NMDA receptor-modulatory compounds and methods of use thereof

Abstract

The disclosure relates to a method for treating a CNS-related disease, disorder or condition in a subject in need thereof using NMDA receptor modulators.

Description

NMDA RECEPTOR-MODULATORY COMPOUNDS AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of United States Provisional5 Application No. 63 / 716,983, filed November 6, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] N-methyl-D-aspartate (NMDA) receptors are heterotetrameric complexes comprised of four subunits: two obligatory NR1 subunits, and two NR2 (NR2A, NR2B, NR2C and NR2D) 10 and / or NR3 (NR3 A and NR3B) subunits. The NMDA receptors possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine, and glutamate agonists and modulators. NMDA receptors are expressed in the peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. The four subtypes of the GluN2 subunit (GluN2A, GluN2B, GluN2C and GluN2D) are15 expressed with different spatiotemporal patterns in the brain. These GluN2 subunits determine the properties of the receptor, including open probability, single-channel conductance, and deactivation rate. Additionally, the different NMDA receptor subtypes confer different pharmacological sensitivities.

[0003] NMDA receptor channels are opened by the concurrent binding of glycine and, 20 glutamate to the receptor subunits. Upon opening, the receptor allows cations (e.g., Ca2) to flow into the cell. Additionally, NMDA receptor channels are blocked by Mg2+at resting membrane potentials, regulating the inflow of cations through the open channel. As the intracellular Ca2+concentration increases, the synaptic membrane depolarizes and releases the Mg2+ion, allowing maximal flow of cations into the cell. This dualistic activation mechanism, 25 of NMDA receptors contributes to synaptic plasticity in some circumstances (mediating learning and memory processes) and exci totoxi city in others.

[0004] Thus, there is a need for new compounds that are positive allosteric modulators of the NMDA receptor, and more specifically subtype specific positive allosteric modulators for treating and preventing conditions associated with NMDA receptor function. The methods and 30 compounds described herein are directed toward this end.BRIEF SUMMARY

[0005] The present disclosure provides methods of treating CNS-related conditions or disorders with NMDA receptor positive allosteric modulators.

[0006] In one aspect, the disclosure provides a method for treating a CNS-related disease, 5 disorder or condition in a subject in need thereof, comprising administering to the subject an effective amount of Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, wherein the CNS-related disease, disorder or condition is selected from the group consisting of neuropsychiatric disorders, neurodegenerative disorders, 10 neurodevelopmental disorders, and neurologic disorders.

[0007] In one aspect, the disclosure provides a compound, wherein said compound is Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, for use in treating a CNS-related disease, disorder or condition in a subject; wherein the CNS-related disease, disorder or condition is selected from the group consisting of15 neuropsychiatric disorders, neurodegenerative disorders, neurodevelopmental disorders, and neurologic disorders.

[0008] In one aspect, the disclosure provides the use of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, in the manufacture of a medicament for treating a CNS-related disease, disorder or condition in a subject, wherein the, 20 CNS-related disease, disorder or condition is selected from the group consisting of neuropsychiatric disorders, neurodegenerative disorders, neurodevelopmental disorders, and neurologic disorders.

[0009] In some embodiments, the neuropsychiatric disorder is selected from the group consisting of mood disorders, anxiety disorder, schizophrenia, bipolar disorder, obsessive-, 25 compulsive disorder, alcohol and substance abuse, post-traumatic stress disorder (PTSD), and attention-deficit hyperactivity disorder (ADHD).

[0010] In some embodiments, the neurodegenerative disorder is selected from the group consisting of Parkinson’s disease, Huntington’s Disease, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinaland bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich’s ataxia, and Lewy body disease.

[0011] In some embodiments, the neurologic disorder is selected from the group consisting of neuropathic pain, nociceptive pain, inflammatory pain, stroke, traumatic brain injury, a seizure 5 disorder, a movement disorder, oculomotor apraxia, Dravet’s syndrome, transient ischemia, global ischemia, hypoxia, and spinal cord trauma.

[0012] In some embodiments, the seizure disorder is selected from the group consisting of epilepsy, status, epilepticus, developmental and epileptic encephalopathy (DEE).

[0013] In some embodiments, the movement disorder is selected from the group consisting of 10 bradykinesia associated with Parkinson’s Disease, dyskinesia, dystonia, chorea, Huntington’s disease, ataxia, tremor, myoclonus and startle, tics, Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.

[0014] In some embodiments, the neurodevelopmental disorder is selected from the group consisting of a GRIN disorder, Rett syndrome, autism, autism spectrum disorder (ASD), Fragile 15 X syndrome, tuberous sclerosis, Smith-Lemli-Opitz syndrome, and Down's syndrome.

[0015] In one aspect, the disclosure provides method for positive allosteric modulation of an NMD A receptor in a subject in need thereof, comprising administering to the subject an effective amount of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof; and, 20 wherein the NMDA receptor comprises a GluN2C subunit and / or a GluN2D subunit.

[0016] In one aspect, the disclosure provides a compound, wherein said compound is Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, for use in positive allosteric modulation of an NMDA receptor in a subject, wherein the NMDA receptor comprises a GluN2C subunit and / or a GluN2D., 25

[0017] In one aspect, the disclosure provides the use of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, in the manufacture of a medicament for positive allosteric modulation of an NMDA receptor in a subject, wherein the NMDA receptor comprises a GluN2C subunit and / or a GluN2D.

[0018] In some embodiments, the NMDA receptor comprises one GluN2C subunit. In some 30 embodiments, the NMDA receptor comprises two GluN2C subunits.

[0019] In some embodiments, the NMDA receptor comprises one GluN2D subunit. In some embodiments, the NMDA receptor comprises two GluN2D subunits.

[0020] In some embodiments, the subject is administered Compound (1). In some embodiments, the subject is administered a pharmaceutically acceptable salt of Compound (1).In some embodiments, the subject is administered an isotopic variant of Compound (1). In some embodiments, the isotopic variant is a deuterated variant. In some embodiments, the subject is administered a prodrug of Compound (1).

[0021] In some embodiments, the prodrug of Compound (1) is a compound of Formula (I)or a pharmaceutically acceptable salt, isotopic variant, or combination thereof,wherein each of R1and R2is independently hydrogen, -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb, provided that both R1and R2are not hydrogen;each Ra is independently -ORc or Ci-ealkyl;Rb is Ci-ealkyl;each Rc is independently hydrogen, Ci-ealkyl, or a counterion; ortwo Rc taken together are a counterion; andeach n and p is independently 1, 2, 3, 4, 5 or 6.15

[0022] In some embodiments, R1is not hydrogen.

[0023] In some embodiments, R2is not hydrogen.

[0024] In some embodiments, R1is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or - (CH2)POC(O)Rb.

[0025] In some embodiments, R2is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -, 20 (CH2)POC(O)Rb.

[0026] In some embodiments, each of R1and R2is independently -P(O)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.

[0027] In some embodiments, each Ra is independently -ORc; and each Rc is independently Na+., 25

[0028] In some embodiments, Rb is Ci-3alkyl.

[0029] In some embodiments, the compound used in the methods, compositions and uses disclosed herein, is selected from the group consisting of any one of Compounds 1-21, or a pharmaceutically acceptable salt thereof set forth in Table 1.

[0030] In one aspect, the disclosure provides a compound of Formula (I), or a30 pharmaceutically acceptable salt, isotopic variant or combination thereof,wherein each of R1and R2is independently hydrogen, -P(O)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb, provided that both R1and R2are not hydrogen;each Ra is independently -ORc or Ci-ealkyl;5 Rb is Ci-ealkyl;each Rc is independently hydrogen, Ci-ealkyl, or a counterion; ortwo Rc taken together are a counterion; andeach n and p is independently 1, 2, 3, 4, 5 or 6.

[0031] In some embodiments, R1is not hydrogen.10

[0032] In some embodiments, R2is not hydrogen.

[0033] In some embodiments, R1is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or - (CH2)POC(O)Rb.

[0034] In some embodiments, R2is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or - (CH2)POC(O)Rb.15

[0035] In some embodiments, each of R1and R2is independently -P(O)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.

[0036] In some embodiments, each Ra is independently -ORc; and each Rc is independently Na+.

[0037] In some embodiments, Rb is Ci-3alkyl.20

[0038] In some embodiments, the compound is selected from the group consisting of any one of Compounds 2-21, or a pharmaceutically acceptable salt thereof set forth in Table 1.DETAILED DESCRIPTION

[0039] The present disclosure provides methods of treating CNS-related conditions or disorders with NMDA receptor positive allosteric modulators., 25 General Definitions

[0040] The term “herein” means the entire application.

[0041] 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, 30 composition and methods described herein, are those well-known and commonly used in the art.

[0042] 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. Combination ofembodiments are not limited to those specific combinations claimed via the 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 5 elements is also disclosed, and any element(s) can be removed from the group.

[0043] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” will be understood to imply the inclusion of a stated integer (or component or element) or group of integers (or components or elements), but not the exclusion of any other integer (or10 component, element) or group of integers (or components or elements).

[0044] Throughout the specification, where compositions are described as having, 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 specific process steps, the 15 processes also may consist essentially of, or consist 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 remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0045] The term “including,” as used herein, means “including but not limited to.”, 20 “Including” and “including but not limited to” are used interchangeably. Thus, these terms will be understood to imply the inclusion of a stated integer (or component, element or method) or group of integers (or components or elements), but not the exclusion of any other integer (or component or element) or group of integers (or components or elements).

[0046] As used herein, “about” or “approximately” means within an acceptable error range for, 25 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.

[0047] The use of the terms “a” and “an” and “the” and similar referents in the context of 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 30 by context.

[0048] The term “or” as used herein should be understood to mean “and / or,” unless the context clearly indicates otherwise.

[0049] 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 theendpoints, 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 contradicted by context. The use of any and all examples, or exemplary language (“such as,” 5 “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.

[0050] All of the publications, patents, and published patent applications referred to in this 10 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 one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly 15 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

[0051] 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, 20 Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York,, 25 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0052] 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 30 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, 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) and the formation and crystallization of chiral salts;or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen etal., Tetrahedron 332 25 (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., 5 Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0053] 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.” 10 Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its 15 asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”, 20

[0054] As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight,, 25 more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or 30 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. The term “diastereomerically pure” denotes that the compound comprises morethan 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more 5 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, such as high- 10 performance liquid chromatography (HPLC).

[0055] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-position / center / carbon compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R- compound. In certain 15 embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S- compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the, 20 enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0056] As used herein, the term “diastereomeric purity” refers to the amount of a compound, 25 having the depicted absolute stereochemistry, expressed as a percentage of the total amount of the depicted compound and its diastereomers. 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% 30 by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the diastereomer. Methods for determining diastereomeric and enantiomeric purity are well-known in the art. Diastereomeric purity can be determined by any analyticalmethod capable of quantitatively distinguishing between a compound and its diastereomers, such as high-performance liquid chromatography (HPLC).

[0057] 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 5 tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like.

[0058] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, Ci- 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.10

[0059] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present 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, 15 the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0060] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-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, 20 (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl, 25 (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (Ce). Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, / .<., 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 (- 30 CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (- CH2CH(CH3)2).

[0061] “Hydroxy” refers to the radical -OH.

[0062] 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 replacedwith a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and 5 when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For 10 purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.Other Definitions

[0063] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency 15 of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0064] “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, 20 parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic, 25 acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic 30 acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term 5 “pharmaceutically acceptable cation” refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.

[0065] As used herein, the term “prodrug” is intended to encompass therapeutically inactive 10 compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. One method for making a prodrug is to design selected moieties that are hydrolyzed or cleaved at a targeted in vivo site of action under physiological conditions to reveal the desired molecule which then produces its therapeutic effect. For example, the prodrug can be converted by an enzymatic activity of the subject. Additionally, prodrugs can be 15 converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For exampie, prodrugs can be slowly converted to the compounds of the disclosure when placed in a formulation or delivery system (e.g., transdermal patch) with a suitable enzyme or chemical reagent. Prodrugs of the disclosure include a cleavable moiety on the C3 hydroxy, C25 hydroxy or both the C3 hydroxy and C25 hydroxy. The cleavable moiety of, 20 the prodrug may be linked to the compound via a linkage such as an ester or ether linkage.

[0066] “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 transporting the subject agents from one organ, or portion of the body, to another organ, or, 25 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 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.30

[0067] A “subject” to which administration is contemplated includes, but is not limited to, 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 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.

