic activity, while other sides appear to be associated with more permissive modification. As shown in FIG. 9A, FIG. 9B, and FIG. 9C, the antiparasitic effects of benzodiazepines are likely due to agonist activity at a TRPM channel while sedative effects are due to positive allosteric modulator activity at host GABAARS. Meclonazepam has both antiparasitic and sedative effects at comparable doses. Our efforts to increase the therapeutic index of antiparasitic benzodiazepines have led to two novel compounds (for example, MYM-III-10 and MYM-V-56) with modifications to the C3 position. The more polar MYM-III-10, with an hydroxyl C3 substituent, exhibits antiparasitic effects at lower doses than those causing sedating effects. This is due to decreased blood brain barrier penetration. The MYM-V-56 (C3 fluorine), as discussed above, was not sedating and showed that antiparasitic activity can be disjointed from host sedation.Discussion of Results

[0163] The above examples identified MYM-V-56 and MYM-III-10, which each contain modifications at the C3 position of MCLZ. Modification at this position is shown to be fruitful for separating sedating and antiparasitic effects of MCLZ-type compounds. Clonazepam is identical to MCLZ except it lacks a methyl group at the C3 position. This difference makes clonazepam approximately three times less potent on schistosomes (causing paralysis at 10 pM, compared to 3 pM for MCLZ), but it binds host GABAARS with approximately three times higher potency (displacement of diazepam radioligand with a Ki = 0.82 nM, compared to 2.4 nM for MCLZ). While substitution of the MCLZ methyl group with a hydroxyl group (MYM-III-10) or fluorine (MYM-V-56) was tolerated, larger substitutions lost or attenuated antiparasitic activity (for example, putting two methyl groupsat the C3 position (MYM-II-74), increasing the length of the alkyl chain to an ethyl group (MYM-V-19), or adding an ester (MYM-II-83)). Putting a ketone at this position (MYM-V- 50) also resulted in a loss of activity, reflecting the impact of lack of the C3 stereocenter on anti schistosomal activity. Based on results on the activity of MYM-V-56 and MYM-III-10, it is expected that small substitutions are tolerated at the C3 position. Interactions between MCLZ and the schistosome TRPM channel Smp_333650 can further help to explain several aspects of the structure-activity relationship observed in our data. The advantages of the nitro functional group at the C7 position is shown from the structure-activity relationship of the chemical series; removing the nitro so that the C7 is unmodified causes a loss of activity (MYM-V-03), as does replacing the nitro with certain other functional groups (MYM-IV-01, MYM-IV-02, MYM-IV-03, MYM-IV-12, MYM-IV-63). This is likely due to electrostatic interactions between the nitro group and arginine, tyrosine and histidine side chains in the binding pocket https: / / paperpile.eom / c / iIXCzg / OTUK. Similarly, the C2’ position confirms the advantages of the chlorine as illustrated by the reduced activity of MYM-V-58, which contains a fluorine with lower electron affinity. Modeling MCLZ interactions with the TRPM binding pocket can provide an explanation due to the interaction with the negatively charged glutamic acid. Finally, the compound MYM-II-53, which contains a methyl group on the N1 position was inactive in our screen, was inactive against the TRPM channel Smp_333650, and was inactive on schistosomes along with several other N1 alkylated compounds. Modeling in the TRPM channel indicates this can be due to H-bonding with the backbone of the SI helix.

[0164] Surprisingly, while both MYM-III-10 and MYM-V-56 were less sedating than MCLZ, both of these compounds still retained positive allosteric modulator activity against GABAARS that would be expected to confer sedation. See, FIG. 5 and FIGs. 6A-6C. For MYM-III-10, one explanation for the difference in sedative effect of relative to MCLZ may relate to pharmacokinetic properties of this hit since it is more polar with a hydroxyl group at the C3 position. A lower ClogP would be expected to have less blood brain barrier penetration and sedation, which is indeed what is observed when levels of this compound were measured in brain tissue. See, FIG. 6C. For MYM-V-56, its activity on GABAARS does differ slightly from MCLZ and MYM-III-10. MYM-V-56 does not have quite as potent affinity as these two compounds for the central benzodiazepine binding site in radioligand binding assays (FIG. 6A), but still does bind with relatively high affinity. MYM-V-56 also displays potent PAM activity at recombinantly expressed GABAARS (FIG. 6B), even thoughreceptors desensitize at higher concentrations. This is surprising from multiple angles. These data alone would be expected to suggest that MYM-V-56 would be sedating, but this was not the case as demonstrated by a rotarod assay even at doses up to 100 mg / kg (FIG. 5).However, from observing these mice it was clear that MYM-V-56 does have hyperactive psychoactive effects may indicate that MYM-V-56 has activity on targets other than GABAARS, or GABAARS with different subunits composition than the typical al -containing channels that cause sedation (e.g., a2-containing channels that mediate anxiolytic effects). These data are also useful preclinical data characterizing binding partners of MYM-V-56, and reassuringly the compound does not have affinity for targets such as the hERG potassium channel that would be a barrier for human clinical development.

