WO2019089940A1

WO2019089940A1 - Methods of treating epilepsy and related neurological conditions

Info

Publication number: WO2019089940A1
Application number: PCT/US2018/058727
Authority: WO
Inventors: Gregory R. Stewart; Matthew Fox; Bryant GAY; J. Michael ANDRESEN; Chani MAHER; Steven Petrou; David Goldstein
Original assignee: Pairnomix, Llc
Priority date: 2017-11-01
Filing date: 2018-11-01
Publication date: 2019-05-09

Abstract

The disclosure provides methods to prevent, inhibit or treat one or more symptoms associated with epilepsy or encephalopathies in a mammal, comprising: administering to the mammal, e.g., a composition having one of more of compounds of formula (I)-(XXXX).

Description

METHODS OF TREATI G EPILEPSY AND RELATED

EUROLOGICAL CGIMDmONS

Cross-Referersce to Related Applications

This application ciaims the benefit of the filing date of U.S. application Serial No. 62/580,012, filed on November 1 , 2017, the disclosure of which is incorporated by reference herein.

In the US, rare diseases are defined as those with less than 200,000 sufferers. Though for each disease this represents only a small fraction of the population, combined, millions of people worldwide live with a rare disease, with estimates of between 5-7% of the global population. The majority of these diseases are genetic, many caused by single gene changes, yet for 95% of these cases, there are no FDA approved drugs. Personalized medicine provides a new research avenue to identify candidate therapies for these diseases (EpiPM Consortium, 2015). Epilepsy affects 4% of the population, typically characterized by unprovoked seizure episodes. In two-thirds of diagnoses, the cause is unknown. Epileptic encephalopathies are a group of rare, severe neurological disorders manifesting in childhood often caused by de novo mutations (McTague, Howell, Cross, Kurian, & Scheffer, 2018).

Standard treatment of epilepsy consists of anti-epileptic drugs. However, some patients with epilepsy are refractory to pharmacological treatment, e.g., 25-30% of those diagnosed with an epileptic condition are refractory to currently prescribed

pharmacologics (Novy et al., 2010; Mayer et al., 2Q02).

Summary

Genetic mutations, e.g., somatic mutations, can impact protein function and those mutations may in turn be associated neural and behavioral symptoms, e.g., symptoms associated with epilepsy, other seizure disorders and epileptic

encephalopathies. The methods described herein are based, in part, on the

identification of molecules that directly or indirectly modulate a iigand gated ion channel, e.g., a chloride channel, for instance, directly or indirectly modulate gamma- aminobutyric acid (GABA) receptor activity, e.g., gamma-aminobutyric acid receptor subunit beta-3 (GABRB3) activity, in one embodiment, those molecules are useful as agonists of gamma-aminobutyric acid receptor type A (designated herein as GABA-A or GABAA) activity, and for disorders characterized by seizures or other encephalopathies, e.g., those that have altered, e.g., GABA activity, e.g., decreased activity associated with a mutation(s) in a gene encoding a subunit of the GABA-A receptor, which mutation encodes a variant channel protein. Thus, compounds that potentiate the activity of GABA (either as direct agonists or indirectly, e.g. through positive ailosteric modulation or PAM) are useful to prevent, inihibit or treat disorders characterized by seizures or other encephalopathies.

The disclosure provides a method to prevent, inhibit or treat one or more symptoms associated with epilepsy or other encephalopathies, e.g., associated with seizures, in a mammal. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising an anticesiodal,

anticonvulsant, hormone replacement, antianginal, anti-inflammatory, vasodilator, antiseptic, antiparasitic, analgesic, anti-epileptic drug (AED), anesthetic, hormonal agent, antiemetic, antifungal, anti-infective, antibiotic, antihistamine,

antimicrobialantipruritic, antiobesity, antiarrhythmic, antianxiety, antidepressant, contraceptive, antispasmodic, or antitussive agent, or combinations thereof. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of any one of formulas (l)-(XXXX), a compound in Table 1 , or a combination thereof. In one embodiment, the agent is not fendiline hydrochloride. In one embodiment, the agent is not dyclonine hydrochloride. In one embodiment, the agent is not drofenine hydrochloride. In one embodiment, the agent is not dimethisoquin hydrochloride. In one embodiment, the agent is not bepridri! hydrochloride. In one embodiment, the agent is not prenyiamine lactate, in one embodiment, the agent is not cloperastine hydrochloride, in one embodiment, the mamma! is a human. In one embodiment, compounds that modulate GABA activity may be useful to prevent, inhibit, or treat disorders including, but not limited to, seizure disorders including epilepsy and associated co-morbidities, e.g., epilepsy, childhood absence 5 (ECA5), epileptic encephalopathy (EE), early infantile EE 43 (EIEE43), autism spectrum disorder, Lenox-Gastaut Syndrome (LGS), global developmental delay, decreased fine and gross motor control, attention deficit hyperactivity disorder

(ADHD), Rett syndrome, Angeiman syndrome, Prader-Willi syndrome. Compounds that modulate GABA activity may also be useful to prevent, inhibit or treated other disorders of the central nervous system (CNS) including, but not limited to, stress, anxiety, mood or psychiatric disorders (e.g. premenstrual dysphoric disorder, post-partum depression, puberty associated depression and schizophrenia), insomnia, migraines, muscle spasms and rgiditiy (e.g. stiff person syndrome), sleep disorders, chronic alcohol intoxication/withdrawal, multiple sclerosis and neuropathic pain. Lastly, compounds that modulate GABA activity might be useful to prevent, inhibit or treat non-CNS disorders including, but not limited to, gastroi testi al tract motility and inflammation, inflammatory bowel disease, gastroparesis, ileus and acute colonic pseudo-obstruction or acute liver injury.

Also provided is a method to prevent, inhibit or treat one or more symptoms associated with loss of or reduced activity of GABA due to mutational dysfunction in the GABA-A receptor in a mammal. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising an anticestodal, anticonvulsant, hormone replacement, antianginal, anti-inflammatory, vasodilator, antiseptic, antiparasitic, analgesic, AED, anesthetic, , hormonal agent, antiemetic, antifungal, anti-infective, antibiotic, antihistamine, antimicrobialantipruritic, antiobesity, antiarrhyihmic, antianxiety, antidepressant, contraceptive, antispasmodic, or antitussive agent, or combinations thereof. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of any one of formulas (i)-(XXXX), a compound in Table 1 , or a

pharmaceutically acceptable salt thereof. In one embodiment, the agent is not fendiline hydrochloride, in one embodiment, the agent is not dyclonine hydrochloride, in one embodiment, the agent is not drofenine hydrochloride. In one embodiment, the agent is not dimethisoquin hydrochloride. In one embodiment, the agent is not bepridrii hydrochloride, in one embodiment, the agent is not prenyiamine lactate, in one embodiment, the agent is not cloperastine hydrochloride, in one embodiment, the mammal is a human.

In one embodiment, the composition is orally, intravenously, intramuscularly, subcutaneously, transdermally, intrathecaliy, intracerebrovascularly, intraparenchymally, intracerebroventriculariy (e.g., ail forms of direct delivery to the central nervous system), intravitreaily or intraretinally (e.g. all forms of direct delivery to the eye, intra- ganglionically (e.g. all forms of direct delivery to the peripheral nervous system), intra- aural (e.g. ail forms of direct delivery to the middle or inner ear and cochlea) or rectaliy administered, in one embodiment, the administration of the composition prevents, inhibits, or treat seizure disorders including epilepsy and associated co-morbidities, e.g., epilepsy, childhood absence 5 (ECA5), epileptic encephalopathy (EE), early infantile EE 43 (EIEE43), autism spectrum disorder, Lenox-Gastaut Syndrome (LGS), global developmental delay, decreased fine and gross motor control, attention deficit hyperactivity disorder (ADHD), Rett syndrome, Angelman syndrome, Prader-Willi syndrome. The administration of the composition may also be used to prevent, inhibit or treat other disorders of the CNS including, but not limited to, stress, anxiety, mood or psychiatric disorders (e.g. premenstrual dysphoric disorder, post-partum depression, puberty associated depression or schizophrenia), insomnia, migraines, muscle spasms and rigidity (e.g. stiff person syndrome), sleep disorders, chronic alcohol

intoxication/withdrawal, multiple sclerosis and neuropathic pain. Lastly, the

administration of the compositions might be useful to prevent, inhibit or treat non-CNS disorder including, but not limited to, gastrointestinal tract motility and inflammation, inflammatory bowel disease, gastroparesis, ileus and acute colonic pseudo-obstruction or acute liver injury.

In one embodiment, the composition is useful to prevent, inhibit or treat epilepsy or symptoms thereof, or related disorders, and comprises administering to a mammal such as a human or non-human mammal an effective amount of clemastine fumarate, carvedilol, loperamide, fendiline hydrochloride, dyclonine hydrochloride, mebeverine hydrochloride, racecadotril, drofenine hydrochloride, dimethisoquin hydrochloride, bepridri! hydrochloride, prenylamine lactate, methyl benethonium chloride, cloperastine hydrochionde, or combinations thereof.

In one embodiment, compounds including but not limited to fendiiine hydrochloride, dyclonine hydrochloride, drofenine hydrochloride, dimethisoquin hydrochloride, bepridril hydrochloride, prenylamine lactate, methyl benethonium chloride or cloperastine hydrochloride, or combinations thereof, may be employed to prevent, inhibit or treat epilepsy and associated co-morbidities, e.g., epilepsy, childhood absence 5 (ECA5), epileptic encephalopathy (EE), early infantile EE 43 (EIEE43), autism spectrum disorder, Lenox-Gastaut Syndrome (LGS), global developmental delay, decreased fine and gross motor control, attention deficit hyperactivity disorder (ADHD), Rett syndrome, Angeiman syndrome, Prader-Willi syndrome. Combinations of compounds as described above may also be useful to prevent, inhibit or treated other disorders of the CNS including, but not limited to, stress, anxiety, mood or psychiatric disorders (e.g. premenstrual dysphoric disorder, post-partum depression, puberty associated depression and schizophrenia), insomnia, migraines, muscle spasms and rigidity (e.g. stiff person syndrome), sleep disorders, chronic alcohol

intoxication/withdrawal, multiple sclerosis and neuropathic pain. Lastly, combinations of compounds as described above might be useful to prevent, inhibit or treat non-CNS disorders including, but not limited to, gastrointestinal tract motility and inflammation, inflammatory bowel disease, gastroparesis, ileus and acute colonic pseudo-obstruction or acute liver injury.

In one embodiment, a method to prevent, inhibit or treat one or more symptoms associated with epilepsy or co-morbidities thereof such as childhood absence 5 (ECA5), epileptic encephalopathy (EE), early infantile EE 43 (EIEE43), autism spectrum disorder, Lenox-Gastaut Syndrome (LGS), global developmental delay, decreased fine and gross motor control, attention deficit hyperactivity disorder (ADHD), Rett syndrome, Angeiman syndrome, or Prader-Willi syndrome is provided.

In one embodiment, a method to prevent, inhibit or treat one or more symptoms associated with disorders of the CNS including, but not limited to, stress, anxiety, mood or psychiatric disorders (e.g., premenstrual dysphoric disorder, porst-partum

depression, puberty associated depression and schizophrenia), insomnia, migraines, muscle spasms and rigidity (e.g., stiff person syndrome), sleep disorders, chronic alcohol intoxication/withdrawal, multiple sclerosis or neuropathic pain is provided.

In one embodiment, a method to prevent, inhibit or treat one or more symptoms associated with non-CNS disorders including, but not limited to, gastrointestinal tract motility and inflammation, inflammatory bowel disease, gastroparesis, ileus and acute colonic pseudo-obstruction or acute liver injury is provided.

In one embodiment, the composition is administered to a mammal such as a human by routes including but not limited to oral, intravenous, intra-arterial, subcutaneous, intranasal, intrathecal, intracerebroventricular, intraparenchymal, trans- retinal, intra-aural, intramuscular, transdermal, or rectal. Also provided herein are compositions having an effective amount of the compounds disclosed herein for use in a method to prevent, inhibit or treat disorders including epilepsy. Thus, the disclosure provides for the use of a composition comprising one or more compounds having, e.g., one of formula (l)-(XXXX), as a treatment for epilepsy and associated co-morbidities, e.g., epilepsy, childhood absence 5 (ECA5), epileptic encephalopathy (EE), early infantile EE 43 (EIEE43), autism spectrum disorder, Lenox-Gastaut Syndrome (LGS), global developmental delay, decreased fine and gross motor control, attention deficit hyperactivity disorder (ADHD), Rett syndrome, Angeiman syndrome, Prader-Willi syndrome. The use of a composition comprising one or more compounds having, e.g., one of formula (l)-(XXXX), may also be useful to prevent, inhibit or treated other disorders of the CNS including, but not limited to, stress, anxiety, mood or psychiatric disorders (e.g. premenstrual dysphoric disorder, post-partum depression, puberty associated depression and schizophrenia), insomnia, migraines, muscle spasms and rigidity (e.g. stiff person syndrome),sleep disorders, chronic alcohol intoxication/withdrawal, multiple sclerosis and neuropathic pain. Lastly, the use of a composition comprising one or more compounds having, e.g., one of formula (l)-(XXXX), might be useful to prevent, inhibit or treat non-CNS disorders including, but not limited to, gastrointestinal tract motility and inflammation, inflammatory bowel disease, gastroparesis, ileus and acute colonic pseudo-obstruction or acute liver injury.

The compounds disclosed herein may be useful to prevent or treat epilepsy or related conditions in veterinary applications.

The compounds disclosed herein may be employed with other therapeutic compounds.

Brief Description of the Figures

Figure 1 A. To test the function of the GABAA wild-type and GABRB3 Y302C cell models, electrophysioiogy was employed to measure chloride flow into ceils after challenging ceils with a high concentration of GABA. The GABAA wild-type cell model allowed a large influx, but the GABRB3 Y302C ceil model only allowed a much smaller response. This indicates the Y3Q2C GABRB3 mutation leads to a significant loss of function when incorporated into GABAA channels.

Figure 1 Β. To evaluate how GABA affects channel opening, concentration- response testing was undertaken in the GABAA wild-type and GABRB3 Y302C ceil models. The GABRB3 Y302C cell model required 60 times as much GABA to reach the same response as the GABAA wild-type ceil model. This change in sensitivity is reflected in a rightward shift of the concentration-response curve.

Figure 2. To identify compounds that activate GABAA channels, a library of approved drugs was screened against the GABAA wild-type ceil model. The screen was run in the presence of a low concentration of GABA to test for the potentiation of GABAA channels through a process such as PAM. A total of 54 compounds were found that activated GABAA channels more than two standard deviations above the mean activation level.

Figures 3A-B. To confirm and further characterize the data from the high throughput screen, 36 compounds were chosen for follow-up concentration-response studies. The effect of each compound on GABAA channel activity was measured on the GABAA wild-type cell model across a range of concentrations. Subsequent concentration-response curves showed 1 1 compounds had strong activity (ECso < 5 μΜ), including androsterone (ECso = 0.6 μΜ) and propofol (ECso = 0.6 μΜ).

Figures 3C-D. To further characterize the top compounds, the activity of 5 compounds was analyzed using electrophysioiogy on the GABAA wild-type cell model, in addition, clonazepam, an antiepileptic drug and known potentiator of GABAA channels, was included as a control compound. One of the 5 compounds, ivermectin, showed activity in this assay, along with the clonazepam control. Ivermectin was active starting at 1 μΜ, while clonazepam was active as low as 30 nM.

Detained Description

Definitions

In describing and claiming the invention, the following terminology will be used in accordance with the definitions set forth below.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one or more than one element.

The term "about," as used herein, means approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. For example, in one aspect, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20%. The term "about", when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range.

As used herein, "individual" (as in the subject of the treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, goats, and rodents including rabbits, mice, rats and ferrets. Non-mammals include, for example, fish and birds.

The term "disease" or "disorder" or "malcondition" are used interchangeably.

The expression "effective amount", when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound or composition that is effective to prevent or inhibit or otherwise treat one or more symptoms of a disease or disorder.

Phrases such as "under conditions suitable to provide" or "under conditions sufficient to yield" or the like, in the context of methods of synthesis, as used herein refers to reaction conditions, such as time, temperature, solvent, reactant

concentrations, and the like, that are within ordinary skill for an experimenter to vary, that provide a useful quantity or yield of a reaction product. It is not necessary that the desired reaction product be the only reaction product or that the starting materials be entirely consumed, provided the desired reaction product can be isolated or otherwise further used.

"Substantially" as the term is used herein means completely or almost completely; for example, a composition that is "substantially free" of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure" is there are only negligible traces of impurities present.

The administration of a composition may be for either a "prophylactic" or "therapeutic" purpose. When provided prophyiacticaliy, the compositions are provided before any symptom or clinical sign of a disease becomes manifest. The prophylactic administration of the composition serves to prevent or attenuate any subsequent symptom or clinical sign. When provided therapeutically, the compositions are provided upon the detection of a symptom or clinical sign of disease.

Thus, a composition may be provided either before the onset of disease or a symptom (so as to prevent or attenuate a symptom) or after the initiation of symptoms or clinical signs of disease.

A composition is said to be "pharmacologically acceptable" if its administration can be tolerated by a recipient mammal. Such an agent is said to be administered in a "therapeutically effective amount" if the amount administered is physiologically significant.

