WO2021168106A1 - Deuterated neurosteroid - Google Patents

Abstract

The present disclosure is directed to deuterated derivatives of the compound of Formula (I).

Description

DEUTERATED NEUROSTEROID

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application

No. 62/978,131, filed February 18, 2020, which is incorporated herein by reference it its entirety.

BACKGROUND

[0002] The compound of Formula (I) is a neurosteroid that modulates the GABAA activity.

See W00066614 and WO2016061527:

Formula (I)

[0003] As such, the compound of Formula (I) has the potential to treat a wide variety of central nervous system disorders. There is a need for derivatives of the compound of Formula (I) with improved properties (such as improved pharmacokinetic properties).

SUMMARY OF THE INVENTION

[0004] The present disclosure is directed, inter alia, to deuterated derivatives of the compound of Formula (I), pharmaceutically acceptable salts thereof, and methods of use thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0005] The present disclosure provides deuterated derivatives of the compound of Formula

(I), and pharmaceutically acceptable salts thereof.

[0006] In some embodiments, the present disclosure provides compounds selected from the group consisting of the following formulas:

pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the present disclosure provides pharmaceutically acceptable salts of the deuterated derivatives of the compound of Formula (I) described herein. In some embodiments, the pharmaceutically acceptable salt is citrate. In some embodiments, the pharmaceutically acceptable salt is hydrobromide are included in the present disclosure as well.

[0008] The compounds of the present disclosure contain multiple chiral centers and therefore stereoisomers of these compounds exist. Unless indicated otherwise, the named or depicted stereoisomer of the compound is 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, or 99.9% by weight pure relative to all of the other stereoisomers.

[0009] The term “isotopic enrichment factor” at a particular position normally occupied by hydrogen means the ratio between the abundance of deuterium at the position and the natural abundance of hydrogen at that position. By way of example, an isotopic enrichment factor of 3500 means that the amount of deuterium at the particular position is 3500 fold greater than natural abundance, or that 52.5% of the compounds have deuterium at the particular position (i.e., 52.5% deuterium incorporation at the given position).

[0010] When a particular position in a compound of the present disclosure is designated by name or structure as containing hydrogen or deuterium, it is to be understood that the position can contain hydrogen at its natural abundance or can be enriched in deuterium with an isotopic enrichment factor of, for example, at least 835 (13% deuterium incorporation), of at least 1670 (26% deuterium incorporation, of at least 3500 (52.5% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0011] When a particular position in a compound of the present disclosure is designated specifically by name or structure as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.

[0012] When a particular position in a compound of the present disclosure is designated specifically by name or structure as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium), at least 3500 times greater than the natural abundance of deuterium (52.5% deuterium incorporation), at least 4500 times greater than the natural abundance of deuterium (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 times greater than the natural abundance of deuterium (82.5% deuterium incorporation), at least 6000 times greater than the natural abundance of deuterium (90% deuterium incorporation), at least 6333.3 times greater than the natural abundance of deuterium (95% deuterium incorporation), at least 6466.7 times greater than the natural abundance of deuterium (97% deuterium incorporation), at least 6600 times greater than the natural abundance of deuterium (99% deuterium incorporation), or at least 6633.3 times greater than the natural abundance of deuterium (99.5% deuterium incorporation).

[0013] When a chemical name or structure is silent as to whether a particular position in a compound normally occupied by hydrogen is isotopically enriched, it is intended that the particular position is occupied by hydrogen at its natural abundance. By way of example, the term “phenyl” without any further designation as to isotopic enrichment indicates that all hydrogen

atoms are present at natural abundance.

[0014] The term “compound,” when referring to a compound of this disclosure, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent hydrogen atoms of the molecules. The relative amount of isotopic variation in a compound of the compound of the present disclosure will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.

[0015] “D” and “d” both refer to deuterium. “H” refers to hydrogen.