[0068] Disease, disorder, and condition are used interchangeably herein and describe any disease state, disorder or condition requiring NMDA receptor modulation.5

[0069] As used herein, the term “treat,” “treating” or “treatment” includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in 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, 10 reduction of the severity, or slowing the progression, of 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.15 Exemplary beneficial clinical results are described herein.

[0070] 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.

[0071] In general, the “effective amount” of a compound refers to an amount sufficient to, 20 elicit the desired biological response. As will be appreciated by those of ordinary skill in this 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., 25

[0072] The terms “pharmaceutically effective amount,” “therapeutically effective amount,” or “therapeutically effective dose” 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 30 etc. The full therapeutic effect 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,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 5 amount of a compound also refers to an amount of the therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.10

[0073] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of 15 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.

[0074] “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., 20 For example, a compound or an agent can be administered, intravenously (i.v.), arterially, intradermally, intramuscularly, intraperitoneally (i.p.), subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and 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, 25 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 some 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 30 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 involving 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 methodsof 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 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.5 solubility, digestibility, bioavailability, stability and toxicity).

[0075] 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 potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, and / or safety as 10 compared to other compounds.Methods of Treatment and Use

[0076] The present disclosure is directed to a method of treating a CNS-related conditions or disorders.

[0077] In one aspect, the disclosure provides a method for positive allosteric modulation of an 15 NMDA receptor in a subject, comprising administering to the subject an effective amount of Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein.

[0078] In one aspect, the disclosure provides a method for positive allosteric modulation of an, 20 NMD A receptor in a subject, comprising administering to the subject an effective amount of a compound of Formula (I)pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein.

[0079] In one aspect, the disclosure provides a method of allosteric modulation comprising, 25 binding an NMD A receptor at an allosteric site with Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein and blocking the effects of an allosteric NMDA receptor modulator (i.e., PAM and / or NAM) in a subject.

[0080] In one aspect, the disclosure provides a method of allosteric modulation comprising binding an NMD A receptor at an allosteric site with a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein and blocking the effects of an allosteric NMDA receptor modulator (i.e., PAM and / or 5 NAM) in a subject.

[0081] In one aspect, the disclosure provides Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein, for use in positive allosteric modulation of an NMDA receptor in a subject.

[0082] In one aspect, the disclosure provides a compound of Formula (I), or a10 pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein, for use in positive allosteric modulation of an NMDA receptor in a subject.

[0083] In one aspect, the disclosure provides Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein, for use as a neutral allosteric ligand (NAL) of an NMDA receptor in a subject.15

[0084] In one aspect, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein, for use as a neutral allosteric ligand (NAL) of an NMDA receptor in a subject.

[0085] In one aspect, the disclosure provides the use of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein, in the, 20 manufacture of a medicament for use in positive allosteric modulation of an NMDA receptor in a subject.

[0086] In one aspect, the disclosure provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein, in the manufacture of a medicament for use in positive allosteric modulation of an NMDA receptor, 25 in a subject.

[0087] In one aspect, the disclosure provides the use of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein, in the manufacture of a medicament for use as a neutral allosteric ligand (NAL) of an NMDA receptor in a subject.30

[0088] In one aspect, the disclosure provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein, in the manufacture of a medicament for use as a neutral allosteric ligand (NAL) of an NMDA receptor in a subject.

[0089] In some embodiments, the NMDA receptor comprises a GluN2C subunit. In some embodiments, the NMDA receptor comprises two GluN2C subunits. In some embodiments, the NMDA receptor comprises a GluN2C subunit and a GluN2A subunit. In some embodiments, the NMDA receptor comprises a GluN2C subunit and a GluN2B subunit. In some5 embodiments, the NMDA receptor comprises a GluN2D subunit. In some embodiments, the NMDA receptor comprises two GluN2D subunits. In some embodiments, the NMDA receptor comprises a GluN2D subunit and a GluN2A subunit. In some embodiments, the NMDA receptor comprises a GluN2D subunit and a GluN2B subunit. In some embodiments, the NMDA receptor comprises a GluN2C subunit and a GluN2D subunit. In some embodiments, 10 the NMDA receptor comprises a GluN2A subunit. In some embodiments, the NMDA receptor comprises two GluN2A subunits. In some embodiments, the NMDA receptor comprises a GluN2A subunit and a GluN2B subunit. In some embodiments, the NMDA receptor comprises a GluN2B subunit. In some embodiments, the NMDA receptor comprises two GluN2B subunits.15

[0090] In certain embodiments, the compound of the present disclosure (e.g., Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof; or a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof), is a positive allosteric modulator (PAM) of NMDA receptors and activates NMDA receptor function. In some embodiments, the compound of the disclosure is a positive allosteric, 20 modulator of an NMDA receptor comprising a GluN2C subunit. In some embodiments, the compound is a positive allosteric modulator of an NMDA receptor comprising a GluNl subunit and GluN2C subunit (GluNl / 2C). In some embodiments, the compound of the disclosure is a positive allosteric modulator of an NMDA receptor comprising two GluNl subunits and two GluN2C subunits. In some embodiments, the compound is a positive allosteric modulator of an, 25 NMDA receptor comprising a GluN2D subunit. In some embodiments, the compound is a positive allosteric modulator of an NMDA receptor comprising a GluNl subunit and GluN2D subunit (GluNl / 2D). In some embodiments, the compound is a positive allosteric modulator of an NMDA receptor comprising two GluNl subunits and two GluN2D subunits.

[0091] In certain embodiments, the compound of the present disclosure (e.g., Compound (1), 30 or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof; or a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof), is a neutral allosteric ligand (NAL) of an NMDA receptor, which binds at allosteric sites and block the effects of a PAM and / or NAM of an NMDA receptor. In some embodiments, the compound of the disclosure is a NAL of an NMDA receptor comprising aGluN2A subunit. In some embodiments, the compound is a NAL of an NMDA receptor comprising a GluNl subunit and GluN2A subunit (GluNl / 2A). In some embodiments, the compound of the disclosure is a NAL of an NMDA receptor comprising two GluNl subunits and two GluN2A subunits. In some embodiments, the compound is a NAL of an NMDA 5 receptor comprising a GluN2B subunit. In some embodiments, the compound is a NAL of an NMDA receptor comprising a GluNl subunit and GluN2B subunit (GluNl / 2B). In some embodiments, the compound is a NAL of an NMDA receptor comprising two GluNl subunits and two GluN2B subunits. In some embodiments, the compound of the disclosure is a NAL of an NMDA receptor comprising a GluN2C subunit. In some embodiments, the compound is a 10 NAL of an NMDA receptor comprising a GluNl / 2C subunit. In some embodiments, the compound of the disclosure is a NAL of an NMDA receptor comprising two GluNl subunits and two GluN2C subunits. In some embodiments, the compound is a NAL of an NMDA receptor comprising a GluN2D subunit. In some embodiments, the compound is a NAL of an NMDA receptor comprising a GluNl / 2D subunit. In some embodiments, the compound of the 15 disclosure is a NAL of an NMDA receptor comprising two GluNl subunits and two GluN2D subunits.

[0092] 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 Compound (1), or a pharmaceutically acceptable salt,, 20 isotopic variant, prodrug, or combination thereof as disclosed herein.

[0093] 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 Compound (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein., 25

[0094] In one aspect, the disclosure provides a method for treating a CNS-related disease, disorder or condition in a subject, comprising administering to the subject an effective amount of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein; wherein the CNS-related disease, disorder or condition is selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a 30 neurodevelopmental disorder and a neurologic disorder.

[0095] In one aspect, the disclosure provides a method for treating a CNS-related disease, disorder or condition in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant or combination thereof as disclosed herein; wherein the CNS-related disease, disorder or conditionis selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.

[0096] 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 5 to the subject an effective amount of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein.

[0097] 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 of Formula (I), or a pharmaceutically10 acceptable salt, isotopic variant, or combination thereof as disclosed herein.

[0098] In one aspect, the disclosure provides a method for preventing a CNS-related disease, disorder or condition in a subject, comprising administering to the subject an effective amount of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein; wherein the CNS-related disease, disorder or condition is selected 15 from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.

[0099] In one aspect, the disclosure provides a method for preventing a CNS-related disease, disorder or condition in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or, 20 combination thereof as disclosed herein; wherein the CNS-related disease, disorder or condition is selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.

[0100] 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, 25 to the subject a pharmaceutical composition comprising Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein; and a pharmaceutically acceptable carrier.

[0101] 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 30 to the subject a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein; and a pharmaceutically acceptable carrier.

[0102] In one aspect, the disclosure provides a method for treating a CNS-related disease, disorder or condition in a subject, comprising administering to the subject a pharmaceuticalcomposition comprising Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein; and a pharmaceutically acceptable carrier; wherein the CNS-related disease, disorder or condition is selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevel opmental disorder and a 5 neurologic disorder.

[0103] In one aspect, the disclosure provides a method for treating a CNS-related disease, disorder or condition in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant or combination thereof as disclosed herein; and a pharmaceutically acceptable 10 carrier; wherein the CNS-related disease, disorder or condition is selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.

[0104] 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 15 to the subject a pharmaceutical composition comprising Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein; and a pharmaceutically acceptable carrier.

[0105] 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, 20 to the subject a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein; and a pharmaceutically acceptable carrier.

[0106] In one aspect, the disclosure provides a method for preventing a CNS-related disease, disorder or condition in a subject, comprising administering to the subject a pharmaceutical, 25 composition comprising Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein; and a pharmaceutically acceptable carrier; wherein the CNS-related disease, disorder or condition is selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.30

[0107] In one aspect, the disclosure provides a method for preventing a CNS-related disease, disorder or condition in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein; and a pharmaceutically acceptable carrier; wherein the CNS-related disease, disorder or condition is selected from the groupconsisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.

[0108] In one aspect, the disclosure provides Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein for use in treating a 5 disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject.

[0109] In one aspect, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein for use in treating a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject.10

[0110] In one aspect, the disclosure provides Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein for use in treating a CNS-related disease, disorder or condition in a subject, wherein the CNS-related disease, disorder or condition is selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.15

[0111] In one aspect, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein for use in treating a CNS-related disease, disorder or condition in a subject, wherein the CNS- related disease, disorder or condition is selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic, 20 disorder.

[0112] In one aspect, the disclosure provides Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein for use in preventing a disease, disorder or condition requiring positive allosteric NMDA receptor modulation in a subject., 25

[0113] In one aspect, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein for use in preventing a disease, disorder or condition requiring positive allosteric NMDA receptor modulation in a subject.

[0114] In one aspect, the disclosure provides Compound (1), or a pharmaceutically acceptable 30 salt, isotopic variant, prodrug, or combination thereof as disclosed herein for use in preventing a CNS-related disease, disorder or condition in a subject wherein the CNS-related disease, disorder or condition is selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.

[0115] In one aspect, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein for use in preventing a CNS-related disease, disorder or condition in a subject, wherein the CNS- related disease, disorder or condition is selected from the group consisting of a neuropsychiatric 5 disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.

[0116] In one aspect, the disclosure provides the use of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein for the manufacture of a medicament for treating a disease, disorder or condition requiring allosteric 10 NMDA receptor modulation in a subject.

[0117] In one aspect, the disclosure provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein for the manufacture of a medicament for treating a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject.15

[0118] In one aspect, the disclosure provides the use of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein for the manufacture of a medicament for treating a CNS-related disease, disorder condition in a subject, wherein the CNS-related disease, disorder or condition is selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a, 20 neurologic disorder.

[0119] In one aspect, the disclosure provides the use a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein for the manufacture of a medicament for treating a CNS-related disease, disorder condition in a subject, wherein the CNS-related disease, disorder or condition is selected from the group, 25 consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.

[0120] In one aspect, the disclosure provides the use of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein for the manufacture of a medicament for preventing a disease, disorder or condition requiring positive 30 allosteric NMDA receptor modulation in a subject.

[0121] In one aspect, the disclosure provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein for the manufacture of a medicament for preventing a disease, disorder or condition requiring positive allosteric NMDA receptor modulation in a subject.1

[0122] In one aspect, the disclosure provides the use of Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein for the manufacture of a medicament for preventing a CNS-related disease, disorder condition in a subject, wherein the CNS-related disease, disorder or condition is selected from the group 5 consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.