The "protection" provided need not be absolute, i.e., need not be totally prevented or eradicated, if there is a statistically significant improvement compared with a control population or set of mammals. Protection may be limited to mitigating the severity or rapidity of onset of symptoms or clinical signs of the disease.

"Treating" or "treatment" within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder. Similarly, as used herein, an "effective amount" or a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition. In particular, a

"therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects. By "chemically feasible" is meant, a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example, a structure within a definition of a claim thai would contain in certain situations a pentavalent carbon atom thai would not exist in nature would be understood to not be wiihin the claim. The structures disclosed herein, in all of their embodiments 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.

When a substituent is specified to be an atom or atoms of specified identity, "or a bond", a configuration is referred to when the substituent is "a bond" that the groups that are immediately adjacent to the specified substituent are directly connected to each other in a chemically feasible bonding configuration.

Ail chirai, diastereomeric, racemic forms of a structure are intended, unless a particular stereochemistry or isomeric form is specifically indicated. Compounds used in the present invention 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 ail within the scope of the invention.

The inclusion of an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule. All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated. For example, any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium (¹H), deuterium (²H), or tritium (³H) in any combination. Similarly, any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as ¹¹C, ⁱ²C, ¹³C, or ¹⁴C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as ¹³N, ¹⁴N, or ¹⁵N. A molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi-molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition. For example, a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or ^,4C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom, it is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as ¹⁴N and ¹⁵N, ³²S and ³⁴S, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule. The isotopes, radiolabeled or stable, can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry. The isotopic forms are incorporated into precursors as required for use in any particular synthetic route. For example, ⁱ⁴C and ³H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, ¹⁴C and ³H are incorporated into precursor molecules, followed by further elaboration as needed.

The term "amino protecting group" or "N-protected" as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Amino protecting groups include acyi groups such as formyi, acetyl, propsonyi, pivaioyl, t-butylacetyl, 2-chioroacetyi, 2-bromoacetyi, trifluoroacetyl, trichloroacetyl,

o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,

4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesuifonyi and the like: alkoxy- or aryioxy-carbonyi groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyi, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,

3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,

4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,

3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1 -methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t- butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2- trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; araikyl groups such as benzyl, triphenylmethyl, benzyioxymethyi and the like; and silyi groups such as trimethy!si!yl and the like. Amine protecting groups also include cyclic amino protecting groups such as phthaloyi and dithiosuecinimidyi, which incorporate the amino nitrogen into a heterocycle. Typically, amino protecting groups include formyi, acetyl, benzoyl, pivaioyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. it is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.

The term "hydroxy! protecting group" or "O-protected" as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in Protective Groups in Organic

Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Hydroxy! protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaioyS, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p- toluenesulfonyl and the like; acyioxy groups (which form urethanes with the protected amine) such as benzyioxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,

p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,

3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,

4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,

3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t- butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyi (Alloc), 2,2,2- trichioroethoxycarbonyl, 2-trimethylsilyiethyioxycarbonyl (Teoc), phenoxycarbonyi, 4- nitrophenoxycarbonyl, fiuorenyi~9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyi, phenylthiocarbonyl and the like; araikyl groups such as benzyl, tiiphenylmethyl, benzyloxymethyi and the like; and silyi groups such as trimethylsilyl and the like, it is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group for the synthetic task at hand.

In general, "substituted" refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and 1); an oxygen atom in groups such as hydroxyl groups, aikoxy groups, aryioxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyi groups including carboxylic acids, carboxyiates, and carboxylaie esters; a sulfur atom in groups such as thiol groups, alkyi and ary! sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, 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, CI, Br, I, OR', OC(0)N(R')2, CN, NO, N0₂, ONO2, azido, CF₃, OCF₃, R\ O (oxo), S (thiono), methylenedioxy, ethy!enedioxy, N(R^*)₂, SR\ SOR^*. SO2R', S0₂N(R')₂, SO3R', C(0)R', C(0)C(0)R\ C(0)CH₂C(0)R\ C(S)R', C(0)0R', OC(0)R', C(0)N(R')₂, OC(0)N(R')₂, C(S)N(R^*)₂, (CH₂)c-₂N(R')C(0)R\ (CH₂)o-2N(R')N(R')₂, N(R')N(R')C(0)R', N(R')N(R')C(0)OR', N(R')N(R')CON(R')₂, N(R^*)S0₂R', N(R^*)S0₂N(R')₂, N(R^*)C(0)OR\ N(R^*)C(0)R\

N(R')C(S)R', N(R')C(0)N(R')₂, N(R')C(S)N(R')₂, N(COR')COR', N(OR')R', C(=NH)N(R')_2l C(0)N(OR')R', or C(=NOR')R' wherein R' can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself be further substituted.

When a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond. When a substituent is more than monovalent., such as O, which is divalent, it can be bonded to the atom it is substituting by more than one bond, i.e., a divalent substituent is bonded by a double bond; for example, a C substituted with O forms a carbonyl group, C=0, which can also be written as "CO", "C(0)", or "C(=0)", wherein the C and the O are double bonded. When a carbon atom is substituted with a double-bonded oxygen (=0) group, the oxygen substituent is termed an "oxo" group. When a divalent substituent such as NR is double-bonded to a carbon atom, the resulting C(=NR) group is termed an "imino" group. When a divalent substituent such as S is double-bonded to a carbon atom, the results C(=S) group is termed a "thiocarbonyl" group.

Alternatively, a divalent substituent such as O or S can be connected by two single bonds to two different carbon atoms. For example, O, a divalent substituent, can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group, termed an "oxy" group, between adjacent or non- adjacent carbon atoms, for example bridging the 1 ,4-carbons of a cyciohexyi group to form a [2.2.1 j-oxabicyeio system. Further, any substituent can be bonded to a carbon or other atom by a linker, such as (CH2)n or (CR^r, wherein n is 1 , 2, 3, or more, and each R' is independently selected. Similarly, a methyienedioxy group can be a substituent when bonded to two adjacent carbon atoms, such as in a phenyl ring.

C(O) and S(0)2 groups can be bound to one or two heteroatoms, such as nitrogen, rather than to a carbon atom. For example, when a C(O) group is bound to one carbon and one nitrogen atom, the resulting group is called an "amide" or

"carboxamide." When a C(O) group is bound to two nitrogen atoms, the functional group is termed a urea. When a S(0)2 group is bound to one carbon and one nitrogen atom, the resulting unit is termed a "sulfonamide." When a S(0)2 group is bound to two nitrogen atoms, the resulting unit is termed a "sulfamate."

Substituted alkyl, alkenyl, alkynyi, cycioalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amiclines, guanidines, and nitriles.

Substituted ring groups such as substituted cycioalkyl, aryl, heterocyciyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycioalkyl, aryl, heterocyciyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyi groups as defined herein.

By a "ring system" as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic. By "spirocyciic" is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.

As to any of the groups described herein, which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds.

Selected substituents within the compounds described herein are present to a recursive degree, in this context, "recursive substituent" means that a substituent may recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number may be present in any given claim. One of ordinary skill in the art of medicinal chemistry and organic chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.

Recursive substituents are an intended aspect of the disclosed subject matter. One of ordinary skill in the art of medicinal and organic chemistry understands the versatility of such substituents. To the degree that recursive substituents are present in a claim of the disclosed subject matter, the total number should be determined as set forth above.

Aikyl groups include straight chain and branched alkyi groups and cycloalkyi groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain aikyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyi, n-hexyl, n-hepty!, and n-octyl groups. Examples of branched aikyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyi, and 2,2-dimethylpropyl groups. Representative substituted aikyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, aikoxy, and halogen groups.

Cycloalkyi groups are cyclic aikyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyi, cyciohexyi, cycloheptyi, and cyciooctyi groups, in some embodiments, the cycloalkyi group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7.

Cycloalkyi groups further include polycyclic cycloalkyi groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyi, and carenyl groups, and fused rings such as, but not limited to, decalinyi, and the like. Cycloalkyi groups also include rings that are substituted with straight or branched chain aikyl groups as defined above. Representative substituted cycloalkyi 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 cyciohexyi groups or mono-, di- or tri-substituted norbornyl or cycloheptyi groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cyc!oalkeny!" alone or in combination denotes a cyclic alkenyl group.

The terms "carbocyclic," "carbocyclyl," and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon, such as a cycioaikyl group or an aryl group. In some embodiments, the carbocycie has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N-1 substituents wherein N is the size of the carbocyclic ring with, for example, alkyi, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryi, heterocyciyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above. A carbocyclyl ring can be a cycioaikyl ring, a cycloalkenyl ring, or an aryl ring. A carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can independently be a cycioaikyl ring, a cycloalkenyl ring, or an aryl ring.

(Cycloalkyi)alkyi groups, also denoted cycloaikylaikyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycioaikyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to

vinyl,

-C(CH₂CH3)=CH₂, cyciohexenyl, cyclopentenyl, cyclohexadienyl, butadienyi, pentadienyi, and hexadienyl among others.

Cycloalkenyl groups include cycioaikyl groups having at least one double bond between 2 carbons. Thus, for example, cycloalkenyl groups include but are not limited to cyciohexenyl, cyclopentenyl, and cyclohexadienyl groups. Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7. Cycioaikyl groups further include polycyclic cycioaikyl groups such as, but not limited to, norbornyl, adamantyl, bo nyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyi, and the like, provided they include at least one double bond within a ring. Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.

(Cycloaikenyl)aikyi groups are alkyi groups as defined above in which a hydrogen or carbon bond of the alkyi group is replaced with a bond to a cycloalkenyl group as defined above.

Alkynyl groups include 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 about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to - C≡CH, -C≡C(CH₃), -C≡C(CH₂CH₃), -CH₂C≡CH, -CH₂C≡C(CH₃), and -CH₂C≡C(CH₂CH₃) among others.

The term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The

heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -0-CH₂-CH₂-CH₃, -CH₂-CH₂CH₂-OH, -CH₂-CH₂-NH-CH₃, -CH₂-S-CH₂-CH₃, -CH ₂CH₂-S(=0)-CH₃, and -CH2CH2-O-CH2CH2-O-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3, or -CH2-CH2-S-S-CH3.

A "cycloheteroalkyl" ring is a cycloaikyl ring containing at least one heteroatom.

A cycloheteroalkyl ring can also be termed a "heterocyclyi," described below.

The term "heteroalkenyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples

include -CH=CH~0-CH₃, -CH=CH-CH₂-OH, -CH₂-CH=N-QCH₃, -CH=CH-N(CH₃)-CH₃, - CH₂-CH=CH-CH₂-SH, and -CH=CH-0-CH₂CH₂-0-CH₃.

Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, hepfaienyi, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, 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 above. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.

Araikyi groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. Representative araikyi groups include benzyl and phenylethyl groups and fused (cycloalkyiaryi)alkyl groups such as 4-ethyl-indanyl. Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. Heterocyclyl groups or the term "heterocyclyl" includes aromatic and non- aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroaiom such as, but not limited to, N, O, and S. Thus a heterocyclyl can be a cycioheteroalkyi, or a heteroaryl, or if polycyciic, any combination thereof, in some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a Cz-heterocyclyi can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C^-heterocyciyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non- aromatic groups. For example, a dioxoianyi ring and a benzdioxoianyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyciic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above. Heterocyclyl groups include, but are not limited to, pyrroiidinyi, piperidiny!, piperazinyi, morpholinyl, pyrroiyi, pyrazolyi, triazoiy!, tetrazo!yl, oxazo!yi, isoxazolyl, thiazolyl, py idinyi, thiophenyl, benzoihiopheny!, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindoiyl, azaindolyl, indazolyi, benzimidazolyl, azabenzimidazolyl, benzoxazolyi, benzothiazolyl, benzothiadiazolyl, imidazopyridiny!, isoxazolopyridinyl, thianaphthaienyl, purinyl, xanthinyl, adeninyi, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyi or quinolinyl groups, which are 2- , 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.

Heteroaryl groups are 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. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrroiyi, pyrazolyi, triazoiyl, tetrazolyi, oxazolyl, isoxazolyl, thiazolyl, pyridinyi, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyi, benzimidazolyl, azabenzimidazolyl, benzoxazolyi, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazoiopyridinyi, thianaphthaienyl, purinyl, xanthinyl, adeninyi, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxa!inyl, and quinazolinyl groups, Heteroaryi groups can be unsubstituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryi groups can be substituted one or more times with groups such as those listed above.

Additional examples of aryi and heteroaryi groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyi, N-hydroxyimidazolyl, anthracenyl (1 -anthracenyi, 2-a nth race nyl, 3- anthracenyi), thiophenyl (2-thienyl, 3-thienyl), fury! (2-furyl, 3-furyl) , indolyi, oxadiazoiyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyi, pyrroiyl (2-pyrrolyi), pyrazolyl (3-pyrazolyi), imidazolyl (1 -imidazolyi, 2-imidazolyl,

4- imidazolyl, 5-imidazolyi), triazoiyl (1 ,2,3-triazol-1 -yl, 1 ,2,3-triazol-2-yl 1 ,2,3-triazol-4-yl, 1 ,2,4 riazol-3-yl), oxazoiyl (2-oxazolyl, 4-oxazoiyl, 5-oxazolyi), thiazolyi (2-thiazolyl, 4- thiazoiyl, 5-thiazoiyl), pyriclyi (2-pyridyl, 3-pyndyi, 4-pyridyl), pyrimidinyi (2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyi, pyridazinyi (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyi, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinoiyl, 7-quinolyl, 8-quinolyl), isoquinolyi (1 -isoquinolyl, 3-isoqiiinolyi, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2- benzo[bjfuranyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyi,

6- benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro- benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),

5- (2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro- benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7- benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro- benzo[b]thiophenyl), 3-(2,3-di ydro-benzo[b]thiop enyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-di ydro-benzo[b]thiop enyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-di ydro-benzo[b]thiop enyl), indolyi (1 -indoiyl, 2-indolyi,

3- indolyi, 4-indolyl, 5-indolyl, 6-indoiyl, 7-indolyi), indazole (1 -indazolyl, 3-indazolyl,

4- indazolyl, 5-indazolyl, 6-indazolyi, 7-indazoiyl), benzimidazolyl (1 -benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyi, 5-benzimidazolyl, 6-benzimidazolyl,

7- benzimidazolyl, 8-benzimidazolyi), benzoxazoiyl (1 -benzoxazolyl, 2-benzoxazoiyl), benzothiazolyl (1 -benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazo!yl,

6- benzothiazoiyl, 7-benzothiazoiyl), carbazoiyl (1 -carbazolyi, 2-carbazolyi, 3-carbazoiyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1 -yl, 5H-dibenz[b,f]azepine- 2-yi, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,1 1 -dihydro-5H-dibenz[b,i]azepine (10,1 1 -dihydro-5H-dibenz[b,f]azepine-1 -yl,

10,1 1 -dihydro-5H-dibenz[b,f]azepine-2-yl, 10,1 1 -dihydro-5H-dibenz[b,f]azepine-3-yl, 10,1 1 -dihydro-5H-dibenz[b,f]azepine-4-yl, 10,1 1 -dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyciylalkyl groups are aikyl groups as defined above in which a hydrogen or carbon bond of an alkyi group as defined above is replaced with a bond to a heterocyclyl group as defined above. Representative heterocycly! alky! groups include, but are not limited to, furan-2-yi methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indoi-2-yi propyl.

Heteroarylalkyl groups are aikyl groups as defined above in which a hydrogen or carbon bond of an alkyi group is replaced with a bond to a heteroaryi group as defined above.

The term "alkoxy" refers to an oxygen atom connected to an alkyi group, including a cycloalkyl group, as are defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyioxy, hexyioxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyioxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyciohexyioxy, and the like. An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an a!lyioxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methy!enedioxy group in a context where two adjacent atoms of a structures are substituted therewith.

The terms "halo" or "halogen" or "halide" by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, e.g., fluorine, chlorine, or bromine.

A "haioaiky!" group includes mono-halo alky! groups, poly-halo alkyi groups wherein all halo atoms can be the same or different, and per-halo alkyi groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fiuoro. Examples of haloalkyl include trifluoromet yl, 1 ,1-dichloroethyi, 1 ,2-dichloroethyi, 1 ,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.

A "haioaikoxy" group includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fiuoro. Examples of haioaikoxy include trifluoromethoxy, 1 ,1 -dichloroethoxy, 1 ,2-dichioroethoxy, 1 ,3- dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.

The term "(Cx-Cy)perfluoroalkyi," wherein x < y, means an alkyi group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein ail hydrogen atoms are replaced by fluorine atoms. In one embodiment, (Cx-C_y)perfluoroalkyl is -(Ci-C6)perfluoroalkyl. in one embodiment, (Cx-C_y)perfluoroaikyi

is -(Ci-C3)perfluoroalkyl. in one embodiment, (Cx-Cy)perfiuoroaikyl is -CF?,.

The term "(Cx-Cy)perfluoroa!kyiene," wherein x < y, means an aikyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein ail hydrogen atoms are replaced by fluorine atoms, in one embodiment, (Cx-Cy)perfluoroalkyiene is -(Ci-C6)perfluoroalkylene. In one embodiment, (Cx-C_y)perfluoroalkylene

is -(Ci-C3)perfluoroalkylene. In one embodiment, (C_x-C_y)perfluoroalky!ene is -CF2-. The terms "aryloxy" and "ary!a!koxy" refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alky! moiety. Examples include but are not limited to phenoxy, naphihyloxy, and benzyloxy.