[0016] “Substituted with deuterium” refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0017] The compounds of the present disclosure are basic and can form pharmaceutically acceptable salts with organic and inorganic acids. Salts with pharmaceutically acceptable acids are encompassed within the present disclosure. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalycilic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, pnenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p- toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphersulfonic acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, D-o-tolyltartaric acid, tartronic acid, α- toluic acid (o, m, p), naphthylamine sulfonic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts may be prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. Salts of the compounds of the present disclosure may be prepared according to methods described in U.S. Patent Application No. 16/517,369, filed July 19, 2019, and International Patent Application No. PCT/US2019/049103, filed on August 30, 2019, the contents of which are hereby incorporated by reference in their entirety.

[0018] The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms may differ from their corresponding salt forms in certain physical properties, such as solubility in polar solvents. The free base forms may differ from their corresponding salt forms in certain pharmacokinetic parameters, such as bioavailability, resulting in different pharmacological effects. [0019] The present disclosure includes the pharmaceutically active free base forms of the compounds and pharmaceutically active salts of these compounds.

[0020] As generally described herein, the disclosed compounds act as GABA modulators.

In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for the inducement of anesthesia and/or sedation in a subject. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder (e.g., sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus) in a subject in need (e.g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome).

[0021] Thus, in one aspect, the present present disclosure provides a method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the present disclosure or a composition thereof. In certain embodiments, the compound is administered by intravenous administration.

[0022] Earlier studies (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-

423 (1987)) demonstrated that certain 3a-hydroxylated steroids are orders of magnitude more potent as modulators of the GABA receptor complex (GRC) than others had reported (see, e.g., Majewska et al., Science 232: 1004-1007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241:346- 353 (1987)). Majewska et al. and Harrison et al. taught that 3a-hydroxylated-5-reduced steroids are only capable of much lower levels of effectiveness. In vitro and in vivo experimental data have now demonstrated that the high potency of these steroids allows them to be therapeutically useful in the modulation of brain excitability via the GRC (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(1):65-71 (1995)).

[0023] Various synthetic steroids have also been prepared as neuroactive steroids. See, for example, U.S. Patent 5,232,917, which discloses neuroactive steroid compounds useful in treating stress, anxiety, insomnia, seizure disorders, and mood disorders, that are amenable to GRC-active agents, such as depression, in a therapeutically beneficial manner. Furthermore, it has been previously demonstrated that these steroids interact at a unique site on the GRC which is distinct from other known sites of interaction (e.g., barbiturates, benzodiazepines, and GABA) where therapeutically beneficial effects on stress, anxiety, sleep, mood disorders and seizure disorders have been previously elicited (see, e.g., Gee, K.W. and Yamamura, H.I., “Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders,” in Central Nervous System Disorders, Horvell, ed., Marcel-Dekker, New York (1985), pp.123-147; Lloyd, K.G. and Morselli, P.L., “Psychopharmacology of GABAergic Drugs,” in Psychopharmacology: The Third Generation of Progress, H.Y. Meltzer, ed., Raven Press, N.Y. (1987), pp.183-195; and Gee et ah, European Journal of Pharmacology, 136:419-423 (1987). These compounds are desirable for their duration, potency, and oral activity (along with other forms of administration).

[0024] Compounds of the present disclosure, as described herein, are generally designed to modulate GABA function, and therefore to act as neuroactive steroids for the treatment and prevention of CNS-related conditions in a subject. Modulation, as used herein, refers to the inhibition or potentiation of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating CNS conditions in mammals including humans and non-human mammals. Thus, and as stated earlier, the present disclosure includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for such methods, and to the use of such compounds for the preparation of medicaments useful for such methods. Methods of using the compound of Formula (I) are described in U.S. Application No. 16/716,252, filed on December 16, 2019, and International Application No. PCT/US2019/066642, filed on December 16, 2019, the contents of which are hereby incorporated by reference in their entirety.

[0025] The compounds of the present disclosure, as described herein, are deuterated (i.e., enriched in deuterium above the natural isotopic abundance) at the indicated positions in order to modify the pharmacokinetic profile compared to undeuterated forms (e.g., Formula (I)). Such changes in pharmacokinetic profile can provide advantages over the undeuterated form, e.g., by providing improved metabolic stability characteristics (e.g., including decreased rate of elimination).