[0123] In one aspect, the disclosure provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof as disclosed herein for the manufacture of a medicament for preventing a CNS-related disease, disorder condition in a 10 subject, wherein the CNS-related disease, disorder or condition is selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, a neurodevelopmental disorder and a neurologic disorder.

[0124] In some embodiments, the CNS-related disease, disorder condition is a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is selected from 15 the group consisting of mood disorders, anxiety disorder, schizophrenia, bipolar disorder, obsessive-compulsive disorder, alcohol and substance abuse, post-traumatic stress disorder (PTSD), and attention-deficit hyperactivity disorder (ADHD).Mood Disorders

[0125] Also provided herein are methods for treating a mood disorder, for example clinical, 20 depression, postnatal depression or postpartum depression, perinatal depression, atypical 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,, 25 suicidality, suicidal ideation, or suicidal behavior.

[0126] 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.30 Some people with clinical depression have trouble sleeping, lose weight, and generally feel agitated and irritable. Clinical depression affects how an individual feels, thinks, and behaves and may lead to a variety of emotional and physical problems. Individuals with clinical depression may have trouble doing day-to-day activities and make an individual feel as if life is not worth living.

[0127] 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 5 (e.g., a treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e.g., a refractory depression as described herein).

[0128] 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 10 experiencing PND.

[0129] 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 perceived15 interpersonal rejection.

[0130] 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.

[0131] Psychotic major depression (PMD) or psychotic depression refers to a major depressive, 20 episode, in particular of melancholic nature, where the individual experiences psychotic symptoms such as delusions and hallucinations.

[0132] 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., 25

[0133] Seasonal affective disorder (SAD) refers to a type of seasonal depression wherein an individual has seasonal patterns of depressive episodes coming on in the fall or winter.

[0134] 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).30

[0135] Double depression refers to fairly depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major depression.

[0136] Depressive Personality Disorder (DPD) refers to a personality disorder with depressive features.

[0137] 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.

[0138] Minor depressive disorder or minor depression refers to a depression in which at least 2 5 symptoms are present for 2 weeks.

[0139] 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 10 reduced. During periods of depression there may be crying, poor eye contact with others, and a negative outlook on life. The risk of suicide among those with the disorder is high at greater than 6% over 20 years, while self-harm occurs in 30-40%. Other mental health issues such as anxiety disorder and substance use disorder are commonly associated with bipolar disorder.

[0140] Depression caused by chronic medical conditions refers to depression caused by 15 chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress.

[0141] 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-resistant depression, 20 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)., 25

[0142] Suicidality, suicidal ideation, suicidal behavior refers to the tendency of an individual to commit suicide. Suicidal ideation concerns thoughts about or an unusual preoccupation with suicide. The range of suicidal ideation varies greatly, from e.g., fleeting thoughts to extensive thoughts, detailed planning, role playing, incomplete attempts. Symptoms include talking about suicide, getting the means to commit suicide, withdrawing from social contact, being30 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.

[0143] Symptoms of depression include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficultysleeping, sleeplessness, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, absence of positive thoughts or plans, excessive sleeping, overeating, appetite loss, insomnia, self-harm, thoughts of suicide, and suicide attempts. The presence, severity, frequency, and duration of symptoms may 5 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

[0144] Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of 10 anxiety disorders.

[0145] 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 15 disorder to affect older adults.

[0146] In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise;, 20 although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes, 25 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).30

[0147] Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in acertain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.5

[0148] 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.

[0149] Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a 10 traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.15

[0150] In some embodiments, the CNS-related disease, disorder condition is a neurodegenerative disorder. Exemplary neurodegenerative disorders include, but are not limited to, Parkinson’s disease, Huntington’s Disease, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's, 20 ataxia, and Lewy body disease.

[0151] In some embodiments, the CNS-related disease, disorder condition is a neurodevelopmental disorder. Exemplary neurodevelopmental disorders include, but are not limited to, a GRIN disorder, Rett syndrome, autism, autism spectrum disorder (ASD) (e.g., Phelan-McDermid Syndrome), Fragile X syndrome, tuberous sclerosis, Smith-Lemli-Opitz, and, 25 Down's syndrome.

[0152] In some embodiments, the CNS-related disease, disorder condition is a neurological disorder. Exemplary neurological disorders include, but are not limited to, neuropathic pain, nociceptive pain, inflammatory pain, stroke, traumatic brain injury, seizure disorders (e.g., epilepsy, status, epilepticus, developmental and epileptic encephalopathy (DEE)), movement 30 disorders, oculomotor apraxia, Dravet’s syndrome, transient ischemia, global ischemia, hypoxia, and spinal cord trauma.Seizure DisordersEpilepsy

[0153] 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 5 epilepsy, juvenile myoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.Epileptogenesis

[0154] Epileptogenesis is a gradual process by which a normal brain develops epilepsy (a 10 chronic condition in which seizures occur). Epileptogenesis results from neuronal damage precipitated by the initial insult (e.g., status epilepticus).Status epilepticus (SE)

[0155] Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status 15 epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status, 20 epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is characterized by, 25 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.

[0156] 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- 30 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.Developmental and epileptic encephalopathy (DEE)

[0157] Developmental and epileptic encephalopathy (DEE) is a group of rare diseases categorized by both seizures and negative developmental consequences. DEE often manifests ininfancy and adolescence. Children afflicted by DEE frequently have severe, drug resistant, seizures and suffer from learning disabilities, impaired communication skills, loss of motor skills, and have increased risk for numerous neuropsychiatric and neurodevelopmental conditions. DEEs are typically caused by genetic mutations that interrupt normal brain function 5 and development.Seizure

[0158] A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person’s body shakes rapidly and uncontrollably.10 During convulsions, the person’s muscles contract and relax repeatedly.

[0159] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.

[0160] Generalized seizures are produced by electrical impulses from throughout the entire 15 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.

[0161] 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., 20 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 sec, then by violent jerking (the "clonic" phase) for 30 to 60 sec, 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., 25

[0162] Absence seizures cause a short loss of consciousness (just a few sec) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of "losing time."

[0163] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body.30 Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.

[0164] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.

[0165] Tonic seizures are characterized by stiffening of the muscles.

[0166] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

[0167] Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent 5 seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non- convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; 10 infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures;neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizure is a generalized seizure associated with Dravet Syndrome, Lennox- Gastaut Syndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 Female Pediatric 15 Epilepsy.Movement Disorders

[0168] As used herein, “movement disorders” refers to a variety of diseases and disorders that are associated with hyperkinetic movement disorders and related abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson’s disease and, 20 Parkinsonism (defined particularly by bradykinesia), dyskinesia, dystonia, chorea, Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics, Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.

[0169] 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,, 25 vocal folds, trunk, legs). Tremor includes hereditary, degenerative, and idiopathic disorders such as Wilson’s disease, Parkinson’s disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid-, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese, arsenic, toluene); drug-induced 30 (narcoleptics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiologic tremor, enhanced physiologic tremor, essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellartremor, Holmes’ tremor (i.e., rubral tremor), palatal 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.5

[0170] Cerebellar tremor or intention tremor is a slow, broad tremor of the extremities that occurs after a purposeful movement. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from, e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inherited degenerative disorder).

[0171] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in 10 which sustained involuntary muscle contractions cause twisting and repetitive motions and / or painful and abnormal postures or positions. Dystonic tremor may affect any muscle in the body. Dystonic tremors occurs irregularly and often can be relieved by complete rest.

[0172] 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, 15 starting on one side of the body but affect both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. Tremor frequency may decrease as the person ages, but severity may increase. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and / or increase their severity. Symptoms generally evolve over time and can be both visible and persistent following onset., 20

[0173] 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.

[0174] Parkinsonian tremor is caused by damage to structures within the brain that control, 25 movement. Parkinsonian tremor is often a precursor to Parkinson’s disease and is typically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk. Onset of parkinsonian tremor typically begins after age 60. Movement starts in one limb or on one side of the body and can progress to include the other side.

[0175] Physiological tremor can occur in normal individuals and have no clinical significance.30 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.

[0176] 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.

[0177] Rubral tremor is characterized by coarse slow tremor which can be present at rest, at 5 posture, and with intention. The tremor is associated with conditions that affect the red nucleus in the midbrain, classical unusual strokes.

[0178] 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 10 in Parkinson’s disease, but is a symptom complex rather than a progressive neurodegenerative disorder.

[0179] Dyskinesia is a movement disorder that often manifests as involuntary muscle movement and includes, but is not limited to, uncontrollable shakes, tics, spasms or tremors. It can affect the face, arms, legs or trunk. Dyskinesia can be caused by a number of conditions, 15 including as a result of Parkinson’s disease medications, such as levodopa; as a side effect of certain medications (tardive dyskinesia); brain injury, neurological conditions such as Tourette’s syndrome or Wilson’s syndrome and autism spectrum disorder.

[0180] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures. Dystonic movements, 20 can be patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.

[0181] Chorea is a neurological disorder characterized by jerky involuntary movements typically affecting the shoulders, hips, and face.

[0182] Huntington’s Disease is an inherited disease that causes nerve cells in the brain to, 25 waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems.Huntington’s disease can hinder walk, talk, and swallowing.

[0183] Ataxia refers to the loss of full control of bodily movements, and may affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0184] Myoclonus and Startle is a response to a sudden and unexpected stimulus, which can be 30 acoustic, tactile, visual, or vestibular.

[0185] 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 movementswhile vocal tics associated with sound. Tics can be characterized as simple or complex. For example, simple motor tics involve only a few muscles restricted to a specific body part.

[0186] Tourette Syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic.5

[0187] Restless Legs Syndrome is a neurologic sensorimotor disorder characterized by an overwhelming urge to move the legs when at rest.

[0188] 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 10 abnormality on EMG recordings with continuous motor unit activity of the paraspinal axial muscles is typically observed. Variants include “stiff-limb syndrome” producing focal stiffness typically affecting distal legs and feet.

[0189] 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 15 responsible for abnormal locomotion, and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

[0190] In some embodiments, the methods, compositions and uses disclosed herein comprise any one of compounds 1-21, or pharmaceutically acceptable salt thereof as set forth in Table 1.

[0191] The compounds provided herein can be administered as the sole active agent or they can, 20 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.Compounds

[0192] The disclosure provides compounds useful in the methods, compositions and uses, 25 disclosed herein.

[0193] In one aspect, provided herein is Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof for use in the methods, pharmaceutical compositions and uses disclosed herein.

[0194] In some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein is Compound (1).

[0195] In some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein is a pharmaceutical salt of Compound (1).5

[0196] In some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein is an isotopic variant of Compound (1). In some embodiments, the isotopic variant is a deuterated variant of Compound (1). In some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein is a pharmaceutically acceptable salt of an isotopic variant of Compound (1). In 10 some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein is a pharmaceutically acceptable salt of a deuterated variant of Compound (1).

[0197] In some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein is a prodrug of Compound (1). In some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein is a 15 pharmaceutically acceptable salt of a prodrug of Compound (1). In some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein is a prodrug of an isotopic variant of Compound (1). In some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein is a prodrug of a deuterated variant of Compound (1). In some embodiments, the compound used in the methods,, 20 pharmaceutical compositions and uses disclosed herein is a pharmaceutically acceptable salt of a prodrug of an isotopic variant of Compound (1). In some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein is a pharmaceutically acceptable salt of a prodrug of a deuterated variant of Compound (1). In some embodiments, the prodrug of Compound (1) is a compound Formula (I), or a pharmaceutically acceptable salt,, 25 isotopic variant, or combination thereof.

[0198] In some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein, is a compound having the structure of Formula (I)pharmaceutically acceptable salt, isotopic variant, or combination thereof,30 wherein each of R1and R2is independently hydrogen, -P(O)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb, provided that both R1and R2are not hydrogen;each Ra is independently -ORc or Ci-ealkyl;Rb is Ci-ealkyl;each Rc is independently hydrogen, Ci-ealkyl, or a counterion; ortwo Rc taken together are a counterion; and5 each n and p is independently 1, 2, 3, 4, 5 or 6.

[0199] In some embodiments, R1is not hydrogen. In some embodiments, R1is not hydrogen and R2is hydrogen. In some embodiments, R1is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb; and R2is hydrogen, -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or - (CH2)POC(O)Rb.10

[0200] In some embodiments, R2is not hydrogen. In some embodiments, R2is not hydrogen and R1is hydrogen. In some embodiments, R1is hydrogen, -P(O)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb; and R2is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.

[0201] In some embodiment, R1is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or - 15 (CH2)POC(O)Rb.