An "acyl" group as the term is 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 also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkyialkyi, heterocyclyl, heterocyciylalkyl, heteroaryl, heteroarylalkyi group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyi group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyi-3- carbonyl) group is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyi, pyridyiacetyi, cinnamoyl, and acryloyi 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.

The term "amine" includes primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, aryiamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, araikyiamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.

An "amino" group is a substituent of the form -NH2, -NHR, -NR2, -NR,3⁺, wherein each R is independently selected, and protonated forms of each, except for -NRs⁺, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary or quaternary amino group. An "alkylamino" group includes a monoaikyiamino, diaikyiamino, and triaikyiamino group.

An "ammonium" ion includes the unsubstituted ammonium ion NH-r , but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.

The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(0)NR2, and -NRC(0)R groups, respectively. Amide groups therefore include but are not limited to primary carboxamide groups (-C(0)NH2) and formamide groups (-NHC(O)H). A "carboxamido" group is a group of the formula C(0)NR2, wherein R can be H, alkyl, aryl, etc. The term "azido" refers to an 3 group. An "azide" can be an organic azide or can be a salt of the azide (N3-) anion. The term "nitro" refers to an NO2 group bonded to an organic moiety. The term "nitroso" refers to an NO group bonded to an organic moiety. The term nitrate refers to an ONO2 group bonded to an organic moiety or to a salt of the nitrate (NO3 ) anion.

The term "urethane" ("carbamoyl" or "carbamyi") includes N- and O-urethane groups, i.e. , -NRC(0)OR and -OC(0)NR2 groups, respectively.

The term "sulfonamide" (or "sulfonamido") includes S- and N-sulfonamide groups, i.e. , -SO2NR2 and -NRSO2R groups, respectively. Sulfonamide groups therefore include but are not limited to suifamoyl groups (-SO2NH2). An organosulfur structure represented by the formula -S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.

The term "amidine" or "amidino" includes groups of the formula -C(NR)NR2. Typically, an amidino group is -C(NH)NH2.

The term "guanidine" or "guanidino" includes groups of the

formula -NRC(NR)NR2. Typically, a guanidino group is™NHC(NH)NH2.

A "salt" as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion. For example, acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH4^1" or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like. A "pharmaceutically acceptable" or "pharmacologically acceptable" salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt. A "zwitterion" is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form. A "zwitterion" is a salt within the meaning herein. The compounds of the present invention may take the form of salts. The term "salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be "pharmaceuticaiiy-acceptable salts." The term

"pharmaceutically-acceptable salt" refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystaliinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.

Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycoiic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maieic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthraniiic, 4-hydroxybenzoic, phenylaceiic, mandelic, embonic (pamoic),

methanesulfonic, ethanesulfonic, benzenesuifonic, pantothenic,

trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, aiginic, β-hydroxybutyric, salicylic, galactaric and gaiacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, /V,/V-dibenzylethylenediamine, chioroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyigiucamine) and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as

intermediates in the synthesis of compounds, for example in their purification by recrystallization. Ail of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. The term "pharmaceutically acceptable salts" refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et ai., Salt Selection for Basic Drugs (1988), Int J. Pharm., 33, 201 -217, incorporated by reference herein.

A "hydrate" is a compound that exists in a composition with water molecules.

The composition can include water in stoichiometic quantities, such as a monohydrate or a dihydraie, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.

A "solvate" is a similar composition except that a solvent other that water replaces the water. For example, methanol or ethanol can form an "aicohoiate", which can again be stoichiometic or non-stoiehiometrie. As the term is used herein a "solvate" refers to a solid form, i.e., a compound in solution in a solvent, while it may be soivated, is not a solvate as the term is used herein.

A "prodrug" as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patient's body, such as enzymes, to the active pharmaceutical ingredient. Examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H.

Bundgaard, Elsevier, 1985.

In addition, where features or aspects of the invention are described in terms of Ivlarkush groups, those skilled in the art will recognize thai the invention is also thereby described in terms of any individual member or subgroup of members of the I larkush group. For example, if a group X is described as selected from the set consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described. Moreover, where features or aspects of the invention are described in terms of arkush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any combination of individual members or subgroups of members of ivlarkush groups. Thus, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of methyl, ethyl, and propyl, claims for X being bromine and Y being methyl are fully described.

If a value of a variable that is necessarily an integer, e.g., the number of carbon atoms in an aikyl group or the number of substituents on a ring, is described as a range, e.g., 0-4, what is meant is that the value can be any integer between 0 and 4 inclusive, i.e., 0, 1 , 2, 3, or 4.

In various embodiments, the compound or set of compounds, such as are used in the inventive methods, can be any one of any of the combinations and/or subcombinations of the above-listed embodiments.

In various embodiments, a compound as shown in any of the Examples, or among the exemplary compounds, is provided.

Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.

Exemplary Methods and Compounds

The present disclosure provides methods to prevent or mitigate, e.g., inhibit or treat, in a mammal one or more symptoms associated with conditions including but not limited to seizure disorders including epilepsy, childhood absence 5 (ECA5), epileptic encephalopathy (EE), early infantile EE 43 (EIEE43), autism spectrum disorder, Lenox- Gastaut Syndrome (LGS), global developmental delay, decreased fine and gross motor control, attention deficit hyperactivity disorder (ADHD), Rett syndrome, Angeiman syndrome, Prader-Willi syndrome. The present disclosure provides methods to prevent or mitigate, e.g., inhibit or treat, in a mammal other disorders of the central nervous system including, but not limited to, stress, anxiety, mood or psychiatric disorders (e.g. premenstrual dysphoric disorder, post-partum depression, puberty associated depression and schizophrenia), insomnia, migraines, muscle spasms and rigidity (e.g. stiff person syndrome),sleep disorders, chronic alcohol intoxication/withdrawal, multiple sclerosis and neuropathic pain. Lastly, the present disclosure provides methods to prevent or mitigate, e.g., inhibit or treat, in a mammal non-CNS disorders including, but not limited to, gastrointestinal tract motility and inflammation, inflammatory bowel disease, gastroparesis, ileus and acute colonic pseudo-obstruction and acute liver injury. In one embodiment, the compounds directly or indirectly modulate the activity of GABA through the GABA-A receptor.

In some embodiments, methods are provided for inhibiting or treating symptoms associated with a disease or condition characterized by seizures or abnormal neural activity, or delaying or preventing the onset of symptoms of the disease or condition. Methods are also provided for reducing the risk, progression or onset of a pathological condition characterized by seizures. Methods are also provided for reducing the risk, lessening the severity, or delaying the progression or onset of a pathological condition characterized by aberrant GABA-A receptors, e.g., mutations in GABRB3, activity, including but not limited to GABA activity in a mammal having epilepsy, epileptic encephalopathy, and the like, in certain embodiments, compositions and methods are provided for altering or modulating aberrant GABA-A activity in a mammal. In certain embodiments, methods are provided for altering or modulating GABR activity in a mammal. In various embodiments, the methods comprise administering to the mammal a composition having one or more of formulas (l)-(XXXX), a compound in Table 1 , or a pharmaceutically acceptable salt (or other pharmaceutically acceptable form) thereof, in an amount effective to prevent, inhibit or treat a symptom of a condition, e.g., epilepsy. in certain embodiments of these methods, the compounds are administered in a therapeutically effective or prophyiacticaliy effective amount.

11 Table 1 . Compounds with Significant Activation in the FL!PR Assay on the wild-type GABAA Cellular Model*

Compound activation Compound Class Known Mechanism

Primidone 35 AED, anticonvulsant allosteric activator

Catharanthine 93 antianginal calcium channel blocker

Benfluorex 92 antiobesity activates s rotonergi pathway

C!ofi!ium tosylate S7 antiarrhythmic potassium channel blocker

Bromazepam 87 antianxiety, sedative aiiosteric activator

Methyl benzethonium

chioride 86 antimicrobial surfactant

Benzydamine hydrochloride 84 analgesic inhibitor

Eniiconazoie 84 antifungal lancsterol oi-demethyiase inhibitor

Sertraline 83 antidepressant selective serotonin reuptake inhibitor

Chiormadinone acetate SO contraceptive progesterone agonist

Dyclonine hydrochloride 80 anesthetic sodium channel biccker

Aiverine citrate salt 80 antispasmodic muscarinic acetylcholine antagonist transient potential vani!ioid

Drofenine hydrochloride 80 antispasmodic agonist

Miconazole 79 antifungal lancsterol c.-demethyiase inhibitor

Nomegestrol acetate 79 hormone replacement progesterone agonist

Tolfenamic acid 77 analgesic inhibitor

Oxybutynin chloride 75 antispasmodic muscarinic acetylcholine antagonist cytochrome inhibitor, potassium

Proadifen hydrochloride 74 investigational channel blocker

Bifonazole 72 antifungal lancsterol ci-demethyiase inhibitor

Cloperastirie hydrochloride 72 antitussive unknown

*Data were generated using a Fluorescent Imaging Plate Reader (FLiPR)-based assay high throughput screening at a single concentration of 10 μΜ for all compounds.

Compounds with activity greater than two standard deviations above the mean of all compounds (71 %) were considered to be significant 'hits' in the assay. Drugs with activation listed in bold (mizolastine and compounds listed thereafter) were 2 standard deviations greater than the mean (72% to 103%). Drugs with activation listed in black (compounds listed before mizolastine) were three standard deviations above the mean (107% to 284%). No activation (0%) was designated as the FLIPR response to 15 nM GABA, and 100% activation was designated as the response 5 nM GABA plus 1 μ,Μ diazepam (the latter is known to potentiate the effects of GABA). Many compounds acted more strongly than the positive control condition (15 nM GABA plus 1 μΜ diazepam) and have % activation over 100%. The drug class and mechanism of action for each compound are also listed. Abbreviation: "R" for "receptor." in one embodimeni, a composition comprises a compound of formula (I):

in one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyl, Ci-e saturated aikyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, Ci, Br, F, I, OH, OAc, CF₃, NH₂, CM, CO2H, CQ2C1-6 saturated or unsaturated a!kyl, NHC1-6 saturated, unsaturated alkyi, or cycloalkyl, or N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2.

In one embodiment, X = CH2, C, N, NH, NHCi-esaturated, unsaturated aikyl, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyl, C1 -6 saturated alkyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF3, NH₂, CN, CO2H, CO2C1 -5 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-6 saturated, unsaturated alkyi, or cycloalkyl)2; X = CH2, C, N, NH, NHCi-esaturated, unsaturated alkyi, or cycloalkyl, O, S, SO, or S0_2; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyl, C1-3 saturated alkyl, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, Ci, Br, F, I, OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-3 saturated or unsaturated aikyl, NHC1-3 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-3 saturated, unsaturated alkyi, or cycloalkyl)2; each X = CH2, C, N, NH, NHCi-ssaturated, unsaturated alkyi, or cycloalkyl, O, S, SO, or SG2; and n = 0-3.

In one embodiment, formula (I) is bisacodyi or perhexiline.

In one embodiment, a composition comprises a compound of formula (II):

In one embodiment, each R = independently H, OCi-e saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyl, cycioheteroalkyl, Ci, Br, F, I, OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, o N(C i-s saturated, unsaturated alkyl, or cycloalkyl)2. In one embodiment, R² = H, Ci-e saturated aikyl, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, or (O).

In one embodiment, each X independently = C, N, O, S, SO, or SO2.

In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = i H, OC1-6 saturated, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, C i-s saturated alkyi, unsaturated aikyl, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, CF₃, NH_2> CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi, o N(Ci-8 saturated, unsaturated aikyl, or cycloalkyl)2_;R² = H, C1-6 saturated alkyi, unsaturated aikyl, cycloalkyi, cycioheteroalkyi, or (O); each X independently = C, N, O, S, SO, or S0_2; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated aikyl, cycloalkyi, cycioheteroalkyi, C1-3 saturated alkyi, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, CF₃, NH_2> CN, CO2H , CQ2C1-3 saturated or unsaturated alkyi, NHC1-3 saturated, unsaturated aikyl, or cycloalkyi; each R² = H, C1-3 saturated aikyl, unsaturated aikyl, cycloalkyi, cycioheteroalkyi, or (O); each X independently = C, N, O, S, SO, S0_2; and n = 0-3.

In one embodiment, formula (II) is drofenine, proadifen, or cloperastine.

In one embodiment, a composition comprises a compound of formula (III):

In one embodiment, each R independently = H, OCi-e saturated, unsaturated aikyl, cycloalkyi, cycioheteroalkyi, C1-6 saturated aikyl, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H , CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi, or N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2.

In one embodiment, R² = H, OH , OCi-e saturated, unsaturated aikyl, cycloalkyi, cycioheteroalkyi, Ci-e saturated aikyl, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, OAc, CF3, NH₂, CN, CO2H , CO2C1-6 saturated or unsaturated aikyl, NHCre saturated, unsaturated aikyl, or cycloalkyi, or N(Ci-e saturated, unsaturated aikyl, or cycloalkyi.

In one embodiment, each X independently = C H2, N, O, S, SO, or SO2.

In one embodiment, n = 0-6

In one embodiment, each R¹ independently = H, OCi -e saturated, unsaturated aikyl, cycloalkyi, cycioheteroalkyi, C1-6 saturated alkyi, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, CF3, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi, or N(Ci-e saturated, unsaturated alkyi, or cycloalkyi^; R² = H, OH, OCi-e saturated, unsaturated alkyi, cycloalkyl, cydoheieroaikyi, Ci-e saturated alkyi, unsaturated a!kyl, cycloalkyl, cycioheteroalkyi, OAc, CF3, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated , unsaturated alkyi, or cycloalkyl, or N(Ci-e saturated, unsaturated alkyi, or cycloalkyl; each X Independently = CH2, N , O, S, SO, or SO2; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, C1-3 saiuraied alkyi, unsaturated alkyi, cycloalkyl, cydoheieroaikyi, CI, Br, F, I , OH, OAc, CF₃, NH_2> CN, CO2H, CQ2C1-3 saturated or unsaturated alkyi, NHC1-3 saturated, unsaturated alkyi, or cycloalkyl;R² = H, OH, OC1-3 saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, C 1-3 saturated alkyi, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, OAc, CF₃, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyi, or NHC1-3 saturated, unsaturated alkyi, or cycloalkyl; each X independently = CH2, N, O, S, SO, or SO2; and n = 0-3.

In one embodiment, formula (i ll) is oxybuiynin .

In one embodiment, a composition comprises a compound of formula (IV):

In one embodimeni, each R independently = H, OCi-e saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, Ci-e saturated alkyi, unsaturated aikyi, cycloalkyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2.

In one embodimeni, R² = H , OH, OC1-6 saiuraied, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, C1 -6 saturated aikyl, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, OAc, CF3, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated aikyl, or cycloalkyl, orN(Ci-e saturated, unsaturated aikyl, or cycloalkyi)₂.

In one embodimeni, R³ = Cs-Taryl or heteroaryl.

In one embodimeni, X = CH2, N, O, S, SO, or SO2

In one embodimeni, n = 0-6.

In one embodimeni, each R¹ independently = H, OCi-e saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, C1-6 saturated aikyl, unsaturated aikyi, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, CF3, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, o N(Ci-8 saturated, unsaturated aikyi, or cycloalkyl)2_; R² = H, OH, OC1-6 saturated, unsaturated aikyl, cycloalkyl, cydoheieroaikyi, Ci-e saturated aikyl, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, OAc, CF3, NH_2> CN, CO2H, CQ2d-s saturated or unsaturated alkyi, NHC1-6 saturated , unsaturated alkyi, or cycloalkyl, orN(Ci-e saturated, unsaturated alkyi, or cycloaikyi)₂.; R³ = Cs-yaryl or heteroaryl; X = CH2, N, O, S, SO, or SO2; and n = 0-6. In one embodimeni, each R independently = H, OC1-3 saturated, unsaturated alkyl, cycloalky!, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CG2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl)2; each R² independently = H, OH, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, OAc, CF3, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, or

C02NH2; X = CH₂, N, O, S, SO, SO2, and n = 0-3.

In one embodiment, formula (IV) is prenylamne or fendilsne.

In one embodiment, a composition comprises a compound of formula (V):

In one embodiment, each R¹ = H , OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-₆ saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-e saturated, unsaturated alkyl, or cycioaikyl)2

In one embodiment, each M independently = Na, K, Li, Hg, or Zn.

In one embodiment, each X independently = CH2, NH, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-s saturated, unsaturated alkyl, or cycloalkyl^; each M independently = Na, K, Li, Hg, or Zn; and each X independently = CH₂, NH, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, C1 -3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, or NHC1-3 saturated, unsaturated alkyl, or cycloalkyl; each M independently = Na, K, Li, Hg, Zn; and each X independently = CH2, NH, O, S, SO, or

In one embodiment, formula (V) is merbromin.