[0026] Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and/or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders (e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], disorders of memory and/or cognition [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer’ s type dementia, Lewis body type dementia, vascular type dementia], movement disorders [e.g., Huntington’s disease, Parkinson’s disease], personality disorders [e.g., anti-social personality disorder, obsessive compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenetic causes of autism such as synaptophathy’s, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular diseases [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and/or withdrawal syndromes [e.g., addition to opiates, cocaine, and/or alcohol], and tinnitus.

[0027] In one aspect, provided is a combination of a compound of the present disclosure 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.

[0028] In one 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 to the subject.

[0029] In one aspect, provided is a method of treating or preventing stress or anxiety in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present disclosure, or a composition thereof.

[0030] In one aspect, provided is a method of alleviating or preventing seizure activity in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present disclosure.

[0031] In one aspect, provided is a method of alleviating or preventing insomnia in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present disclosure, or a composition thereof. [0032] In one aspect, provided is a method of inducing sleep and maintaining substantially the level of REM sleep that is found in normal sleep, wherein substantial rebound insomnia is not induced, comprising administering an effective amount of a compound of the present disclosure.

[0033] In one aspect, provided is a method of alleviating or preventing PMS or PND in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present disclosure.

[0034] In one aspect, provided is a method of treating or preventing mood disorders in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present disclosure. In certain embodiments the mood disorder is depression.

[0035] In one aspect, provided is a method of inducing anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the present disclosure.

[0036] In one aspect, provided is a method of cognition enhancement or treating memory disorder by administering to the subject a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the disorder is Alzheimer’s disease. In certain embodiments, the disorder is Rett syndrome.

[0037] In one aspect, provided is a method of treating attention disorders by administering to the subject a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the attention disorder is ADHD.

[0038] In certain embodiments, the compound is administered to the subject chronically.

In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

Neurodegenerative Diseases and Disorders

[0039] The compounds described herein can be used in a method described herein, for example in the treatment of a disorder described herein such as a neurodegenerative disease.

[0040] The term“neurodegenerative disease” includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons.

[0041] Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer’s disease (including the associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e.g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug- induced or medication-induced Parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication- induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette’s syndrome; head trauma; hearing impairment and loss; Huntington’s disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesias and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson’s disease, postencephalitic parkinsonism, and progressively supranuclear palsy); muscular spasms and disorders associated with muscular spasticity or weakness including chorea (such as benign hereditary chorea, drug- induced chorea, hemiballism, Huntington’s disease, neuroacanthocytosis, Sydenham’s chorea, and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremor (such as rest tremor, postural tremor, and intention tremor) and dystonia (including axial dystonia, dystonic writer’s cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson’s disease; seizure; status epilecticus; stroke; tinnitus; tubular sclerosis, and viral infection induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder. Mood disorders

[0042] The compounds described herein can be used in a method described herein, for example in the treatment of a disorder described herein such as a mood disorder.

[0043] 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.

[0044] 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).

[0045] 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.

[0046] 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.

[0047] 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. [0048] 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.

[0049] 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.

[0050] 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).

[0051] Double depression refers to fairly depressed mood (dysthymia) that lasts for at least

2 years and is punctuated by periods of major depression.

[0052] Depressive Personality Disorder (DPD) refers to a personality disorder with depressive features.

[0053] 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.

[0054] Minor depressive disorder or minor depression refers to a depression in which at least 2 symptoms are present for 2 weeks.

[0055] 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 consequnces. 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.

[0056] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress.

[0057] Treatment-resistant depression refers to a condition where the individuals have been treated for depression, but the symptoms do not improve. For example, antidepressants or physchological counseling (psychotherapy) do not ease depression symptoms for individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve symptoms, but come back. Refractory depression occurs in patients suffering from depression who are resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and/or anxiolytic drugs, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation and/or transcranial magnetic stimulation).

