CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No.

62/748,016, filed October 19, 2018, the entire contents of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

[0002] Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal

membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately -70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K ⁺ , Na ⁺ , CL, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, a change of potential from -70 mV to -50 mV. This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase membrane permeability to Na ⁺ ions. The reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.

[0003] In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by g-aminobutyric acid (GABA), a neurotransmitter. GABA has a profound influence on overall brain excitability because up to 40% of the neurons in the brain utilize GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the

conductance of chloride ions across the neuronal membrane. GABA interacts with its

recognition site on the GRC to facilitate the flow of chloride ions down an electrochemical gradient of the GRC into the cell. An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential, rendering the neuron less susceptible to excitatory inputs, i.e., reduced neuron excitability. In other words, the higher the chloride ion concentration in the neuron, the lower the brain excitability and level of arousal.

[0004] It is well-documented that the GRC is responsible for the mediation of anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA or facilitate the effects of GABA (e.g., the therapeutically useful barbiturates and benzodiazepines (BZs), such as Valium®) produce their therapeutically useful effects by interacting with specific regulatory sites on the GRC. Accumulated evidence has now indicated that in addition to the

benzodiazepine and barbiturate binding site, the GRC contains a distinct site for neuroactive steroids. See, e.g., Lan, N. C. et al., Neurochem. Res. (1991) 16:347-356.

[0005] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3a-hydroxy-5-reduced pregnan-20-one and 3a-2l-dihydroxy-5-reduced pregnan-20-one, metabolites of hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M. D. et al, Science 232: 1004-1007 (1986); Harrison, N. L. et al, J

Pharmacol. Exp. Ther. 241:346-353 (1987)).

[0006] New and improved neuroactive steroids are needed that act as modulating agents for brain excitability, as well as agents for the prevention and treatment of CNS-related diseases.

The compounds, compositions, and methods described herein are directed toward this end

SUMMARY OF THE INVENTION

[0007] Provided herein are neuroactive steroids designed, for example, to act as GABA modulators. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder.

[0008] In an aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition.

In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a prophylactically effective amount.

[0009] In an aspect, provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; [0010] In some embodiments, the compound of Formula (I) is a compound of formula (I -a):

or a pharmaceutically acceptable salt thereof;

[0011] In some embodiments, the compound of Formula (I) is a compound of formula (I-bl), or (l-b2):

or a pharmaceutically acceptable salt thereof;

[0012] In some embodiments, the compound of formula (I) is a compound of formula (I -cl):

-cl)

or a pharmaceutically acceptable salt thereof;

[0013] In some embodiments, the compound of formula (I) is a compound of formula (I-c2):

or a pharmaceutically acceptable salt thereof; [0014] In some embodiments, the compound of formula (I) is a compound of formula (I-d):

or a pharmaceutically acceptable salt thereof;

[0015] In some embodiments, the compound of formula (I) is a compound of formula (I-e):

or a pharmaceutically acceptable salt thereof;

[0016] In some embodiments, the compound of formula (I) is a compound of formula (I-f):

or a pharmaceutically acceptable salt thereof;

[0017] In some embodiments, the compound of formula (I) is a compound of formula (I-g):

or a pharmaceutically acceptable salt thereof;

In some embodiments, the compound of formula (I) is a compound of Formula (I-h):

or a pharmaceutically acceptable salt thereof;

[0018] In some embodiments, the compound of formula (I) is a compound of Formula (I-i):

or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound of formula (I) is a compound of Formula (I-j 1):

-j l),

or a pharmaceutically acceptable salt thereof,

[0020] In some embodiments, the compound of formula (I) is a compound of Formula (I-j2):

or a pharmaceutically acceptable salt thereof, [0021] In some embodiments, the compound of formula (I) is a compound of Formula (I-

-kl)

or a pharmaceutically acceptable salt thereof,

[0022] In some embodiments, the compound of formula (I) is a compound of Formula (I-

or a pharmaceutically acceptable salt thereof,

[0023] In some embodiments, the compound of formula (I) is a compound of Formula (1-11) or (1-12):

or a pharmaceutically acceptable salt thereof,

[0024] In some embodiments, the compound of formula (I) is a compound of Formula (1-12):

or a pharmaceutically acceptable salt thereof,

[0025] In some embodiments, the compound of formula (I) is a compound of Formula (I- ml): -ml),

[0026] In some embodiments, the compound of formula (I) is a compound of Formula (I- m2):

or a pharmaceutically acceptable salt thereof,

[0027] In some embodiments, the compound of formula (I) is a compound of Formula (I- nl):

or a pharmaceutically acceptable salt thereof,

[0028] In some embodiments, the compound of formula (I) is a compound of Formula (I-

or a pharmaceutically acceptable salt thereof,

[0029] In some embodiments, the compound of formula (I) is a compound of Formula (I) is of Formula (I-o):

or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the compound of formula (I) is a compound of Formula (I) is of Formula (I-p)

or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the compound of formula (I) is a compound of Formula (I) is of Formula (I-q)

[0032] In some embodiments, the compound of formula (I) is a compound of Formula (I) is of Formula (I-r)

or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the compound of Formula (I) is of Formula (Is)

or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the compound of Formula (I) is of Formula (I-t)

or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the compound of Formula (I) is of Formula (I-u)

or a pharmaceutically acceptable salt thereof.

[0036] In an aspect, provided herein is a pharmaceutically acceptable salt of a compound described herein (e.g., a compound of Formula (I)).

[0037] In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, e.g., by continuous intravenous infusion.

[0038] Compounds of the present invention as described herein, act, in certain embodiments, as GABA modulators, e.g., effecting the GABAA receptor in either a positive or negative manner. As modulators of the excitability of the central nervous system (CNS), as mediated by their ability to modulate GABAA receptor, such compounds are expected to have CNS -activity.

[0039] In an aspect, described herein is a method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus.

[0041] In some embodiments, the CNS-related disorder is depression. In some embodiments, the CNS-related disorder is postpartum depression. In some embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0042] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0043] As generally described herein, the present invention provides neuroactive steroids designed, for example, to act as GABA modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder (e.g., a disorder as described herein, for example depression, such as post-partum depression or major depressive disorder).

DEFINITIONS

Chemical definitions

[0044] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5 ^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 ^rd Edition, Cambridge University Press, Cambridge, 1987.

[0045] Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al. , Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al, Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0046] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i. e. , in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the“R” form of the compound and is, thus, in enantiomeric excess of the“R” form. The term“enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0047] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the

enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising

enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S- compound in such compositions can, for example, comprise, at least about 95% by weight S- compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0048] The articles“a” and“an” may be used herein to refer to one or to more than one (i. e. at least one) of the grammatical objects of the article. By way of example“an analogue” means one analogue or more than one analogue.

[0049] When a range of values is listed, it is intended to encompass each value and sub range within the range. For example“Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C ₄ , C5, Ce, C1-6, C1-5, Ci-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0050] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

[0051] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some

embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some

embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (Cr _> ).

Additional examples of alkyl groups include n-heptyl (C7), n-octyl ( C ) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i. e. , unsubstituted (an“unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted Ci-10 alkyl (e.g., -CEE). In certain embodiments, the alkyl group is substituted Ci-10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH ₃ )2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i- Bu (-CH ₂ CH(CH ₃ )2). [0052] “Alkylene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (- CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH ₃ )CH2-,-CH2CH(CH ₃ )-, - C(CH ₃ )2CH2-,-CH ₂ C(CH ₃ )2-), substituted propylene (-CH(CH ₃ )CH ₂ CH2-, -CH ₂ CH(CH ₃ )CH2-, - CH ₂ CH ₂ CH(CH ₃ )-, -C(CH ₃ )2CH ₂ CH2-, -CH ₂ C(CH ₃ )2CH2-, -CH ₂ CH ₂ C(CH ₃ )2-), and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. Alkylene groups may be substituted or unsubstituted with one or more substituents as described herein.

[0053] “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2- 10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”).

In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in l-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), l-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Cr,)_ and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-1 ₀ alkenyl. In certain embodiments, the alkenyl group is substituted C2-1 ₀ alkenyl.

[0054] “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some

embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in l-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), l-propynyl (C3), 2-propynyl (C3), l-butynyl (C ₄ ), 2-butynyl (C ₄ ), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (G,). and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (G). and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i. e. , unsubstituted (an“unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl.

[0055] The term“heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-7 alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroCi- ₆ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroCi-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms (“heteroCi-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an“unsubstituted heteroalkyl”) or substituted (a“substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-io alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-io alkyl.

[0056] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C ₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as l-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl).“Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene,

acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2, 4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and

tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i. e. , unsubstituted (an“unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted Ce 14 aryl. In certain embodiments, the aryl group is substituted C6-14 aryl.

[0057] In certain embodiments, an aryl group substituted with one or more of groups selected from halo, Ci-Cs alkyl, Ci-Cs haloalkyl, cyano, hydroxy, Ci-Cs alkoxy, and amino.

[0058] Examples of representative substituted aryls include the following

wherein one of R ⁵⁶ and R ⁵⁷ may be hydrogen and at least one of R ⁵⁶ and R ⁵⁷ is each

independently selected from Ci-Cs alkyl, Ci-Cs haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-Cs alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR ⁵⁸ COR ⁵⁹ , NR ⁵⁸ S0R ⁵⁹ NR ⁵⁸ S0 ₂ R ⁵⁹ , COOalkyl, COOaryl, CONR ⁵⁸ R ⁵⁹ , CONR ⁵⁸ OR ⁵⁹ , NR ⁵⁸ R ⁵⁹ ,

SChNR ⁵⁸ R ⁵⁹ , S-alkyl, SOalkyl, S0 ₂ alkyl, Saryl, SOaryl, S0 ₂ aryl; or R ⁵⁶ and R ⁵⁷ may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R ⁶⁰ and R ⁶¹ are independently hydrogen, Ci-Cs alkyl, C1-C4 haloalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, substituted C6-C10 aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl .

[0059] ‘Fused aryl” refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

[0060] “Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 p electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0061] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a“substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.

[0062] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.

Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6- membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0063] Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR ⁶⁵ , O, and S; and R ⁶⁵ is independently hydrogen, Ci-Cs alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl.

[0064] “Carbocyclyl” or“carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C ₄ ), cyclobutenyl (Cr). cyclopentyl (C5), cyclopentenyl (Cs). cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C ₇ ), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C ₇ ), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2. l]heptanyl (C ₇ ), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (Cs>), cyclononenyl (C9), cyclodecyl (C 10), cyclodecenyl (C 10), octahydro- l//-indcnyl (C9), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (Cio), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.“Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i. e. , unsubstituted (an“unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10 carbocyclyl.

[0065] In some embodiments,“carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5) . Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C ₄ ).

Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl ( C ) . Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-10 cycloalkyl.

[0066] “Heterocyclyl” or“heterocyclic” refers to a radical of a 3- to lO-membered non aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i. e. , unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3- 10 membered heterocyclyl.

[0067] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0068] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.

Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0069] “Nitrogen-containing heterocyclyl” group means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2- pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.

[0070] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,.

heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0071] “Acyl” refers to a radical -C(0)R ²⁰ , where R ²⁰ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein.“Alkanoyl” is an acyl group wherein R ²⁰ is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=0)CH ₃ ), cyclohexylcarbonyl,

cyclohexylmethylcarbonyl, benzoyl (-C(=0)Ph), benzylcarbonyl (-C(=0)CH2Ph),— C(0)-C i -C alkyl, -C(0)-(CH ₂ )t(C ₆ -Cio aryl), -C(O)-(CH ₂ )t(5-l0 membered heteroaryl), -C(0)-(CH ₂ )t(C ₃ - Cio cycloalkyl), and -C(O)-(CH ₂ ) _t (4-l0 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R ²¹ is Ci-Cs alkyl, substituted with halo or hydroxy; or C3 -C10 cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C1 ₀ aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0072] “Alkoxy” refers to the group -OR ²⁹ where R ²⁹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0073] In certain embodiments, R ²⁹ is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-C10 aryl, aryloxy, carboxyl, cyano, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(0)2- and aryl- S(0)2-. Exemplary‘substituted alkoxy’ groups include, but are not limited to, -0-(CH2)t(C ₆ -Cio aryl), -O-(CH2)t(5-l0 membered heteroaryl), -0-(CH2)t(C ₃ -Cio cycloalkyl), and -O-(CH2)t(4-l0 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are -OCF3, -OCH2CF3, -OCFhPh, -OCFh-cyclopropyl, -OCH2CH2OH, and - OCH ₂ CH ₂ NMe2.

[0074] ‘Amino” refers to the radical -NFh.

[0075] ‘Oxo group” refers to -C(=0)-.

[0076] ‘Substituted amino” refers to an amino group of the formula -N(R ³⁸ )2 wherein R ³⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R ³⁸ is not a hydrogen. In certain embodiments, each R ³⁸ is independently selected from hydrogen, Ci-Cs alkyl, C ₃ -C8 alkenyl, C ₃ -C8 alkynyl, C ₆ -C1 ₀ aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C ₃ -C1 ₀ cycloalkyl; or Ci-Cs alkyl, substituted with halo or hydroxy; C ₃ -C8 alkenyl, substituted with halo or hydroxy; C3-C8 alkynyl, substituted with halo or hydroxy, or -(CH2)t(C6-Cio aryl), -(CH2)t(5-lO membered heteroaryl), -(CH2)t(C3-Cio cycloalkyl), or -(CH2)t(4-lO membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R ³⁸ groups are joined to form an alkylene group.

[0077] Exemplary“substituted amino” groups include, but are not limited to, -NR ³⁹ -Ci-Cs alkyl, -NR ³⁹ -(CH ₂ )t(C ₆ -Cio aryl), -NR ³⁹ -(CH ₂ )t(5-lO membered heteroaryl), -NR ³⁹ -(CH ₂ )t(C ₃ - C ₁₀ cycloalkyl), and -NR ³⁹ -(CH ₂ ) _t (4-lO membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R ³⁹ independently represents H or Ci-Cs alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt the term‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.

[0078] “Carboxy” refers to the radical -C(0)OH.

[0079] “Cyano” refers to the radical -CN.

[0080] “Halo” or“halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[0081] “Haloalkyl” refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.

[0082] “Hydroxy” refers to the radical -OH.

[0083] “Nitro” refers to the radical -NO2.

[0084] hioketo” refers to the group =S.