[0165] These results illustrate that compounds can be prepared where the characteristic sedative effects of meclonazepam can be reduced and separated from the anti-parasite effect. Such modification eliminates the main problematic side effect of the meclonazepam drug class that had previously prevented the clinical development of meclonazepam. Compounds modified according to the present disclosure thus provide compounds having a greater therapeutic index with respect to imparting anthelmintic effects without unacceptable host sedation.Additional Aspects

[0166] The following exemplary aspects are provided, the numbering of which is not to be construed as designating levels of importance:

[0167] Aspect 1 provides a method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound according to Formula I, or a salt thereof to the patient in need thereof:Formula I whereinR1is H, C2-C6alkyl, C2-C6haloalkyl, C3-C6cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3, or haloalkyl;R2and R4 are each independently H, F, Cl, Br, I, methyl, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, -NH2, -NHR, -NRR, CN, or -OR, wherein at least one of R2and R4 is other than H;W is C-R3, C-NO2, C-CH3, C-F, or C-Y; R3is H, alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl;L is pyridyl, phenyl, cyclohexyl,, each of which may be optionally substituted by one, two, or more Rs;X is each independently C-R5or N;R5is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or -CO2H;G is C-Y or N;Y is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -C02H, -CCR, -OR, pyridinyl, phenyl, or R6;R7 is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, or N;T is N or CH;J is O, Z, NH, or NR, or J and the double bond to the carbon to which it is attached are replaced with JI and J2, wherein JI and J2 are each independently H, R, OR, SR, NHR, or NR2, or J together with the carbon to which it is attached forms a triazole or imidazole together with R1and the nitrogen to which it is attached;R9 is H, alkyl, cycloalkyl, fluoroalkyl, F, Cl, Br, I, alkyl, or CF3;Z is O or S; each instance of R is independently H, alkyl, or acyl; and wherein the compound is other than meclonazepam.

[0168] Aspect 2 provides the method of Aspect 1, wherein when one of R2and R4 is methyl and the other of R2and R4 is H, then J is other than carbonyl, Y is other than nitro, or L is other than 2-chlorophenyl.

[0169] Aspect 3 provides the method of Aspect 1, wherein when one of R2and R4 is methyl and the other of R2and R4 is H, then J is other than carbonyl, Y is other than nitro, and L is other than 2-chlorophenyl.

[0170] Aspect 4 provides the method of Aspect 1, wherein the compound activates a schistosome TRP.

[0171] Aspect 5 provides the method of Aspect 1, wherein the compound activates Smp_333650.

[0172] Aspect 6 provides the method of Aspect 1, wherein the compound activates Smp_246790.

[0173] Aspect 7 provides the method of Aspect 1, wherein the compound activates Smp_000050.

[0174] Aspect 8 provides the method of Aspect 1, wherein the compound activates Smp_165170.

[0175] Aspect 9 provides the method of Aspect 1, wherein the compound activates a schistosome TRP other than Smp_333650 and other than Smp_246790.

[0176] Aspect 10 provides the method of Aspect 1, wherein the compound activates a heterotetrameric schistosome TRP.

[0177] Aspect 11 provides the method of Aspect 1, wherein the compound activates a heterotetrameric schistosome TRP containing a subunit Smp_333650 or Smp_246790.

[0178] Aspect 12 provides the method of Aspect 1, wherein the compound activates a heterotetrameric or homotetrameric schistosome TRP containing subunits other than Smp_333650 and other than Smp_246790.

