Agents for delivering NMDA receptor modulating compounds and methods of use thereof

Abstract

Provided herein are compounds of Formulae (I) and (X): (I) and (X), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof, pharmaceutical compositions thereof and methods of use thereof for treating and preventing conditions related to NMDA receptor modulation.

Description

000221-0085-WO1 (SGE-203WO) AGENTS FOR DELIVERING NMDA RECEPTOR MODULATING COMPOUNDS AND METHODS OF USE THEREOF Cross Reference To Related Applications

[0001] This application claims priority to and the benefit of U.S. Provisional Application 5 No.63 / 653,054, filed May 29, 2024, the disclosure of which, is incorporated by reference herein in its entirety. Background

[0002] NMDA receptors are heteromeric complexes comprised of NR1, NR2, and / or NR3 subunits and possess distinct recognition sites for exogenous and endogenous ligands. These 10 recognition sites include binding sites for glycine, and glutamate agonists and modulators. NMDA receptors are expressed in peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activating these receptors contributes to synaptic plasticity in some circumstances and excitotoxicity in others. These receptors are ligand-gated ion channels that admit Ca2+after binding of the glutamate and glycine, and are fundamental to 15 excitatory neurotransmission and normal CNS function. Positive modulators may be useful as therapeutic agents with potential clinical uses as cognitive enhancers and in the treatment of psychiatric disorders in which glutamatergic transmission is reduced or defective (see, e.g., Horak et al., J. Neuroscience, 2004, 24(46), 10318-10325). In contrast, negative modulators may be useful as therapeutic agents with potential clinical uses in the treatment of psychiatric 20 disorders in which glutamatergic transmission is pathologically increased (e.g., treatment resistant depression).

[0003] There is a need to develop therapeutics that facilitate the delivery of NMDA receptor modulators for treating conditions associated with NMDA receptor function. Compounds, compositions, and methods described herein are directed toward this end. 25 Summary

[0004] In one aspect, the disclosure provides a compound of Formula (I):, or a pharmaceutically acceptable salt, isotopic variant, or a combination thereof, wherein: Agent is 1each of R1and R2is independently hydrogen or a cleavable moiety, provided that at least one of R1and R2is not hydrogen; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or 5 unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6 carbocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-8 membered heteroaryl; each of R15and R16is independently hydrogen or substituted or unsubstituted C1-6alkyl; or 10 R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 carbocyclyl; R18is hydrogen or substituted or unsubstituted C1-6alkyl; R19is hydrogen or substituted or unsubstituted C1-6 alkyl; each of R20and R20’is independently hydrogen, hydroxyl, substituted or 15 unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl; R22is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, or substituted or unsubstituted C6-10aryl; and the point of attachment to R1or R2. 20

[0005] In some embodiments, the compound of Formula (I) is a compound of Formula (II),2or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0006] In some embodiments, the compound of Formula (II) is a compound of Formula (II- 5or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0007] In one aspect, the disclosure provides a compound of Formula (X):, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: 10 each of a and b is independently 0 or 1, provided that a and b are not both 0; and each instance of Z is independently hydrogen, -C(O)(C1-20alkyl), or -C(O)-(C(RZ1)(RZ2))1-6-C(O)(Agent), provided that at least two instances of Z are -C(O)-(C(RZ1)(RZ2))1-6-C(O)(Agent) and wherein: each instance of RZ1and RZ2is independently hydrogen or C1-6 alkyl; and 15 each instance of Agent is independently a compound of Formula (X-I):, wherein: Y is hydrogen or a bond, provided that one instance of Y is a bond and the other is hydrogen, wherein said bond is the point of attachment between Agent and the associated 20 C(O); 3R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-8 membered heteroaryl; 5 each of R15and R16is independently hydrogen or substituted or unsubstituted C1-6 alkyl; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 carbocyclyl; R18is hydrogen or substituted or unsubstituted C1-6 alkyl; 10 R19is hydrogen or substituted or unsubstituted C1-6alkyl; R20is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6 carbocyclyl; R20’is hydrogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6carbocyclyl; and 15 R22is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, or substituted or unsubstituted C6-10aryl.

[0008] In some embodiments, the compound of Formula (X-I) is a compound of Formula (X-II) 20pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound of Formula (X-II) is a compound of Formula4pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0009] In some embodiments, the compound of Formula (I) or (X) is any one of compounds 1-78, or a pharmaceutically acceptable salt, isotopic variant, or combination 5 thereof.

[0010] In one aspect, the disclosure provides a pharmaceutical composition comprising a compound of any one of Formulae (I), (II), (II-A), (II-B), or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to the disclosure, and a pharmaceutically acceptable carrier. 10

[0011] In one aspect, the disclosure provides a method for treating a CNS-related condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formulae (I), (II), (II-A), (II-B), or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure. 15

[0012] In one aspect, the disclosure provides a method for effecting negative allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formulae (I), (II), (II-A), (II- B), or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure. 20

[0013] In one aspect, the disclosure provides a compound of any one of Formulae (I), (II), (II-A), (II-B), or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, for use in treating a CNS-related condition in a subject.

[0014] In one aspect, the disclosure provides a compound of any one of Formulae (I), (II), 25 (II-A), (II-B), or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, for use in effecting negative allosteric modulation of an NMDA receptor. 5

[0015] In one aspect, the disclosure provides a use of a compound of any one of Formulae (I), (II), (II-A), (II-B), or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, in the manufacture of a medicament for treating a CNS-related condition in a subject. 5

[0016] In one aspect, the disclosure provides a use of a compound of any one of Formulae (I), (II), (II-A), (II-B), or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, in the manufacture of a medicament for effecting negative allosteric modulation of an NMDA receptor. 10

[0017] In some embodiments, the CNS-related condition is selected from the group consisting of an adjustment disorder, a stress or stress-related disorder (including post- traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., 15 frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a 20 substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome 25 and Tuberous Sclerosis complex), pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of 30 epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome 6(CSWS) and Landau Kleffer syndrome (LKS)), melanoma, hepatic encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), and tinnitus. Detailed Description 5

[0018] The present disclosure provides compounds that facilitate the delivery of NMDA receptor modulators (e.g., negative allosteric modulators) that are useful as therapeutic agents for treating, for example, CNS-related conditions. General Definitions

[0019] The term “herein” means the entire application. 10

[0020] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. Generally, nomenclature used in connection with the compounds, compositions, and methods described herein, are those well-known and commonly used in the art. 15

[0021] It should be understood that any of the embodiments described herein, including those described under different aspects of the disclosure and different parts of the specification (including embodiments described only in the Examples), can be combined with one or more other embodiments of the disclosure, unless explicitly disclaimed or improper. Combinations of embodiments are not limited to those specific combinations claimed via the 20 multiple dependent claims. 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. 25

[0022] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (element or component) or group of integers (elements or components), but not the exclusion of any other integer (element or component) or group of integers (elements or components).

[0023] Throughout the specification, where compositions are described as having, 30 including, or comprising (or variations thereof), specific components, it is contemplated that compositions also may consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising (or variations thereof), specific process steps, the processes also may consist essentially of, or 7consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remain operable. Moreover, two or more steps or actions can be conducted simultaneously. 5

[0024] The term “including” as used herein, means “including but not limited to.” “Including” and “including but not limited to” are used interchangeably. Thus, these terms will be understood to imply the inclusion of a stated integer (element or component) or group of integers (elements or components), but not the exclusion of any other integer (element or component) or group of integers (elements or components). 10

[0025] As used herein, “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0026] The use of the terms “a” and “an” and “the” and similar referents in the context of 15 describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0027] The term “or” as used herein should be understood to mean “and / or,” unless the context clearly indicates otherwise. 20

[0028] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range and including the endpoints, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly 25 contradicted by context. The use of any and all examples, or exemplary language (“such as,” “for example,” “e.g.,” etc.) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential. 30

[0029] All of the publications, patents, and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. In addition, any particular embodiment of the present disclosure 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 8one 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 disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. Chemical Definitions 5

[0030] 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, 102ndEd., 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 10 described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 8thEdition, John Wiley & Sons, Inc., New Jersey, 2020; Larock, Comprehensive Organic Transformations, 3rdEdition, John Wiley & Sons, Inc., New Jersey, 2018; Kurti and Czako, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier, Inc., 2005; and Carruthers & Coldham, Modern15 Methods of Organic Synthesis, 4thEdition, Cambridge University Press, Cambridge, 2004.

[0031] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, 20 including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), supercritical fluid chromatograph (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., 25 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 disclosure additionally encompasses compounds described herein as individual isomers substantially free of other 30 isomers, and alternatively, as mixtures of various isomers.

[0032] 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 9“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 5 R- and S- sequencing rules of Cahn, Ingold, 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 an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.” 10

[0033] 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% 15 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 20 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. As used herein, the term “diastereomeric purity” refers to the amount of a compound having the depicted absolute stereochemistry, expressed as a percentage of the total amount of the depicted compound and its diastereomers. 25

[0034] The term “diastereomerically pure” 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 30 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 diastereomer. Methods for determining diastereomeric and enantiomeric purity are well-known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomers, 10such as high-performance liquid chromatography (HPLC) or supercritical fluid chromatograph (SFC).

[0035] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition 5 comprising enantiomerically pure R–position / center / carbon 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 10 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 15 can be formulated with little or no excipient or carrier.

[0036] Compounds described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like. 20

[0037] When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C1–6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, 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.

[0038] The following terms are intended to have the meanings presented therewith below 25 and are useful in understanding the description and intended scope of the present disclosure. It should also be understood that when described herein any of the moieties defined herein may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further 30 understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0039] “Aliphatic” refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein. 11

[0040] “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 6 carbon atoms (“C1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms 5 (“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 (“C1alkyl”). Examples of C1–6alkyl groups include methyl (C1), 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), 10 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6). 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 4 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu 15 (-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0041] As used herein, “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” refer to a divalent radical of an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” “alkynylene,” 20 “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein. 25

[0042] “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., 30 substituted with one or more halo, -NO2, -OH, C1-C6alkoxy, C1-C6alkyl (e.g., methyl) groups, including but not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3), -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), or C1-C6cycloalkyl, and the like. 12Alkylene abbreviations include, but are not limited to, -(CH(CH3))–, –(CH(CH2CH3))–, –(CH(CH2CH2CH3))–, –(CH(CH2CH2CH2CH3)),-(CH2CH(CH2CH2CH2CH3)), -(CH2CH2CH(CH2CH2CH2CH3)), –(CH(CH3)CH2), -(CH(CH3)CH2CH2), -(CH(CH3)CH2CH2CH2)–, –( CH2CH(CH3)CH2)–, -(CH2CH(CH3)CH2CH2)–, 5 and -(CH2CH2CH(CH3)CH2CH2)–.

[0043] “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 10 does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–10alkenyl”). 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 (“C2–6alkenyl”). In some 15 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 (“C2–3alkenyl”). 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 1–butenyl). 20 Examples of C2–4alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1–butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an 25 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 C2–10 alkenyl. In certain embodiments, the alkenyl group is substituted C2–10 alkenyl. 30

[0044] “Alkenylene” refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are 13not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like. 5

[0045] “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 10 carbon atoms (“C2–10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9alkynyl”). 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 (“C2–5alkynyl”). In some 15 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 (“C2alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2–4 alkynyl groups include, without limitation, ethynyl (C2), 1–propynyl (C3), 20 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), 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 25 “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 C2–10alkynyl. In certain embodiments, the alkynyl group is substituted C2–10alkynyl.

[0046] “Alkynylene” refers to a linear alkynyl group wherein two hydrogens are removed 30 to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0047] 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, 14nitrogen, 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 5 saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–9alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 10 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–7alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1–6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms 15 (“heteroC1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1–3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group 20 is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2–6alkyl”). 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 heteroC1–10alkyl. In certain embodiments, the heteroalkyl group is a 25 substituted heteroC1–10 alkyl.

[0048] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more 30 heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2– 10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–9alkenyl”). In some embodiments, 15a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double 5 bond, and 1, 2, or 3 heteroatoms (“heteroC2–6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2–5alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1or 2 heteroatoms (“heteroC2–4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, 10 and 1 heteroatom (“heteroC2–3alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2–6alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an 15 unsubstituted heteroC2–10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2–10 alkenyl.

[0049] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted 20 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 heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2– 10alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least 25 one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–8alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple 30 bond, and 1, 2, or 3 heteroatoms (“heteroC2–6alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2–5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms (“heteroC2–4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 16heteroatom (“heteroC2–3alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2–6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or 5 more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2–10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2–10alkynyl.

[0050] “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 ^ electrons shared in a cyclic array) 10 having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). “Aryl” also includes ring systems wherein the aryl ring, as defined herein, 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 15 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, 20 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 25 aryl group is unsubstituted C6–14aryl. In certain embodiments, the aryl group is substituted C6–14 aryl.

[0051] In certain embodiments, an aryl group is substituted with one or more of groups selected from halo, C1-C8alkyl, C1-C8haloalkyl, cyano, hydroxy, C1-C8alkoxy, and amino.

[0052] Examples of representative substituted aryls include the following 3017wherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, 5 SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56and R57may 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. R60and R61are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, substituted C6-C10 aryl, 5-10 membered heteroaryl, or substituted 5- 10 10 membered heteroaryl.

[0053] “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.

[0054] “Aralkyl” is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. 15

[0055] “Heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ^ 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 20 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 ring25 members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein theheteroaryl 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, 30 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). 18

[0056] 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 5 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 10 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 15 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. 20

[0057] 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 groupscontaining three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and 25 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 30 include, without limitation, triazinyl and tetrazinyl, respectively.

[0058] Examples of representative heteroaryls include the following: 19wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl. 5

[0059] “Nitrogen-containing heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ^ electrons shared in a cyclic array) having ring carbon atoms and containing at least one nitrogen atom. Examples of nitrogen-containing heteroaryl groups included, but are not limited to, pyrrolyl, pyridinyl, pyridinonyl, pyridazinyl, and pyrimidinyl. 10

[0060] “Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0061] “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 15 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 (“C3–6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5–10carbocyclyl”). Exemplary C3–620 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3–8carbocyclyl groups include, without limitation, the aforementioned C3–6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), 25 cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3–10 carbocyclyl groups include, without limitation, the aforementioned C3–8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), 20cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group includes either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic 5 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 10 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.

[0062] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group 15 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 (“C3–6cycloalkyl”). 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 20 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3–6cycloalkyl groups include the aforementioned C5–6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3–8 cycloalkyl groups include the aforementioned C3–6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an 25 “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 C3–10cycloalkyl.

[0063] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10–membered non– aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each 30 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 21saturated 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 5 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 10 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.

[0064] 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 15 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 20 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 25 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0065] 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, 30 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, 22oxadiazolinyl, 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– 5 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 C6 aryl ring (also referred 10 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. 15

[0066] “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 20 particularly from 1 to 3 heteroatoms.

[0067] “Acyl” refers to a radical -C(O)R20, where R20is 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” 25 is an acyl group wherein R20is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), ––C(O)- C1-C8 alkyl, –C(O)-(CH2)t(C6-C10 aryl), –C(O)-(CH2)t(5-10 membered heteroaryl), –C(O)- (CH2)t(C3-C10 cycloalkyl), and –C(O)-(CH2)t(4-10 membered heterocyclyl), wherein t is an 30 integer from 0 to 4. In certain embodiments, R21is C1-C8alkyl, substituted with halo or hydroxy; or C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, 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-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy. 23

[0068] “Alkoxy” refers to the group –OR29where R29is 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. In some embodiments, an 5 alkoxy group has 1 to 6 carbon atoms (“C1–6 alkoxy”). In some embodiments, an alkoxy group has 1 to 5 carbon atoms (“C1–5 alkoxy”). In some embodiments, an alkoxy group has 1 to 4 carbon atoms (“C1–4alkoxy”). In some embodiments, an alkoxy group has 1 to 3 carbon atoms (“C1–3 alkoxy”). In some embodiments, an alkoxy group has 1 to 2 carbon atoms (“C1– 2 alkoxy”). In some embodiments, an alkoxy group has 1 carbon atom (“C1 alkoxy”). 10 Examples of C1-6alkoxy groups include methoxy (C1), ethoxy(C2), n-propoxy (C3), isopropoxy (C3), 2-methoxyethoxy (C3), n-butoxy (C4), tert-butoxy (C4), sec-butoxy (C4), n- pentoxy (C5), n-hexoxy (C6), and 1,2-dimethylbutoxy (C6). 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. 15

[0069] In certain embodiments, R29is 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-C10aryl, 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– 20 S(O)2- and aryl-S(O)2-. Exemplary ‘substituted alkoxy’ groups include, but are not limited to, –O-(CH2)t(C6-C10aryl), –O-(CH2)t(5-10 membered heteroaryl), –O-(CH2)t(C3-C10cycloalkyl), and –O-(CH2)t(4-10 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-C4alkyl, halo, unsubstituted C1-C4alkoxy, unsubstituted 25 C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular exemplary ‘substituted alkoxy’ groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0070] “Amino” refers to the radical -NH2.

[0071] “Substituted amino” refers to an amino group of the formula -N(R38)2 wherein R38is 30 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, or an amino protecting group, wherein at least one of R38is not a hydrogen. In certain embodiments, each R38is independently selected from hydrogen, C1-C8alkyl, C3-C8alkenyl, 24C3-C8alkynyl, C6-C10aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-C10 cycloalkyl; or C1-C8 alkyl, substituted with halo or hydroxy; C3-C8 alkenyl, substituted with halo or hydroxy; C3-C8 alkynyl, substituted with halo or hydroxy, or -(CH2)t(C6-C10aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2)t(C3-C10cycloalkyl), or 5 -(CH2)t(4-10 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-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy; or both R38groups are joined to form an alkylene group.

[0072] Exemplary “substituted amino” groups include, but are not limited to, –NR39-C1-C810 alkyl, –NR39-(CH2)t(C6-C10aryl), –NR39-(CH2)t(5-10 membered heteroaryl), –NR39- (CH2)t(C3-C10cycloalkyl), and –NR39-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R39independently represents H or C1-C8 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 15 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-C4haloalkoxy 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 20 as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.

[0073] “Carboxy” refers to the radical -C(O)OH.

[0074] “Cyano” refers to the radical -CN.

[0075] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In 25 certain embodiments, the halo group is either fluoro or chloro.

[0076] “Hydroxyl” refers to the radical -OH.

[0077] “Nitro” refers to the radical –NO2.

[0078] “Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, 30 cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

[0079] “Heterocyclylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, 25pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0080] “Nitrogen-containing heterocyclyl” group means a 5- to 8- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, 5 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.

[0081] “Thioketo” refers to the group =S. 10

[0082] “Imino” refers to the group =N-RN, wherein RNis hydrogen, alkyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl, or any combination of selections therefrom.

[0083] “Oxo” refers to the group =O.

[0084] “Thiol” refers to the group -SH.

[0085] A “wavy bond”” in the structures depicted herein refers to the point of15 attachment of the group.

[0086] 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, 20 “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 25 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 30 described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents 26and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

[0087] Exemplary carbon atom substituents include, but are not limited to, halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –ORaa, –ON(Rbb)2, –N(Rbb)2, –N(Rbb)3+X–, –N(ORcc)Rbb, 5 10–OC(=O)SRaa, –SC(=O)ORaa, –SC(=O)Raa, –P(=O)2Raa, –OP(=O)2Raa, –P(=O)(Raa)2, –OP(=O)(Raa)2, –OP(=O)(ORcc)2, –P(=O)2N(Rbb)2, –OP(=O)2N(Rbb)2, –P(=O)(NRbb)2, –OP(=O)(NRbb)2, –NRbbP(=O)(ORcc)2, –NRbbP(=O)(NRbb)2, –P(Rcc)2, –P(Rcc)3, –OP(Rcc)2, –OP(Rcc)3, –B(Raa)2, –B(ORcc)2, –BRaa(ORcc), C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, 15 C2–10 alkynyl, C3–10 carbocyclyl, 3–14 membered heterocyclyl, C6–14 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 Rddgroups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; 20 each instance of Raais, independently, selected from C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, or two Raagroups 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, 25 or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, –C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, –SO2Raa, –C(=NRcc)ORaa, –C(=NRcc)N(Rcc)2, –SO2N(Rcc)2, –SO2Rcc, –SO2ORcc, –SORaa, –C(=S)N(Rcc)2, –C(=O)SRcc, –C(=S)SRcc, –P(=O)2Raa, –P(=O)(Raa)2, –P(=O)2N(Rcc)2, –P(=O)(NRcc)2, C1–10 alkyl, C1–10 30 perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, or two Rbbgroups 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 Rddgroups; 27each instance of Rccis, independently, selected from hydrogen, C1–10alkyl, C1–10 perhaloalkyl, C2–10 alkenyl, C2–10 alkynyl, C3–10 carbocyclyl, 3–14 membered heterocyclyl, C6–14 aryl, and 5–14 membered heteroaryl, or two Rccgroups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein 5 each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –ORee, –ON(Rff)2, –N(Rff)2, –N(Rff)3+X–, –N(ORee)Rff, –SH, –SRee, –SSRee, –C(=O)Ree, –CO2H, –CO2Ree, –OC(=O)Ree, –OCO2Ree, 10 –C(=O)N(Rff)2, –OC(=O)N(Rff)2, –NRffC(=O)Ree, –NRffCO2Ree, –NRffC(=O)N(Rff)2, –C(=NRff)ORee, –OC(=NRff)Ree, –OC(=NRff)ORee, –C(=NRff)N(Rff)2, –OC(=NRff)N(Rff)2, –NRffC(=NRff)N(Rff)2, –NRffSO2Ree, –SO2N(Rff)2, –SO2Ree, –SO2ORee, –OSO2Ree, –S(=O)Ree, –Si(Ree)3, –OSi(Ree)3, –C(=S)N(Rff)2, –C(=O)SRee, –C(=S)SRee, –SC(=S)SRee, –P(=O)2Ree, –P(=O)(Ree)2, –OP(=O)(Ree)2, 15 –OP(=O)(ORee)2, C1–6 alkyl, C1–6 perhaloalkyl, 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 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; 20 each instance of Reeis, independently, selected from C1–6alkyl, C1–6perhaloalkyl, C2–6alkenyl, C2–6alkynyl, C3–10carbocyclyl, C6–10aryl, 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 Rgggroups; 25 each instance of Rffis, independently, selected from hydrogen, C1–6 alkyl, C1–6 perhaloalkyl, C2–6 alkenyl, C2–6 alkynyl, C3–10 carbocyclyl, 3–10 membered heterocyclyl, C6–10aryl and 5–10 membered heteroaryl, or two Rffgroups 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 30 independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC1–6 alkyl, –ON(C1–6 alkyl)2, –N(C1–6 alkyl)2, –N(C1–6 alkyl)3+X–, –NH(C1–6 alkyl)2+X–, –NH2(C1–6 alkyl)+X–, –NH3+X–, –N(OC1–6 alkyl)(C1–6 alkyl), –N(OH)(C1–6alkyl), –NH(OH), –SH, –SC1–6alkyl, –SS(C1–6alkyl), –C(=O)(C1–628alkyl), –CO2H, –CO2(C1–6alkyl), –OC(=O)(C1–6alkyl), –OCO2(C1–6alkyl), –C(=O)NH2, –C(=O)N(C1–6 alkyl)2, –OC(=O)NH(C1–6 alkyl), –NHC(=O)( C1–6 alkyl), –N(C1–6 alkyl)C(=O)(C1–6 alkyl), –NHCO2(C1–6 alkyl), –NHC(=O)N(C1–6 alkyl)2, –NHC(=O)NH(C1–6alkyl), –NHC(=O)NH2, –C(=NH)O(C1–6alkyl),–OC(=NH)(C1–6alkyl), 5 –OC(=NH)OC1–6 alkyl, –C(=NH)N(C1–6 alkyl)2, –C(=NH)NH(C1–6 alkyl), –C(=NH)NH2, –OC(=NH)N(C1–6 alkyl)2, –OC(NH)NH(C1–6 alkyl), –OC(NH)NH2, –NHC(NH)N(C1–6 alkyl)2, –NHC(=NH)NH2, –NHSO2(C1–6alkyl), –SO2N(C1–6alkyl)2, –SO2NH(C1–6alkyl), –SO2NH2, –SO2C1–6 alkyl, –SO2OC1–6 alkyl, –OSO2C1–6 alkyl, –SOC1–6 alkyl, –Si(C1–6 alkyl)3, –OSi(C1–6 alkyl)3 –C(=S)N(C1–6 alkyl)2, C(=S)NH(C1–6 alkyl), C(=S)NH2, 10 –C(=O)S(C1–6alkyl), –C(=S)SC1–6alkyl, –SC(=S)SC1–6alkyl, –P(=O)2(C1–6alkyl), –P(=O)(C1–6alkyl)2, –OP(=O)(C1–6alkyl)2, –OP(=O)(OC1–6alkyl)2, C1–6alkyl, C1–6 perhaloalkyl, C2–6 alkenyl, C2–6 alkynyl, C3–10 carbocyclyl, C6–10 aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X–is a counterion. 15

[0088] 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–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HSO4–, SO4-2sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic 20 acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0089] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom 25 substitutuents include, but are not limited to, hydrogen, –OH, –ORaa, –N(Rcc)2, –CN,–C(=NRcc)N(Rcc)2, –SO2N(Rcc)2, –SO2Rcc, –SO2ORcc, –SORaa, –C(=S)N(Rcc)2, –C(=O)SRcc, –C(=S)SRcc, –P(=O)2Raa, –P(=O)(Raa)2, –P(=O)2N(Rcc)2, –P(=O)(NRcc)2, C1–10 alkyl, C1–10 perhaloalkyl, C2–10 alkenyl, C2–10 alkynyl, C3–10 carbocyclyl, 3–14 membered heterocyclyl, 30 C6–14aryl, and 5–14 membered heteroaryl, or two Rccgroups attached to a nitrogen atom 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 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above. 29Other Definitions

[0090] “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 5 recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0091] “Pharmaceutically acceptable salt” refers to a salt of a compound disclosed herein 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 10 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,15 methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, 20 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, 25 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, 30 calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1–79.