[0085] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g.,“substituted” or“unsubstituted” alkyl, “substituted” or“unsubstituted” alkenyl,“substituted” or“unsubstituted” alkynyl,“substituted” or“unsubstituted” carbocyclyl,“substituted” or“unsubstituted” heterocyclyl,“substituted” or “unsubstituted” aryl or“substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a“substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

[0086] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, - NOi, -N ₃ , -SO2H, -SO3H, -OH, -OR ^aa , -ON(R ^bb ) ₂ . -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^CC , -C(=0)R ^aa , -CO2H, -CHO, -C(OR ^cc ) ₂ , -C0 ₂ R ^aa , -OC(=0)R ^aa , -OC0 ₂ R ^aa , - C(=0)N(R ^bb ) ₂ , -OC(=0)N(R ^bb ) ₂ , -NR ^bb C(=0)R ^aa , -NR ^bb C0 ₂ R ^aa , -NR ^bb C(=0)N(R ^bb ) ₂ , - C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , - OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=0)NR ^bb S0 ₂ R ^aa , -NR ^bb S0 ₂ R ^aa , -S0 ₂ N(R ^bb ) ₂ , -S0 ₂ R ^aa , -S0 ₂ OR ^aa , -OS0 ₂ R ^aa , -S(=0)R ^aa , -OS(=0)R ^aa , -Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ -C(=S)N(R ^bb ) ₂ , -C(=0)SR ^aa , -C(=S)SR ^aa , -SC(=S)SR ^aa , -SC(=0)SR ^aa , -OC(=0)SR ^aa , -SC(=0)OR ^aa , - SC(=0)R ^aa , -P(=0) ₂ R ^aa , -OP(=0) ₂ R ^aa , -P(=0)(R ^aa ) ₂ , -OP(=0)(R ^aa ) ₂ , -OP(=0)(OR ^cc ) ₂ , - P(=0) ₂ N(R ^bb ) ₂ , -0P(=0) ₂ N(R ^bb ) ₂ , -P(=0)(NR ^bb ) ₂ , -OP(=0)(NR ^bb ) ₂ , -NR ^bb P(=0)(OR ^cc ) ₂ , - NR ^bb P(=0)(NR ^bb ) ₂ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), Ci-10 alkyl, Ci-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C ₃ -io carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=0)R ^aa , =NNR ^bb C(=0)OR ^aa , =NNR ^bb S(=0) ₂ R ^aa , =NR ^bb , or =NOR ^cc ;

[0087] each instance of R ^aa is, independently, selected from Ci-10 alkyl, Ci-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C ₃ -io carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R ^aa groups are joined to form a 3-14 membered heterocyclyl or 5- 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

[0088] each instance of R ^bb is, independently, selected from hydrogen, -OH, -OR ^aa , - N(R ^cc )i, -CN, -C(=0)R ^aa , -C(=0)N(R ^cc )i, -C0 ₂ R ^aa , -S0 ₂ R ^aa , -C(=NR ^cc )OR ^aa , - C(=NR ^CC )N(R ^cc ) ₂ , -S0 ₂ N(R ^cc ) ₂ , -S0 ₂ R ^cc , -S0 ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=0)SR ^cc , - C(=S)SR ^CC , -P(=0) ₂ R ^aa , -P(=0)(R ^aa ) ₂ , -P(=0) ₂ N(R ^cc ) ₂ , -P(=0)(NR ^cc ) ₂ , CI-IO alkyl, Ci-io haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R ^bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

[0089] each instance of R ^cc is, independently, selected from hydrogen, Ci-10 alkyl, C i-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R ^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

[0090] each instance of R ^dd is, independently, selected from halogen, -CN, -NO2, -N3, -

C(=0)SR ^ee , -C(=S)SR ^ee , -SC(=S)SR ^ee , -P(=0) ₂ R ^ee , -P(=0)(R ^ee ) ₂ , -OP(=0)(R ^ee ) ₂ , - OP(=0)(OR ^ee )2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two geminal R ^dd substituents can be joined to form =0 or =S;

[0091] each instance of R ^ee is, independently, selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;

[0092] each instance of R ^ff is, independently, selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two R ^ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups; and

[0093] each instance of R ^gg is, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, - OH, -OC1-6 alkyl, -ON(Ci e alkyl) ₂ , -N(Ci-e alkyl) ₂ , -N(Ci-e alkyl) ₃ ⁺ X-, -NH(Ci e alkyl) ₂ ⁺ X-, -NH ₂ (CI 6 alkyl) ⁺ X , -NH ₃ ⁺ C-, -N(OCi e alkyl)(Ci-6 alkyl), -N(OH)(Ci e alkyl), -NH(OH), - SH, -SC1-6 alkyl, -SS(Ci-e alkyl), -C(=0)(Ci e alkyl), -CO2H, -C0 ₂ (Ci e alkyl), -OC(=0)(Ci e alkyl), -OC0 ₂ (Ci e alkyl), -C(=0)NH ₂ , -C(=0)N(Ci e alkyl) ₂ , -OC(=0)NH(Ci e alkyl), - NHC(=0)( Ci-6 alkyl), -N(Ci-e alkyl)C(=0)( Ci-e alkyl), -NHC0 ₂ (Ci e alkyl), -NHC(=0)N(Ci e alkyl) ₂ , -NHC(=0)NH(Ci e alkyl), -NHC(=0)NH ₂ , -C(=NH)0(Ci e alkyl), -OC(=NH)(Ci e alkyl), -OC(=NH)OCi e alkyl, -C(=NH)N(Ci-e alkyl) ₂ , -C(=NH)NH(Ci e alkyl), -C(=NH)NH ₂ , -OC(=NH)N(Ci 6 alkyl) ₂ , -OC(NH)NH(Ci e alkyl), -OC(NH)NH ₂ , -NHC(NH)N(Ci e alkyl) ₂ , - NHC(=NH)NH ₂ , -NHS0 ₂ (CI-6 alkyl), -S0 ₂ N(CI-6 alkyl) ₂ , -S0 ₂ NH(Ci e alkyl), -SO2NH2,- SO2C1-6 alkyl, -SO2OC1 6 alkyl, -OSO2C1 6 alkyl, -SOC1-6 alkyl, -Si(Ci-6 alkyl)3, -OSi(Ci-6 alkyl) ₃ -C(=S)N(CI-6 alkyl) ₂ , C(=S)NH(Ci-e alkyl), C(=S)NH ₂ , -C(=0)S(Ci-e alkyl), - C(=S)SCi-e alkyl, -SC(=S)SCi-e alkyl, -P(=0) ₂ (Ci-6 alkyl), -P(=0)(Ci-e alkyl) ₂ , -OP(=0)(Ci-e alkyl)2, -OP(=0)(OCi-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R ^gg substituents can be joined to form =0 or =S; wherein X is a counterion.

[0094] A‘‘counterion” or“anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F . CE, Br, E), NOi . Cl Or . OH . H2PO4 . HSOr .

sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-l -sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0095] These and other exemplary substituents are described in more detail in the Detailed Description, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Other definitions

[0096] As used herein, the term“modulation” refers to the inhibition or potentiation of GABA receptor function. A“modulator” (e.g. , a modulator compound) may be, for example, an agonist, partial agonist, antagonist, or partial antagonist of the GABA receptor. [0097] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0098] “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, l,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalene sulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al, J. Pharm. Sci. (1977) 66(1): 1-79.

[0099] The term“prodrug” is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the subject. [0100] In some embodiments, the compound of Formula (I) is a prodrug, wherein the prodrug includes a cleavable moiety on the C3 hydroxy as depicted in Formula. Exemplary hydroxyl containing prodrugs include, for example, esters.

[0101] ‘Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as“hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.“Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0102] ‘Stereoisomers”: It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed“isomers.” Isomers that differ in the arrangement of their atoms in space are termed“stereoisomers.” Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images of each other are termed“enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a“racemic mixture”.

[0103] ‘Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of p electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. [0104] A“subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non human animal, e.g. , a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and“subject” are used interchangeably herein.

[0105] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -R ^aa , -N(R ^bb )2, -C(=0)SR ^aa , -C(=0)R ^aa , -C0 ₂ R ^aa . - C(=0)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=0)R ^aa , -S0 ₂ R ^aa , - Si(R ^aa ) ₃ . -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -P(=0) ₂ R ^aa , -P(=0)(R ^aa ) ₂ , -P(=0)(OR ^cc ) ₂ , -P(=0) ₂ N(R ^bb ) ₂ , and - P(=0)(NR ^bb ) ₂ , wherein R ^aa , R ^bb , and R ^cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0106] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), /-butyldimethylsilyl (TBDMS), /-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

[0107] In certain embodiments, the substituent present on an sulfur atom is an sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -R ^aa , -N(R ^bb ) ₂ , -C(=0)SR ^aa , -C(=0)R ^aa , -C0 ₂ R ^aa , -C(=0)N(R ^bb ) ₂ , - C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=0)R ^aa , -S0 ₂ R ^aa , -Si(R ^aa ) ₃ . -P(R ^CC ) ₂ , - P(R ^CC )3, -P(=0) ₂ R ^aa , -P(=0)(R ^aa ) ₂ , -P(=0)(OR ^cc ) ₂ , -P(=0) ₂ N(R ^bb ) ₂ , and -P(=0)(NR ^bb ) ₂ , wherein R ^aa , R ^bb , and R ^cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W.

Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0108] In certain embodiments, the substituent present on a nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amino protecting groups include, but are not limited to, -OH, -OR ^aa , -N(R ^CC ) ₂ , -C(=0)R ^aa , -C(=0)OR ^aa , - C(=0)N(R ^cc ) ₂ , -S(=0) ₂ R ^aa , -C(=NR ^cc )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^CC )N(R ^CC ) ₂ , -S0 ₂ N(R ^cc ) ₂ , - S0 ₂ R ^cc , -S0 ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=0)SR ^cc , -C(=S)SR ^cc , Ci-10 alkyl, C _2-i o alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-l4-membered heterocyclyl, Ce-14 aryl, and 5-l4-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups, and wherein R ^aa , R ^bb , R ^cc and R ^dd are as defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0109] Exemplary amino protecting groups include, but are not limited to amide groups (e.g., -C(=0)R ^aa ), which include, but are not limited to, formamide and acetamide; carbamate groups (e.g., -C(=0)OR ^aa ), which include, but are not limited to, 9-fluorenylmethyl carbamate (Fmoc), /-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., - S(=0)2R ^aa ), which include, but are not limited to. /i-tolucncsulfonamidc (Ts),

methane sulfonamide (Ms), and /V-|2-(trimethylsilyl)ethoxy |methylamine (SEM).

[0110] Disease, disorder, and condition are used interchangeably herein.

[0111] As used herein, and unless otherwise specified, the terms“treat,”“treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

[0112] In general, the“effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g. , to treat a CNS-related disorder, is sufficient to induce anesthesia or sedation. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject An effective amount encompasses therapeutic and prophylactic treatment.

[0113] As used herein, and unless otherwise specified, a“therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term

“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0114] As used herein, and unless otherwise specified, a“prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term“prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

Compounds

[0115] One aspect of the invention provides substituted, unsaturated steroids and related organic compounds. The substituted unsaturated steroids and related organic compounds are contemplated to be useful in the methods, compositions, and kits described herein.

[0116] In some embodiments, provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

represents a single or a double bond as valency permits;

each of R ^2a , R ^2b , R ^4a , R ^4b , R ^6a , R ^6b , R ^7a , R ^7b , R ^12a , and R ^12b is independently hydrogen, halogen, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ ,-NHC(=0)R ^A1 , - NHC(=0)OR ^A1 , -S(=0)R ^A2 , -SC R ^A2 , or -S(=0)20R ^A1 , wherein each instance of R ^A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when atached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^A1 groups are joined to form an heterocyclic or heteroaryl ring; and R ^A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each of R ¹¹ and R ¹⁶ is independently hydrogen, halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ³ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R ⁵ is hydrogen or methyl when both of the are single bonds; and when one of the is a double bond, R ⁵ and one of R ^4a or R ^4b is absent; or R ⁵ and one of R ^6a or R ^6b is absent; R ¹⁹ is hydrogen or substituted or unsubstituted alkyl;

Each of R ^21a , R ^21b , and R ^21c is independently hydrogen, -substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and

n is 0, 1, 2, or 3;

provided that the following compound, and salts thereof, is specifically excluded:

Groups R ^2a , R ^2b , R ^4a , R ^4b , R ^6a , R ^6b , R ^7a , R ^7b , R ^12a , andR ^12b

[0117] In some embodiments, each of R ^2a , R ^2b , R ^4a , R ^4b , R ^6a , R ^6b , R ^7a , R ⁷¹¹ , R ^12a , and R ^12b are independently hydrogen, halogen, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. [0118] In some embodiments, each of R ^2a , R ^2b , R ^4a , R ^4b , R ^6a , R ^6b , R ^7a , R ^b , R ^12a , and R ^12b are independently hydrogen, hydroxyl, alkoxy, cyano, C1-C6 substituted or unsubstituted alkyl.

[0119] In some embodiments, each of R ^2a , R ^2b , R ^4a , R ^4b , R ^6a , R ^6b , R ^7a , R ^b , R ^12a , and R ^12b are independently hydrogen.

[0120] In some embodiments, R ^2a , R ^2b , R ^4a , R ^4b , R ^6a , R ^6b , R ^7a , R ^7b , R ^12a , and R ^12b are all hydrogen

Groups R" and R ¹⁶

[0121] In some embodiments, each of R ¹¹ and R ¹⁶ is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl.

[0122] In some embodiments, each of R ¹¹ and R ¹⁶ is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl.

[0123] In some embodiments, each of R ¹¹ and R ¹⁶ is independently hydrogen.

[0124] In some embodiments, R ¹¹ and R ¹⁶ are both hydrogen.

Group R ³

[0125] In some embodiments, R ³ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl.

[0126] In some embodiments, R ³ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl.

[0127] In some embodiments, R ³ is a group of formula:

wherein each instance of R ^3a is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, methoxymethyl, methoxyethyl, or ethoxymethyl, -OR ^F1 , wherein R ^F1 is substituted or unsubstituted alkyl, or -CH2X, or -CHX2, wherein X is halo; and each instance of R ^3b and R ^3c is independently hydrogen, halo, or substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.

[0128] In some embodiments R ³ is unsubstituted alkyl

[0129] In some embodiments R ³ is C1-C4 unsubstituted alkyl

[0130] In some embodiments R ³ is methyl Group IV

[0131] In some embodiments, R ⁵ is hydrogen

[0132] In some embodiments, R ⁵ is methyl

[0133] In some embodiments, the compound of Formula (I) is a compound of formula (I -a):

[0134] In some embodiments, the compound of Formula (I) is a compound of formula (I-bl), or (l-b2):

[0135] In some embodiments, the compound of formula (I) is a compound of formula (I-cl):

-cl)

[0136] In some embodiments, the compound of formula (I) is a compound of formula (I-c2):

[0137] In some embodiments, the compound of formula (I) is a compound of formula (I-d):

[0138] In some embodiments, the compound of formula (I) is a compound of formula (I-e):

Group R ¹⁹

[0139] In some embodiments, R ¹⁹ is hydrogen or C1-C ₆ substituted or unsubstituted alkyl.

