NMDA receptor-modulating compounds and methods of use thereof

Abstract

Compounds are provided according to Formula (A) and pharmaceutically acceptable salts, isotopically labeled derivatives, and isotopically labeled derivatives of the pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present disclosure are contemplated useful for the prevention and treatment of a variety of CNS-related conditions.

Description

NMDA RECEPTOR-MODULATING COMPOUNDS AND METHODS OF USE THEREOF Cross Reference To Related Applications

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 634,291, filed April 15, 2024, the disclosure of which, is incorporated by reference herein in its entirety. Background

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

[0003] There is a need for new compounds that are allosteric modulators of the NMDA receptor for the prevention and treatment of conditions associated with NMDA receptor function. Compounds, compositions, and methods described herein are directed toward this end. Summary

[0004] In one aspect, the disclosure provides a compound of Formula (A):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:wherein: each of R1aand R1bis independently hydrogen or C1-6alkyl; or R1aand R1b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl, or a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6alkyl; X1is halogen, C1-6alkyl optionally substituted with 1-5 halogen, -OROor -SRS, wherein each of ROand RSis independently hydrogen or C1-6 alkyl; X2is C6-10 aryl or 5-8 membered heteroaryl; and X3is C1-6alkyl, C1-6alkoxy or C6-10aryl; n is 0 or 1; R4is -OH, C1-6 alkoxy, -OC(O)(C1-6 alkyl), or -O-CH2-(5-8 membered heteroaryl); R4’is hydrogen or C1-6alkyl; R5is absent or hydrogen; each of R25aand R25bis independently hydrogen, C1-6 alkyl optionally substituted with 1-5 halogen, or C3-6carbocyclyl; or R25aand R25b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl; R25cis hydrogen, or C1-6 alkyl; and is a single bond or a double bond, wherein when is a single bond, R5is hydrogen, and wherein when is a double bond, R5is absent; and provided that the compound is not.

[0005] In some embodiments, the disclosure provides a compound of Formula (A) is a compound of Formula (I):or a pharmaceutically acceptable salt, isotopic variant, or a combination thereof, wherein:wherein: each of R1aand R1bis independently hydrogen or C1-6alkyl; or R1aand R1b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl; X1is -OROor -SRS, wherein each of ROand RSis independently hydrogen or C1-6alkyl; X2is C6-10 aryl or 5-8 membered heteroaryl; and X3is C1-6 alkyl or C1-6 alkoxy; R4is -OH, C1-6alkoxy, -OC(O)(C1-6alkyl), or -O-CH2-(5-8 membered heteroaryl); R5is absent or hydrogen; each of R25aand R25bis independently hydrogen, C1-6 alkyl optionally substituted with 1-5 halogen, or C3-6carbocyclyl; or R25aand R25b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl; and is a single bond or a double bond, wherein when is a single bond, R5is hydrogen, and whenis a double bond, R5is absent.

[0006] In some embodiments, the disclosure provides a compound of Formula (A), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof wherein: R1aand R1b, together with the carbon atom to which they are attached, form a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6 alkyl; X1is halogen, C1-6alkyl optionally substituted with 1-5 halogen; X3is C6-10aryl; n is 0; R4’is C1-6alkyl; and R25cis C1-6alkyl.

[0007] In some embodiments, the compound of Formula (A) is a compound of Formula (A-1):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

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

[0009] In another aspect, the compound of Formula (A) is a compound of Formula (A-2):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0010] In some embodiments, the compound of Formula (I) is a compound of Formula (I-B):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0011] In some embodiments, the compound of Formula (A) is a compound of Formula (A-3):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0012] In some embodiments, the compound of Formula (I) is a compound of Formula (I-C):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0013] In some embodiments, the disclosure provides a compound of any one of the Formulae disclosed herein (i.e., (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein R1is ,.

[0014] In some embodiments, the disclosure provides a compound of any one of the Formulae disclosed herein (i.e., (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein R1is . In some embodiments, X1is -ORO. In some embodiments, X1is -OH. In some embodiments, X1is halogen. In some embodiments, X1is fluoro. In some embodiments, X1is C1-6alkyl optionally substituted with 1-5 halogen. In some embodiments, X1is -CH3, -CHF2, or -CF3. In some embodiments, R1aand R1bare both hydrogen. In some embodiments, each of R1aand R1bis independently C1-6 alkyl. In some embodiments, R1aand R1bare both -CH3. In some embodiments, R1aand R1bare both -CD3.

[0015] In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a cyclopropyl ring. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a cyclobutyl ring.

[0016] In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6alkyl. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a 3-8 membered heterocyclyl comprising at least one O, and optionally substituted with one more substituents independently selected from C1-6 alkyl. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane or 1,3-dioxane, wherein said oxetane and 1,3-dioxane are optionally substituted with one more substituents independently selected from C1-6 alkyl. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane or 1,3-dioxane. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane or 1,3-dioxane, wherein said oxetane and 1,3-dioxane are substituted with one more substituents independently selected from C1-6alkyl. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane or 1,3-dioxane, wherein said oxetane and 1,3-dioxane are optionally substituted with one or more -CH3. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane or 1,3-dioxane, wherein said oxetane and 1,3-dioxane are substituted with one or more -CH3. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a 1,3-dioxane substituted with two -CH3.

[0017] In some embodiments, the disclosure provides a compound of any one of the Formulae disclosed herein (i.e., (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein R1is. In some embodiments, X2is C6-10aryl. In some embodiments, X2is phenyl. In some embodiments, X2is 5-8 membered heteroaryl. In some embodiments, X2is 5-6 membered heteroaryl. In some embodiments, X2is pyrazolyl, pyridyl, or isoxazolyl. In some embodiments, X2is 3-pyrazolyl, 5-pyrazolyl, 2-pyridyl, 4-pyridyl, or 5-isoxazolyl.

[0018] In some embodiments, the disclosure provides a compound of any one of the Formulae disclosed herein (i.e., (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein R1is . In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments X3is C1-6alkyl. In some embodiments, X3is -CH3. In some embodiments X3is C1-6alkoxy. In some embodiments,X3is -OC(CH3)3. In some embodiments X3is C6-10 aryl. In some embodiments X3is C6-10 phenyl.

[0019] In some embodiments, the disclosure provides a compound of any one of the Formulae disclosed herein (i.e., (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein R4is -OH. In some embodiments, R4is C1-6alkoxy. In some embodiments, R4is -OCH3. In some embodiments, R4is -OC(O)(C1-6 alkyl). In some embodiments, R4is -OC(O)CH3. In some embodiments, R4is -O-CH2-(5-8 membered heteroaryl). In some embodiments, R4is -O-CH2-(pyridyl). In some embodiments, R4is in the alpha configuration. In some embodiments, R4is in the beta configuration.

[0020] In some embodiments, the disclosure provides a compound of any one of the Formulae disclosed herein (i.e., (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein R4’is H. In some embodiments, R4’is C1-6 alkyl. In some embodiments, R4’is -CH3. In some embodiments, R4’is in the alpha configuration. In some embodiments, R4’is in the beta configuration.

[0021] In some embodiments, the disclosure provides a compound of any one of the Formulae disclosed herein (i.e., (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein each of R25aand R25bis independently C1-6alkyl optionally substituted with 1-5 halogen. In some embodiments, R25aand R25bare both -CH3. In some embodiments, R25aand R25bare both -CD3. In some embodiments, one of R25aand R25bis -CH3 and the other is -CF3.

[0022] In some embodiments, the disclosure provides a compound of any one of the Formulae disclosed herein (i.e., (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein R24cis H. In some embodiments, R24cis C1-6 alkyl. In some embodiments, R24cis -CH3.

[0023] In some embodiments, the disclosure provides a compound of Formula (A), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:each of R1aand R1bis independently C1-6alkyl; X1is -OH; X2is 5-8 membered heteroaryl; R4is -OH; R5is absent;each of R25aand R25bis independently C1-6 alkyl; R25cis hydrogen, or C1-6alkyl; and is a double bond.

[0024] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:each of R1aand R1bis independently C1-6alkyl; X1is -OH; X2is 5-8 membered heteroaryl; R4is -OH; R5is absent; each of R25aand R25bis independently C1-6 alkyl; and is a double bond.

[0025] In some embodiments, the disclosure provides a compound of Formula (A), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:each of R1aand R1bis independently C1-6 alkyl; X1is -OH; X2is 5-8 membered heteroaryl; R4is -OH; R5is hydrogen; each of R25aand R25bis independently C1-6alkyl; R25cis hydrogen, or C1-6 alkyl; and is a single bond.

[0026] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:each of R1aand R1bis independently C1-6 alkyl; X1is -OH; X2is 5-8 membered heteroaryl;R4is -OH; R5is hydrogen; each of R25aand R25bis independently C1-6alkyl; and is a single bond.

[0027] In some embodiments, the compound of Formula (A) is any one of compounds 1-38, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound is any one of compounds 1-38. In some embodiments, the compound is a pharmaceutically acceptable salt of any one of compounds 1-38. In some embodiments, the compound is an isotopic variant of any one of compounds 1-38. In some embodiments, the compound is an isotopic variant of a pharmaceutically acceptable salt of any one of compounds 1-38.

[0028] In some embodiments, the compound provided herein is a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C). In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C). In some embodiments, the compound provided herein is an isotopic variant of a compound of any one of Formulae (A-3), (A), (A-I), (A-2), (I), (I-A), (I-B), and (I-C). In some embodiments, the compound provided herein is an isotopic variant of a pharmaceutically acceptable salt of a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C).

[0029] In some embodiments, the disclosure provides a compound of any one of the Formulae disclosed herein (i.e., (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein one or more hydrogen atoms are replaced by deuterium. In some embodiments, one or more hydrogen atoms are replaced by tritium.

[0030] In one aspect, the disclosure provides a pharmaceutical composition comprising a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to the disclosure, and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of any one of Formulae (A), (A- I), (A-3), (I), (I-A), (I-B), and (I-C), and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising an isotopic variant of a compoundof any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C). In some embodiments, the disclosure provides a pharmaceutical composition comprising an isotopic variant of a pharmaceutically acceptable salt of a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C).

[0031] In one aspect, the disclosure provides a method for treating a CNS-related condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure.

[0032] In one aspect, the disclosure provides a method for effecting allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I- C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure.

[0033] In one aspect, the disclosure provides a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, for use in treating a CNS-related condition in a subject.

[0034] In one aspect, the disclosure provides a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, for use in effecting allosteric modulation of an NMDA receptor.

[0035] In one aspect, the disclosure provides a use of a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, in the manufacture of a medicament for treating a CNS-related condition in a subject.

[0036] In one aspect, the disclosure provides a use of a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, in the manufacture of a medicament for effecting allosteric modulation of an NMDA receptor.

[0037] In some embodiments, the CNS-related condition is selected from the group consisting of: an adjustment disorder, stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder(including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder, a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), epilepsies related to mTor, melanoma, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

[0038] In some embodiments, the CNS-related condition is selected from the group consisting of: an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer’s disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or another psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (includingobsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (including acute and chronic pain), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), a seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease), stroke, traumatic brain injury, a movement disorder (including Huntington’s disease and Parkinson’s disease), GRIN disorders, 22q11.2 deletion syndrome, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), and tinnitus.

[0039] In some embodiments, the CNS-related condition is selected from the group consisting of: an adjustment disorder, a stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), a personality disorder (including obsessive- compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome), pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, sensory hypersensitivity, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffersyndrome (LKS)), melanoma, neuropsychiatric lupus, hepatic encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), and tinnitus.

[0040] In some embodiments, the CNS-related condition is selected from the group consisting of: an autism spectrum disorder (ASD), Tuberous Sclerosis Complex (TSC), multiple sclerosis (MS), Alzheimer’s disease (AD), and Niemann-Pick type C (NPC).

[0041] In one aspect, the disclosure provides a method for reversing the anesthetic, dissociative, sedative, or cognitive-impairing effects of ketamine or a ketamine analog, comprising administering to a subject a compound of any one of Formulae (A), (A-I), (A-2), (A- 3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to the disclosure, and a pharmaceutically acceptable carrier.

[0042] In one aspect, the disclosure provides a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to the disclosure, and a pharmaceutically acceptable carrier, for use in reversing the anesthetic, dissociative, sedative, or cognitive-impairing effects of ketamine or a ketamine analog in a subject.

[0043] In one aspect, the disclosure provides for the use of a compound of any one of Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to the disclosure, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for reversing the anesthetic, dissociative, sedative, or cognitive-impairing effects of ketamine or a ketamine analog in a subject. Detailed Description

[0044] The present disclosure provides compounds that are NMDA receptor allosteric modulators. The compounds of the disclosure are useful as therapeutic agents for treating, for example, CNS-related conditions. General Definitions

[0045] The term “herein” means the entire application.

[0046] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. Generally, nomenclature used in connection with the compounds, compositions, and methods described herein, are those well-known and commonly used in the art.

[0047] It should be understood that any of the embodiments described herein, including those described under different aspects of the disclosure and different parts of the specification(including embodiments described only in the Examples), can be combined with one or more other embodiments of the disclosure, unless explicitly disclaimed or improper. Combinations of embodiments are not limited to those specific combinations claimed via the multiple dependent claims. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.

[0048] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (element or component) or group of integers (elements or components), but not the exclusion of any other integer (element or component) or group of integers (elements or components).

[0049] 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 (or variations thereof), specific process steps, the 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 remain operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0050] The term “including” as used herein, means “including but not limited to.” “Including” and “including but not limited to” are used interchangeably. Thus, these terms will be understood to imply the inclusion of a stated integer (element or component) or group of integers (elements or components), but not the exclusion of any other integer (element or component) or group of integers (elements or components).

[0051] As used herein, “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0052] 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 by context.

[0053] The term “or” as used herein should be understood to mean “and / or,” unless the context clearly indicates otherwise.

[0054] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range and including the endpoints, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (“such as,” “for example,” “e.g.,” etc.) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0055] All of the publications, patents, and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. Chemical Definitions

[0056] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 102ndEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 8thEdition, John Wiley & Sons, Inc., New Jersey, 2020; Larock, Comprehensive Organic Transformations, 3rdEdition, John Wiley & Sons, Inc., New Jersey, 2018; Kurti and Czako, Strategic Applications of Named Reactions inOrganic Synthesis, Elsevier, Inc., 2005; and Carruthers & Coldham, Modern Methods of OrganicSynthesis, 4thEdition, Cambridge University Press, Cambridge, 2004.

[0057] As used herein, a “ketamine analog” refers to any compound analogous to naturally occurring ketamine wherein one or more positions on the ketamine molecule have been substituted. In general, the term covers all compounds which exhibit ketamine-like activity but which may, if desired, have a different potency or pharmacological profile.

[0058] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high- performance liquid chromatography (HPLC), supercritical fluid chromatograph (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0059] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non–superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric carbon center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the (R)- and (S)- sequencing rules of Cahn, Ingold, and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (–)- isomers, respectively). A chiral compound can exist as either an individual enantiomer or diastereomer, or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a “racemic mixture.”