[0092] “Pharmaceutically acceptable carrier” refers to compositions, carriers, diluents, and reagents which are pharmaceutically acceptable materials that are capable of administration to or upon a subject. A pharmaceutically acceptable carrier can be involved with carrying or 30transporting the subject agents from one organ, or portion of the body, to another organ, or portion of the body. The carrier can be in the form of a solid, semi-solid or liquid diluent, cream or a capsule. The active ingredient can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient and in amounts 5 suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.

[0093] “Isotopic variant” refers to a compound disclosed herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof), wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number 10 different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,17O,18O,32P,33P,33S,34S,35S,18F, and37Cl. Compounds disclosed herein which contain the aforementioned isotopes and / or other isotopes 15 of other atoms are within the scope of this disclosure. Certain isotopic variants of the compounds of the present application, for example, those into which radioactive isotopes (e.g., 3H and 14C) are incorporated, may be useful in drug and / or substrate distribution assays.Further, substitution with heavier isotopes (e.g., 2H) can afford certain therapeutic advantagesresulting from greater metabolic stability, for example, increased in vivo half-life or reduced 20 dosage requirements and, hence, may be preferred in some circumstances. Isotopic variants of compounds and pharmaceutically acceptable salts thereof disclosed herein can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples, by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent. 25

[0094] A “subject” to which administration is contemplated includes, but is not limited to, a human subject (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 30 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.

[0095] “Disease,” “disorder,” and “condition” are used interchangeably herein.

[0096] As used herein, the term “treat,” “treating,” or “treatment” includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition 31in a manner to improve or stabilize a subject’s condition. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation, amelioration, reduction of the severity, or slowing the progression of 5 one or more symptoms or conditions associated with a condition, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. 10

[0097] As used herein, and unless otherwise specified, the term “prophylactic,” “prevention,” and variations thereof, contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder, or condition.

[0098] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this 15 art, the effective amount of a compound of the disclosure 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.

[0099] The terms “pharmaceutically effective amount,” “therapeutically effective amount,” 20 and “therapeutically effective dose” are used interchangeably herein and refer to an amount sufficient to treat a disease in a patient, e.g., effecting a beneficial and / or desirable alteration in the health of a patient suffering from a disease, treatment, healing, inhibition or amelioration of a physiological response or condition, delaying or minimizing one or more symptoms associated with the disease, disorder, or condition etc. The full therapeutic effect 25 does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, the nature and extent of disease, the therapeutics or combination of therapeutics selected for administration, 30 and the mode of administration. The skilled worker can readily determine the effective amount for a given situation by routine experimentation. The terms “pharmaceutically effective amount,” “therapeutically effective amount,” or “therapeutically effective dose” also refer to the amount required to improve the clinical symptoms of a patient. A therapeutically effective amount of a compound also refers to an amount of the therapeutic 32agent, 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 5 therapeutic agent.

[0100] 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 10 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.

[0101] As used herein, and unless otherwise specified, “pharmacokinetics” can be defined 15 as the study of bodily absorption, distribution, metabolism, and excretion of drugs. “Pharmacokinetics” can also be defined as the characteristic interactions of a drug and a body in terms of its absorption, distribution, metabolism, and excretion; or a branch of pharmacology concerned with the way drugs are taken into, move around, and are eliminated from, a body. 20

[0102] “Administering” or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and 25 transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. In some30 embodiments, the administration includes both direct administration, including self- administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug, or to have the drug administered by another, and / or who provides a patient with a prescription for a drug is administering the drug to the patient. When a method is part of a therapeutic regimen 33involving more than one agent or treatment modality, the disclosure contemplates that the agents may be administered at the same or differing times and via the same or differing routes of administration. Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age of the subject, whether the subject 5 is active or inactive at the time of administering, whether the subject is cognitively impaired at the time of administering, the extent of the impairment, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity).

[0103] The term “cleavable moiety” refers to a chemical moiety that may be cleaved via 10 hydrolysis, reduction, or an enzymatic reaction. Cleavable moieties include, but are not limited to acid-labile moieties, hydrolysis-labile moieties, enzymatically-cleavable moieties, reduction-labile moieties, and self-immolative moieties.

[0104] The term “self-immolative moiety,” as used herein, refers to a bivalent chemical moiety that comprises a covalent, scissile bond as one of its bivalent bonds and a stable, 15 covalent bond with a therapeutic agent as its other bivalent bond, wherein the bond with the therapeutic agent becomes labile upon cleavage of the scissile bond. The self-immolative group can be any such group known to those of skill in the art. Examples of self-immolative moieties include, but are not limited to, disulfide groups, hydrazones, acetal self-immolative moieties, carboxyacetal self-immolative moieties, carboxy(methylacetal) self-immolative20 moieties, para-hydroxybenzyl carbonyl self-immolative moieties, flipped ester self- immolative moieties, and trimethyl lock, or 2-hydroxyphenyl carbamate (2-HPC) self- immolative moieties. Other suitable self-immolative moieties are known in the art as described, for example, in C. Blencowe et al., Polym. Chem.2011, 2, 773-790 and Kratz et al., ChemMedChem.2008, 3(1), 20-53; Huvelle et al., Org. Biomot. Chem.2017, 15(16), 25 3435-3443; and Alouane. et al., Angewandte Chemie International Edition 2015, 54 (26), 7492-7509; and Levine et al., Chem. Sci.20123(8), 2412-2420; the disclosure of each of which is hereby incorporated by reference in its entirety.

[0105] The term “acid labile” refers to a molecule or compound that is sensitive to acids and can be cleaved or undergo significant changes in its structure or properties when exposed 30 to acidic conditions.

[0106] As generally described herein, the disclosure provides compounds useful for preventing and / or treating a broad range of disorders, including, but not limited to, NMDA- receptor mediated disorders. These compounds are expected to show improved in vivo 34potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, and / or safety as compared to other compounds. Compounds

[0107] In one aspect, the disclosure provides a compound of Formula (I): 5, or a pharmaceutically acceptable salt, isotopic variant, or a combination thereof, wherein: Agent iseach of R1and R2is independently hydrogen or a cleavable moiety, provided that at 10 least one of R1and R2is not hydrogen; R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-8 membered heteroaryl; 15 each of R15and R16is independently hydrogen or substituted or unsubstituted C1-6alkyl; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl; R18is hydrogen or substituted or unsubstituted C1-6 alkyl; 20 R19is hydrogen or substituted or unsubstituted C1-6 alkyl; each of R20and R20’is independently hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl; R22is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or 25 substituted or unsubstituted C6-10aryl; and is the point of attachment to R1or R2. For the sake of clarity, R1may be attached to either one of the twopositions and R2 may be attached to either one of the35two positions, provided that R1 is attached to Agent at one of the twopositions, and R2 is attached to Agent at the other of the twopositions.

[0108] In some embodiments, the compound of the disclosure is a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: 5 each of R1and R2is independently hydrogen or a cleavable moiety, provided that at least one of R1and R2is not hydrogen; R3is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, or 5-8 membered heteroaryl, wherein each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6carbocyclyl, C6-10aryl, and 5-8 membered heteroaryl is independently 10 optionally substituted with 1-5 RA; each of R15and R16is independently hydrogen or C1-6 alkyl optionally substituted with 1-5 RB; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6 carbocyclyl optionally substituted with 1-5 RB; 15 R18is hydrogen or C1-6 alkyl optionally substituted with 1-5 RC; R19is hydrogen or C1-6alkyl optionally substituted with 1-5 RD; each of R20and R20’is independently hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein each of said C1-6 alkyl and C3-6 carbocyclyl is independently optionally substituted with 1-5 RE; 20 each instance of RA, RB, RC, RD, and RE, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and C1-6alkoxy optionally substituted with 1-5 halo; R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or C6-10aryl, wherein each of said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl is independently 25 optionally substituted with 1-5 RFand each of said C3-6 carbocyclyl and C6-10 aryl is independently optionally substituted with 1-5 RG; each instance of RF, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C1-6 alkoxy optionally substituted with 1-5 halo, C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered 30 heterocyclyl, wherein each of said C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl is independently optionally substituted with 1-5 RF1; 36each instance of RF1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, C1-6 alkyl optionally substituted with 1-5 halo, and C1-6 alkoxy optionally substituted with 1-5 halo; and each instance of RG, when present, is independently selected from the group 5 consisting of halo, cyano, nitro, amino, C1-6 alkyl optionally substituted with 1-5 halo, and C1-6 alkoxy optionally substituted with 1-5 halo.

[0109] In some embodiments, the compound of Formula (I) is a compound of Formula (II)pharmaceutically acceptable salt, isotopic variant, or combination thereof. 10

[0110] In some embodiments, the compound of Formula (II) is a compound of Formula (II- A) or (II-B)pharmaceutically acceptable salt, isotopic variant, or combination thereof. Groups R1and R2– as they relate to Formulae (I), (II), (II-A), and (II-B) 15

[0111] In some embodiments, each of R1and R2is independently hydrogen or a cleavable moiety, provided that at least one of R1and R2is not hydrogen. In some embodiments, each of R1and R2is independently hydrogen or a cleavable moiety, provided that at least one of R1and R2is a cleavable moiety. In some embodiments, R1is hydrogen and R2is a cleavable moiety. In some embodiments, R1is a cleavable moiety and R2is hydrogen. In some 20 embodiments, each of R1and R2is independently a cleavable moiety. 37

[0112] In some embodiments, each instance of a cleavable moiety is independently selected from the group consisting of: -C(R’)(R’’)X1, -C(O)X2, -S(O)2OH, -S(O)2O-M+, -P(O)(OH)2, and -P(O)(O-M+)2, wherein: each of R’ and R’’ is independently hydrogen or C1-6alkyl; 5 X1is -OC(O)(C1-6 alkyl), -OC(O)(C1-6 alkoxy), or -N(RN1)(RN2); X2is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -N(RN1)(RN2), or 5-6 membered oxygen-containing heterocyclyl optionally substituted with 1-4 hydroxyl, wherein: each instance of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkoxy as they 10 relate to X1and X2is independently optionally substituted with 1-5 substituents independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, -C(O)OH, -C(O)O-M+, -C(O)(C1-6 alkyl), -C(O)(C1-6 alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OS(O)2OH, -OS(O)2O-M+, -OP(O)(OH)2, and -OP(O)(O-M+)2, wherein each instance of R is independently 15 hydrogen or -C(O)(C1-20 alkyl) and each instance of M+is independently Li+, Na+, K+, or NH4+; and each of RN1and RN2is independently hydrogen or C1-6alkyl; or RN1and RN2, together with the nitrogen atom to which they are attached, form a 5-10 membered monocyclic or bicyclic heteroaryl or 5-10 membered monocyclic or bicyclic 20 heterocyclyl.

[0113] In some embodiments, each instance of a cleavable moiety is independently -S(O)2OH, -S(O)2O-M+, -P(O)(OH)2, or -P(O)(O-M+)2. In some embodiments, each instance of a cleavable moiety is independently -S(O)2OH, -S(O)2O-Na+, -P(O)(OH)2, or -P(O)(O- Na+)2. 25

[0114] In some embodiments, each instance of a cleavable moiety is independently C(R’)(R’’)X1or -C(O)X2. In some embodiments, R’ and R’’ are both hydrogen. In some embodiments, R’ and R’’ are both C1-6alkyl. In some embodiments, R’ and R’’ are both -CH3. In some embodiments, one of R’ or R’’ is hydrogen and the other is C1-6 alkyl. In some embodiments, one of R’ or R’’ is hydrogen and the other is -CH3. 30

[0115] In some embodiments, X1is -OC(O)(C1-6alkyl), -OC(O)(C1-6alkoxy), or -N(RN1)(RN2). In some embodiments, X1is -OC(O)(C1-6alkyl) or -OC(O)(C1-6alkoxy). In some embodiments, X1is -OC(O)(C1-6 alkyl). In some embodiments, X1is -OC(O)(C1-6 alkoxy). In some embodiments, X1is -N(RN1)(RN2). 38

[0116] In some embodiments, X2is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, -N(RN1)(RN2), or 5-6 membered oxygen-containing heterocyclyl optionally substituted with 1-4 hydroxyl. In some embodiments, X2is C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, -N(RN1)(RN2), or 5-6 membered oxygen-containing heterocyclyl optionally substituted with 5 1-4 hydroxyl. In some embodiments, X2is C1-6 alkyl, C2-6 alkenyl, or C1-6 alkoxy. In some embodiments, X2is C1-6 alkyl or C2-6 alkenyl. In some embodiments, X2is C1-6 alkyl. In some embodiments, X2is C2-6alkenyl. In some embodiments, X2is C2-6alkynyl. In some embodiments, X2is C1-6 alkoxy. In some embodiments, X2is -N(RN1)(RN2). In some embodiments, X2is 5-6 membered oxygen-containing heterocyclyl optionally substituted 10 with 1-4 hydroxyl.

[0117] In some embodiments, each instance of a cleavable moiety is independently -CH2X1or -C(O)X2. In some embodiments, each instance of a cleavable moiety is independently selected from the group consisting of: -CH2OC(O)(C1-6 alkyl), -C(O)(C1-6 alkyl), -CH2OC(O)(C1-6alkoxy), -C(O)(C2-6alkenyl), -C(O)(C1-6alkoxy), -CH2N(RN1)(RN2), 15 -C(O)N(RN1)(RN2), and -C(O)(5-6 membered oxygen-containing heterocyclyl). In some embodiments, each instance of said C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is independently optionally substituted with amino, -C(O)OH, -C(O)O-M+, -C(O)(C1-6alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OP(O)(OH)2, or -OP(O)(O-M+)2. In some embodiments, each instance of said C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is independently20 optionally substituted with amino, -C(O)OH, -C(O)O-Li+, -C(O)O-Na+, -C(O)O-K+, -C(O)O- NH4+, -C(O)(C1-6alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OP(O)(OH)2, or -OP(O)(O-Na+)2. In some embodiments, each instance of said C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is independently optionally substituted with amino, -C(O)OH, -C(O)O-Li+, -C(O)O-Na+, -C(O)O-K+, -C(O)O-NH4+, -C(O)(C1-6alkoxy), 25 -C(O)OCH(CH2OC(O)C(CH2)14CH3)2, -C(O)OCH(CH2OH)2, -C(O)CH2CH(OH)CH2OH, -OP(O)(OH)2, or -OP(O)(O-Na+)2.

[0118] In some embodiments, each instance of a cleavable moiety is independently -CH2X1or -C(O)X2. In some embodiments, each instance of a cleavable moiety is independently selected from the group consisting of: -CH2OC(O)(C1-6 alkyl-Rx), -C(O)(C1-6 alkyl-Rx), 30 -CH2OC(O)(C1-6alkoxy-Rx), -C(O)(C2-6alkenyl-Rx), -C(O)(C1-6alkoxy-Rx), -CH2N(RN1)(RN2), -C(O)N(RN1)(RN2), and -C(O)(5-6 membered oxygen-containing heterocyclyl), wherein Rx is absent, amino, -C(O)OH, -C(O)O-M+, -C(O)(C1-6 alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OP(O)(OH)2, or -OP(O)(O-M+)2. In some embodiments, Rxis absent, amino, -C(O)OH, -C(O)O-Li+, -C(O)O-Na+, -C(O)O-K+, -C(O)O- 39NH4+, -C(O)(C1-6alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OP(O)(OH)2, or -OP(O)(O-Na+)2. In some embodiments, Rx is absent, amino, -C(O)OH, -C(O)O-Li+, -C(O)O-Na+, -C(O)O-K+, -C(O)O-NH4+, -C(O)(C1-6 alkoxy), -C(O)OCH(CH2OC(O)C(CH2)14CH3)2, -C(O)OCH(CH2OH)2, -C(O)CH2CH(OH)CH2OH, 5 -OP(O)(OH)2, or -OP(O)(O-Na+)2.

[0119] In some embodiments, each instance of a cleavable moiety is independently selected from the group consisting of: 10405

[0120] In some embodiments, each instance of a cleavable moiety is independently -CH2X1.

[0121] In some embodiments, each instance of a cleavable moiety is independently selected from the group consisting of: -CH2OC(O)(C1-6alkyl), -CH2OC(O)(C1-6alkoxy), and -CH2N(RN1)(RN2). In some embodiments, each instance of a cleavable moiety is 10 independently -CH2OC(O)(C1-6 alkyl). In some embodiments, each instance of a cleavable moiety is independently -CH2OC(O)(C1-6alkoxy). In some embodiments, each of said C1-6alkyl and C1-6 alkoxy is independently optionally substituted with amino, -C(O)OH, or -C(O)OCH(CH2OR)2. In some embodiments, each of said C1-6 alkyl and C1-6 alkoxy is independently optionally substituted with amino, -C(O)OH, or 15 -C(O)OCH(CH2OC(O)C(CH2)14CH3)2. In some embodiments, each instance of a cleavable moiety is independently -CH2N(RN1)(RN2), wherein RN1and RN2, together with the nitrogen atom to which they are attached, form a 5-10 membered monocyclic or bicyclic heteroaryl or 5-10 membered monocyclic or bicyclic heterocyclyl. In some embodiments, RN1and RN2, together with the nitrogen atom to which they are attached, form a 5-10 membered 20 monocyclic or bicyclic heteroaryl. In some embodiments, RN1and RN2, together with the nitrogen atom to which they are attached, form a 5-10 membered monocyclic or bicyclic heterocyclyl.

[0122] In some embodiments, each instance of a cleavable moiety is independently selected from the group consisting of: -CH2OC(O)(C1-6alkyl-Rx), -CH2OC(O)(C1-6alkoxy-Rx), and 41-CH2N(RN1)(RN2). In some embodiments, each instance of a cleavable moiety is independently -CH2OC(O)(C1-6 alkyl-Rx). In some embodiments, each instance of a cleavable moiety is independently -CH2OC(O)(C1-6 alkoxy-Rx). In some embodiments, Rx is absent, amino, -C(O)OH, or -C(O)OCH(CH2OR)2. In some embodiments, Rxis absent, 5 amino, -C(O)OH, or -C(O)OCH(CH2OC(O)C(CH2)14CH3)2.

[0123] In some embodiments, each instance of a cleavable moiety is independently selected from the group consisting of: 10.

[0124] In some embodiments, each instance of a cleavable moiety is independently -C(O)X2. In some embodiments, each instance of a cleavable moiety is independently selected from the group consisting of: -C(O)(C1-6 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C1-6 alkoxy), -C(O)N(RN1)(RN2), and -C(O)(5-6 membered oxygen-containing heterocyclyl). In 15 some embodiments, each instance of a cleavable moiety is independently -C(O)(C1-6alkyl). In some embodiments, each instance of a cleavable moiety is independently -C(O)(C2-6 alkenyl). In some embodiments, each instance of a cleavable moiety is independently -C(O)(C1-6alkoxy). In some embodiments, each instance of a cleavable moiety is independently -C(O)N(RN1)(RN2), wherein each of RN1and RN2is independently hydrogen or 20 C1-6 alkyl. In some embodiments, each instance of a cleavable moiety is independently -C(O)(5-6 membered oxygen-containing heterocyclyl substituted with 1-4 hydroxyl). In some embodiments, each instance of said C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is independently optionally substituted with amino, -C(O)OH, -C(O)O-M+, -C(O)(C1-6 alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OP(O)(OH)2, or -OP(O)(O-M+)2. In some 25 embodiments, each instance of said C1-6alkyl, C2-6alkenyl, and C1-6alkoxy is independently optionally substituted with amino, -C(O)OH, -C(O)O-Li+, -C(O)O-Na+, -C(O)O-K+, -C(O)O- 42NH4+, -C(O)(C1-6alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OP(O)(OH)2, or -OP(O)(O-Na+)2. In some embodiments, each instance of said C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is independently optionally substituted with amino, -C(O)OH, -C(O)O-Li+, -C(O)O-Na+, -C(O)O-K+, -C(O)O-NH4+, -C(O)(C1-6alkoxy), 5 -C(O)OCH(CH2OC(O)C(CH2)14CH3)2, -C(O)OCH(CH2OH)2, -C(O)CH2CH(OH)CH2OH, -OP(O)(OH)2, or -OP(O)(O-Na+)2.