[0140] In some embodiments, R ¹⁹ is hydrogen or C1-C ₆ unsubstituted alkyl.

[0141] In some embodiments, R ¹⁹ is hydrogen or C1-C4 unsubstituted alkyl.

[0142] In some embodiments, R ¹⁹ is hydrogen or methyl

[0143] In some embodiments, R ¹⁹ is hydrogen

[0144] In some embodiments, R ¹⁹ is methyl

[0145] In some embodiments, the compound of formula (I) is a compound of formula (I-f):

[0146] In some embodiments, the compound of formula (I) is a compound of formula (I-g):

Group R ²¹

[0147] In some embodiments, R ^21a and R ^21b are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; and R ^21c is hydrogen, substituted or unsubstituted heteroaryl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted 5-membered heteroaryl, with 1 heteroatom, substituted or unsubstituted 5- membered heteroaryl, with 2 heteroatoms, substituted or unsubstituted 5-membered heteroaryl, with 3 heteroatoms, substituted or unsubstituted 5-membered heteroaryl, with 4 heteroatoms; and n is 0, 1, 2, or 3.

[0148] In some embodiments, R ^21a and R ^21b are independently hydrogen, substituted or unsubstituted alkyl; and R ^21c is independently hydrogen, substituted or unsubstituted heteroaryl selected from the group consisting of substituted or unsubstituted imidazolyl, pyrazolyl, 1,2,3- triazolyl, l,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, quinolonyl, isoquinolonyl, dihydroquinolonyl, and dihydroisoquinolonyl; and

n is 0, 1, 2, or 3.

[0149] In some embodiments, R ^21a and R ^21b are independently hydrogen and; and R ^21c is hydrogen, substituted or unsubstituted heteroaryl selected from the group consisting of substituted or unsubstituted imidazolyl, pyrazolyl, l,2,3-triazolyl, l,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl; and

n is 0, 1, 2, or 3.

[0150] In some embodiments, R ^21a and R ^21b are hydrogen; and R ^21c is hydrogen, substituted or unsubstituted heteroaryl selected from the group consisting of substituted or unsubstituted pyrazolyl, l,2,3-triazolyl, or tetrazolyl; and

n is 0, 1, 2, or 3.

[0151] In some embodiments, R ^21a and R ^21b are hydrogen; and R ^21c is: r hydrogen;

wherein each instance of R ^D is, independently, hydrogen, -CN, or methyl; and

n is 1

e is 1, or 2.

[0152] In some embodiments, R ^21a and R ^21b are hydrogen; and R ^21c is:

wherein each instance of R ^D is, independently, hydrogen, -CN, or methyl; and n is 1

e is 1, or 2.

[0153] In some embodiments, n is 0. In some embodiments, n is 1. In some other embodiments, n is 2.

[0154] In some embodiments, the compound of formula (I) is a compound of Formula (I-h):

or a pharmaceutically acceptable salt thereof;

wherein:

wherein each occurrence of R ^21a , R ^21b and R ^21c is independently hydrogen, -substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and

n is 0, 1, 2, or 3;

[0155] In some embodiments, the compound of formula (I) is a compound of Formula (I-i):

or a pharmaceutically acceptable salt thereof.

wherein: R ^21c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0156] In some embodiments, the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof. [0157] In some embodiments, R ^21c is:

wherein each instance of R ^D is, independently, hydrogen, halogen, -NO2, -CN, -OR ^GA , - N(R ^ga ) ₂ , -C(=0)R ^ga , -C(=0)OR ^ga , -OC(=0)R ^ga , -OC(=0)OR ^ga , -C(=0)N(R ^ga ) ₂ , - N(R ^GA )C(=0)R ^GA , -OC(=0)N(R ^ga ) ₂ , -N(R ^GA )C(=0)OR ^ga , -S(=0) ₂ R ^ga , -S(=0) ₂ OR ^ga , - OS(=0) ₂ R ^ga , -S(=0) ₂ N(R ^ga ) ₂ , or -N(R ^GA )S(=0) ₂ R ^ga ; substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C ₂ -6 alkenyl, substituted or unsubstituted C ₂ -6 alkynyl, substituted or unsubstituted C3-4 carbocylyl, substituted or unsubstituted 3- to 4- membered heterocylyl, or optionally two R ^GA are taken with the intervening atoms to form a substituted or unsubstituted 3- to 4- membered carbocyclic or heterocyclic ring;

wherein each instance of R ^GA is independently hydrogen, substituted or unsubstituted Ci- 6 alkyl, substituted or unsubstituted C ₂ -6 alkenyl, substituted or unsubstituted C ₂ -6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R ^GA groups are taken with the intervening atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring; and

e is 1, 2, 3, 4, or 5. [0158] In some embodiments, R ^21c is:

wherein each instance of R ^D is, independently, hydrogen, halogen, -N0 ₂ , -CN, -OR ^GA , -

N(R ^ga ) ₂ , -C(=0)R ^ga , -C(=0)0R ^ga , -0C(=0)R ^ga , -0C(=0)0R ^ga , -C(=0)N(R ^ga ) ₂ , - N(R ^GA )C(=0)R ^ga , -0C(=0)N(R ^ga ) ₂ , -N(R ^GA )C(=0)0R ^ga , -S(=0) ₂ R ^ga , -S(=0) ₂ 0R ^ga , - 0S(=0) ₂ R ^ga , -S(=0) ₂ N(R ^ga ) ₂ , or -N(R ^GA )S(=0) ₂ R ^ga ; substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C ₂ -6 alkenyl, substituted or unsubstituted C ₂ -6 alkynyl, substituted or unsubstituted C3-4 carbocylyl, substituted or unsubstituted 3- to 4- membered heterocylyl, or optionally two R ^GA are taken with the intervening atoms to form a substituted or unsubstituted 3- to 4- membered carbocyclic or heterocyclic ring;

wherein each instance of R ^GA is independently hydrogen, substituted or unsubstituted Ci- 6 alkyl, substituted or unsubstituted C ₂ -6 alkenyl, substituted or unsubstituted C ₂ -6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R ^GA groups are taken with the intervening atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring; and

e is 1, 2, 3, or 4.

[0159] In some embodiments, the compound of formula (I) is a compound of Formula (I-j 1):

or a pharmaceutically acceptable salt thereof,

wherein, each R ^E is independently hydrogen, halogen, alkyl, hydroxyl, or cyano

e is 0, 1, 2 or 3 [0160] In some embodiments, the compound of formula (I) is a compound of Formula (I-j2):

or a pharmaceutically acceptable salt thereof,

wherein, each R ^E is independently hydrogen, halogen, alkyl, hydroxyl, or cyano

e is 0, 1, 2 or 3.

[0161] In some embodiments, the compound of formula (I) is a compound of Formula (I-j2) or a pharmaceutically acceptable salt thereof, wherein R ^E is independently hydrogen, or cyano e is 0, 1, 2 or 3.

[0162] In some embodiments, the compound of formula (I) is a compound of Formula (I-kl):

-kl),

or a pharmaceutically acceptable salt thereof,

wherein, each R ^E is independently hydrogen, halogen, alkyl, hydroxyl, or cyano

e is 0, 1, 2.

[0163] In some embodiments, the compound of formula (I) is a compound of Formula (I-

or a pharmaceutically acceptable salt thereof, wherein, each R ^E is independently hydrogen, halogen, alkyl, hydroxyl, or cyano

e is 0, 1, 2.

[0164] In some embodiments, the compound of formula (I) is a compound of Formula (1-11) or (1-12):

or a pharmaceutically acceptable salt thereof,

wherein, each R ^E is independently hydrogen, halogen, alkyl, hydroxyl, or cyano

[0165] In some embodiments, the compound of formula (I) is a compound of Formula (1-12):

or a pharmaceutically acceptable salt thereof, wherein, each R ^E is independently hydrogen, halogen, alkyl, hydroxyl, or cyano.

[0166] In some embodiments, the compound of formula (I) is a compound of Formula (I- ml):

-ml),

or a pharmaceutically acceptable salt thereof,

wherein, each R ^E is independently hydrogen, halogen, alkyl, hydroxyl, or cyano

[0167] In some embodiments, the compound of formula (I) is a compound of Formula (I- m2):

or a pharmaceutically acceptable salt thereof,

wherein, each R ^E is independently hydrogen, halogen, alkyl, hydroxyl, or cyano [0168] In some embodiments, the compound of formula (I) is a compound of Formula (I- nl):

-nl),

or a pharmaceutically acceptable salt thereof,

wherein, each R ^E is independently hydrogen, halogen, alkyl, hydroxyl, or cyano e is 0, 1, 2

[0169] In some embodiments, the compound of formula (I) is a compound of Formula (I-

or a pharmaceutically acceptable salt thereof,

wherein, each R ^E is independently hydrogen, halogen, alkyl, hydroxyl, or cyano e is 0, 1, 2.

[0170] In some embodiments, the compound of formula (I) is a compound of Formula (I) is of Formula (I-o):

or a pharmaceutically acceptable salt thereof. [0171] In some embodiments, the compound of formula (I) is a compound of Formula (I) is of Formula (I-p)

or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the compound of formula (I) is a compound of Formula (I) is of Formula (I-q)

[0173] In some embodiments, the compound of formula (I) is a compound of Formula (I) is of Formula (I-r)

wherein m is 0, 1, 2 or 3;

p is 0, 1, or 3;

each R32 is independently halogen, alkyl, hydroxyl, or cyano;

or a pharmaceutically acceptable salt thereof. [0174] In some embodiments, the compound of Formula (I) is of Formula (Is)

wherein u is 0, 1, or 2; each X is independently -C(RN)-, -C(RN)2-, -0-, -S-, -N-, or N(RN)- wherein RN is independently hydrogen, substituted or unsubstituted Cl-6 alkyl, C(=0)RGA, - C(=0)ORGA, -C(=0)N(RGA)2, -S(=0)2RGA, or -S(=0)2N(RGA)2; and

each instance of RGA is independently hydrogen, substituted or unsubstituted Cl-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring;

or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the compound of Formula (I) is of Formula (I-t)

wherein each R35 is independently halogen, alkyl, hydroxyl, or cyano; and r is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof. [0176] In some embodiments, the compound of Formula (I) is of Formula (I-u)

wherein s is 0, 1, or 2; each X is independently -C(RN)-, -C(RN)2-, -0-, -S-, -N-, or N(RN)- wherein RN is independently hydrogen, substituted or unsubstituted Cl-6 alkyl, C(=0)RGA, - C(=0)ORGA, -C(=0)N(RGA)2, -S(=0)2RGA, or -S(=0)2N(RGA)2; and

each instance of RGA is independently hydrogen, substituted or unsubstituted Cl-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring;

or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, a pharmaceutical composition comprises a compound described herein or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0178] In some embodiments, a method of treating a CNS-related disorder in a subject in need thereof, comprises administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS- related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus. In some

embodiments, the CNS-related disorder is depression. In some embodiments, the CNS-related disorder is postpartum depression. In some embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0179] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 below:

Table 1





50

[0180] In one aspect, provided herein is a pharmaceutically acceptable salt of a compound described herein (e.g., a compound of Formula (I).

[0181] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g. , a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a prophylactically effective amount.

[0182] Compounds of the present invention as described herein, act, in certain embodiments, as GABA modulators, e.g., effecting the GABAA receptor in either a positive or negative manner. As modulators of the excitability of the central nervous system (CNS), as mediated by their ability to modulate GABAA receptor, such compounds are expected to have CNS-activity.

[0183] Thus, in another aspect, provided are methods of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention. In certain embodiments, CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, e.g., by continuous intravenous infusion.

[0184] Exemplary compounds of the invention may be synthesized from the following known starting materials using methods known to one skilled in the art or certain references, In one aspect, provided herein is a pharmaceutically acceptable salt of a compound described herein (e.g., a compound of Formula (I).

Alternative Embodiments

[0185] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be ² H (D or deuterium) or ³ H (T or tritium); carbon may be, for example, ¹³ C or ¹⁴ C; oxygen may be, for example, ¹⁸ 0; nitrogen may be, for example, ¹⁵ N, and the like. In other embodiments, a particular isotope (e.g., ³ H, ¹³ C, ¹⁴ C, ¹⁸ 0, or ¹⁵ N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.

Pharmaceutical Compositions

[0186] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a prophylactically effective amount.

[0187] In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0188] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0189] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0190] When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0191] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject’s life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

[0192] The pharmaceutical compositions of the present invention may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject’s body. Furthermore, in still yet other embodiments, the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.

[0193] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term“unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

[0194] With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

[0195] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0196] Injection dose levels range from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 5 g/day for a 40 to 80 kg human patient. [0197] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0198] Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.

[0199] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or

Formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0200] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0201] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, l7th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0202] The compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0203] The present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of the present invention. The acid which may be used to prepare the

pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i. e. , a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0204] In another aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as for intravenous (IV) administration.

[0205] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of

Pharmacy, 2 I ^st Edition (Lippincott Williams & Wilkins, 2005).

[0206] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be employed include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0207] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are a-, b- and g- cyclodextrins consisting of 6, 7 and 8 a-1 ,4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, substituted or unsubstituted methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether b-cyclodextrin, e.g., for example, sulfobutyl ether b-cyclodextrin, also known as CAPTISOL®. See, e.g., U.S. 5,376,645. In certain embodiments, the composition comprises hexapropyl^-cyclodextrin. In a more particular embodiment, the composition comprises hexapropyl^-cyclodextrin (10-50% in water).

[0208] The injectable composition can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0209] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient’s symptoms, and the like.

[0210] The compositions are presented in unit dosage forms to facilitate accurate dosing. The term“unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-fdled, pre-measured ampules or syringes of the liquid compositions. In such compositions, the compound is usually a minor component (from about 0.1% to about 50% by weight or preferably from about 1% to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0211] The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.

[0212] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 2l ^st ed., Lippincott Williams & Wilkins, 2005.

[0213] In one aspect, provided is a kit comprising a composition (e.g., a solid composition) comprising a compound of Formula (I).

Methods of Use and Treatment

[0214] In an aspect, compounds described herein, e.g., compounds of Formula (I) are envisioned to be useful as therapeutic agents for treating a CNS-related disorder (e.g., sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a convulsive disorder, epileptogenesis, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus) in a subject in need (e.g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome). Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and/or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders (e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], disorders of memory and/or cognition [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g, Alzheimer’s type dementia, Lewis body type dementia, vascular type dementia], movement disorders [e.g., Huntington’s disease, Parkinson’s disease], personality disorders [e.g., anti-social personality disorder, obsessive compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenetic causes of autism such as synaptophathy’s, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular diseases [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and/or withdrawal syndromes [e.g., addition to opiates, cocaine, and/or alcohol], and tinnitus.

[0215] In certain embodiments, CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder.