[0060] As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “(S)-” form of the compound is substantially free from the “(R)-” form of the compound and is, thus, in enantiomeric excess of the “(R)-” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, morethan 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0061] 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 more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight, of the diastereomer.

[0062] Methods for determining diastereomeric and enantiomeric purity are well-known in the art. For example, enantiomeric or diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its enantiomers or diastereomers, such as high-performance liquid chromatography (HPLC) or supercritical fluid chromatograph (SFC).

[0063] 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 embodiments, the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (R)-compound and at most about 5% by weight (S)- compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0064] 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 ortritium); C may be in any isotopic form, including12C,13C, and14C; N may be in any isotopic form, including13N,14N, and15N; O may be in any isotopic form, including16O and18O; F may be in any isotopic form, including18F and19F; S may be in any isotopic form, including32S,33S,34S, and36S; and the like.

[0065] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1–6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0066] 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 be understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0067] “Aliphatic” refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein.

[0068] “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6). Common alkyl abbreviations include Me (-CH3), Et (- CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (- CH2CH(CH3)2).

[0069] As used herein, “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” refer to a divalent radical of an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.

[0070] “Alkylene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical. Alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (- CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (- CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Alkyleneabbreviations include, but are not limited to, -(CH(CH3))–, –(CH(CH2CH3))–, – (CH(CH2CH2CH3))–, –(CH(CH2CH2CH2CH3))–, -(CH2CH(CH2CH2CH2CH3))– , -(CH2CH2CH(CH2CH2CH2CH3))–, –(CH(CH3)CH2)–, -(CH(CH3)CH2CH2)– , -(CH(CH3)CH2CH2CH2)–, –( CH2CH(CH3)CH2)–, -(CH2CH(CH3)CH2CH2)–, and -(CH2CH2CH(CH3)CH2CH2)–.

[0071] “Alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon– carbon double bonds), and optionally one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C2-20alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon–carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1– propenyl (C3), 2–propenyl (C3), 1–butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0072] “Alkenylene” refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical. Exemplary divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-).

[0073] “Alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon– carbon triple bonds), and optionally one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds) (“C2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In someembodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon–carbon triple bonds can be internal (such as in 2– butynyl) or terminal (such as in 1–butynyl). Examples of C2–4alkynyl groups include, without limitation, ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. Examples of C2–6 alkenyl groups include the aforementioned C2–4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.

[0074] “Alkynylene” refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical. Exemplary divalent alkynylene groups include, but are not limited to, ethynylene, propynylene, and the like.

[0075] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-7 alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In some embodiments, a heteroalkylgroup is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”).

[0076] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1or 2 heteroatoms (“heteroC2-4alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6alkenyl”).

[0077] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkynyl”). In some embodiments, a heteroalkynyl grouphas 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-5alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms (“heteroC2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC2-3alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-6 alkynyl”).

[0078] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ^ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). “Aryl” also includes ring systems wherein the aryl ring, as defined herein, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0079] “Fused aryl” refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

[0080] “Aralkyl” is a subset of alkyl and aryl, as defined herein, and refers to an alkyl group substituted by an aryl group.

[0081] “Heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ^ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0082] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0083] Exemplary 5 membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5 membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5 membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5 membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6 membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6 membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6 membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.

[0084] Examples of representative heteroaryls include the following:wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, C1-8 alkyl, C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl.

[0085] “Nitrogen-containing heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ^ electrons shared in a cyclic array) having ring carbon atoms and containing at least one nitrogen atom. Examples of nitrogen- containing heteroaryl groups included, but are not limited to, pyrrolyl, pyrazolyl, isoxazolyl, pyridyl, pyridinonyl, pyridazinyl, and pyrimidinyl.

[0086] “Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein, and refers to an alkyl group substituted by a heteroaryl group.

[0087] “Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3–6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl(C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group includes either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged, or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[0088] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8).

[0089] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

[0090] In some embodiments, a heterocyclyl group is a 5-10 membered non–aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non– aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0091] Exemplary 3 membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4 membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5 membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione. Exemplary 5 membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5 membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6 membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6 membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6 membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7 membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8 membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5 membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6 membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0092] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen,oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteroalkenyl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0093] “Alkoxy” refers to the group –OR29where R29is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, an alkoxy group has 1 to 6 carbon atoms (“C1-6 alkoxy”). In some embodiments, an alkoxy group has 1 to 5 carbon atoms (“C1-5 alkoxy”). In some embodiments, an alkoxy group has 1 to 4 carbon atoms (“C1-4 alkoxy”). In some embodiments, an alkoxy group has 1 to 3 carbon atoms (“C1-3alkoxy”). In some embodiments, an alkoxy group has 1 to 2 carbon atoms (“C1-2 alkoxy”). In some embodiments, an alkoxy group has 1 carbon atom (“C1 alkoxy”). Examples of C1-6 alkoxy groups include methoxy (C1), ethoxy (C2), n-propoxy (C3), isopropoxy (C3), 2-methoxyethoxy (C3), n-butoxy (C4), tert-butoxy (C4), sec-butoxy (C4), n-pentoxy (C5), n-hexoxy (C6), and 1,2-dimethylbutoxy (C6). Particular alkoxy groups are lower alkoxy, i.e., with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0094] “Amino” refers to the radical -NH2.

[0095] “Carboxy” refers to the radical -C(O)OH.

[0096] “Cyano” refers to the radical -CN.

[0097] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[0098] “Hydroxyl” refers to the radical -OH.

[0099] “Nitro” refers to the radical –NO2.

[0100] “Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

[0101] “Heterocyclylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0102] “Nitrogen-containing heterocyclyl” group means a 5- to 8- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.

[0103] “Thioketo” refers to the group =S.

[0104] “Imino” refers to the group =N-RN, wherein RNis hydrogen, alkyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl, or any combination of selections therefrom.

[0105] “Oxo” refers to the group =O.

[0106] “Thiol” refers to the group -SH.

[0107] A “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HSO4–, SO4-2sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid- 5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0108] In general, the term “substituted” means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. “Optionally substituted” means “substituted” or “unsubstituted.” Other Definitions

[0109] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0110] “Pharmaceutically acceptable salt” refers to a salt of a compound disclosed herein that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non–toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition 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, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N– methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counter–ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1–79.

[0111] “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 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.

[0112] “Isotopic variant” refers to a compound disclosed herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof), wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,17O,18O,32P,33P,33S,34S,35S,18F, and37Cl. Compounds disclosed herein which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopic variants of the compounds of the present application,for example, those into which radioactive isotopes (e.g., 3H and 14C) are incorporated, may beuseful in drug and / or substrate distribution assays. Further, substitution with heavier isotopes(e.g., 2H) can afford certain therapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopic variants of compounds and pharmaceutically acceptable salts thereof disclosed herein can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples, by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.

[0113] A “subject” to which administration is contemplated includes, but is not limited to, a human subject (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain 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.

[0114] “Disease,” “disorder,” and “condition” are used interchangeably herein.

[0115] 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 a manner to improve or stabilize a subject's condition. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation, amelioration, reduction of the severity, or slowing the progression of 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.

[0116] 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.

[0117] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, theeffective 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.

[0118] The terms “pharmaceutically effective amount,” “therapeutically effective amount,” and “therapeutically effective dose” are used interchangeably herein and refer to an amount sufficient to treat a disease in a patient, e.g., effecting a beneficial and / or desirable alteration in the health of a patient suffering from a disease, treatment, healing, inhibition or amelioration of a physiological response or condition, delaying or minimizing one or more symptoms associated with the disease, disorder, or condition etc. The full therapeutic effect 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 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.

[0119] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0120] As used herein, and unless otherwise specified, “pharmacokinetics” can be defined as the study of bodily absorption, distribution, metabolism, and excretion of drugs.“Pharmacokinetics” can also be defined as the characteristic interactions of a drug and a body in terms of its absorption, distribution, metabolism, and excretion; or a branch of pharmacology concerned with the way drugs are taken into, move around, and are eliminated from, a body.

[0121] “Administering” or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. In 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 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 methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administering, whether the subject is cognitively impaired at the time of administering, the extent of the impairment, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity).

[0122] 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 compared to other compounds. Compounds

[0123] In one aspect, the disclosure provides a compound of Formula (A):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R1is, wherein: each of R1aand R1bis independently hydrogen or C1-6alkyl; or R1aand R1b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl, or a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6 alkyl; X1is halogen, C1-6alkyl optionally substituted with 1-5 halogen, -OROor -SRS, wherein each of ROand RSis independently hydrogen or C1-6 alkyl; X2is C6-10 aryl or 5-8 membered heteroaryl; and X3is C1-6alkyl, C1-6alkoxy or C6-10aryl; n is 0 or 1; R4is -OH, C1-6 alkoxy, -OC(O)(C1-6 alkyl), or -O-CH2-(5-8 membered heteroaryl); R4’is hydrogen or C1-6alkyl; R5is absent or hydrogen; each of R25aand R25bis independently hydrogen, C1-6 alkyl optionally substituted with 1-5 halogen, or C3-6carbocyclyl; or R25aand R25b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl; R25cis hydrogen, or C1-6 alkyl; and is a single bond or a double bond, wherein when is a single bond, R5is hydrogen, and wherein when is a double bond, R5is absent; and provided that the compound is not.

[0124] In some embodiments, the present disclosure provides a compound of Formula (A), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein R1aand R1b, together with the carbon atom to which they are attached, form a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6alkyl; X1is halogen, C1-6 alkyl optionally substituted with 1-5 halogen; X3is C6-10 aryl; n is 0; R4’is C1-6 alkyl; and R25cis C1-6alkyl.

[0125] In some embodiments, the present disclosure provides a compound, wherein the compound has the structure of Formula (I):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:wherein: each of R1aand R1bis independently hydrogen or C1-6 alkyl; or R1aand R1b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl; X1is -OROor -SRS, wherein each of ROand RSis independently hydrogen or C1-6 alkyl; X2is C6-10 aryl or 5-8 membered heteroaryl; and X3is C1-6alkyl or C1-6alkoxy; R4is -OH, C1-6alkoxy, -OC(O)(C1-6alkyl), or -O-CH2-(5-8 membered heteroaryl); R5is absent or hydrogen; each of R25aand R25bis independently hydrogen, C1-6alkyl optionally substituted with 1-5 halogen, or C3-6carbocyclyl; orR25aand R25b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl; and is a single bond or a double bond, wherein when is a single bond, R5is hydrogen, and when is a double bond, R5is absent.

[0126] In some embodiments, the compound of Formula (A)is a compound of Formula (A-1):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0127] In some embodiments, the compound of Formula (I)is a compound of Formula (I-A):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0128] In some embodiments, the compound of Formula (A)is a compound of Formula (A-2):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0129] In some embodiments, the compound of Formula (I) is a compound of Formula (I-B):isotopic variant, or combination thereof.

[0130] In some embodiments, the compound of Formula (A)is a compound of Formula (A-3):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

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

[0132] In some embodiments, the compound of the disclosure is a compound of Formula (A) wherein:each of R1aand R1bis independently C1-6 alkyl; X1is -OH; X2is 5-8 membered heteroaryl; R4is -OH; R5is absent; each of R25aand R25bis independently C1-6 alkyl; R25cis hydrogen, or C1-6alkyl; and double bond.

[0133] In some embodiments, the compound of the disclosure is a compound of Formula (I) wherein:each of R1aand R1bis independently C1-6alkyl; X1is -OH; X2is 5-8 membered heteroaryl;R4is -OH; R5is absent; each of R25aand R25bis independently C1-6 alkyl; and is a double bond.

[0134] In some embodiments, the compound of the disclosure is a compound of Formula (A) wherein:each of R1aand R1bis independently C1-6alkyl; X1is -OH; X2is 5-8 membered heteroaryl; R4is -OH; R5is hydrogen; each of R25aand R25bis independently C1-6 alkyl; R25cis hydrogen, or C1-6alkyl; and is a single bond.

[0135] In some embodiments, the compound of the disclosure is a compound of Formula (I) wherein:each of R1aand R1bis independently C1-6 alkyl; X1is -OH; X2is 5-8 membered heteroaryl; R4is -OH; R5is hydrogen; each of R25aand R25bis independently C1-6alkyl; and is a single bond.

[0136] In some embodiments, the compound of the disclosure is a compound of Formula (A), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:each of R1aand R1bis independently C1-6 alkyl; X1is -OH; R4is -OH;R5is absent; each of R25aand R25bis independently C1-6alkyl; R25cis hydrogen, or C1-6alkyl; and is a double bond.

[0137] In some embodiments, the compound of the disclosure is a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:each of R1aand R1bis independently C1-6alkyl; X1is -OH; R4is -OH; R5is absent; each of R25aand R25bis independently C1-6 alkyl; and is a double bond.

[0138] In some embodiments, the compound of the disclosure is a compound of Formula (A), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:each of R1aand R1bis independently C1-6 alkyl; X1is -OH; R4is -OH; R5is hydrogen; each of R25aand R25bis independently C1-6 alkyl; R25cis hydrogen, or C1-6alkyl; and is a single bond.

[0139] In some embodiments, the compound of the disclosure is a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:each of R1aand R1bis independently C1-6alkyl; X1is -OH; R4is -OH; R5is hydrogen;each of R25aand R25bis independently C1-6 alkyl; and is a single bond.Groups R1, X1, X2, X3, R1a, R1b, RO, and RS – as they relate to Formulae (A), (A-I), (A-2), (A-3),(I), (I-A), (I-B), and (I-C)

[0140] In some embodiments,, , . In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is or . In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is . In some embodiments,

[0141] In some embodiments, when R1is, X1is halogen, C1-6alkyl optionally substituted with 1-5 halogen, -OROor -SRS, wherein each of ROand RSis independently hydrogen or C1-6 alkyl. In some embodiments, when R1is, X1is -OROor -SRS, wherein each of ROand RSis independently hydrogen or C1-6 alkyl. In some embodiments, X1is halogen. In some embodiments, X1is fluoro. In some embodiments, X1is C1-6alkyl optionally substituted with 1-5 halogen. In some embodiments, X1is C1-6alkyl. In some embodiments, X1is C1-6alkyl substituted with 1-5 halogen. In some embodiments, X1is -CHF2 or -CF3. In some embodiments, X1is -CHF2. In some embodiments, X1is -CF3. In some embodiments, X1is -ORO. In some embodiments, ROis hydrogen (i.e., X1is -OH). In some embodiments, ROis C1-6alkyl (i.e., X1is -O(C1-6 alkyl)). In some embodiments, ROis -CH3. In some embodiments, X1is-SRS. In some embodiments, RSis hydrogen (i.e., X1is -SH). In some embodiments, RSis C1-6 alkyl (i.e., X1is -S(C1-6alkyl)). In some embodiments, RSis -CH3.

[0142] In some embodiments, when R1is, each of R1aand R1bis independently hydrogen or C1-6 alkyl; or R1aand R1b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl or a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6alkyl. In some embodiments, when R1is, each of R1aand R1bis independently hydrogen or C1-6alkyl; or R1aand R1b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl.