[0125] In some embodiments, each instance of a cleavable moiety is independently -C(O)X2. In some embodiments, each instance of a cleavable moiety is independently selected from the group consisting of: -C(O)(C1-6 alkyl-Rx), -C(O)(C2-6 alkenyl-Rx), 10 -C(O)(C1-6alkoxy-Rx), -C(O)N(RN1)(RN2), and -C(O)(5-6 membered oxygen-containing heterocyclyl). In some embodiments, each instance of a cleavable moiety is independently -C(O)(C1-6 alkyl-Rx). In some embodiments, each instance of a cleavable moiety is independently -C(O)(C2-6 alkenyl-Rx). In some embodiments, each instance of a cleavable moiety is independently -C(O)(C1-6alkoxy-Rx). In some embodiments, Rxis absent, amino, 15 -C(O)OH, -C(O)O-M+, -C(O)(C1-6 alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OP(O)(OH)2, or -OP(O)(O-M+)2. In some embodiments, Rx is absent, amino, -C(O)OH, -C(O)O-Li+, -C(O)O-Na+, -C(O)O-K+, -C(O)O-NH4+, -C(O)(C1-6alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OP(O)(OH)2, or -OP(O)(O-Na+)2. In some embodiments, Rx is absent, amino, -C(O)OH, -C(O)O-Li+, -C(O)O-Na+, -C(O)O-K+, 20 -C(O)O-NH4+, -C(O)(C1-6alkoxy), -C(O)OCH(CH2OC(O)C(CH2)14CH3)2, -C(O)OCH(CH2OH)2, -C(O)CH2CH(OH)CH2OH, -OP(O)(OH)2, or -OP(O)(O-Na+)2.

[0126] In some embodiments, each instance of a cleavable moiety is independently selected from the group consisting of: 2543, 5 ,

[0127] In one aspect, the disclosure provides a compound of Formula (X):, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: 10 each of a and b is independently 0 or 1, provided that a and b are not both 0; and each instance of Z is independently hydrogen, -C(O)(C1-20alkyl), or -C(O)- (C(RZ1)(RZ2))1-6-C(O)(Agent), provided that at least two instances of Z are -C(O)- (C(RZ1)(RZ2))1-6-C(O)(Agent) and wherein: 15 each instance of RZ1and RZ2is independently hydrogen or C1-6alkyl; and each instance of Agent is independently a compound of Formula (X-I): 44wherein: Y is hydrogen or a bond, provided that one instance of Y is a bond and the other is hydrogen, wherein said bond is the point of attachment between Agent and the associated 5 C(O); R3is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, substituted or unsubstituted C6-10aryl, or substituted or unsubstituted 5-8 membered heteroaryl; 10 each of R15and R16is independently hydrogen or substituted or unsubstituted C1-6 alkyl; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 carbocyclyl; R18is hydrogen or substituted or unsubstituted C1-6alkyl; 15 R19is hydrogen or substituted or unsubstituted C1-6alkyl; R20is hydrogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 carbocyclyl; R20’is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl; and 20 R22is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or substituted or unsubstituted C6-10aryl. For the sake of clarity, when Y is a bond, the bond is the point of attachment to the C(O) group adjacent to the Agent in -C(O)-(C(RZ1)(RZ2))1-6-C(O)(Agent). 25 Integers a and b – as they relate to Formula (X)

[0128] In some embodiments, each of a and b is independently 0 or 1, provided that a and b are not both 0. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a is 1 and b is 1. 45Group Z – as it relates to Formula (X)

[0129] In some embodiments, each instance of Z is independently hydrogen, -C(O)(C1-20 alkyl), or -C(O)-(C(RZ1)(RZ2))1-6-C(O)(Agent), provided that at least two instances of Z are -C(O)-(C(RZ1)(RZ2))1-6-C(O)(Agent). In some embodiments, one instance of Z is hydrogen. 5 In some embodiments, one instance of Z is -C(O)(C1-20 alkyl). In some embodiments, one instance of Z is -C(O)(CH2)14CH3. In some embodiments, two instances of Z are -C(O)- (C(RZ1)(RZ2))1-6-C(O)(Agent). In some embodiments, each instance of Z is -C(O)- (C(RZ1)(RZ2))1-6-C(O)(Agent). In some embodiments, each of RZ1and RZ2is independently hydrogen or C1-6 alkyl. In some embodiments, each instance of RZ1and RZ2is hydrogen. In 10 some embodiments, each instance of RZ1and RZ2is C1-6alkyl. In some embodiments, two instances of Z are -C(O)-(CH2)3-C(O)(Agent). In some embodiments, each instance of Z is -C(O)-(CH2)3-C(O)(Agent).

[0130] In some embodiments, each instance of Agent is independently a compound of Formula (X-I): 15, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: Y is hydrogen or a bond, provided that one instance of Y is a bond and the other is hydrogen, wherein said bond is the point of attachment between Agent and the associated C(O); 20 R3is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, C6-10 aryl, or 5-8 membered heteroaryl, wherein each of said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, and 5-8 membered heteroaryl is independently optionally substituted with 1-5 RA; each of R15and R16is independently hydrogen or C1-6alkyl optionally 25 substituted with 1-5 RB; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6 carbocyclyl optionally substituted with 1-5 RB; R18is hydrogen or C1-6alkyl optionally substituted with 1-5 RC; 46R19is hydrogen or C1-6alkyl optionally substituted with 1-5 RD; each of R20and R20’is independently hydrogen, hydroxyl, C1-6 alkyl, or C3-6 carbocyclyl, wherein each of said C1-6 alkyl and C3-6 carbocyclyl is independently optionally substituted with 1-5 RE; 5 each instance of RA, RB, RC, RD, and RE, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10 aryl, and C1-6alkoxy optionally substituted with 1-5 halo; R22is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or C6-10 aryl, wherein each of said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl is independently optionally substituted 10 with 1-5 RFand each of said C3-6carbocyclyl and C6-10aryl is independently optionally substituted with 1-5 RG; each instance of RF, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C1-6 alkoxy optionally substituted with 1-5 halo, C3-6 carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein 15 each of said C3-6 carbocyclyl, C6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl is independently optionally substituted with 1-5 RF1; each instance of RF1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, C1-6 alkyl optionally substituted with 1-5 halo, and C1-6 alkoxy optionally substituted with 1-5 halo; and 20 each instance of RG, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C1-6alkyl optionally substituted with 1-5 halo, and C1-6 alkoxy optionally substituted with 1-5 halo.

[0131] In some embodiments, the compound of Formula (X-I) is a compound of Formula (X-II): 25pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0132] In some embodiments, the compound of Formula (X-II) is a compound of Formula (X-II-A) or (X-II-A): 47or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. Agent – as it relates to Formulae (I), (II), (II-A), (II-B), (X), (X-I), (X-II), (X-II-A), and (X- II-B) 5

[0133] In some embodiments, each instance of Agent is independently any one of the structures in Table A:48ĴĹ50515253545556ĵķFor the sake of clarity, in the above Table A,represents the point of attachment to R1or R2in Formulae (I), (II), (II-A), and (II-B) or the point of attachment to Y in Formulae (X), (X-I), (X-II), (X-II-A), and (X-II-B). Unless otherwise defined,can represent the point of attachment to either R1or R2in Formulae (I), (II), (II-A), and (II-B). 59

[0134] In some embodiments, each instance of Agent is independently 5In some embodiments, each instance of Agent is independently. 60

[0135] In some embodiments, each instance of Agent is independently 561. Groups R3 and RA – as they relate to Formulae (I), (II), (II-A), (II-B), (X-I), (X-II), (X-II-A), and (X-II-B)

[0136] In certain embodiments, R3is hydrogen, substituted or unsubstituted C1-6alkyl, 5 substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6 carbocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R3is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 5-8 membered heteroaryl, wherein each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, C6-10 aryl, and 5-8 membered 10 heteroaryl is independently optionally substituted with 1-5 RA.

[0137] In certain embodiments, R3is substituted or unsubstituted C1-6alkyl. In some embodiments, R3is C1-6 alkyl optionally substituted with 1-5 RA. In some embodiments, R3is C1-6 alkyl optionally substituted with 1-3 RA. In some embodiments, R3is C1-3 alkyl optionally substituted with 1-5 RA. In some embodiments, R3is C1-3alkyl optionally 15 substituted with 1-3 RA. In some embodiments, R3is methyl optionally substituted with 1-3 RA. In some embodiments, R3is C1-3 alkyl substituted with 1-5 RA. In some embodiments, R3is C1-3alkyl substituted with 1-3 RA. In some embodiments, R3is methyl substituted with 1-3 RA. In some embodiments, R3is -CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R3is -CH3. In some embodiments, R3is -CH2F. In some embodiments, R3is -CHF2. In 20 some embodiments, R3is -CF3.

[0138] In certain embodiments, each instance of RA, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10 aryl, and substituted or unsubstituted C1-6 alkoxy. In some embodiments, each instance of RA, when present, is independently selected from the group consisting of halo, 25 hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RA, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C1-6alkoxy substituted with 1-5 halo. In some embodiments, each instance of RA, when present, is independently selected from the group consisting of fluoro, hydroxyl, and unsubstituted 62C1-6alkoxy. In some embodiments, each instance of RA, when present, is independently selected from the group consisting of fluoro, hydroxyl, and -OCH3. In some embodiments, each instance of RA, when present, is fluoro. Groups R15, R16, and RB– as they relate to Formulae (I) and (X) 5

[0139] In certain embodiments, R15is hydrogen or substituted or unsubstituted C1-6 alkyl. In some embodiments, R15is hydrogen or C1-6 alkyl optionally substituted with 1-5 RB. In certain embodiments, R15is hydrogen.

[0140] In certain embodiments, R16is hydrogen or substituted or unsubstituted C1-6 alkyl. In some embodiments, R16is hydrogen or C1-6 alkyl optionally substituted with 1-5 RB. In 10 certain embodiments, R16is hydrogen.

[0141] In certain embodiments, each of R15and R16is independently hydrogen or substituted or unsubstituted C1-6 alkyl; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 carbocyclyl. In certain embodiments, each of R15and R16is independently hydrogen or C1-6alkyl optionally 15 substituted with 1-5 RB; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6 carbocyclyl optionally substituted with 1-5 RB. In certain embodiments, R15and R16are both hydrogen.

[0142] In certain embodiments, each instance of RB, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, 20 thioketo, C6-10aryl, and substituted or unsubstituted C1-6alkoxy. In some embodiments, each instance of RB, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10 aryl, and C1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RB, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C1-625 alkoxy substituted with 1-5 halo. In some embodiments, each instance of RB, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3. Groups R18, R19, RC, and RD– as they relate to Formulae (I), (II), (X-I), and / or (X-II)

[0143] In certain embodiments, R18is hydrogen or substituted or unsubstituted C1-6 alkyl. In some embodiments, R18is hydrogen or C1-6 alkyl optionally substituted with 1-5 RC. In 30 some embodiments, R19is hydrogen or -CH3. In some embodiments, R18is hydrogen. In some embodiments, R18is -CH3.

[0144] In certain embodiments, R19is hydrogen or substituted or unsubstituted C1-6 alkyl. In some embodiments, R19is hydrogen or C1-6 alkyl optionally substituted with 1-5 RD. In 63some embodiments, R19is hydrogen or -CH3. In certain embodiments, R19is hydrogen. In some embodiments, R19is -CH3.

[0145] In certain embodiments, each instance of RC, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, 5 thioketo, C6-10 aryl, and substituted or unsubstituted C1-6 alkoxy. In some embodiments, each instance of RC, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RC, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C1-6 10 alkoxy substituted with 1-5 halo. In some embodiments, each instance of RC, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3.

[0146] In certain embodiments, each instance of RD, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and substituted or unsubstituted C1-6alkoxy. In some embodiments, each 15 instance of RD, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10 aryl, and C1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RD, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3. 20 Groups R20, R20’, and RE– as they relate to Formulae (I) and (X)

[0147] In certain embodiments, R20is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6 carbocyclyl. In certain embodiments, R20is hydrogen, hydroxyl, C1-6 alkyl, or C3-6 carbocyclyl, wherein each of said C1-6 alkyl and C3-6 carbocyclyl is independently optionally substituted with 1-5 RE. In certain embodiments, R2025 is hydrogen.

[0148] In certain embodiments, R20’is hydrogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6carbocyclyl. In some embodiments, R20’is hydrogen, hydroxyl, C1-6 alkyl, or C3-6 carbocyclyl, wherein each of said C1-6 alkyl and C3-6 carbocyclyl is independently optionally substituted with 1-5 RE. In some embodiments, R20’30 is unsubstituted C1-6alkyl. In some embodiments, R20’is unsubstituted C1-3alkyl. In some embodiments, R20’is -CH3.

[0149] In certain embodiments, each of R20and R20’is independently hydrogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 carbocyclyl. In 64some embodiments, each of R20and R20’is independently hydrogen, hydroxyl, C1-6alkyl, or C3-6 carbocyclyl, wherein each of said C1-6 alkyl and C3-6 carbocyclyl is independently optionally substituted with 1-5 RE. In some embodiments, R20and R20’are not both hydroxyl. In some embodiments, R20is hydrogen and R20’is -CH3. 5

[0150] In certain embodiments, each instance of RE, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and substituted or unsubstituted C1-6alkoxy. In some embodiments, each instance of RE, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10 aryl, and C1-6 alkoxy 10 optionally substituted with 1-5 halo. In some embodiments, each instance of RE, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C1-6alkoxy substituted with 1-5 halo. In some embodiments, each instance of RE, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3. Groups R22, RF, RF1, and RG – as they relate to Formulae (I), (II), (II-A), (II-B), (X-I), (X-15 II), (X-II-A), and (X-II-B)

[0151] In certain embodiments, R22is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6 carbocyclyl, or substituted or unsubstituted C6-10 aryl. In certain embodiments, R22is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or C6-10 aryl, 20 wherein each of said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl is independently optionally substituted with 1-5 RFand said each of C3-6carbocyclyl and C6-10aryl is independently optionally substituted with 1-5 RG. In some embodiments, R22is unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, unsubstituted C3-6 carbocyclyl, or unsubstituted C6-10aryl. In certain embodiments, R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 25 C3-6 carbocyclyl, or C6-10 aryl, wherein each of said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl is independently substituted with 1-5 RFand said each of C3-6 carbocyclyl and C6-10 aryl is independently substituted with 1-5 RG.

[0152] In certain embodiments, R22is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R22is C1-6 alkyl optionally substituted with 1-5 RF. In certain embodiments, 30 R22is C1-6alkyl optionally substituted with 1-3 RF. In certain embodiments, R22is C1-6alkyl optionally substituted with 1 RF. In some embodiments, R22is methyl optionally substituted with 1-3 RF. In some embodiments, R22is methyl optionally substituted with 1 RF. 65

[0153] In certain embodiments, R22is substituted C1-6alkyl. In certain embodiments, R22is C1-6 alkyl substituted with 1-5 RF. In certain embodiments, R22is C1-6 alkyl substituted with 1-3 RF. In certain embodiments, R22is C1-6 alkyl substituted with 1 RF. In some embodiments, R22is methyl substituted with 1-3 RF. In some embodiments, R22is methyl 5 substituted with 1 RF. In certain embodiments, R22is unsubstituted C1-6 alkyl. In some embodiments, R22is -CH3, -CH2F, -CHF2, -CF3, or -CH2OCH3. In some embodiments, R22is -CH3, -CH2F, or -CH2OCH3. In some embodiments, R22is -CH3. In some embodiments, when R22is -CH3, R3is not -CH3 or hydrogen. In some embodiments, R22is -CH2F. In some embodiments, R22is -CH2OCH3. 10

[0154] In certain embodiments, each instance of RF, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, substituted or unsubstituted C1-6alkoxy, substituted or unsubstituted C3-6 carbocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-8 membered heteroaryl, and substituted or unsubstituted 5-8 membered heterocyclyl. In some embodiments, each instance of RF, when present, is 15 independently selected from the group consisting of halo, hydroxyl, cyano, C1-6 alkoxy optionally substituted with 1-5 halo, C3-6 carbocyclyl, C6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein each of said C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl is independently optionally substituted with 1-5 RF1. In some embodiments, each instance of RF, when present, is independently 20 selected from the group consisting of halo, hydroxyl, cyano, C1-6alkoxy substituted with 1-5 halo, C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein each of said C3-6 carbocyclyl, C6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl is independently substituted with 1-5 RF1. In some embodiments, each instance of RF, when present, is independently selected from the group consisting of 25 halo, hydroxyl, and -OCH3. In some embodiments, each instance of RF, when present, is independently selected from the group consisting of fluoro, hydroxyl, and -OCH3. In some embodiments, each instance of RF, when present, is independently selected from the group consisting of fluoro and -OCH3.

[0155] In some embodiments, each instance of RF1, when present, is independently selected 30 from the group consisting of halo, cyano, nitro, amino, C1-6alkyl optionally substituted with 1-5 halo, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RF1, when present, is independently selected from the group consisting of fluoro, -CH3, -CF3, -OCH3, and -OCF3. 66

[0156] In certain embodiments, each instance of RG, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C1-6 alkyl optionally substituted with 1-5 halo, and C1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RG, when present, is independently selected from the group 5 consisting of fluoro, -CH3, -CF3, -OCH3, and -OCF3.

[0157] In some embodiments, the compound of Formulae (I) or (X) is any one of the compounds in Table 1, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. Table 16768697071727374

[0158] In some embodiments, the compound is any one of compounds 1-78. In some embodiments, the compound is a pharmaceutically acceptable salt of any one of compounds 1-78. In some embodiments, the compound is an isotopic variant of any one of compounds 1-78. In some embodiments, the compound is an isotopic variant of a pharmaceutically 5 acceptable salt of any one of compounds 1-78.

[0159] In some embodiments, the compound of Formula (I) is any one of compounds 1-75, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound is any one of compounds 1-75. In some embodiments, the compound is a pharmaceutically acceptable salt of any one of compounds 1-75. In some 10 embodiments, the compound is an isotopic variant of any one of compounds 1-75. In some embodiments, the compound is an isotopic variant of a pharmaceutically acceptable salt of any one of compounds 1-75.

[0160] In some embodiments, the compound of Formula (X) is any one of compounds 76- 78, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some 15 embodiments, the compound is any one of compounds 76-78. In some embodiments, the compound is a pharmaceutically acceptable salat of any one of compounds 76-78. In some embodiments, the compound is an isotopic variant of any one of compounds 76-78. In some embodiments, the compound is an isotopic variant of a pharmaceutically acceptable salt of any one of compounds 76-78. 75

[0161] It is to be understood that in any of the preceding embodiments, the compound may be in a non-salt form, or in the form of a pharmaceutically acceptable salt, an isotopic variant, or any chemically permissible combination thereof. For example, in some embodiments, the compound provided herein is a compound of any one of Formulae (I), (II), (II-A), (II-B), or 5 (X). In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of a compound of any one of Formulae (I), (II), (II-A), (II-B), or (X). In some embodiments, the compound provided herein is an isotopic variant of a compound of any one of Formulae (I), (II), (II-A), (II-B), or (X). In some embodiments, the compound provided herein is an isotopic variant of a pharmaceutically acceptable salt of a compound of any one 10 of Formulae (I), (II), (II-A), (II-B), or (X). Alternative Embodiments

[0162] In some embodiments, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,11C,13C, or14C; oxygen may be, for example18O; 15 nitrogen may be, for example15N, and the like. In other embodiments, a particular isotope (e.g., 2H, 13C, 14C, 18O, or 15N) can represent at least 1%, at least 5%, at least 10%, at least15%, 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 20 element that occupies a specific site of the compound.

[0163] In certain embodiments, compounds described herein have one or more hydrogen atoms independently replaced by deuterium or tritium. In some embodiments, compounds described herein have one or more hydrogen atoms replaced by deuterium. In some embodiments, compounds described herein have one or more hydrogen atoms replaced by 25 tritium. Pharmaceutical Compositions

[0164] In another aspect, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound described herein (e.g., a compound of any one of Formulae (I), (II), (II-A), (II-B), or (X), or a 30 pharmaceutically acceptable salt, isotopic variant, or combination thereof). In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of any one of Formulae (I), (II), (II-A), (II-B), or (X) and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of compound of any one of Formulae (I), (II), 76(II-A), (II-B), or (X) and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising an isotopic variant of a compound of any one of Formulae (I), (II), (II-A), (II-B), or (X) and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical 5 composition comprising an isotopic variant of a pharmaceutically acceptable salt of a compound of any one of Formulae (I), (II), (II-A), (II-B), or (X) and a pharmaceutically acceptable carrier.

[0165] When employed as pharmaceuticals, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be 10 prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

[0166] When used to prevent the onset of a disease, condition or disorder, the compounds provided herein are administered to a subject at risk for developing the disease, condition or disorder, typically on the advice and under the supervision of a physician, and at the dosages 15 described herein. Subjects at risk for developing a particular condition include, but are not limited to, those having a family history of the condition, or those who have been identified by a screening or evaluation method to be particularly susceptible to developing the condition.

[0167] The pharmaceutical compositions provided herein may also be administered 20 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 indefinitely (e.g., for the rest of the subject’s life).

[0168] In some embodiments, with respect to the pharmaceutical composition, the carrier is 25 a parenteral carrier, oral or topical carrier.

[0169] The present disclosure also relates to a compound described herein (e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition thereof) for use as a pharmaceutical or a medicament. 30

[0170] In some embodiments, the compound or pharmaceutically acceptable salt thereof of the present disclosure is provided in an effective amount in the pharmaceutical composition. In some embodiments, the compound or pharmaceutically acceptable salt thereof of the present disclosure is provided in a therapeutically effective amount. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound or 77pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof.

[0171] Generally, the compounds provided herein are administered in a therapeutically 5 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. 10

[0172] The pharmaceutical compositions provided herein can be administered by a variety of routes including oral, parenteral, rectal, transdermal, intradermal, intrathecal, subcutaneous, intravenous, intramuscular, and intranasal.

[0173] The compositions for oral administration can take the form of bulk liquid solutionsor suspensions, or bulk powders. More commonly, however, the compositions are presented 15 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 20 compositions, 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 carriers and processing aids helpful for forming the desired dosing form.

[0174] Liquid forms suitable for oral administration may include a suitable aqueous or 25 nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms (e.g., pills, tablets, capsules) 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 corn starch; a lubricant such as magnesium stearate; 30 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.

[0175] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active 78compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0176] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 5 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. 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 10 formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0177] The compounds provided herein can also be administered by a transdermal device. 15 Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0178] The present disclosure also provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, e.g., a composition suitable for injection, such as for intravenous (IV) administration, or for oral 20 administration.