In one embodiment, a composition comprises a compound of formula (VI):

In one embodiment, each R independently = H, OCi-e saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, Ci-e saturated alkyi, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-s saturated, unsaturated alkyl, or cycloalkyl)2

In one embodiment, R² = H, OH, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, C1 -6 saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, OAc, CF3, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-e saturated, unsaturated alkyl, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyi, or cycloaikyl)2, C5- raryl or heteroaryi

In one embodiment, each X independently = CH, N, O, or S.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, Ci, Br, F, I , OH, OAc, CF₃, NH_2> CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl; R² = H, OH, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, OAc, CF3, NH_2> CN, C0₂H, C0₂Ci-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycioaikyl, Cs yaryl or heteroaryi; and each X independently = CH, N, O, or S.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, C1 -3 saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, Ci, Br, F, I, OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-3 saturated or unsaturated alkyi, or NHC1-3 saturated, unsaturated alkyl, or cycioaikyl; R² = H, OH, OC1-3 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, OAc, CF₃, NH₂, CN, CO2H, NHC1-3 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-3 saturated, unsaturated alkyl, or cycloalkyi)2, or Cs-earyl or heteroaryi; and each X independently = CH, N, O, or S.

In one embodiment, formula (VI) is etomidate.

In one embodiment, a composition comprises a compound of formula (VII):

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyi, cycioaikyl, cycioheteroa!kyi, CI, Br, F, I , OH, OAc, NO2, CF₃, NH₂, CN, CO2H, C0₂Ci -₅ saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, Cs-yaryl or heteroaryl.

In one embodiment, each X independenily = CH2, N, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C i-s saturated alkyl, unsaturated aikyl, cycloalkyl, cycioheieroalkyi, Ci, Br, F, I , OH, OAc, NO2, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2, Cs- aryl or heteroaryl; and each X independently = CH₂, N, O, S, SO, or S0₂

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated aikyl, cycloalkyl, cycioheieroalkyi, Ci, Br, F, I , OH, OAc, NO2, CF₃, NH₂, CN, CO2H, CO2C1-3 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)₂, or Cs-earyl or heteroaryl; and each X independently =

In one embodiment, formula (VII) is niclosamide.

In one embodiment, a composition comprises a compound of formula (VII I):

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, Ci, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-6 saturated, unsaturated aikyl, or cycloalkyl^, Cs-7aryl or heteroaryl,

in one embodiment, each X independently = CH₂, N, O, S, SO, or SO2.

in one embodiment, R² = Mono, di, o trigiycoside, o OC(O) C3-5 aikenyi,

in one embodiment, each R independently = H, OCi-e saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated aikyl, unsaturated alkyl, cycloalkyl, cycioheieroalkyi, Ci, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2, Cs-yaryl or heteroaryl; and R² = Mono, di, or triglycoside, or OC(O) C3-5 aikenyi.

In one embodimeni, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saiuraied alkyl, unsaturated aikyl, cycloalkyl, cycioheieroalkyi, Ci, Br, F, I , OH, OAc, CF3, NH_2> CN, CO2H, CO2C1-3 saturated or unsaturated aikyl, NHC1-3 saturated, unsaturated aikyl, or cycloalkyl, N(Ci-₃ saturated, unsaturated alkyl, or cycloalky!)2, or Cs-yary! or heteroaryl; and each R² independently Triglycoside or OC(O) C3-5 alkenyl.

In one embodiment, iormula (VII I) is escin.

In one embodiment, a composition comprises a compound of formula (IX):

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-s saturated, unsaturated alkyl, or cycloalkyl^, Cs-raryl or heteroaryl.

In one embodiment, R² = Mono, di, or triglycoside, orOC(O) C3-5 alkenyl.

In one embodiment, each X independently = CH2, N, O, S, SO, or SO2.

In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci -e saturated, unsaturated alkyl, or cycloalkyl, Cs-yaryl or heteroaryl; R² = Mono, di, or triglycoside, orOC(O) C3-5 alkenyl; and each X independently = CH₂, N, O, S, SO, or SO2..

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1 -3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(Ci -3 saturated, unsaturated alkyl, or cycloalkyl^, or Cs earyl or heteroaryl; R² = Mono, di, or triglycoside; and each X independently = CH₂, N, O, S, SO, or SO2

In one embodiment, formula (IX) is ivermectin or vermectin B1 .

In one embodiment, a composition comprises a compound of formula (X):

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, Ci -e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, Cs-yaryl or heteroaryl.

In one embodiment, each X independently = CH2, C, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or SO2.

In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH_2> CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)₂, Cs- aryl or heteroaryl; each X independently = CH₂, C, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or S0_2; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, Ac, CF₃, C0₂H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyi, N(C1 -3 saturated, unsaturated alkyl, or cycloalkyl)₂, or Cs-earyl or heteroaryl; each X independently = CH₂, C, NH, NC i-ssaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or S0_2; and n = 0-3.

In one embodiment, formula (X) is melengestrol acetate, chlormadinone acetate, or nomegestrol acetate.

In one embodiment, a co a compound of formuia (XI):

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, Ac, CF₃, NH_2> CN, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-s saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi^, Cs-yaryi or heteroaryl.

In one embodiment, each X independently = CH2, C, NH, NCi ^saturated, unsaturated aikyi, or cycloalkyi, O, S, SO, or SO2.

In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, Ci-e saturated alkyl, unsaturated aikyi, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF3, NH₂, CN, C(0)CH₂OAc, CO2H, C0₂C-, saturated or unsaturated alkyl, NHC i-s saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi^, Cs-Taryi or heteroaryl; each X independently = CH2, C, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, O, S, SO,

In one embodiment, each R independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saiuraied alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, C(0)CH₂OAc, CO2H , CO2C1-3 saturated or unsaturated alkyl, NHC1 -3 saturated, unsaiuraied alkyl, or cycloalkyl, N(Ci-3 saturated, unsaturated alkyl, or cycioaikyl)2, or Cs-earyl or heteroaryl; each X

independently = CH2, C, NH, NCi-3saturated, unsaiuraied alkyl, or cycloalkyl, O, S, SO,

In one embodiment, formula (XI) is androsterone or epiandrosterone.

In one embodiment, a composition comprises a compound of formula (XII):

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF_3> NH₂, CN, C(0)CH₂OAc, CO2H , CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^, Cs-yaryl or heteroaryl.

In one embodiment, each X independently = CH2, C, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2.

in one embodiment, each R² independently = H, OH, OC1 -6 saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, C1 -6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, OAc, CF3, NH2, CN, C02H,C(0)CH20Ac, C02C1 -6 saturated or unsaturated alkyl, NHC1 -6 saturated, unsaturated alkyl, or cycloalkyl, N(C1 -8 saturated, unsaturated aikyi, or cycloalkyl)2, C5-7aryi or heteroaryl

In one embodiment, n = 0-6.

In one embodiment, each R independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, C1-6 saturated alkyl, unsaturated aikyi, cycloalkyl, cycioheteroalkyi, C I, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN , C(0)CH₂OAc, CO2H , CO2C1 -6 saturated or unsaturated alkyl, NHC1 -8 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl, Cs yaryl or heteroaryl; each X independently = CH2, C, NH, NC i-ssaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S02_; and n = 0-6.

In one embodiment, formula (XI I) is alfadolone acetate or alfaxalone.

In one embodiment, a composition comprises a compound of formula (XIII):

In one embodirneni, each R independently = H, OCi-e saturated, unsaturated alky!, cycloalkyi, cycloheteroalky!, Ci-s saturated aikyl, unsaturated alkyi, cycloalky!, cycioheteroaikyi, CI, Br, F, I, OH, CF₃, NH₂, CN, C0₂H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi, o NiCi-s saturated, unsaturated aikyl, or cycloalkyl)2.

In one embodiment, each X independeniiy = CH₂, NH, NHd-esaturated, unsaturated aikyl, or cycloalkyi, O, S, SO, orS02.

In one embodiment, each n independently = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated aikyl, cycloalkyi, cycioheteroaikyi, C1-6 saturated aikyl, unsaturated aikyl, cycloalkyi, cycioheteroaikyi, Ci, Br, F, I, OH, CF₃, NH₂, CN, CO2H, CO2C1-8 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi, o N(Ci-8 saturated, unsaturated aikyl, or cycloalkyl)2.; each X independently = CH2, NH, NHCi-ssaturated, unsaturated aikyl, or cycloalkyi, O, S, SO, orS02; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated aikyl, cycloalkyi, cycioheteroaikyi, C1-3 saturated alkyi, unsaturated aikyl, cycloalkyi, cycioheteroaikyi, Ci, Br, F, I, OH, CF₃, NH_2> CN, CO2H, CO2C1-3 saturated or unsaturated aikyl, NHC1-3 saturated, unsaturated aikyl, or cycloalkyi, or N(Ci-3 saturated, unsaturated aikyl, or cycloalkyi^; each X independently = CH2, N, NH, NHCi-esaturated, unsaturated aikyl, or cycloalkyi, O, S, SO, or SO2; and each n independently = 0-3.

In one embodiment, formula (XIII) is bepridil.

In one embodiment, a composition comprises a compound of formula (XIV):

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyi, cycloalkyi, cycioheteroaikyi, C1-6 saturated aikyl, unsaturated aikyl, cycloalkyi, cycioheteroaikyi, Ci, Br, F, I, OH, OAc, Ac, CF3, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHCI-B saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi^, Cs-jaryi or heteroaryl.

In one embodiment, each X independently = CH2, NH, NCi-esaturated, unsaturated aikyl, or cycloalkyi, O, S, SO, or SO2.

In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated aikyl, cycloalkyi, cycioheteroaikyi, C1-6 saturated aikyl, unsaturated aikyl, cycloalkyi, cycioheteroaikyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi^, Canary! or heteroaryl; each X independently = CH2, NH, NCi-ssaturated, unsaturated alkyi, or cycioaikyi, O, S,

In one embodimeni, each R independently = H, OC1-3 saturated, unsaturated alkyl, cycloalky!, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, Ac, CF3, NH₂, CN, NO2, CO2H, CO2C1 -3 saturated or unsaturated alkyl, NHC1 -3 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl, or Cs-earyl or heteroaryl; each X independently = CH2, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or

In one embodiment, formula (XIV) Is THIP (Gaboxadol).

In one embodiment, a composition comprises a compound of formula (XV):

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, Ac, CF3, NH_2> CN, N0₂, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCI-B saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^, Cs-jaryi or heteroaryl.

In one embodiment, X = CH_2> NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, Ci, Br, F, I , OH, OAc, Ac, CF₃, NH_2> CN, N0_2> C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, Canary! or heteroaryl; and X = CH2, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1 -3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, Ci, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1.3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl^, or Cs-earyl or heteroaryl; and X = CH2, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, formula (XV) is meciofenamic acid, mefenamic acid, or tolfenamic acid.

In one embodiment, a composition comprises a compound of formula (XVI):

In one embodirneni, each R independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, Ci-s saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated alkyl, NHC1 -5 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi)₂, Cs-raryl or heteroaryl.

In one embodiment, each X independently = CH₂, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, each n independently = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated alkyl, NHCI-B saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, Cs-jaryi or heteroaryl; each X independently = CH₂, NH, NCi-asaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2; and each n independently = 0-8.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH_2> CN, N0_2> CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or Cs- saryl or heteroaryl; each X independently = CH₂, NH, NCi-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S0_2; and each n independently = 0-3,

In one embodiment, formula (XVI) is mizolastine.

In one embodiment, a composition comprises a compound of formula (XVII):

In one embodiment, each R independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH20Ac, C0₂H, CO2C1-6 saturated or unsaturated alkyl, NHC1 -5 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl^, Cs-raryl or heteroaryl.

In one embodiment, each X independently = CH2, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH₂, CN, NO2, C(0)CH20Ac, C0₂H, CO2C1-6 saturated or unsaturated alkyl, NHCI-B saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, Cs-jaryl or heteroaryl; and each X independently = CH2, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S,

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, NO2, C0₂Ci..₆ saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl)₂, or Cs-earyl or heteroaryi; and each X independently = CH2, NH, NCi-asaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, formula (XVII) is tropisetron.

In one embodiment, a composition comprises a compound of formula (XVI II):

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, C1 -6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, Ac, CF3, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-e saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^, C5-7aryl or heteroaryi.

In one embodiment, each X independently = CH2, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)_2> Cs-yary! or heteroaryi; and each X independently = CH2, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S,

In one embodiment, each R independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-earyl or heteroaryi; and each X independently = CH2, NH, NCi ^saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or

In one embodiment, formula (XVii i) is nitazoxanide.

In one embodiment, a composition comprises a compound of formula (XIX):

In one embodiment, each R independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CMS saturated alkyi, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated aikyl, NHC1 -5 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi)₂, Cs-raryl or heteroaryl.

In one embodiment, each X independently = CH₂, N, NH, Nd-esaturated, unsaturated aikyl, or cycloalkyl, O, S, SO, S0₂, CI, or Br.

In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, CMS saturated alkyi, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated aikyl, NHCI-B saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi)₂, Cs-7aryl or heteroaryl; each X independently = CH₂, N, NH, NCi-ssaturated, unsaturated aikyl, or cycloalkyl, O, S, SO, SO2, Ci, or Br; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, C 1-13 saturated alkyi, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH_2> CN, N0_2> CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-₃ saturated, unsaturated alkyi, or cycioaikyl)₂, or Cs-earyl or heteroaryl;

each X independently = CH₂, N, NH, NCrssaturated, unsaturated aikyl, or cycloalkyl, O,

n = 0-3.

In one embodiment, formula (XIX) is thonzonium bromide.

In one embodiment, a composition comprises a compound of formula (XX):

In one embodiment, each R¹ independently = H, OCre saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, Ci -15 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated aikyl, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)₂, Cs-7aryl or heteroaryl. In one embodirneni, each X independently = CH2, N, NH, NC-i-esaturated, unsaturated aikyi, or cycloalkyi, O, S, SO, SO2, C!, or Br.

In one embodiment, each n independently = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CMS saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCI-B saturated, unsaturated aikyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, Cs-jaryi or heteroaryl; each X independently = CH2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, SO2, CI, or Br; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated aikyi, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1-3

saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-₃ saturated, unsaturated alkyl, or cycioaikyl)2, or Cs-earyl or heteroaryl;

each X independently = CH2, N, NH, NCi-3saturated, unsaturated alkyl, or cycloalkyi, O, S, SO, SO2, Ci, or Br; and each n independently = 0-3.

In one embodiment, formula (XX) is benzethonium chloride.

In one embodiment, a composition comprises a compound of formuia (XXI):

In one embodiment, each R independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, C1-6 saturated alkyl, unsaturated aikyi, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-e saturated, unsaturated aikyi, or cycloalkyl)2_! Cs-7aryl or heteroaryl.

In one embodiment, each R² independently = H, OH, OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, OAc, CF3, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, o NfC i-s saturated, unsaturated alkyl, or cycloalkyl)2, Cs-yaryl or heteroaryl.

In one embodiment, each X independently = CH2, N, O, S, SO, or SO2.

In one embodiment, each n independently = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, C1-6 saturated alkyl, unsaturated aikyi, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, CF3, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated aikyi, or cycloalkyi, o N(Ci-8 saturated, unsaturated aikyi, or cycloalkyl)2.; each R² independently = H, OH, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, Ci-e saturated a!kyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, OAc, CFs, NH₂, CN, CO2H, CO2C 1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, o N(Ci-s saturated, unsaturated alkyl, or cycloalkyl)2; R³ = Cs ?aryl or heteroaryl; each X independently = CH₂, N, O, S, SO, or SO2 _; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, CF₃, NH_{2 >} CN, CO2H, CQ2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl)₂, or C5-6 aryl or heteroaryl;

each R² independently = H, OH, OC1-3 saturated , unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, OAc, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-₃ saturated, unsaturated alkyl, or cycloalkyl^; each X independently = CH2, N, O, S, SO, S0_2; and each n independently = 0-3.

In one embodiment, formula (XXI) is dimethisoquin.

In one embodiment, a composition comprises a compound of formula (XXI I):

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂0Ac, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C i-e saturated, unsaturated alkyl, or cycloalkyl^, Cs jaryl or heteroaryl.

In one embodiment, each X independently = CH2, N, NH, NCi ^saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1 -6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-e saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^, Cs-7aryl or heteroaryl; each X independently = CH₂, N, NH, NC i-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S0_2; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H , CO2C1-3 saturated or unsaturated alkyi, NHC1 -3 saturated, unsaturated a!kyl, or cycloalkyl, N(Ci-3 saturated, unsaturated alkyi, or cycloalkyl)2, or Cs-e aryl or heteroaryl;

each X independently = CH2, N, NH, NCi-3saturated, unsaturated alkyi, or cycloalkyi, O, S, SO, or S0_2; and n = 0-3.

In one embodiment, formula (XXil) is ralfinamide.

In one embodiment, a composiiion comprises a compound of formula (XXIII):

R¹

1 X

il -I v I _

In one embodiment, each R independently = H, OCi-e saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, Ci-s saturated alkyi, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHCI-B saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl, Cs-jaryi or heteroaryl. In one embodiment, each X independently = CH₂, N, NH, NCi-esaturated, unsaturated aikyl, or cycloalkyl, O, S, SO, or S0₂.

In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyi, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH_2> CN, N0_2> C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl^, Cs-7aryl or heteroaryl; each X independently = CH2, N, NH, NCi-ssaturated, unsaturated aikyl, or cycloalkyi, O, S, SO, or S0_2; and n = 0-6.