[0143] In some embodiments, each of R1aand R1bis independently hydrogen or C1-6alkyl. In some embodiments, one of R1aand R1bis hydrogen and the other is C1-6alkyl. In some embodiments, each of R1aand R1bis independently C1-6 alkyl. In some embodiments, each of R1aand R1bis independently hydrogen, -CH3, or -CD3. In some embodiments, R1aand R1bare both hydrogen. In some embodiments, R1aand R1bare both -CH3. In some embodiments, R1aand R1bare both -CD3.

[0144] In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a cyclopropyl. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a cyclobutyl.

[0145] In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6alkyl. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a 3-8 membered heterocyclyl comprising at least one O, and optionally substituted with one more substituents independently selected from C1-6 alkyl. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane or 1,3-dioxane, wherein said oxetane and 1,3-dioxane are optionally substituted with one more substituents independently selected from C1-6 alkyl. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane or 1,3-dioxane. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane or 1,3-dioxane, wherein said oxetane and 1,3-dioxane are substituted with one more substituents independently selected from C1-6 alkyl. In someembodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane, wherein said oxetane is optionally substituted with one or more -CH3. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane or 1,3-dioxane, wherein said oxetane and 1,3-dioxane are substituted with one or more -CH3. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form an oxetane. In some embodiments, R1aand R1b, together with the carbon atom to which they are attached, form a 1,3-dioxane substituted with two -CH3.

[0146] In some embodiments, when R1is, X2is C6-10 aryl or 5-8 membered heteroaryl. In some embodiments, X2is C6-10aryl. In some embodiments, X2is phenyl. In some embodiments, X2is 5-8 membered heteroaryl. In some embodiments, X2is pyrazolyl, pyridyl, or isoxazolyl. In some embodiments, X2is pyrazolyl. In some embodiments, X2is pyridyl. In some embodiments, X2is isoxazolyl. In some embodiments, X2is 3-pyrazolyl, 5-pyrazolyl, 2-pyridyl, 4-pyridyl, or 5-isoxazolyl. In some embodiments, X2is 3-pyrazolyl. In some embodiments, X2is 5-pyrazolyl. In some embodiments, X2is 2-pyridyl. In some embodiments, X2is 4-pyridyl. In some embodiments, X2is 5-isoxazolyl.

[0147] In some embodiments, when R1is , n is 0 or 1, X3is C1-6 alkyl, C1-6 alkoxyor C6-10 aryl. In some embodiments, when R1is , X3is C1-6 alkyl or C1-6 alkoxy. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, X3is C1-6alkyl. In some embodiments, X3is -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, or -C(CH3)3. In some embodiments, X3is -CH3. In some embodiments, X3is C1-6 alkoxy. In some embodiments, X3is -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OC(CH3)3. In some embodiments, X3is -OC(CH3)3. In some embodiments, X3is C6-10aryl. In some embodiments, X3is phenyl. Group R4– as it relates to Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)

[0148] In certain embodiments, R4is -OH, C1-6alkoxy, -OC(O)(C1-6alkyl), or -O-CH2-(5-8 membered heteroaryl). In some embodiments, R4is -OH. In some embodiments, R4is s C1-6alkoxy. In some embodiments, R4is -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OC(CH3)3. In some embodiments, R4is -OCH3. In some embodiments, R4is -OC(O)(C1-6alkyl). In some embodiments, R4is -OC(O)CH3, -OC(O)CH2CH3, -OC(O)CH2CH2CH3, -OC(O)CH(CH3)2, -OC(O)CH2CH2CH2CH3, -OC(O)CH2CH(CH3)2, or -OC(O)C(CH3)3. In some embodiments, R4is -OC(O)CH3. In someembodiments, R4is -O-CH2-(5-8 membered heteroaryl). In some embodiments, R4is -O-CH2- (pyridyl). In some embodiments, R4is -O-CH2-(2-pyridyl). In certain embodiments, R4is in the alpha position. In certain embodiments, R4is in the beta position. Group R4’– as it relates to Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)

[0149] In certain embodiments, R4’is -H, or C1-6 alkyl. In some embodiments, R4’is H. In some embodiments, R4’is a C1-6alkyl. In some embodiments, R4’is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, or -C(CH3)3. In some embodiments, R4’is -CH3. In certain embodiments, R4’is in the alpha position. In certain embodiments, R4’is in the beta position. In some embodiments, R4is in the alpha position and R4’is in the beta position. In some embodiments, R4is in the beta position and R4’is in the alpha position. Groups R25a, R25band R25c– as they relate to Formulae (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C)

[0150] In some embodiments, each of R25aand R25bis independently hydrogen, C1-6 alkyl optionally substituted with 1-5 halogen, or C3-6 carbocyclyl; or R25aand R25b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl. In some embodiments, each of R25aand R25bis independently hydrogen, C1-6 alkyl optionally substituted with 1-5 fluoro, or C3-6 carbocyclyl; or R24aand R24b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl.

[0151] In some embodiments, R25aand R25bare both hydrogen. In some embodiments, one of R25aand R25bis hydrogen and the other is C1-6 alkyl optionally substituted with 1-5 halogen. In some embodiments, one of R25aand R25bis hydrogen and the other is C1-6alkyl optionally substituted with 1-5 fluoro. In some embodiments, one of R25aand R25bis hydrogen and the other is C1-6 alkyl substituted with 1-5 halogen. In some embodiments, one of R25aand R25bis hydrogen and the other is C1-6 alkyl substituted with 1-5 fluoro. In some embodiments, one of R25aand R25bis hydrogen and the other is -CF3. In some embodiments, one of R25aand R25bis hydrogen and the other is C1-6 alkyl. In some embodiments, one of R25aand R25bis hydrogen and the other is -CH3. In some embodiments, R25aand R25bare both C1-6 alkyl optionally substituted with 1-5 halogen. In some embodiments, one of R25aand R25bis hydrogen and the other is -CH3. In some embodiments, each of R25aand R25bis independently C1-6 alkyl optionally substituted with 1-5 fluoro. In some embodiments, each of R25aand R25bis independently C1-6 alkyl substituted with 1-5 halogen. In some embodiments, each of R25aand R25bis independently C1-6alkyl substituted with 1-5 fluoro. In some embodiments, R25aand R25bare both -CF3. In some embodiments, each of R25aand R25bis independently C1-6 alkyl. In some embodiments, R25aandR25bare both -CH3. In some embodiments, R25aand R25bare both -CD3. In some embodiments, one of R25aand R25bis C1-6alkyl substituted with 1-5 halogen and the other is C1-6alkyl. In some embodiments, one of R25aand R25bis C1-6alkyl substituted with 1-5 fluoro and the other is C1-6alkyl. In some embodiments, one of R25aand R25bis -CF3 and the other is -CH3.

[0152] In some embodiments, one of R25aand R25bis C3-6 carbocyclyl. In some embodiments, one of R25aand R25bis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, one of R25aand R25bis cyclopropyl. In some embodiments, each of R25aand R25bis independently C3-6 carbocyclyl. In some embodiments, each of R25aand R25bis independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R25aand R25bare both cyclopropyl.

[0153] In some embodiments, R25aand R25b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl. In some embodiments, R25aand R25b, together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R25aand R25b, together with the carbon atom to which they are attached, form a cyclopropyl.

[0154] In some embodiments, R25cis hydrogen or C1-6alkyl. In some embodiments, R25cis hydrogen. In some embodiments, R25cis C1-6 alkyl. In some embodiments, R25cis -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, or -C(CH3)3. In some embodiments, R25cis -CH3.

[0155] In some embodiments, the compound of Formula (A) is any one of the compounds in Table 1, or a pharmaceutically salt, isotopic variant, or combination thereof. Table 1

[0156] It is to be understood that in any of the preceding embodiments, the compound may be in a non-salt form, or in the form of a pharmaceutically acceptable salt, an isotopic variant, or any chemically permissible combination thereof. For example, in some embodiments, the compound is in a non-salt form. In other embodiments, the compound is in the form of a pharmaceutically acceptable salt. In certain other embodiments, the compound is in the form of an isotopic variant. In certain other embodiments, the compound is in a non-salt form or in the form of an isotopic variant. In some embodiments, the compound is in a non-salt form or in theform of a pharmaceutically acceptable salt. In some embodiments, the compound is in the form of a pharmaceutically acceptable salt and an isotopic variant. Alternative Embodiments

[0157] In some embodiments, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,11C,13C, or14C; oxygen may be, for example18O; nitrogen may be,for example 15N, and the like. In other embodiments, a particular isotope (e.g., 2H, 13C, 14C, 18O,or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.

[0158] In certain embodiments, compounds described herein have one or more hydrogen atoms independently replaced by deuterium or tritium. In some embodiments, compounds described herein have one or more hydrogen atoms replaced by deuterium. In some embodiments, compounds described herein have one or more hydrogen atoms replaced by tritium. Pharmaceutical Compositions

[0159] In another aspect, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound described herein (e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof).

[0160] When employed as pharmaceuticals, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

[0161] When used to prevent the onset of a disease, condition or disorder, the compounds provided herein are administered to a subject at risk for developing the disease, condition or disorder, typically on the advice and under the supervision of a physician, and at the dosages described herein. Subjects at risk for developing a particular condition include, but are not limited to, those having a family history of the condition, or those who have been identified by a screening or evaluation method to be particularly susceptible to developing the condition.

[0162] The pharmaceutical compositions provided herein may also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or indefinitely (e.g., for the rest of the subject’s life).

[0163] In some embodiments, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, oral or topical carrier.

[0164] The present disclosure also relates to a compound described herein (e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition thereof) for use as a pharmaceutical or a medicament.

[0165] In some embodiments, the compound or pharmaceutically acceptable salt thereof of the present disclosure is provided in an effective amount in the pharmaceutical composition. In some embodiments, the compound or pharmaceutically acceptable salt thereof of the present disclosure is provided in a therapeutically effective amount. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof.

[0166] 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 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.

[0167] The pharmaceutical compositions provided herein can be administered by a variety of routes including oral, parenteral, rectal, transdermal, intradermal, intrathecal, subcutaneous, intravenous, intramuscular, and intranasal.

[0168] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions, 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 1to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0169] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms (e.g., pills, tablets, capsules) may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel®, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0170] 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 weight with the remainder being the injectable carrier and the like.

[0171] 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 formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well- known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0172] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0173] The present disclosure also provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, e.g., a composition suitable for injection, such as for intravenous (IV) administration, or for oral administration.

[0174] Pharmaceutically acceptable carriers include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection, oral, etc. General considerations in the formulation and / or manufacture of pharmaceutical compositionsagents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, Ε. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0175] The above-described components for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, and Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, each of which is incorporated herein by reference.

[0176] 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.

[0177] The present disclosure also relates to the pharmaceutically acceptable formulations of a compound described herein (e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I- B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof). In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ- cyclodextrins consisting of 6, 7, and 8 ^-l ,4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S.5,376,645. In certain embodiments, the formulation comprises hexapropyl-^-cyclodextrin. In a more particular embodiment, the formulation comprises hexapropyl-^-cyclodextrin (10-50% in water).

[0178] The present disclosure also relates to the pharmaceutically acceptable acid addition salt of a compound described herein (e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I- A), (I-B), and (I-C)). The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0179] For the prevention and / or treatment of long-term conditions the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oraldoses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg / kg, from about 0.1 to about 10 mg / kg, or from about 1 to about 5 mg / kg of the compound provided herein.

[0180] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0181] When used to prevent the onset of a condition, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0182] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the subject, the disease or disorder to be treated and the particular mode of administration. As the skilled artisan will appreciate, specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease or disorder, the patient’s disposition to the disease or disorder and the judgment of the treating physician.

[0183] The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration. Methods of Treatment and Use

[0184] Compounds of the present disclosure (e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), as described herein, are generally designed to be allosteric modulators of NMDA receptor function, and therefore are useful for the treatment and prevention of, e.g., CNS-related conditions in a subject. In some embodiments, the compound is an allosteric modulator of GluN1 / 2A-containing NMDA receptors. In some embodiments, the compound is an allosteric modulator of GluN1 / 2B-containing NMDA receptors. In some embodiments, the compound is an allosteric modulator of GluN1 / 2C-containing NMDA receptors. In someembodiments, the compound is an allosteric modulator of GluN1 / 2D-containing NMDA receptors.

[0185] In some embodiments, the compounds described herein (e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), as described herein, are generally designed to penetrate the blood brain barrier (e.g., designed to be transported across the blood brain barrier).

[0186] In certain embodiments, the compound of the present disclosure, e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, is a negative allosteric modulator (NAM) of an NMDA receptor and inhibits NMDA receptor function. In some embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors. In some embodiments, the compound is a NAM of GluN1 / 2B-containing NMDA receptors. In some embodiments, the compound is a NAM of GluN1 / 2C-containing NMDA receptors. In some embodiments, the compound is a NAM of GluN1 / 2D-containing NMDA receptors.

[0187] In certain embodiments, the compound of the present disclosure, e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), 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 is a PAM of GluN1 / 2A-containing NMDA receptors. In some embodiments, the compound is a PAM of GluN1 / 2B-containing NMDA receptors. In some embodiments, the compound is a PAM of GluN1 / 2C-containing NMDA receptors. In some embodiments, the compound is a PAM of GluN1 / 2D-containing NMDA receptors.

[0188] In certain embodiments, the compound of the present disclosure, e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, is a neutral allosteric ligand (NALs) of NMDA receptors, which binds at allosteric sites and block the effects of a PAM and / or NAM of an NMDA receptor. In some embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors. In some embodiments, the compound is a NAL of GluN1 / 2B-containing NMDA receptors. In some embodiments, the compound is a NAL of GluN1 / 2C-containing NMDA receptors. In some embodiments, the compound is a NAL of GluN1 / 2D-containing NMDA receptors.

[0189] As will be appreciated by one of ordinary skill in the art, a given compound’s activity at an NMDA receptors may depend on the particular subunits that constitute it. For example, a compound may be a PAM of GluN1 / 2A-containing NMDA receptors and a NAM or NAL ofGluN1 / 2B-containing NMDA receptors. All such combinations of activities (e.g., PAM, NAM, and NAL) at the various subunit combinations that constitute NMDA receptors (e.g., GluN1 / 2A, GluN1 / 2B, GluN1 / 2C, and GluN1 / 2D) are contemplated herein.

[0190] In certain embodiments, the compound of the present disclosure, e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, is a NAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0191] In certain embodiments, the compound of the present disclosure, e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, is a PAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0192] In certain embodiments, the compound of the present disclosure, e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, is a NAL of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0193] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0194] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0195] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0196] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0197] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0198] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0199] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0200] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0201] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0202] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0203] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0204] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0205] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0206] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0207] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0208] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0209] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0210] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0211] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0212] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0213] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0214] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0215] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0216] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0217] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0218] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0219] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0220] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0221] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0222] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0223] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0224] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0225] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0226] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0227] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0228] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0229] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0230] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0231] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0232] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0233] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0234] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0235] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0236] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0237] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0238] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0239] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0240] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0241] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0242] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0243] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0244] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0245] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0246] In certain embodiments, the compound is a NAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0247] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0248] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0249] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0250] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0251] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0252] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0253] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0254] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0255] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0256] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0257] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0258] In certain embodiments, the compound is a PAM of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0259] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0260] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0261] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0262] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAL of GluN1 / 2D-containing NMDA receptors.