[0202] In some embodiment, R2is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or - (CH2)POC(O)Rb.

[0203] In some embodiments, each or R1and R2is independently -P(O)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb., 20

[0204] In some embodiments, each Ra is independently -ORc; and each Rc is independently Na+. In some embodiments, each Ra is independently -ORc; and each Rc is independently K+. In some embodiments, each Ra is independently -ORc; and two Rc taken together are Ca2+. In some embodiments, each Ra is independently -ORc; and two Rc taken together are Mg2+.

[0205] In some embodiments, each Rc is independently a counterion; or two Rc taken together, 25 are a counterion. In some embodiments, each Rc is independently a counterion. In some embodiments, two Rc taken together are a counterion. Exemplary counterions include, but are not limited to, NH4 +, Na+, K+, Ca+2or Mg+2. In some embodiments, each Rc is independently NH4 +, Na+, or K+. In some embodiments, each Rc is independently Na+, or K+. In some embodiments, each Rc is independently Na+. In some embodiments, each Rc is independently 30 K+. In some embodiments, two Rc taken together are Ca+2or Mg+2. In some embodiments, two Rc taken together are Ca+2. In some embodiments, two Rc taken together are Mg+2.

[0206] In some embodiments, Rb is Ci-3alkyl. In some embodiments, Rb is methyl. In some embodiments, Rb is ethyl.

[0207] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0208] In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0209] In some embodiments, the compound is an isotopic variant of a compound of Formula (I). In some embodiments, the compound is a deuterated variant of a compound of Formula (I).

[0210] In some embodiments, the compound used in the methods, pharmaceutical compositions and uses disclosed herein is any one of the compounds or pharmaceutically acceptable salts set forth in Table 1.Table 1.or a pharmaceutically acceptable salt thereof.Pharmaceutical Compositions

[0211] In one aspect, the disclosure provides a pharmaceutical composition comprising a compound as disclosed herein and a pharmaceutically acceptable carrier.

[0212] In some embodiments, the pharmaceutical composition comprises a compound of Formula (I) (including any compound according to Table 1), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof; and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I) (including 5 any compound according to Table 1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (I) (including any compound according to Table 1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises an isotopic variant of a compound of Formula (I) (including any compound according 10 to Table 1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a deuterated variant of a compound of Formula (I) (including any compound according to Table 1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of an isotopic variant of a compound of Formula (I) (including any compound according to 15 Table 1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a deuterated variant of a compound of Formula (I) (including any compound according to Table 1); and a pharmaceutically acceptable carrier.

[0213] In certain embodiments, the pharmaceutical composition comprises an effective, 20 amount of the active ingredient or a pharmaceutically acceptable salt of the active ingredient (e.g., Compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof). In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient or a pharmaceutically acceptable salt of the active ingredient., 25

[0214] In some embodiments, the pharmaceutical composition comprises Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof; and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises Compound (1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound (1); and 30 a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises an isotopic variant of Compound (1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a deuterated variant of Compound (1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of an isotopic variantof Compound (1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a deuterated variant of Compound (1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a prodrug of Compound (1); and a pharmaceutically 5 acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a prodrug of Compound (1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a prodrug of an isotopic variant of Compound (1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a prodrug of a deuterated variant of 10 Compound (1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a prodrug of an isotopic variant of Compound (1); and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a prodrug of a deuterated variant of Compound (1); and a pharmaceutically acceptable carrier. 15

[0215] In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient or a pharmaceutically acceptable salt of the active ingredient (e.g., Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof). In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient or a pharmaceutically acceptable salt of, 20 the active ingredient.

[0216] In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, oral or topical carrier.

[0217] The present disclosure also relates to a compound described herein (e.g., a compound of Formula (I), or a compound according to Table 1, or a pharmaceutically acceptable salt,, 25 isotopic variant, prodrug, or combination of the foregoing, or pharmaceutical composition of any of the foregoing) for use as a pharmaceutical or a medicament.

[0218] Generally, the compounds provided herein are administered in a therapeutically 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 30 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.

[0219] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to oral (enteral), parenteral, rectal, transdermal, intradermal,intrathecal, subcutaneous, intravenous, intramuscular, and intranasal. In some embodiments, the pharmaceutical composition is administered orally.

[0220] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in 5 unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or 10 pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0221] Liquid forms suitable for oral administration may include a suitable aqueous or 15 nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a, 20 sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0222] 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 compound in such compositions is typically a minor component, often being from about 0.05 to 10% by, 25 weight with the remainder being the injectable carrier and the like.

[0223] 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 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 30 formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhancethe dermal penetration or stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0224] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the 5 reservoir or porous membrane type, or of a solid matrix variety.

[0225] 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.

[0226] The above-described components for orally administrable, injectable, or topically 10 administrable compositions are merely representative. Other materials as well as processing 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, which is incorporated herein by reference.

[0227] Although the descriptions of pharmaceutical compositions provided herein are15 principally directed to pharmaceutical compositions that are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can, 20 design and / or perform such modification with ordinary experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005.Kits, 25

[0228] In one aspect, the disclosure provides a kit comprising a pharmaceutical composition comprising Compound (1), or a pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof as disclosed herein, and instructions describing a method for treating a CNS-related disease, disorder or condition in a subject.

[0229] In some embodiments, the kit comprises a plurality of therapeutically efficacious 30 dosages of Compound (1) and instructions describing a method for treating a CNS-related disease, disorder or condition in a subject.Enumerated Embodiments

[0230] The disclosure also includes the following embodiments:

[0231] Embodiment 1. A method for treating a CNS-related disease, disorder or condition in a subject in need thereof, comprising administering to the subject an effective amount ofCompoundpharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, or a pharmaceutical5 composition thereof, wherein the CNS-related disease, disorder or condition is selected from the group consisting of neuropsychiatric disorders, neurodegenerative disorders, neurodevelopmental disorders, and neurologic disorders.

[0232] Embodiment 2. The method according to embodiment 1, wherein the neuropsychiatric disorder is selected from the group consisting of mood disorders, anxiety disorder,10 schizophrenia, bipolar disorder, obsessive-compulsive disorder, alcohol and substance abuse, post-traumatic stress disorder (PTSD), and attention-deficit hyperactivity disorder (ADHD).

[0233] Embodiment 3. The method according to embodiment 1, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson’s disease, Huntington’s Disease, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s 15 disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich’s ataxia, and Lewy body disease.

[0234] Embodiment 4. The method according to embodiment 1, wherein the neurologic disorder is selected from the group consisting of neuropathic pain, nociceptive pain,, 20 inflammatory pain, stroke, traumatic brain injury, a seizure disorder, a movement disorder, oculomotor apraxia, Dravet’s syndrome, transient ischemia, global ischemia, hypoxia, and spinal cord trauma.

[0235] Embodiment 5. The method according to embodiment 4, wherein the seizure disorder is selected from the group consisting of epilepsy, status, epilepticus, developmental and epileptic, 25 encephalopathy (DEE).

[0236] Embodiment 6. The method according to embodiment 4, wherein the movement disorder is selected from the group consisting of bradykinesia associated with Parkinson’s Disease, dyskinesia, dystonia, chorea, Huntington’s disease, ataxia, tremor, myoclonus and startle, tics, Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait30 disorders.

[0237] Embodiment 7. The method according to embodiment 1, wherein the neurodevelopmental disorder is selected from the group consisting of a GRIN disorder, Rett syndrome, autism, autism spectrum disorder (ASD), Fragile X syndrome, tuberous sclerosis, Smith-Lemli-Opitz syndrome, and Down's syndrome.5

[0238] Embodiment 8. A method for positive allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to the subject an effective amount of Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, or a pharmaceutical composition thereof; and wherein the NMDA receptor comprises a GluN2C subunit and / or a GluN2D subunit.

[0239] Embodiment 9. The method according to embodiment 8, wherein the NMDA receptor comprises one GluN2C subunit.

[0240] Embodiment 10. The method according to embodiment 8, wherein the NMDA receptor comprises two GluN2C subunits.15

[0241] Embodiment 11. The method according to embodiment 8, wherein the NMDA receptor comprises one GluN2D subunit.

[0242] Embodiment 12. The method according to embodiment 8, wherein the NMDA receptor comprises two GluN2D subunits.

[0243] Embodiment 13. The method according to any one of embodiments 1-12, wherein the, 20 subject is administered Compound (1).

[0244] Embodiment 14. The method according to any one of embodiments 1-12, wherein the subject is administered a pharmaceutically acceptable salt of Compound (1).

[0245] Embodiment 15. The method according to any one of embodiments 1-14, wherein the subject is administered an isotopic variant of Compound (1)., 25

[0246] Embodiment 16. The method according to embodiment 15, wherein the isotopic variant is a deuterated variant.

[0247] Embodiment 17. The method according to any one of embodiments 1-16, wherein the subject is administered a prodrug of Compound (1).

[0248] Embodiment 18. The method according to embodiment 17, wherein the prodrug of 30 Compound (1) is a compound of Formula (I)or a pharmaceutically acceptable salt, isotopic variant, or combination thereof,wherein each of R1and R2is independently hydrogen, -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb, provided that both R1and R2are not5 hydrogen;each Ra is independently -ORc or Ci-ealkyl;Rb is Ci-ealkyl;each Rc is independently hydrogen, Ci-ealkyl, or a counterion; ortwo Rc taken together are a counterion; and10 each n and p is independently 1, 2, 3, 4, 5 or 6.

[0249] Embodiment 19. The method according to embodiment 18, wherein R1is not hydrogen.

[0250] Embodiment 20. The method according to embodiment 18, wherein R2is not hydrogen.

[0251] Embodiment 21. The method according to embodiment 18, wherein R1is -P(O)(Ra)2, - C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.15

[0252] Embodiment 22. The method according to embodiment 18, wherein R2is -P(O)(Ra)2, - C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.

[0253] Embodiment 23. The method according to embodiment 18, wherein each of R1and R2is independently -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.

[0254] Embodiment 24. The method according to any one of embodiments 18-23, wherein, 20 each Ra is independently -ORc; and each Rc is independently Na+.

[0255] Embodiment 25. The method according to any one of embodiments 18-23, wherein Rb is C1-3alkyl.

[0256] Embodiment 26. The method according to any one of embodiments 1-25, wherein the compound is selected from the group consisting of any one of Compounds 1-21, or a, 25 pharmaceutically acceptable salt thereof set forth in Table 1.

[0257] Embodiment 27. A compound, wherein said compound is Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, or a pharmaceutical composition thereof, for use in treating a CNS-related disease, disorder or condition in a subject; wherein the CNS-related disease, disorder or condition is selected from the group consisting of neuropsychiatric disorders, neurodegenerative disorders, neurodevelopmental disorders, and neurologic disorders.

[0258] Embodiment 28. The compound for use according to embodiment 27, wherein the neuropsychiatric disorder is selected from the group consisting of mood disorders, anxiety disorder, schizophrenia, bipolar disorder, obsessive-compulsive disorder, alcohol and substance abuse, post-traumatic stress disorder (PTSD), and attention-deficit hyperactivity disorder (ADHD).

[0259] Embodiment 29. The compound for use according to embodiment 27, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson’s disease, Huntington’s Disease, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich’s ataxia, and Lewy body disease.

[0260] Embodiment 30. The compound for use according to embodiment 27, wherein the neurological disorder is selected from the group consisting of neuropathic pain, nociceptive pain, inflammatory pain, stroke, traumatic brain injury, a seizure disorder, a movement disorder,, 20 oculomotor apraxia, Dravet’s syndrome, transient ischemia, global ischemia, hypoxia, and spinal cord trauma.

[0261] Embodiment 31. The compound for use according to embodiment 30, wherein the seizure disorder is selected from the group consisting of epilepsy, status, epilepticus, developmental and epileptic encephalopathy (DEE)., 25

[0262] Embodiment 32. The compound for use according to embodiment 30, wherein the movement disorder is selected from the group consisting of bradykinesia associated with Parkinson’s Disease, dyskinesia, dystonia, chorea, Huntington’s disease, ataxia, tremor, myoclonus and startle, tics, Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.

[0263] Embodiment 33. The compound for use according to embodiment 27, wherein the neurodevelopmental disorder is selected from the group consisting of a GRIN disorder, Rett syndrome, autism, autism spectrum disorder (ASD), Fragile X syndrome, tuberous sclerosis, Smith-Lemli-Opitz syndrome, and Down's syndrome.5

[0264] Embodiment 34. A compound, wherein said compound is Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, or a pharmaceutical composition thereof, for use in positive allosteric modulation of an NMD A receptor in a subject, wherein the NMD A receptor comprises a GluN2C subunit and / or a GluN2D.10

[0265] Embodiment 35. The compound for use according to embodiment 34, wherein the NMD A receptor comprises one GluN2C subunit.