[0179] Aspect 13 provides the method of Aspect 1, wherein the compound has a structure according t

[0180] Aspect 14 provides the method of Aspect 1, wherein the compound has a structure according t

[0181] Aspect 15 provides the method of Aspect 1, wherein the compound has a structure according t

[0182] Aspect 16 provides a method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound according to Formula II, or a salt thereof to the patient in need thereof:whereinR1is H, C2-C6alkyl, C2-C6haloalkyl, C3-C6cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3, or haloalkyl;R2and R4 are each independently H, F, Cl, Br, I, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, and -OR, wherein at least one of R2and R4 is other than H; R3is H alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl;X is C-R5orN;R5is H, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or - CO2H;G is C-Y orN;Y is H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, -OR, pyridinyl, phenyl, or R6;R7 is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, or N;R9 is H, alkyl, cycloalkyl, fluoroalkyl, or haloalkyl;Z is O or S; and each instance of R is independently H, alkyl, or acyl.

[0183] Aspect 17 provides the method of Aspect 1 or 16, wherein R2 and R4 taken together with the carbon to which they are attached provide an S-stereocenter.

[0184] Aspect 18 provides the method of any one of Aspects 1-17, wherein R2 and R4 taken together with the carbon to which they are attached provide an R- stereocenter.

[0185] Aspect 19 provides the method of any one of Aspects 1-18, wherein the compound is an enantiomerically purified form.

[0186] Aspect 20 provides the method of any one of Aspects 1-19, wherein the compound is an enantiomerically purified form having an enantiomeric excess of at least 90% ee.

[0187] Aspect 21 provides the method of any one of Aspects 1-20, which is in a racemic mixture.

[0188] Aspect 22 provides the method of any one of Aspects 1-21, wherein R1is H, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, CD3, fS')-CDFH, (A)-CDFH, fS')- CH3CHCF3, or (A)-CH3CHCF3.

[0189] Aspect 23 provides the method of any one of Aspects 1-22, wherein R1is H.

[0190] Aspect 24 provides the method of any one of Aspects 1-23, wherein R2is F, Cl, Br, I, trifluoromethyl, CF2H, CH2F, trichloromethyl, methyl, ethyl, OH, or OAc.

[0191] Aspect 25 provides the method of any one of Aspects 1-24, wherein is H or R3methyl.

[0192] Aspect 26 provides the method of any one of Aspects 1-25, wherein is H R3

[0193] Aspect 27 provides the method of any one of Aspects 1-26, wherein R4 is F, Cl, Br, I, trifluoromethyl, CF2H, CH2F, trichloromethyl, ethyl, OH, or OAc.

[0194] Aspect 28 provides the method of any one of Aspects 1-27, wherein R4 is OH, OAc, F, or ethyl.

[0195] Aspect 29 provides the method of any one of Aspects 1-28, wherein X is C-Rs.

[0196] Aspect 30 provides the method of any one of Aspects 1-29, wherein R5is F, Br, Cl, I, cyano, nitro, methyl, or -CO2H.

[0197] Aspect 31 provides the method of any one of Aspects 1-30, wherein R5is F or Cl.

[0198] Aspect 32 provides the compound of any one of Aspects 1-31, wherein G is C-Y.

[0199] Aspect 33 provides the method of any one of Aspects 1-32, wherein Y is nitro, - CO2H, chloro, bromo, trifluoromethyl, cyano, methoxy, hydroxy, cyclopropyl, 2-pyridinyl, 3- pyridinyl, 4-pyridinyl,wherein R7 if present is methyl, cyano, trifluoromethyl, hydroxy or methoxy, and R8 if present is methyl, cyano, trifluoromethyl, hydroxy or methoxy.

[0200] Aspect 34 provides the method of any one of Aspects 1-33, wherein Y is nitro.

[0201] Aspect 35 provides the method of any one of Aspects 1-34, wherein R is H, methyl, or acetyl.

[0202] Aspect 36 provides the method of any one of Aspects 1-35, wherein Z is O.

[0203] Aspect 37 provides the method of any one of Aspects 1-36, wherein Q is CH.

[0204] Aspect 38 provides the method of any one of Aspects 1-37, wherein one of R2and R4 is other than H, alkyl, and OR.

[0205] Aspect 39 provides the method of any one of Aspects 1-38, wherein one of R2and R4 is a halogen.

[0206] Aspect 40 provides the method of any one of Aspects 1-39, wherein one of R2and R4is F.

[0207] Aspect 41 provides the method of any one of Aspects 1-40, wherein R5is other than Cl.