[0179] Pharmaceutically acceptable carriers 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, oral, etc. General considerations in the formulation and / or manufacture of pharmaceutical 25 compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, Ε. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0180] The above-described components for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials as well as processing 30 techniques and the like are set forth in Part 8 of Remington’s The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, and Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, each of which is incorporated herein by reference. 79

[0181] The compounds of this disclosure 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.

[0182] The present disclosure also relates to the pharmaceutically acceptable formulations 5 of a compound described herein (e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof). In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ- cyclodextrins consisting of 6, 7, and 8 α-l ,4-linked glucose units, respectively, optionally 10 comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. 5,376,645. Incertain embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In a more 15 particular embodiment, the formulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0183] The present disclosure also relates to the pharmaceutically acceptable acid addition salt of a compound described herein (e.g., a compound of Formulae (I) or (X)). The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non- 20 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.

[0184] For the prevention and / or treatment of long-term conditions the regimen for 25 treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. 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, from about 0.1 to about 10 mg / kg, or from about 1 to about 5 mg / kg of the compound provided herein. 30

[0185] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0186] When used to prevent the onset of a condition, 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 80for 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.

[0187] The amount of active ingredient that may be combined with the carrier materials to 5 produce a single dosage form will vary depending upon the subject, the disease or disorder to be treated and the particular mode of administration. As the skilled artisan will appreciate, specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, 10 the severity and course of the disease or disorder, the patient’s disposition to the disease or disorder and the judgment of the treating physician.

[0188] 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 15 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. Methods of Treatment and Use

[0189] Compounds of the present disclosure (e.g., a compound of Formulae (I) or (X), and 20 pharmaceutically acceptable salts, isotopic variants, and combinations thereof), as described herein, are generally designed to facilitate the delivery of allosteric modulators of NMDA receptor function, and therefore are useful for the treatment and prevention of, e.g., CNS- related conditions in a subject.

[0190] In some embodiments, the compounds described herein (e.g., a compound of 25 Formulae (I) or (X), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), as described herein, are generally designed to penetrate the blood brain barrier (e.g., designed to be transported across the blood brain barrier).

[0191] In certain embodiments, the compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination 30 thereof, facilitates the delivery of a positive allosteric modulator (PAM) of NMDA receptors that activates NMDA receptor function.

[0192] In certain embodiments, the compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination 81thereof, facilitates the delivery of a negative allosteric modulator (NAM) of an NMDA receptor that inhibits NMDA receptor function.

[0193] In certain embodiments, the compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination 5 thereof, facilitates the delivery of a neutral allosteric ligand (NAL) of NMDA receptors that binds at allosteric sites and block the effects of a PAM and / or NAM of an NMDA receptor.

[0194] In some embodiments, the compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, is useful for delivering and releasing a positive allosteric modulator (PAM) of 10 NMDA receptor at a target site (e.g., any target tissue).

[0195] In some embodiments, the compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, is useful for delivering and releasing a negative allosteric modulator (NAM) of NMDA receptor at a target site (e.g., any target tissue). 15

[0196] In some embodiments, the compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, is useful for delivering and releasing a neutral allosteric ligand (NAL) of NMDA receptor at a target site (e.g., any target tissue).

[0197] In some embodiments, the compound of the present disclosure, e.g., a compound 20 of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, is useful for improving the bioavailability and other pharmacokinetic characteristics of a positive allosteric modulator (PAM) of NMDA receptor.

[0198] In some embodiments, the compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination 25 thereof, is useful for improving the bioavailability and other pharmacokinetic characteristics of a negative allosteric modulator (NAM) of NMDA receptor.

[0199] In some embodiments, the compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, is useful for improving the bioavailability and other pharmacokinetic characteristics 30 of a neutral allosteric ligand (NAL) of NMDA receptor.

[0200] In one aspect, the disclosure provides a method for effecting allosteric modulation of an NMDA receptor in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. In some embodiments, the 82method is for effecting positive allosteric modulation of an NMDA receptor in a subject. In some embodiments, the method is for effecting negative allosteric modulation of an NMDA receptor in a subject. In some embodiments, the method comprises binding an NMDA receptor at an allosteric site with a compound disclosed herein and blocking the effects of an 5 allosteric NMDA receptor modulator (i.e., PAM and / or NAM) in a subject.

[0201] In one aspect, the disclosure provides a method for treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as 10 disclosed herein. In some embodiments, treating the disease, disorder, or condition requires positive allosteric NMDA receptor modulation in a subject. In some embodiments, treating the disease, disorder, or condition requires negative allosteric NMDA receptor modulation in a subject. In some embodiments, treating the disease, disorder, or condition requires a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the 15 effects of a PAM or NAM of an NMDA receptor in a subject.

[0202] In one aspect, the disclosure provides a method for treating a CNS-related condition in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. In some embodiments, treating the CNS- 20 related condition requires positive allosteric NMDA receptor modulation in a subject. In some embodiments, treating the CNS-related condition requires negative allosteric NMDA receptor modulation in a subject. In some embodiments, treating the CNS-related condition requires a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor in a subject. 25

[0203] In one aspect, the disclosure provides a method for preventing a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. In some embodiments, preventing the disease, disorder, or condition 30 requires positive allosteric NMDA receptor modulation in a subject. In some embodiments, preventing the disease, disorder, or condition requires negative allosteric NMDA receptor modulation in a subject. In some embodiments, preventing the disease, disorder, or condition requires a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor in a subject. 83

[0204] In one aspect, the disclosure provides a method for preventing a CNS-related condition in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. In some embodiments, preventing the 5 CNS-related condition requires positive allosteric NMDA receptor modulation in a subject. In some embodiments, preventing the CNS-related condition requires negative allosteric NMDA receptor modulation in a subject. In some embodiments, preventing the CNS-related condition requires a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor in a subject. 10

[0205] In some embodiments, the disclosure provides a method of delivering and releasing a positive allosteric modulator (PAM) of NMDA receptor at a target site (e.g., any target tissue) using a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0206] In some embodiments, the disclosure provides a method of delivering and releasing 15 a negative allosteric modulator (NAM) of NMDA receptor at a target site (e.g., any target tissue) using a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0207] In some embodiments, the disclosure provides a method of delivering and releasing a neutral allosteric ligand (NAL)of NMDA receptor at a target site (e.g., any target tissue) 20 using a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0208] In some embodiments, the disclosure provides a method of improving the bioavailability and other pharmacokinetic characteristics of a positive allosteric modulator (PAM) of NMDA receptor using a compound of the present disclosure, e.g., a compound of 25 Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0209] In some embodiments, the disclosure provides a method of improving the bioavailability and other pharmacokinetic characteristics of a negative allosteric modulator (NAM) of NMDA receptor using a compound of the present disclosure, e.g., a compound of 30 Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0210] In some embodiments, the disclosure provides a method of improving the bioavailability and other pharmacokinetic characteristics of a neutral allosteric ligand (NAL) of NMDA receptor using a compound of the present disclosure, e.g., a compound of 84Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0211] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed 5 herein for use in effecting allosteric modulation of an NMDA receptor in a subject. In some embodiments, the compound, pharmaceutically acceptable salt, isotopic variant, combination, or pharmaceutical composition is for use in effecting positive allosteric modulation of an NMDA receptor in a subject. In some embodiments, the compound, pharmaceutically acceptable salt, isotopic variant, combination, or pharmaceutical composition is for use in 10 effecting negative allosteric modulation of an NMDA receptor in a subject. In some embodiments, the compound, pharmaceutically acceptable salt, isotopic variant, combination, or pharmaceutical composition is for use in blocking the effects of a PAM or NAM of an NMDA receptor.

[0212] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable 15 salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating the disease, disorder or condition facilitates the delivery of 20 a positive allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating the disease, disorder or condition facilitates the delivery of a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or 25 combination thereof, or pharmaceutical composition as disclosed herein for use in treating the disease, disorder or condition facilitates the delivery of a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0213] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable 30 salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a CNS-related condition in a subject. In some embodiments, the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a CNS-related condition in a subject facilitates the delivery of a positive allosteric NMDA receptor modulator. In some 85embodiments, the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a CNS-related condition in a subject facilitates the delivery of a negative allosteric NMDA receptor modulator. In some embodiments, the compound or pharmaceutically acceptable 5 salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein is for use in treating a CNS-related condition in a subject facilitates the delivery of a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0214] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable 10 salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject. In some embodiments the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing the disease, disorder or condition facilitates the 15 delivery of a positive allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing the disease, disorder or condition facilitates the delivery of a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or 20 combination thereof, or pharmaceutical composition as disclosed herein for use in preventing the disease, disorder or condition facilitates the delivery of a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0215] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable 25 salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a CNS-related condition in a subject. In some embodiments, the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a CNS-related condition in a subject facilitates the delivery of a positive allosteric NMDA receptor 30 modulator. In some embodiments, the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a CNS-related condition in a subject facilitates the delivery of a negative allosteric NMDA receptor modulator. In some embodiments, the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical 86composition as disclosed herein is for use in preventing a CNS-related condition in a subject facilitates the delivery of a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0216] In some embodiments, the disclosure provides a compound or a pharmaceutically 5 acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for delivering and releasing a positive allosteric modulator (PAM) of NMDA receptor at a target site (e.g., any target tissue) using a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 10

[0217] In some embodiments, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for delivering and releasing a negative allosteric modulator (NAM) of NMDA receptor at a target site (e.g., any target tissue) using a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, 15 isotopic variant, or combination thereof.

[0218] In some embodiments, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for delivering and releasing a neutral allosteric ligand (NAL)of NMDA receptor at a target site (e.g., any target tissue) using a compound of the present disclosure, 20 e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0219] In some embodiments, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for improving the bioavailability and other pharmacokinetic characteristics 25 of a positive allosteric modulator (PAM) of NMDA receptor using a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0220] In some embodiments, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as 30 disclosed herein for improving the bioavailability and other pharmacokinetic characteristics of a negative allosteric modulator (NAM) of NMDA receptor using a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 87

[0221] In some embodiments, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for improving the bioavailability and other pharmacokinetic characteristics of a neutral allosteric ligand (NAL) of NMDA receptor using a compound of the present 5 disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0222] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for effecting allosteric modulation of an 10 NMDA receptor in a subject. In some embodiments, the medicament is for effecting positive allosteric modulation of an NMDA receptor in a subject. In some embodiments, the medicament is for effecting negative allosteric modulation of an NMDA receptor in a subject. In some embodiments, the medicament is for blocking the effects of a PAM or NAM of an NMDA receptor. 15

[0223] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation in a subject. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or 20 combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for treating the disease, disorder or condition facilitates the delivery of a positive allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for 25 treating the disease, disorder or condition facilitates the delivery of a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for treating the disease, disorder or condition facilitates the delivery of a neutral allosteric ligand (NAL) of an NMDA receptor 30 which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0224] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for treating a CNS-related condition in a 88subject. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for treating the CNS-related condition facilitates the delivery of a positive allosteric NMDA receptor modulator. In some embodiments, the 5 compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for treating the CNS-related condition facilitates the delivery of a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed 10 herein used in the manufacture of a medicament for treating the CNS-related condition facilitates the delivery of a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0225] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as 15 disclosed herein in the manufacture of a medicament for preventing a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for preventing the disease, disorder or condition facilitates the 20 delivery of a positive allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for preventing the disease, disorder or condition facilitates the delivery of a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically 25 acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for preventing the disease, disorder or condition facilitates the delivery of a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor. 30

[0226] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for preventing a CNS-related condition in a subject. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein 89used in the manufacture of a medicament for preventing the CNS-related condition facilitates the delivery of a positive allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for 5 preventing the CNS-related condition facilitates the delivery of a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for preventing the CNS-related condition facilitates the delivery of a neutral allosteric ligand (NAL) of an NMDA receptor which binds 10 at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0227] In some embodiments, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for delivering and releasing a positive allosteric modulator (PAM) of NMDA receptor at a target site (e.g., any 15 target tissue) using a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0228] In some embodiments, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for delivering and 20 releasing a negative allosteric modulator (NAM) of NMDA receptor at a target site (e.g., any target tissue) using a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0229] In some embodiments, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical 25 composition as disclosed herein in the manufacture of a medicament for delivering and releasing a neutral allosteric ligand (NAL)of NMDA receptor at a target site (e.g., any target tissue) using a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0230] In some embodiments, the disclosure provides the use of a compound or a 30 pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for improving the bioavailability and other pharmacokinetic characteristics of a positive allosteric modulator (PAM) of NMDA receptor using a compound of the present disclosure, e.g., a compound of 90Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0231] In some embodiments, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical 5 composition as disclosed herein in the manufacture of a medicament for improving the bioavailability and other pharmacokinetic characteristics of a negative allosteric modulator (NAM) of NMDA receptor using a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 10

[0232] In some embodiments, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for improving the bioavailability and other pharmacokinetic characteristics of a neutral allosteric ligand (NAL) of NMDA receptor using a compound of the present disclosure, e.g., a compound of 15 Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0233] Exemplary diseases, disorders, and conditions requiring allosteric NMDA receptor modulation include, but are not limited to, a gastrointestinal (GI) disorder (e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, 20 Crohn’s disease), structural disorders affecting the GI tract, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistula), colon polyps, cancer, and colitis), diabetes, a metabolic disorder, an autoimmune disorder, and a sterol synthesis disorder. In some embodiments, the disease, disorder, or condition requiring allosteric NMDA receptor modulation is diabetes. 25

[0234] Additional exemplary diseases, disorders, and conditions requiring allosteric NMDA receptor modulation include, but are not limited to, Smith-Lemli-Opitz Syndrome (SLOS), desmosterolosis, sitosterolemia, cerebrotendinous xanthomatosis (CTX), Mevalonate Kinase Deficiency (MKD), SC4MOL gene mutation (SMO Deficiency), Niemann-Pick disease, autism spectrum disorders (ASD), and disorders associated with phenylketonuria. 30

[0235] Exemplary CNS-related conditions requiring allosteric modulation of an NMDA receptor include, but are not limited to, an adjustment disorder, stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other 91forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., 5 schizophrenia and schizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance- related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder, a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), 10 Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensory hypersensitivity, a metabolic encephalopathy 15 (including phenylketoneuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., 20 stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), epilepsies related to mTor, melanoma, postoperative cognitive 25 dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

[0236] Exemplary CNS-related conditions requiring positive allosteric modulation of an NMDA receptor include, but are not limited to, an adjustment disorder, an anxiety disorder 30 (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer’s disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or another psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a 92substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, 5 attention deficit hyperactivity disorder, pain (including acute and chronic pain), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), a seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease), stroke, traumatic brain injury, a movement disorder 10 (including Huntington’s disease and Parkinson’s disease), GRIN disorders, 22q11.2 deletion syndrome, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), and tinnitus.

[0237] Exemplary CNS-related conditions requiring negative allosteric modulation of an NMDA receptor include, but are not limited to, an adjustment disorder, a stress or stress- 15 related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder 20 (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), a personality disorder (including obsessive- 25 compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and 30 headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic 93brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), melanoma, hepatic 5 encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), and tinnitus.

[0238] Exemplary CNS-related conditions requiring a neutral allosteric ligand (NAL) of an NMDA receptor, which binds at an allosteric site and blocks the effects of a PAM or NAM of 10 an NMDA receptor include, but are not limited to, an autism spectrum disorder (ASD), Tuberous Sclerosis Complex (TSC), multiple sclerosis (MS), Alzheimer’s disease (AD), and Niemann-Pick type C (NPC).

[0239] In some embodiments, the CNS-related condition is a mood disorder selected from depression, post-partum depression, bipolar disorder, dysthymic disorder, and suicidality. In 15 some embodiments, the CNS-related condition is a mood disorder selected from clinical depression, post-partum depression, atypical depression, melancholic depression, psychotic major depression, catatonic 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 20 conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, and suicidal behavior.

[0240] In some embodiments, the CNS-related condition is selected from a seizure, status epilepticus, Dravet’s disease, or Tuberous Sclerosis Complex. In some embodiments, the CNS-related condition is a seizure selected from a grand-mal seizure, an absence seizure, a 25 myoclonic seizure, a clonic seizure, a tonic seizure, and an atonic seizure.

[0241] In some embodiments, the CNS-related condition is a movement disorder selected from Parkinson’s disease, Parkinsonism, dystonia, chorea, Huntington’s disease, ataxia, levodopa-induced dyskinesia, tremor, myoclonus and startle, tics and Tourette syndrome, restless leg syndrome, stiff person syndrome, and gait disorders. 30

[0242] In some embodiments, the CNS-related condition is a tremor selected from a cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, and rubral tremor.

[0243] In some embodiments, the CNS-related condition is Huntington’s disease.

[0244] In some embodiments, the CNS-related condition is Parkinson’s disease. 94

[0245] In some embodiments, the CNS-related condition is neuropsychiatric lupus.

[0246] 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 5 disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition disclosed herein.

[0247] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating or preventing brain excitability in a subject susceptible to or 10 afflicted with a condition associated with brain excitability.

[0248] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain 15 excitability.

[0249] In yet another aspect, the present disclosure provides a combination of a compound of the present disclosure, e.g., a compound of Formulae (I) or (X), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or 20 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. Movement Disorders

[0250] Also described herein are methods for treating a movement disorder. As used 25 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 30 syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.

[0251] 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). Tremor includes hereditary, degenerative, and idiopathic disorders such as Wilson’s disease, Parkinson’s disease, and essential tremor, respectively; 95metabolic 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, 5 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 10 tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor. Other forms of tremor include cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, or rubral tremor.

[0252] Cerebellar tremor or intention tremor is a slow, broad tremor of the extremities 15 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).

[0253] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and / or 20 painful and abnormal postures or positions. Dystonic tremor may affect any muscle in the body. Dystonic tremor occurs irregularly and often can be relieved by complete rest.

[0254] 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 25 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. 30

[0255] 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 occur in patients with essential tremor. 96

[0256] 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 5 one limb or on one side of the body and can progress to include the other side.

[0257] 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. 10

[0258] 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.

[0259] 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 15 nucleus in the midbrain, classical unusual strokes.

[0260] 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 20 progressive neurodegenerative disease.

[0261] 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. 25

[0262] Chorea is a neurological disorder characterized by jerky involuntary movements typically affecting the shoulders, hips, and face.

[0263] 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. 30

[0264] Ataxia refers to the loss of full control of bodily movements, and may affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0265] Myoclonus and Startle is a response to a sudden and unexpected stimulus, which can be acoustic, tactile, visual, or vestibular. 97

[0266] 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 5 complex. For example, simple motor tics involve only a few muscles restricted to a specific body part.

[0267] Tourette Syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic.

[0268] Restless Legs Syndrome is a neurologic sensorimotor disorder characterized by an 10 overwhelming urge to move the legs when at rest.

[0269] 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 15 paraspinal axial muscles is typically observed. Variants include “stiff-limb syndrome” producing focal stiffness typically affecting distal legs and feet.

[0270] 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, 20 neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait. Mood disorders

[0271] Also provided herein are methods for treating a mood disorder, for example clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical 25 depression, melancholic depression, psychotic major depression, cationic 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. 30

[0272] 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 98generally 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. 5

[0273] 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, 10 the PND is refractory depression (e.g., a refractory depression as described herein).

[0274] 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. 15

[0275] 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. 20

[0276] 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.

[0277] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, in particular of melancholic nature, where the individual experiences 25 psychotic symptoms such as delusions and hallucinations.

[0278] 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.

[0279] Seasonal affective disorder (SAD) refers to a type of seasonal depression wherein 30 an individual has seasonal patterns of depressive episodes coming on in the fall or winter.

[0280] 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). 99

[0281] Double depression refers to fairly depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major depression.

[0282] Depressive Personality Disorder (DPD) refers to a personality disorder with depressive features. 5

[0283] 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.

[0284] Minor depressive disorder or minor depression refers to a depression in which at least 2 symptoms are present for 2 weeks. 10

[0285] 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 15 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.

[0286] Depression caused by chronic medical conditions refers to depression caused by 20 chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress.

[0287] 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 psychological counseling (psychotherapy) do not ease depression symptoms for individuals with treatment-resistant depression. In some cases, individuals with treatment- 25 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). 30

[0288] 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 100from 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.

[0289] Symptoms of depression include persistent anxious or sad feelings, feelings of 5 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 10 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). Anxiety Disorders

[0290] Provided herein are methods for treating anxiety disorders. Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. 15 Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0291] 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 20 disorder to affect older adults.

[0292] 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, 25 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 30 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). 101

[0293] 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 5 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 10 experience only compulsions.

[0294] 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. 15

[0295] 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 20 behaviors, and depression. Epilepsy

[0296] 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 myoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West 25 syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood. Epileptogenesis

[0297] Epileptogenesis is a gradual process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptogenesis results from neuronal damage 30 precipitated by the initial insult (e.g., status epilepticus). Status epilepticus (SE)

[0298] 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, 102complex 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. 5 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 10 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.

[0299] 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- 15 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. Seizure

[0300] A seizure is the physical findings or changes in behavior that occur after an episode 20 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.

[0301] 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 25 helps doctors diagnose whether or not a patient has epilepsy.

[0302] 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. 30

[0303] 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 103seconds, 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.

[0304] Absence seizures cause a short loss of consciousness (just a few seconds) with few 5 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."

[0305] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. 10 Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.

[0306] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.

[0307] Tonic seizures are characterized by stiffening of the muscles. 15

[0308] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

[0309] 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- 20 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 25 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. 30 Enumerated Embodiments

[0310] 1. A compound, wherein the compound has the structure of Formula (I):, or a pharmaceutically acceptable salt, isotopic variant, or a combination thereof, wherein: 104Agent iseach of R1and R2is independently hydrogen or a cleavable moiety, provided that at least one of R1and R2is not hydrogen; 5 R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-8 membered heteroaryl; each of R15and R16is independently hydrogen or substituted or unsubstituted C1-610 alkyl; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl; R18is hydrogen or substituted or unsubstituted C1-6 alkyl; R19is hydrogen or substituted or unsubstituted C1-6 alkyl; 15 each of R20and R20’is independently hydrogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 carbocyclyl; R22is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or substituted or unsubstituted C6-10 aryl; and 20 is the point of attachment to R1or R2.