[0216] In an aspect, provided is a method of alleviating or preventing seizure activity in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention. In some embodiments, the method alleviates or prevents epileptogenesis. [0217] In yet another aspect, provided is a combination of a compound of the present invention and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.

[0218] In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the present invention to the subject.

[0219] In yet another aspect, provided is a method of treating or preventing stress or anxiety in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0220] In yet another aspect, provided is a method of alleviating or preventing insomnia in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0221] In yet another aspect, provided is a method of inducing sleep and maintaining substantially the level of REM sleep that is found in normal sleep, wherein substantial rebound insomnia is not induced, comprising administering an effective amount of a compound of the present invention.

[0222] In yet another aspect, provided is a method of alleviating or preventing premenstrual syndrome (PMS) or postnatal depression (PND) in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.

[0223] In yet another aspect, provided is a method of treating or preventing mood disorders in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention. In certain embodiments the mood disorder is depression.

[0224] In yet another aspect, provided is a method of cognition enhancement or treating memory disorder by administering to the subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the disorder is Alzheimer’s disease. In certain embodiments, the disorder is Rett syndrome.

[0225] In yet another aspect, provided is a method of treating attention disorders by administering to the subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the attention disorder is ADHD. [0226] In certain embodiments, the compound is administered to the subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

Neuroendocrine Disorders and Dysfunction

[0227] Provided herein are methods that can be used for treating neuroendocrine disorders and dysfunction. As used herein,“neuroendocrine disorder” or“neuroendocrine dysfunction” refers to a variety of conditions caused by imbalances in the body’s hormone production directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. Because the hypothalamus and the pituitary gland are two areas of the brain that regulate the production of hormones, damage to the hypothalamus or pituitary gland, e.g., by traumatic brain injury, may impact the production of hormones and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women’s health disorder or condition (e.g., a women’s health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women’s health disorder or condition is polycystic ovary syndrome.

[0228] Symptoms of neuroendocrine disorder include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, and somatic symptoms; including but not limited to fatigue, poor memory, anxiety, depression, weight gain or loss, emotional lability, lack of concentration, attention difficulties, loss of lipido, infertility, amenorrhea, loss of muscle mass, increased belly body fat, low blood pressure, reduced heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

Neurodegenerative Diseases and Disorders

[0229] The methods described herein can be used for treating neurodegenerative diseases and disorders. The term“neurodegenerative disease” includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer’s disease (including the associated symptoms of mild, moderate, or severe cognitive impairment);

amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e.g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug-induced or medication-induced Parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette’s syndrome; head trauma; hearing impairment and loss; Huntington’s disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesias and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson’s disease, postencephalitic parkinsonism, and progressively supranuclear palsy); muscular spasms and disorders associated with muscular spasticity or weakness including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballism, Huntington’s disease,

neuroacanthocytosis, Sydenham’s chorea, and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremor (such as rest tremor, postural tremor, and intention tremor) and dystonia (including axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic injury which follows cerebral stroke,

thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson’s disease; seizure; status epilecticus; stroke; tinnitus; tubular sclerosis, and viral infection induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder. Mood disorders

[0230] Also provided herein are methods for treating a mood disorder, for example clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cataonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior. In some embodiments, the method described herein provides therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremor (e.g., Parkinson’s Disease), women’s health disorders or conditions).

[0231] Clinical depression is also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental disorder characterized by pervasive and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression have trouble sleeping, lose weight, and generally feel agitated and irritable. Clinical depression affects how an individual feels, thinks, and behaves and may lead to a variety of emotional and physical problems. Individuals with clinical depression may have trouble doing day-to-day activities and make an individual feel as if life is not worth living.

[0232] Peripartum depression refers to depression in pregnancy. Symptoms include irritability, crying, feeling restless, trouble sleeping, extreme exhaustion (emotional and/or physical), changes in appetite, difficulty focusing, increased anxiety and/or worry, disconnected feeling from baby and/or fetus, and losing interest in formerly pleasurable activities.

[0233] Postnatal depression (PND) is also referred to as postpartum depression (PPD), and refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleeping and eating habits, reduced sexual desire, crying episodes, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e.g., a refractory depression as described herein).

[0234] In some embodiments, a subject having PND also experienced depression, or a symptom of depression during pregnancy. This depression is referred to herein as) perinatal depression. In an embodiment, a subject experiencing perinatal depression is at increased risk of experiencing PND.

[0235] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain or increased appetite. Patients suffering from AD also may have excessive sleep or somnolence (hypersomnia), a sensation of limb heaviness, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection. [0236] Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, failures to react to pleasurable stimuli, depressed mood more pronounced than that of grief or loss, excessive weight loss, or excessive guilt.

[0237] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, in particular of melancholic nature, where the individual experiences psychotic symptoms such as delusions and hallucinations.

[0238] Catatonic depression refers to major depression involving disturbances of motor behavior and other symptoms. An individual may become mute and stuporose, and either is immobile or exhibits purposeless or bizarre movements.

[0239] Seasonal affective disorder (SAD) refers to a type of seasonal depression wherein an individual has seasonal patterns of depressive episodes coming on in the fall or winter.

[0240] Dysthymia refers to a condition related to unipolar depression, where the same physical and cognitive problems are evident. They are not as severe and tend to last longer (e.g., at least 2 years).

[0241] Double depression refers to fairly depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major depression.

[0242] Depressive Personality Disorder (DPD) refers to a personality disorder with depressive features.

[0243] Recurrent Brief Depression (RBD) refers to a condition in which individuals have depressive episodes about once per month, each episode lasting 2 weeks or less and typically less than 2-3 days.

[0244] Minor depressive disorder or minor depression refers to a depression in which at least 2 symptoms are present for 2 weeks.

[0245] Bipolar disorder or manic depressive disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During periods of mania the individual may feel or act abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the consequences. The need for sleep is usually reduced. During periods of depression there may be crying, poor eye contact with others, and a negative outlook on life. The risk of suicide among those with the disorder is high at greater than 6% over 20 years, while self-harm occurs in 30-40%. Other mental health issues such as anxiety disorder and substance use disorder are commonly associated with bipolar disorder.

[0246] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress. [0247] Treatment-resistant depression refers to a condition where the individuals have been treated for depression, but the symptoms do not improve. For example, antidepressants or physchological counseling (psychotherapy) do not ease depression symptoms for individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve symptoms, but come back. Refractory depression occurs in patients suffering from depression who are resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and/or anxiolytic drugs, as well as non-pharmacological treatments (e.g., psychotherapy,

electroconvulsive therapy, vagus nerve stimulation and/or transcranial magnetic stimulation).

[0248] Post-surgical depression refers to feelings of depression that follow a surgical procedure (e.g., as a result of having to confront one’s mortality). For example, individuals may feel sadness or empty mood persistently, a loss of pleasure or interest in hobbies and activities normally enjoyed, or a persistent felling of worthlessness or hopelessness.

[0249] Mood disorder associated with conditions or disorders of women’s health refers to mood disorders (e.g., depression) associated with (e.g., resulting from) a condition or disorder of women’s health (e.g., as described herein).

[0250] Suicidality, suicidal ideation, suicidal behavior refers to the tendency of an individual to commit suicide. Suicidal ideation concerns thoughts about or an unusual preoccupation with suicide. The range of suicidal ideation varies greatly, from e.g., fleeting thoughts to extensive thoughts, detailed planning, role playing, incomplete attempts. Symptoms include talking about suicide, getting the means to commit suicide, withdrawing from social contact, being preoccupied with death, feeling trapped or hopeless about a situation, increasing use of alcohol or drugs, doing risky or self-destructive things, saying goodbye to people as if they won’t be seen again.

[0251] Symptoms of depression include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, sleeplessness, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, absence of positive thoughts or plans, excessive sleeping, overeating, appetite loss, insomnia, self-harm, thoughts of suicide, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary on a case to case basis. Symptoms of depression, and relief of the same, may be ascertained by a physician or psychologist (e.g., by a mental state examination).

[0252] In some embodiments, the method comprises monitoring a subject with a known depression scale, e.g., the Hamilton Depression (HAM-D) scale, the Clinical Global Impression- Improvement Scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS).

In some embodiments, a therapeutic effect can be determined by reduction in Hamilton

Depression (HAM-D) total score exhibited by the subject. Reduction in the HAM-D total score can happen within 4, 3, 2, or 1 days; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less.

The therapeutic effect can be assessed across a specified treatment period. For example, the therapeutic effect can be determined by a decrease from baseline in HAM-D total score after administering a compound described herein, e.g., a compound of Formula (I) (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or for life).

[0253] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the baseline HAM-D total score of the subject (i.e., prior to treatment with a compound described herein, e.g., a compound of Formula (I) is at least 24. In some embodiments, the baseline HAM-D total score of the subject is at least 18. In some embodiments, the baseline HAM-D total score of the subject is between and including 14 and 18. In some embodiments, the baseline HAM-D total score of the subject is between and including 19 and 22. In some embodiments, the HAM-D total score of the subject before treatment with a compound described herein, e.g. , a compound of Formula (I) is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the HAM-D total score of the subject after treatment with a compound described herein, e.g. , a compound of Formula (I) is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I) is less than 10, 7, 5, or 3. In some embodiments, the decrease in HAM-D total score is from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a HAM-D total score at about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with a compound described herein, e.g. , a compound of Formula (I). In some embodiments, the decrease in the baseline HAM-D total score to HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 fold). In some embodiments, the percentage decrease in the baseline HAM-D total score to HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I) is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as a decrease in the HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), relative to the baseline HAM-D total score (e.g., 12, 24, 48 hours after

administration; or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days, or more) is at least 10, 15, or 20 points.

[0254] In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder provides a therapeutic effect (e.g., as measured by reduction in Hamilton Depression Score (HAM-D)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the method of treating the depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant reduction in HAM-D total score) within the first or second day of the treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method of treating the depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant reduction in HAM-D total score) within less than or equal to 14 days since the beginning of the treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method of treating the depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant reduction in HAM-D total score) within less than or equal to 21 days since the beginning of the treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method of treating the depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g, as determined by a statistically significant reduction in HAM-D total score) within less than or equal to 28 days since the beginning of the treatment with a compound described herein, e.g. , a compound of Formula (I). In some embodiments, the therapeutic effect is a decrease from baseline in HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I) (e.g., treatment with a compound described herein, e.g., a compound of Formula (I), once a day for 14 days). In some embodiments, the HAM-D total score of the subject before treatment with a compound described herein, e.g., a compound of Formula (I), is at least 24. In some embodiments, the HAM-D total score of the subject before treatment with a compound described herein, e.g., a compound of Formula (I), is at least 18. In some embodiments, the HAM-D total score of the subject before treatment with a compound described herein, e.g., a compound of Formula (I) is between and including 14 and 18. In some embodiments, the decrease in HAM-D total score after treating the subject with a compound described herein, e.g., a compound of Formula (I), relative to the baseline HAM-D total score is at least 10. In some embodiments, the decrease in HAM-D total score after treating the subject with a compound described herein, e.g. , a compound of Formula (I), relative to the baseline HAM-D total score is at least 15 (e.g., at least 17). In some embodiments, the HAM-D total score associated with treating the subject with a compound described herein, e.g., a compound of Formula (I), is no more than a number ranging from 6 to 8. In some embodiments, the HAM-D total score associated with treating the subject with a compound described herein, e.g., a compound of Formula (I), is no more than 7.

[0255] In some embodiments, the method provides therapeutic effect (e.g., as measured by reduction in Clinical Global Impression-Improvement Scale (CGI)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS-disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating the depressive disorder, e.g., major depressive disorder provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease from baseline in CGI score at the end of a treatment period (e.g., 14 days after administration).

[0256] In some embodiments, the method provides therapeutic effect (e.g., as measured by reduction in Montgomery-Asberg Depression Rating Scale (MADRS)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS-disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating the depressive disorder, e.g., major depressive disorder provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease from baseline in MADRS score at the end of a treatment period (e.g., 14 days after administration).

[0257] A therapeutic effect for major depressive disorder can be determined by a reduction in Montgomery-Asberg Depression Rating Scale (MADRS) score exhibited by the subject. For example, the MADRS score can be reduced within 4, 3, 2, or 1 days; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire (regarding apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts) which psychiatrists use to measure the severity

of depressive episodes in patients with mood disorders.

[0258] In some embodiments, the method provides therapeutic effect (e.g., as measured by reduction in Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. In some embodiments, the therapeutic effect is an improvement measured by the EPDS.

[0259] In some embodiments, the method provides therapeutic effect (e.g., as measured by reduction in Generalized Anxiety Disorder 7-Item Scale (GAD-7)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less.

Anxiety Disorders

[0260] Provided herein are methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive compulsive disorder, phobia, post-traumatic stress disorder). Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0261] Generalized anxiety disorder is a common chronic disorder characterized by long- lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.

[0262] In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).

[0263] Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.

[0264] The single largest category of anxiety disorders is that of phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.

[0265] Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.

Women’s Health Disorders

[0266] Provided herein are methods for treating conditions or disorders related to women’s health. Conditions or disorders related to women’s health include, but are not limited to, gynecological health and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy issues (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and issues related to women’s overall health and wellness (e.g., menopause).

[0267] Gynecological health and disorders affecting women include menstruation and menstrual irregularities; urinary tract health, including urinary incontinence and pelvic floor disorders; and such disorders as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

[0268] Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur in the one to two weeks before a women’s period. Symptoms vary but can include bleeding, mood swings, tender breasts, food cravings, fatigue, irritability, acne, and depression.

[0269] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. The symptoms of PMDD are similar to PMS but more severe and may interfere with work, social activity, and relationships. PMDD symptoms include mood swings, depressed mood or feelings of hopelessness, marked anger, increased interpersonal conflicts, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, change in appetite, feeling out of control or overwhelmed, sleep problems, physical problems (e.g., bloating, breast tenderness, swelling, headaches, joint or muscle pain).

[0270] Pregnancy issues include preconception care and prenatal care, pregnancy loss (miscarriage and stillbirth), preterm labor and premature birth, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

[0271] Miscarriage refers to a pregnancy that ends on its own, within the first 20 weeks of gestation.

[0272] Abortion refers to the deliberate termination of a pregnancy, which can be performed during the first 28 weeks of pregnancy.

[0273] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency.

[0274] Polycystic ovary syndrome (PCOS) refers to an endocrine system disorder among women of reproductive age. PCOS is a set of symptoms resulting from an elevated male hormone in women. Most women with PCOS grow many small cysts on their ovaries.

Symptoms of PCOS include irregular or no menstrual periods, heavy periods, excess body and facial hair, acne, pelvic pain, difficulty getting pregnant, and patches of thick, darker, velvety skin. PCOS may be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0275] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancers.

[0276] Issues related to women’s overall health and wellness include violence against women, women with disabilities and their unique challenges, osteoporosis and bone health, and menopause.