In one embodiment, formula (XXill) is ralfinamide.

In one embodiment, a composition comprises a compound of formula (XXIV):

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, C1-6 saturated alkyi, unsaturated aikyl, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi, Cs-v-aryi or heteroaryl.

In one embodiment, each X independently = CH_2> NH, NCi-ssaturated, unsaturated alkyi, or cycloalkyl, O, S, SO, or S0₂.

In one embodiment, n = 0-6.

In one embodiment, each R independently = H, OCi-e saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, C1-6 saturated aikyl, unsaturated aikyl, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated alkyl, NHC 1-6 saturated, unsaturated a!kyl, or cycloalkyi, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl)2, Cs-raryl or heteroaryl; each X independently = CH2, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, o S0₂ ; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH_2> CN, NO2, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyi, or cycloalkyi, N(Ci-3 saturated, unsaturated alkyi, or cycioaikyl)₂, or Cs-e aryl or heteroaryl;

each X independently = CH2, NH, NCi-3saturated, unsaturated alkyi, or cycloalkyi, O, S, SO, o S0₂; and n = 0-3.

In one embodiment, formula (XXIV) is primidone.

In one embodiment, a composition comprises a compound of formula (XXV):

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH_2> CN, N0_2> C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi^, Cs-7aryl or heteroaryl.

In one embodiment, each X independently = CH2, N, NH, NCi-esaturated, unsaturated alkyi, or cycloalkyi, O, S, SO, or S0₂.

In one embodiment, each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, Ci-e saturated alkyl, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated alkyi, NHC 1 -6 saturated, unsaturated alkyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi^, Canary! or heteroaryl; each X independently = CH₂, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or SO2; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, C1 -3 saturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH₂, CN, NO2, C0₂H, CG2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-3 saturated, unsaturated alkyi, or cycloalkyi, or Cs-e aryl or heteroaryl;

each X independently = CH₂, N, NH, NCi-3saturated, unsaturated alkyl, or cycloalkyi, O, S, SO, SO2; and each n independently = 0-3.

In one embodiment, formula (XXV) is benfluorex.

In one embodiment, a composition comprises a compound of formula (XXVI):

In one embodiment, each R independently = H, OCi-e saturated, unsaturated alky!, cycloalkyl, cycloheteroalky!, Ct-12 saturated alkyl, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1 -5 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl, Cs-raryl or heteroaryl.

In one embodiment, each X independently = CH2, N, NH, Nd-esaturated, unsaturated aikyl, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, each n independently = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, C1-12 saturated alkyi, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, Ac, CF₃, NH_2> CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl^, Cs-7aryl or heteroaryl; each X independently = CH₂, N, NH, NCi-ssaturated, unsaturated aikyl, or cycloalkyl, O, S, SO, or S0_2; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH_2> CN, N0_2> CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-3 saturated, unsaturated alkyi, or cycioaikyl)2, or C5-6 aryl or heteroaryl;

each X independently = CH2, N, NH, NCrssaturated, unsaturated aikyl, or cycloalkyl, O, S, SO, or SO2; and each n independently = 0-3.

In one embodiment, formula (XXVI) is methyl benzethonium chloride.

In one embodiment, a composition comprises a compound of formula (XXVII):

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, C1 -6 saturated alkyl, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, Ac, CF3, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated aikyl, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl, Cs-7aryl or heteroaryl. In one embodirneni, each X independently = CH2, N, NH, NC i-ssat.urat.ed, unsaturated alkyi, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, each n = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C i-s saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHCI-B saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, Cs-jaryi or heteroaryl; each X independently = CH2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2; and each n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH_2> CN, NO2, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-3 saturated, unsaturated alkyi, or cycioaikyl)2, or Cs-earyl or heteroaryl;

each X independently = CH2, N, NH, NCi-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S0₂; and each n independently = 0-3.

In one embodiment, formula (XXVI i) is clemizole.

In one embodiment, a composition comprises a compound of formula (XXVIII):

In one embodiment, each R¹ independently = H, OCre saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, Ci-e saturated alkyl, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC 1-6 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^, Canary! or heteroaryl.

In one embodiment, each X independently = CH2, NH, NCi-esaturated, unsaturated alkyi, or cycloalkyl, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, C1 -6 saturated alkyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, C5-?aryi or heteroaryl; and each X independently = CH₂, NH, NCi-ssaturated, unsaturated alkyi, or cycloalkyl, O, S,

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated a!kyl, or cycloalkyi, N(Ci-3 saturated, unsaturated alkyl, or cycloalkyi, or Cs-earyl or heteroaryl; and each X independently = CH2, NH, NCi-₃saturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or

In one embodiment, iormula (XXVIII) is apigenin.

In one embodiment, a composiiion comprises a compound of formula (XXIX):

In one embodiment, each R¹ independently = H, OCre saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, Cs-7aryl or heteroaryl.

In one embodiment, each X independently = CH2, NH₂, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or SO2.

In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, Cs-v-aryl or heteroaryl; each X independently = CH2, NH₂, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or S0_2; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-3 saturated, unsaturated alkyl, or cycloalkyi, or Cs-e aryl or heteroaryl;

each X independently = CH2, NH2, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or SO2; and n = 0-3.

In one embodiment, formula (XXIX) is vigabatrin.

In one embodiment, a composition comprises a compound of formula (XXX):

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF3, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC 1-6 saturated, unsaturated a!kyl, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyl, or cyc!oa!kyi)2, Cs-raryl or heteroary!.

In one embodiment, each X independently = CH2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or SO2.

In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH_2> CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCI-B saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi)2, Cs-jaryi or heteroaryl; each X independently = CH2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, O, in one embodiment, each R independently = H, OC1-3 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-₃ saturated, unsaturated alkyi, or cycioaikyl, or Cs-eary! or heteroaryl;

each X independently = CH2, N, NH, NCi-3saturated, unsaturated alkyl, or cycioaikyl, O,

In one embodiment, formula (XXX) is catharanthine.

In one embodiment, a composition comprises a compound of formula (XXXI):

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, C1-6 saturated alkyl, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi)₂, Cs-v-ary! or heteroaryl.

In one embodiment, each X independently = CH₂, N, NH, NCi-ssaturated, unsaturated alkyi, or cycioaikyl, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OCi-e saturated, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, C1-6 saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC 1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl)2, Cs-yaryi or heteroaryl; and each X independently = CH2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, O, In one embodiment., each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-3 saturated aikyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1 -3 saturated or unsaturated alkyl, NHC1 -3 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-3 saturated, unsaturated alkyl, or cycioaikyl)2, or Cs-e aryl or heteroaryi; and each X independently = CH2, N, NH, NC1-3 saturated, unsaturated alkyl, or cycloalkyi, O, S, SO,

In one embodiment, formula (XXXI) is bromazepam.

In one embodiment, a composition comprises a compound of formula (XXXI I):

In one embodiment, each R¹ independently = H, OCre saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, Ci -e saturated alkyl, unsaturated aikyl, cycloalkyi, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-e saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi, Cs-7aryl or heteroaryi.

In one embodiment, each X independently = CH2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or SO2.

In one embodiment, each n independently = 0-6.

In one embodiment, each R ¹ independently = H, OC 1-6 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, C1 -6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi, Cs-v-aryl or heteroaryi; each X independently = CH2, N, NH, NCi-esaturated, unsaturated aikyl, or cycloalkyi, O, S, SO, or SO2; and each n independently = 0-6.

In one embodiment, formula (XXXI I) is benzydamine.

In one embodiment, a composition comprises a compound of formula (XXXI II):

In one embodiment, each R¹ independently = H, OC 1-3 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, C1 -3 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1.3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-3 saturated, unsaturated alkyl, or cycloalkyi, C5-6 aryl or heteroaryi; each X

independently = CH2, N, NH, NCi-3saturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or SO2; and n = 0-3. In one embodimeni, a compound of formula (XXXIII) is iacosamide.

In one embodimeni, a composition comprises a compound of formula (XXXIV):

In one embodiment, each R independently = H, OC 1 -3 saturated, unsaturated alkyi, cycioalkyl, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1 -3 saturated or unsaturated alkyl, NHC1 -3 saturated, unsaturated alkyl, or cycioalkyl, N(Ci-3 saturated, unsaturated alkyi, or cycioalkyl)?, Cs earyl or heteroaryi; each X independently = CH2, N, NH, NCi-3saturated, unsaturated alkyl, or cycioalkyl, O, S, SO, or S02; and each n independently = 0-3.

In one embodiment, a compound of formula (XXXIV) is enilconazole, miconazole, or isoconazoie.

In one embodiment, a composition comprises a compound of formula (XXXV):

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyi, cycioalkyl, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated alkyl, cycioalkyl, cycioheteroalkyi, CO2H, CO2C1-3 saturated or unsaturated alkyl, CI, Br, F, I, OH, OAc, Ac, NH2, CN, CF3, NHC1-3 saturated, unsaturated alkyi, or cycioalkyl, or N(Ci-3 saturated, unsaturated alkyl, or cycioalkyl; R² = H, OC1-3 saturated, unsaturated alkyl, cycioalkyl, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated alkyl, cycioalkyl, cycioheteroalkyi, CI, Br, F, i, OH, NH₂, CN, Ac, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-3 saturated, unsaturated alkyi, or cycioalkyl, X = CH2, NH, NHCi-3saturated, unsaturated alkyi, or cycioalkyl, O, S, SO, or

In one embodiment, a compound of formula (XXXV) is sertraline or indatraiine.

In one embodiment, a composition comprises a compound of formula (XXXVI):

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyi, cycioalkyl, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, CO2H, CO2C1 -3 saturated or unsaturated alkyl, CI, Br, F, I, OH, OAc, Ac, NH2, CN, CF3, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl)2; each R² independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1 -3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl; each X independently CH2, N, NH, NHCi-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, S02_; a d each n independently = 0-3.

In one embodiment, a compound of formula (XXXVI) is dyclonine.

In one embodiment, a composition comprises a compound of formula (XXXVII):

In one embodiment, R¹ = H, OC1 -3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, CO2C1-3 saturated or unsaturated alkyl

each R² independently = OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl^ each X independently = CH2, NH, NHCi-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2; and each n independently = 0-3.

In one embodiment, a compound of formula (XXXVII) is aiverine.

In one embodiment, a composition comprises a compound of formula (XXXVIII):

In one embodiment, each R independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl)?, Cs earyl or heteroaryi; and each X independently = CH2, N, NH, NCi-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO,

In one embodiment, a compound of formula (XXXVill) is bifonazole.

In one embodiment, a composition comprises a compound of formula (XXXIX):

In one embodiment, each R independently = OC1-3 saturated, OC5-6 aryi or heteroaryl, unsaturated alkyl, cycioaiky!, cycloheteroalkyl, or C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl; R² = CH2, O, NH, or NC1-3 saturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl; each R³ independently = CN, C1-3 saturated or unsaturated alky!, OC1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(Ci -3 saturated, unsaturated alkyl, or cycloalkyl)?; each X independently = CH or N; and each n independently = 0-3.

In one embodiment, a compound of formula (XXXIX) is vinpocetine.

In one embodiment, a composition comprises a compound of formula (XXXX):

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-₃ saturated, unsaturated alkyl, or cycloalkyl^, Cs-earyl or heteroaryl; each X

independents CH2, N, NH, NCi-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S02; and each n independently = 0-3.

In one embodiment, a compound of formula (XXXX) is clofilium.

The compounds described herein may thus be employed to prevent, inhibit or treat, one or more symptoms associated with epileptic encephalopathies. Epileptic encephalopathies are a group of rare, severe neurological disorders manifesting in childhood that, may be strongly associated with de novo mutations. As described below, a simple rapidly generated, cellular assay was developed to model an individual's rare- genetic disorder and this model or a wild-type model may be applied to high throughput screening methods to identify approved drugs for patient specific indications. While the GABRB3 mutation of an individual patient is disclosed, other patients with mutations in this gene (or other genes the products of which directly or indirectly interact with GABA- A), may benefit from the same compounds that were identified to potentiate GABA activity in the cell model expressing the wild-type GABA-A receptor, in various embodiments, compositions and methods are provided for mitigating in a mammal one more symptoms associated with a disease characterized by seizures, or delaying or preventing the onset of symptoms thereof. Methods are also provided for reducing the risk, lessening the severity, or delaying the progression or onset, of a disease characterized by dysfunction of GABR in a mammal. In certain embodiments, methods are provided for preventing or delaying the onset of a seizure activity in a mammal. In certain embodiments, compositions and methods are provided for modulating GABR activity in a mammal. In certain embodiments, compositions and methods are provided for altering function the activity of GABA through the GABA-A receptor in a mammal.

Accordingly, in various embodiments, a compound of formula (l)-(XXXX), a compound in Table 1 , or formulations thereof and/or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, or prodrug thereof, or a derivative, inhibits or treats epilepsy, in certain embodiments, the compounds or formulations thereof are used to prevent or delay the onset of one or more symptoms and/or to ameliorate one or more symptoms, and/or to prevent or delay the progression of the disease. In certain embodiments, the compound or formulations thereof are used in a method of mitigating in a mammal one or more symptoms associated with a pathological condition characterized by seizures, or delaying or preventing the onset of symptoms of the condition. In certain embodiments, methods of reducing the risk, lessening the severity, or delaying the progression or onset of a disease characterized by seizures of a mammal are also provided, in certain embodiments, methods of directly or indirectly impacting GABR in a mammal are provided.

Typically each of these methods involve administering one or more compounds or formulations thereof and/or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomer thereof; or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, or prodrug thereof, or a derivative thereof, in an amount sufficient, to produce the desired activity, e.g., mitigating one or more symptoms associated with epilepsy or epileptic encephalopathies, or delaying or preventing the onset of said symptoms, and/or reducing the risk, lessening the severity, or delaying the progression or onset of a disease, such as one characterized by altered GABR activity.

Pharmaceutical Compositions

Pharmaceutical compositions having one or more of the compounds described herein, suitable for administration, e.g., nasal, parenteral, central or peripheral nervous system, or oral administration, such as by intravenous, intramuscular, topical, intrathecal, or subcutaneous routes, optionally further comprising sterile aqueous or non-aqueous solutions, suspensions, and emulsions. The compositions can further comprise auxiliary agents or excipients, as known in the art. The composition having one or more of the compounds described herein is generally presented in the form of individual doses (unit doses).

Preparations for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, and/or emulsions, which may contain auxiliary agents or excipients known in the art. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Carriers or occlusive dressings can be used to increase skin permeability and enhance antigen absorption. Liquid dosage forms for oral administration may generally comprise a liposome solution containing the liquid dosage form. Suitable forms for suspending liposomes include emulsions, suspensions, solutions, syrups, and eiixirs containing inert diluents commonly used in the art, such as purified water. Besides the inert diluents, such compositions can also include adjuvants, wetting agents, emulsifying and suspending agents, or sweetening, flavoring, or perfuming agents.

When a composition having one or more of the compounds described herein is used for administration to an individual, it can further comprise salts, buffers, adjuvants, or other substances which are desirable for improving the efficacy of the composition.

In one embodiment, the pharmaceutical composition is part of a controlled release system, e.g., one having a pump, or formed of polymeric materials (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fia. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smoien and Bali (eds.), Wiley, New York (1984); Ranger & Peppas, J. Macromol. Sci. Rev. Macromoi. Chem., 23:61 (1983): see also Levy et al., Science. 228:190 (1985); During et al., Ann. Neurol., 25:351 (1989); Howard et al., J. Neurosurg., 7Ί :105 (1989)). Other controlled release systems are discussed in the review by Langer (Science. 249:1527 (1990)).

The pharmaceutical compositions having one or more of the compounds described herein comprise a therapeutically effective amount of compounds, for instance, those identified by the screening methods, and a pharmaceutically acceptable carrier. In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeiae for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the pharmaceutical composition is administered. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable soiutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. These compositions can be formulated as a suppository. Oral formulation can include standard carriers such as pharmaceutical grades of mannstoi, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in

"Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will contain a therapeutically effective, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

The compositions may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent. For oral administration, the compound(s) may be combined with one or more excipients and used in the form of ingestible capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions should contain at least 0.1 % of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such useful compositions is such that an effective dosage level will be obtained.

The compositions may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, aiginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. Various other materials may be present. For instance, a syrup or elixir may contain the compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form, including sustained-release preparations or devices, should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.

The composition can also be administered topically, or by infusion or injection through all forms of parenteral routes including but not limited to: intravenous;

intramuscular; subcutaneous; transdermal; intrathecal, intracerebrovascular, intraparenchymal or iniracerebroventricular (e.g., all forms of direct delivery to the central nervous system); intravitreal or intraretinal (e.g. ail forms of direct delivery to the eye); intra-ganglionic (e.g. all forms of direct delivery to the peripheral nervous system); intra-aural (e.g. all forms of direct delivery to the middle or inner ear and cochlea); or rectal. Solutions of the compound(s) can be prepared in water or a suitable buffer, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of undesirable microorganisms, except for infusion into the central nervous system or other regions where use of a preservative or other formulation agents are contrainclicated.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanoi, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of undesirable microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chiorobutanoi, phenol, sorbsc acid, thimerosai, and the like, in many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride.