[0311] 2. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment 1, wherein: each of R1and R2is independently hydrogen or a cleavable moiety, provided that at least one of R1and R2is not hydrogen; 25 R3is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, or 5- 8 membered heteroaryl, wherein each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 105carbocyclyl, C6-10aryl, and 5-8 membered heteroaryl is independently optionally substituted with 1-5 RA; each of R15and R16is independently hydrogen or C1-6 alkyl optionally substituted with 1-5 RB; or 5 R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6 carbocyclyl optionally substituted with 1-5 RB; R18is hydrogen or C1-6alkyl optionally substituted with 1-5 RC; R19is hydrogen or C1-6 alkyl optionally substituted with 1-5 RD; each of R20and R20’is independently hydrogen, hydroxyl, C1-6 alkyl, or C3-6 10 carbocyclyl, wherein each of said C1-6alkyl and C3-6carbocyclyl is independently optionally substituted with 1-5 RE; each instance of RA, RB, RC, RD, and RE, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and C1-6alkoxy optionally substituted with 1-5 halo; 15 R22is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or C6-10 aryl, wherein each of said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl is independently optionally substituted with 1-5 RFand each of said C3-6carbocyclyl and C6-10aryl is independently optionally substituted with 1-5 RG; each instance of RF, when present, is independently selected from the group 20 consisting of halo, hydroxyl, cyano, C1-6alkoxy optionally substituted with 1-5 halo, C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein each of said C3-6 carbocyclyl, C6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl is independently optionally substituted with 1-5 RF1; 25 each instance of RF1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, C1-6 alkyl optionally substituted with 1-5 halo, and C1-6alkoxy optionally substituted with 1-5 halo; and each instance of RG, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C1-6 alkyl optionally substituted with 1-5 halo, 30 and C1-6alkoxy optionally substituted with 1-5 halo. 106

[0312] 3. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 1 or 2, wherein the compound of Formula (I) is a compound of Formula (II):5

[0313] 4. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 3, wherein the compound of Formula (II) is a compound of Formula (II-A) or (II-B):

[0314] 5. The compound or a pharmaceutically acceptable salt, isotopic variant, or 10 combination thereof, according to any one of Embodiments 1-4, wherein R1is hydrogen and R2is a cleavable moiety.

[0315] 6. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-4, wherein R1is a cleavable moiety and R2is hydrogen. 15

[0316] 7. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-4, wherein each of R1and R2is independently a cleavable moiety.

[0317] 8. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-7, wherein each instance of a 107cleavable moiety is independently selected from the group consisting of: C(R’)(R’’)X1, -C(O)X2, -S(O)2OH, -S(O)2O-M+, -P(O)(OH)2, and -P(O)(O-M+)2, wherein: each of R’ and R’’ is independently hydrogen or C1-6 alkyl; X1is -OC(O)(C1-6alkyl), -OC(O)(C1-6alkoxy), or -N(RN1)(RN2); 5 X2is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -N(RN1)(RN2), or 5-6 membered oxygen-containing heterocyclyl optionally substituted with 1-4 hydroxyl, wherein: each instance of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6alkoxy as they relate to X1and X2is independently optionally substituted with 1-5 substituents independently selected from the group consisting of halo, hydroxyl, cyano, nitro, 10 amino, -C(O)OH, -C(O)O-M+, -C(O)(C1-6alkyl), -C(O)(C1-6alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OS(O)2OH, -OS(O)2O-M+, -OP(O)(OH)2, and -OP(O)(O-M+)2, wherein each instance of R is independently hydrogen or -C(O)(C1-20 alkyl) and each instance of M+is independently Li+, Na+, K+, or NH4+; and each of RN1and RN2is independently hydrogen or C1-6alkyl, or RN1and 15 RN2, together with the nitrogen atom to which they are attached, form a 5-10 membered monocyclic or bicyclic heteroaryl or 5-10 membered monocyclic or bicyclic heterocyclyl.

[0318] 9. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 8, wherein each instance of a cleavable 20 moiety is independently -CH2X1or -C(O)X2.

[0319] 10. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 9, wherein each instance of a cleavable moiety is independently selected from the group consisting of: -CH2OC(O)(C1-6 alkyl), -C(O)(C1-6alkyl), -CH2OC(O)(C1-6alkoxy), -C(O)(C2-6alkenyl), -C(O)(C1-6alkoxy), 25 -CH2N(RN1)(RN2), -C(O)N(RN1)(RN2), and -C(O)(5-6 membered oxygen-containing heterocyclyl).

[0320] 11. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 10, wherein each instance of C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is independently optionally substituted with amino, -C(O)OH, 30 -C(O)O-M+, -C(O)(C1-6alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OP(O)(OH)2, or -OP(O)(O-M+)2. 108

[0321] 12. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 11, wherein each instance of a cleavable moiety is independently selected from the group consisting of: 5 10, , , , , 109

[0322] 13. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 10, wherein each instance of a cleavable 5 moiety is independently selected from the group consisting of: -CH2OC(O)(C1-6 alkyl), -CH2OC(O)(C1-6alkoxy), and -CH2N(RN1)(RN2).

[0323] 14. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 13, wherein each of said C1-6 alkyl and C1-6 alkoxy is independently optionally substituted with amino, -C(O)OH, or 10 -C(O)OCH(CH2OR)2.

[0324] 15. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 14, wherein each instance of a cleavable moiety is independently selected from the group consisting of: 15.

[0325] 16. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 10, wherein each instance of a cleavable moiety is independently selected from the group consisting of: -C(O)(C1-6alkyl), -C(O)(C2-620 alkenyl), -C(O)(C1-6alkoxy), -C(O)N(RN1)(RN2), and -C(O)(5-6 membered oxygen- containing heterocyclyl). 110

[0326] 17. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 16, wherein each of said C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is independently optionally substituted with -C(O)OH, -C(O)O-M+, -C(O)(C1-6alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OP(O)(OH)2, or 5 -OP(O)(O-M+)2.

[0327] 18. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 17, wherein each instance of a cleavable moiety is independently selected from the group consisting of: 10, , , , 111

[0328] 19. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-18, wherein R3is C1-6 alkyl 5 optionally substituted with 1-5 RA.

[0329] 20. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 19, wherein R3is -CH3, -CH2OCH3, -CH2F, CHF2, or -CF3.

[0330] 21. The compound or pharmaceutically acceptable salt, isotopic variant, or 10 combination thereof, according to Embodiment 20, wherein R3is -CF3.

[0331] 22. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-2 and 5-21, wherein R15and R16are both hydrogen.

[0332] 23. The compound or a pharmaceutically acceptable salt, isotopic variant, or 15 combination thereof, according to any one of Embodiments 1-2 and 5-22, wherein R18is -CH3.

[0333] 24. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-3 and 5-23, wherein R19is hydrogen. 20

[0334] 25. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-3 and 5-23, wherein R19is -CH3.

[0335] 26. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-2 and 5-25, wherein R20is 25 hydrogen.

[0336] 27. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-2 and 5-26, wherein R20’is -CH3. 112

[0337] 28. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-27, wherein R22is C1-6 alkyl optionally substituted with 1-5 RF.

[0338] 29. The compound or a pharmaceutically acceptable salt, isotopic variant, or 5 combination thereof, according to Embodiment 28, wherein R22is unsubstituted C1-6 alkyl.

[0339] 30. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 29, wherein R22is -CH3.

[0340] 31. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 28, wherein R22is C1-6 alkyl substituted with 10 1-5 RF.

[0341] 32. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 31, wherein R22is -CH2OCH3.

[0342] 33. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 31, wherein R22is -CH2F. 15

[0343] 34. A compound, wherein the compound has the structure of Formula (X):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: each of a and b is independently 0 or 1, provided that a and b are not both 0; and each instance of Z is independently hydrogen, -C(O)(C1-20alkyl), or -C(O)- 20 (C(RZ1)(RZ2))1-6-C(O)(Agent), provided that at least two instances of Z are -C(O)-(C(RZ1)(RZ2))1-6-C(O)(Agent) and wherein: each of RZ1and RZ2is independently hydrogen or C1-6alkyl; and each instance of Agent is independently a compound of Formula (X-I):25 wherein: 113Y is hydrogen or a bond, provided that one instance of Y is a bond and the other is hydrogen, wherein said bond is the point of attachment between Agent and the associated C(O); R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted 5 C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-8 membered heteroaryl; each of R15and R16is independently hydrogen or substituted or unsubstituted C1-6 alkyl; or 10 R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl; R18is hydrogen or substituted or unsubstituted C1-6 alkyl; R19is hydrogen or substituted or unsubstituted C1-6 alkyl; R20is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or 15 substituted or unsubstituted C3-6 carbocyclyl; R20’is hydrogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6carbocyclyl; and R22is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 20 carbocyclyl, or substituted or unsubstituted C6-10aryl.

[0344] 35. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 34, wherein a and b are both 1.

[0345] 36. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 34 or 35, wherein one instance of Z is 25 -C(O)(C1-20 alkyl).

[0346] 37. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 36, wherein one instance of Z is -C(O)(CH2)14CH3.

[0347] 38. The compound or a pharmaceutically acceptable salt, isotopic variant, or 30 combination thereof, according to any one of Embodiments 34-37, wherein two instances of Z are -C(O)-(C(RZ1)(RZ2))1-6-C(O)(Agent). 114

[0348] 39. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 38, wherein two instances of Z are -C(O)- (CH2)3-C(O)(Agent).

[0349] 40. The compound or a pharmaceutically acceptable salt, isotopic variant, or 5 combination thereof, according to Embodiment 34 or 35, wherein each instance of Z is -C(O)-(C(RZ1)(RZ2))1-6-C(O)(Agent).

[0350] 41. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 40, wherein each instance of Z is -C(O)- (CH2)3-C(O)(Agent). 10

[0351] 42. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 34-41, wherein each instance of Agent is independently a compound of Formula (X-I):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: 15 Y is hydrogen or a bond, provided that one instance of Y is a bond and the other is hydrogen, wherein said bond is the point of attachment between Agent and the associated C(O); R3is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, or 5- 8 membered heteroaryl, wherein each of said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-620 carbocyclyl, C6-10 aryl, and 5-8 membered heteroaryl is independently optionally substituted with 1-5 RA; each of R15and R16is independently hydrogen or C1-6alkyl optionally substituted with 1-5 RB; or R15and R16, taken together with the carbon atoms to which they are attached, form a 25 C3-6carbocyclyl optionally substituted with 1-5 RB; R18is hydrogen or C1-6 alkyl optionally substituted with 1-5 RC; R19is hydrogen or C1-6 alkyl optionally substituted with 1-5 RD; 115each of R20and R20’is independently hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein each of said C1-6 alkyl and C3-6 carbocyclyl is independently optionally substituted with 1-5 RE; each instance of RA, RB, RC, RD, and RE, when present, is independently 5 selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10 aryl, and C1-6 alkoxy optionally substituted with 1-5 halo; R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or C6-10aryl, wherein each of said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl is independently optionally substituted with 1-5 RFand each of said C3-6 carbocyclyl and C6-10 aryl is 10 independently optionally substituted with 1-5 RG; each instance of RF, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C1-6 alkoxy optionally substituted with 1-5 halo, C3-6 carbocyclyl, C6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein each of said C3-6carbocyclyl, C6-10aryl, 5-8 membered 15 heteroaryl, and 5-8 membered heterocyclyl is independently optionally substituted with 1-5 RF1; each instance of RF1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, C1-6 alkyl optionally substituted with 1-5 halo, and C1-6 alkoxy optionally substituted with 1-5 halo; and 20 each instance of RG, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C1-6alkyl optionally substituted with 1-5 halo, and C1-6 alkoxy optionally substituted with 1-5 halo.

[0352] 43. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 34-42, wherein the compound of 25 Formula (X-I) is a compound of Formula (X-II):116

[0353] 44. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 43, wherein the compound of Formula (X-II) is a compound of Formula (X-II-A) or (X-II-B):5

[0354] 45. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 34-44, wherein R3is -CF3.

[0355] 46. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 34-42 and 45, wherein each of R15and R16is independently hydrogen. 10

[0356] 47. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 34-42 and 45-46, wherein R18is -CH3.

[0357] 48. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 34-43 and 45-47, wherein R19is 15 hydrogen.

[0358] 49. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 34-43 and 45-47, wherein R19is -CH3.

[0359] 50. The compound or a pharmaceutically acceptable salt, isotopic variant, or 20 combination thereof, according to any one of Embodiments 34-42 and 45-49, wherein R20is hydrogen.

[0360] 51. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 34-42 and 45-50, wherein R20’is -CH3. 117

[0361] 52. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 34-51, wherein R22is C1-6 alkyl optionally substituted with 1-5 RF.

[0362] 53. The compound or a pharmaceutically acceptable salt, isotopic variant, or 5 combination thereof, according to Embodiment 52, wherein R22is unsubstituted C1-6 alkyl.

[0363] 54. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 53, wherein R22is -CH3.

[0364] 55. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 52, wherein R22is C1-6 alkyl substituted with 10 1-5 RF.

[0365] 56. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 55, wherein R22is -CH2OCH3.

[0366] 57. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 55, wherein R22is -CH2F. 15

[0367] 58. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 34-44, wherein each instance of Agent is independently. 20

[0368] 59. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 58, wherein each instance of Agent is independently 118.

[0369] 60. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 58, wherein each instance of Agent is 5 independently.

[0370] 61. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to Embodiment 59, wherein each instance of Agent is: 10. 119

[0371] 62. A compound selected from any one of compounds 1-78 in Table 1, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0372] 63. The compound according to any one of Embodiments 1-62.

[0373] 64. The pharmaceutically acceptable salt of a compound according to any one of 5 Embodiments 1-62.

[0374] 65. The isotopic variant of a compound according to any one of Embodiments 1- 62.

[0375] 66. The isotopic variant of a pharmaceutically acceptable salt of a compound according to any one of Embodiments 1-62. 10

[0376] 67. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-66, and a pharmaceutically acceptable carrier.

[0377] 68. A method for treating a CNS-related condition in a subject in need thereof, comprising administering to the subject an effective amount of the compound or a 15 pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-66, or the pharmaceutical composition according to Embodiment 67.

[0378] 69. The method according to Embodiment 68, wherein the CNS-related condition is selected from the group consisting of an adjustment disorder, a stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including 20 obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar 25 disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving 30 mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), pain (including neuropathic pain, injury- 120related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and 5 monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep 10 syndrome (CSWS) and Landau Kleffer syndrome (LKS)), melanoma, hepatic encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), and tinnitus.

[0379] 70. The method for effecting negative allosteric modulation of an NMDA receptor 15 in a subject, comprising administering to the subject an effective amount of the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-66, or the pharmaceutical composition according to Embodiment 67.

[0380] 71. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-66, or the pharmaceutical 20 composition according to Embodiment 67, for use in treating a CNS-related condition in a subject.

[0381] 72. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to Embodiment 71, wherein the CNS-related condition is selected from the group consisting of an adjustment 25 disorder, a stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating 30 disorder, a mood disorder (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder 121and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive 5 disorder, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure 10 disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including 15 continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), melanoma, hepatic encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa- induced dyskinesia (LID), and tinnitus.

[0382] 73. The compound or a pharmaceutically acceptable salt, isotopic variant, or 20 combination thereof, according to any one of Embodiments 1-66, or the pharmaceutical composition according to Embodiment 67, for use in effecting negative allosteric modulation of an NMDA receptor in a subject.

[0383] 74. Use of the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-66, or the pharmaceutical 25 composition according to Embodiment 67, in the manufacture of a medicament for treating a CNS-related condition in a subject.

[0384] 75. The use according to Embodiment 74, wherein the CNS-related condition is selected from the group consisting of an adjustment disorder, a stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including 30 obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder (including 122depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to 5 opiates, cocaine, and / or alcohol), a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), pain (including neuropathic pain, injury- 10 related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex 15 (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), melanoma, hepatic 20 encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), and tinnitus.

[0385] 76. Use of the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of Embodiments 1-66, or the pharmaceutical 25 composition according to Embodiment 67, in the manufacture of a medicament for effecting negative allosteric modulation of an NMDA receptor in a subject. Examples

[0386] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this 30 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.

[0387] The absolute configuration of an asymmetric center can be determined using methods known to one skilled in the art. In some embodiments, the absolute configuration of 123an asymmetric center in a compound can be elucidated from the X-ray single-crystal structure of the compound. In some embodiments, the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding asymmetric center in another compound obtained from the 5 same or similar synthetic methodologies. In some embodiments, the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding asymmetric center in another compound coupled with a spectroscopic technique, e.g., NMR spectroscopy, e.g., 1H NMRspectroscopy or19F NMR spectroscopy. 10 Abbreviations

[0388] AgOTf: silver trifluoromethanesulfonate / silver triflate; DCE: 1,2-dichloroethane; Pd / C: palladium on carbon; H2: molecular hydrogen (g); N2: molecular nitrogen (g); THF: tetrahydrofuran; H2O: water; DCM: dichloromethane; Na2SO4: anhydrous sodium sulfate; EtOAc: ethyl acetate; PE: petroleum ether; CDCl3: deuterated chloroform / chloroform-d3; 15 DCC: N,N’-dicyclohexylcarbodiimide; DMAP: 4-dimethylaminopyridine; TFA: trifluoroacetic acid; Na2CO3: sodium carbonate; DMSO: dimethyl sulfoxide; DMSO-d6: deuterated dimethyl sulfoxide; DIPEA: N,N-diisopropylethylamine; NaHCO3: sodium bicarbonate; Bu4NHSO4: tetrabutylammonium hydrogen sulfate; TEA: triethylamine; DHP: 3,4-dihydro-2H-pyran; PTSA / TsOH: p-toluenesulfonic acid; Ac2O: acetic anhydride; NaH: 20 sodium hydride; TBAI: tetrabutylammonium iodide; DMF: N,N-dimethylformamide; MeOH: methanol; MgSO4: anhydrous magnesium sulfate; ACN / MeCN: acetonitrile; SEM: 2- (trimethylsilyl)ethoxymethyl; SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride; MW: microwave; HCl: hydrochloric acid; SO2Cl2: sulfuryl chloride; NaBH4: sodium borohydride; H2O2: hydrogen peroxide; LiOH: lithium hydroxide; NMM: N-methylmorpholine; KOtBu: 25 potassium tert-butoxide; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; Na2S2O3: sodium thiosulfate; AcOH: acetic acid; NH4Cl: ammonium chloride; K2CO3: potassium carbonate; K2Cr2O7: potassium dichromate; H2SO4: sulfuric acid; BnOH: benzyl alcohol; Cbz: N- carboxybenzyl; CbzCl: benzyl chloroformate; NaOH: sodium hydroxide; LiOH·H2O: lithium hydroxide monohydrate; NH3: ammonia; DIC: N,N’-diisopropylcarbodiimide; DPTS: 4- 30 (dimethylamino)pyridinium-4-toluenesulfate. Materials and Methods

[0389] 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 124of 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. 5

[0390] 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. 10 Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, 5thEdition, John Wiley & Sons, New Jersey, 2014, and references cited therein.

[0391] 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 SFC. The following schemes are presented with details as to the 15 preparation of representative compounds 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, 20 CHIRALCEL®OB-H, CHIRALCEL®OD, CHIRALCEL®OD-H, CHIRALCEL®OF, CHIRALCEL®OG, CHIRALCEL®OJ and CHIRALCEL®OK.

[0392] 1H NMR reported herein (e.g., for the region between δ (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 integrations) of a compound. Exemplary general method for preparative 25 HPLC: Column: Waters RBridge prep 10 μm C18, 19*250 mm. Mobile phase: acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3.H2O). Flow rate: 25 mL / min.

[0393] 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 μm at 45 C. 30

[0394] Exemplary general method for SFC: Column: CHIRALPAK®AD CSP (250 mm * 30 mm, 10 μm), 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-3 150×4.6mm I.D., 3um Mobile phase: A: CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 12540% 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: 35oC.

[0395] Example 1: Synthesis of 4-((((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3- hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- 5 cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)methoxy)-4-oxobutanoic acid (1)

[0396] A synthesis of 1.1 is provided in International Application No.PCT / US2023 / 080694, the entire disclosure of which is incorporated herein by reference.

[0397] Synthesis of 1.2 10

[0398] To a solution of 1.1 (5 g, 12.0 mmol) in DCE (50 mL) was added AgOTf (6.78 g, 26.4 mmol) and 2,6-di-tert-butylpyridine (5.73 g, 30.0 mmol) at 20 °C. The reaction was cooled to 0 °C and 1-benzyl-4-chloromethyl butanedioate (4.62 g, 18 mmol; Combi-Blocks, Inc.) was added and the resulting mixture was stirred at 20 °C for 16 h. The reaction was quenched with H2O (100 mL) and extracted with DCM (2 x 50 mL). The combined organic 15 layer was washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (0^7% of EtOAc in PE) to give 1.2 (4.5 g, 7.07 mmol, 59.0% yield).1H NMR (400 MHz, CDCl3) δH7.38- 7.30 (m, 5H), 5.32-5.27 (m, 2H), 5.14 (s, 2H), 3.77-3.70 (m, 1H), 2.72-2.65 (m, 4H), 1.99- 1.81 (m, 5H), 1.76-1.63 (m, 4H), 1.62-1.50 (m, 4H), 1.43-1.21 (m, 10H), 1.11-1.02 (m, 5H), 20 0.96 (s, 3H), 0.91-0.87 (m, 3H), 0.67 (s, 3H).

[0399] Synthesis of 1

[0400] To a solution of 1.2 (3.5 g, 5.49 mmol) in THF (40 mL) was added Pd / C (dry, 10%Pd, 500 mg) under N2, the suspension was degassed under vacuum and then purged with H2three times. The mixture was stirred under H2(15 psi) at 20 °C for 16 h. The reaction 25 mixture was filtered through a pad of celite and eluted with THF (3 x 50 mL). The volatiles 126were removed and the resulting residue was purified by silica gel chromatography (0^17% of EtOAc in PE) to give 1 (478.9 mg, 0.876 mmol, 16.0% yield).1H NMR (400 MHz, CDCl3): δH 5.34-5.29 (m, 2H), 3.77-3.71 (m, 1H), 2.74-2.61 (m, 4H), 2.01-1.65 (m, 11H), 1.53-1.21 (m, 11H), 1.13-1.02 (m, 7H), 0.97-0.87 (m, 6H), 0.68 (s, 3H). LC-ELSD / MS MS5 ESI calcd for C29H45O6F3Na [M+Na]+569.8, found 569.2.13C NMR (101 MHz, CDCl3) δC 177.12, 171.80, 88.30, 77.96, 73.55, 73.28, 56.08, 53.14, 42.98, 40.45, 40.03, 39.57, 38.87, 35.67, 34.05, 33.62, 32.48, 29.04, 28.60, 27.67, 27.51, 26.49, 25.77, 24.25, 23.04, 21.01, 13.54, 12.04.19F NMR (376.5 MHz, CDCl3): δF -78.76.