[0277] Menopause refers to the 12 months after a woman’s last menstrual period and marks the end of menstrual cycles. Menopause typically occurs in a woman’s 40s or 50s. Physical symptoms such as hot flashes and emotional symptoms of menopause may disrupt sleep, lower energy, or trigger anxiety or feelings of sadness or loss. Menopause includes natural menopause and surgical menopause, which is a type of induced menopause due to an event such as surgery (e.g., hysterectomy, oophorectomy; cancer). It is induced when the ovaries are gravely damaged by, e.g., radiation, chemotherapy, or other medications.

Epilepsy

[0278] The compound of Formula (I), or pharmaceutically acceptable salt, or a

pharmaceutically acceptable composition thereof, can be used in a method described herein, for example in the treatment of a disorder described herein such as epilepsy, status epilepticus, or seizure.

[0279] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

Epileptogenesis

[0280] The compounds and methods described herein can be used to treat or prevent epileptogenesis. Epileptogenesis is a gradual process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptogenesis results from neuronal damage precipitated by the initial insult (e.g., status epilepticus).

Status epilepticus (SE)

[0281] Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.

[0282] Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non- convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non- convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0283] The compound of Formula (I) or pharmaceutically acceptable salt, or a

pharmaceutically acceptable composition thereof, can also be administered as a prophylactic to a subject having a CNS disorder e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; prior to the onset of a seizure.

Seizure

[0284] A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term“seizure” is often used interchangeably with“convulsion.” Convulsions are when a person’s body shakes rapidly and uncontrollably. During convulsions, the person’s muscles contract and relax repeatedly.

[0285] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.

[0286] Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

[0287] There are six types of generalized seizures. The most common and dramatic, and therefore the most well-known, is the generalized convulsion, also called the grand-mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the "tonic" phase of the seizure) for 30 to 60 seconds, then by violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the "postictal" or after-seizure phase). During grand- mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.

[0288] Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of "losing time."

[0289] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.

[0290] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time. [0291] Tonic seizures are characterized by stiffening of the muscles.

[0292] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

[0293] Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures;

infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizure is a generalized seizure associated with Dravet Syndrome, Lennox- Gastaut Syndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 Female Pediatric Epilepsy.

Movement Disorders

[0294] Also described herein are methods for treating a movement disorder. As used herein, “movement disorders” refers to a variety of diseases and disorders that are associated with hyperkinetic movement disorders and related abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson’s disease and parkinsonism (defined particularly by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.

Tremor

[0295] The methods described herein can be used to treat tremor, for example the compound of Formula (I) can be used to treat cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, or rubral tremor. Tremor includes hereditary, degenerative, and idiopathic disorders such as Wilson’s disease, Parkinson’s disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid-, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese, arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiologic tremor, enhanced physiologic tremor, essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes’ tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug- induced tremor, and psychogenic tremor.

[0296] Tremor is an involuntary, at times rhythmic, muscle contraction and relaxation that can involve oscillations or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk, legs).

[0297] Cerebellar tremor or intention tremor is a slow, broad tremor of the extremities that occurs after a purposeful movement. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from, e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inherited degenerative disorder).

[0298] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and/or painful and abnormal postures or positions. Dystonic tremor may affect any muscle in the body. Dystonic tremors occurs irregularly and often can be relieved by complete rest.

[0299] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor may be mild and nonprogressive in some, and may be slowly progressive, starting on one side of the body but affect both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. Tremor frequency may decrease as the person ages, but severity may increase. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and/or increase their severity. Symptoms generally evolve over time and can be both visible and persistent following onset.

[0300] Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz) rhythmic muscle contractions that occurs in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs and the patient may shake uncontrollably when asked to stand in one spot. Orthostatic tremor may occurs in patients with essential tremor.

[0301] Parkinsonian tremor is caused by damage to structures within the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson’s disease and is typically seen as a“pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk. Onset of parkinsonian tremor typically begins after age 60. Movement starts in one limb or on one side of the body and can progress to include the other side. [0302] Physiological tremor can occur in normal individuals and have no clinical significance. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. The tremor classically has a frequency of about 10 Hz.

[0303] Psychogenic tremor or hysterical tremor can occur at rest or during postural or kinetic movement. Patient with psychogenic tremor may have a conversion disorder or another psychiatric disease.

[0304] Rubral tremor is characterized by coarse slow tremor which can be present at rest, at posture, and with intention. The tremor is associated with conditions that affect the red nucleus in the midbrain, classical unusual strokes.

[0305] Parkinson’s Disease affects nerve cells in the brain that produce dopamine.

Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms found in Parkinson’s Disease, but is a symptom complex rather than a progressive neurodegenerative disease.

[0306] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures. Dystonic movements can be patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.

[0307] Chorea is a neurological disorder characterized by jerky involuntary movements typically affecting the shoulders, hips, and face. Huntington’s Disease is an inherited disease that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington’s disease can hinder walk, talk, and swallowing.

[0308] Ataxia refers to the loss of full control of bodily movements, and may affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0309] Myloclonus and Startle is a response to a sudden and unexpected stimulus, which can be acoustic, tactile, visual, or vestibular.

[0310] Tics are an involuntary movement usually onset suddenly, brief, repetitive, but non- rhythmical, typically imitating normal behavior and often occurring out of a background of normal activity. Tics can be classified as motor or vocal, motor tics associated with movements while vocal tics associated with sound. Tics can be characterized as simple or complex. For example simple motor tics involve only a few muscles restricted to a specific body part.

Tourette Syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic. [0311] Restless Legs Syndrome is a neurologic sensorimotor disorder characterized by an overwhelming urge to move the legs when at rest.

[0312] Stiff Person Syndrome is a progressive movement disorder characterized by involuntary painful spasms and rigidity of muscles, usually involving the lower back and legs. Stiff-legged gait with exaggerated lumbar hyperlordosis typically results. Characteristic abnormality on EMG recordings with continuous motor unit activity of the paraspinal axial muscles is typically observed. Variants include“stiff-limb syndrome” producing focal stiffness typically affecting distal legs and feet.

[0313] Gait disorders refer to an abnormality in the manner or style of walking, which results from neuromuscular, arthritic, or other body changes. Gait is classified according to the system responsible for abnormal locomotion, and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

Anesthesia / Sedation

[0314] Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug which alone provides the correct combination of effects, or occasionally with a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achieve very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience.

[0315] Sedation is the reduction of irritability or agitation by administration of a pharmacological agent, generally to facilitate a medical procedure or diagnostic procedure.

[0316] Sedation and analgesia include a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[0317] Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are typically unaffected.

[0318] Moderate sedation/analgesia (conscious sedation) is a drug-induced depression of consciousness during which the patient responds purposefully to verbal command, either alone or accompanied by light tactile stimulation. No interventions are usually necessary to maintain a patent airway. Spontaneous ventilation is typically adequate. Cardiovascular function is usually maintained. [0319] Deep sedation/analgesia is a drug-induced depression of consciousness during which the patient cannot be easily aroused, but responds purposefully (not a reflex withdrawal from a painful stimulus) following repeated or painful stimulation. Independent ventilatory function may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

[0320] General anesthesia is a drug-induced loss of consciousness during which the patient is not arousable, even to painful stimuli. The ability to maintain independent ventilatory function is often impaired and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

[0321] Sedation in the intensive care unit (ICU) allows the depression of patients' awareness of the environment and reduction of their response to external stimulation. It can play a role in the care of the critically ill patient, and encompasses a wide spectrum of symptom control that will vary between patients, and among individuals throughout the course of their illnesses.

Heavy sedation in critical care has been used to facilitate endotracheal tube tolerance and ventilator synchronization, often with neuromuscular blocking agents.

[0322] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for a prolonged period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1 month, 2 months). Long-term sedation agents may have long duration of action. Sedation agents in the ICU may have short elimination half-life.

[0323] Procedural sedation and analgesia, also referred to as conscious sedation, is a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows a subject to tolerate unpleasant procedures while maintaining cardiorespiratory function.

Examples

[0324] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Materials and Methods

[0325] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. , reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0326] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0327] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the preparation of representative oxysterols that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

Exemplary chiral columns available for use in the separation/purification of the

enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD- 10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

[0328] ¹ H-NMR reported herein (e.g., for the region between d (ppm) of about 0.5 to about 4 ppm) will be understood to be an exemplary interpretation of the NMR spectrum (e.g., exemplary peak integratations) of a compound. Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 pm C18, 19*250 mm. Mobile phase: acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3.H2O). Flow rate: 25 mL/min.

[0329] Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 □m Cl 8, 19*250 mm. Mobile phase: acetonitrile, water (NH4HCO3) (30 L water, 24 g

NH4HCO3, 30 mL NH3.H2O). Flow rate: 25 mL/min.

[0330] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min Flow rate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50mm, 3.5 Dm at 45 C. [0331] Exemplary general method for prep HPLC (Column: Waters Xbridge 150*25 5u; Condition: water (lOmM NHrHCCLj-ACN; Begin B: 60; End B: 80; Gradient Time(min):7; 100%B Hold Time(min): 2)

[0332] Exemplary general method for prep HPLC (Column: Waters Xbridge 150*25 5u; Condition: water (lOmM NHrHCCLj-ACN; Begin B: 55; End B: 75; Gradient Time(min):7; 100%B Hold Time(min): 2)

[0333] Exemplary general method for prep HPLC (Instrument: AE; Column: Xtimate Cl 8 l50*25mm*5 Dm; Condition: water (0.225%FA)-ACN; Begin B: 58; End B: 78; Gradient Time (min): 7; 100%B Hold Time (min): 3; FlowRate (mL/min): 25; Injections: 7)

[0334] Exemplary general method for SFC: Column: CHIRALPAK® AD CSP (250 mm * 30 mm, 10 pm), Gradient: 45% B, A= NH3H2O, B= MeOH, flow rate: 60 mL/min. For example, AD_3_EtOH_DEA_5_40_25ML would indicate: "Column: Chiralpak AD-3

150x4.6mm I.D., 3um Mobile phase: A: C02 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5mL/min Column temp: 35°C".

[0335] LC-ELSD/MS: Mobile Phase: l .5mL/4L TFA in water (solvent A) and 0.75mL/4L TFA in acetonitrile (solvent B), using the elution gradient 30%-90% (solvent B) over 0.9 minutes and holding at 90% for 0.6 minutes at a flow rate of 1.2 mL/min; Column: Xtimate C18 2. l*30mm, 3 Dm; Wavelength: UV 220 nm; Column temperature: 50°C; MS ionization: ESI; Detector: PDA & ELSD.

Abbreviations:

[0336] PE: petroleum ether; EtOAc: ethyl acetate; THF: tetrahydrofuran; DCM:

dichloromethane; MTBE: methyl tert-butyl ether; 9-BBN: 9-borabicyclo[3.3. l]nonane; BHT: 2,6-di-tert-butyl-4-methylphenol; DMP: Dess-Martin periodinane; LDA: lithium

diisopropylamide; MAD: methyl aluminum bis(2,6-di-t-butyl-4-methylphenoxide); NBS: N- bromosuccinimide .

EXAMPLE 1: Synthesis of l-((3R,5S,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl- 2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-lH-cyclope nta[a]phenanthren-17- yl)ethan-l-one (A5)

Synthesis of A2

A suspension of LiCl (1.23 g, 29.1 mmol, anhydrous) in THF (200 mL, anhydrous) was stirred at l0°C for 30 min under N2 followed by FeCb (2.46g, 15.2 mmol, anhydrous). The mixture was cooled to -30°C and MeMgBr (18.5 mL, 3M in THF) was added dropwise. After stirring at - 30°C for 30 min, A1 (4 g, 13.9 mmol, CAS# 15375-19-6) was added. After stirring at -l5°C for 2 h, citric acid (500 mL, 10% aq.) was added and the mixture was extracted with EtOAc (2 x 300 mL). The combined organic solution was washed with brine (2 x 300 mL), dried over NaiSOr. filtered, concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 0% to 10%) to give A2 (3.27 g,) as a solid.

Ή NMR (400 MHz, CDCb) 5H 5.39 (d, J= 5.6 Hz, 1H), 2.53-2.38 (m, 1H), 2.29-1.92 (m, 6H),

1.75-1.59 (m, 3H), 1.55-1.47 (m, 3H), 1.44-1.30 (m, 4H), 1.28-1.18 (m, 4H), 1.14-1.02 (m, 1H),

0.91 (s, 3H), 0.82 (s, 3H); LC-ELSD/MS: purity 99%, MS ESI calcd. for C20H29O1 [M- H2O+HG 285.2, found 285.2.

Synthesis of A3

To a mixture of EtPPhiBr (11.6 g, 31.5 mmol) in THF (200 mL) was added t-BuOK (3.53 g,

31.5 mmol) at l5°C under N2. After stirring at 50°C for 1 h, A2 (3.2 g, 10.5 mmol) was added in portions below 40°C. After stirring at 30°C for 3 h, the reaction mixture was quenched with saturated NH4CI aqueous (20 mL) at 0°C and extracted with EtOAc (2 X 100 mL). The combined organic solution was concentrated under vacuum to give an oil, which was purified by trituration with MeOH/H20 (1 : 1, 140 mL) to give A3 (3.5 g) as a solid. The solid (3.5g) was purified by flash column (0~2% of EtOAc in PE) to give A2 (2.97 g) as a solid.

¾ NMR (400 MHz, CDCb) 5H 5.35 (d, J=5.8 Hz, 1H), 5.24-5.11 (m, 1H), 2.49-2.18 (m, 4H), 2.14-2.05 (m, 1H), 1.99-1.90 (m, 1H), 1.79-1.66 (m, 2H), 1.66-1.64 (m, 3H), 1.63-1.56 (m, 3H), 1.53-1.49 (m, 1H), 1.46-1.24 (m, 7H), 1.22 (s, 3H), 1.12-0.95 (m, 1H), 0.89 (s, 3H), 0.81 (s, 3H). Synthesis of A4

To a solution of A3 (2.7 g, 8.58 mmol) in THF (30 mL) was added 9-BBN dimer (4. l7g, 17.1 mmol). The mixture was stirred at 40°C for 12 h and then cooled to l5°C. Ethanol (20 mL) was added, the reaction cooled to 0°C and NaOH aqueous (17.1 mL, 5.0 M, 85.8 mmol) and then hydrogen peroxide (8.58 mL, 10 M, 85.8 mmol) were added dropwise. After stirring at 78°C for 1 h, the mixture was cooled to l5°C and water (200 mL) was added. The resulting solid was filtered, dissolved in DCM (300 mL), washed with saturated aqueous NaiSiOi. filtered and evaporated to give A4 (2.8 g impure) as a solid.