[0208] Aspect 42 provides the method of any one of Aspects 1-41, wherein when one ofR2and R4 is halogen, then at least one of R5is other than halogen and H.

[0209] Aspect 43 provides the method of any one of Aspects 1-42, wherein when one ofR2and R4 is halogen, then at least one of Y is other than halogen, H, and NO2.

[0210] Aspect 44 provides the method of any one of Aspects 1-43, wherein R1is H, R3is H, X is C-Rs, G is C-Y, Q is C-H, and Z is O.

[0211] Aspect 45 provides the method of any one of Aspects 1-44, wherein R1is H, R3is H, X is C-Rs, G is C-Y, Q is C-H, Z is O, and R5is Cl.

[0212] Aspect 46 provides the method of any one of Aspects 1-45, wherein R1is H, R3is H, X is C-Rs, G is C-Y, Q is C-H, Z is O, and Y is nitro or -CO2H.

[0213] Aspect 47 provides the method of any one of Aspects 1-46, wherein R1is H, R3is H, X is C-Rs, G is C-Y, Q is C-H, Z is O, R5is Cl, and Y is nitro or -CO2H.

[0214] Aspect 48 provides the method of any one of Aspects 1-47, wherein R1is H, R3isH, X is C-Rs, G is C-Y, Q is C-H, Z is O, R5is Cl, Y is nitro or -CO2H, one of R2and R4 is halogen, and one of R2and R4 is a halogen.

[0215] Aspect 49 provides the method of any one of Aspects 1-48, wherein R1is H, R3isH, X is C-Rs, G is C-Y, Q is C-H, Z is O, R5is Cl, Y is nitro or -CO2H, one of R2and R4 is halogen, and one of R2and R4 is F.

[0216] Aspect 50 provides a method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound according to Formula III, Formula IV, Formula V, or a salt thereof to the patient in need thereof:whereinR2and R4 are each independently H, F, Cl, Br, I, CF3, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, and -OR, wherein at least one of R2and R4 is other than H; R3is alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl; and U is CH2, CRH, CR2, or CO.

[0217] Aspect 51 provides a method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound having the following structure, or a salt thereof:

[0218] Aspect 52 provides a method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound having the following structure, or a salt thereof:

[0219] Aspect 53 provides a method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound having the following structure, or a salt thereof:

[0220] Aspect 54 provides a method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound having the following structure, or a salt thereof:

[0221] Aspect 55 provides a method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound having the following structure, or a salt thereof:enantiopurified form.

[0222] Aspect 56 provides a method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound having the following structure, or a salt thereof:

[0224] Aspect 58 provides a compound having the following structure, or a salt thereof:

[0225] Aspect 59 provides a compound having the following structure, or a salt thereof:

[0227] Aspect 61 provides a compound having the following structure, or a salt thereof:enantiopurified form.

[0228] Aspect 62 provides a compound having the following structure, or a salt thereof:

[0229] Aspect 63 provides a compound having a structure according to Formula II, or a salt thereof:Formula II whereinR1is H, alkyl, cycloalkyl, deuterated alkyl, CDs, fluoroalkyl, CF3, or haloalkyl;R2and R4 are each independently H, Cl, Br, F, I, C2-C6haloalkyl, C2-C6alkyl, and -OR, wherein at least one of R2and R4 is other than H; R3is H, F, Cl, Br, I, or alkyl;X is C-R5or N;R5is Cl, Br, F, I, cyano, nitro, alkyl, or -CO2H;G is C-Y or N;Y is H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, -OR, pyridinyl, phenyl, or R6;R7 is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H or N;Z is O or S; each instance of R is independently H, alkyl, or acyl, when R2or R4 is -OR, then Y if present is other than F, Cl, Br, NO2, and OCF3, X is C-Rs, and R5if present is other than H and halogen, and when R2or R4 is -F or Cl, then Y if present is other than F, Cl, Br, and NO2, X is C- Rs, and R5if present is other than H and halogen.