[0401] Example 2: Synthesis of sodium 6-(((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-10 3-hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)-6-oxohexanoate (2); tert-butyl ((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan-2-yl) adipate (42); and 6-(((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-15 dimethyl-3-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan- 2-yl)oxy)-6-oxohexanoic acid (43)

[0402] Synthesis of 42

[0403] To a stirred solution of 6-(tert-butoxy)-6-oxohexanoic acid (1.21 g, 6.00 mmol) in 20 DCM (20.0 mL) was added DCC (0.99 g, 4.80 mmol) and DMAP (0.058 g, 0.48 mmol) at room temperature. 1.1 (1 g, 2.40 mmol) was added and the mixture was stirred for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography 25 (8% of EtOAc in PE) to afford 42 (1 g, 1.66 mmol, 69% yield).1H NMR (400 MHz, 127DMSO-d6): δH5.73 (s, 1H), 4.88-4.86 (m, 1H), 2.49-2.23 (m, 2H), 2.19-2.15 (m, 2H), 1.92- 1.76 (m, 5H), 1.76-1.62 (m, 3H), 1.59-1.46 (m, 7H), 1.39-1.35 (m, 14H), 1.22-1.01 (m, 11H), 0.90-0.87 (m, 6H), 0.62 (s, 3H).

[0404] Synthesis of 43 5

[0405] A solution of 42 (1g, 1.60 mmol) in DCM (5.0 mL) was cooled to 0 °C and TFA (5 mL) was added. The resulting solution was warmed to room temperature and stirred for 6 h. The volatiles were removed and the resulting residue was dissolved in EtOAc (300 mL) before being washed with water (3 x 100 mL). The combined organic layer was dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was washed with10 pentane to afford 43 (0.850 g, 1.56 mmol, 90% yield).1H NMR (400 MHz, DMSO-d6): δH12.13 (brs, 1H), 5.73 (brs, 1H), 4.88-4.86 (m, 1H), 2.29-2.18 (m, 4H), 1.92-1.70 (m, 6H), 1.69-1.46 (m, 9H), 1.39-1.31 (m, 5H), 1.29-1.00 (m, 11H), 0.90-0.87 (m, 6H), 0.62 (s, 3H).

[0406] Synthesis of 2

[0407] To a stirred solution of 43 (0.632 g, 1.16 mmol) in THF (1 mL) was added a 15 solution of Na2CO3 (0.061 g, 0.580 mmol) in water (3 mL). The reaction mixture was stirred at room temperature for 30 min. The volatiles were removed and the resulting residue was lyophilized to afford 2 (0.610 g, 1.08 mmol, 91.7% yield).1H NMR (400 MHz, DMSO-d6): δH 5.96 (s, 1H), 4.86-4.85 (m, 1H), 2.21-2.10 (m, 2H), 1.92-1.76 (m, 8H), 1.62-1.34 (m, 14H), 1.20-1.01 (m, 11H), 0.90-0.88 (m, 6H), 0.62 (s, 3H).19F NMR (376 MHz, DMSO-d6): 20 δF-77.105. LC-ELSD / MS MS ESI calcd for [M+Na]+C30H46F3NaO5567.34, found 567.30.

[0408] Example 3: Synthesis of (((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3- hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)methyl acetate (3)25

[0409] To a solution of 1.1 (1 g, 2.40 mmol) and bromomethyl acetate (780 mg, 7.19 mmol) in DCM (10.0 mL) was added DIPEA (1.25 mL, 7.19 mmol) and DMAP (87.9 mg, 0.720 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). 128The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (10% of EtOAc in PE) to afford 3 (366 mg, 0.749 mmol, 30.9% yield).1H NMR (400 MHz, DMSO-d6): δH5.73 (s, 1H), 5.21 (q, J = 6.4 Hz, 2H), 3.71-3.68 (m, 1H), 5 2.02 (s, 3H), 1.94-1.50 (m, 11H), 1.91-1.14 (m, 9H), 1.10-1.01 (m, 4H), 0.95-0.91 (m, 6H), 0.82 (d, J = 6.8 Hz, 3H), 0.65 (s, 3H).19F NMR (376 MHz, DMSO-d6): δF -77.125. LC- ELSD / MS MS ESI calcd for [M+Na]+C27H42F3NaO4511.29, found 511.30.

[0410] Example 4: Synthesis of (((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3- hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- 10 cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)methyl pentanoate (4)

[0411] Synthesis of B

[0412] To a stirred solution of A (2.0 g, 19.5 mmol) in DCM (20 mL) and water (20 mL) was added NaHCO3 (6.22 g, 74.1 mmol) and Bu4NHSO4 (662 mg, 1.95 mmol) at 0 °C, and 15 the resulting mixture was stirred for 10 min. Chloromethyl chlorosulfate (3.86 g, 23.4 mmol) was then added and the resulting solution was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography 20 (5^10% of EtOAc in PE) to afford B (1.7 g, 11.3 mmol, 58.0% yield).1H NMR (400 MHz, DMSO-d6): δH 5.74 (s, 2H), 2.40-2.34 (m, 2H), 1.68-1.60 (m, 2H), 1.40-1.32 (m, 2H), 0.94- 0.89 (m, 3H).

[0413] Synthesis of 4

[0414] To a stirred solution of B (722 mg, 4.80 mmol) in DCM (7.0 mL) was added DMAP 25 (43.9 mg, 0.360 mmol), 1.1 (500 mg, 1.20 mmol), and TEA (419 µL, 2.99 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted 129with water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was washed brine (50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (5^7% of EtOAc in PE) to afford 4 (0.265 g, 0.499 mmol, 41.5%).1H NMR (400 MHz, DMSO-d6): δH5.74 (s, 1H), 5.27 (d, J = 6.8 5 Hz, 1H), 5.19 (d, J = 6.4 Hz, 1H), 3.78-3.69 (m, 1H), 2.32-2.29 (m, 2H), 1.91-1.47 (m, 13H), 1.35-1.03 (m, 15H), 0.94-0.82 (m, 12H), 0.65 (s, 3H).19F NMR (376 MHz, DMSO-d6): δF - 77.124. LC-ELSD / MS MS ESI calcd for [M+Na]+C30H49F3NaO4553.36, found 553.30.

[0415] Example 5: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H-10 cyclopenta[a]phenanthren-3-yl acetate (5)

[0416] Synthesis of 5.1

[0417] To a solution of 1.1 (1.4 g, 3.36 mmol) in DCM (14 mL) was added DHP (565 mg, 6.72 mmol) and PTSA hydrate (127 mg, 0.672 mmol) at 0 °C, and the resulting solution was 15 warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (5^10% of EtOAc in PE) to afford 5.1 (1.4 g, 2.80 mmol, 82.1% yield). 20

[0418] Synthesis of 5.2

[0419] To a solution of 5.1 (1.4 g, 2.79 mmol) in DMF (14 mL) was added NaH (1 g, 41.8 mmol) at 0 °C and the resulting mixture was stirred for 10 min. Ac2O (4.26 g, 41.8 mmol) and TBAI (513 mg, 1.39 mmol) were added, the mixture was heated to 70 °C, and then stirred for 15 h. The reaction mixture was quenched with saturated aqueous NaHCO3(25 130mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (5^7% of EtOAc in PE) to afford 5.2 (500 mg, 0.921 mmol, 33% yield). 5

[0420] Synthesis of 5

[0421] To a solution of 5.2 (360 mg, 663 µmol) in MeOH (4 mL) was added PTSA hydrate (25.1 mg, 0.132 mmol) at 0 °C and the resulting mixture was stirred for 30 min and allowed to warm to room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 (3 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layer was 10 washed with brine (15 mL), dried over MgSO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (5^10% of EtOAc in PE) to afford 5 (260 mg, 0.567 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6): δH 4.17 (d, J =3.6 Hz, 1H), 3.66-3.68 (m, 1H), 2.83 (t, J = 14.0 Hz, 1H), 2.49 (t, J = 1.6 Hz, 1H), 2.03 (s, 3H), 1.96-1.72 (m, 3H), 1.70-1.53 (m, 7H), 1.39-1.17 (m, 8H), 1.15-1.03 (m, 4H), 0.91 (s,15 3H), 0.91-0.81 (m, 6H), 0.64 (s, 3H).19F NMR (376 MHz, DMSO-d6): δF -75.343. LC- ELSD / MS MS ESI calcd for [M+Na]+C26H41F3O3481.29, found 481.30.

[0422] Example 6: Synthesis of (2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy- 10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17- yl)butan-2-yl heptanoate (6) 20

[0423] To a stirred solution of 1.1 (1.2 g, 2.88 mmol) in DCM (15 mL) was added TEA (727 mg, 7.19 mmol) and DMAP (70.3 mg, 576 µmol) at 0 °C, and the mixture was stirred for 2 min. Heptanoyl chloride (769 mg, 5.18 mmol) was added and the resulting solution was stirred at room temperature for 16 h. The reaction mixture was diluted with water (30 mL) 25 and extracted with DCM (100 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and the volatiles were removed. The residue was purified by reverse-phase chromatography (50% MeOH / ACN (1:1) in water) to afford 6 (510 mg, 0.965 mmol, 34% yield). 1H NMR (400 MHz, DMSO-d6): δH 5.73 (s, 1H), 4.81 (m, 1H),2.50-2.40 (m, 2H), 2.23-1.65 (m, 13), 1.63-1.48 (m, 14H), 1.46-1.18 (m, 8H), 1.08-0.89 (m, 1319H), 0.62 (s, 3H).19F NMR (376 MHz, DMSO-d6): δF-77.111. LC-ELSD / MS MS ESI calcd for [M+Na]+C31H50F3NaO3551.36, found 551.4.

[0424] Example 7: Synthesis of (2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-acetoxy- 10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17- 5 yl)butan-2-yl acetate (7)

[0425] To a stirred solution of 1.1 (600 mg, 1.44 mmol) and DMAP (87.86 mg, 0.72 mmol) in pyridine (6 ml) was added Ac2O (2 mL, 21.6 mmol) and the resulting mixture was heated at 120 °C for 16 h. The mixture was quenched with water (50 mL) and extracted with EtOAc 10 (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over MgSO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (0^5% of EtOAc in PE) to afford 7 (552 mg, 1.10 mmol, 76.5% yield).1H NMR (400 MHz, DMSO-d6): δH 4.87-4.83 (m, 1H), 2.80 (m, 1H), 2.49 (m, 1H),1.96-1.53 (m, 16H), 1.36-1.34 (m, 4H), 1.23-1.01 (m, 11H), 0.91-0.88 (m, 6H), 0.62 (s, 3H).19F NMR15 (376 MHz, DMSO-d6): δF-75.370. LC-ELSD / MS MS ESI calcd for [M+Na]+C28H43F3O4Na 523.31, found 523.30.

[0426] Example 8: Synthesis of sodium 3-(((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)- 3-hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)-3-oxopropanoate (8); tert-butyl20 ((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan-2-yl) malonate (44); and 3-(((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13- dimethyl-3-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan- 2-yl)oxy)-3-oxopropanoic acid (45) 132

[0427] Synthesis of 44

[0428] To a solution of 1.1 (1 g, 2.40 mmol) and 3-(tert-butoxy)-3-oxopropanoic acid (768 mg, 4.80 mmol) in DCM (10.0 mL) was added DCC (990 mg, 4.80 mmol) and DMAP (58.6 5 mg, 0.480 mmol) at room temperature, and the resulting solution was stirred for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (10% of EtOAc in PE) to afford 44 (1 g, 1.79 mmol, 73.1% yield).1H10 NMR (400 MHz, DMSO-d6): δH5.73 (s, 1H), 4.91-4.89 (m, 1H), 1.92-1.70 (m, 6H), 1.62- 1.56 (m, 3H), 1.49-1.46 (m, 2H), 1.40-1.35 (m, 14H), 1.26-1.12 (m, 12H), 0.91-0.87 (m, 6H), 0.63 (s, 3H).

[0429] Synthesis of 45

[0430] To a solution of 44 (500 mg, 0.894 mmol) in DCM (5 mL) was added TFA (135 µL, 15 1.78 mmol) at 0 °C and the resulting mixture was stirred at room temperature for 16 h. The volatiles were removed and the resulting residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and the volatiles were removed to afford 45 (450 mg, 0.895 mmol, 99.1% yield).1H NMR (400 MHz, DMSO-d6): δH12.66 (brs, 1H), 5.75 (s, 1H), 4.90-4.88 (m, 1H), 1.93-1.7020 (m, 6H), 1.62-1.46 (m, 5H), 1.40-1.35 (m, 6H), 1.29-1.18 (m, 4H), 1.16-1.02 (m, 8H), 0.91- 0.87 (m, 6H), 0.63 (s, 3H).

[0431] Synthesis of 8

[0432] To a solution of 45 (700 mg, 1.39 mmol) in THF (14.0 mL) was added Na2CO3(73.6 mg, 0.695 mmol) as a solution in water (14 mL) and the resulting mixture was stirred at 25 room temperature for 15 min. The volatiles were removed to afford 8 (720 mg, 1.37 mmol, 13397.6% yield).1H NMR (400 MHz, DMSO-d6): δH5.74 (s, 1H), 4.81-4.79 (m, 1H), 2.86 (s, 2H), 1.94-1.69 (m, 6H), 1.63-1.35 (m, 10H), 1.20-0.97 (m, 11H), 0.91-0.87 (m, 6H), 0.63 (s, 3H). LC-ELSD / MS MS ESI calcd for [M-H]- C27H41F3O5501.29, found 501.53.

[0433] Example 9: Synthesis of sodium 5-(((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)- 5 3-hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)-5-oxopentanoate (9); tert-butyl ((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan-2-yl) glutarate (46); and 5-(((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-10 dimethyl-3-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan-

[0434] Synthesis of 46

[0435] To a solution of 1.1 (800 mg, 1.92 mmol) and 5-(tert-butoxy)-5-oxopentanoic acid 15 (722 mg, 3.84 mmol) in DCM (8.00 mL) at room temperature was added DCC (792 mg, 3.84 mmol) and DMAP (46.9 mg, 384 µmol), and the resulting mixture was stirred for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel20 chromatography (10% of EtOAc in PE) to give 46 (900 mg, 1.53 mmol, 79.5 % yield). 1HNMR (400 MHz, DMSO-d6): δH 5.74 (s, 1H), 4.89-4.87 (m, 1H), 2.29-2.20 (m, 4H), 1.99- 1.60 (m, 12H), 1.50-1.46 (m, 2H), 1.39-1.35 (m, 12H), 1.01-1.02 (m, 12H), 0.89-0.87 (m, 6H), 0.63 (s, 3H). LC-ELSD / MS MS ESI calcd for [M+H]+calcd for C33H54F3O5587.39, found 587.75. 25

[0436] Synthesis of 47 134

[0437] To a solution of 46 (450 mg, 766 µmol) in DCM (4.50 mL) was added TFA (1.45 mL, 19.1 mmol) at 0°C and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine (2 x 100 mL), dried over Na2SO4, 5 filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (12% of EtOAc in PE) to give 47 (370 mg, 0.697 mmol, 89.1% yield). 1HNMR (400 MHz, DMSO-d6): δH12.1 (bs,1H), 5.74 (s, 1H), 4.89-4.87 (m, 1H), 2.50-2.22 (m, 4H), 1.93-1.66 (m, 8H), 1.63-1.54 (m, 3H), 1.50-1.43 (m, 2H), 1.35 (s, 5H), 1.20-1.18 (m, 3H), 1.14-1.01 (m, 8H), 0.89-.87 (m, 6H), 0.63 (s, 3H). ELSD / MS MS ESI calcd for [M-H]- 10 C29H45F5O5529.32, found 529.60.

[0438] Synthesis of 9

[0439] To a solution of 47 (700 mg, 1.31 mmol) in THF (14.0 mL) was added Na2CO3 (55.5 mg, 524 µmol) as a solution in water (14.0 mL) and the resulting mixture was stirred at room temperature for 1 h. The volatiles were removed to give 9 (650 mg, 1.18 mmol, 89.7%15 yield). 1H NMR (400 MHz, DMSO-d6): δH 5.84 (br s, 1H), 4.87-4.83 (m, 1H), 2.21 (t, J =7.4 Hz, 2H), 1.96-1.56 (m, 13H), 1.48 (br s, 2H), 1.35 (br s, 5H), 1.25-0.99 (m, 11H), 0.87- 0.93 (m, 6H), 0.63 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δC 176.120, 172.322, 131.780,128.923, 126.069, 123.299, 71.857, 71.592, 71.333, 71.067, 55.504, 52.541, 42.440, 40.123, 39.915, 39.706, 39.497, 39.289, 39.080, 38.872, 38.597, 38.878, 35.846, 35.127, 33.874, 20 33.600, 32.332, 27.590.19F NMR (376 MHz, DMSO-d6): δF-77.109. LC-ELSD / MS MS ESI calcd for [M-Na]- C29H44F3O5529.30, found 529.60.

[0440] Example 10: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- 25135

[0441] Synthesis of 10.1

[0442] To a stirred solution of 1.1 (5 g, 12.00 mmol) in DCM (50 mL) was added TEA (3.4 mL, 24.00 mmol) and SEMCl (4.80 g, 28.8 mmol) at 0 °C, and the resulting mixture was stirred at 25 °C for 2.5 h. The mixture was quenched with water (100 mL) and extracted with 5 DCM (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over MgSO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (0^5 % of EtOAc in PE) to afford 10.1 (5.0 g, 9.14 mmol, 76.18 % yield).

[0443] Synthesis of 10.2

[0444] To a stirred solution of 10.1 (1.6 g, 2.93 mmol) in DMF (12 mL) was added 10 pentanoic acid (4.48 g, 43.89 mmol), DCC (3.62 g, 17.58 mmol), and DMAP (1.07 g, 8.79 mmol), and the resulting mixture was heated at 120 °C under microwave irradiation for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over MgSO4, filtered, and the volatiles were removed. The residue was purified by silica gel 15 chromatography (0^5% of EtOAc in PE) to afford 10.2 (1.2 g, 1.90 mmol, 65 % yield).

[0445] Synthesis of 10

[0446] To a stirred solution of 10.2 (1.2 g, 1.90 mmol) in 1,4-dioxane (6 mL) was addedHCl (6 mL, 4.0M in 1,4-dioxane) at 0 °C and the resulting mixture was stirred at room temperature for 7 h. The reaction mixture was quenched with water (50 mL) and extracted 20 with EtOAc (2 x 100 mL). The combined organic layer was dried over MgSO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (5^10 % of EtOAc in PE) to afford 10 (474 mg, 0.947 mmol, 47.26 % yield). 1H NMR (400 MHz,DMSO-d6): δH 4.17 (d, J = 4.0 Hz, 1H), 3.70-3.68 (m, 1H), 2.80 (t, J = 20 Hz,1H), 2.50 (m, 1H), 2.29 (t, J = 7.4 Hz, 2H), 1.96-1.67 (m, 6H), 1.56-1.47 (m, 6H), 1.39-1.15 (m, 10H),25 1.05-1.00 (m, 4H), 0.91-0.84 (m, 12H), 0.64 (s, 3H).13C NMR (100 MHz, DMSO-d6): δC 171.1, 129.8, 127.0, 124.1, 121.2, 82.5, 66.62, 55.6, 53.2, 42.4, 41.4, 34.9, 34.5, 33.4, 32.3, 27.6, 26.9, 26.4, 25.7, 25.3, 23.8, 22.5, 22.3, 21.4, 20.5, 15.6, 13.5, 11.8.19F NMR (376 MHz, DMSO-d6): δF -75.3. LC-ELSD / MS MS ESI calcd for [M+Na]+C29H47F3NaO3523.3, found 523.3. 30

[0447] Example 11: Synthesis of sodium 4-(((3R,5R,8R,9S,10S,13S,14S,17R)-17- ((2S,3R)-3-hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl)oxy)-4-oxobutanoate (11) 136

[0448] Synthesis of 11.1

[0449] To a stirred solution of 10.1 (1.5 g, 2.7 mmol) and 4-(tert-butoxy)-4-oxobutanoic acid (21.4 g, 41.1 mmol) in DMF (5 mL) was added DCC (3.3 g, 19.7 mmol) and DMAP 5 (1.67 g, 13.7 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 3 h under microwave irradiation. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (10% of EtOAc in PE) to give 11.1 (1.2 g, 1.71 mmol, 63% 10 yield).

[0450] Synthesis of 11.2

[0451] To a stirred solution of 11.1 (1.2 g, 1.70 mmol) in 1,4-dioxane (5.0 mL) was added HCl (5 mL, 4M in 1,4-dioxane) at 0 °C and the resulting solution was stirred at 60 °C for 16 h. The volatiles were removed and the resulting residue was dissolved in EtOAc (300 mL) 15 and washed with water (2 x 100 mL). The organic layer was dried over MgSO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (40% of EtOAc in PE) to give 11.2 (0.50 g, 0.968 mmol, 56% yield).1H NMR (400 MHz, DMSO- d6): δH 12.30 (brs, 1H), 5.76 (s, 1H), 4.16-4.15 (m, 1H), 3.66-3.31 (m, 1H), 2.79-2.7 (m, 1H), 2.49-2.43 (m, 3H), 1.95-1.70 (m, 6H), 1.67-1.36 (m, 7H), 1.22-1.06 (m, 10H), 0.99-0.82 (m, 20 9H), 0.63 (s, 3H).

[0452] Synthesis of 11

[0453] To a stirred solution of 11.2 (0.50 g, 0.96 mmol) in THF (1 mL) was added Na2CO3(0.041 g, 0.38 mmol) as a solution in water (3 mL). The reaction mixture was stirred at room 137temperature for 30 min and the volatiles were removed. The resulting residue was lyophilized to give 11 (0.457 g, 0.848 mmol, 87% yield).1H NMR (400 MHz, DMSO-d6): δH 4.20 (s, 1H), 3.67-3.65 (m, 1H), 2.81 (t, J = 13.8 Hz, 1H), 2.34 (t, J = 6.8 Hz, 3H), 2.09 (t, J = 7 Hz, 2H), 1.95-1.92 (m, 1H), 1.83-1.79 (m, 2H), 1.77-1.53 (m, 7H), 1.39-1.34 (m, 3H), 1.26- 51.15 (m, 6H), 1.05-1.00 (m, 4H), 0.90 (s, 3H), 0.84-0.79 (m, 6H), 0.63 (s, 3H). 13C NMR(100 MHz, DMSO-d6): δC 174.3, 171.5, 130.0, 127.1, 124.3, 121.4, 82.4, 82.1, 81.8, 81.6, 66.6, 55.6, 53.1, 42.4, 41.4, 36.2, 35.0, 33.4, 32.4, 31.9, 31.6, 28.9, 27.4, 26.9, 25.8, 25.3, 24.2, 23.8, 22.6, 22.1, 20.5, 15.6, 11.8, 11.6. 19F NMR (376 MHz, DMSO-d6): δF -75.33.LC-ELSD / MS MS ESI calcd for [M-Na]- C28H43F3O5515.28, found 515.54. 10

[0454] Example 12: Synthesis of sodium (E)-4-(((2R,3S)-3- ((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)-4- oxobut-2-enoate (12); tert-butyl ((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy- 10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-15 yl)butan-2-yl) fumarate (48); and (E)-4-(((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3- hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)-4-oxobut-2-enoic acid (49)

[0455] Synthesis of 48 20

[0456] To a stirred solution of 1.1 (0.80 g, 1.92 mmol) and (E)-4-(tert-butoxy)-4-oxobut-2- enoic acid (1.58 g, 7.68 mmol) in DCM (20 mL) was added DCC (1.32 g, 7.68 mmol) andDMAP (0.093 g, 0.76 mmol) at 25 °C, and the resulting mixture was stirred for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, 25 filtered, and the volatiles were removed. The residue was purified by silica gel 138chromatography (8% of EtOAc in PE) to afford 48 (0.75 g, 1.31 mmol, 68% yield).1H NMR (400 MHz, DMSO-d6): δH 6.63 (dd, J = 16 Hz, 2H), 5.73 (s, 1H), 4.99-4.96 (m, 1H), 1.87-1.70 (m, 6H), 1.68-1.49 (m, 3H), 1.46-1.26 (m, 16H), 1.26-1.15 (m, 5H), 1.14-1.01 (m, 6H), 1.00-0.93 (m, 6H), 0.62 (s, 3H). 5

[0457] Synthesis of 49

[0458] A solution of 48 (0.75 g, 1.06 mmol) in DCM (8.0 mL) was cooled to 0 °C, TFA (8 mL) was added, and the resulting mixture was stirred at 25 °C for 16 h. The volatiles were removed, and the resulting residue was dissolved in EtOAc (300 mL) and washed with water (3 x 100 mL). The organic layer was dried over Na2SO4, filtered, and the volatiles were 10 removed. The resulting residue was washed with pentane to afford 49 (0.538 g, 1.05 mmol, 90% yield).1H NMR (400 MHz, DMSO-d6): δH13.19 (s, 1H), 6.63 (dd, J = 16 Hz, 2H), 5.73 (s, 1H), 4.99-4.97 (m, 1H), 1.93-1.76 (m, 6H), 1.62-1.25 (m, 10H), 1.29-1.00 (m, 11H) 0.99-0.92 (m, 6H), 0.62 (s, 3H).