[0266] Embodiment 36. The compound for use according to embodiment 34, wherein the NMDA receptor comprises two GluN2C subunits.

[0267] Embodiment 37. The compound for use according to embodiment 34, wherein the 15 NMDA receptor comprises one GluN2D subunit.

[0268] Embodiment 38. The compound for use according to embodiment 34, wherein the NMDA receptor comprises two GluN2D subunits.

[0269] Embodiment 39. The compound for use according to any one of embodiments 27-38, wherein the subject is administered Compound (1)., 20

[0270] Embodiment 40. The compound for use according to any one of embodiments 27-38, wherein the subject is administered a pharmaceutically acceptable salt of Compound (1).

[0271] Embodiment 41. The compound for use according to any one of embodiments 27-40, wherein the subject is administered an isotopic variant of Compound (1).

[0272] Embodiment 42. The compound for use according to embodiment 41, wherein the, 25 isotopic variant is a deuterated variant.

[0273] Embodiment 43. The compound for use according to any one of embodiments 27-42, wherein the subject is administered a prodrug of Compound (1).

[0274] Embodiment 44. The compound for use according to embodiment 43, wherein the prodrug of Compound (1) is a compound of Formula (I)or a pharmaceutically acceptable salt, isotopic variant, or combination thereof,wherein each of R1and R2is independently hydrogen, -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb, provided that both R1and R2are not5 hydrogen;each Ra is independently -ORc or Ci-ealkyl;Rb is Ci-ealkyl;each Rc is independently hydrogen, Ci-ealkyl, or a counterion; or two Rc taken together are a counterion; and10 each n and p is independently 1, 2, 3, 4, 5 or 6.

[0275] Embodiment 45. The compound for use according to embodiment 44, wherein R1is not hydrogen.

[0276] Embodiment 46. The compound for use according to embodiment 44, wherein R2is not hydrogen.15

[0277] Embodiment 47. The compound for use according to embodiment 44, wherein R1is - P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.

[0278] Embodiment 48. The compound for use according to embodiment 44, wherein R2is - P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.

[0279] Embodiment 49. The compound for use according to embodiment 44, wherein each of, 20 R1and R2is independently -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.

[0280] Embodiment 50. The compound for use according to any one of embodiments 44-49, wherein each Ra is independently -ORc; and each Rc is independently Na+.

[0281] Embodiment 51. The compound for use according to any one of embodiments 44-49, wherein Rb is C1-3alkyl., 25

[0282] Embodiment 52. The compound for use according to any one of embodiments 27-51, wherein the compound is selected from the group consisting of any one of Compounds 1-21, or a pharmaceutically acceptable salt thereof set forth in Table 1.

[0283] Embodiment 53. Use of Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, in the manufacture of a medicament for treating a CNS-related disease, disorder or condition in a subject, wherein the CNS-related disease, disorder or condition is selected from the group consisting of neuropsychiatric disorders, 5 neurodegenerative disorders, neurodevelopmental disorders, and neurologic disorders.

[0284] Embodiment 54. The use according to embodiment 53, wherein the neuropsychiatric disorder is selected from the group consisting of mood disorders, anxiety disorder, schizophrenia, bipolar disorder, obsessive-compulsive disorder, alcohol and substance abuse, post-traumatic stress disorder (PTSD), and attention-deficit hyperactivity disorder (ADHD). 10

[0285] Embodiment 55. The use according to embodiment 53, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson’s disease, Huntington’s Disease, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich’s ataxia, and Lewy body disease.15

[0286] Embodiment 56. The use according to embodiment 53, wherein the neurologic disorder is selected from the group consisting of neuropathic pain, nociceptive pain, inflammatory pain, stroke, traumatic brain injury, a seizure disorder, a movement disorder, oculomotor apraxia, Dravet’s syndrome, transient ischemia, global ischemia, hypoxia, and spinal cord trauma.

[0287] Embodiment 57. The use according to embodiment 56, wherein the seizure disorder is, 20 selected from the group consisting of epilepsy, status, epilepticus, developmental and epileptic encephalopathy (DEE).

[0288] Embodiment 58. The use according to embodiment 56, wherein the movement disorder is selected from the group consisting of bradykinesia associated with Parkinson’s Disease, dyskinesia, dystonia, chorea, Huntington’s disease, ataxia, tremor, myoclonus and startle, tics,, 25 Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.

[0289] Embodiment 59. The use according to embodiment 53, wherein the neurodevelopmental disorder is selected from the group consisting of a GRIN disorder, Rett syndrome, autism, autism spectrum disorder (ASD), Fragile X syndrome, tuberous sclerosis, Smith-Lemli-Opitz syndrome, and Down's syndrome.30

[0290] Embodiment 60. Use of Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, in the manufacture of a medicament for positive allosteric modulation of an NMDA receptor in a subject, wherein the NMD A receptor comprises a GluN2C subunit and / or a GluN2D.5

[0291] Embodiment 61. The use according to embodiment 60, wherein the NMDA receptor comprises one GluN2C subunit.

[0292] Embodiment 62. The use according to embodiment 60, wherein the NMDA receptor comprises two GluN2C subunits.

[0293] Embodiment 63. The use according to embodiment 60, wherein the NMDA receptor 10 comprises one GluN2D subunit.

[0294] Embodiment 64. The use according to embodiment 60, wherein the NMDA receptor comprises two GluN2D subunits.

[0295] Embodiment 65. The use according to any one of embodiments 53-64, wherein the subject is administered Compound (1).15

[0296] Embodiment 66. The use according to any one of embodiments 53-64, wherein the subject is administered a pharmaceutically acceptable salt of Compound (1).

[0297] Embodiment 67. The use according to any one of embodiments 53-66, wherein the subject is administered an isotopic variant of Compound (1).

[0298] Embodiment 68. The use according to embodiment 67, wherein the isotopic variant is a, 20 deuterated variant.

[0299] Embodiment 69. The use according to any one of embodiments 53-68, wherein the subject is administered a prodrug of Compound (1).

[0300] Embodiment 70. The use according to embodiment 69, wherein the prodrug of Compound (1) is a compound of Formula (I).25or a pharmaceutically acceptable salt, isotopic variant, or combination thereof,wherein each of R1and R2is independently hydrogen, -P(O)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb, provided that both R1and R2are not hydrogen;each Ra is independently -ORc or Ci-ealkyl;Rb is Ci-ealkyl;each Rc is independently hydrogen, Ci-ealkyl, or a counterion; ortwo Rc taken together are a counterion; andeach n and p is independently 1, 2, 3, 4, 5 or 6.

[0301] Embodiment 71. The use according to embodiment 70, wherein R1is not hydrogen. 10

[0302] Embodiment 72. The use according to embodiment 70, wherein R2is not hydrogen.

[0303] Embodiment 73. The use according to embodiment 70, wherein R1is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb.

[0304] Embodiment 74. The use according to embodiment 70, wherein R2is -P(O)(Ra)2, - C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb.15

[0305] Embodiment 75. The use according to embodiment 70, wherein each of R1and R2is independently -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb.

[0306] Embodiment 76. The use according to any one of embodiments 70-75, wherein each Ra is independently -ORc; and each Rc is independently Na+.

[0307] Embodiment 77. The use according to any one of embodiments 70-75, wherein Rb is, 20 Ci-salkyl.

[0308] Embodiment 78. The use according to any one of embodiments 53-77, wherein the compound is selected from the group consisting of any one of Compounds 1-21, or a pharmaceutically acceptable salt thereof set forth in Table 1.

[0309] Embodiment 79. A compound of Formula (I).25or a pharmaceutically acceptable salt, isotopic variant, or combination thereof,wherein each of R1and R2is independently hydrogen, -P(O)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb, provided that both R1and R2are not hydrogen;each Ra is independently -ORc or Ci-ealkyl;Rb is Ci-ealkyl;each Rc is independently hydrogen, Ci-ealkyl, or a counterion; ortwo Rc taken together are a counterion; andeach n and p is independently 1, 2, 3, 4, 5 or 6.

[0310] Embodiment 80. The compound or pharmaceutically acceptable salt, isotopic variant, 5 or combination thereof, according to embodiment 79, wherein R1is not hydrogen.

[0311] Embodiment 81. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to embodiment 79, wherein R2is not hydrogen.

[0312] Embodiment 82. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to embodiment 79, wherein R1is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb.

[0313] Embodiment 83. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to embodiment 79, wherein R2is -P(O)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb.

[0314] Embodiment 84. The compound or pharmaceutically acceptable salt, isotopic variant, 15 or combination thereof, according to embodiment 79, wherein each of R1and R2is independently -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb.

[0315] Embodiment 85. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of embodiments 79-84, wherein each Ra is independently -ORc; and each Rc is independently Na+., 20

[0316] Embodiment 86. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of embodiments 79-84, wherein Rb is C1-3alkyl.

[0317] Embodiment 87. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of embodiments 79-86, wherein the compound is selected from the group consisting of any one of Compounds 2-21, or a pharmaceutically, 25 acceptable salt thereof set forth in Table 1.

[0318] Embodiment 88. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of embodiments 79-87, and a pharmaceutically acceptable carrier.Examples30

[0319] Example 1: Synthesis of methyl (£)-3-bromoacrylate (A3)

[0320] Step 1: Synthesis of (E)-3-bromoacrylic acid (A2)

[0321] A mixture of propiolic acid (Al) (20.0 g, 285 mmol) in 40% HBr (150 mL) was stirred at 110 °C for 2 h. The mixture was cooled in ice water. The precipitate was filtered out and washed with excess water to give (E)-3 -bromoacrylic acid (A2) (25.0 g, 58%).

[0322] 1H NMR (400 MHz, CDC13) 59.69 (br. s., 1H), 7.76 (d, J= 14.4 Hz, 1H), 6.54 (d, J = 13.6 Hz, 1H).

[0323] Step 2: Synthesis of methyl (E)-3-bromoacrylate (A3)

[0324] To a suspension of (E)-3 -bromoacrylic acid (A2) (8.50 g, 56.3 mmol) in MeOH (15 mL) was added 98% sulfuric acid (2.80 g, 28.1 mmol). The mixture was stirred at 25 °C for 24 h. TLC showed the starting material was consumed. The reaction mixture was distilled in vacuum. The distillation was washed with water (20 mL), and the organic layer was separated out and dried over anhydrous sodium sulfate to give (£)-methyl 3 -bromoacrylate (A3) (7.00 g, 75%) as colorless oil.

[0325] *H NMR (400 MHz, CDCI3) 57.61 (d, J= 14.0 Hz, 1H), 6.53 (d, J= 14.0 Hz, 1H), 3.76 (s, 3H).

[0326] Example 2: Synthesis of methyl (l?)-5-((35',85',95',101?,13?,14*,171?)-3-hydroxy- 10,13-dimethyl-2,3,4,7,8,9,10,ll,12,13,14,15,16,17-tetradecahydro-lH-

[0327] Step 1: Synthesis of (3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-(prop-l-en-2-yl)~ 2, 3, 4, 7, 8,9, 10,11, 12, 13, 14, 15, 16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-3-ol (A5)

[0328] To a suspension of PhsPMeBr (67.5 g, 189 mmol) in anhydrous THF (300 mL) under N2 (g) was added LBuOK (21.2 g, 189 mmol), and the resulting mixture was stirred at 60 °C for 30 min. A4 (20 g, 63.1 mmol) was added and the resulting mixture was stirred at 60 °C for 4 h. The reaction mixture was poured into ice water (500 mL) and extracted with EtOAc (500 mL x 5 2). The combined organic layer was dried over anhydrous Na2SC>4, filtered, and volatiles removed. The residue was purified by silica gel chromatography (PE: EA=15: 1) to give A5 (18.0 g, 57.2 mmol, 91%), which was used directly in the next step.

[0329] Step 2: Synthesis of (3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-(prop-l-en-2-yl)~ 2, 3, 4, 7, 8,9, 10,11, 12, 13, 14, 15, 16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-3-yl acetate 10 (A6)

[0330] To a solution of A5 (18.0 g, 57.2 mmol) in anhydrous DCM (150 mL) was added AC2O (8.75 g, 85.8 mmol) and DMAP (13.9 g, 114 mmol), and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with DCM (150 mL x 3). The combined organic layer was washed with saturated NaHCOs (150 mL) and brine 15 (150 mL), dried over anhydrous Na2SC>4, filtered, and volatiles removed to give A6 (20.0 g, 56.1 mmol, 99%), which was used directly in the next step.