Sterile injectable solutions are prepared by incorporating the eompound(s)in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter, heat or irradiation sterilization.

Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compound(s) can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

Useful dosages of the compositions can be determined by comparing their in vitro activity and in vivo activity in animal models.

The invention will be further described by the following non-limiting examples.

Example 1

Materials and Method

Next Generation Sequencing

Agilent SureSelect + I liSeq was carried out. A minimum of 30x coverage was required for confirmation of a variant. 99.71 % of coding bases in the genes were covered > 30x. In-house validation attributes a minimum sensitivity of 97.5% (with 95% confidence) for regions covered >30x. Genes covered were ADSL, ALG13, ARHGEF9, ARX, ATP1A3, CBL, CDKLS, CHD2, CHRNA2, CHRNA4, CHRNB2, CNTNAP2, CREBBP, CSNK1G1, DNM1, DOCK7, EHMT1, EP300, FASN, FOXG1, GABRA 1, GABRB3. GATAD2B, GRIN2A, HCN1, KCNB1, KCNQ2, KCNT1, KIAA 1279, LGI1, MAGi2, MDBS, MECP2, MEF2C, NRXN1, PCDH19, RIGA, PiGQ, PLCB1, PNKP, POLG, PRRTW, QARS, RYR3, SCN1A, SCN2A, SCN8A, SLC13AS, SLC16AD,

SLC25A22, SLC2A 1, SLC35A2, SLC9A6, SMARCA2, SPTAN1, STXBP1, SYNGAP1,

TBC1D24, TCF4, UBE2A, UBE3A, WRD45, ZEB2.

Results

Genetic mutations, e.g., somatic or germline mutations, can impact protein function and those mutations may in turn be associated with neural and behavioral symptoms, e.g., symptoms associated with epilepsy, other seizure disorders and epileptic encephalopathies. The methods described herein are based, in part, on the identification of molecules that directly or indirectly modulate ion channel activity, e.g., chloride channel (GABAAR) activity, e.g., directly or indirectly modulate GABRB3- bearing channel activity. In another embodiment, molecules that are useful in increasing the activity of ion channels that are not mutated (wild-iype chloride ion channels such as wild-type GABRB3-containing channels) may also be employed as a therapeutic, e.g., for disorders including but not limited to those characterized by seizures or other encephalopathies.

GABRB3 encodes a β3 subunit of the GABAA ligand-gated ionotropic receptors. GABAA receptors are activated by GABA, the major inhibitory neurotransmitter of the brain, as well as barbiturates and benzodiazepines, which bind to a separate allosteric effector site and potentiate the activity of GABA. GABAA receptors are widely expressed in the brain and act as primary mediators of fast inhibitory synaptic transmission in the adult central nervous system. The inward flow of chloride ions through the pore following GABA activation leads to hyperpolarization of the cell, and thereby helps to regulate neuronal firing and activity. GABAA receptors are heteropentameric channels composed of five height classes of subunit (a 1 -6, β1-3, γ1— 3, δ, π, ε, θ and ρ1-3). The vast majority of the central nervous system receptors is composed of two a subunits, two β subunits and one γ or δ subunit, which are grouped to form a central pore that allows the passage of chloride and bicarbonate anions.

As described herein, a patient was diagnosed with Lenox-Gastaut Syndrome (LGS) and symptomatic generalized epilepsy, associated with global developmental delay, decreased fine and gross motor control, and attention deficit hyperactivity disorder (ADHD). Sequencing identified a heterozygous mutation in the GABRB3 gene with a guanine (G) in place of an adenine (A) at position 905 in the DNA sequence

(c.905A>G) in one of two copies of the gene. Expression of that nucleotide substitution results in a GABRB3 amino acid sequence with cysteine in place of tyrosine at position 302, GABRB3 Tyr3Q2Cys (Y302C).

The Y302C mutation described herein, as well as other missense mutations of the GABRB3 gene, typically give rise to ioss-of-function mutations with greatly decreased chloride ion conductance or flow compared to wild-type channels. To identify compounds that may alter the activity of the protein encoded by the mutant GABRB3 gene, a ceil line expressing the Y302C mutation may be employed to identify compounds that alter the mutant channel chloride ion conductance or flow via the GABA-A receptor. For comparison, a wild-type GABA-A receptor expressing ceil line may also be used. A cell line expressing GABAA channels comprised of a GABRB3 subunits with a Y302C mutation was created by site-directed mutagenesis, which was then transfected into HEK293 cells along with wild-type copies of GABRA3 (encoding the a3 subunit) and GABRG2 (encoding the γ2 subunit) to create GABAA receptors containing GABRB3 Y302C mutation. For comparative purposes, a wild-type copy of the GABRB3 gene was transfected into HEK293 ceils along with wild-type copies of GABRA3 and GABRG2 to create a cell line expressing wild-type GABAA receptor. Patch clamp elecirophysiology was conducted to characterize cells expressing mutant and wild-type GABRB3. Y302C mutant cells were observed to have a severe loss-of- funciion phenotype resulting in nearly absent inward chloride ion flow or current compared to wild-type chloride channels. Specifically, the mutant cells were observed to have almost completely lost the current response to GABA activation as the EC50 (half maximal effective concentration) in concentration-response testing was 63 times higher compared to wild-type ceils. Because the mutant channel was not activated, a wild-type cell line was used for screening to identify compounds that increase chloride flow through the wild-type GABA-A channel.

Following electrophysiological characterization of the wild-type channel properties, a high-throughput drug screen was developed and a library of 1 ,320 approved, off-patent drugs (including drugs approved in the US and outside the US) was evaluated. A total of 50 compounds out of 1 ,320 (3.8%) that were screened demonstrated significant activator activity on ion flow or conductance, defined as activation that was greater than two standard deviations from the overall mean activation of all compounds tested. Those compounds included FDA-approved drugs that do not report clinical utility in epilepsy or seizure disorders, as well as other compounds that do not report clinical utility in epilepsy or seizure disorders. These compounds may be used prophylacticaily or therapeutically and for design of related compounds. Compounds that activate chloride ion flow through wild-type or mutant channels may be of therapeutic value in treating epilepsy related to GABRB3 ioss-of- function mutations including GABRB3 Y302C mutations. Compounds that activate chloride ion flow through wild-type channels may be of therapeutic value in treating a wider range of epilepsies, other seizure-related disorders, and other nervous system diseases and disorders (described below) associated with diminished chloride ion flow via the GABA-A receptor Compounds that activate chloride ion flow through wild-type channels may be of therapeutic in treating conditions, such as epilepsy, in a more general manner where compounds that increase GABA activity act to compensate or correct other pathological changes that may or may not be related to GABAergic dysfunction.

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All publications, patents and patent applications are incorporated herein by reference. While in the foregoing specification, this invention has been described in relation to certain preferred embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details herein may be varied considerably without departing from the basic principles of the invention.

Claims

WHAT IS GLAUMED IS:

1 . A method to prevent, inhibit or treat one or more symptoms associated with epilepsy or encephalopathies in a mammal, comprising: administering to the mammal an effective amount of a composition comprising a compound of any one of formulas {!)- (XXXX), a pharmaceutically acceptable salt thereof, or a combinantion thereof.

2. The method of claim 1 wherein the compound is a compound in Table 1 . 3. The method of claim 1 or 2 wherein the mammal is a human.

4. The method of any one of claims 1 , 2 or 3 wherein the compound is an an anticestodal, anticonvulsant, hormone replacement, antianginal, anti-inflammatory, vasodilator, antiseptic, antiparasitic, analgesic, AED, , anesthetic, hormonal agent, antiemetic, antifungal, anti-infective, antibiotic, antihistamine, antimicrobialantipruritic, antiobesity, antiarrhythmic, antianxiety, antidepressant, contraceptive, antispasmodic, or antitussive agent, or combinations thereof.

5. The method of any one of claims 1 to 4 wherein the composition comprises compound of formula (I):

wherein each R¹ independently = H, OC1 -5 saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF3, NH₂, CN, CO2H, CO2C1 -5 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-6 saturated, unsaturated alkyi, or eycloalkyl)2.;

wherein X = CH2, C, N, NH, NHCi-ssaturated, unsaturated alkyi, or cycloalkyl, O, S, SO, or S0_2; and

wherein n = 0-6.

6. The method of any one of claims 1 to 5 wherein the composition comprises a compound of formula (II):

wherein each R¹ = independently H, OCi-e saturated, unsaturated aikyl, cycioaikyi, cydoheteroaiky!, Ci-e saturated alkyi, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, CF₃, NH₂, CN, C0₂H, C0₂Ci-₆ saturated or unsaturated aikyl, NHCi-e saturated, unsaturated aikyl, or cycioaikyi, o N(Ci-8 saturated, unsaturated aikyl, or cycloalkyl)_2;

wherein R² = H, Ci-e saturated aikyl, unsaturated aikyl, cycioaikyi,

cycioheteroalkyi, or (O);

wherein each X independently = C, N, O, S, SO, or SO2; and

wherein n = 0-6.

7. The method of any one of claims 1 to 6 wherein the composition comprises a compound of formula (Ml):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated aikyl, cycioaikyi, cycioheteroalkyi, Ci-e saturated alkyi, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, CF₃, NH₂, CN, C0₂H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi, o N(Ci-s saturated, unsaturated aikyl, or cycloalkyl)_2;

wherein R² = H, OH, OCi-e saturated, unsaturated aikyl, cycioaikyi,

cycioheteroalkyi, C1 -6 saturated aikyl, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, OAc, CF3, NH₂, CN, C0₂H, CO2C1-6 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated aikyl, or cycioaikyi, or N(Ci-e saturated, unsaturated alkyi, or cycioaikyi)₂ wherein each X independently = CH2, N, O, S, SO, or S0_2; and

wherein n = 0-6.

8. The method of any one of claims 1 to 7 wherein the composition comprises a compound of formula (IV):

wherein each R¹ independently = H, OC1 -5 saturated, unsaturated a!kyi, cycloalkyi, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated aikyl, cydoaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-B saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi, o N(Ci-6 saturated, unsaturated alkyi, or cycloalkyl)2;

wherein R² = H, OH, OC1-6 saturated, unsaturated alkyi, cycloalkyi,

cycloheteroalkyl, C1-6 saturated alkyl, unsaturated aikyl, cycloalkyi, cycloheteroalkyl, OAc, CF3, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-e saturated, unsaturated alkyi, or cycloalkyi, orN(Ci-6 saturated, unsaturated aikyl, or cycloalkyl)2._;

wherein R³ = C5-7a yl or heteroaryl;

wherein X = CH₂, N, O, S, SO, or SO2, and

wherein n = 0-6.

9, The method of any one of claims 1 to 8 wherein the composition comprises a compound of formula (V):

wherein each R¹ = H, OC1-6 saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF3, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyl, or cydoaikyl, or NiCre saturated, unsaturated aikyl, or cycloalkyi;

wherein each M independently = Na, K, Li, Hg, or Zn; and

wherein each X independently = CH2, NH, O, S, SO, or SO2.

10, The method of any one of claims 1 to 9 wherein the composition comprises a compound of formula (VI):

wherein each R¹ independently = H, OO-e saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated aikyl, cycioaikyl, cycioheteroa!kyi, CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2;

wherein R² = H, OH, OCi-e saturated, unsaturated aikyl, cycioaikyl, cycloheteroalkyl, C1 -6 saturated aikyl, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, OAc, CF3, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHCi-e saturated, unsaturated aikyl, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyi, or cycioaikyl)2, C5- raryi or heteroaryi; and

wherein each X independently = CH, N, O, or S.

1 1 . The method of any one of claims 1 to 10 wherein the composition comprises a compound of formula (VII):

wherein each R¹ independently = H, OCi-e saturated, unsaturated aikyl, cycioaikyi, cycloheteroalkyl, C1-6 saturated aikyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, NO2, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycioaikyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2, Cs-rary! or heteroaryi; and

wherein each X independently = CH2, N, O, S, SO, or SO2.

12. The method of any one of claims 1 to 1 1 wherein the composition comprises a a compound of formula (VII I):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioalkyl, or N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, Cs-yaryl or heteroaryl;and

wherein R² = Mono, di, or iriglycoside, or OC(O) C3-5 alkenyl; and

wherein each X independently = CH₂, N, O, S, SO, or SO2

The method of any one of claims 1 to 12 wherein the composition comprises a pound of formula (IX):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated alkyi, cycioalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyi, cycioalkyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, CF₃, NH₂, CM, CO2H, CQ2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyl, or cycioalkyl, or N(Ci-s saturated, unsaturated alkyi, or cycloalkyl)₂, Cs-raryl or heteroaryl;

wherein R² = Mono, di, or triglycoside, orOC(O) C3-5 alkenyl;

wherein each X independently = CH2, N, O, S, SO, or SO2; and

wherein n = 0-6.

14. The meihod of any one of claims 1 to 13 wherein the composition comprises a compound of formula (X):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated alkyi, cycioalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyi, cycioalkyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CM, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyl, or cycioalkyl, N(Ci-e saturated, unsaturated alkyi, or cycioalkyl^, Cs-yaryl or heteroaryl;

wherein each X independently = CH2, C, NH, NCi-ssaturated, unsaturated alkyl, or cycioalkyl, O, S, SO, or SO2; and

wherein = 0-6, The method of any one of claims 1 to 14 wherein the composition comprises a pound of formula (XI):

wherein each R¹ independently = H, OC i-6 saturated, unsaturated aikyi, cycioaikyi, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated a!kyi, cycloalkyl, cycioheteroa!kyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated alky!, NHC1 -8 saturated, unsaturated a!kyi, or cycioaikyi, or N(Ci-6 saturated, unsaturated alkyl, or cycioaikyi)₂, C5-7aryi or heteroaryl;

wherein each X independently = CH₂, C, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyi, O, S, SO, or S0_2; and

wherein n = 0-6.

The method of any one of claims 1 to 15 wherein the composition comprises a pound of formula (XII):

wherein each R independently = H, OCi-s saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, C1-6 saturated aikyl, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, C(0)CH₂OAc, CO2H, C0₂Ci-₆ saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, N(Ci-e saturated, unsaturated aikyi, or cycloalkyl)₂, Cs-yaryl or heteroaryl;

wherein each R² independently = H, OC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, C1-6 saturated aikyl, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, C(0)CH₂OAc, CO2H, C0₂Ci-₆ saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)₂, Cs-7aryl or heteroaryl;

wherein each X independently = CH₂, C, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S0_2; and

wherein n = 0-6.

17, The method of any one of claims 1 to 16 wherein the composition comprises a compound of formula (XIII):

wherein each R¹ independently = H, OC1 -5 saturated, unsaturated alkyi, cyc!oa!kyi, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated alky!, cycloalkyl, cycioheteroaikyi, CI, Br, F, I, OH, CF₃, NH₂, CN, CO2H, C0₂Ci-₆ saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloaikyl, o N(Ci-6 saturated, unsaturated aikyl, or eyeloalkyl)2.:

wherein each X independently = CH2, NH, NHCi-esaturated, unsaturated aikyl, or cycloalkyl, O, S, SO, o S02; and

wherein each n independently = 0-8.

18, The method of any one of claims 1 to 17 wherein the composition comprises a compound of formula (XIV):

wherein each R¹ independently = H, OC1 -5 saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH₂, CN, NO2, C(0)CH₂0Ac, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated aikyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyi, or cycloaikyl^, Cs-v-aryl or heteroaryl; wherein each X independently = CH2, NH, NCi-gsaturated, unsaturated aikyl, or cycloalkyl, O, S, SO, or S0_2; and

wherein n = 0-6.

19. The method of any one of claims 1 to 18 wherein the composition a compound of formula (XV):

wherein each R^! independently = H, OC1-6 saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, C1-6 saturated aikyl, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂0Ac, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyi, or cycloaikyl^, Cs-yary! or heteroaryl; and wherein X = CH2, NH, NC i-ssat.urat.ed, unsaturated a!kyl, or cycloalkyl, O, S,

20. The method of any one of claims 1 to 19 wherein the composition comprises a composition comprises a compound of formula (XVI):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, C1-6 saturated aikyl, unsaturated aikyi, cycloalkyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CM, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated aikyi, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl^, Cs jaryi or heteroaryl; wherein each X independently = CH2, NH, NCi-ssaturated, unsaturated aikyi, or cycloalkyl, O, S, SO, or S0_2; and

wherein each n independently = 0-6,

21 . The method of any one of claims 1 to 20 wherein the composition comprises a compound of formula (XVII):

wherein each R¹ independently = H, OCi-e saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated aikyi, cycloalkyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH20Ac, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1 -5 saturated, unsaturated aikyi, or cycloalkyl, N(Ci-6 saturated, unsaturated aikyl, or cycloalkyl^, Cs-raryl or heteroaryl; and wherein each X independently = CH₂, NH, NCi-ssaturated, unsaturated aikyl, or cycloalkyl, O, S, SO, or SO2.

22. The method of any one of claims 1 to 21 wherein the composition comprises a compound of formula (XVIII):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated alkyi, cyc!oa!kyi, cycloheteroalkyl, C1-6 saturated aikyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CM, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2, Cs jaryl or heteroaryl; and wherein each X independently = CH2, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or SO2

23. The meihod of any one of claims 1 to 22 wherein the composition comprises a compound of formula (XIX):

wherein each R¹ independently = H, OC1 -5 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CMS saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH₂, CN, N0₂, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2, Cs-v-ary! or heteroaryl; wherein each X independently = CH2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, SO2, CI, or Br; and

wherein n = 0-6.