Ή NMR (400 MHz, CDCb) 5H 5.30 (d, J= 5.6 Hz, 1H), 3.78-3.62 (m, 1H), 2.14-1.79 (m, 6H), 1.70-1.58 (m, 3H), 1.54-1.47 (m, 2H), 1.45-1.25 (m, 8H), 1.24-1.13 (m, 7H), 1.07-0.94 (m, 1H), 0.88 (s, 3H), 0.59 (s, 3H)

Synthesis of A5

To a solution of A4 (2.8 g, 8.42 mmol) in DCM (30 mL) was added silica gel (4 g) and PCC (3.59 g, 16.8 mmol) at 20°C. After stirring at 20 °C for 3h, the resulting mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography eluting with (petroleum ether/ethyl acetate = 5/1) to give A5 (1.82 g) as a solid.

Ή NMR (400 MHz, CDCb) 5H 5.44-5.29 (m, 1H), 2.59 (t, J=9A Hz, 1H), 2.34-2.15 (m, 3H), 2.13 (s, 3H), 2.08-1.96 (m, 1H), 1.94-1.78 (m, 2H), 1.75-1.61 (m, 3H), 1.55-1.45 (m, 2H), 1.43- 1.24 (m, 6H), 1.23-1.20 (m, 4H), 1.09-0.94 (m, 1H), 0.88 (s, 3H), 0.54 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for C22H ₃₃ O1 [M-H ₂ 0+H] ⁺ 313.3, found 313.3. %de >99 (by 1H NMR ) EXAMPLE 2 & 3 Synthesis of l-(2-((3R,5S,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13- trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro- lH-cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl)-lH-pyrazole-4-carbonitrile (A7) & l-(2-((3R,5S,8S,10S,13S,14S,17R)-3- hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17 -tetradecahydro-lH- cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-lH-pyrazole-4-ca rbonitrile (A8)

To a solution of A5 (800 mg, 2.42 mmol) in MeOH (20 mL) was added HBr (97.7mg, 0.48 mmol, 40% in water) and Bn (405 mg, 2.54 mmol) at 20°C. After stirring at 20°C for 12 h, the mixture was quenched by sat.aq NaHC03 (10 mL), treated with water (20 mL), extracted with EtOAc (2 x 30 mL). The combined organic solution was washed with brine (30 mL), dried over anhydrous Na2S04, filtered, concentrated to afford A6 (950 mg, crude) as a solid used directly for the next step.

Synthesis of A7 & A8

To a solution of A6 (300 mg, crude) in acetone (5 mL) were added lH-pyrazole-4-carbonitrile (68.2 mg, 0.7327 mmol), KICO3(302 mg, 2.19 mmol). After stirring at 25°C for 12 h, water (20 mL) was added and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic solution was separated, dried over NaiSOr. filtered and concentrated. The residue was purified by prep-HPLC to give A7 (65 mg) and A8 (5 mg) as solids. A7 (65 mg) was triturated from n- hexane (10 mL) at 20°C to give A7 (46 mg) as a solid. A7: Ή NMR (400 MHz, CDCb) d _H 7.86 (s, 1H), 7.81 (s, 1H), 5.42-5.30 (m, 1H), 5.12-4.79 (m, 2H), 2.67 (t, J=93 Hz, 1H), 2.35-2.18 (m, 3H), 2.12-1.99 (m, 1H), 1.98-1.83 (m, 2H), 1.83-1.59 (m, 4H), 1.51-1.25 (m, 7H), 1.22 (s, 3H), 1.18 (s, 1H), 1.08-0.97 (m, 1H), 0.89 (s, 3H), 0.60 (s, 3H); LC-ELSD/MS purity 99%;; MS ESI calcd. for C26H36N3O2 [M +H] ⁺ 422.3, found 422.3. %de >99 (by 1H NMR )

A8: Ή NMR (400 MHz, CDCb) d _H 7.86 (s, 1H), 7.82 (s, 1H), 5.35 (s, 1H), 5.15-4.79 (m, 2H), 2.83 (d, =8.4 Hz, 1H), 2.10-1.85 (m, 7H), 1.69-1.62 (m, 2H), 1.54-1.26 (m, 9H), 1.21 (s, 2H), 1.23-1.18 (m, 1H), 1.15-1.03 (m, 1H), 0.88 (s, 3H), 0.87 (s, 3H); LC-ELSD/MS purity 99%;; MS ESI calcd. for C26H34N3 O 1 [M-H ₂ 0+H] ⁺ 404.2, found 404.2. %de >99 (by 1H NMR )

EXAMPLE 4 & 5: Synthesis of l-((3R,5S,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13- trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro- lH-cyclopenta[a]phenanthren- 17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-l-one (A9) & l-((3R,5S,8S,10S,13S,14S,17S)-3- hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17 -tetradecahydro-lH- cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-lH-tetrazol-l-yl )ethan-l-one (A10)

To a solution of A6 (220 mg, crude) in THF (5 mL) was added 5-methyl-lH-l,2,3,4-tetrazole (54.2 mg, 0.65 mmol), K2CO3 (222 mg, 1.61 mmol). After stirring at 25°C for 12 h, the mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over NaiSO . filtered and concentrated. The residue was purified by flash column

(10-60% of EtOAc in PE) to give A9 (20 mg) and A10 (22 mg) as solids.

A9: Ή NMR (400 MHz, CDCb) d _H 5.36 (s, 3H), 2.70 (t, J=93 Hz, 1H), 2.56 (s, 3H), 2.35-2.20 (m, 3H), 2.13-2.01 (m, 1H), 1.96-1.58 (m, 6H), 1.54-1.27 (m, 8H), 1.22 (s, 3H), 1.11-0.97 (m, 1H), 0.89 (s, 3H), 0.65 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for C24H37N4O2 [M +H] ⁺ 413.3, found 413.3.

A10: ¾ NMR (400 MHz, CDCb) d 5.43-5.35 (m, 1H), 5.25-4.90 (m, 2H), 2.73 (t, J= 9.2 Hz, 1H), 2.48 (s, 3H), 2.37-2.23 (m, 3H), 2.11-2.01 (m, 1H), 1.96-1.62 (m, 6H), 1.49-1.26 (m, 9H), 1.23 (s, 3H), 0.89 (s, 3H), 0.62 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for

C24H37N4O2 [M +H] ⁺ 413.3, found 413.3. EXAMPLE 6 & 7: Synthesis of l-((3R,5S,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13- trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro- lH-cyclopenta[a]phenanthren- 17-yl)-2-(lH-l,2,3-triazol-l-yl)ethan-l-one (All) & l-((3R,5S,8S,10S,13S,14S,17S)-3- hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17 -tetradecahydro-lH- cyclopenta[a]phenanthren-17-yl)-2-(2H-l,2,3-triazol-2-yl)eth an-l-one (A12)

To a solution of A6 (350 mg, crude) in THF (5 mL) were added 1H-1, 2, 3-triazole (70.4 mg, 1.02 mmol), K2CO3 (353 mg, 2.56 mmol). After stirring at 25°C for 12 h, water (40 mL) was added and the mixture extracted with EtOAc (2 x 50 mL). The combined organic solution was dried over Na2SC>4, filtered and concentrated. The residue was purified by prep-HPLCto give All (34 mg) and A12 (27 mg) both as solids. Regioisomers assigned based on Ή NMR of triazole protons.

All: ¾ NMR (400 MHz, CDCb) 5H 7.76 (d, .7=0.8 Hz, 1H), 7.65 (d, .7=0.8 Hz, 1H), 5.40-5.36 (m, 1H), 5.32-5.11 (m, 2H), 2.72 (t, .7=9.3 Hz, 1H), 2.36-2.21 (m, .7=2.5 Hz, 3H), 2.08-2.00 (m, 1H), 1.97-1.85 (m, 2H), 1.84-1.60 (m, 4H), 1.53-1.27 (m, 8H), 1.22 (s, 3H), 1.08-0.98 (m, 1H), 0.89 (s, 3H), 0.61 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for C24H36N3O2 [M +H] ⁺ 398.3, found 398.3. %de >99 (by LC-ELSD/MS )

A12: ¾ NMR (400 MHz, CDCb) 5H 7.68 (s, 2H), 5.40-5.34 (m, 1H), 5.25 (d, J= 2.8 Hz, 2H), 2.65 (t, .7=9.3 Hz, 1H), 2.38-2.19 (m, 3H), 2.12-1.98 (m, 1H), 2.12-1.98 (m, 1H), 1.96-1.82 (m, 2H), 1.81-1.62 (m, 3H), 1.53-1.26 (m, 8H), 1.22 (s, 3H), 1.09-0.96 (m, 1H), 0.89 (s, 3H), 0.65 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for C24H36N3O2 [M +H] ⁺ 398.3, found 398.3. %de >99 (by LC-ELSD/MS )

EXAMPLE 8: Synthesis of l-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl- 2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-lH-cyclope nta[a]phenanthren-17-

Synthesis of A 14

To a solution of BHT (8 g, 36.3 mmol) in toluene (17.4 mL) under nitrogen at 0°C was added AlMe3 (2 M in toluene, 9.05 mL, 18.1 mmol) dropwise. After stirring 25°C for 1 h, the above solution as MAD solution was added a solution of A13 (3.5 g, 12.2 mmol, CAS# 1093397-63-7) in DCM (26.3 mL) dropwise at -70°C. After stirring at -70°C for 1 h under N2, MeMgBr (10.1 mL, 30.5 mmol, 3M in ethyl ether) was added dropwise. After stirring at -70°C for another 2 h, the reaction mixture was poured into saturated aqueous citric acid (200 mL) at below l0°C and extracted with EtOAc (2 x 50 mL). The combined organic solution was dried over NaiSCri, filtered and concentrated in vacuum. The residue was purified by flash column (0-30% of EtOAc in PE) to give A14 (2 g, 54.3%) as an oil.

Ή NMR (400 MHz, CDCb) 5H 5.44 (d, J= 5.6 Hz, 1H), 2.52-2.40 (m, 1H), 2.25-2.09 (m, 3H), 2.08-1.93 (m, 4H), 1.79-1.58 (m, 3H), 1.55-1.49 (m, 2H), 1.48-1.42 (m, 1H), 1.41-1.27 (m, 3H), 1.26 (s, 3H), 1.25-1.18 (m, 2H), 1.10 (s, 3H), 0.82 (s, 3H); LC-ELSD/MS purity 99.5%, MS ESI calcd. for C20H29O1 [M-H ₂ 0+H] ⁺ 285.2, found 285.2.

Synthesis of A15

To a mixture of EtPPhsBr (12.2 g, 33.0 mmol) in THF (50 mL) was added t-BuOK (3.7 g, 33.0 mmol) at 20°C under N2. After stirring at 50°C for 30 min. A14 (3.35 g, 11 mmol) was added in portions below 40°C. After stirring at 40°C for 3 h, the reaction mixture was quenched with saturated NH4CI aqueous (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic solution was concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give A15 (1.8 g, 52.1%) as an oil.

Ή NMR (400 MHz, CDCb) 5H 5.41-5.39 (m, 1H), 5.25-5.15 (m, 1H), 2.45-2.35 (m, 3H), 2.30- 2.15 (m, 1H), 2.05-1.95 (m, 5H), 1.75-1.50 (m, 10H), 1.45-1.15 (m, 7H), 1.08 (s, 3H), 0.79 (s, 3H). Synthesis of A16

A solution of A15 (1.8 g, 5.72 mmol) in THF (10 mL) was added 9-BBN dimer (2.78 g, 11.4 mmol). After stirring at 30°C for 2 h, ethanol (10 mL) at l5°C, followed by NaOH aqueous (11.4 mL, 5.0 M, 57.2 mmol) at 0°C and then hydrogen peroxide (5.72 mL, 10 M, 57.2 mmol) were added dropwise. After stirring at 50°C for 1 h, the mixture was cooled to l5°C, water (100 mL) was added and the resulting solid filtered. The solid was dissolved in THF (80 mL), washed with saturated aqueous NaiSiOi. filtered and concentrated in vacuum. The residue was purified by flash column (0-25% of EtOAc in PE) to give A16 (1.25 g, 65.7%) as a solid.

Ή NMR (400 MHz, CDCb) 5H 5.35-5.30 (m, 1H), 3.75-3.65 (m, 1H), 2.05-1.85 (m, 6H), 1.80- 1.50 (m, 6H), 1.45-1.35 (m, 3H), 1.35-1.15 (m, 13H), 1.07 (s, 3H), 0.57(s, 3H).

Synthesis of A17

To a solution of A16 (100 mg, 0.3 mmol) in DCM (5 mL) was added DMP (254 mg, 0.6 mmol) at 25°C. After stirring at 25°C for 0.5 h, the mixture was quenched with saturated NaHCCb (80 mL) and saturated NaiSiCh (80 mL) and extracted with DCM (2 x 80 mL). The organic solution was dried over NaiSCri, filtered, concentrated. The residue was purified by flash column (5-30% of EtOAc in PE) to give A17 (60 mg, 60.4%) as a solid.

*H NMR (400 MHz, CDCb) 5H 5.40 (br d, J= 5.6 Hz, 1H), 2.59 (t, J= 9.2 Hz, 1H), 2.37-2.30 (m, 1H), 2.24-2.14 (m, 2H), 2.13 (s, 3H), 2.05-1.92 (m, 3H), 1.86-1.76 (m, 1H), 1.75-1.59 (m, 4H), 1.56-1.49 (m, 1H), 1.47-1.34 (m, 3H), 1.33-1.15 (m, 8H), 1.07 (s, 3H), 0.52 (s, 3H); LC- ELSD/MS purity 99%, MS ESI calcd. for C22H33O1 [M-H ₂ 0+H] ⁺ 313.2, found 313.2. EXAMPLE 9: Synthesis of l-(2-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl - 2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-lH-cyclope nta[a]phenanthren-17-yl)-2- oxoethyl)-lH-pyrazole-4-carbonitrile (A19)

To a solution of A17 (100 mg, 0.3 mmol) in MeOH (2 mL) were added HBr (12.2 mg, 0.06 mmol, 40% in water) and Bn (48.3 mg, 0.3 mmol) at 25°C. After stirring at 25°C for 4 h, the mixture was quenched by saturated aqueous NaHC03 (10 mL), treated with water (20 mL), and extracted with EtOAc (2 x 30 mL). The combined organic solution was washed with brine (30 mL), dried over anhydrous Na2S04, filtered, concentrated to afford A18 (130 mg) as a solid used directly for the next step.

Ή NMR (400 MHz, CDCb) 5H 5.39 (br d, J= 5.6 Hz, 1H), 3.97-3.87 (m, 2H), 2.89 (t, J= 9.2 Hz, 1H), 2.38-2.30 (m, 1H), 2.27-2.15 (m, 2H), 2.03- 1.95 (m, 3H), 1.88-1.58 (m, 5H),

1.52- 1.39 (m, 4H), 1.33-1.18 (m, 8H), 1.07 (s, 3H), 0.55 (s, 3H).