[0263] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAL of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0264] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAL of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0265] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0266] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0267] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0268] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a PAM of GluN1 / 2D-containing NMDA receptors.

[0269] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a NAM of GluN1 / 2B-containing NMDA receptors, a PAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0270] In certain embodiments, the compound is a NAL of GluN1 / 2A-containing NMDA receptors, a PAM of GluN1 / 2B-containing NMDA receptors, a NAM of GluN1 / 2C-containing NMDA receptors, and a NAM of GluN1 / 2D-containing NMDA receptors.

[0271] In one embodiment, the compounds disclosed herein have a modulatory effect at micromolar concentrations (e.g., about 0.1 µM, about 0.5 µM, about 1 µM, about 10 µM, about 50 µM, about 100 µM, about 250 µM, about 500 µM, about 750 µM, about 1000µM) at recombinant human GluN1 / GluN2A, GluN1 / GluN2B, GluN1 / GluN2C and GluN1 / GluN2D receptor subtypes of greater than about 50% (e.g., greater than about 50% to about 500%, greater than about 50% to about 450%, greater than about 50% to about 400%, greater than about 50% to about 350%, or greater than about 50% to about 300%, greater than about 50% to about 250%, greater than about 50% to about 200%, greater than about 50% to about 150%, greater than about 50% to about 100%), greater than 60% (e.g., greater than about 60% to about 500%, greater than about 60% to about 450%, greater than about 60% to about 400%, greater than about 60% to about 350%, or greater than about 60% to about 300%, greater than about 60% to about 250%, greater than about 60% to about 200%, greater than about 60% to about 150%, greater than about 60% to about 100%), greater than 70% (e.g., greater than about 70% to about 500%, greater thanabout 70% to about 450%, greater than about 70% to about 400%, greater than about 70% to about 350%, or greater than about 70% to about 300%, greater than about 70% to about 250%, greater than about 70% to about 200%, greater than about 70% to about 150%, greater than about 70% to about 100%), greater than 80% (e.g., greater than about 80% to about 500%, greater than about 80% to about 450%, greater than about 80% to about 400%, greater than about 80% to about 350%, or greater than about 80% to about 300%, greater than about 80% to about 250%, greater than about 80% to about 200%, greater than about 80% to about 150%, greater than about 80% to about 100%), greater than 90% (e.g., greater than about 90% to about 500%, greater than about 90% to about 450%, greater than about 90% to about 400%, greater than about 90% to about 350%, or greater than about 90% to about 300%, greater than about 90% to about 250%, greater than about 90% to about 200%, greater than about 90% to about 150%, greater than about 90% to about 100%), greater than 100% (e.g., greater than about 50% to about 500%, greater than about 100% to about 450%, greater than about 100% to about 400%, greater than about 100% to about 350%, or greater than about 100% to about 300%, greater than about 100% to about 250%, greater than about 100% to about 200%, greater than about 100% to about 150%), greater than 150% (e.g., greater than about 150% to about 500%, greater than about 150% to about 450%, greater than about 150% to about 400%, greater than about 150% to about 350%, or greater than about 150% to about 300%, greater than about 150% to about 250%, greater than about 150% to about 200%), greater than 200%(e.g., greater than about 200% to about 500%, greater than about 200% to about 450%, greater than about 200% to about 400%, greater than about 200% to about 350%, or greater than about 200% to about 300%, greater than about 200% to about 250%), greater than 250% (e.g., greater than about 250% to about 500%, greater than about 250% to about 450%, greater than about 250% to about 400%, greater than about 250% to about 350%, or greater than about 250% to about 300%), greater than 300% (e.g., greater than about 300% to about 500%, greater than about 300% to about 450%, greater than about 300% to about 400%, greater than about 300% to about 350%), greater than 350% (e.g., greater than about 350% to about 500%, greater than about 350% to about 450%, greater than about 350% to about 400%), greater than 400% (greater than about 400% to about 500%, greater than about 450% to about 450%), greater than 450% (e.g., greater than about 450% to about 500%). In one embodiment, the compounds disclosed herein have a modulatory effect at micromolar concentrations (e.g., about 0.1 µM, about 0.5 µM, about 1 µM, about 10 µM, about 50 µM, about 100 µM, about 250 µM, about 500 µM, about 750 µM, about 1000µM) at recombinant human GluN1 / GluN2A, GluN1 / GluN2B, GluN1 / GluN2C and GluN1 / GluN2D receptor subtypes of up to about 1%, up to about 5%, up to about 10%, up to about 20%; up to about 30%, up toabout 40%, up to about 50%, up to about 60%; up to about 70%, up to about 80%, up to about 90%, or up to about 100%.

[0272] In one embodiment, the compounds disclosed herein have a modulatory effect at micromolar concentrations (e.g., about 0.1 µM, about 0.5 µM, about 1 µM, about 10 µM, about 50 µM, about 100 µM, about 250 µM, about 500 µM, about 750 µM, about 1000µM)at recombinant human GluN1 / GluN2A, GluN1 / GluN2B, GluN1 / GluN2C and GluN1 / GluN2D receptor subtypes of greater than 50% (e.g., greater than 50% to 500%, greater than 50% to 450%, greater than 50% to 400%, greater than 50% to 350%, or greater than 50% to 300%, greater than 50% to 250%, greater than 50% to 200%, greater than 50% to 150%, greater than 50% to 100%), greater than 60% (e.g., greater than 60% to 500%, greater than 60% to 450%, greater than 60% to 400%, greater than 60% to 350%, or greater than 60% to 300%, greater than 60% to 250%, greater than 60% to 200%, greater than 60% to 150%, greater than 60% to 100%), greater than 70% (e.g., greater than 70% to 500%, greater than 70% to 450%, greater than 70% to 400%, greater than 70% to 350%, or greater than 70% to 300%, greater than 70% to 250%, greater than 70% to 200%, greater than 70% to 150%, greater than 70% to 100%), greater than 80% (e.g., greater than 80% to 500%, greater than 80% to 450%, greater than 80% to 400%, greater than 80% to 350%, or greater than 80% to 300%, greater than 80% to 250%, greater than 80% to 200%, greater than 80% to 150%, greater than 80% to 100%), greater than 90% (e.g., greater than 90% to 500%, greater than 90% to 450%, greater than 90% to 400%, greater than 90% to 350%, or greater than 90% to 300%, greater than 90% to 250%, greater than 90% to 200%, greater than 90% to 150%, greater than 90% to 100%), greater than 100% (e.g., greater than 50% to 500%, greater than 100% to 450%, greater than 100% to 400%, greater than 100% to 350%, or greater than 100% to 300%, greater than 100% to 250%, greater than 100% to 200%, greater than 100% to 150%), greater than 150% (e.g., greater than 150% to 500%, greater than 150% to 450%, greater than 150% to 400%, greater than 150% to 350%, or greater than 150% to 300%, greater than 150% to 250%, greater than 150% to 200%), greater than 200% (e.g., greater than 200% to 500%, greater than 200% to 450%, greater than 200% to 400%, greater than 200% to 350%, or greater than 200% to 300%, greater than 200% to 250%), greater than 250% (e.g., greater than 250% to 500%, greater than 250% to 450%, greater than 250% to 400%, greater than 250% to 350%, or greater than 250% to 300%), greater than 300% (e.g., greater than 300% to 500%, greater than 300% to 450%, greater than 300% to 400%, greater than 300% to 350%), greater than 350% (e.g., greater than 350% to 500%, greater than 350% to 450%, greater than 350% to 400%), greater than 400% (greater than 400% to 500%, greater than 450% to 450%), greater than 450% (e.g., greater than 450% to 500%). In one embodiment, thecompounds disclosed herein have a modulatory effect at micromolar concentrations (e.g., about 0.1 µM, about 0.5 µM, about 1 µM, about 10 µM, about 50 µM, about 100 µM, about 250 µM, about 500 µM, about 750 µM, about 1000µM) at recombinant human GluN1 / GluN2A, GluN1 / GluN2B, GluN1 / GluN2C and GluN1 / GluN2D receptor subtypes of up to 1%, up to 5%, up to 10%, up to 20%, up to 30%, up to 40%, up to 50%, up to 60%, up to 70%, up to 80%, up to 90%, or up to 100%.

[0273] In one aspect, the disclosure provides a method for effecting allosteric modulation of an NMDA receptor in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. In some embodiments, the method is for effecting positive allosteric modulation of an NMDA receptor in a subject. In some embodiments, the method is for effecting negative allosteric modulation of an NMDA receptor in a subject. In some embodiments, the method comprises binding an NMDA receptor at an allosteric site with a compound disclosed herein and blocking the effects of an allosteric NMDA receptor modulator (i.e., PAM and / or NAM) in a subject.

[0274] In one aspect, the disclosure provides a method for treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. In some embodiments, treating the disease, disorder, or condition requires positive allosteric NMDA receptor modulation in a subject. In some embodiments, treating the disease, disorder, or condition requires negative allosteric NMDA receptor modulation in a subject. In some embodiments, treating the disease, disorder, or condition requires a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor in a subject.

[0275] In one aspect, the disclosure provides a method for treating a CNS-related condition in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. In some embodiments, treating the CNS-related condition requires positive allosteric NMDA receptor modulation in a subject. In some embodiments, treating the CNS-related condition requires negative allosteric NMDA receptor modulation in a subject. In some embodiments, treating the CNS-related condition requires a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor in a subject.

[0276] In one aspect, the disclosure provides a method for preventing a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. In some embodiments, preventing the disease, disorder, or condition requires positive allosteric NMDA receptor modulation in a subject. In some embodiments, preventing the disease, disorder, or condition requires negative allosteric NMDA receptor modulation in a subject. In some embodiments, preventing the disease, disorder, or condition requires a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor in a subject.

[0277] In one aspect, the disclosure provides a method for preventing a CNS-related condition in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. In some embodiments, preventing the CNS-related condition requires positive allosteric NMDA receptor modulation in a subject. In some embodiments, preventing the CNS-related condition requires negative allosteric NMDA receptor modulation in a subject. In some embodiments, preventing the CNS-related condition requires a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor in a subject.

[0278] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in effecting allosteric modulation of an NMDA receptor in a subject. In some embodiments, the compound, pharmaceutically acceptable salt, isotopic variant, combination, or pharmaceutical composition is for use in effecting positive allosteric modulation of an NMDA receptor in a subject. In some embodiments, the compound, pharmaceutically acceptable salt, isotopic variant, combination, or pharmaceutical composition is for use in effecting negative allosteric modulation of an NMDA receptor in a subject. In some embodiments, the compound, pharmaceutically acceptable salt, isotopic variant, combination, or pharmaceutical composition is for use in blocking the effects of a PAM or NAM of an NMDA receptor.

[0279] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed hereinfor use in treating the disease, disorder or condition is a positive allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating the disease, disorder or condition is a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating the disease, disorder or condition is a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0280] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a CNS-related condition in a subject. In some embodiments, the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a CNS-related condition in a subject is a positive allosteric NMDA receptor modulator. In some embodiments, the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a CNS-related condition in a subject is a negative allosteric NMDA receptor modulator. In some embodiments, the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein is for use in treating a CNS-related condition in a subject a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0281] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject. In some embodiments the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing the disease, disorder or condition is a positive allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing the disease, disorder or condition is a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing the disease, disorder or condition is a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0282] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a CNS-related condition in a subject. In some embodiments, the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a CNS-related condition in a subject is a positive allosteric NMDA receptor modulator. In some embodiments, the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a CNS-related condition in a subject is a negative allosteric NMDA receptor modulator. In some embodiments, the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein is for use in preventing a CNS-related condition in a subject a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0283] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for effecting allosteric modulation of an NMDA receptor in a subject. In some embodiments, the medicament is for effecting positive allosteric modulation of an NMDA receptor in a subject. In some embodiments, the medicament is for effecting negative allosteric modulation of an NMDA receptor in a subject. In some embodiments, the medicament is for blocking the effects of a PAM or NAM of an NMDA receptor.

[0284] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation in a subject. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for treating the disease, disorder or condition is a positive allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for treating the disease, disorder or condition is a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for treating the disease, disorder or condition is a neutralallosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0285] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for treating a CNS-related condition in a subject. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for treating the CNS-related condition is a positive allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for treating the CNS-related condition is a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for treating the CNS- related condition is a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0286] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for preventing a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for preventing the disease, disorder or condition is a positive allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for preventing the disease, disorder or condition is a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for preventing the disease, disorder or condition is a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0287] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for preventing a CNS-related condition in asubject. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for preventing the CNS-related condition is a positive allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for preventing the CNS-related condition is a negative allosteric NMDA receptor modulator. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein used in the manufacture of a medicament for preventing the CNS-related condition is a neutral allosteric ligand (NAL) of an NMDA receptor which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor.

[0288] Exemplary diseases, disorders, and conditions requiring allosteric NMDA receptor modulation include, but are not limited to, Smith-Lemli-Opitz Syndrome (SLOS), desmosterolosis, sitosterolemia, cerebrotendinous xanthomatosis (CTX), Mevalonate Kinase Deficiency (MKD), SC4MOL gene mutation (SMO Deficiency), Niemann-Pick disease, autism spectrum disorders (ASD), and disorders associated with phenylketonuria.

[0289] Exemplary CNS-related conditions requiring allosteric modulation of an NMDA receptor include, but are not limited to, an adjustment disorder, stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive- compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post- partum psychosis), a sleep disorder (including insomnia), a substance-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder, a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensoryhypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), epilepsies related to mTor, melanoma, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

[0290] Exemplary CNS-related conditions requiring positive allosteric modulation of an NMDA receptor include, but are not limited to, an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer’s disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or another psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (including acute and chronic pain), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), a seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease), stroke, traumatic brain injury, a movement disorder (including Huntington’s disease and Parkinson’s disease), GRIN disorders, 22q11.2 deletion syndrome, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), and tinnitus.

[0291] Exemplary CNS-related conditions requiring negative allosteric modulation of an NMDA receptor include, but are not limited to, an adjustment disorder, a stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (includingobsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), melanoma, neuropsychiatric lupus, hepatic encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa- induced dyskinesia (LID), and tinnitus.

[0292] Exemplary CNS-related conditions requiring a neutral allosteric ligand (NAL) of an NMDA receptor, which binds at an allosteric site and blocks the effects of a PAM or NAM of an NMDA receptor include, but are not limited to, an autism spectrum disorder (ASD), Tuberous Sclerosis Complex (TSC), multiple sclerosis (MS), Alzheimer’s disease (AD), and Niemann- Pick type C (NPC).

[0293] In some embodiments, the CNS-related condition is a mood disorder selected from depression, post-partum depression, bipolar disorder, dysthymic disorder, and suicidality. In some embodiments, the CNS-related condition is a mood disorder selected from clinical depression, post-partum depression, atypical depression, melancholic depression, psychoticmajor depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, and suicidal behavior.

[0294] In some embodiments, the CNS-related condition is selected from a seizure, status epilepticus, Dravet’s disease, or Tuberous Sclerosis Complex. In some embodiments, the CNS- related condition is a seizure selected from a grand-mal seizure, an absence seizure, a myoclonic seizure, a clonic seizure, a tonic seizure, and an atonic seizure.