24. The method of any one of claims 1 to 23 wherein the composition comprises comprises a compound of formula (XX):

wherein each R^! independently = H, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, C1-15 saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, C0₂H, C0₂Ci-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyl, or cyc!oa!kyl)2, Cs-yaryi or heteroaryl; wherein each X independently = CH2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, SO2, CI, or Br; and

wherein each n independently = 0-6.

25. The method of any one of claims 1 to 24 wherein the composition comprises comprises a compound of formula (XXI):

wherein each R¹ independently = H, OC1 -5 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, CF₃, NH₂, CN , CO2H , CO2C1-B saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, o N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl^, Cs-yaryl or heteroaryl;

wherein each R² independently = H, OH, QCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, OAc, CF3, NH2, CN , CO2H , CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, Cs-yaryl or heteroaryl;

wherein each X independently = CH2, N , O, S, SO, or SO2^■ and

wherein each n independently = 0-8.

26, The method of any one of claims 1 to 25 wherein the composition comprises comprises a compound of formula (XXI I) :

wherein each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, Ci -e saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H , CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl, Cs-yaryl or heteroaryl; wherein each X independently = CH2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S0_2; and

wherein n = 0-6. The method of any one of claims 1 to 26 wherein the composition comprises a pound of formula (XXIII):

R¹

wherein each R¹ independently = H, OC i-6 saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated alkyl, NHC1 -5 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi)₂, Cs-raryl or heteroaryl; wherein each X independently = CH₂, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or S0_2; and

wherein n = 0-6.

28. The method of any one of claims 1 to 14 wherein the composition comprises a compound of formula (XXIV):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, Cre saturated alkyl, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated aikyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)₂, Cs-7aryl or heteroaryl; wherein each X independently = CH₂, NH, NC i-ssatu ated, unsaturated alkyi, cycioaikyl, O, S, SO, or SO2 ; and

wherein n = 0-6.

29. The method of any one of claims 1 to 28 wherein the composition comprises a composition comprises a compound of formula (XXV):

wherein each R^! independently = H, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated aikyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)_2> Cs-yaryi or heteroaryl; wherein each X independently = CH₂, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S_s SO, or S0_2; and

wherein each n independently = 0-6.

30. The method of any one of claims 1 to 29 wherein the composition comprises a compound of formula (XX

wherein each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroaikyl, C1-12 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCI-B saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, Cs-jaryi or heteroaryl;

wherein each X independently = CH₂, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2, and

wherein each n independently = 0-6.

31 . The method of any one of claims 1 to 30 wherein the composition comprises a compound of formula (XXVil):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroaikyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, Ac, CF₃, NH_2> CN, N0_2> C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated alkyl, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^, Canary! or heteroaryl; wherein each X independently = CH2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2; and

wherein each n = 0-6.

32. The method of any one of claims 1 to 31 wherein the composition comprises a compound of formula (XXVII I):

wherein each R¹ independently = H, OC i-6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, Ci-e saturated alkyi, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated alkyi, NHC1 -5 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyi, or cycloalkyi)₂, Cs-raryl or heteroaryl; and wherein each X independently = CH₂, NH, NCi-esaturaied, unsaturated alkyi, or cycioaikyl, O, S, SO, or S0₂.

33. The method of any one of claims 1 to 32 wherein the composition comprises a compound of formula (XXIX):

wherein each R¹ independently = H, OC1 -5 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH₂, CN, N0₂, C(0)CH₂OAc, C0₂H, CO2C1-6 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated aikyl, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)₂, Cs-7aryl or heteroaryl; wherein each X independently = CH₂, NH₂, NH, NCi-esaturated , unsaturated alkyi, or cycioaikyl, O, S, SO, or S0_2; and

wherein n = 0-6.

34. The method of any one of claims 1 to 33 wherein the composition comprises a compound of formula (XXX):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated aikyl, cycioaikyl, cycloheteroalkyl, C1-6 saturated aikyl, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂0Ac, CO2H, CO2C1-6 saturated or unsaturated aikyl, IMHC1 -6 saturated, unsaturated aikyl, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi)₂, Cs jaryi or heteroaryl; wherein each X independently = CH₂, N, NH, NCi-ssaturated, unsaturated aikyl, or cycioaikyl, O, S, SO, or S0_2; and

wherein n = 0-6. The method of any one of claims 1 to 34 wherein the composition comprises a pound of formula (XXXI):

wherein each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycioaikyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CM, N0₂, C(0)CH₂OAc, C0₂H, C0₂Ci-6 saturated or unsaturated alkyl, NHd-e saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi^, Cs jaryi or heteroaryl; and wherein each X independently = CH₂, N, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or S0₂

38. The method of any one of claims 1 to 35 wherein the composition comprises a compound of formula (XXXII

wherein each R^! independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂OAc, C0₂H, C0₂Ci-6 saturated or unsaturated alkyl, NHCi-e saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)₂, or Cs-jaryi or heteroaryl; wherein each X independently = CH₂, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or S0_2; and

wherein each n independently = 0-8.

37, The method of any one of claims 1 to 36 wherein the composition comprises a compound of formula (XXXIII):

wherein each R^! independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated aikyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C0₂H, CQ₂Ci-₃ saturated or unsaturated alkyl, NHC1 -3 saturated, unsaturated a!kyl, or cycloalkyl, N(Ci-3 saturated, unsaturated a!kyi, or cycloalkyl)2,or Cs-e aryi or heteroaryl;

wherein each X independently = CH2, N, NH, NCi-3saturated, unsaturated aikyi, or cycioaikyi, O, S, SO, or S0₂; and

wherein n = 0-3.

38. The method of any one of claims 1 to 37 wherein the composition comprises a compound of formula (XXXIV):

wherein each R¹ independently = H, OC1-3 saturated, unsaturated aikyl, cycioaikyi, cycloheteroaikyl, C1-3 saturated aikyi, unsaturated alkyi, cycioaikyi, cycioheteroaikyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1 -3 saturated or unsaturated alkyl, NHC1 -3 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-3 saturated, unsaturated alkyi, or cycioaikyi, or Cs-earyl or heteroaryl;

wherein each X independently = CH₂, N, NH, NCi-asaturated, unsaturated alkyl, or cycioaikyi, O, S, SO, or SO2, and

wherein each n independently = 0-3.

39. The method of any one of claims 1 to 38 wherein the composition comprises a compound of formula (XXXV):

wherein each R¹ independently = H, OC1-3 saturated, unsaturated aikyl, cycioaikyi, cycloheteroaikyl, C1-3 saturated alkyi, unsaturated aikyi, cycioaikyi, cycloheteroaikyl, CO2H, CG2C1-3 saturated or unsaturated aikyl, Ci, Br, F, I, OH, OAc, Ac, NH₂, CN, CF3, NHC1-3 saturated, unsaturated alkyi, or cycioaikyi, or N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl)_2; wherein R² = H, OC1-3 saturated, unsaturated alkyl, cycioaikyi, cycioheteroaikyi, C1-3 saturated aikyi, unsaturated aikyi, cycioaikyi, cycioheteroaikyi, Ci, Br, F, I, OH, NH₂, CN, Ac, CO2H, CO2C1 -3 saturated or unsaturated alkyi, NHC1-3 saturated, unsaturated alkyi, or cycioaikyi, or N(Ci -3 saturated, unsaturated alkyi, or cycioaikyl)2; wherein X = CH2, NH, NHCi-3saturated, unsaturated alkyl, or cycloalkyl, O, S,

SO, or S0₂; and

wherein n = 0-3.

5 40. The method of any one of claims 1 to 39 wherein the composition comprises a compound of formula (XXXVI):

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheferoaikyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl,

10 cycloheteroaikyl, CO2H, CO2C1-3 saturated or unsaturated alkyl, CI, Br, F, I, OH, OAc, Ac, NH2, CN, CPs, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-3

saturated, unsaturated alkyl, or cycloalkyl^;

wherein each R² independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroaikyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl,

15 cycloheteroaikyl, CI, Br, F, I, OH, OAc, Ac, NH₂, CN, CO2H, CO2C1-3 saturated or

unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl^;

wherein each X independently = CH2, N, NH, NHCi-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, SO2, and

20 wherein each n independently = 0-3.

41 . The method of any one of claims 1 to 40 wherein the composition comprises a compound of formula (XXXVII):

wherein R¹ = H, OC 1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroaikyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroaikyl, CO2H, or C02Ci-3 saturated or unsaturated alkyl:

wherein each R² independently = OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroaikyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroaikyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH2, CN, CQi , CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl;

wherein each X independently = CH2, NH, NHCi-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2; and

wherein each n independently = 0-3,

42. The method of any one of claims 1 to 41 wherein the composition comprises a compound of formula (XXXVIII):

x~x

wherein each R^¾ independently = H, OC1-3 saturated, unsaturated aikyl, cycioalkyl, cycloheteroalkyl, C1-3 saturated aikyl, unsaturated alkyi, cycioalkyl, cycioheteroalkyi, CI, Br, F, i, OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1-3 saturated or unsaturated alkyi, NHC1-3 saturated, unsaturated aikyl, or cycioalkyl, N(C 1-3 saturated, unsaturated alkyi, or cycioalkyl^, or Cs earyl or heteroaryl; and

wherein each X independently = CH2, N, NH, NCi -3saturated, unsaturated alkyl, or cycioalkyl, O, S, SO, or SO2

43. The meihod of any one of claims 1 to 42 wherein the composition comprises a compound of formula (XXXIX):

wherein each R¹ independently = OC1-3 saturated, OC5-8 aryi or heteroaryl, unsaturated aikyl, cycioalkyl, cycioheteroalkyi, or C1 -3 saturated alkyl, unsaturated alkyi, cycioalkyl, cycioheteroalkyi;

wherein R² = CH2, O, NH, or NC1 -3 saturated, unsaturated alkyl, cycioaiky, or cycloheterocyloalkyl; each R³ independently = CN, C1-3 saturated or unsaturated alkyi, OC1-3 saturated or unsaturated aikyl, NHC1-3 saturated, unsaturated aikyl, or cycioalkyl, or N(Ci-3 saturated, unsaturated alkyl, or cycioalkyl^;

wherein each X independently = CH or N; and

wherein each n independently = 0-3.

44. The meihod of any one of claims 1 to 43 wherein the composition comprises a compound of formula (XXXX):

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycioaikyl, cycioheteroalkyi, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, N0₂, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-3 saturated, unsaturated alkyl, or cycioaikyl)2, or Cs-earyl or heteroaryl;

wherein each X independently^ CH2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or SO2; and

wherein each n independently = 0-3.

45. A method to prevent, inhibit or treat one or more symptoms associated with epilepsy, childhood absence 5 (ECA5), epileptic encephalopathy (EE), early infantile EE 43 (EIEE43), autism spectrum disorder, Lenox-Gastaut Syndrome (LGS), global developmental delay, decreased fine and gross motor control, attention deficit hyperactivity disorder (ADHD), Rett syndrome, Angeiman syndrome, or Prader-Willi syndrome in a mammal, comprising: administering to the mammal an effective amount of a composition comprising a compound of any one of formulas (l)-(XXXX), a pharmaceutically acceptable salt thereof, or a combination thereof. 48. A method to prevent, inhibit or treat one or more symptoms associated with stress, anxiety, mood or psychiatric disorders, insomnia, migraines, muscle spasms and rigiditiy, sleep disorders, chronic alcohol intoxication/withdrawal, multiple sclerosis or neuropathic pain in a mammal, comprising: administering to the mammal an effective amount of a composition comprising a compound of any one of formulas (l)-(XXXX), a pharmaceutically acceptable salt thereof, or a combination thereof.

47. A method to prevent, inhibit or treat one or more symptoms associated with gastrointestinal tract motility and inflammation, inflammatory bowel disease, g astro pa res is, ileus and acute colonic pseudo-obstruction or acute liver injury in a mammal, comprising: administering to the mammal an effective amount of a composition comprising a compound of any one of formulas (i)-(XXXX), a

pharmaceutically acceptable salt thereof, or a combination thereof.

48. The method of any one of claims 45 to 47 wherein the compound is a compound in Table 1 .

49. The method of any one of claims 45 to 48 wherein the mammal is a human. 50, The method of any one of claims 45 to 49 wherein the compound is an an anticestodai, anticonvulsant, hormone replacement, antianginal, anti-inflammatory, vasodilator, antiseptic, antiparasitic, analgesic, AED, , anesthetic, , hormonal agent, antiemetic, antifungal, anti-infective, antibiotic, antihistamine, antimicrobialantipruritic, antiobesity, antiarrhyihmic, antianxiety, antidepressant, contraceptive, antispasmodic, or antitussive agent, or combinations thereof.

The method of any one of claims 45 to 50 wherein the composition comprises a pound of formula (I):

wherein each R¹ independently = H, OCi-e saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF₃, NH₂, CM, C0₂H, CQ₂Ci-₆ saturated or unsaturated alkyi, NHCi-e saturated, unsaturated aikyl, or cycloalkyi, or N(Ci-s saturated, unsaturated aikyl, or cycloalkyi^.;

wherein X = CH2, C, N, NH, NHC1 ^saturated, unsaturated alkyi, or cycioaikyl, O, S, SO, or S0_2; and

wherein n = 0-6. 52. The method of any one of claims 45 to 51 wherein the composition comprises a compound of formula (II):

wherein each R¹ = independently H, OC1-6 saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF₃, NH₂, CN, C0₂H, CO2C1-B saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi, o N(Ci-6 saturated, unsaturated alkyi, or cycloalkyl)_2;

wherein R² = H, Ci-e saturated alkyi, unsaturated alkyi, cycioaikyl,

cycloheteroalkyl, or (O);

wherein each X independently = C, N, O, S, SO, or S0₂, and

wherein n = 0-6. 53, The method of any one of claims 45 to 52 wherein the composition comprises a compound of formula (III):

wherein each R¹ independently = H, OC1 -5 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-B saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, o N(Ci-6 saturated, unsaturated alkyl, or cycioaikyl;

wherein R² = H, OH, OC1-6 saturated, unsaturated alkyl, cycioaikyl,

cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, OAc, CF3, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-e saturated, unsaturated alkyl, or cycioaikyl, or N(Ci-e saturated, unsaturated alkyl, or cycloalkyi)2' wherein each X independently = CH2, N, O, S, SO, or SO2; and

wherein n = 0-6,

54, The method of any one of claims 45 to 53 wherein the composition comprises a compound of formula (IV):

wherein each R¹ independently = H, OC1 -5 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, CF3, NH₂, CN, CO2H, CO2C1 -5 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, or N(Ci-6 saturated, unsaturated alkyl, or cycioaikyl;

wherein R² = H, OH, OC1-6 saturated, unsaturated alkyl, cycioaikyl,

cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, OAc, CFs, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-e saturated, unsaturated alkyl, or cycioaikyl, or N(Ci-e saturated, unsaturated alkyl, or cycloalkyfb., wherein R³ = C5-7aryl or heteroaryl;

wherein X = CH₂, N, O, S, SO, or SO2, and

wherein n = 0-6,

55. The method of any one of claims 45 to 54 wherein the composition comprises a compound of formula (V):

wherein each R¹ = H , OC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated a!kyl, cycioaikyi, cycloheteroa!kyl, CI, Br, F, I, OH, OAc, CFs, NH₂, CN , C0₂H, CQ2C1 6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyl, or cycioaikyi, or N(Ci-6 saturated, unsaturated aikyl, or cyc!oa!kyrk;

wherein each M independently = Na, K, Li, Hg, or Zn; and

wherein each X independently = CH₂, NH, O, S, SO, or SO2.

The method of any one of claims 45 to 55 wherein the composition comprises pound of formula (VI) :

wherein each R¹ independently = H, OCi-e saturated, unsaturated aikyl, cycioaikyi, cycloheteroalkyl, C1-6 saturated aikyl, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF₃, NH₂, CN , CO2H, C0₂Ci-₆ saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated aikyl, or cycioaikyi, N(Ci-e saturated, unsaturated aikyi, or cycloalkyl)2;

wherein R² = H, OH, OCi-e saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, OAc, CF3, NH₂, CN, CO2H , C0₂Ci-6 saturated or unsaturated alkyl, NHCi-e saturated, unsaturated aikyi, or cycioaikyi, N(Ci-6 saturated, unsaturated alkyl, or cycioaikyl)₂, C5- yaryl or heteroaryi; and

wherein each X independently = CH, N , O, or S.

57. The method of any one of claims 45 to 56 wherein the composition comprises a compound of formula (VI I) :

wherein each R¹ independently = H, OC i-6 saturated, unsaturated alkyi, cycloaikyl, cycloheteroaikyl, Ci-e saturated alkyi, unsaturated alkyi, cycloaikyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, NO2, CF₃, NH₂, CN, CO2H , CO2C1 -6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloaikyl, N(C i-s saturated, unsaturated alkyl, or cycloalkyl)2, Cs-yaryl or heteroaryl; and

wherein each X independently = CH₂, N , O, S, SO, or SO2.