Synthesis of A19

To a solution of A18 (130 mg, crude) in acetone (2 mL) were added l//-pyrazole-4-carbonitrile (35.4 mg, 0.38 mmol) and K ₂ C03(l3 l mg, 0.95 mmol). After stirring at 25°C for 12 h, the mixture was added water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic solution was dried over NaiSCri. filtered and concentrated. The residue was purified by flash column (10-50% of EtOAc in PE) to give A19 (40 mg, 30%) as an off solid.

*H NMR (400 MHz, CDCb) 5H 7.86 (s, 1H), 7.81 (s, 1H), 5.41 (br d, J= 5.6 Hz, 1H), 5.06-4.87 (m, 2H), 2.68 (t, J=9.2 Hz, 1H), 2.42-2.19 (m, 3H), 2.07-1.94 (m, 3H), 1.93-1.75 (m, 2H), 1.74- 1.59 (m, 3H), 1.52-1.41 (m, 3H), 1.37-1.16 (m, 9H), 1.08 (s, 3H), 0.58 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for C26H35N3O2 [M+l] ⁺ 421.3, found 422.3.

EXAMPLE 10 & 11 : Synthesis _O f l-((3R,5R,8S, l0S, l3S, l4S, l7S)-3-hydroxy-3, l0,l3- trimethyl-2,3,4,5,6,7,8, l0,l2,l3, l4, l5,l6,l7-tetradecahydro-lH-cyclopenta[a]phenanthren-l7- yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-l-one (A20) & l-((3R,5R,8S,l0S, l3S, l4S,l7S)-3- hydroxy-3,l0,l3-trimethyl-2,3,4,5,6,7,8, l0,l2,l3,l4, l5, l6,l7-tetradecahydro-lH- cyclopenta[a]phenanthren- 17 -yl)-2-(5-methyl- lH-tetrazol- 1 -yl)ethan- 1 -one (A21 ) .

To a solution of A18 (250 mg, crude) in THF (2 mL) were added 5-methyl- 1//- 1 2.3.4-tctrazolc (61.6 mg, 0.73 mmol) and K2CO3 (252 mg, 1.83 mmol). After stirring at 25°C for 12 h, the reaction was diluted with water (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic solution was separated, dried over NaiSO . filtered and concentrated. The residue was purified by flash column (10-80% of EtOAc in PE) to give A20 (50 mg, 19.9%) and A21 (44 mg, 17.5%) both as solids. A20 (50 mg, 0.12 mmol) was added CH3CN (2 mL) and H2O (25 mL) lyophilization to give A20 (45 mg, 90.1%) as a solid. Regioisomers assigned based on Ή NMR.

A20: ¾ NMR (400 MHz, CDCb) 5H 5.45-5.39 (m, 1H), 5.36 (s, 2H), 2.70 (t, J= 9.2 Hz, 1H), 2.57 (s, 3H), 2.40-2.19 (m, 3H), 2.06-1.96 (m, 3H), 1.92-1.60 (m, 5H), 1.52-1.42 (m, 3H), 1.38- 1.15 (m, 9H), 1.08 (s, 3H), 0.63 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for C24H35N4O1 [M-H2O+HG 395.2, found 395.2. %de >99 (by LC-ELSD/MS )

A21: ¾ NMR (400 MHz, CDCb) 5H 5.43 (br d, J= 5.2 Hz, 1H), 5.22-5.00 (m, 2H), 2.73 (t,

J= 9.2 Hz, 1H), 2.56-2.38 (m, 4H), 2.34-2.20 (m, 2H), 2.08-1.95 (m, 3H), 1.93-1.60 (m, 5H), 1.50-1.39 (m, 2H), 1.38-1.19 (m, 9H), 1.09 (s, 3H), 0.91-0.81 (m, 1H), 0.60 (s, 3H); LC- ELSD/MS purity 99%, MS ESI calcd. for C24H35N4O1 [MTEO+Hf 395.2, found 395.2. %de >99 (by LC-ELSD/MS ) EXAMPLE 12 & 13: Synthesis l-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13- trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro- lH-cyclopenta[a]phenanthren- 17-yl)-2-(2H-l ,2,3-triazol-2-yl)ethan- 1-one (A23) & l-((3R,5R,8S,10S,13S,14S,17S)-3- hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17 -tetradecahydro-lH- cyclopenta[a]phenanthren-17-yl)-2-(lH-l,2,3-triazol-l-yl)eth an-l-one (A22)

To a solution of A18 (250 mg, crude) in THF (2 mL) were added IH- 1,2, 3 -triazole (50.6 mg, 0.73 mmol) and K2CO3 (252 mg, 1.83 mmol). After stirring at 25°C for 12 h, the mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic solution was separated, dried over NaiSOr. filtered and concentrated. The residue was purified by flash column (10-80% of EtOAc in PE) to give A23 (22mg, 9.09 %) and A22 (33 mg, 14%) both as solids. Regioisomers assigned based on Ή NMR of triazole.

A23: ¾ NMR (400 MHz, CDCb) 5H 7.69 (s, 2H), 5.46-5.37 (m, 1H), 5.25 (s, 2H), 2.65 (t,

J= 9.2 Hz, 1H), 2.33-2.17 (m, 3H), 2.06-1.95 (m, 3H), 1.90-1.58 (m, 5H), 1.50-1.40 (m, 3H), 1.35-1.17 (s, 9H), 1.08 (s, 3H), 0.63 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for C24H35N3O2 [M+l] ⁺ 397.3, found 398.3. %de >99 (by LC-ELSD/MS )

A22: ¾ NMR (400 MHz, CDCb) 5H 7.76 (s, 1H), 7.65 (s, 1H), 5.42 (br d, J= 5.6 Hz, 1H), 5.32- 5.12 (m, 2H), 2.72 (t, J=9.2 Hz, 1H), 2.45-2.20 (m, 3H), 2.07-1.95 (m, 3H), 1.91-1.60 (m, 5H), 1.52-1.41 (m, 2H), 1.37-1.17 (m, 9H), 1.08 (s, 3H), 0.92-0.81 (m, 1H), 0.59 (s, 3H).

LC-ELSD/MS purity 99%, MS ESI calcd. for C24H35N3 O2 [M+l] ⁺ 397.3, found 398.3. %de >99 (by LC-ELSD/MS )

Example 14: Synthesis of l-((3R,5S,8S,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-

10,13-dimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetrade cahydro-lH- cyclopenta[a]phenanthren-17-yl)ethan-l-one

Synthesis of 14.1

To stirred solution of trimethylsulfoxonium iodide (1.59 g, 7.3 mmol) in DMSO (10 mL) was added t-BuOK (813 mg, 7.3 mmol). After heating at 60°C for lh under N2, (5a)-Androst-9(l 1)- ene-3, l7-dione, 14.0 (1.6 g, 5.6 mmol) was added. After stirring at 25°C for 16 h, the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuum to give 14.1 (2.0 g) as a solid.

Ή NMR (400 MHz, CDCb) 5H 5.40 (d, J= 5.6 Hz, 1H), 2.63 (s, 2H), 2.52-2.41 (m, 1H), 2.20- 1.98 (m, 6H), 1.89 (t, J= 13.2 Hz, 1H), 1.77-1.29 (m, 10H), 1.16-1.02 (m, 1H), 0.99 (s, 3H), 0.98-0.92 (m, 1H), 0.83 (s, 3H).

Synthesis of 14.2

To anhydrous ethanol (50 mL) was added Na (1.52 g, 66.5 mmol) in ten portions. The mixture was stirred at 25°C for 2 hours. To the fresh prepared ethoxysodium (66.5 mmol) in EtOH (50 mL) was added 1.1 (2.0 g, 6.7 mmol) in EtOH (5 mL) at 25°C. After stirring at 65°C for 16 h, the reaction mixture was cooled to 0°C and quenched with water (200 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (2 x 100 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by flash column (0-30% of EtOAc in PE) to give 14.2 (1.0 g, 43.4%) as an solid.

Ή NMR (400 MHz, CDCb) 5H 5.46-5.39 (m, 1H), 3.55 (q, J= 6.8 Hz, 2H), 3.25 (s, 2H), 2.53- 2.43 (m, 1H), 2.30-1.99 (m, 6H), 1.88-1.65 (m, 4H), 1.88-1.65 (m, 4H), 1.60-1.49 (m, 4H), 1.42- 1.28 (m, 1H), 1.23 (t, J= 7.2 Hz, 3H), 1.17-1.03 (m, 1H), 0.93 (s, 3H), 0.84 (s, 3H).

Synthesis of 14.3

To a suspension of EtPPhiBr (3.82 g, 10.3 mmol) in THF (10 mL) was added t-BuOK (1.15 g,

10.3 mmol) at 25°C under N2. After stirring at 40°C for 30 mins, 14.2 (1.2 g, 3.5 mmol) was added at 40°C. After stirring at 40°C for 3 h, the reaction mixture was quenched with saturated

NH4CI aqueous (30 mL) at 25°C. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by flash column (0-20% of EtOAc in PE) to give 14.3 (900 mg,

72.5%) as a solid.

*H NMR (400 MHz, CDCb) 5H 5.40-5.32 (m, 1H), 5.23-5.11 (m, 1H), 3.53 (q, J= 7.2 Hz, 2H), 3.23 (s, 2H), 2.47-2.18 (m, 4H), 2.14-2.05 (m, 1H), 1.97-1.89 (m, 1H), 1.78-1.69 (m, 3H), 1.68- 1.60 (m, 5H), 1.58-1.48 (m, 2H), 1.44-1.23 (m, 6H), 1.20 (t, J= 6.9 Hz, 3H), 1.10-0.99 (m, 1H), 0.89 (s, 3H), 0.81 (s, 3H)

Synthesis of 14.4

To a solution of 14.3 (900 mg, 2.5 mmol) in anhydrous THF (10 mL) was added 9-BBN dimer (1.82 g, 7.5 mmol) at 25°C under N2. After stirring at 50°C for 2 h, the mixture was cooled and diluted with EtOH (10 mL) at 0°C. NaOH (1 g in 5.0 mL water, 5 M, 25.0 mmol) was then added very slowly followed by H2O2 (2.5 mL, 25.0 mmol, 10 M) very slowly until the inner temperature no longer rises and the inner temperature was maintained below 30°C. After stirring at 50°C for 1 h, the mixture was poured into sat. Na2S20 ₃ (50 mL), stirred for 30 mins and then extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous Na2S0 ₄ , filtered and concentrated in vacuum to give 14.4 (2.7 g) as a solid. The residue (300 mg) was purified by flash column (0-30% of EtOAc in PE) to give 14.4 (32 mg, 10.7%) as a solid.

Ή NMR (400 MHz, CDCb) 5H 5.31 (d, J= 6.0 Hz, 1H), 3.76-3.64 (m, 1H), 3.53 (q, J= 6.8 Hz, 2H), 3.22 (s, 2H), 2.12-1.59 (m, 10H), 1.53-1.47 (m, 2H), 1.45-1.16 (m, 14H), 1.13-1.12 (m,

1H), 1.07-0.93 (m, 1H), 0.88 (s, 3H), 0.60 (s, 3H). LCMS purity>99%, MS ESI calcd. for CrrHroOsNa [M+Na] ⁺ 399.3, found 399.3.

Synthesis of 14

To a solution of 14.4 (300 mg, 0.8 mmol) and (lR)-l-phenylethan-l -amine (581 mg, 4.8 mmol) in DCE (5 mL) at 25°C was NaCNBhb (402 mg, 6.4 mmol). After stirring at 50°C for 16 h, the reaction was quenched with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under vacuum. The residue was purified by flash column (0-30% of EtOAc in PE) to give 14 (200 mg, 52.0%) as a solid.

Ή NMR (400 MHz, CDCb) 5H 7.39-7.28 (m, 4H), 7.25-7.18 (m, 1H), 5.35 (d, J= 5.6 Hz, 1H), 3.90 (q, J= 6.4 Hz, 1H), 3.53 (q, J= 6.8 Hz, 2H), 3.23 (s, 2H), 2.78-2.68 (m, 1H), 2.43-2.35 (m, 1H), 2.08-1.96 (m, 3H), 1.92-1.62 (m, 8H), 1.41-1.25 (m, 10H), 1.20 (t, J= 7.2 Hz, 4H), 1.16- 1.09 (m, 1H), 1.05-0.95 (m, 1H), 0.90 (s, 6H), 0.73 (s, 3H)

LC-ELSD/MS purity 98.1%, MS ESI calcd. for C32H50NO2 [M+H] ⁺ 480.4, found 480.4. EXAMPLE 15: Synthesis of l-((3R,5R,8S,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-

10,13-dimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetrade cahydro-lH- cyclopenta[a]phenanthren-17-yl)ethan-l-one

Synthesis of 15.1

To a stirred solution of trimethylsulfonium iodide (4.24 g, 20.8 mmol) in DMSO (25 mL) and THF (12 mL) was added NaH (831 mg, 20.8 mmol, 60 % in mineral oil) at 0°C. After stirring for 1.0 h under N2, the mixture was added a solution of (5P)-Androst-9( 1 1 )-cnc-3.17-dionc, 15.0 (5 g, 17.4 mmol) in DMSO (15 mL) at 0°C. After stirring at 25°C for 2 h, the reaction was diluted with water (300 mL) and extracted with EtOAc (2 x 200 mL). The combined organic phase was washed with water (2 x 100 mL), brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated to give 15.1 (5 g, 95.7%) as an oil.

Ή NMR (400 MHz, CDCb) 5H 5.62-5.43 (m, 1H), 2.66-2.34 (m, 3H), 2.25-2.04 (m, 6H), 2.01- 1.85 (m, 2H), 1.81-1.71 (m, 1H), 1.66-1.50 (m, 3H), 1.45-1.25 (m, 2H), 1.23-0.97 (m, 5H), 0.87- 0.78 (m, 4H).

Synthesis of 15.2 & 15.2a

To anhydrous EtOH (50 mL) was added Na (1.9 g, 83 mmol) at 25°C in potions under N2. After stirring at 75 °C for 1 h, to the ethoxy sodium solution was added 6.1 (5 g, 16.6 mmol) in anhydrous ethanol (50 mL) at 75°C. After stirring at 75°C for 16 h, the reaction was quenched with water (200ml). The reaction mixture was concentrated to remove most of the solvent. The mixture was then extracted with EtOAc (2 x 150 mL). The combined organic phase was washed with brine (150 mL), dried over anhydrous NaiSOr. filtered and concentrated. The residue was purified by flash column (0-25% of EtOAc in PE) to give 15.2a (2.3 g, 39.9%) and 15.2 (1.8 g, 31.3%) both as oils.