[0230] Aspect 64 provides a compound having a structure according to Formula II, or a salt thereof:Formula II whereinR1is H, C2-C6alkyl, C2-C6haloalkyl, C3-C6cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3, or haloalkyl,;R2and R4 are each independently H, F, Cl, Br, I, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, and -OR, wherein at least one of R2and R4 is other than H; R3is H alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl;X is C-R5or N;R5is H, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or -CO2H;G is C-Y or N;Y is H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, -OR, pyridinyl, phenyl, or R6;R7 is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, or N;R9 is H, alkyl, cycloalkyl, fluoroalkyl, haloalkyl, F, Cl, Br, I, alkyl, or CF3;Z is O or S; and each instance of R is independently H, alkyl, or acyl, wherein the compound exhibits reduced affinity for Gamma-aminobutyric acid receptor subunit alpha- 1 relative to meclonazepam.

[0231] Aspect 65 provides the compound of Aspect 63 or 64, wherein R2and R4 taken together with the carbon to which they are attached provide an 5-stereocenter.

[0232] Aspect 66 provides the compound of Aspect 63 or 64, wherein R2and R4 taken together with the carbon to which they are attached provide an A’-stereocenter.

[0233] Aspect 67 provides the compound of any one of Aspects 63-66, which is an enantiomerically purified form.

[0234] Aspect 68 provides the compound of any one of Aspects 63-67, which is an enantiomerically purified form having an enantiomeric excess of at least 90% ee.

[0235] Aspect 69 provides the compound of any one of Aspects 63-68, which is in a racemic mixture.

[0236] Aspect 70 provides the compound of any one of Aspects 63-69, wherein R1is H, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, CDs, fS')-CDFH, (A)-CDFH, (S)- CH3CHCF3, or (A)-CH3CHCF3.

[0237] Aspect 71 provides the compound of any one of Aspects 63-70, wherein R1is H.

[0238] Aspect 72 provides the compound of any one of Aspects 63-71, wherein R2is F, Cl, Br, I, trifluoromethyl, CF2H, CH2F, trichloromethyl, methyl, ethyl, OH, or OAc.

[0239] Aspect 73 provides the compound of any one of Aspects 63-72, wherein is H or R3methyl.

[0240] Aspect 74 provides the compound of any one of Aspects 63-73, wherein is H R3

[0241] Aspect 75 provides the compound of any one of Aspects 63-74, wherein R4 is F, Cl, Br, I, trifluoromethyl, CF2H, CH2F, trichloromethyl, ethyl, OH, or OAc.

[0242] Aspect 76 provides the compound of any one of Aspects 63-75, wherein R4 is OH, OAc, F, or ethyl.

[0243] Aspect 77 provides the compound of any one of Aspects 63-76, wherein X is C-Rs.

[0244] Aspect 78 provides the compound of any one of Aspects 63-77, wherein R5is F, Br, Cl, I, cyano, nitro, methyl, or -CO2H.

[0245] Aspect 79 provides the compound of any one of Aspects 63-78, wherein R5is F or Cl.

[0246] Aspect 80 provides the compound of any one of Aspects 63-79, wherein G is C-Y.

[0247] Aspect 81 provides the compound of any one of Aspects 63-80, wherein Y is nitro, -CO2H, chloro, bromo, trifluoromethyl, cyano, methoxy, hydroxy, cyclopropyl, 2-pyridinyl,3-pyridinyl, 4-pyridinyl,wherein R7 if present is methyl, cyano, trifluoromethyl, hydroxy or methoxy, and R8if present is methyl, cyano, trifluoromethyl, hydroxy or methoxy.

[0248] Aspect 82 provides the compound of any one of Aspects 63-81, wherein Y is nitro.

[0249] Aspect 83 provides the compound of any one of Aspects 63-82, wherein R is H, methyl, or acetyl.

[0250] Aspect 84 provides the compound of any one of Aspects 63-83, wherein Z is O.

[0251] Aspect 85 provides the compound of any one of Aspects 63-84, wherein Q is CH.

[0252] Aspect 86 provides the compound of any one of Aspects 63-85, wherein one of R2and R4 is other than H, alkyl, and OR.

[0253] Aspect 87 provides the compound of any one of Aspects 63-86, wherein one of R2and R4 is a halogen.

[0254] Aspect 88 provides the compound of any one of Aspects 63-87, wherein one of R2and R4 is F.

[0255] Aspect 89 provides the compound of any one of Aspects 63-88, wherein R5is other than a halogen.

[0256] Aspect 90 provides the compound of any one of Aspects 63-89, wherein R5is other than Cl.

[0257] Aspect 91 provides the compound of any one of Aspects 63-90, wherein Y is other than nitro.