[0331] Step 3: Synthesis of methyl (R, E)-5-((3S,8S,9S, 10R, 13R, 14S, 17R)-3-acetoxy-10, 13- dimethyl-2, 3, 4, 7,8, 9,10, 11, 12, 13, 14, 15, 16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-l 7- yl)hex-2 -enoate (A7), 20

[0332] To a solution of A6 (30.0 g, 84.1 mmol) in anhydrous THF (150 mL) under N2 (g) at 30 °C was added 9-BBN (0.5 M in THF, 185 mL, 92.5 mmol), and the resulting mixture was stirred at 75 °C for 3 h. The reaction mixture was cooled to 30 °C, and A3 (15.2 g, 92.5 mmol), CsF (25.5 g, 168 mmol), and Pd( / -Bu3P)2 (4.55 g, 8.40 mmol) were added, and the resulting mixture was stirred at 75 °C for 16 h. The reaction was cooled, quenched with water (300 mL),, 25 and extracted with EtOAc (300 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered through a pad of silica gel, and volatiles removed. The residue was triturated from methanol to give A7 (20.0 g, 45.2 mmol, 54%), which was used directly in the next step.

[0333] Step 4: Synthesis of methyl (R, E)-5-((3S,8S,9S, 10R, 13R, 14S, 17 R)- 3 -hydroxy- 10, 13- dimethyl-2, 3, 4, 7,8, 9,10, 11, 12, 13, 14, 15, 16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-l 7- 30 yl)hex-2 -enoate (A 8)

[0334] To a suspension of A7 (20.0 g, 45.1 mmol) in anhydrous methanol (250 mL) was added AcCl (2.82 g, 36.0 mmol), and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated to remove most of the methanol. The residue was diluted with EtOAc (500 mL), washed with aqueous NaHCOs (500 mL), brine (300 mL), dried overanhydrous Na2SC>4, filtered, and volatiles removed. The residue was purified by silica gel chromatography (PE: EA: DCM=8: 1: 1) to give A8 (12.0 g, 29.9 mmol, 67%), which was used directly in the next step.

[0335] Step 5: Synthesis of methyl (R)-5-((3S,8S,9S, 10R, 13R, 14S, 17 R)- 3 -hydroxy- 10, 13- 5 dimethyl-2, 3, 4, 7,8, 9,10, 11, 12, 13, 14, 15, 16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-l 7- yl)hexanoate (A9)

[0336] To a solution of A8 (12.0 g, 29.9 mmol) in THF (150 mL) was added 5% Pt / C (2 g), and the resulting mixture was degassed and purged with EE (g) three times. The mixture was stirred under a EE (g) balloon at 25 °C for 4 h. The reaction mixture was filtered through a pad 10 of Celite, and volatiles were removed to give A9 (12.0 g, 29.8 mmol, 100%).

[0337] 'H NMR (400 MHz, CDCh) 55.34 (d, J= 5.0 Hz, 1H), 3.66 (s, 3H), 3.57-3.45 (m, 1H), 2.33-2.21 (m, 4H), 2.05-1.65 (m, 7H), 1.48-1.32 (m, 6H), 1.31-0.88 (m, 17H), 0.67 (s, 3H).

[0338] Example 3: Synthesis of (35',85',95',101?,131?,145',171?)-17-((l?)-6-hydroxy-6- methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,l 1,12,13,14,15,16,17-tetradecahydro-LH- 15 cyclopenta [a] phenanthren-3-< / -3-ol (2)

[0339] Step 1: Synthesis of methyl (R)-5-((8S,9S, 10R, 13R, 14S, 17R)-10, 13 -dimethyl- 3 -oxo- 2, 3, 4, 7, 8,9, 10,11, 12, 13, 14, 15, 16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-l 7- yl)hexanoate (A10), 20

[0340] To a solution of A9 (1.00 g, 2.48 mmol) in DCM (20 mL) was added DMP (2.10 g, 4.96 mmol) at 0 °C, and the resulting mixture was stirred at 25 °C for 0.5 h. The mixture was quenched with saturated aqueous NaHCO3 / Na2S2C>3 (1:3) (15 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered, and volatiles removed. The residue was purified by column chromatography, 25 on silica gel (PEZEtOAc = 50 / 1) to give A10 (600 mg, 1.50 mmol, 60%).

[0341] 'H NMR (400 MHz, CDC13) 65.34-5.29 (m, 1H), 3.66 (s, 3H), 3.29-3.26 (m, 1H), 2.84-2.83 (m, 1H), 2.50-2.42 (m, 1H), 2.34-2.18 (m, 3H), 2.08-1.95 (m, 3H), 1.85-1.57 (m, 3H), 1.54-1.20 (m, 10H), 1.18 (s, 3H), 1.17-0.67 (m, 8H), 0.54 (s, 3H).

[0342] Step 2: Synthesis of methyl (R)-5-((3S,8S,9S, 10R, 13R, 14S, 17 R)- 3 -hydroxy- 10, 13- 5 dimethyl-2, 3, 4, 7,8, 9,10, 11, 12, 13, 14, 15, 16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-l 7- yl-3-d)hexanoate (All)

[0343] To a solution of A10 (548 mg, 1.37 mmol) in MeOH (5 mL) was added NaBD4 (69.3 mg, 1.65 mmol) at 20 °C, and the resulting mixture was stirred for 30 min. The mixture was quenched with saturated aqueous NH4CI (15 mL) and extracted with EtOAc (2 x 20 mL). The 10 combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SC>4, filtered, and volatiles removed. The residue was purified by column chromatography on silica gel (PE / EtOAc = 15 / 1) to afford All (290 mg, 0.718 mmol, 52%).

[0344] 'H NMR (400 MHz, CDCI3) 85.35-5.34 (m, 1H), 3.66 (s, 3H), 2.30-2.23 (m, 4H), 2.05-1.90 (m, 3H), 1.90-1.57 (m, 7H), 1.53-1.30 (m, 10H), 1.30-0.92 (m, 10H), 0.67 (s, 3H). 15

[0345] Step 3: (3S,8S,9S,10R,13R,14S,17R)-17-((R)-6-hydroxy-6-methylheptan-2-yl)-10,13- dimethyl-2, 3, 4, 7,8, 9,10, 11, 12, 13, 14, 15, 16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-3- d-3-ol (2)

[0346] To a solution of All (250 mg, 619 pmol) in THF (3 mL) was added MeLi (1.93 mL, 3.09 mmol) at 0 °C under N2 (g), and the resulting mixture was stirred at 20 °C for 12 h. The, 20 mixture was quenched with saturated aqueous NH4CI (5 mL) at 0 °C. The mixture was treated with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and volatiles removed. The residue was purified by column chromatography on silica gel (PE / EtOAc = 3 / 1) to afford 2 (132 mg, 0.327 mmol, 53%, deuterated ratio: 97%)., 25

[0347] 'H NMR (400 MHz, CDCI3) 65.35-5.34 (m, 1H), 2.30-2.27 (m, 2H), 1.99-1.92 (m, 2H), 1.92-1.81 (m, 5H), 1.55-1.27 (m, 11H), 1.25-1.15 (m, 4H), 1.25-1.15 (m, 17H), 0.64 (s, 3H).

[0348] LCMS MS ESI calcd. for C27H42D [M+H-2H2O]+368, found 368

[0349] HRMS MS ESI calcd. for C27H42D [M+H-2H2O]+368.3422, found 368.3405.30

[0350] Example 4: Synthesis of (3N,8N,9N,101?,13?,14*,171?)-17-((l?)-6-hydroxy-6- (methyl-< / 3)heptan-2-yl-7,7,7-< / 3)-10,13-dimethyl-2,3,4,7,8,9,10,ll,12,13,14,15,16,17- tetradecahydro-TH-cyclopenta[a]phenanthren-3-ol (3)

[0351] Step 1: Synthesis of (3S,8S,9S,10R,13R,14S,17R)-17-((R)-6-hydroxy-6-(methyl- ds)heptan-2-yl-7, 7, 7-dp-K), 13 -dime thy 1-2, 3, 4, 7, 8,9, 10,11, 12, 13, 14, 15, 16,17-tetradecahydro- lH-cyclopenta[a]phenanthren-3-ol (3)5

[0352] To a suspension of Mg (597 mg, 24.6 mmol) and I2 (1 mg, 0.004 mmol) in ether (2 mL) was added solution of CD3I (1.78 g, 12.3 mmol) in ether (8 mL) dropwise under N2 (g) at 25 °C, and the resulting mixture was stirred at 35 °C for 2 h. To a solution of A9 (500 mg, 1.24 mmol) in THF (5 mL) was added the freshly prepared CDsMgl (12.3 mmol in 10 mL of ether) at 0 °C, and the resulting mixture was stirred 25 °C for 1 h. Saturated aqueous NH4CI (10 mL) was 10 added, and the mixture was extracted with EtOAc (30 mL). The organic layer was separated, dried over anhydrous Na2SC>4, filtered, volatiles removed, re-crystallized from MeCN (100 mL), and purified by silica gel column (PE / DCM / EtOAc = 5 / 1 / 1 to 3 / 1 / 1) to give 3 (294 mg, 0.719 mmol, D-ratio: 93.5%).

[0353] 'H NMR (400 MHz, CDCI3) 65.40-5.30 (m, 1H), 3.62-3.52 (m, 1H), 2.34-2.26 (m, 15 2H), 2.05-1.92 (m, 2H), 1.89-1.78 (m, 3H), 1.61-1.32 (m, 12H), 1.29-0.91 (m, 16H), 0.67 (s, 3H).

[0354] HRMS MS ESI calcd. for C27H39D6O [M+H-H2O]+391.3842, found 391.3850.

[0355] Example 5: Synthesis of (((l?)-6-((35,85,95,10?,13?,14A,171?)-3-hydroxy-10,13- dimethyl-2,3,4,7,8,9,10,ll,12,13,14,15,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-, 20 17-yl)-2-methylheptan-2-yl)oxy)methyl acetate (4)

[0356] Step 1: Synthesis of (R)-6-((3S,8S,9S,10R,13R,14S,17R)-3-((tert- butyldimethylsilyl)oxy)-10, 13 -dime thy 1-2, 3, 4, 7, 8,9,10, 11, 12, 13, 14, 15,16, 17 -tetradecahydro- 1H- cyclopenta[a]phenanthren-l 7-yl)-2-methylheptan-2-ol (A12)

[0357] To a suspension of 1 (4.00 g, 9.93 mmol; ASW Med Chem) in DCM (80.0 mL) was 5 added imidazole (2.71 g, 39.7 mmol) and tert-butyldimethylchlorosilane (4.49 g, 29.8 mmol) at 20 °C under N2 (g), and the resulting mixture was stirred at 20 °C for 16 h. The mixture was poured into water (50 mL), stirred for 20 min, and extracted with DCM (3 x 40 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered, volatiles removed, and purified by silica gel chromatography (0-10% of ethyl acetate in 10 petroleum ether) to give All (4.80 g, 9.29 mmol, 94 %).