[0459] Synthesis of 12 15

[0460] To a stirred solution of 49 (0.538 g, 1.05 mmol) in THF (1 mL) was added Na2CO3 (0.044 g, 0.418 mmol) as a solution in water (3 mL), and the resulting mixture was stirred at 25 °C for 30 min. The volatiles were removed and the resulting residue was lyophilized to afford 12 (0.448 g, 0.835 mmol, 78% yield).1H NMR (400 MHz, DMSO-d6): δH 6.68 (d, J = 16 Hz, 1H), 6.21 (d, J =16 Hz, 1H), 5.76 (bs, 1H), 4.94-4.92 (m, 1H), 1.93-1.70 (m, 6H), 20 1.62-1.59 (m, 3H), 1.49-1.46 (m, 2H), 1.35-1.21 (m, 5H) 1.18-1.04 (m, 11H), 0.92-0.90 (m, 6H), 0.63 (s, 3H).13C NMR (100 MHz, DMSO-d6): δC167.7, 165.4, 143.2, 128.9, 126.0, 72.0, 71.6, 71.3, 71.0, 55.4, 52.5, 42.4, 35.1, 33.6, 32.3, 27.5, 26.6, 26.0, 25.4, 23.8, 22.8, 20.5, 12.6, 12.3, 11.7. 19F NMR (376 MHz, DMSO-d6): δF -77.10. LC-ELSD / MS MS ESIcalcd for [M-Na]- C28H41F3O5513.27, found 513.42. 25

[0461] Example 13: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl heptanoate (13) 139

[0462] Synthesis of 13.1

[0463] To a stirred solution of heptanoic acid (3.80 g, 29.30 mmol) in DMF (12 mL) was added DCC (3.62 g, 17.58 mmol) and DMAP (0.715 g, 5.86 mmol) followed by 10.1 (1.6 g, 5 2.93 mmol), and the resulting mixture was heated to 120 °C and stirred for 2.5 h under microwave irradiation. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (2 x 100 mL), dried over MgSO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (0^5% EtOAc in hexane) to afford 13.1 (1.3 g, 10 1.97 mmol, 63% yield).

[0464] Synthesis of 13

[0465] To a stirred solution of 13.1 (1.3 g, 1.97 mmol) in 1,4-dioxane (6 mL) was added HCl (6 mL, 4M in 1,4-dioxane) at 0 °C and the resulting solution was warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with water (50 mL) and 15 extracted with EtOAc (2 x 300 mL). The combined organic layer was dried over MgSO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (5^10% of EtOAc in PE) to afford 13 (510 mg, 0.965 mmol, 49% yield). 1H NMR (400 MHz, DMSO-d6): δH 4.16 (d, J = 3.6 Hz, 1H), 3.31 (m, 1H), 2.75-2.51 (m, 1H), 2.31 (t, J = 7.2 Hz, 3H), 1.96-1.70 (m, 6H), 1.56-1.50 (m, 6H), 1.48-1.24 (m, 14H),20 1.16-1.02 (m, 4H), 0.87 (s, 3H), 0.86-0.81 (m, 9H), 0.63 (s, 3H). 13C NMR (100 MHz,DMSO-d6): δC 171.1, 129.8, 127.0, 124.1, 121.3, 82.7, 82.4, 82.1, 81.8, 66.6, 55.6, 53.2, 42.4, 41.4, 34.9, 33.4, 32.3, 30.8, 27.8, 26.9, 25.7, 25.3, 24.3, 23.8, 22.5, 22.4, 21.9, 20.5, 15.62. 14019F NMR (376 MHz, DMSO-d6): -75.22. LC-ELSD / MS MS ESI calcd for [M+Na]+C31H51F3NaO3 is 551.3, found 551.40.

[0466] Example 14: Synthesis of (((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3- hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- 5 cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)methyl isopropyl carbonate (14)

[0467] To a solution of 1.1 (1.30 g, 3.12 mmol) in DMF (13.00 mL) was added NaH (150 mg, 3.74 mmol, 60% wt dispersion in mineral oil) at 0 °C under N2 and the reaction was stirred for 1 h. Chloromethyl isopropyl carbonate (714 mg, 4.68 mmol) dissolved in DMF (1 10 mL) was added dropwise and the reaction was stirred at 25 °C for 16 h. The mixture was quenched with ice cold water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (8^10% of EtOAc in PE) to afford 14 (425 mg, 0.798 mmol, 25% yield).1H NMR (40015 MHz, DMSO-d6): δH 5.73 (s, 1H), 5.24 (s, 2H), 4.79-4.76 (m, 1H), 3.73-3.71 (m, 1H), 1.93- 1.60 (m, 9H), 1.50-1.46 (m, 2H), 1.35-1.14 (m, 15H), 1.05-1.00 (m, 4H), 0.95 (d, J = 6.4 Hz, 3H), 0.91 (s, 3H), 0.82 (d, J = 6.8 Hz, 3H), 0.64 (s, 3H).13C NMR (100 MHz, DMSO-d6): δC 153.5, 127.5 (q, J = 286.0), 90.4,77.2, 71.5 (q, J = 26.1), 71.3, 55.5, 52.5, 42.4, 40.1, 40.0, 39.9, 39.7, 39.5, 39.3, 39.1, 38.8, 38.4, 35.1, 33.6, 32.3, 27.5, 26.8, 26.0, 25.4, 23.8, 22.9,20 21.4, 20.5,13.4. 19F NMR (376 MHz, DMSO-d6): δF -77.11. LC-ELSD / MS MS ESI calcdfor [M+Na]+C29H47F3NaO5555.33, found 555.40.

[0468] Example 15: Synthesis of 2-((((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3- hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)methyl)benzo[d]isothiazol-3(2H)-one25 1,1-dioxide (15) 141

[0469] Synthesis of D

[0470] To a solution of C (5.00 g, 27.3 mmol; MilliporeSigma) in SO2Cl2 (35.00 mL) wasadded sodiated hydroxylmethanesulfonic acid (18.3 g, 136 mmol) under N2 and the reaction 5 was stirred at 85 °C for 16 h. Excess SO2Cl2was removed under reduced pressure and the resulting residue was diluted with DCM (100 mL). Aqueous saturated NaHCO3(100 mL) was carefully added and the organic layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and the volatiles were removed to afford D (5.50 g, 23.7 mmol, 87.0% yield).1H NMR (400 MHz, CDCl3): δH7.99-7.96 (m, 1H), 7.95-7.89 (m, 3H), 5.58 (s, 2H). 10

[0471] Synthesis of 15

[0472] To a solution of 1.1 (750.0 mg, 1.800 mmol) in DMC (7.00 mL) was added D(2.502 g, 10.80 mmol), DMAP (65.99 mg, 540.1 μmol), and TEA (546.6 mg, 753 μL, 5.401 mmol) at 25 °C under N2, and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with ice cold water (50 mL) and the resulting solid was filtered. 15 The solid was triturated (50% of EtOAc in PE), filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (1^2% of MeOH in DCM) to afford 15 (290 mg, 474 μmol, 26.3% yield).1H NMR (400 MHz, DMSO-d6): δH 8.32 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.11 (t, J = 6.8 Hz, 1H), 8.03 (t, J = 6.8 Hz, 1H), 5.73 (s, 1H), 5.20 (d, J = 4.0 Hz, 2H), 3.78-3.76 (m, 1H), 1.93-1.76 (m, 5H), 1.63-1.46 (m, 6H), 20 1.34-1.13 (m, 9H), 1.08-0.96 (m, 7H), 0.95-0.84 (m, 6H), 0.61 (s, 3H).13C NMR (100 MHz, DMSO-d6): δC 158.9, 137.0, 136.3, 135.3, 126.1, 125.8, 125.5, 121.6, 75.3, 71.6, 71.3, 67.3, 55.5, 52.6, 42.5, 40.1, 39.9, 39.7, 39.5, 39.2, 39.0, 38.8, 38.4, 37.7, 35.1, 33.6, 32.3, 27.6, 26.6, 26.0, 25.4, 23.8, 22.9, 20.5, 12.8, 11.9, 11.8.19F NMR (376 MHz, DMSO-d6): δF - 77.08. LC-ELSD / MS MS ESI calcd for [M-H]- C32H43F3NO5S 610.29, found 610.60.25

[0473] Example 16: Synthesis of 1,3-bis(palmitoyloxy)propan-2-yl ((2R,3S)-3- ((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- 142(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan-2-yl) glutarate (16)5

[0474] Synthesis of F

[0475] To a stirred solution of E (1 g, 11.1 mmol) in DCM (50 mL) was added pyridine (1.76 g, 1.80 mL, 22.2 mmol) and palmitoyl chloride (6.10 g, 22.2 mmol) at 25 °C, and the resulting mixture was stirred for 16 h. The reaction mixture was diluted with MeOH (10 mL) and water (10 mL), and stirred for 30 min. The precipitate was filtered and dried to afford F 10 (4 g, 7.06 mmol, 63% yield), which was used directly in the next step.

[0476] Synthesis of G

[0477] A stirred solution of F (3 g, 5.29 mmol) in THF (30 mL) and water (2 mL) wascooled to 0 °C, NaBH4(300 mg, 7.94 mmol) was added, and the reaction mixture was stirred for 1 h. The reaction mixture was filtered and the collected solid was dried to afford G (2.8 15 g, 4.92 mmol, 93% yield), which was used directly in the next step.1H NMR (400 MHz, DMSO-d6): δH4.19-4.08 (m, 5H), 2.43 (d, J= 4.8 Hz, 1H), 2.34 (t, J= 7.6 Hz, 4H), 1.64-1.61 (m, 4H), 1.28-1.25 (m, 48H), 0.89-0.86 (m, 6H).

[0478] Synthesis of H

[0479] To a stirred solution of G (2.80 g, 4.92 mmol) in DCM (10 mL), pyridine (10 mL),20 and THF (10 mL) was added dihydro-2H-pyran-2,6(3H)-dione (1.12 g, 9.84 mmol) and 143DMAP (601 mg, 4.92 mmol) at 25 °C, and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with HCl (50 mL, 1M aqueous) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and the volatiles were removed. The residue was 5 purified by silica gel chromatography (30% of EtOAc in PE) to afford H (1.80 g, 2.64 mmol, 53 % yield).1H NMR (400 MHz, DMSO-d6): δH 12.08 (bs, 1H), 5.19-5.18 (m, 1H), 4.26- 4.22 (m, 2H), 4.15-4.10 (m, 2H), 2.50-2.22 (m, 8H), 1.72 (t, J= 7.2 Hz, 2H), 1.51-1.48 (m, 4H), 1.23 (s, 48H), 0.86-0.83 (m, 6H).

[0480] Synthesis of 1610

[0481] To a stirred solution of 1.1 (0.40 g, 0.96 mmol) and H (1.31 g, 1.91 mmol) in DCM(20 mL) was added DCC (0.594 g, 2.88 mmol) and DMAP (0.035 g, 0.288 mmol) at room temperature, and the resulting mixture was stirred for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and the volatiles 15 were removed. The residue was purified by silica gel chromatography (10% of EtOAc in PE) to give 16 (0.75 g, 0.693 mmol, 72% yield). 1H NMR (400 MHz, CDCl3): δH 5.40-5.20 (m,1H), 4.90-5.10 (m, 1H), 4.32-4.29 (m, 2H), 4.28-4.11 (m, 2H), 2.41-2.32 (m, 8H), 2.03 (s, 1H), 1.95-1.75 (m, 6H), 1.75-1.58 (m, 10H) 1.41-1.25 (m, 58H), 1.09-1.05 (m, 7H), 0.96- 0.86 (m,12 H), 0.66 (s, 3H). 13C NMR (100 MHz, CDCl3): δC 173.5, 172.4, 172.3, 73.7,20 73.4, 73.1, 73.0, 69.3, 62.2, 56.2, 53.4, 43.1, 40.6, 40.2, 39.3, 39.0, 35.8, 34.2, 33.8, 33.8, 33.4, 32.6, 32.1, 29.9, 29.8, 29.8, 29.7, 29.5, 29.4, 29.3, 27.8, 27.4, 26.6, 25.9, 25.0, 24.4, 23.2, 22.9, 21.2, 20.3, 14.3, 13.0, 12.7, 12.2.19F NMR (376 MHz, DMSO-d6): δF -78.79. LC-ELSD / MS MS ESI calcd for [M+NH4]+C64H115F3NO91098.85, found 1098.8.

[0482] Example 17: Synthesis of (2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-25 hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)butan-2-yl isopropyl carbonate (17)144

[0483] To a stirred solution of 1.1 (0.70 g, 1.68 mmol) in THF (10 mL) was added pyridine (0.665 g, 8.40 mmol) and isopropyl carbonochloridate (2.0 g, 16.8 mmol) at room temperature and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined 5 organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (10% of EtOAc in PE) to afford 17 (0.69 g, 1.37 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6):δH 5.73 (s, 1H), 4.75-4.68 (m, 2H), 1.92-1.79 (m, 6H), 1.76-1.59 (m, 3H), 1.59-1.43 (m, 2H), 1.35-1.21 (m, 5H), 1.19-1.01 (m, 17H), 0.90-0.86 (m, 6H) 0.63 (s, 3H). 13C NMR (10010 MHz, DMSO-d6): δC153.5, 131.7, 128.8, 126.0, 123.1, 75.7, 71.8, 71.6, 71.3, 71.0, 70.8, 55.5, 52.4, 42.4, 38.4, 35.1, 33.5, 32.3, 27.5, 26.6, 26.0, 25.4, 23.7, 22.8, 21.5, 12.6, 12.2, 11.7. 19F NMR (376 MHz, DMSO-d6): δF -77.11. LC-ELSD / MS MS ESI calcd for[M+Na]+C28H45F3NaO4525.32, found 525.30.

[0484] Example 18: Synthesis of sodium 4-(((2R,3S)-3-15 ((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)-4- oxobutyl phosphate (18) and (2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy- 10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17- yl)butan-2-yl 4-(phosphonooxy)butanoate (50) 145

[0485] Synthesis of J

[0486] To a stirred solution of I (10 g, 116 mmol) in MeOH (150 mL) was added TEA (130 mL, 929 mmol) and the resulting mixture was stirred at 60 °C for 16 h. The reaction mixture 5 was diluted with PE (2 x 500 mL) and the volatiles were removed to afford J (10 g, 84.7 mmol, 72.9% yield).1H NMR (400 MHz, DMSO-d6): δH 4.47 (t, J = 5.2 Hz, 1H), 3.57 (s 3H), 3.40-3.36 (m, 2H), 2.34-2.31 (m, 2H), 1.69-1.62 (m, 2H).

[0487] Synthesis of K

[0488] To a stirred solution of J (2.5 g, 21.2 mmol) in DCM (25 mL) was added dibenzyl 10 diisopropylphosphoramidite (8.77 g, 25.4 mmol) and 1H-tetrazole (2.22 g, 31.7 mmol) as a solution in MeCN (80 mL). The reaction was stirred under N2at 25 °C for 16 h. The reaction mixture was cooled to 0 °C, H2O2 (1.44 g, 1.32 mL, 30% wt, 12.7 mmol) was added, and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was 15 washed with brine (100 mL), dried over MgSO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (20^30% of EtOAc in PE) to afford K (3.0 g, 7.93 mmol, 37% yield).1H NMR (400 MHz, DMSO-d6): δH 7.41-7.33 (m,10H), 1465.03 (d, J = 8.0 Hz, 4H), 3.98 (q, J = 6.7 Hz, 2H), 3.57 (s, 3H), 2.33 (t, J = 7.4 Hz, 2H), 1.85- 1.79 (m, 2H). LC-ELSD / MS MS ESI calcd for [M+H]+C19H24O6P 379.12, found 379.39.

[0489] Synthesis of L

[0490] To a stirred solution of K (3.00 g, 7.93 mmol) in THF (30.0 mL) was added LiOH 5 (380 mg, 15.9 mmol) as a solution in water (18 ml) and the reaction was stirred at 0 °C for 1 h. The volatiles were removed below 30 °C. The aqueous layer was extracted with EtOAc (2 x 100 mL). The aqueous layer was then acidified to a pH of ~1 with aqueous HCl (1.5N) and extracted again with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over MgSO4, filtered, and the volatiles were removed to give L (2.50 g,10 6.86 mmol, 86% yield). 1H NMR (400 MHz, DMSO-d6): δH 12.08 (s,1H), 7.40-7.31 (m,10H), 5.03 (d, J = 8.0 Hz, 4H), 3.98 (q, J = 6.7 Hz, 2H), 2.28-2.21 (m, 2H), 1.82-1.76 (m, 2H). LC-ELSD / MS MS ESI calcd for [M+H]+C18H22O6P 365.11, found 365.38.

[0491] Synthesis of 18.1

[0492] To a stirred solution of 1.1 (1.00 g, 2.40 mmol) in DCM (10.00 mL) was added L 15 (1.75 g, 4.80 mmol), DMAP (58.7 mg, 0.48 mmol), and DCC (991 mg, 4.80 mmol) at 25 °C under N2, and the reaction was stirred at 25 °C for 24 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over MgSO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (20^30% of EtOAc in PE) to 20 afford 18.1 (700 mg, 0.918 mmol, 37% yield).

[0493] Synthesis of 50

[0494] To a stirred solution of 18.1 (700 mg, 0.91 mmol) in MeOH (50.0 mL) was added Pd / C (586 mg, 50% wt Pd, 2.75 mmol) and the reaction was stirred at 25 °C under H2 (50 psi) for 3 h. The reaction was filtered through a pad of celite, eluted with MeOH (150 mL),25 and the volatiles were removed to give 50 (300 mg,0.515 mmol, 74% yield). 1H NMR (400MHz, DMSO-d6): δH 5.73 (bs,1H), 4.49 (bs, 1H) ,3.80-3.33 (m, 2H), 2.51-2.49 (m, 2H), 198- 1.90 (m, 2H), 187-1.60 (m,6H), 1.69-1.59 (m, 5H), 1.49-1.46(m, 5H), 1.35-1.20 (m, 5H), 1.19-1.09 (m, 7H), 0.90-0.88 (m, 5H), 0.62 (s, 3H). LC-ELSD / MS MS ESI calcd for [M+H]+C28H47F3O7P 583.29, found 583.66. 30

[0495] Synthesis of 18

[0496] To a stirred solution of 50 (300 mg, 0.51 mmol) in THF (3.00 mL) and water (5.00 mL) was added Na2CO3 (49.1 mg, 0.46 mmol) and the reaction was stirred at 25 °C for 30 min. The volatiles were removed and the resulting residue was lyophilized to give 18 (280 mg, 0.447 mmol, 86.8% yield). 1H NMR (400 MHz, D2O): δH 5.03 (bs,1H), 3.79 (q, J = 6.0147Hz, 2H) ,2.47 (t, J = 7.4 Hz, 2H), 2.04-2.87 (m, 10H), 1.82-1.66 (m, 3H), 1.45 (m, 5H), 1.30- 1.44 (m, 11H), 1.00(s, 6H), 0.71 (s, 3H).19F NMR (376 MHz, DMSO-d6): δF -77.99.

[0497] Example 19: Synthesis of (2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3- hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- 5 cyclopenta[a]phenanthren-17-yl)butan-2-yl propylcarbamate (19)

[0498] Synthesis of 19.1

[0499] To a solution of 1.1 (800.0 mg, 1.920 mmol) in DCM (20.00 mL) was added 4- nitrophenyl chloroformate (1.548 g, 7.682 mmol), DMAP (70.39 mg, 576.1 μmol), and 10 NMM (582.8 mg, 0.63 mL, 5.761 mmol) at 0 °C under N2, and the reaction was stirred at 25 °C for 16 h. The crude mixture containing 19.1 was used directly in the next step.

[0500] Synthesis of 19

[0501] To the crude mixture containing 19.1 (900 mg, 1.55 mmol) in DCM (20.00 mL) wasadded propylamine (274 mg, 382 μL, 4.64 mmol) and NMM (626 mg, 0.68 mL, 6.19 mmol) 15 at 0 °C under N2, and the reaction was stirred at 25 °C for 4 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (8^12% of EtOAc in PE) to afford 19 (730 mg, 1.46 mmol, 94.0% yield). 1H NMR (400 MHz, DMSO-20 d6): δH 6.95 (t, J = 5.4 Hz, 1H), 5.73 (s, 1H), 4.72-4.70 (m, 1H), 2.91-2.88 (m, 2H), 1.94-1.60 (m, 9H), 1.56-1.35 (m, 9H), 1.22-1.06 (m, 11H), 0.98-0.80 (m, 9H), 0.63 (s, 3H). 13C NMR(100 MHz, DMSO-d6): δCδ 155.8,127.5 (q, J = 285.1), 71.5 (q, J = 26.1), 71.0, 55.5, 52.7, 42.4, 41.9, 40.1, 40.0, 39.9, 39.7, 39.4, 39.3, 39.0, 38.8, 38.7, 38.5, 35.1, 33.6, 32.3, 27.6, 14826.6, 26.0, 25.4, 23.8, 22.9, 22.7, 20.6, 12.3, 11.8, 11.2. 19F NMR (376 MHz, DMSO-d6): δF-77.123. LC-ELSD / MS MS ESI calcd for [M+H]+C28H47F3NO3502.24, found 502.57.