[0258] Aspect 92 provides the compound of any one of Aspects 63-91, wherein Y is other than a halogen.

[0259] Aspect 93 provides the compound of any one of Aspects 63-92, wherein R1is H,R3is H, X is C-Rs, G is C-Y, Q is C-H, and Z is O.

[0260] Aspect 94 provides the compound of any one of Aspects 63-93, wherein R1is H,R3is H, X is C-Rs, G is C-Y, Q is C-H, Z is O, and R5is Cl.

[0261] Aspect 95 provides the compound of any one of Aspects 63-94, wherein R1is H,R3is H, X is C-R5, G is C-Y, Q is C-H, Z is O, and Y is nitro or -CO2H.

[0262] Aspect 96 provides a pharmaceutical composition comprising the compound of any one of Aspects 57-95.

[0263] Aspect 97 provides a pharmaceutical composition comprising the compound of any one of Aspects 57-96 formulated for use as an anthelmintic agent.

[0264] Aspect 98 provides a method of inactivating a parasitic worm, comprising contacting the parasitic worm with the compound of any one of Aspects 63-96 or the pharmaceutical composition of Aspect 97 or 98.

[0265] Aspect 99 provides the method of any one of Aspects 1-56 or 98, wherein the parasitic worm is an intestinal parasite.

[0266] Aspect 100 provides the method of any one of Aspects 1-56 or 98-99, wherein the parasitic worm is a flatworm.

[0267] Aspect 101 provides the method of any one of Aspects 1-56 or 98-100, wherein the parasitic worm is Schistosoma mansoni.

[0268] Aspect 102 provides the method of any one of Aspects 1-56 or 98-101, wherein the parasitic worm is Schistosoma haematobium.

[0269] Aspect 103 provides the method of any one of Aspects 1-56 or 98-102, wherein the parasitic worm is an intestinal flatworm.

[0270] Aspect 104 provides the method of any one of Aspects 1-56 or 98-103, wherein the parasitic worm is a juvenile worm.

[0271] Aspect 105 provides the method of any one of Aspects 1-56 or 98-104, wherein the parasitic worm is praziquantel-resistant.

[0272] Aspect 106 provides the method of any one of Aspects 1-56 or 98-105, wherein the patient is a human.

[0273] Aspect 107 provides the method of any one of Aspects 1-56 or 98-106, wherein the patient is a non-human animal.

[0274] Aspect 108 provides the method of any one of Aspects 1-56 or 98-107, wherein the patient is a livestock animal.

[0275]

[0276] Aspect 109 provides the method or pharmaceutical composition of any one of Aspects 1-56 or 97-108, which is configured to administer the compound at an amount less than the minimum amount effective to therapeutically induce sedative effects, hypnotic effects, CNS effects, GAB Anergic effects, anxiolytic effects, nervous system effects, brain effects, antiseizure effects, muscle relaxant effects, and other GABA-imparted effects in a patient.

[0277] Aspect 110 provides the method or pharmaceutical composition of any one of Aspects 1-56 or 97-109, which is configured to provide an amount of the compound to the patient that does not induce, or minimizes, one or more of sedative effects, hypnotic effects, CNS effects, GAB Anergic effects, anxiolytic effects, nervous system effects, brain effects, antiseizure effects, muscle relaxant effects, and other GABA-imparted effects in a patient.

[0278] Aspect 111 provides the catalyst or method of any one or any combination of Aspects 1-110 optionally configured such that all elements or options recited are available to use or select from.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound according to Formula II, or a salt thereof to the patient in need thereof:whereinR1is H, C2-C6alkyl, C2-C6haloalkyl, C3-C6cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3, or haloalkyl;R2and R4 are each independently H, F, Cl, Br, I, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, and -OR, wherein at least one of R2and FU is other than H; R3is H alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl;X is C-R5or N;R5is H, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or -CO2H;G is C-Y or N;Y is H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, -OR, pyridinyl, phenyl, or R6;R7 is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, or N;R9 is H, alkyl, cycloalkyl, fluoroalkyl, haloalkyl, F, Cl, Br, I, alkyl, or CF3;Z is O or S; andeach instance of R is independently H, alkyl, or acyl.

2. A method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound according to Formula III, Formula IV, Formula V, or a salt thereof to the patient in need thereof:Formula V whereinR2and R4 are each independently H, F, Cl, Br, I, CF3, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)s, and -OR, wherein at least one of R2and R4 is other than H; iRs3alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl; and U is CH2, CRH, CR2, or CO.