[0358] 'H NMR (400 MHz, CDCI3) 8H 5.35-5.28 (m, 1H), 3.54-3.42 (m, 1H), 2.34-2.13 (m, 2H), 2.04-1.92 (m, 2H), 1.86-1.77 (m, 2H), 1.76-1.67 (m, 1H), 1.62-1.51 (m, 3H), 1.46-1.33 (m, 8H), 1.28-1.24 (m, 1H), 1.21 (s, 6H), 1.19-1.01 (m, 6H), 1.00 (s, 3H), 0.96-0.90 (m, 6H), 0.89- 0.87 (m, 9H), 0.67 (s, 3H), 0.54 (s, 6H).15

[0359] Step 2: Synthesis of (((R)-6-((3S,8S,9S,10R,13R,14S,17R)-3-((tert- butyldimethylsilyl)oxy)-10, 13 -dime thy 1-2, 3, 4, 7, 8,9,10, 11, 12, 13, 14, 15,16, 17 -tetradecahydro- 1 Iley clopenta [a] phenanthren-17-yl)-2-methylheptan-2-yl)oxy)methyl acetate (A13)

[0360] To a solution of chloromethyl acetate (157 mg, 1.45 mmol) in DCE (5.00 mL) was added 2,6-di-tert-butylpyridine (555 mg, 2.90 mmol) at 0 °C under N2 (g), and the resulting, 20 mixture was stirred for 30 min. All (500 mg, 0.97 mmol) was added, and the reaction was stirred at 40 °C for 16 h. The mixture was quenched with H2O (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, volatiles removed, and purified by silica gel chromatography (0- 15% of ethyl acetate in petroleum ether) to give A13 (100 mg, 0.170 mmol, 18 %)., 25

[0361] 'H NMR (400 MHz, CDCI3) 8H 5.34 (s, 2H), 5.32-5.28 (m, 1H), 3.56-3.40 (m, 1H), 2.32-2.22 (m, 1H), 2.19-2.12 (m, 1H), 2.06 (s, 3H), 2.03-1.92 (m, 2H), 1.85-1.76 (m, 2H), 1.75- 1.67 (m, 1H), 1.62-1.55 (m, 2H), 1.53-1.32 (m, 10H), 1.30-1.23 (m, 2H), 1.21 (s, 6H), 1.17-1.03 (m, 5H), 1.00 (s, 3H), 0.93-0.90 (m, 3H), 0.89-0.83 (m, 10H), 0.67 (s, 3H), 0.06 (s, 6H).

[0362] Step 3: Synthesis of (((R)-6-((3S,8S,9S,10R,13R,14S,17R)-3-hydroxy-10,13-dimethyl- 30 2,3,4, 7,8,9,10,11,12, 13, 14, 15,16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2- methylheptan-2-yl)oxy)methyl acetate (4)

[0363] A solution of A13 (100 mg, 0.17 mmol) in TBAF (1.00 mL, 1 M in THF, 1.00 mmol) was stirred at 25 °C under N2 (g) for 2 h. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine(10 mL), dried over anhydrous Na2SO4, filtered, volatiles removed, and purified by silica gel chromatography (5%-20% of ethyl acetate in petroleum ether) to give 4 (21.6 mg, 0.0450 mmol, 27 %).

[0364] 1H NMR (400 MHz, CDC13) 6H5.38-5.31 (m, 3H), 3.60-3.45 (m, 1H), 2.36-2.18 (m, 5 2H), 2.06 (s, 3H), 2.03-1.92 (m, 2H), 1.88-1.77 (m, 3H), 1.62-1.56 (m, 2H), 1.52-1.33 (m, 10H), 1.30-1.24 (m, 1H), 1.22 (s, 6H), 1.19-1.04 (m, 5H), 1.03-0.96 (m, 5H), 0.96-0.89 (m, 4H), 0.68 (s, 3H).

[0365] LC-ELSD / MS MS ESI calcd. for CsoHsoCUNa [M+Na]+497.3 found 497.2.

[0366] Example 6: Synthesis of (l?)-6-((35',85',95',101?,131?,145',171?)-3-hydroxy-10,13- 10 dimethyl-2, 3, 4, 7, 8, 9, 10,11,12,13,14,15,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren- 17-yl)-2-methylheptan-2-yl acetate (5)

[0367] Step 1: Synthesis of (R)-6-((3S,8S,9S,10R,13R,14S,17R)-3-((tert- butyldimethylsilyl)oxy)-10, 13 -dime thy 1-2, 3, 4, 7, 8,9,10, 11, 12, 13, 14, 15,16, 17 -tetradecahydro- 1H- 15 cyclopenta[a]phenanthren-17-yl)-2-methylheptan-2-yl acetate (A14)

[0368] To a solution of A12 (0.20 g, 0.39 mmol) in pyridine (10.0 mL) was added AC2O (0.120 g, 0.110 mL, 1.20 mmol) and l-(pyridin-4-yl)pyrrolidine (11.0 mg, 77.0 pmol) under N2 (g) and the resulting mixture was stirred at 80 °C for 16 h. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with, 20 10% aqueous NaCl, dried over anhydrous Na2SO4, filtered, and volatiles removed to give A14 (0.220 g, 0.390 mmol, 100%), which was used directly in the next step.

[0369] Step 2: Synthesis of (R)'-6-(f Sf> S,9S,\QR,\3R,\ S,\7R)-3-hydroxy-10, 13-dimethyl- 2, 3, 4, 7, 8,9, 10,11, 12, 13, 14, 15, 16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-l 7-yl)-2- methylheptan-2-yl acetate (5), 25

[0370] To A14 (0.200 g, 0.360 mmol) was added TBAF (0.470 g, 1.80 mL, 1 M in THF, 1.80 mmol) under N2 (g), and the resulting mixture was stirred at 25 °C for 16 h. The reaction wasquenched with H₂O (2 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layer was washed with 10% aqueous NaCl (2 x 5 mL), dried over anhydrous Na₂SO₄, filtered, and volatiles removed. The residue was purified by silica gel chromatography (0%-30% of EtOAc in petroleum ether) to give 5 (31.6 mg, 70.0 pmol, 20 %).5

[0371] 'H NMR (400 MHz, CDCI3) 8 ppm 5.40-5.30 (m, 1H), 3.60 - 3.42 (m, 1H), 2.34-2.18 (m, 2H), 2.05-1.93 (m, 4H), 1.88-1.78 (m, 3H), 1.56 (s, 6H), 1.54-1.45 (m, 3H), 1.44-1.37 (m, 8H), 1.35-1.30 (m, 2H), 1.27-1.15 (m, 3H), 1.09-1.05 (m, 2H), 1.01 (s, 5H), 0.95-0.88 (m, 5H), 0.68 (s, 3H).

[0372] LC-ELSD / MS MS ESI calcd. for C27H43 [M+H-H0Ac-H2O] 367.3 found 367.3. 10

[0373] Example 7: Synthesis ol (3. S.8. S.9. S.l() / ?.13 / ?.14. S.17 / 0-17-(( / 0-6-hydroxy-6- methylheptan-2-yl)-10.13-dimethyl-2.3.4.7.8.9.10.11.12.13.14.15.16.17-tetradecahydro-l / / - cyclopenta [a] phenanthren-3-yl acetate & (l?)-6-((35',85',95',101?,13?,14A,171?)-3-acetoxy- 10,13-dimethyl-2,3,4,7,8,9,10,l 1.12.13.14.15.16.17-tetradecahydro-l / / - cyclopenta[a]phenanthren-17-yl)-2-methylheptan-2-yl acetate (6 & 7)

[0374] Step 1: Synthesis of (3S,8S,9S,10R,13R,14S,17R)-17-((R)-6-hydroxy-6-methylheptan-2- yl)-10, 13-dimethyl-2, 3, 4, 7, 8,9, 10,11, 12, 13, 14, 15, 16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl acetate (6)

[0375] To a solution of 1 (1.00 g, 2.48 mmol) in pyridine (10.0 mL) was added acetic, 20 anhydride (254 mg, 2.48 mmol) at 25 °C under N2 (g), and the resulting mixture was stirred at 25 °C for 16 h. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with 10% aqueous NaCl, dried over anhydrous Na2SO4, filtered, and volatiles removed. The residue was triturated with MeCN at 25 °C to give 6 (732 mg, 1.65 mmol, 66 %).

[0376] 1H NMR (400 MHz, CDC13) 6 ppm 5.38-5.31 (m, 1 H), 4.68-4.52 (m, 1 H), 2.38-2.28 (m, 2 H), 2.05-1.91 (m, 5 H), 1.90-1.80 (m, 3 H), 1.70-1.51 (m, 5 H), 1.48-1.32 (m, 9 H), 1.32- 1.18 (m, 9 H), 1.12-1.07 (m, 1 H), 1.05-0.98 (m, 5 H), 0.95-0.86 (m, 4 H), 0.67 (s, 3 H).

[0377] LC-ELSD / MS MS ESI calcd. for C27H43 [M+H-HOAc] 367.3 found 367.3.5

[0378] Step 2: Synthesis of (R)-6-(f3S)& S,9SfQRf3R, SflR)-3-acetoxy-10,13-dimethyl- 2, 3, 4, 7, 8,9, 10,11, 12, 13, 14, 15, 16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-l 7-yl)-2- methylheptan-2-yl acetate (7)

[0379] To a solution of 6 (0.500 g, 1.10 mmol) in pyridine (10.0 mL) was added AC2O (0.340 g, 0.320 mL, 3.40 mmol) and l-(pyridin-4-yl)pyrrolidine (33.0 mg, 0.220 mmol) at 50 °C under 10 N2 (g), and the resulting mixture was stirred at 50 °C for 16 h. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with 10% aqueous NaCl (20 mL), dried over anhydrous Na2SC>4, filtered, and volatiles removed. The residue was purified by silica gel chromatography (0%-40% of EtOAc in petroleum ether) to give 7 (238 mg, 488 pmol, 43 %).15

[0380] 'H NMR (400 MHz, CDCI3) 8 ppm 5.39-5.32 (m, 1 H), 4.65-4.56 (m, 1 H), 2.34-2.28 (m, 2 H), 2.03 (s, 3 H), 2.01-1.98 (m, 1 H), 1.96 (s, 3 H), 1.94-1.81 (m, 3 H), 1.79-1.65 (m, 2 H), 1.63-1.54 (m, 4 H), 1.52-1.44 (m, 2 H), 1.42 (s, 7 H), 1.41-1.22 (m, 4 H), 1.21-1.08 (m, 5 H), 1.05-0.96 (m, 5 H), 0.94-0.85 (m, 4 H), 0.67 (s, 3 H).

[0381] LC-ELSD / MS MS ESI calcd. for C27H43 [M+H-2HOAc] 367.5 found 367.5., 20

[0382] Compounds 8-21 can be synthesized using the methods described for compounds 2-7 using appropriately substituted reactions and reagents.

[0383] Example 8: NMDA Receptor Modulation

[0384] Whole-cell Patch Clamp of Mammalian Cells (Syncropatch 384i (Nanion Technologies)), 25

[0385] Whole-cell patch clamp electrophysiology was used to investigate the effects of compounds on GluNl / GluN2A, GluNl / GluN2B, GluNl / GluN2C, and GluNl / GluN2D N- methyl-D-aspartate (NMDA) glutamate receptor subtypes expressed in mammalian cells.

[0386] Cell Culture

[0387] Human embryonic kidney (HEK293) cells expressing recombinant human30 GluNl / GluN2A, GluNl / GluN2B, GluNl / GluN2C, or GluNl / GluNlD subunits under the control of a tetracycline-inducible expression system were used. Cells were maintained in Dulbecco’s Modified Eagle’s Medium (DMEM) with 1% glutamine, 10% Tetracycline System Approved fetal bovine serum (FBS), and NMDA receptor inhibitors. Cells were cultured in a humidified 5% CO2 incubator at 37 °C. Cells were induced tetracycline (50 ng / mL forGluNl / GluN2A and GluNl / GluN2B; 200 ng / mL for GluNl / GluN2C, 1 pg / mL for GluNl / GluN2D) 18-24 hours prior to testing. A cocktail of channel blockers was added to the media to prevent cell death. Cells were 60-80% confluent at the time of harvest. Cells were detached from the flask TrypLE Enzyme Express (Thermo Fisher) at 37 °C, and then cold 5 extracellular solution was added to the flask, followed by incubation at 4 °C and then trituration of the cells. The cell solution was then placed on a shaker on the Syncropatch platform at 10 °C with a shake speed of a minimum 200 rpm for at least 30 min prior to testing. Extracellular (EC) solution contained (in mM) - 140 NaCl, 4 KC1, 5 CaCh, 10 HEPES, 5 Glucose, pH 7.4 with NaOH. All external solutions contained 0.2% DMSO and 0.01% Kolliphor® EL (C5135, 10 Sigma) throughout the experiment. Intracellular (IC) solution contained (in mM) - 120 CsF, 10 EGTA, 10 NaCl, 10 HEPES, 4 NaATP, 2 MgCh, pH 7.2 with CsOH.

[0388] Plate Preparation

[0389] First, the DMSO Master Plate was prepared, in which the DMSO stock of each test compound was serially diluted in 100% DMSO to 1000X the final assay concentration.15

[0390] Immediately prior to assay testing, the compounds were diluted 1: 100 by transferring solutions from the DMSO Master Plate to the Intermediate Plate pre-filled with EC solution using a Biomek FX automated liquid handling system. Compounds were then diluted further with extracellular solution into two pre-incubation plates - 1) compound from the Intermediate Plate was mixed with EC solution at a 1:5 dilution to create a 2X Compound Pre-incubation, 20 Plate which was diluted a further 1:2 when added to the Syncropatch for the initial compound pre-incubation. And 2) compound from the Intermediate plate was mixed with EC solution at a 1:10 Dilution to create IX Compound Pre-incubation Plates, which was used for subsequent compound pre-incubations. Finally, a Compound + Agonist Plate was prepared by mixing compound from the 2X Compound Pre-incubation Plate with 2X concentration of co-agonists in, 25 a 1: 1 ratio.