[0502] Example 20: Synthesis of sodium 5-(((2R,3S)-3- ((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- 5 (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)- 3,3-dimethyl-5-oxopentanoate (20); 1-(tert-butyl) 5-((2R,3S)-3- ((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan-2-yl) 3,3- dimethylpentanedioate (51); and 5-(((2R,3S)-3-((3R,5R,8R,9S,10S,13S,14S,17R)-3-10 hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid (52)

[0503] Synthesis of N

[0504] To a solution of M (5 g, 35.2 mmol) in THF (60.0 mL) was added KOtBu (4.50 g, 15 40.0 mL, 1.00 molar, 40.0 mmol) at 0 °C under N2and the reaction was stirred at 25 °C for 1 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and the volatiles were removed to give N (3.3 g, 15.3 mmol, 43.4% yield).1H NMR (400 MHz, DMSO-d6): δH11.99 (s, 1H), 2.26-2.26 (m, 4H), 1.40 (s, 9H), 1.04-1.04 (m, 6H). 20

[0505] Synthesis of 51 149

[0506] To a solution of 1.1 (500.0 mg, 1.200 mmol) in DCM (10.00 mL) was added N(1.038 g, 4.801 mmol), DMAP (73.32 mg, 0.600 mmol), and DCC (743.0 mg, 0.644 mL, 3.601 mmol) at 0 °C under N2, and the reaction mixture was stirred at 25 °C for 16 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The 5 combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (8^10% of EtOAc in PE) to afford 51 (600 mg, 0.976 mmol, 81.3% yield).1H NMR (400 MHz, CDCl3): δH 5.00-4.98 (m, 1H), 2.37-2.36 (m, 2H), 2.30 (s, 2H), 2.01 (s, 1H), 1.98-1.90 (m, 4H), 1.86-1.73 (m, 4H), 1.72-1.60 (m, 3H), 1.45 (s, 10H), 1.41-1.37 (m, 3H), 1.32-1.1810 (m, 5H), 1.15-1.11 (m, 7H), 1.07-1.06 (m, 6H), 0.96-0.92 (m, 6H), 0.66 (s, 3H).

[0507] Synthesis of 52

[0508] To a solution of 51 (600.0 mg, 0.975 mmol) in DCM (6.00 mL) was added TFA(2.782 g, 1.86 mL, 24.40 mmol) at 0 °C under N2 and the reaction mixture was stirred at 25 °C for 3 h. The mixture was quenched with water (50 mL) and extracted with DCM (2 x 50 15 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (15^20% of EtOAc in PE) to give 52 (530 mg, 0.949 mmol, 96% yield). 1H NMR (400 MHz, DMSO-d6): δH 12.01 (br s, 1H), 5.74 (s, 1H), 4.88 (q, J = 3.2 Hz, 1H), 2.30 (d, J = 29.6 Hz, 2H), 2.26 (s, 2H), 1.93-1.60 (m, 9H), 1.50-1.35 (m, 7H), 1.30-1.01 (m, 20 2H), 0.97-1.18 (m, 14H), 0.83-0.94 (m, 7H), 0.66 (s, 3H).

[0509] Synthesis of 20

[0510] To a solution of 52 (530 mg, 0.949 mmol) in THF (5.00 mL) was addedNa2CO3(40.2 mg, 0.379 mmol) and water (5.00 mL) at 25 °C under N2, and the reaction mixture was stirred at 25 °C for 15 min. The volatiles were removed to give 20 (530 mg,25 0.913 mmol, 95% yield). 1H NMR (400 MHz, DMSO-d6): δH 5.87 (br s, 1H), 4.87-4.85 (m,1H), 2.40 (s, 2H), 1.93-1.47 (m, 13H), 1.35 (s, 5H), 0.97-1.14 (m, 17H), 0.86-0.94 (m, 6H), 0.63 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δC 174.977, 171.733, 131.790, 128.930,123.375, 71.854, 71.595, 71.333, 71.038, 55.516, 52.539, 50.168, 45.511, 42.419, 40.121, 39.913, 39.704, 39.495, 39.287, 39.078, 38.870, 38.681, 38.487, 35.122, 33.605, 32.312,30 27.597, 27.418, 26.699, 26.079, 25.421, 23.790, 22.896, 20.568, 12.750, 12.479, 11.765. 19FNMR (376 MHz, DMSO-d6): δF-77.09. LC-ELSD / MS MS ESI calcd for [M-Na]- C31H48F3O5557.45, found 557.35. 150

[0511] Example 21: Synthesis of (((3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl)oxy)methyl pentanoate (21)5

[0512] Synthesis of 21.1

[0513] To a solution of 1.1 (3.00 g, 7.20 mmol) in DCM (30.0 mL) was added DMP (8.25 g, 19.4 mmol) at 0 °C under N2 and the resulting mixture was stirred for 5 min. The reaction was then stirred at 25 °C for 3 h and was quenched with saturated aqueous NaHCO3(50 mL) and Na2S2O3(50 mL). The reaction mixture was extracted with DCM (2 x 100 mL) and the 10 combined organic layer was washed with saturated aqueous NaHCO3 (2 x 50 mL), saturated aqueous Na2S2O3(2 x 50 mL), and brine (2 x 50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The resulting residue was purified by silica gel chromatography (5^10% of EtOAc in PE) to afford 21.1 (2.70 g, 6.42 mmol, 89.1 % yield).1H NMR (400 MHz, DMSO-d6): δH 5.74 (s, 1H), 2.51 (s, 1H), 2.06 (s, 3H), 1.89-1.76 (m, 4H), 1.63-1.4915 (m, 7H), 1.38-1.36 (m, 4H), 1.29-0.99 (m, 11H), 0.98 (s, 3H), 0.20 (s, 3H). LC-ELSD / MS MS ESI calcd for [M-H]- C24H36F3O2413.27, found 413.56.

[0514] Synthesis of 21.2

[0515] To a solution of 21.1 (2.70 g, 6.51 mmol) in DMSO (30.00 mL) was added Ac2O(15.00 mL, 159.0 mmol) and AcOH (7.50 mL, 131 mmol) at 25 °C under N2, and the 20 resulting mixture was stirred at 60 °C for 20 h. The mixture was diluted with EtOAc (50 mL) and neutralized with saturated aqueous NaHCO3(100 mL). The reaction mixture was extracted with EtOAc (2 x 100 mL) and the combined organic layer was washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The residue was 151purified by silica gel chromatography (10^15% of EtOAc in PE) to afford 21.2 (1.50 g, 3.16 mmol, 48.5% yield).

[0516] Synthesis of 21.3

[0517] To a solution of 21.2 (1.40 g, 2.95 mmol) in DCM (7.00 mL) was added SO2Cl25 (349 μL, 4.13 mmol) at 0 °C and the reaction was stirred for 10 min under N2. The reaction was warmed to 25 °C and stirred for 40 min. The reaction mixture was concentrated under a stream of N2, re-dissolved in toluene, and then the volatiles were removed (this process was carried out 2 times). The resulting residue was again dissolved in toluene (4 mL) and added to a solution of n-valeric acid (361 mg, 385 μL, 3.54 mmol) and DBU (750 μL, 5.01 mmol) 10 in toluene (7.00 mL) that had been pre-stirred for 2 h, and the resulting mixture was further stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100mL). The combined organic layer was washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (5^10% of EtOAc in PE) to afford 21.3 (730 mg, 1.38 15 mmol, 46.8% yield).1H NMR (400 MHz, DMSO-d6): δH 5.44 (s, 2H), 2.43-2.41 (m, 1H), 2.36-2.33 (m, 3H), 2.11 (s, 4H), 1.93-1.72 (m, 3H), 1.69-1.60 (m, 3H), 1.59-1.47 (m, 6H), 1.38-1.31 (m, 7H), 1.26-1.19 (m, 3H), 1.16-1.04 (m, 6H), 0.93-0.88 (m, 6H), 0.69 (s, 3H).

[0518] Synthesis of 21

[0519] To a solution of 21.3 (700.0 mg, 1.324 mmol) in THF (21.0 mL) and MeOH (1.420 mL) was added NaBH4(25.04 mg, 23.43 μL, 662.0 μmol) at 0 °C under N2and the reaction was stirred at 25 °C for 1 h. The mixture was diluted with water (10 mL) and quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (10^15% of 25 EtOAc in PE) and re-purified by preparative SFC (column: LUX CELLULOSE-4 (30mm *250mm, 5µ), gradient: 20%B (hold), A = CO2, B = 0.1% DEA in MeOH, flow rate: 95 mL / min, column temp.: 30 °C, injections: 5, run time: 1.5 h) to afford 21 (150.0 mg, 282.6 μmol, 21.3 % yield).1H NMR (400 MHz, DMSO-d6): δH 5.41-5.40 (m, 2H), 3.97 (d, J = 4.8 Hz, 1H), 3.70-3.70 (m, 1H), 2.35-2.31 (m, 2H), 2.12-2.09 (m, 1H), 1.97-1.90 (m, 1H), 1.87- 30 1.82 (m, 3H), 1.71-1.65 (m, 3H), 1.56-1.51 (m, 4H), 1.51-1.15 (m, 13H), 1.16-0.98 (m, 6H), 0.98-0.90 (m, 6H), 0.88-0.80 (m, 3H), 0.62 (s, 3H).13C NMR (100 MHz, DMSO-d6): δC171.8, 126.4 (q, J = 285.3), 82.2, 78.5 (q, J =27.5), 66.7, 56.0, 52.4, 42.0, 41.6, 40.4, 40.1, 39.9, 39.7, 39.5, 39.2, 39.0, 38.8, 38.2, 35.1, 33.5, 33.4, 31.9, 29.8, 27.2, 26.4, 25.9, 25.4, 15224.2, 23.8, 22.7, 21.6, 21.5, 20.6, 13.5. 19F NMR (376 MHz, DMSO-d6): δF -75.77. LC-ELSD / MS MS ESI calcd for [M+Na]+C30H49F3NaO4 553.35, found 553.4.

[0520] Example 22: Synthesis of (((3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- 5 cyclopenta[a]phenanthren-3-yl)oxy)methyl heptanoate (22)

[0521] Synthesis of 22.1

[0522] To a solution of 21.2 (400 mg, 843 μmol) in DCM (3.00 mL) was added SO2Cl2(171 mg, 0.103 mL, 1.26 mmol) at 0 °C under N2and the resulting reaction mixture was 10 stirred at 0 °C for 10 min and then further stirred at 25 °C for 40 min. The reaction mixture was concentrated under N2. The residue was dissolved in toluene (2 x 3 mL) and the volatiles were removed. The resulting residue was again dissolved in toluene (0.4 mL) and added to a solution of heptatonic acid (143 mg, 0.155 mL, 1.10 mmol) and DBU (218 mg, 0.216 mL, 1.43 mmol) in toluene (3.00 mL) that was pre-stirred for 2 h. The resulting mixture was 15 stirred at 25 °C for 1 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (5% of EtOAc in PE) to give 22.1 (140 mg, 0.24 mmol, 29% yield).1H NMR (400 MHz, DMSO-d6): δH5.47-5.41 (m, 2H), 2.48-2.48 (m, 1H), 2.33 (t, J = 7.6 Hz, 20 2H), 2.11-2.10 (m, 4H), 1.97-1.86 (m, 3H), 1.78-1.70 (m, 1H), 1.68-1.58 (m, 8H), 1.55-1.31 153(m, 14H), 1.20-1.03 (m, 7H), 0.97 (s, 3H), 0.88-0.88 (m, 3H), 0.65 (s, 3H). LC-ELSD / MS MS ESI calcd for [M+NH4]+C32H55F3NO4574.41, found 574.77.

[0523] Synthesis of 22

[0524] To a solution of 22.1 (300.0 mg, 538.8 μmol) in THF (4.00 mL) was added NaBH45 (10.19 mg, 269.4 μmol) and MeOH (0.40 mL) at 0 °C under N2, and the reaction was stirred at 25 °C for 2 h. The mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and the volatiles were removed. The product was purified by SFC (column: LUX CELLULOSE-4 (30mm *250mm, 5µ), gradient: 15% B (hold), A = 10 CO2, B = 1:1 MeCN:iPrOH, flow rate: 100 mL / min, column temp.: 30 °C, injections: 8) to give 22 (76.0 mg, 0.15 mmol, 29% yield).1H NMR (400 MHz, DMSO-d6): δH5.42-5.41 (m, 2H), 3.97 (d, J = 4.8 Hz, 1H), 3.65-3.75 (m, 1H), 2.31 (t, J = 7.4 Hz, 2H), 2.10-2.08 (m, 1H), 1.98-1.96 (m, 1H), 1.85-1.68 (m, 3H), 1.57-1.54 (m, 3H), 1.52-1.50 (m, 4H), 1.50-1.19 (m, 17H), 1.19-1.04 (m, 6H), 0.98-0.93 (m, 3H), 0.88-0.81 (m, 6H), 0.63-0.62 (m, 3H). 13C15 NMR (100 MHz, DMSO-d6): δC 171.8, 126.8 (q, J = 220.1), 82.2, 78.5 (q, = 26.1), 66.7, 56.0, 52.4, 42.0, 41.6, 38.2, 35.2, 33.8, 33.5, 31.9, 30.9, 29.9, 28.1, 27.2, 26.0, 25.4, 24.3, 23.8, 22.7, 21.9, 21.5.19F NMR (376 MHz, DMSO-d6): δF-75.8. LC-ELSD / MS MS ESI calcd for [M+Na]+C32H53F3O4Na 581.39, found 581.40.

[0525] Example 23: Synthesis of potassium 6-(((2R,3S)-3-20 ((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butan-2-yl)oxy)-6-

[0526] To a stirred solution of 43 (0.530 g, 0.97 mmol) in THF (3 mL) was added K2CO325 (0.060 g, 0.43 mmol) as a solution in water (3 mL) and the reaction mixture was stirred at 25 °C for 30 min. The volatiles were removed and the resulting residue was lyophilized to afford 23 (0.53 g, 0.909 mmol, 91% yield).1H NMR (400 MHz, DMSO-d6): δH6.0 (bs, 1H), 4.85 (d, J = 3.6 Hz, 1H), 2.22 (t, J =7.2 Hz, 2H), 1.91-1.89 (m, 2H), 1.78-1.50 (m, 9H), 1.48- 1.41 (m, 11H), 1.37-1.19 (11H), 0.90 (d, J = 8.8 Hz, 6H), 0.62 (s, 3H). 13C NMR (100 MHz,154DMSO-d6): δC175.4, 172.3, 131.8, 128.9 (q, J = 285.5 Hz), 71.42 (q, J = 25.8 ...

Claims

CLAIMS What is Claimed is:

1. A compound, wherein the compound has the structure of Formula (I):, 5 or a pharmaceutically acceptable salt, isotopic variant, or a combination thereof, wherein: Agent iseach of R1and R2is independently hydrogen or a cleavable moiety, provided that at least one of R1and R2is not hydrogen; 10 R3is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, substituted or unsubstituted C6-10aryl, or substituted or unsubstituted 5-8 membered heteroaryl; each of R15and R16is independently hydrogen or substituted or unsubstituted 15 C1-6alkyl; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 carbocyclyl; R18is hydrogen or substituted or unsubstituted C1-6alkyl; R19is hydrogen or substituted or unsubstituted C1-6alkyl; 20 each of R20and R20’is independently hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl; R22is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 25 carbocyclyl, or substituted or unsubstituted C6-10aryl; and the point of attachment to R1or R2. 1882. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to claim 1, wherein the compound of Formula (I) is a compound of Formula (II):

53. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to any one of claims 1-2, wherein R1is hydrogen and R2is a cleavable moiety.

4. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to any one of claims 1-2, wherein R1is a cleavable moiety and R2is 10 hydrogen.

5. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to any one of claims 1-4, wherein each instance of a cleavable moiety is independently selected from the group consisting of: C(R’)(R’’)X1, -C(O)X2, -S(O)2OH, -S(O)2O-M+, -P(O)(OH)2, and -P(O)(O-M+)2, wherein: 15 each of R’ and R’’ is independently hydrogen or C1-6alkyl; X1is -OC(O)(C1-6 alkyl), -OC(O)(C1-6 alkoxy), or -N(RN1)(RN2); X2is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -N(RN1)(RN2), or 5-6 membered oxygen-containing heterocyclyl optionally substituted with 1-4 hydroxyl, wherein: each instance of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6alkoxy as they relate to 20 X1and X2is independently optionally substituted with 1-5 substituents independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, -C(O)OH, -C(O)O-M+, -C(O)(C1-6alkyl), -C(O)(C1-6alkoxy), -C(O)OCH(CH2OR)2, -C(O)CH2CH(OR)CH2OR, -OS(O)2OH, -OS(O)2O-M+, -OP(O)(OH)2, and -OP(O)(O-M+)2, wherein each instance of R is independently hydrogen or -C(O)(C1-20 alkyl) 25 and each instance of M+is independently Li+, Na+, K+, or NH4+; and 189each of RN1and RN2is independently hydrogen or C1-6alkyl, or RN1and RN2, together with the nitrogen atom to which they are attached, form a 5-10 membered monocyclic or bicyclic heteroaryl or 5-10 membered monocyclic or bicyclic heterocyclyl.

56. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to claim 5, wherein each instance of a cleavable moiety is independently -CH2X1or -C(O)X2.

7. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to claim 1, wherein each instance of a cleavable moiety is independently 10 selected from the group consisting of: 15, , , , 19058. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to any one of claims 1-7, wherein R3is C1-6 alkyl optionally substituted with 1-5 RA.

9. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to any one of claims 1 and 3-7, wherein R15and R16are both hydrogen.10 10. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to any one of claims 1 and 3-7, wherein R18is -CH3.

11. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to any one of claims 1-7, wherein R19is hydrogen.

12. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination15 thereof, according to any one of claims 1-7, wherein R19is -CH3.

13. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to any one of claims 1 and 3-7, wherein R20is hydrogen.

14. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to any one of claims 1 and 3-7, wherein R20’is -CH3.20 15. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to any one of claims 1-7, wherein R22is C1-6alkyl optionally substituted with 1-5 RF.

16. A compound, wherein the compound has the structure of Formula (X):191, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: each of a and b is independently 0 or 1, provided that a and b are not both 0; and 5 each instance of Z is independently hydrogen, -C(O)(C1-20alkyl), or -C(O)- (C(RZ1)(RZ2))1-6-C(O)(Agent), provided that at least two instances of Z are -C(O)-(C(RZ1)(RZ2))1-6-C(O)(Agent) and wherein: each of RZ1and RZ2is independently hydrogen or C1-6 alkyl; and each instance of Agent is independently a compound of Formula (X-I): 10wherein: Y is hydrogen or a bond, provided that one instance of Y is a bond and the other is hydrogen, wherein said bond is the point of attachment between Agent and the associated C(O); 15 R3is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2- 6 alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, substituted or unsubstituted C6-10aryl, or substituted or unsubstituted 5-8 membered heteroaryl; each of R15and R16is independently hydrogen or substituted or unsubstituted 20 C1-6alkyl; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 carbocyclyl; R18is hydrogen or substituted or unsubstituted C1-6alkyl; R19is hydrogen or substituted or unsubstituted C1-6 alkyl; 25 R20is hydrogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6carbocyclyl; 192R20’is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6 carbocyclyl; and R22is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or 5 substituted or unsubstituted C6-10 aryl.

17. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to claim 16, wherein a and b are both 1.

18. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to claim 16, wherein each instance of Agent is independently a compound 10 of Formula (X-I):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: Y is hydrogen or a bond, provided that one instance of Y is a bond and the other is hydrogen, wherein said bond is the point of attachment between Agent and the associated 15 C(O); R3is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, C6-10 aryl, or 5- 8 membered heteroaryl, wherein each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, C6-10aryl, and 5-8 membered heteroaryl is independently optionally substituted with 1-5 RA; 20 each of R15and R16is independently hydrogen or C1-6 alkyl optionally substituted with 1-5 RB; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6 carbocyclyl optionally substituted with 1-5 RB; R18is hydrogen or C1-6alkyl optionally substituted with 1-5 RC; 25 R19is hydrogen or C1-6alkyl optionally substituted with 1-5 RD; each of R20and R20’is independently hydrogen, hydroxyl, C1-6 alkyl, or C3-6 carbocyclyl, wherein each of said C1-6 alkyl and C3-6 carbocyclyl is independently optionally substituted with 1-5 RE; 193each instance of RA, RB, RC, RD, and RE, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10 aryl, and C1-6 alkoxy optionally substituted with 1-5 halo; R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or C6-10aryl, 5 wherein each of said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl is independently optionally substituted with 1-5 RFand each of said C3-6 carbocyclyl and C6-10 aryl is independently optionally substituted with 1-5 RG; each instance of RF, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C1-6 alkoxy optionally substituted with 1-5 halo, 10 C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein each of said C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl is independently optionally substituted with 1-5 RF1; each instance of RF1, when present, is independently selected from the group 15 consisting of halo, cyano, oxo, nitro, amino, C1-6 alkyl optionally substituted with 1-5 halo, and C1-6 alkoxy optionally substituted with 1-5 halo; and each instance of RG, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C1-6 alkyl optionally substituted with 1-5 halo, and C1- 6 alkoxy optionally substituted with 1-5 halo.20 19. The compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to claim 18, wherein the compound of Formula (X-I) is a compound of Formula (X-II):

20. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination25 thereof, according to claim 16, wherein each instance of Agent is independently 194.

21. A compound selected from any one of compounds 1-78 in Table 1, or apharmaceutically acceptable salt, isotopic variant, or combination thereof.

522. A pharmaceutical composition comprising a compound or a pharmaceuticallyacceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-21, and a pharmaceutically acceptable carrier.

23. A method for treating a CNS-related condition in a subject in need thereof,comprising administering to the subject an effective amount of a compound or a 10 pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-21, or a pharmaceutical composition according to claim 22.

24. A method for effecting negative allosteric modulation of an NMDA receptor in asubject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any 15 one of claims 1-21, or a pharmaceutical composition according to claim 22.

25. A compound or a pharmaceutically acceptable salt, isotopic variant, or combinationthereof, according to any one of claims 1-21, or a pharmaceutical composition according to claim 22, for use in treating a CNS-related condition in a subject.

26. A compound or a pharmaceutically acceptable salt, isotopic variant, or combination20 thereof, according to any one of claims 1-21, or a pharmaceutical composition according to claim 22, for use in effecting negative allosteric modulation of an NMDA receptor in a subject. 19527. Use of a compound or a pharmaceutically acceptable salt, isotopic variant, orcombination thereof, according to any one of claims 1-21, or a pharmaceutical composition according to claim 22, in the manufacture of a medicament for treating a CNS-related condition in a subject.5 28. Use of a compound or a pharmaceutically acceptable salt, isotopic variant, orcombination thereof, according to any one of claims 1-21, or a pharmaceutical composition according to claim 22, in the manufacture of a medicament for effecting negative allosteric modulation of an NMDA receptor in a subject. 196

Images