58. The method of any one of claims 45 to 57 wherein the composition comprises a compound of formula (VIII):

wherein each R¹ independently = H, OC1 -5 saturated, unsaturated alkyi, cycloaikyl, cycloheteroaikyl, Ci-e saturated alkyl, unsaturated alkyl, cycloaikyl, cycloheteroaikyl, CI, Br, F, I, OH, OAc, CF3, NH₂, CN, CO2H , CO2C1 -5 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyl, or cycloaikyl, or N(Ci-e satur unsaturated alkyi, or cycloaikyl^, Cs-yaryl or heteroaryl;and

wherein R² = Mono, di, or trigiycoside, or OC(O) C3-5 aikenyl; and

wherein each X independently = CH2, N, O, S, SO, or SO2.

The method of any one of claims 45 to 58 wherein the composition comprises a pound of formula (IX):

wherein each R¹ independently = H , OC1-6 saturated, unsaturated alkyi, cycloaikyl, cycloheteroaikyl, Ci -e saturated alkyl, unsaturated alkyi, cycloaikyl, cycioheteroalkyi, C I, Br, F, I, OH, OAc, CF₃, NH₂, CN , CO2H , CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, Cs-yaryl or heteroaryl;

wherein R² = Mono, di, or iriglycoside, orOC(O) C3-5 alkenyl;

wherein n = 0-6; and

wherein each X independently = CH₂, N, O, S, SO, or SO2.

I

60. The method of any one of claims 45 to 59 wherein the composition comprises a compound of formula (X):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheieroaikyi, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, Cs-yaryl or heteroaryl;

wherein each X independently = CH2, C, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S0_2; and

wherein = 0-6.

61 . The method of any one of claims 45 to 60 wherein the composition comprises a compound of formula (XI):

wherein each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I , OH, OAc, Ac, CF₃, NH₂, CN, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1 -8 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl^, C aryl or heteroaryl;

wherein n = 0-6.

62. The method of any one of claims 45 to 61 wherein the composition comprises a compound of formula (XI I):

wherein each R independently = H, OCi-e saturated, unsaturated alky!, cycloalkyl, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^, Cs-yaryl or eteroaryl;

wherein R² = H, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, C1 -6 saturated aikyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CFs, NH2, CN, C(0)CH20Ac, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHCi-₆ saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, Cs-raryl or heteroaryl;

wherein each X independently = CH2, C, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2; and

wherein n = 0-6.

63. The method of claim 62 wherein R² = OC1-6 saturated, unsaturated alkyl, cycloheteroalkyl, C1-6 saturated aikyl, unsaturated alkyl, OAc, Ac, C(0)CH20Ac, CO2H, or CO2C1-6 saturated or unsaturated alkyl.

64. The method of any one of claims 45 to 63 wherein the composition comprises a compound of formula (XIII):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF3, NH₂, CN, CO2H, CO2C1 -6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-6 saturated, unsaturated alkyl, or eycloalkyl)₂.;

wherein each n independently = 0-6.

65. The method of any one of claims 45 to 64 wherein the composition comprises a compound of formula (XIV):

In one embodiment, each R^¾ independently = H, OC1-6 saturated, unsaturated aikyi, cycioaikyi, cycloheteroaikyl, Ci-e saturated alkyl, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H , CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated aikyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)₂, Cs-yaryi or heteroaryl; each X independently = CH₂, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyi, O, S, SO, or S0₂, and n = 0-6.

66, The method of any one of claims 45 to 65 wherein the composition a compound of formula (XV):

wherein each R ¹ independently = H, OC1-6 saturated, unsaturated aikyi, cycioaikyi, cycloheteroaikyl, Ci-e saturated alkyl, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H , CO2C1-6 saturated or unsaturated aikyi, NHC 1-6 saturated, unsaturated aikyi, or cycioaikyi, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl)2, Cs-yaryi or heteroaryl; and wherein X = CH2, NH, NCi-esaturated, unsaturated alkyi, or cycloaikyl, O, S,

67. The method of any one of claims 45 to 66 wherein the composition comprises a composition comprises a compound of formula (XVI):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated aikyi, cycioaikyi, cycloheteroaikyl, Ci-e saturated alkyl, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN , NO2, C(0)CH₂OAc, CO2H , CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, or cycloaikyl^, Cs jaryi or heteroaryl; wherein each X independently = CH₂, NH, NCi-ssaiiirated, unsaturated alkyl, or cyc!oa!kyl, O, S, SO, or S0_2; and

wherein each n independently = 0-6.

68. The method of any one of claims 45 to 67 wherein the composition comprises a compound of formula (XVII):

wherein each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycioalkyl, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycioalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH20Ac, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioalkyl, N(Ci-e saturated, unsaturated alkyl, or cycioalkyl, Cs-yaryl or heteroaryl; and each X independently = CH2, NH, NCi-ssaturated, unsaturated alkyl, or cycioalkyl, O, S, SO, or SO2

69. The method of any one of claims 45 to 68 wherein the composition comprises a compound of formula (XVIII):

wherein each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycioalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycioalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, C0₂H, C0₂Ci-6 saturated or unsaturated alkyl, NHCI-B saturated, unsaturated alkyl, or cycioalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi)₂, Cs-jary! or heteroaryl; and wherein each X independently = CH₂, NH, NCi-ssaturated, unsaturated alkyl, or cycioalkyl, O, S, SO, or S0₂.

70. The method of any one of claims 45 to 69 wherein the composition comprises a compound of formula (XIX):

wherein each R¹ independently = H, OC i-6 saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, CMS saturated alky!, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1 -5 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyi, or cycloalkyl, Cs-raryl or heteroaryl;

wherein each X independently = CH2, N, NH, NCi-esaturated, unsaturated alkyi, or cycloalkyl, O, S, SO, SO2, CI, or Br; and

wherein n = 0-6.

71 . The method of any one of claims 45 to 70 wherein the composition comprises comprises a compound of formula (XX):

wherein each R¹ independently = H, OCi-e saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, CMS saturated alkyi, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, Ci, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl^, Cs-rary! or heteroaryl; each X independently = CH_2> N, NH, NCi-ssaturated, unsaturated aikyl, or cycloalkyl, O, S, SO, SO2, CI, or Br; and each n independently = 0-6.

72. The method of any one of claims 45 to 71 wherein the composition comprises comprises a compound of formul

wherein each R¹ independently = H, OC1-6 saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, Ci, Br, F, I , OH, OAc, CF₃, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-e saturated, unsaturated alkyi, or cycloalkyl^, Cs-7aryl or heteroaryl;

wherein each R² independently = H, OH, OCi-e saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, Ci-e saturated aikyl, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, OAc, CF3, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-e saturated, unsaturated aikyl, or cycloaikyl)₂, Cs-Taryi or heteroaryl;

wherein each X independently = CH₂, N, O, S, SO, or S0₂._; and wherein each n independently = 0-8.

73. The method of any one of claims 45 to 72 wherein the composition comprises comprises a compound of formula (XXII):

wherein each R¹ independently = H, OCi-e saturated, unsaturated aikyl, cycioaikyl, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated aikyl, cycioaikyl, cycioheteroaikyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂OAc, C0₂H, C02Ci-6 saturated or unsaturated aikyl, NHC1 -5 saturated, unsaturated a!kyi, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi)₂, Cs-jaryi or heteroaryl; wherein each X independently = CH2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or S0₂, and

wherein n = 0-6. 74. The method of any one of claims 45 to 73 wherein the composition comprises a compound of formula (XXiil):

wherein each R¹ independently = H, OCi-e saturated, unsaturated aikyl, cycioaikyl, cycloheteroalkyl, C1-6 saturated aikyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH_2> CN, N0_2> C(0)CH₂OAc, C0₂H, C0₂Ci-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)₂, Cs-7aryl or heteroaryl; wherein each X independently = CH₂, N, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or S0_2; and

wherein n = 0-6.

75. The method of any one of claims 45 to 74 wherein the composition comprises a compound of formula (XXIV):

wherein each R^! independently = H, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂OAc, CO2H , CO2C1-6 saturated or unsaturated alkyl, NHC 1-6 saturated, unsaturated a!kyl, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl)2, Cs-raryl or heteroaryl; wherein each X independently = CH2, NH, NCi-ssaturaied, unsaturated alkyl, cycioaikyl, O, S, SO, or SO2.; and

wherein n = 0-6.

76. The method of any one of claims 45 to 75 wherein the composition comprises a composition comprises a compound of formula (XXV):

wherein each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCI-B saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycioaikyl, Cs-jaryi or heteroaryl; wherein each X independently = CH2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or SO2, and

wherein each n independently = 0-6.

77. The method of any one of claims 45 to 76 wherein the composition comprises a compound of formula (XXVI):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, C1-12 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC 1 -6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, Canary! or heteroaryl; whereineach X independently = CH₂, N, NH, NCrssaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or S0_2; and

wherein each n independently = 0-6.

The method of any one of claims 45 to 77 wherein the composition comprises a pound of formula (XXVII):

wherein each R¹ independently = H, OC i-6 saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyi, Ci-e saturated aikyl, unsaturated a!kyl, cycioaikyl, cycioheteroa!kyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1 -5 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-6 saturated, unsaturated aikyl, or cycloalkyi)2, Cs-raryl or heteroaryl; wherein each X independently = CH₂, N, NH, NCi-esaturated, unsaturated alkyi, or cycioaikyl, O, S, SO, or S0_2; and

wherein each n = 0-6.

79. The method of any one of claims 45 to 78 wherein the composition comprises a compound of formula (XXVIII):

wherein each R¹ independently = H, OCi-e saturated, unsaturated aikyl, cycioaikyl, cycloheteroalkyi, Ci-e saturated aikyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi)2, Cs-7aryl or heteroaryl; and wherein each X independently = CH₂, NH, NCi-ssaturated, unsaturated alkyi, or cycioaikyl, O, S, SO, or SO2.

The method of any one of claims 45 to 79 wherein the composition comprises a pound of formula (XXIX):

wherein each R^! independently = H, OC1-6 saturated, unsaturated aikyl, cycioaikyl, cycloheteroalkyi, Ci-e saturated aikyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, C0₂Ci-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)₂, Cs-yaryi or heteroaryl; wherein each X independently = CH₂, NH2, NH, NCi-esaturated, unsaturated alkyi, or cycioaikyl, O, S, SO, or S0_2i and wherein n = 0-6,

81 . The method of any one of claims 45 to 80 wherein the composition comprises a compound of formula (XXX):

wherein each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycioaikyi, cycloheteroaikyl, Ci-e saturated alkyl, unsaturated alkyl, cycioaikyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi)2, Cs-v-ary! or heteroaryl; wherein each X independently = CH2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyi, O, S, SO, or S0_2; and

wherein n = 0-6.

82, The method of any one of claims 45 to 81 wherein the composition comprises a compound of formula (XXXI):

wherein each R¹ independently = H, OCi-e saturated, unsaturated alkyl, cycioaikyi, cycloheteroaikyl, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyi, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCI-B saturated, unsaturated alkyl, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi)2, Cs-jaryi or heteroaryl; and wherein each X independently = CH2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyi, O, S, SO, or SO2.

83. The method of any one of claims 45 to 82 wherein the composition comprises a compound of formula (XXXII

wherein each R¹ independently = H, OC1 -5 saturated, unsaturated alkyl, cycioaikyi, cycloheteroaikyl, Ci-e saturated alkyl, unsaturated alkyl, cycioaikyi, cycioheteroa!kyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1 -5 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-yaryl or heteroaryl; wherein each X independently = CH₂, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or S0_2; and

wherein each n independently = 0-6.

84. The method of any one of claims 45 to 83 wherein the composition comprises a compound of formula (XXXIII):

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycioaikyl, cycloheieroaikyi, C1-3 saturated alkyl, unsaturated alkyl, cycioaikyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1 -3 saturated or unsaturated alkyl, NHC1 -3 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-3 saturated, unsaturated alkyl, or cycioaikyl)₂,or Cs-e aryl or heteroaryl; wherein each X independently = CH2, N, NH, NCi-3saturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or SO2; and wherein n = 0-3.

85. The method of any one of claims 45 to 84 wherein the composition comprises a compound of formula (XXXIV):

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycioaikyl, cycioheteroalkyi, C1-3 saturated alkyl, unsaturated alkyl, cycioaikyl, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, N0₂, CO2H, CO2C1 -3 saturated or unsaturated alkyl, NHC1 -3 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-3 saturated, unsaturated alkyl, or cycioaikyl)₂, or Cs-earyl or heteroaryl; wherein each X independently = CH2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or SO2; and wherein each n independently = 0-3. 86. The method of any one of claims 45 to 85 wherein the composition comprises a compound of formula (XXXV):

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CO2H, CO2C1-3 saturated or unsaturated alkyl, CI, Br, F, i, OH, OAc, Ac, NH2, CN, CF3, NHC1-3 saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-3 saturated, unsaturated alkyl, or cycloalkyi wherein R² = H, OC1-3 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN, Ac, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated a!kyi, or cycloalkyi, or N(Ci-3 saturated, unsaturated alkyl, or cycioaiky!)2;

wherein X = CH2, NH, NHCi-3saturated, unsaturated aikyl, or cycloalkyi, O, S,

wherein n = 0-3.

87, The method of any one of claims 45 to 86 wherein the composition comprises a compound of formula (XXXVI):

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-3 saturated aikyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CO2H, CO2C1-3 saturated or unsaturated alkyl, CI, Br, F, I, OH, OAc, Ac, NH2, CN, CF3, NHC1-3 saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-3 saturated, unsaturated alkyl, or cycloalkyi; wherein each R² independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated aikyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-3 saturated, unsaturated alkyl, or cycloalkyi;

wherein each X independently = CH2, N, NH, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, S02_; and

wherein each n independently = 0-3.

88. The method of any one of claims 45 to 87 wherein the composition comprises a compound of formula (XXXVII):

wherein R = H, OC1-3 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyi, C1-3 saturated alkyi, unsaturated alkyi, cycioaikyl, cycloheteroalkyi, CO2H, or C02Ci-3 saturated or unsaturated alkyi; wherein each R² independently = OC1-3 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyi, C1-3 saturated alkyi, unsaturated aikyl, cycioaikyl, cycloheteroalkyi, CI, Br, F, i, OH, OAc, Ac, CF₃, NH₂, CN, CO2H, CO2C1-3 saturated or unsaturated alkyi, NHC1-3 saturated, unsaturated alkyi, or cycioaikyl, or N(Ci-3 saturated, unsaturated alkyi, or cycioaikyl;

wherein each X independently = CH2, NH, NHC-i-ssaiuraied, unsaturated aikyl, or cycioaikyl, O, S, SO, or S0_2; and

wherein each n independently = 0-3.

89. The meihod of any one of claims 45 to 88 wherein the composition comprises a compound of formula (XXXVI II):

wherein each R independently = H, OC1 -3 saturated, unsaturated aikyl, cycioaikyl, cycloheteroalkyi, C1 -3 saturated alkyi, unsaturated alkyi, cycioaikyl, cycloheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CFs, NH₂, CN, NO2, CO2H, CO2C1-3 saturated or unsaturated alkyi, NHC1-3 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-3 saturated, unsaturated alkyi, or cycioaikyl^, or Cs-earyl or heteroaryl; and

wherein each X independently = CH2, N, NH, NCi-ssaturated, unsaturated aikyl, or cycioaikyl, O, S, SO, or SO2. 90. The method of any one of claims 45 to 89 wherein the composition comprises a compound of formula (XXXiX):

wherein each R¹ independently = OC1-3 saturated, OC5-6 aryi or heteroaryl, unsaturated aikyl, cycioaikyl, cycloheteroalkyi, or C1-3 saturated alkyi, unsaturated alkyi, cycloalkyl, cycloheteroalkyl; R² = CH2, O, NH, or NC1-3 saturated, unsaturated alkyl, cycioaiky, or cycioheterocyioaikyl; each R³ independently = CN, C1-3 saturated or unsaturated alkyl, OC1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-3 saturated, unsaturated alkyl, or cycloalkyl^;

wherein each X independently = CH or N; and

wherein each n independently = 0-3.

The method of any one of claims 45 to 90 wherein the composition comprises a pound of formula (XXX

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, CO2H, CO2C1.3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-3 saturated, unsaturated alkyl, or cycioaikyl)2, or Cs-earyl or heteroaryl;

wherein each X independents CH2, N, NH, NCi-asaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2; and

wherein each n independently = 0-3. 92. The method of any one of claims 1 to 91 wherein the composition is administered orally, topically or via infusion or injection through all forms of parenteral routes, including but not limited to: intravenous; intramuscular; subcutaneous;

transdermal; intrathecal, intracerebrovascular, intraparenchymal or

intracerebroventricular (e.g., all forms of direct delivery to the CNS); intravitreal or intraretinal (e.g. all forms of direct delivery to the eye); intra-ganglionic (e.g. all forms of direct delivery to the peripheral nervous system); intra-aural (e.g. ail forms of direct delivery to the middle or inner ear and cochlea); or rectal.

93. The method of any one of claims 1 to 92 wherein the amount administered is about 1 mg to about 75 mg per clay, about 10 mg to about 50 mg per day, about 20 mg to about 40 mg per day, or about 5 mg to about 50,000 mg per day.