3. A method of treating a parasitic worm infection in a patient, comprising administering a therapeutically effective amount of a compound according to Formula I, or a salt thereof to the patient in need thereof:Formula I whereinR1is H, C2-C6alkyl, C2-C6haloalkyl, C3-C6cycloalkyl, deuterated alkyl, CD3, fluoroalkyl, CF3, or haloalkyl;R2and R4 are each independently H, F, Cl, Br, I, methyl, C2-C6alkyl, C2-C6haloalkyl, cycloalkyl, -CHO, -Si(R)3, -NH2, -NHR, -NRR, CN, or -OR, wherein at least one of R2and R4 is other than H;W is C-R3, C-NO2, C-CH3, C-F, or C-Y; R3is H, alkyl, cycloalkyl, F, Cl, Br, I, or haloalkyl;L is pyridyl, phenyl, cyclohexyl,, each of which may be optionally substituted by one, two, or more Rs;X is each independently C-R5or N;R5is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or -CO2H;G is C-Y or N;Y is each independently H, F, Cl, Br, I, cyano, nitro, alkyl, cycloalkyl, haloalkyl, fluoroalkyl, CF3, CF2CF3, -CO2H, -CCR, -OR, pyridinyl, phenyl, or R6;R7 is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;R8is H, alkyl, cycloalkyl, fluoroalkyl, cyano, -OR;Q is C-H, C-R9, or N;T is N or CH;J is O, Z, NH, or NR, or J and the double bond to the carbon to which it is attached are replaced with JI and J2, wherein JI and J2 are each independently H, R, OR, SR, NHR, or NR2, or J together with the carbon to which it is attached forms a triazole or imidazole together with R1and the nitrogen to which it is attached;R9 is H, alkyl, cycloalkyl, fluoroalkyl, F, Cl, Br, I, alkyl, or CF3;Z is O or S; each instance of R is independently H, alkyl, or acyl; and wherein the compound is other than meclonazepam.

4. The method of claim 3, wherein the compound has the following structure, or a salt thereof:

5. The method of any one of claims 1-3, wherein R2and R4 taken together with the carbon to which they are attached provide an 5-stereocenter.

6. The method of any one of claims 1-3, wherein R2and R4 taken together with the carbon to which they are attached provide an A’-stereocenter.

7. The method of any one of claims 1-3, wherein the compound is an enantiomerically purified form having an enantiomeric excess of at least 90% ee.

8. The method of any one of claims 1-3, wherein R4 is F, Cl, Br, I, trifluoromethyl, CF2H, CH2F, trichloromethyl, ethyl, OH, or OAc.

9. The method of any one of claims 1-3, wherein R4 is OH, OAc, F, or ethyl.

10. The method of any one of claims 1-3, wherein Rs, if present, is F or Cl.

11. The method of any one of claims 1-3, wherein Y, if present, is nitro or -CO2H.

12. The method of any one of claims 1-3, wherein one of R2and R4 is halogen or -OR.

13. The method of any one of claims 1-3, wherein one of R2and R4 is F.

14. The method of any one of claims 1-3, wherein the parasitic worm infection is praziquantel-resistant.

15. The method of any one of claims 1-3, wherein the patient is a human.

16. The method of any one of claims 1-3, wherein the patient is a non-human animal.

17. The method of any one of claims 1-3, wherein the compound has less activity atGAB AAR relative to meclonazepam, or the compound has insufficient activity at GAB AAR to impart a therapeutic GABA-imparted effect on the patient.

18. The method of any one of claims 1-3, wherein the compound is administered to the patient at amount less than a minimum amount effective to therapeutically induce sedative effects, hypnotic effects, CNS effects, GAB Anergic effects, anxiolytic effects, nervous system effects, brain effects, antiseizure effects, muscle relaxant effects, and other GABA-imparted effects in the patient.

19. A compound having the following structure, or a salt thereof:

20. A pharmaceutical composition having a compound of claim 19 and a pharmaceutically acceptable salt, wherein the compound is at an amount less than a minimum amount effective to therapeutically induce sedative effects, hypnotic effects, CNS effects, GAB Anergic effects, anxiolytic effects, nervous system effects, brain effects, antiseizure effects, muscle relaxant effects, and other GABA-imparted effects in a patient.

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