[0295] In some embodiments, the CNS-related condition is a movement disorder selected from Parkinson’s disease, Parkinsonism, dystonia, chorea, Huntington’s disease, ataxia, levodopa- induced dyskinesia, tremor, myoclonus and startle, tics and Tourette syndrome, restless leg syndrome, stiff person syndrome, and gait disorders.

[0296] In some embodiments, the CNS-related condition is a tremor selected from a cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, and rubral tremor.

[0297] In some embodiments, the CNS-related condition is Huntington’s disease.

[0298] In some embodiments, the CNS-related condition is Parkinson’s disease.

[0299] In some embodiments, the CNS is neuropsychiatric lupus.

[0300] In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the present disclosure, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition disclosed herein.

[0301] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability.

[0302] In one aspect, the disclosure provides a method for reversing the anesthetic, dissociative, sedative, or cognitive-impairing effects of ketamine or a ketamine analog, comprising administering to a subject a compound of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0303] In one aspect, the disclosure provides a method of reversing ketamine or ketamine analog induced sedation or anesthesia, comprising administering to a subject a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0304] In one aspect, the disclosure provides a method of reversing ketamine or ketamine analog induced dissociative or cognitive-impairing effects, comprising administering to a subject a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0305] In one aspect, the disclosure provides a method of reducing the recovery period for ketamine or ketamine analog induced sedation or anesthesia, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0306] In one aspect, the disclosure provides a method of reducing the duration of ketamine- induced sedation or anesthesia in a subject, comprising administering to said subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0307] In one aspect, the disclosure provides a method for reducing an adverse effect caused by ketamine or a ketamine analog, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0308] In one aspect, the disclosure provides a method for reducing Emergence Phenomena (EP) associated with ketamine or ketamine analog induced sedation or anesthesia, comprising administering to a subject a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0309] In one aspect, the disclosure provides of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein for use in reversing the anesthetic, dissociative, sedative, or cognitive-impairing effects of ketamine or a ketamine analog.

[0310] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, for use in reversing ketamine or ketamine analog induced sedation or anesthesia in a subject.

[0311] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein,for use in reversing ketamine or ketamine analog induced dissociative or cognitive-impairing effects in a subject.

[0312] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, for use in reducing the recovery period from ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0313] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, for use in reducing the duration of ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0314] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, for use in reducing an adverse effect caused by ketamine or a ketamine analog in a subject.

[0315] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, for use in reducing Emergence Phenomena (EP) associated with ketamine or ketamine analog induced sedation or anesthesia in a subject.

[0316] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, in the manufacture of a medicament for reversing the anesthetic, dissociative, sedative, or cognitive-impairing effects of ketamine or a ketamine analog in a subject.

[0317] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, in the manufacture of a medicament for reversing ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0318] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, in the manufacture of a medicament for reversing ketamine or ketamine analog induced dissociative or cognitive-impairing effects in a subject.

[0319] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, in the manufacture of a medicament for reducing the recovery period for ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0320] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, in the manufacture of a medicament for reducing the duration of ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0321] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, in the manufacture of a medicament for reducing an adverse effect caused by ketamine or a ketamine analog in a subject.

[0322] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein, in the manufacture of a medicament for reducing Emergence Phenomena (EP) associated with ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0323] In some embodiments, the Emergence Phenomena is characterized by vivid dreams, illusions, floating sensation with image distortion, euphoria, fearfulness, hallucinations, confusion, excitement, and irrational behavior or a combination thereof. In some embodiments, the Emergence Phenomena is characterized by vivid dreams. In some embodiments, the Emergence Phenomena is characterized by illusions. In some embodiments, the Emergence Phenomena is characterized by floating sensation with image distortion. In some embodiments, the Emergence Phenomena is characterized by euphoria. In some embodiments, the Emergence Phenomena is characterized by fearfulness. In some embodiments, the Emergence Phenomena is characterized by hallucinations. In some embodiments, the Emergence Phenomena is characterized by confusion. In some embodiments, the Emergence Phenomena is characterized by excitement. In some embodiments, the Emergence Phenomena is characterized by irrational behavior.

[0324] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein in the manufacture of a medicament for treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability.

[0325] In yet another aspect, the present disclosure provides a combination of a compound of the present disclosure, e.g., a compound of Formula (A), (A-I), (A-2), (A-3), (I), (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents.Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration. Movement Disorders

[0326] Also described herein are methods for treating a movement disorder. As used herein, “movement disorders” refers to a variety of diseases and disorders that are associated with hyperkinetic movement disorders and related abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson’s disease and Parkinsonism (defined particularly by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.

[0327] Tremor is an involuntary, at times rhythmic, muscle contraction and relaxation that can involve oscillations or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk, legs). Tremor includes hereditary, degenerative, and idiopathic disorders such as Wilson’s disease, Parkinson’s disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid-, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese, arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiologic tremor, enhanced physiologic tremor, essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes’ tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor. 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.

[0328] 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).

[0329] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and / or painful and abnormal postures or positions. Dystonic tremors may affect any muscle in the body. Dystonic tremors occur irregularly and often can be relieved by complete rest.

[0330] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor may be mild and nonprogressive in some, and may be slowly progressive, starting on one side of the body but affect both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. Tremor frequency may decrease as the person ages, but severity may increase. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and / or increase their severity. Symptoms generally evolve over time and can be both visible and persistent following onset.

[0331] 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.

[0332] Parkinsonian tremor is caused by damage to structures within the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson’s disease and is typically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk. Onset of parkinsonian tremor typically begins after age 60. Movement starts in one limb or on one side of the body and can progress to include the other side.

[0333] Physiological tremor can occur in normal individuals and have no clinical significance. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. The tremor classically has a frequency of about 10 Hz.

[0334] 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.

[0335] Rubral tremor is characterized by coarse slow tremor which can be present at rest, at posture, and with intention. The tremor is associated with conditions that affect the red nucleus in the midbrain, classical unusual strokes.

[0336] Parkinson’s disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms found in Parkinson’s disease, but is a symptom complex rather than a progressive neurodegenerative disease.

[0337] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures. Dystonic movementscan be patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.

[0338] Chorea is a neurological disorder characterized by jerky involuntary movements typically affecting the shoulders, hips, and face.

[0339] Huntington’s Disease is an inherited disease that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington’s disease can hinder walk, talk, and swallowing.

[0340] Ataxia refers to the loss of full control of bodily movements, and may affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0341] Myoclonus and Startle is a response to a sudden and unexpected stimulus, which can be acoustic, tactile, visual, or vestibular.

[0342] Tics are an involuntary movement usually onset suddenly, brief, repetitive, but non- rhythmical, typically imitating normal behavior and often occurring out of a background of normal activity. Tics can be classified as motor or vocal, motor tics associated with movements while vocal tics associated with sound. Tics can be characterized as simple or complex. For example, simple motor tics involve only a few muscles restricted to a specific body part.

[0343] Tourette Syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic.

[0344] Restless Legs Syndrome is a neurologic sensorimotor disorder characterized by an overwhelming urge to move the legs when at rest.

[0345] Stiff Person Syndrome is a progressive movement disorder characterized by involuntary painful spasms and rigidity of muscles, usually involving the lower back and legs. Stiff-legged gait with exaggerated lumbar hyperlordosis typically results. Characteristic abnormality on EMG recordings with continuous motor unit activity of the paraspinal axial muscles is typically observed. Variants include “stiff-limb syndrome” producing focal stiffness typically affecting distal legs and feet.

[0346] Gait disorders refer to an abnormality in the manner or style of walking, which results from neuromuscular, arthritic, or other body changes. Gait is classified according to the system responsible for abnormal locomotion, and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait. Mood disorders

[0347] Also provided herein are methods for treating a mood disorder, for example clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cationic depression, seasonalaffective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior.

[0348] Clinical depression is also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental disorder characterized by pervasive and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression have trouble sleeping, lose weight, and generally feel agitated and irritable. Clinical depression affects how an individual feels, thinks, and behaves and may lead to a variety of emotional and physical problems. Individuals with clinical depression may have trouble doing day-to-day activities and make an individual feel as if life is not worth living.

[0349] Postnatal depression (PND) is also referred to as postpartum depression (PPD), and refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleeping and eating habits, reduced sexual desire, crying episodes, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e.g., a refractory depression as described herein).

[0350] In some embodiments, a subject having PND also experienced depression, or a symptom of depression during pregnancy. This depression is referred to herein as) perinatal depression. In an embodiment, a subject experiencing perinatal depression is at increased risk of experiencing PND.

[0351] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain or increased appetite. Patients suffering from AD also may have excessive sleep or somnolence (hypersomnia), a sensation of limb heaviness, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.

[0352] 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.

[0353] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, in particular of melancholic nature, where the individual experiences psychotic symptoms such as delusions and hallucinations.

[0354] 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.

[0355] 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.

[0356] 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).

[0357] Double depression refers to fairly depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major depression.

[0358] Depressive Personality Disorder (DPD) refers to a personality disorder with depressive features.

[0359] 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.

[0360] Minor depressive disorder or minor depression refers to a depression in which at least 2 symptoms are present for 2 weeks.

[0361] Bipolar disorder or manic depressive disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During periods of mania the individual may feel or act abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the consequences. The need for sleep is usually reduced. During periods of depression there may be crying, poor eye contact with others, and a negative outlook on life. The risk of suicide among those with the disorder is high at greater than 6% over 20 years, while self-harm occurs in 30-40%. Other mental health issues such as anxiety disorder and substance use disorder are commonly associated with bipolar disorder.

[0362] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress.

[0363] 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 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).

[0364] Suicidality, suicidal ideation, suicidal behavior refers to the tendency of an individual to commit suicide. Suicidal ideation concerns thoughts about or an unusual preoccupation with suicide. The range of suicidal ideation varies greatly from e.g., fleeting thoughts to extensive thoughts, detailed planning, role playing, incomplete attempts. Symptoms include talking about suicide, getting the means to commit suicide, withdrawing from social contact, being preoccupied with death, feeling trapped or hopeless about a situation, increasing use of alcohol or drugs, doing risky or self-destructive things, saying goodbye to people as if they won’t be seen again.

[0365] Symptoms of depression include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, sleeplessness, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, absence of positive thoughts or plans, excessive sleeping, overeating, appetite loss, insomnia, self-harm, thoughts of suicide, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary on a case to case basis. Symptoms of depression, and relief of the same, may be ascertained by a physician or psychologist (e.g., by a mental state examination). Anxiety Disorders

[0366] Provided herein are methods for treating anxiety disorders. Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0367] Generalized anxiety disorder is a common chronic disorder characterized by long- lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.

[0368] In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks’ potential implications, persistent fear offuture attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e., extreme hypochondriasis).

[0369] Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.

[0370] 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.

[0371] Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression. Epilepsy

[0372] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood. Epileptogenesis

[0373] Epileptogenesis is a gradual process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptogenesis results from neuronal damage precipitated by the initial insult (e.g., status epilepticus). Status epilepticus (SE)

[0374] Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.

[0375] Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non- convulsive status epilepticus, or typical absence non-convulsive status epilepticus. Seizure

[0376] A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person’s body shakes rapidly and uncontrollably. During convulsions, the person’s muscles contract and relax repeatedly.

[0377] 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.

[0378] Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in arelatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

[0379] There are six types of generalized seizures. The most common and dramatic, and therefore the most well-known, is the generalized convulsion, also called the grand-mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the “tonic” phase of the seizure) for 30 to 60 seconds, then by violent jerking (the “clonic” phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the “postictal” or after-seizure phase). During grand- mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.

[0380] Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of “losing time.”

[0381] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.

[0382] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.

[0383] Tonic seizures are characterized by stiffening of the muscles.

[0384] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

[0385] Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizure is a generalized seizure associated with Dravet Syndrome, Lennox- Gastaut Syndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 Female Pediatric Epilepsy.Enumerated Embodiments

[0386] The disclosure also includes the following embodiments:

[0387] A-1. A compound, wherein the compound has the structure of Formula (I):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:wherein: each of R1aand R1bis independently hydrogen or C1-6alkyl; or R1aand R1b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl; X1is -OROor -SRS, wherein each of ROand RSis independently hydrogen or C1-6alkyl; X2is C6-10aryl or 5-8 membered heteroaryl; and X3is C1-6 alkyl or C1-6 alkoxy; R4is -OH, C1-6alkoxy, -OC(O)(C1-6alkyl), or -O-CH2-(5-8 membered heteroaryl); R5is absent or hydrogen; each of R25aand R25bis independently hydrogen, C1-6 alkyl optionally substituted with 1-5 halogen, or C3-6 carbocyclyl; or R25aand R25b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl; is a single bond or a double bond, wherein when is a single bond, R5is hydrogen, and wherein whenis a double bond, R5is absent.

[0388] A-2. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-1, wherein the compound of Formula (I) is a compound of Formula (I-A):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0389] A-3. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-1, wherein the compound of Formula (I) is apharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0390] A-4. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-1, wherein the compound of Formula (I) is apharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0391] A-5. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-4, wherein R1is

[0392] A-6. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-5, wherein R1is.

[0393] A-7. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-6, wherein X1is -ORO.

[0394] A-8. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-7, wherein X1is -OH.

[0395] A-9. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-6, wherein R1aand R1bare both hydrogen.

[0396] A-10. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-6, wherein each of R1aand R1bis independently C1-6 alkyl.

[0397] A-11. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-10, wherein R1aand R1bare both -CH3.

[0398] A-12. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-10, wherein R1aand R1bare both -CD3.

[0399] A-13. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-6, wherein R1aand R1b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl.

[0400] A-14. The compound according to Embodiment A-13, or pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein R1aand R1b, together with the carbon atom to which they are attached, form a cyclopropyl.

[0401] A-15. The compound according to Embodiment A-5, wherein R1is.

[0402] A-16. The compound according to Embodiment A-15, wherein X2is C6-10aryl.

[0403] A-17. The compound according to Embodiment A-16, wherein X2is phenyl.

[0404] A-18. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-15, wherein X2is 5-8 membered heteroaryl.

[0405] A-19. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-18, wherein X2is pyrazolyl, pyridyl, or isoxazolyl.

[0406] A-20. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-19, wherein X2is 3-pyrazolyl, 5-pyrazolyl, 2-pyridyl, 4-pyridyl, or 5-isoxazolyl.

[0407] A-21. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-4, wherein R4is -OH.

[0408] A-22. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-4, wherein R4is C1-6 alkoxy.

[0409] A-23. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-22, wherein R4is -OCH3.

[0410] A-24. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-4, wherein R4is -OC(O)(C1-6 alkyl).

[0411] A-25. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiments A-24, wherein R4is -OC(O)CH3.

[0412] A-26. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-4, wherein R4is -O-CH2-(5-8 membered heteroaryl).

[0413] A-27. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-26, wherein R4is -O-CH2-(pyridyl).

[0414] A-28. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-4 and A-21 to A-27, wherein R4is in the beta configuration.

[0415] A-29. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-4, wherein each of R25aand R25bis independently C1-6alkyl optionally substituted with 1-5 halogen.