15.2: Ή NMR (400 MHz, CDCb) 5H 5.44 (d, J= 6.0 Hz, 1H), 3.53 (q, J= 6.8 Hz, 2H), 3.47- 3.40 (m, 2H), 2.50-2.39 (m, 1H), 2.22-2.05 (m, 4H), 2.03-1.93 (m, 3H), 1.83-1.53 (m, 6H), 1.42- 1.28 (m, 3H), 1.25-1.14 (m, 5H), 1.09 (s, 3H), 0.80 (s, 3H). 15.2a: Ή NMR (400 MHz, CDCb) d _H 5.41 (d, J= 5.2 Hz, 1H), 3.51 (q, J= 6.8 Hz, 2H), 3.20 (s, 2H), 2.51-2.38 (m, 1H), 2.24-1.91 (m, 8H), 1.84-1.56 (m, 4H), 1.53-1.42 (m, 3H), 1.27-1.16 (m, 7H), 1.12 (s, 3H), 0.81 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C22H33O2 [M+H-H2OG 329.2, found 329.2.

Synthesis of 15.3

To a mixture of EtPPl Br (5.45 g, 14.7 mmol) in THF (45 mL) was added /-BuOK (1.64 g, 14.7 mmol) under N2. After stirring at 50°C for 30 mins. 15.2 (1.7 g, 4.9 mmol) in THF (5 mL) was added. After stirring at 40°C for 2 h, the reaction mixture was quenched with 10% NH4CI aqueous (200 mL). The aqueous layer was collected and extracted with EtOAc (2 x 150 mL).

The combined organic phase was concentrated. The residue was purified by flash column (0-10% of EtOAc in PE) to give 15.3 (1.1 g, 62.8%) as an oil.

*H NMR (400 MHz, CDCb) d _H 3 5.45-5.37 (m, 1H), 5.22-5.14 (m, 1H), 3.53 (q, J= 7.2 Hz,

2H), 3.47-3.40 (m, 2H), 2.41-2.18 (m, 4H), 2.03-1.94 (m, 3H), 1.75-1.58 (m, 8H), 1.51-1.27 (m, 5H), 1.24-1.17 (m, 5H), 1.07 (s, 3H), 0.79 (s, 3H).

Synthesis of 15.4

To a solution of 15.3 (1.1 g, 3.06 mmol) in THF (20 mL) was added 9-BBN dimer (1.48 g, 6.12 mmol). After stirring at 45 °C for 2 h, the resulting mixture was treated with ethanol (2 mL) at l5°C and then by NaOH aqueous (6 mL, 5.0 M, 30 mmol) at 0°C. Hydrogen peroxide (3 mL, 10 M, 30 mmol) was then added dropwise at 0°C. After stirring at 78°C for 1 h, the mixture as cooled to l5°C and quenched with saturated aqueous Na2S2Cb (200 mL). The aqueous phase was collected and extracted with EtOAc (2 x 150 mL). The combined organic phase was washed with brine (150 mL), dried over anhydrous NarSOr. filtered and concentrated. The residue was purified by flash column (0-40% of EtOAc in PE) to give 15.4 (1 g, 86.9%) as an oil.

Ή NMR (400 MHz, CDCb) d _H 5.36 (br s, 1H), 3.75- 3.66 (m, 1H), 3.53 (q, J= 6.8 Hz, 2H), 3.47-3.40 (m, 2H), 2.02-1.87 (m, 5H), 1.84-1.60 (m, 7H), 1.54-1.29 (m, 7H), 1.25-1.12 (m, 9H), 1.06 (s, 3H), 0.57 (s, 3H).

Synthesis of 15

To a solution of 15.4 (1 g, 2.65 mmol) in DCM (10 mL) was added DMP (2.24 g, 5.3 mmol) in portions. After stirring at 25°C for 20 mins, the mixture was quenched with saturated NaHC03 aqueous (150 mL), The aqueous phase was collected and extracted with DCM (2 x 150 mL). The combined organic phase was washed with saturated Na2S2Cb aqueous (2 x 200 mL), brine (200 mL) dried over anhydrous NarSOr. filtered and concentrated. The residue was purified by flash column (0-25% of EtOAc in PE) to give 15 (720 mg, 72.5%) as a solid. Ή NMR (400 MHz, CDCb) d _H 5.41 (br d, J= 6.0 Hz, 1H), 3.54 (q, J= 6.8 Hz, 2H), 3.47- 3.40 (m, 2H), 2.60 (t, J= 9.2 Hz, 1H), 2.38-2.30 (m, 1H), 2.24-2.16 (m, 2H), 2.13 (s, 3H), 2.04-1.92 (m, 3H), 1.85-1.63 (m, 5H), 1.60-1.58 (m, 1H), 1.51-1.16 (m, 11H), 1.06 (s, 3H), 0.52 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C24H37O2 [M+H-H2OG 357.3, found 357.3.

EXAMPLE 16: Synthesis of l-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3-

(methoxymethyl)-10,13-dimethyl-2,3,4,5,6,7,8,10,12,13,14, 15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-17-yl)ethan-l-one

Synthesis of 16.1 & 16.1a

To anhydrous methanol (25 mL) was added Na (2.5 g, 109 mmol) in five portions. After stirring at 25°C for 2 h, 15.1 (3.3 g, 10.9 mmol) in THF (25 mL) was added. After stirring at 60°C for 5 h, the reaction mixture was cooled to 0°C and quenched by addition of H2O (100 mL). The solution was purified together with another batch (from 2.6 g of 15.1). The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (2 xlOO mL), dried over anhydrous NaiSOr. filtered and concentrated. The residue was purified by flash column (0-40% of EtOAc in PE) to give 16.1a (2.0 g, 31.7%) and 16.1 (2.0 g, 31.7%) as solids. The stereochemistry of C3 for these two compounds were assigned based on the chemical shift of methylene at C3 side chain: equatorial orientation is in higher field than axial orientation.

16.1a: Ή NMR (400 MHz, CDCb) d _H 5.38 (d, J= 5.6 Hz, 1H), 3.34 (s, 3H), 3.15 (s, 2H), 2.59- 2.24 (m, 2H), 2.23-2.03 (m, 6H), 1.98-1.67 (m, 5H), 1.67-1.34 (m, 6H), 1.33-1.28 (m, 1H), 1.10 (s, 4H), 0.78 (s, 3H). 100% de based on H-NMR.

16.1: *H NMR (400 MHz, CDCb) d _H 5.45 (d, J= 5.6 Hz, 1H), 3.45-3.35 (m, 5H), 2.45 (dd, J = 18.8, 8.0 Hz, 1H), 2.20-1.96 (m, 7H), 1.66-1.50 (m, 8H), 1.39-1.18 (m, 4H), 1.09 (s, 3H), 0.80 (s, 3H). LC-ELSD/MS purity 99%, 100% de based on H-NMR. MS ESI calcd. for C21H31O2 [M+H-H ₂ 0] ⁺ 315.2, found 315.2.

Synthesis of 16.2

To a mixture of EtPPl Br (12.6 g, 34.2 mmol) in THF (50 mL) was added t-BuOK (3.83 g, 34.2 mmol) at l5°C under N2. After stirring at 50°C for 30 min, 16.1 (1.9 g, 5.71 mmol) was added in portions below 40°C. After stirring at 40°C for 1 h, the reaction mixture was quenched with 10% NH4CI aqueous (100 mL) at l5°C. The aqueous layer was collected and extracted with EtOAc (200 mL). The combined organic phase was concentrated under vacuum. The residue was purified by trituration with MeOH/EhO (1 : 1, 300 mL) at reflux to give 16.2 (8 g), which was further purified by column chromatography on silica gel (PE/EtOAc= 1/10-1/5) to afford 16.2 (1.5 g, 77%) as a solid.

¾ NMR (400 MHz, CDCl3) 5 _H 5.40 (d, J= 2.0 Hz, 1H), 5.25-5.15 (m, 1H), 3.52-3.21 (m, 5H), 2.64-2.19 (m, 5H), 2.03 (s, 5H), 1.78-1.51 (m, 8H), 1.46 - 1.30 (m, 3H), 1.22-1.12 (m, 2H), 1.07 (s, 3H), 0.78 (s, 3H).

Synthesis of 16.3

To a solution of 16.2 (1.5 g, 4.35 mmol) in THF (10 mL) was added 9-BBN dimer (3.17 g, 13.0 mmol) at l5°C. After stirring at 40°C for 1 h, the resulting mixture was diluted with ethanol (18 mL, 130 mmol) at l5°C, NaOH aqueous (26 mL, 5M, 130 mmol) at -l0°C, and finally by H2O2 (13 mL, 10 M, 130 mmol) dropwise. After the addition, the mixture was stirred at 80°C for an hour. The aqueous was collected and extracted with EtOAc (100 mL). The combined organic phase was washed with brine (2 x 100 mL), dried over anhydrous Na2S04, filtered and concentrated under vacuum to give 16.3 (2.8 g) as a solid.

Ή NMR (400 MHz, CDCb) 5H 5.34 (s, 1H), 3.73-3.62 (m, 1H), 3.43-3.33 (m, 5H), 1.86-1.83 (m, 4H), 1.68-1.61 (m, 8 H), 1.52-1.47 (m, 6H), 1.39-1.27 (m, 4H), 1.20 - 1.10 (m, 3H), 1.05 (s, 3H), 0.56 (s, 3H).

Synthesis of 16

To a solution of 16.3 (2.8 g, 7.72 mmol) in DCM (20 mL) was added Dess-martin (6.52 g, 15.4 mmol) at 25°C. After at 25°C for 10 min, the mixture was quenched with saturated

NaHCCb/NaiSiCb aqueous (1 : 1, 400 mL) at 25°C. The organic phase was separated and washed with saturated NaHCCb/NaiSiCb aqueous (1 : 1, 400 mL), brine (200 mL), dried over NaiSCri, filtered and concentrated under vacuum. The residue was purified by flash column (5-15% of EtOAc in PE) to give 16 (800 mg, 28.7%) as a solid. Ή NMR (400 MHz, CDCb) d _H 5.41 (d, J= 5.6 Hz, 1H), 3.45-3.33 (m, 5H), 2.59 (t, J= 9.29 Hz, 1H), 2.36-2.17 (m, 3H), 2.12 (s, 3H), 2.00-1.92 (m, 3H), 1.86-1.57 (m, 7H), 1.50-1.17 (m, 8H), 1.06 (s, 3H), 0.52 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C23H35O2 [M+H- H ₂ 0] ⁺ 343.3, found 343.3.

Example 17: Synthesis of l-(2-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl) -

10,13-dimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetrade cahydro-lH- cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-lH-pyrazole-4-ca rbonitrile

Synthesis of 17.1

To a solution of 16 (200 mg, 0.55 mmol) in MeOH (2 ml) was added HBr (0.02 mL, 0.55 mmol, 40% in water) and Bn (106 mg, 0.66 mmol) at 25°C. After stirring at 25°C for 2 h, the mixture was quenched with sat.aq NaHC03 (10 mL), diluted with water (20 mL), and extracted with EtOAc (2 x 30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, filtered, concentrated in vacuum to afford 17.1 (260 mg, crude) as a solid used directly for the next step.

Synthesis of 17

To a solution of 17.1 (260 mg, 0.5916 mmol) in acetone (5 mL) were added lH-pyrazole-4- carbonitrile (66 mg, 0.7099 mmol) and K2CO3 (163 mg, 1.18 mmol). After stirring at 25°C for 16 h, the mixture was added to water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was separated, dried over anhydrous NaiSOr. filtered and concentrated. The residue was purified by flash column (20-50% of EtOAc in PE) to give 17 (61 mg, 22.8%) as a solid.

Ή NMR (400 MHz, DMSO-de) d _H 7.86 (s, 1H), 7.81 (s, 1H), 5.45-5.40 (m, 1H), 5.12-4.80 (m, 2H), 3.44-3.38 (m, 5H), 2.68 (t , J= 8.88 Hz, 1H), 2.44-2.12 (m, 3H), 2.06-1.92 (m, 3H), 1.88- 1.58 (m, 5H), 1.49-1.13 (m, 9H), 1.07 (s, 3H), 0.58 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C27H36N3O2 [M+H-H ₂ 0] ⁺ 434.3, found 434.3. Example 18: Biological data

[0337] Steroid Inhibition of TBPS Binding

[ ³⁵ S]-t-Butylbicyclophosphorothionate (TBPS) binding assays using rat brain cortical membranes in the presence of 5 mM GABA has been described (Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al , Mol. Pharmacol. 1994, 46, 977-985; Lewin, A.H et al , Moί Pharmacol. 1989, 35, 189-194).

[0338] Briefly, cortices are rapidly removed following decapitation of carbon dioxide- anesthetized Sprague-Dawley rats (200-250 g). The cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass/teflon homogenizer and centrifuged at 1500 x g for 10 min at 4 °C. The resultant supernatants are centrifuged at 10,000 x g for 20 min at 4 °C to obtain the P2 pellets. The P2 pellets are resuspended in 200 mM NaCl/50 mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000 x g for 10 min at 4 °C. This washing procedure is repeated twice and the pellets are resuspended in 10 volumes of buffer. Aliquots (100 mL) of the membrane suspensions are incubated with 3 nM [ ³⁵ S]-TBPS and 5 mL aliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final 0.5%) in the presence of 5 mM GABA. The incubation is brought to a final volume of 1.0 mL with buffer. Nonspecific binding is determined in the presence of 2 mM unlabeled TBPS and ranged from 15 to 25 %. Following a 90 min incubation at room temp, the assays are terminated by filtration through glass fiber filters (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsed three times with ice- cold buffer. Filter bound radioactivity is measured by liquid scintillation spectrometry. Non linear curve fitting of the overall data for each drug averaged for each concentration is done using Prism (GraphPad). The data are fit to a partial instead of a full inhibition model if the sum of squares is significantly lower by F-test. Similarly, the data are fit to a two component instead of a one component inhibition model if the sum of squares is significantly lower by F-test. The concentration of test compound producing 50% inhibition (IC50) of specific binding and the maximal extent of inhibition (Imax) are determined for the individual experiments with the same model used for the overall data and then the means + SEM.s of the individual experiments are calculated. Picrotoxin serves as the positive control for these studies as it has been demonstrated to robustly inhibit TBPS binding.

[0339] Various compounds are or can be screened to determine their potential as modulators of [ ³⁵ S]-TBPS binding in vitro. These assays are or can be performed in accordance with the above. [0340] In Table 2 below, A indicates a TBPS IC50 (uM) < 0.01 DM, B indicates a TBPS IC50 (uM) of 0.01 DM to < 0.1 DM, C indicates a TBPS IC50 (DM) of 0.1□Mto<l.0DM, D indicates a TBPS IC50 (DM) of 1.0 DM to < 10 DM, and E means > 10 DM.

TABLE 2.

100

101

102

Equivalents and Scope

[0341] In the claims articles such as“a,”“an,” and“the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include“or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0342] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms“comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0343] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims.

Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0344] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.