[0058] 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.

[0059] Premenstrual dysphoric disorder (PMDD) refers to a severe, at times disabling extension of premenstrual syndrome (PMS). PMDD causes extreme modd shifts with symptoms that typically begin seven to ten days before a female’s period starts and continues for the first few days of a female’s period. Symptoms include sadness or hopelessness, anxiety or tension, extreme moodiness, and marked irritability or anger.

[0060] Symptoms of depression include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, irritability, fatigue, loss of interest in pleasurable activities or hobbies, 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).

[0061] In some embodiments, depressions that can be treated by the disclosed compounds include major depressive disorder (MDD), postpartum depression (PPD) or postnatal depression, treatment resistant depression or refractory depression, treatment resistant depression postpartum depression, psychotic major depression, depression with anxiety, atypical depression, seasonal affective disorder, dysthymia, bipolar disorder, post-traumatic stress disorder (PTSD), suicidality, and suicidal ideation. Symptoms of depression include, but are not limited to, a state of feeling sad, a significant increase or decrease in appetite and time spent sleeping, inactivity, difficulty in thinking or concentrating, feelings of dejection, feelings of hopelessness, negative thinking, agitation, inability to focus, increased sleeping, lethargy, and suicidal tendencies. Depression may be caused by numerous factors known to those in the art such as genetic disposition, hormonal changes, abuse, medications, conflict, death or loss, major events, personal problems, other illnesses, substance abuse, and accidents. In one aspect, the depressions treated by the compound of the invnetion, or salt thereof, or composition is one that is caused by a traumatic brain injury, a neuroendocrine disorder or a neuroendocrine mood disorder, or an endogenous neurosteroid deficiency (such as e.g., a progesterone, allopregnanolone, or pregnanolone deficiency). In some aspects, the neuroendocrine disorder or a neuroendocrine mood disorder is caused by a traumatic brain injury. In some aspects, the depression described herein is caused by imbalances in the body’s hormone production directly related to the pituitary or the hypothalamus. In other aspects, the depression described herein is caused by imbalances in the body’s hormone production directly related to the pituitary or the hypothalamus, and their axes following a traumatic brain injury.

Anxiety Disorders

[0062] The compounds described herein can be used in a method described herein, for example in the treatment of a disorder described herein such as an anxiety disorder.

[0063] 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.

[0064] 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.

[0065] In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks’ potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).

[0066] 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.

[0067] 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.

[0068] 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.

Eating Disorders

[0069] The compounds described herein can be used in a method described herein, for example in the treatment of a disorder described herein such as an eating disorder. Eating disorders feature disturbances in eating behavior and weight regulation, and are associated with a wide range of adverse psychological, physical, and social consequences. An individual with an eating disorder may start out just eating smaller or larger amounts of food, but at some point, their urge to eat less or more spirals out of control. Eating disorders may be characterized by severe distress or concern about body weight or shape, or extreme efforts to manage weight or food intake. Eating disorders include anorexia nervosa, bulimia nervosa, binge-eating disorder, cachexia, and their variants.

[0070] Individuals with anorexia nervosa typically see themselves as overweight, even when they are underweight. Individuals with anorexia nervosa can become obsessed with eating, food, and weight control. Individuals with anorexia nervosa typically weigh themselves repeatedly, portion food carefully, and eat very small quantities of only certain foods. Individuals with anorexia nervosa may engage in binge eating, followed by extreme dieting, excessive exercise, self-induced vomiting, or misuse of laxatives, diuretics, or enemas. Symptoms include extremely low body weight, severe food restriction, relentless pursuit of thinness and unwillingness to maintain a normal or healthy weight, intense fear of gaining weight, distorted body image and self-esteem that is heavily influenced by perceptions of body weight and shape, or a denial of the seriousness of low body weight, lack of menstruation among girls and women. Other symptoms include the thinning of the bones, brittle hair and nails, dry and yellowish skin, growth of fine hair all over the body, mild anemia, muscle wasting, and weakness, severe constipation, low blood pressure or slowed breathing and pulse, damage to the structure and function of the heart, brain damage, multi-organ failure, drop in internal body temperature, lethargy, sluggishness, and infertility.