[0416] A-30. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-29, wherein R25aand R25bare both -CH3.

[0417] A-31. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-29, wherein R25aand R25bare both -CD3.

[0418] A-32. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-29, wherein one of R25aand R25bis -CH3and the other is -CF3.

[0419] A-33. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-1, wherein:each of R1aand R1bis independently C1-6 alkyl; X1is -OH; X2is 5-8 membered heteroaryl; R4is -OH; R5is absent; each of R25aand R25bis independently C1-6alkyl; and is a double bond.

[0420] A-34. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment A-1, wherein the compound of Formula (I) is selected from any one of compounds 1-20, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0421] A-35. The compound according to any one of Embodiments A-1 to A-34.

[0422] A-36. The pharmaceutically acceptable salt of a compound according to any one of Embodiments A-1 to A-34.

[0423] A-37. The isotopic variant of a compound according to any one of Embodiments A-1 to A-34.

[0424] A-38. The isotopic variant of a pharmaceutically acceptable salt of a compound according to any one of Embodiments A-1 to A-34.

[0425] A-39. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-38, and a pharmaceutically acceptable carrier.

[0426] A-40. A method for treating a CNS-related condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiment A-1 to A-38, or a pharmaceutical composition according to Embodiment A-39.

[0427] A-41. The method according to Embodiment A-40, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia andschizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post- partum psychosis), a sleep disorder (including insomnia), a substance-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder, a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), epilepsies related to mTor, melanoma, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

[0428] A-42. The method according to Embodiment A-41, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer’s disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or another psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (including acute and chronic pain), sensory hypersensitivity, a metabolic encephalopathy(including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), a seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease), stroke, traumatic brain injury, a movement disorder (including Huntington’s disease and Parkinson’s disease), GRIN disorders, 22q11.2 deletion syndrome, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), and tinnitus.

[0429] A-43. The method according to Embodiment A-41, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, a stress or stress- related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome), pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), melanoma, neuropsychiatric lupus, hepatic encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), and tinnitus.

[0430] A-44. The method according to Embodiment A-41, wherein the CNS-related condition is selected from the group consisting of: an autism spectrum disorder (ASD), Tuberous Sclerosis Complex (TSC), multiple sclerosis (MS), Alzheimer’s disease (AD), and Niemann- Pick type C (NPC).

[0431] A-45. A method for effecting allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-38, or a pharmaceutical composition according to Embodiment A-39.

[0432] A-46. A compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-38, or a pharmaceutical composition according to Embodiment A-39, for use in treating a CNS-related condition in a subject.

[0433] A-47. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to Embodiment A-46, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder, a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepaticencephalopathy and anti-NMDA receptor encephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike- and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), epilepsies related to mTor, melanoma, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

[0434] A-48. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to Embodiment A-47, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer’s disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or another psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (including acute and chronic pain), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), a seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease), stroke, traumatic brain injury, a movement disorder (including Huntington’s disease and Parkinson’s disease), GRIN disorders, 22q11.2 deletion syndrome, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), and tinnitus.

[0435] A-49. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to Embodiment A-47, wherein the CNS-related condition is selected from the group consisting of: an adjustmentdisorder, a stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome), pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), melanoma, neuropsychiatric lupus, hepatic encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa- induced dyskinesia (LID), and tinnitus.

[0436] A-50. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to Embodiment A-47, wherein the CNS-related condition is selected from the group consisting of: an autism spectrum disorder (ASD), Tuberous Sclerosis Complex (TSC), multiple sclerosis (MS), Alzheimer’s disease (AD), and Niemann-Pick type C (NPC).

[0437] A-51. A compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-38, or a pharmaceuticalcomposition according to Embodiment 39, for use in effecting allosteric modulation of an NMDA receptor.

[0438] A-52. Use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-38, or a pharmaceutical composition according to Embodiment A-39, in the manufacture of a medicament for treating a CNS-related condition in a subject.

[0439] A-53. The use according to Embodiment A-52, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post- partum psychosis), a sleep disorder (including insomnia), a substance-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder, a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), epilepsies related to mTor, melanoma,postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

[0440] A-54. The use according to Embodiment A-53, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer’s disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or another psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (including acute and chronic pain), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), a seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease), stroke, traumatic brain injury, a movement disorder (including Huntington’s disease and Parkinson’s disease), GRIN disorders, 22q11.2 deletion syndrome, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), and tinnitus.

[0441] A-55. The use according to Embodiment A-53, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, a stress or stress- related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins(e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome), pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), melanoma, neuropsychiatric lupus, hepatic encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), and tinnitus.

[0442] A-56. The use according to Embodiment A-53, wherein the CNS-related condition is selected from the group consisting of: an autism spectrum disorder (ASD), Tuberous Sclerosis Complex (TSC), multiple sclerosis (MS), Alzheimer’s disease (AD), and Niemann- Pick type C (NPC).

[0443] A-57. Use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments A-1 to A-38, or a pharmaceutical composition according to Embodiment A-39, in the manufacture of a medicament for effecting allosteric modulation of an NMDA receptor.

[0444] B-1. A compound, wherein the compound has the structure of Formula (A):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R1iswherein: each of R1aand R1bis independently hydrogen or C1-6alkyl; or R1aand R1b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl, or a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6 alkyl X1is halogen, C1-6alkyl optionally substituted with 1-5 halogen, -OROor -SRS, wherein each of ROand RSis independently hydrogen or C1-6 alkyl; X2is C6-10 aryl or 5-8 membered heteroaryl; and X3is C1-6alkyl, C1-6alkoxy or C6-10aryl; n is 0 or 1; R4is -OH, C1-6 alkoxy, -OC(O)(C1-6 alkyl), or -O-CH2-(5-8 membered heteroaryl); R4’is hydrogen or C1-6alkyl; R5is absent or hydrogen; each of R25aand R25bis independently hydrogen, C1-6 alkyl optionally substituted with 1-5 halogen, or C3-6 carbocyclyl; or R25aand R25b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl; R25cis hydrogen, or C1-6 alkyl; and is a single bond or a double bond, wherein when is a single bond, R5is hydrogen, and wherein when is a double bond, R5is absent; and provided that the compound is not.

[0445] B-2. The compound of Embodiment B-1, wherein the compound of Formula (A) is a compound of Formula (I):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:, wherein: each of R1aand R1bis independently hydrogen or C1-6alkyl; or R1aand R1b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl; X1is -OROor -SRS, wherein each of ROand RSis independently hydrogen or C1-6alkyl; X2is C6-10 aryl or 5-8 membered heteroaryl; and X3is C1-6 alkyl or C1-6 alkoxy; R4is -OH, C1-6alkoxy, -OC(O)(C1-6alkyl), or -O-CH2-(5-8 membered heteroaryl); R5is absent or hydrogen; each of R25aand R25bis independently hydrogen, C1-6 alkyl optionally substituted with 1-5 halogen, or C3-6carbocyclyl; or R25aand R25b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl; and is a single bond or a double bond, wherein when is a single bond, R5is hydrogen, and wherein whenis a double bond, R5is absent.

[0446] B-3. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof of Embodiment B-1, wherein: R1aand R1b, together with the carbon atom to which they are attached, form a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6 alkyl; X1is halogen, C1-6alkyl optionally substituted with 1-5 halogen; X3is C6-10aryl; n is 0; R4’is C1-6alkyl; and R25cis C1-6alkyl.

[0447] B-4. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-1, wherein the compound of Formula (A) is a compound of Formula (A-1):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0448] B-5. The compound or according to Embodiment B-2, wherein the compound of Formula (I) is a compound of Formula (I-A):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0449] B-6. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-1, wherein the compound of Formula (A) is apharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0450] B-7. The compound according to Embodiment B-2, wherein the compound of Formula (I) is a compound of Formula (I-B):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0451] B-8. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-1, wherein the compound of Formula (A) is apharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0452] B-9. The compound according to Embodiment B-2, wherein the compound of Formula (I) is a compound of Formula (I-C):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0453] B-10. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B9, wherein R1is

[0454] B-11. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-10, wherein R1is.

[0455] B-12. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-11, wherein X1is -ORO.

[0456] B-13. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-12, wherein X1is -OH.

[0457] B-14. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-10, wherein X1is halogen.

[0458] B-15. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-10, wherein X1is C1-6 alkyl optionally substituted with 1-5 halogen.

[0459] B-16. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-10, wherein X1is -CH3, -CHF2, or -CF3.

[0460] B-17. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-11, wherein R1aand R1bare both hydrogen.

[0461] B-18. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-11, wherein each of R1aand R1bis independently C1-6alkyl.

[0462] B-19. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-18, wherein R1aand R1bare both -CH3.

[0463] B-20. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-18, wherein R1aand R1bare both -CD3.

[0464] B-21. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-11, wherein R1aand R1b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl.

[0465] B-22. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-21, wherein R1aand R1b, together with the carbon atom to which they are attached, form a cyclopropyl.

[0466] B-23. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-21, wherein R1aand R1b, together with the carbon atom to which they are attached, form a cyclobutyl.

[0467] B-24. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-11, wherein R1aand R1b, together with the carbon atom to which they are attached, form a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6alkyl.

[0468] B-25. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-24, wherein R1aand R1b, together with the carbon atom to which they are attached, form a 3-8 membered heterocyclyl comprising at least one O, and optionally substituted with one more substituents independently selected from C1-6 alkyl.

[0469] B-26. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-25, wherein R1aand R1b, together with the carbon atom to which they are attached, form an oxetane or 1,3-dioxane, wherein said oxetane and 1,3-dioxane are optionally substituted with one more substituents independently selected from C1-6 alkyl.

[0470] B-27. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-24 to B-26, wherein the 3-8 membered heterocyclyl, is substituted with one more substituents independently selected from - CH3.

[0471] B-28. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-10, wherein R1is.

[0472] B-29. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-28, wherein X2is C6-10aryl.

[0473] B-30. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-29, wherein X2is phenyl.

[0474] B-31. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-28, wherein X2is 5-8 membered heteroaryl.

[0475] B-32. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-31, wherein X2is pyrazolyl, pyridyl, or isoxazolyl.

[0476] B-33. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-32, wherein X2is 3-pyrazolyl, 5-pyrazolyl, 2-pyridyl, 4-pyridyl, or 5-isoxazolyl.

[0477] B-34. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1to B-9, wherein R1is and n is 0.

[0478] B-35. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-34, wherein X3is C6-10aryl.

[0479] B-36. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-34, wherein X3is phenyl.

[0480] B-37. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-9, wherein R4is -OH.

[0481] B-38. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-9, wherein R4is C1-6 alkoxy.

[0482] B-39. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-38, wherein R4is -OCH3.

[0483] B-40. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-9, wherein R4is -OC(O)(C1-6 alkyl).

[0484] B-41. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-40, wherein R4is -OC(O)CH3.

[0485] B-42. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-9, wherein R4is -O-CH2-(5-8 membered heteroaryl).

[0486] B-43. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-42, wherein R4is -O-CH2-(pyridyl).

[0487] B-44. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-9 and B-37 to B43, wherein R4is in the beta configuration.

[0488] B-45. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1, B-3, B-4, B-6, and B-8, wherein R4’is -H.

[0489] B-46. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1, B-3, B-4, B-6, and B-8, wherein R4’is C1-6 alkyl.

[0490] B-47. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1, B-3, B-4, B-6, and B-8, wherein R4’is -CH3.

[0491] B-48. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-9 and B-45 to B47, wherein R4’is in the beta configuration.

[0492] B-49. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-9, wherein each of R25aand R25bis independently C1-6alkyl optionally substituted with 1-5 halogen.

[0493] B-50. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-49, wherein R25aand R25bare both -CH3.

[0494] B-51. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-49, wherein R25aand R25bare both -CD3.

[0495] B-52. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-49, wherein one of R25aand R25bis -CH3and the other is -CF3.

[0496] B-53. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-1, B-3, B-4, B-6, or B-8, wherein R25cis hydrogen.

[0497] B-54. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-1, B-3, B-4, B-6, or B-8, wherein R25cis C1-6 alkyl.

[0498] B-55. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-1 or B-2, wherein:each of R1aand R1bis independently C1-6alkyl; X1is -OH; X2is 5-8 membered heteroaryl; R4is -OH; R5is absent; each of R25aand R25bis independently C1-6 alkyl; and is a double bond.

[0499] B-56. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-1 or B-2, wherein:each of R1aand R1bis independently C1-6 alkyl; X1is -OH; X2is 5-8 membered heteroaryl; R4is -OH; R5is hydrogen; each of R25aand R25bis independently C1-6alkyl; and is a single bond.

[0500] B-57. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to Embodiment B-1, wherein the compound of Formula (A) is selected from the group consisting of any one of compounds 1 or 3-38, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0501] B-58. The compound according to any one of Embodiments B-1 to B-57.

[0502] B-58-1. The compound according to Embodiment B-1, wherein the compound

[0503] B-58-2. The compound according to Embodiment B-1, wherein the compound

[0504] B-58-3. The compound according to Embodiment B-1, wherein the

[0505] B-58-4. The compound according to Embodiment B-1, wherein the compound

[0506] B-58-5. The compound according to Embodiment B-1, wherein the

[0507] B-58-6. The compound according to Embodiment B-1, wherein the

[0509] B-59-8. The compound according to Embodiment B-1, wherein the

[0511] B-58-10. The compound according to Embodiment B-1, wherein the compound is

[0512] B-58-11. The compound according to Embodiment B-1, wherein the compound is

[0518] B-58-17. The compound according to Embodiment B-1, wherein the compound is

[0523] B-58-22. The compound according to Embodiment B-1, wherein the compound is

[0529] B-58-28. The compound according to Embodiment B-1, wherein the compound is

[0531] B-58-30. The compound according to Embodiment B-1, wherein the compound is

[0533] B-58-32. The compound according to Embodiment B-1, wherein the compound is

[0535] B-58-34. The compound according to Embodiment B-1, wherein the compound is

[0540] B-59. The pharmaceutically acceptable salt of the compound according to any one of Embodiments B1 to B-58.

[0541] B-60. The isotopic variant of the compound according to any one of Embodiments B-1 to B-58.

[0542] B-61. The isotopic variant of the pharmaceutically acceptable salt of a compound according to any one of Embodiments B-1 to B-58.

[0543] B-62. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-61, and a pharmaceutically acceptable carrier.

[0544] B-63. A method for treating a CNS-related condition in a subject in need thereof, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-61, or the pharmaceutical composition according to Embodiment B- 62.

[0545] B-64. The method according to Embodiment B-63, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post- partum psychosis), a sleep disorder (including insomnia), a substance-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder, a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, anepilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), epilepsies related to mTor, melanoma, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

[0546] B-65. The method according to Embodiment B-64, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer’s disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or another psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (including acute and chronic pain), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), a seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease), stroke, traumatic brain injury, a movement disorder (including Huntington’s disease and Parkinson’s disease), GRIN disorders, 22q11.2 deletion syndrome, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), and tinnitus.

[0547] B-66. The method according to Embodiment B-64, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, a stress or stress- related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / oralcohol), a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome), pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), melanoma, neuropsychiatric lupus, hepatic encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), and tinnitus.