[0391] Voltage Protocol

[0392] Each experiment sequentially included cell catching, sealing, whole-cell formation, liquid application, recording and data acquisition. Whole-cell patch clamp recordings were performed using multi-hole high resistance chips on the SyncroPatch 384i (Nani on30 Technologies). A steady-state voltage pulse at -80mV was applied throughout the assay and a 10 second recording window was triggered around 1 second prior to application of co-agonists. Currents were leak corrected and sampled at 5kHz.

[0393] Application Protocol

[0394] A fast application was used, in which ligands were rapidly applied and then rapidly removed from the well. To test for modulator activity the co-agonists glutamate (GluNl / GluN2A: 1 pM, GluNl / GluN2B: 1.5 pM, GluNl / GluN2C: 3.5 pM; GluNl / GluN2D: 9 pM) and glycine 5 (100 pM for all subtypes) were applied three times to show activation reproducibility, followed by 60 sec pre-incubation of test compound alone. The test compound was then re-applied in the presence of co-agonists seven times. No washout periods were applied during the assay (total of ten applications).

[0395] Analysis10

[0396] The voltage protocol generation data collection and analysis were performed on PatchControl384 and DataControll384. The maximum inward current obtained from the voltage pulse was used in the analysis. For each concentration tested, the change in peak current amplitude from baseline was calculated using the following equation: ((Icomp / Icontrol)-l)*100, where Icomp is the peak amplitude in the presence of the test compound and co-agonists from 15 the first or fifth compound / co-agonist application, and Icontrol is the peak amplitude in the presence of co-agonist alone from the third co-agonist application. For experiments with GluNl / GluN2C and GluNl / GluN2D cell lines, the baseline steady state current was subtracted from all sweeps and then the co-agonist evoked peak current amplitude was measured. Test compounds were evaluated at 8 concentrations, with at least 2 replicate wells per concentration., 20 The effect of all concentrations was then fitted with a four-parameter logistic curve fit using least squares regression and the EC50 and Emax / Emin were calculated. (GraphPad Prism). For compounds that were tested on multiple plates, the geometric mean of the EC50, and arithmetic mean of the Emax / Emin were calculated using the parameters derived from the curve fits on each individual assay., 25

[0397] The results for Compound (1) on the various GluNl / GluN2 subtype NMDA receptors are shown in Table 2:Table 2* N / A: Not Applicable due to no clear activity / curve fit.

[0398] Example 9: Maximal Electroshock Seizure Threshold (MEST)

[0399] This study was to evaluate the effects of Theophylline (128 mg / kg, i.p. at 30 min prior) and Compound (1) (0.15, 0.5, 1.5, 5 and 10 mg / kg, i.v., at 15 min prior) on Maximal Electroshock Seizure Threshold in Male Wistar Rats.5

[0400] Materials

[0401] 120 male Wistar Rats (body weights were 164.2 ± 0.8 g at the time of testing) were housed in groups of three under controlled conditions (temperature of 22.5 ± 0.5 °C and 12: 12 light-dark cycle). Water and food were available ad libitum. The rats were acclimated for 5 days under these conditions.10

[0402] Drugs: anhydrous Theophylline; sulfobutylether-P-cyclodextrin (SBECD);dimethylacetamide (DMAC); hydroxypropylmethyl-cellulose; Compound (1).

[0403] Maximal Electroshock Seizure Threshold (MEST)

[0404] Rats were allowed to acclimate to the test room for at least 40 min before use. Rats were randomly assigned into 8 groups. Rats were i.v. administered with 5% DMAC+95% (30% 15 SBECD in water) or Compound (1) (0.15, 0.5, 1.5, 5, 10 mg / kg) at 15 min before MEST; and i.p. administered with 0.2% methyl cellulose (MC) or Theophylline (128 mg / kg) at 30 min prior to MEST test, then returned to their home cage. Ocular anesthetic (2% tetracaine) was applied to the corneas and just before stimulation. The electroshock apparatus was set to deliver initially a 40-mA stimulus, with a 0.8-sec duration, a pulse width of 0.8 msec, and a frequency of 50 Hz., 20 The constant current was generated by a Grass S88x (Grass Technologies of Astro-Med, Inc., West Warwick, RI) stimulator coupled with a photoelectric stimulus isolation unit (A2585, WPI Inc., USA). For bilateral transcorneal stimulation, silver electrodes were soaked with 0.2% Agar before each current application and shortly pressed on the corneas during the stimulation.During the stimulation, rats were restrained and released into the observation cage immediately, 25 after the stimulation. The current strength and the presence or absence of hind-limb tonic convulsions were recorded. Once the first tonic convulsion was observed, the current was decreased by 2 mA for the next animal until no tonic convulsion was found. Each group comprised 15 rats, and each rat was used only once. The electroconvulsive shock threshold (i.e., the current strength required to elicit hind-limb extension at 180° angle to the torso) was30 calculated from the last 10 animals of each group as the mean current. A lower threshold current as compared to the vehicle suggests increased cortical excitability.

[0405] Plasma and Brain Collection

[0406] 15 minutes after Compound (1) (0.15, 0.5, 1.5, 5, 10 mg / kg) administration, the plasma and brain samples were collected for the rats.

[0407] Results

[0408] The mean threshold intensity for 0.2% MC was 41.6 mA, for Theophylline was 21.6 mA with a negative change of 48.1%.

[0409] Theophylline (128 mg / kg, i.p.) increased cortical excitability compared to 0.2% MC treated group.

[0410] Compound (1) (0.15 and 0.5 mg / kg) did not change cortical excitability compared to vehicle-treated group.

[0411] Compound (1) (1.5, 5, 10 mg / kg) increased cortical excitability compared to vehicle-treated group.

[0412] All convulsions occurred after application of electrical stimulation on test day (< 30 min).

[0413] No apparent sedative effects were observed in rats treated with Compound (1).

Claims

CLAIMSWhat is claimed:

1. A method for treating a CNS-related disease, disorder or condition in a subject in need thereof, comprising administering to the subject an effective amount of Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, or a pharmaceutical composition thereof, wherein the CNS-related disease, disorder or condition is selected from the group consisting of neuropsychiatric disorders, neurodegenerative disorders, neurodevelopmental disorders, and neurologic disorders.

2. A method for positive allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to the subject an effective amount of Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, or a pharmaceutical composition thereof; and wherein the NMDA receptor comprises a GluN2C subunit and / or a GluN2D subunit.

3. The method according to claim 2, wherein the NMDA receptor comprises one GluN2C subunit.

4. The method according to claim 2, wherein the NMDA receptor comprises two GluN2C subunits.

5. The method according to claim 2, wherein the NMDA receptor comprises one GluN2D subunit.

6. The method according to claim 2, wherein the NMDA receptor comprises two GluN2D subunits.

7. The method according to any one of claims 1-6, wherein the prodrug of Compound (1) is a compound of Formula (I)or a pharmaceutically acceptable salt, isotopic variant, or combination thereof,wherein each of R1and R2is independently hydrogen, -P(O)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb, provided that both R1and R2are not hydrogen;each Ra is independently -ORc or Ci-ealkyl;Rb is Ci-ealkyl;each Rc is independently hydrogen, Ci-ealkyl, or a counterion; ortwo Rc taken together are a counterion; andeach n and p is independently 1, 2, 3, 4, 5 or 6.

8. The method according to any one of claims 1-7, wherein the compound is selected from the group consisting of any one of Compounds 1-21, or a pharmaceutically acceptable salt thereof set forth in Table 1.

9. A compound, wherein said compound is Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, or a pharmaceutical composition thereof, for use in treating a CNS-related disease, disorder or condition in a subject; wherein the CNS-related disease, disorder or condition is selected from the group consisting of neuropsychiatric disorders, neurodegenerative disorders, neurodevelopmental disorders, and neurologic disorders.

10. A compound, wherein said compound is Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, or a pharmaceutical composition thereof, for use in positive allosteric modulation of an NMD A receptor in a subject, wherein the NMD A receptor comprises a GluN2C subunit and / or a GluN2D.

11. The compound for use according to claim 10, wherein the NMDA receptor comprises one GluN2C subunit.

12. The compound for use according to claim 10, wherein the NMDA receptor comprises two GluN2C subunits.

13. The compound for use according to claim 10, wherein the NMDA receptor comprises one GluN2D subunit.

14. The compound for use according to claim 10, wherein the NMDA receptor comprises two GluN2D subunits.

15. The compound for use according to any one of claims 9-14, wherein the prodrug of Compound (1) is a compound of Formula (I)or a pharmaceutically acceptable salt, isotopic variant, or combination thereof,wherein each of R1and R2is independently hydrogen, -P(0)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)P0C(0)Rb, provided that both R1and R2are not hydrogen;each Ra is independently -ORc or Ci-ealkyl;Rb is Ci-ealkyl;each Rc is independently hydrogen, Ci-ealkyl, or a counterion; or two Rc taken together are a counterion; andeach n and p is independently 1, 2, 3, 4, 5 or 6.

16. The compound for use according to any one of claims 9-15, wherein the compound is selected from the group consisting of any one of Compounds 1-21, or a pharmaceutically acceptable salt thereof set forth in Table 1.

17. Use of Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, in the manufacture of a medicament for treating a CNS-related disease, disorder or condition in a subject, wherein the CNS-related disease, disorder or condition is selected from the group consisting of neuropsychiatric disorders, neurodegenerative disorders, neurodevelopmental disorders, and neurologic disorders.

18. Use of Compound (1)pharmaceutically acceptable salt, isotopic variant, prodrug, or combination thereof, in the manufacture of a medicament for positive allosteric modulation of an NMDA receptor in a subject, wherein the NMD A receptor comprises a GluN2C subunit and / or a GluN2D.

19. The use according to claim 18, wherein the NMDA receptor comprises one GluN2C subunit.

20. The use according to claim 18, wherein the NMDA receptor comprises two GluN2C subunits.

21. The use according to claim 18, wherein the NMDA receptor comprises one GluN2D subunit.

22. The use according to claim 18, wherein the NMDA receptor comprises two GluN2D subunits.

23. The use according to any one of claims 17-22, wherein the prodrug of Compound (1) is a compound of Formula (I)or a pharmaceutically acceptable salt, isotopic variant, or combination thereof,wherein each of R1and R2is independently hydrogen, -P(O)(Ra)2, -C(O)Rb, - C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb, provided that both R1and R2are not hydrogen;each Ra is independently -ORc or Ci-ealkyl;Rb is Ci-ealkyl;each Rc is independently hydrogen, Ci-ealkyl, or a counterion; ortwo Rc taken together are a counterion; andeach n and p is independently 1, 2, 3, 4, 5 or 6.

24. The use according to any one of claims 17-23, wherein the compound is selected from the group consisting of any one of Compounds 1-21, or a pharmaceutically acceptable salt thereof set forth in Table 1.

25. A compound of Formula (I)or a pharmaceutically acceptable salt, isotopic variant, or combination thereof,wherein each of R1and R2is independently hydrogen, -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)pOC(O)Rb, provided that both R1and R2are not hydrogen;each Ra is independently -ORc or Ci-ealkyl;Rb is Ci-ealkyl;each Rc is independently hydrogen, Ci-ealkyl, or a counterion; ortwo Rc taken together are a counterion; andeach n and p is independently 1, 2, 3, 4, 5 or 6.

26. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 25, wherein R1is not hydrogen.

27. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 25, wherein R2is not hydrogen.

28. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 25, wherein R1is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.

29. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 25, wherein R2is -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.

30. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 25, wherein each of R1and R2is independently -P(O)(Ra)2, -C(O)Rb, -C(O)(CH2)nC(O)Rb, or -(CH2)POC(O)Rb.

31. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 25-30, wherein each Ra is independently -ORc; and each Rc is independently Na+.

32. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 25-30, wherein Rb is C1-3alkyl.

33. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 25-32, wherein the compound is selected from the group consisting of any one of Compounds 2-21, or a pharmaceutically acceptable salt thereof set forth in Table 1.

34. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 25-33, and a pharmaceutically acceptable carrier.

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