[0548] B-67. The method according to Embodiment B-64, wherein the CNS-related condition is selected from the group consisting of an autism spectrum disorder (ASD), Tuberous Sclerosis Complex (TSC), multiple sclerosis (MS), Alzheimer’s disease (AD), and Niemann- Pick type C (NPC).

[0549] B-68. A method for effecting allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-61, or the pharmaceutical composition according to Embodiment B-62.

[0550] B-69. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-61, or the pharmaceutical composition according to Embodiment B-62, for use in treating a CNS-related condition in a subject.

[0551] B-70. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to Embodiment B-69, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), ananxiety disorder (including obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder, a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike- and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), epilepsies related to mTor, melanoma, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

[0552] B-71. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to Embodiment B-70, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer’s disease and other formsof dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or another psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (including acute and chronic pain), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), a seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease), stroke, traumatic brain injury, a movement disorder (including Huntington’s disease and Parkinson’s disease), GRIN disorders, 22q11.2 deletion syndrome, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), and tinnitus.

[0553] B-72. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to Embodiment B-70, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, a stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome), pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders(including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), melanoma, neuropsychiatric lupus, hepatic encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa- induced dyskinesia (LID), and tinnitus.

[0554] B-73. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to Embodiment B-70, wherein the CNS-related condition is selected from the group consisting of: an autism spectrum disorder (ASD), Tuberous Sclerosis Complex (TSC), multiple sclerosis (MS), Alzheimer’s disease (AD), and Niemann-Pick type C (NPC).

[0555] B-74. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiment B-1 to B-61, or the pharmaceutical composition according to Embodiment B-62, for use in effecting allosteric modulation of an NMDA receptor.

[0556] B-75. Use of the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-61, or the pharmaceutical composition according to Embodiment B-62, in the manufacture of a medicament for treating a CNS-related condition in a subject.

[0557] B-76. The use according to Embodiment B-75, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post- partum psychosis), a sleep disorder (including insomnia), a substance-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder,a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), epilepsies related to mTor, melanoma, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

[0558] B-77. The use according to Embodiment B-76, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer’s disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or another psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (including acute and chronic pain), sensory hypersensitivity, a metabolic encephalopathy (including phenylketonuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), a seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease), stroke, traumaticbrain injury, a movement disorder (including Huntington’s disease and Parkinson’s disease), GRIN disorders, 22q11.2 deletion syndrome, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), and tinnitus.

[0559] B-78. The use according to Embodiment B-76, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, a stress or stress- related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder, PTSD, social phobia, social anxiety disorder, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), an eating disorder, a mood disorder (including depression (e.g., postpartum depression) and treatment resistant depression (TRD), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder, a sleep disorder (including insomnia), a substance abuse-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), a personality disorder (including obsessive-compulsive personality disorder (OCD)), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), an addictive disorder, a neurodevelopmental disorder (including Rett syndrome), pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches)), sensory hypersensitivity, seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, 22q11.2 deletion syndrome, a GRIN disorder, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), melanoma, neuropsychiatric lupus, hepatic encephalopathy, epilepsies related to mTor, catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), and tinnitus.

[0560] B-79. The use according to Embodiment B-76, wherein the CNS-related condition is selected from the group consisting of an autism spectrum disorder (ASD), TuberousSclerosis Complex (TSC), multiple sclerosis (MS), Alzheimer’s disease (AD), and Niemann- Pick type C (NPC).

[0561] B-80. Use of the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of Embodiments B-1 to B-61, or the pharmaceutical composition according to Embodiment B-62, in the manufacture of a medicament for effecting allosteric modulation of an NMDA receptor.

[0562] B-81. A method for reversing the anesthetic, dissociative, sedative, or cognitive- impairing effects of ketamine or a ketamine analog, comprising administering to a subject a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62.

[0563] B-82. A method of reversing ketamine or ketamine analog induced sedation or anesthesia, comprising administering to a subject a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62.

[0564] B-83. A method of reducing the recovery period for ketamine or ketamine analog induced sedation or anesthesia, comprising administering to a subject in need thereof a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-61.

[0565] B-84. A method of reducing the duration of ketamine or a ketamine induced sedation or anesthesia in a subject, comprising administering to said subject an effective amount of a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62.

[0566] B-85. A method for reducing an adverse effect caused by ketamine or a ketamine analog, comprising administering to a subject in need thereof a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62.

[0567] B-86. A method for reducing Emergence Phenomena (EP) associated with ketamine or a ketamine analog induced sedation or anesthesia, comprising administering to a subject a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62.

[0568] B-87. The compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, for use in reversing the anesthetic, dissociative, sedative, or cognitive-impairing effects of ketamine or a ketamine analog in a subject.

[0569] B-88. The compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, for use in reversing ketamine or ketamine analog induced sedation or anesthesia in a subject.

[0570] B-89. The compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, for use in reducing the recovery period from ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0571] B-90. The compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, for use in reducing the duration of ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0572] B-91. The compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, for use in reducing an adverse effect caused by ketamine or a ketamine analog in a subject.

[0573] B-92. The compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, for use in reducing Emergence Phenomena (EP) associated with ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0574] B-93. Use of a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, in the manufacture of a medicament for reversing the anesthetic, dissociative, sedative, or cognitive-impairing effects of ketamine or a ketamine analog in a subject.

[0575] B-94. Use of a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, in the manufacture of a medicament for reversing ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0576] B-95. Use of a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, in the manufacture of a medicament for reducing the recovery period from ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0577] B-96. Use of a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, in the manufacture of a medicament for reducing the duration of ketamine or a ketamine analog induced sedation or anesthesia in a subject.

[0578] B-97. Use of a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, in the manufacture of a medicament for reducing an adverse effect caused by ketamine or a ketamine analog in a subject.

[0579] B-98. Use of a compound according to any one of Embodiments B-1 to B-61, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to Embodiment B-62, in the manufacture of a medicament for reducing Emergence Phenomena (EP) associated with ketamine or a ketamine analog induced sedation or anesthesia in a subject. Examples

[0580] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting their scope.

[0581] The absolute configuration of an asymmetric center can be determined using methods known to one skilled in the art. In some embodiments, the absolute configuration of an asymmetric center in a compound can be elucidated from the X-ray single-crystal structure of the compound. In some embodiments, the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding asymmetric center in another compound obtained from the same or similar synthetic methodologies. In some embodiments, the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding asymmetric center in another compound coupledwith a spectroscopic technique, e.g., NMR spectroscopy, e.g., 1H NMR spectroscopy or 19FNMR spectroscopy.Abbreviations

[0582] NH4HCO3: ammonium bicarbonate; NH3·H2O: ammonia-water; H2O: water; MeOH: methanol; HBr: hydrobromic acid; H2SO4: sulfuric acid; Ph3PMeBr: methyltriphenylphosphonium bromide; t-BuOK: potassium tert-butoxide; THF: tetrahydrofuran; Ac2O: acetic anhydride; DMAP: 4-dimethylaminopyridine; DCM: dichloromethane; 9-BBN: 9- borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium; CsF: cesium fluoride; AcCl: acetyl chloride; Pt / C: platinum on carbon; H2: molecular hydrogen; TBS: tert- butyldimethylsilyl; Tf2O: trifluoromethanesulfonic anhydride; DIPEA: N,N- diisopropylethylamine; SeO2: selenium dioxide; MeMgBr: methylmagnesium bromide; CDCl3: deuterated chloroform; EtOAc: ethyl acetate; PE: petroleum ether;Na2SO4: sodium sulfate; N2: molecular nitrogen; NaHCO3: sodium bicarbonate; NH4Cl: ammonium chloride; TBSOTf: tert- butyldimethylsilyl trifluoromethansulfonate; Pd(OH)2 / C: palladium hydroxide on carbon; HF·py: hydrogen fluoride pyridine complex (Olah’s reagent); py: pyridine; MeLi: methyllithium; Et2O: diethyl ether; IPA / i-PrOH: isopropanol; DEA: diethanolamine; BnCl: benzyl chloride; DCE: 1,2- dichloroethane; MeOTf: methyl trifluoromethanesulfonate; lutidine: 2,6-di-tert-butylpyridine; Pd / C: palladium on carbon; TBAF: tetrabutylammonium fluoride; SEM: 2- (trimethylsilyl)ethoxymethyl; SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride; NaOH: sodium hydroxide; NaH: sodium hydride; LAH / LiAlH4: lithium aluminum hydride; Ms2O: methanesulfonic anhydride; AcOH: acetic acid; CD3I: iodomethane-d3; I2: molecular iodine; ACN / MeCN: acetonitrile; KI: potassium iodide; LiOH: lithium hydroxide; CO2: carbon dioxide; EtOH: ethanol; MeNHOMe∙HCl: N,O-dimethylhydroxylamine hydrochloride; HATU: 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; TMSCF3: trifluoromethyltrimethylsilane; 1-Me-Im / NMI: N- methylimidazole; TsCl: 4-toluenesulfonyl chloride; TEA: triethylamine; HCl: hydrochloric acid; DMSO-d6: deuterated dimethylsulfoxide; Ag2O: silver oxide; K2OsO4: potassium osmate; NaIO4: sodium periodate; TsOH: p-toluenesulfonic acid; PPTS: pyridinium para- toluenesulfonate; ZnEt2: diethyl zinc; CH2I2: diiodomethane; NH4HF2: ammonium bifluoride; TMSOTf: trimethylsilyl trifluoromethansulfonate; Na2CO3: sodium carbonate; MgSO4: magnesium sulfate. Materials and Methods

[0583] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unlessotherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0584] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, 5thEdition, John Wiley & Sons, New Jersey, 2014, and references cited therein.

[0585] The compounds provided herein may be isolated and purified by known standardprocedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or SFC. The following schemes are presented with details as to the preparation of representative compounds that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation / purification of the enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

[0586] 1H NMR reported herein (e.g., for the region between δ (ppm) of about 0.5 to about 4 ppm) will be understood to be an exemplary interpretation of the NMR spectrum (e.g., exemplary peak integrations) of a compound. Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19*250 mm; Mobile Phase: acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3·H2O); Flow Rate: 25 mL / min.

[0587] Exemplary general method for analytical HPLC: Column: XBridge C18, 4.6*50mm, 3.5 μm at 45 °C; Mobile Phase: A - water (10 mM NH4HCO3) and B – acetonitrile; Gradient: 5%-95% B in 1.6 or 2 min; Flow Rate: 1.8 or 2 mL / min.

[0588] Exemplary general method for SFC: Column: CHIRALPAK® AD CSP (250 mm * 30 mm, 10 μm); Mobile Phase: A - NH3H2O, B – MeOH; Gradient: 45%; Flow Rate: 60 mL / min.

[0589] Example 1: Synthesis of (3S,4R,8S,9S,10R,13R,14S,17R)-17-((R)-6-hydroxy-6- methylheptan-2-yl)-3-(2-hydroxyethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17- tetradecahydro-1H-cyclopenta[a]phenanthren-4-ol (1)

[0590] Synthesis of B

[0591] A solution of A (20 g, 285 mmol; Oakwood Chemicals) in 40% HBr (150 mL) wasstirred at 110 °C for 2 h. The mixture was cooled in ice water and the precipitated solid wasfiltered and washed with excess water to give B (25 g, 165.6 mmol, 58.1% yield).1H NMR(400 MHz, CDCl3) ^H 9.69 (br. s., 1H), 7.76 (d, J = 14.4 Hz, 1H), 6.54 (d, J = 13.6 Hz, 1H).

[0592] Synthesis of C

[0593] To a suspension of B (8.5 g, 56.3 mmol) in MeOH (15 mL) was added 98% sulfuricacid (2.80 g, 28.1 mmol) and the resulting was stirred at 25 °C for 24 h. The reaction mixture was distilled in vacuo. The distillate was washed with water (20 mL), and the organic layer was separated and dried over anhydrous Na2SO4to give C (7 g, 42.4 mmol, 75.4% yield).1H NMR(400 MHz, CDCl3) ^H 7.61 (d, J = 14.0 Hz, 1H), 6.53 (d, J = 14.0 Hz, 1H), 3.76 (s, 3H).

[0594] Synthesis of E

[0595] To a suspension of Ph3PMeBr (67.5 g, 189 mmol) in anhydrous THF (300 mL) underN2(g) was added t-BuOK (21.2 g, 189 mmol) and the resulting mixture was stirred at 60 °C for 30 min. D (20 g, 63.1 mmol; ASW MedChem, Inc.) 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 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (PE:EtOAc = 15:1) to give E (18 g, 57.2 mmol, 90.9% yield), which was used directly in the next step.

[0596] Synthesis of F

[0597] To a solution of E (18 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 NaHCO3(150 mL) and brine (150 mL), dried over anhydrous Na2SO4, filtered, and the volatiles were removed to give F (20 g, 56.1 mmol, 98.5% yield), which was used directly in the next step.

[0598] Synthesis of G

[0599] To solution of F (30 g, 84.1 mmol) in anhydrous THF (150 mL) under N2 (g) at 30 °Cwas 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 C (15.2 g, 92.5 mmol), CsF (25.5 g, 168 mmol) and Pd(t-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), 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 the volatiles were removed. The residue was triturated from MeOH to give K (20 g, 45.2 mmol, 53.7% yield), which was used directly in the next step.

[0600] Synthesis of H

[0601] To suspension of G (20 g, 45.1 mmol) in anhydrous MeOH (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 MeOH. The residue was diluted with EtOAc (500 mL), washed with aqueous NaHCO3 (500 mL) and brine (300 mL), dried over anhydrous Na2SO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (PE:EtOAc:DCM = 8:1:1) to give H (12 g, 29.9 mmol, 66.6% yield), which was used directly in the next step.

[0602] Synthesis of 1.1

[0603] To a solution of H (12 g, 29.9 mmol) in THF (150 mL) was added 5% Pt / C (2 g) andthe resulting mixture was degassed and purged with H2 (g) three times. The mixture was stirred under a H2 (g) balloon at 25 °C for 4 h. The reaction mixture was filtered through a pad of Celite, and the volatiles were removed to give 1.1 (12 g, 29.8 mmol, 100% yield).1H NMR(400 MHz, CDCl3) ^^ 5.34 (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).

[0604] Synthesis of 1.2A & 1.2B

[0605] A synthesis of 1.1 is provided in US2019 / 359646, the entire disclosure of which isincorporated herein by reference.

[0606] To a solution of 2-((tert-butyldimethylsilyl)oxy)ethyl, trifluoromethanesulfonic anhydride (30.5 g, 99.2 mmol), and DIPEA (16.2 mL, 99.2 mmol) in toluene (100 mL) was added 1.1 (5 g, 12.4 mmol) in toluene (10 mL) and the resulting mixture was stirred at 45 °C for 16 h. The mixture was poured into saturated aqueous NaHCO3(30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, the volatiles were removed, and the resulting residue was purified by silica gel chromatography (0^5% EtOAc in PE) to give a mixture of 1.2A & 1.2B (4.9 g), which was used directly in the next step.

[0607] Synthesis of 1.3

[0608] To a solution of 1.2A & 1.2B (2 g, 3.56 mmol) in dioxane (10 mL) was added SeO2(789 mg, 7.12 mmol) and pyridine (1 ml) under N2 (g) and the resulting mixture was stirred at 100 °C for 2 h. The mixture was poured into H2O (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (0^35% EtOAc in PE) to give 1.3 (210 mg, 0.454 mmol, 12.8% yield).1H NMR (400 MHz, CDCl3) δH5.73 (d, J = 3.6 Hz, 1H), 4.29 (s, 1H), 3.84-3.72 (m, 2H), 3.67 (s,5H), 3.31 (d, J = 11.6 Hz, 1H), 2.39-1.64 (m, 14H), 1.45-1.06 (m, 13H), 1.00-0.79 (m, 6H), 0.67 (s, 3H). LC-ELSD / MS MS ESI calcd. For C28H45O4[M-H2O+H]+445.3, found 445.3.

[0609] Synthesis of 1

[0610] To 1.3 (140 mg, 0.302 mmol) in THF (10 mL) was added MeMgBr (1.00 mL, 3 M inEt2O) dropwise at 25 °C and the resulting mixture was stirred for 1 h under N2 (g). The reaction mixture was poured into 10% aqueous NH4Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the volatiles were removed to give 1 (76.9 mg, 0.166 mmol, 55.3%).1H NMR (400 MHz, CDCl3) δH 5.72 (d, J = 3.6 Hz, 1H), 4.29 (d, J = 2.4 Hz, 1H), 3.83-3.72 (m, 2H), 3.66 (s, 2H), 3.30 (d, J = 11.6 Hz, 1H), 2.19-1.80 (m, 4H), 1.73-1.38 (m, 14H), 1.26-0.84 (m, 22H), 0.68 (s, 3H). LC-ELSD / MS MS ESI calcd. For C29H49O3 [M-H2O+H]+445.3, found 445.3.

[0611] Example 2: Synthesis of (3S,4R,5R,8S,9S,10R,13R,14S,17R)-17-((R)-6-hydroxy-6- methylheptan-2-yl)-3-(2-hydroxyethoxy)-10,13-dimethylhexadecahydro-1H-

[0612] Synthesis of 2.1

[0613] To a solution of 1.3 (331 mg, 0.715 mmol) in DCM (5 mL) was added TBSOTf (0.490 mL, 2.14 mmol) and DIPEA (0.743 mL, 4.28 mmol) at 0 °C, and the resulting mixture was stirred at 25 °C for 1 h. The mixture was poured into H2O (20 mL) and extracted with DCM (3 x20 mL). The combined organic layer was washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (0^10% EtOAc in PE) to give 2.1 (315 mg, 0.456 mmol, 64% yield).1H NMR (400 MHz, CDCl3) δH 5.49 (s, 1H), 4.23-4.17 (m, 1H), 3.77-3.70 (m, 2H), 3.67 (s, 3H), 3.49 (s, 1H), 3.15-3.08 (m, 1H), 2.33-2.21 (m, 2H), 2.08-1.57 (m, 8H), 1.53 (s, 7H), 1.36-1.18 (m, 2H), 1.15 (s, 4H), 1.11 (s, 4H), 0.93 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 5.6 Hz, 20H), 0.67 (s, 3H), 0.06 (s, 9H), 0.00 (s, 3H).

[0614] Synthesis of 2.2

[0615] To a solution of 2.1 (315 mg, 0.456 mmol) in MeOH (4 mL) and THF (4 mL) was added Pd / C (150 mg) at 25 °C and the resulting mixture was stirred under H2 (g) (50 psi) at 50 °C for 16 h. The mixture was filtered through a pad of celite, the volatiles were removed, and the residue was purified by silica gel chromatography (0^25% of EtOAc in PE) to give 2.2 (246 mg, 0.355 mmol, 78%yield).1H NMR (400 MHz, CDCl3) δH3.82 (s, 1H), 3.76-3.68 (m, 2H), 3.66 (s, 3H), 3.65-3.57 (m, 1H), 3.55-3.44 (m, 1H), 3.17-3.06 (m, 1H), 2.41-2.13 (m, 2H), 2.07- 1.88 (m, 2H), 1.85-1.63 (m, 7H), 1.57 (m, 11H), 1.51 (s, 10H), 1.14-1.03 (m, 4H), 1.02-0.91 (m, 8H), 0.90 (s, 11H), 0.88-0.71 (m, 2H), 0.63 (s, 3H), 0.59-0.47 (m, 1H), 0.04 (d, J = 9.2 Hz, 6H).

[0616] Synthesis of 2.3

[0617] To a solution of 2.2 (246 mg, 0.354 mmol) in THF (2 mL) was added HF-py (2 mL, 70% in Py) at 0 °C and the resulting mixture was stirred at 20 °C for 16 h. The mixture was poured into water (20 mL) and the aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, the volatiles were removed, and the resulting residue was purified by silica gel chromatography (0^30% EtOAc in PE) to give 2.3 (109 mg, 0.235 mmol, 66% yield).1H NMR (400 MHz, CDCl3) δH 3.89 (s, 1H), 3.80-3.69 (m, 2H), 3.66 (s, 3H), 3.65-3.59 (m, 2H), 3.31-3.23 (m, 1H), 2.35-2.18 (m, 2H), 1.95 (d, J = 12.4 Hz, 1H), 1.85-1.65 (m, 7H), 1.45-1.32 (m, 7H), 1.31-1.16 (m, 3H), 1.15-1.01 (m, 7H), 1.00-0.79 (m, 7H), 0.64 (s, 3H), 0.60-0.52 (m, 1H).

[0618] Synthesis of 2

[0619] To 2.3 (109 mg, 0.234 mmol) in THF (10 mL) was added MeMgBr (0.780 mL, 3 M in Et2O) dropwise at 25 °C and the resulting mixture was stirred for 2 h under N2(g). The mixture was poured into 10% aqueous NH4Cl (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the volatiles were removed. The residue was purified by silica gel chromatography (0^30% of EtOAc in PE) to give 2 (33.2 mg, 0.071 mmol, 30.7% yield).1H NMR (400 MHz, CDCl3) δH3.89 (s, 1H), 3.78-3.71 (m, 2H), 3.68-3.59 (m, 2H), 3.30-3.22 (m, 1H), 2.19-1.86 (m, 3H), 1.85-1.63 (m, 6H), 1.46-1.31 (m, 8H), 1.21 (s, 10H), 1.03 (s, 7H), 0.91 (d, J = 6.4 Hz, 8H), 0.68-0.49 (m, 4H). LC-ELSD / MS MS ESI calcd for C29H52O4Na [M+Na]+487.4, found 487.4.

[0620] Example 3: Synthesis of (3S,4R,8S,9S,10R,13R,14S,17R)-3-(2-hydroxy-2- methylpropoxy)-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-1H-cyclopenta[a]phenanthren-4-ol (3)

[0621] Synthesis of 3.2

[0622] To a solution of 3.1 (5.00 g, 12.4 mmol, ASW MedChem, Inc.) in toluene (50 mL) was added t-BuOK (4.17 g, 37.2 mmol) under N2 (g) and the resulting mixture was stirred at 25 ℃ for 3 h. Tert-butyl-2-bromoacetate (4.82 g, 24.8 mmol) was added at 25 ℃, and the mixture was stirred under N2(g) for 16 h. The mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washe...

Claims

CLAIMS What is Claimed is:

1. A compound, wherein the compound has the structure of Formula (A):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:wherein: each of R1aand R1bis independently hydrogen or C1-6alkyl; or R1aand R1b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl, or a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6 alkyl X1is halogen, C1-6alkyl optionally substituted with 1-5 halogen, -OROor -SRS, wherein each of ROand RSis independently hydrogen or C1-6 alkyl; X2is C6-10 aryl or 5-8 membered heteroaryl; and X3is C1-6alkyl, C1-6alkoxy or C6-10aryl; n is 0 or 1; R4is -OH, C1-6 alkoxy, -OC(O)(C1-6 alkyl), or -O-CH2-(5-8 membered heteroaryl); R4’is hydrogen or C1-6alkyl; R5is absent or hydrogen; each of R25aand R25bis independently hydrogen, C1-6 alkyl optionally substituted with 1- 5 halogen, or C3-6 carbocyclyl; or R25aand R25b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl; R25cis hydrogen, or C1-6 alkyl; is a single bond or a double bond, wherein when is a single bond, R5is hydrogen, and wherein when is a double bond, R5is absent; andprovided that the compound is not:.

2. The compound of claim 1, wherein the compound of Formula (A) is a compound of Formula (I):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:, wherein: each of R1aand R1bis independently hydrogen or C1-6alkyl; or R1aand R1b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl; X1is -OROor -SRS, wherein each of ROand RSis independently hydrogen or C1-6alkyl; X2is C6-10 aryl or 5-8 membered heteroaryl; and X3is C1-6alkyl or C1-6alkoxy; R4is -OH, C1-6 alkoxy, -OC(O)(C1-6 alkyl), or -O-CH2-(5-8 membered heteroaryl); R5is absent or hydrogen; each of R25aand R25bis independently hydrogen, C1-6alkyl optionally substituted with 1- 5 halogen, or C3-6carbocyclyl; or R25aand R25b, together with the carbon atom to which they are attached, form a C3-6 carbocyclyl; and is a single bond or a double bond, wherein when is a single bond, R5is hydrogen, and wherein when is a double bond, R5is absent.

3. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof of claim 1, wherein: R1aand R1b, together with the carbon atom to which they are attached, form a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6alkyl; X1is halogen, C1-6 alkyl optionally substituted with 1-5 halogen; X3is C6-10 aryl; n is 0; R4’is C1-6 alkyl; and R25cis C1-6 alkyl.

4. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 1, wherein the compound of Formula (A) is a compound of Formulapharmaceutically acceptable salt, isotopic variant, or combination thereof.

5. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 1, wherein the compound of Formula (A) is a compound of Formulapharmaceutically acceptable salt, isotopic variant, or combination thereof.

6. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 1, wherein the compound of Formula (A) is a compound of Formula (A-3):pharmaceutically acceptable salt, isotopic variant, or combination thereof.

7. The compound or pharmaceutically acceptable salt, isotopic variant, or combination8. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 7, wherein X1is -ORO.

9. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 7, wherein X1is halogen.

10. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 7, wherein X1is C1-6alkyl optionally substituted with 1-5 halogen.

11. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 7, wherein R1aand R1bare both hydrogen.

12. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 7, wherein each of R1aand R1bis independently C1-6 alkyl.

13. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 7, wherein R1aand R1b, together with the carbon atom to which they are attached, form a C3-6carbocyclyl.

14. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 7, wherein R1aand R1b, together with the carbon atom to which they are attached, form a 3-8 membered heterocyclyl optionally substituted with one more substituents independently selected from C1-6 alkyl.

15. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 7, wherein.

16. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 15, wherein X2is C6-10 aryl.

17. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 15, wherein X2is 5-8 membered heteroaryl.

18. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-6, wherein R1is and n is 0.

19. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 18, wherein X3is C6-10aryl.

20. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-6, wherein R4is -OH.

21. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-6 and 20, wherein R4is in the beta configuration.

22. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1, and 3-6, wherein R4’is -H.

23. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-6 and 22, wherein R4’is in the beta configuration.

24. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-6, wherein each of R25aand R25bis independently C1-6alkyl optionally substituted with 1-5 halogen.

25. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 1, and 3-6, wherein R25cis hydrogen.

26. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 1, wherein the compound of Formula (A) is selected from the group consisting of any one of compounds 1 or 3-38, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

27. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-26, and a pharmaceutically acceptable carrier.

28. A method for treating a CNS-related condition in a subject in need thereof, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-26, or the pharmaceutical composition according to claim 27.

29. The method according to claim 28, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, stress or stress-related disorder (including post- traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder, a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensory hypersensitivity, a metabolic encephalopathy (including phenylketoneuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffersyndrome (LKS)), epilepsies related to mTor, melanoma, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

30. A method for effecting allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-26, or the pharmaceutical composition according to claim 27.

31. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-26, or the pharmaceutical composition according to claim 27, for use in treating a CNS-related condition in a subject.

32. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to claim 31, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, stress or stress-related disorder (including post-traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive- compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post- partum psychosis), a sleep disorder (including insomnia), a substance-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder, a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and Tuberous Sclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensory hypersensitivity, a metabolic encephalopathy (including phenylketoneuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptorencephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), epilepsies related to mTor, melanoma, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

33. The compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-26, or the pharmaceutical composition according to claim 27, for use in effecting allosteric modulation of an NMDA receptor.

34. Use of the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-26, or the pharmaceutical composition according to claim 27, in the manufacture of a medicament for treating a CNS-related condition in a subject.

35. The use according to claim 34, wherein the CNS-related condition is selected from the group consisting of: an adjustment disorder, stress or stress-related disorder (including post- traumatic stress disorder (PTSD)), an anxiety disorder (including obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention deficit hyperactive disorder (ADHD)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), treatment resistant depression (TDR), bipolar disorder, dysthymic disorder, and suicidality), a schizophrenia spectrum disorder (e.g., schizophrenia and schizoaffective disorder), a psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder and / or withdrawal syndrome (e.g., addiction to opiates, cocaine, and / or alcohol), an addictive disorder, a personality disorder (including OCD), an autism spectrum disorder (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome and TuberousSclerosis complex), attention deficit disorder, pain (including neuropathic pain, injury-related pain syndromes, acute pain, chronic pain, postoperative pain, cancer pain, and headaches (e.g., migraine headaches and cluster headaches))), sensory hypersensitivity, a metabolic encephalopathy (including phenylketoneuria), an encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), a vascular disease (e.g., stroke, ischemia, and vascular malformations), traumatic brain injury, a movement disorder (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, GRIN disorders, 22q11.2 deletion syndrome, an epilepsy aphasia spectrum (EAS) disorder (including continuous spike-and-wave during sleep syndrome (CSWS) and Landau Kleffer syndrome (LKS)), epilepsies related to mTor, melanoma, postoperative cognitive dysfunction, cancer-related cognitive impairment (CRCI), catamenial migraine, catamenial mood disturbances, premenstrual dysphoric disorder (PMDD), glioma, Levodopa-induced dyskinesia (LID), Niemann-Pick type C (NPC), and tinnitus.

36. Use of the compound or pharmaceutically acceptable salt, isotopic variant, or combination thereof according to any one of claims 1-26, or the pharmaceutical composition according to claim 27, in the manufacture of a medicament for effecting allosteric modulation of an NMDA receptor.

37. A method for reversing the anesthetic, dissociative, sedative, or cognitive-impairing effects of ketamine or a ketamine analog, comprising administering to a subject a compound according to any one of claims 1-26, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to claim 27.

38. The compound according to any one of clams 1-26, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to claim 27, for use in reversing the anesthetic, dissociative, sedative, or cognitive-impairing effects of ketamine or a ketamine analog in a subject.

39. Use of a compound according to any one of claims 1-26, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to claim 27, in the manufacture of a medicament for reversing the anesthetic, dissociative, sedative, or cognitive-impairing effects of ketamine or a ketamine analog in a subject.

Images