[0071] Individuals with bulimia nervosa have recurrent and frequent episodes of eating unusually large amounts of food and feel a lack of control over these episodes. This binge eating is followed by behavior that compensates for the overeating such as forced vomiting, excessive use of laxatives or diuretics, fasting, excessive exercise, or a combination of these behaviors. [0072] Unlike anorexia nervosa, people with bulimia nervosa usually maintain what is considered a healthy or normal weight, while some are slightly overweight. But like people with anorexia nervosa, they typically fear gaining weight, want desperately to lose weight, and are unhappy with their body size and shape. Usually, bulimic behavior is done secretly because it is often accompanied by feelings of disgust or shame. The binge eating and purging cycle can happen anywhere from several times a week to many times a day. Other symptoms include chronically inflamed and sore throat, swollen salivary glands in the neck and jaw area, worn tooth enamel, and increasingly sensitive and decaying teeth as a result of exposure to stomach acid, acid reflux disorder and other gastrointestinal problems, intestinal distress and irritation from laxative abuse, severe dehydration from purging of fluids, electrolyte imbalance (that can lead to a heart attack or stroke).

[0073] Individuals with binge-eating disorder lose control over their eating. Unlike bulimia nervosa, periods of binge eating are not followed by compensatory behaviors like purging, excessive exercise, or fasting. Individuals with binge-eating disorder often are overweight or obese. Obese individuals with binge-eating disorder are at higher risk for developing cardiovascular disease and high blood pressure. They also experience guilt, shame, and distress about their binge eating, which can lead to more binge eating.

[0074] Cachexia is also known as“wasting disorder,” and is an eating-related issue experienced by many cancer patients. Individuals with cachexia may continue to eat normally, but their body may refuse to utilize the vitamins and nutrients that it is ingesting, or they will lose their appetite and stop eating. When an individual experiences loss of appetite and stops eating, they can be considered to have developed anorexia nervosa.

Epilepsy

[0075] The compounds described herein can be used in a method described herein, for example in the treatment of a disorder described herein such as epilepsy, status epilepticus, or seizure, for example as described in WO2013/112605 and WO/2014/031792, the contents of which are incorporated herein in their entirety.

[0076] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

Status epilepticus (SE)

[0077] 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.

[0078] 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.

[0079] Compositions described herein can also be administered as a prophylactic to a subject having a CNS disorder e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; prior to the onset of a seizure.

Seizure [0080] 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.

[0081] 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.

[0082] Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

[0083] 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.

[0084] 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.”

[0085] 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.

[0086] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.

[0087] Tonic seizures are characterized by stiffening of the muscles.

[0088] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall. [0089] 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.

[0090] In one aspect, provided herein is a method of treating an epileptic disorder in a subject, such as e.g., epilepsy characterized by a mutation in one or more genes in the subject (e.g., ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAOl, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLEl, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX), refractory epilepsy, refractory pediatric epilepsy, epileptic encephalopathies, Lenox-Gastaut syndrome, infantile spasms or Dravet syndrome, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

Tremor

[0091] The compounds described herein can be used in a method described herein, for example in the treatment of a disorder described herein such as tremor.

[0092] 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). [0093] 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).

[0094] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and/or painful and abnormal postures or positions. Dystonic tremor may affect any muscle in the body. Dystonic tremors occurs irregularly and often can be relieved by complete rest.

[0095] Essential tremor or benign essential tremor is the most common type of tremor.

[0096] 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.

[0097] Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz) rhythmic muscle contractions that occurs in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs and the patient may shake uncontrollably when asked to stand in one spot. Orthostatic tremor may occurs in patients with essential tremor.

[0098] 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.

[0099] 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 withdrawl, or medical conditions including an overactive thyroid and hypoglycemia. The tremor classically has a frequency of about 10 Hz. [0100] 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.

[0101] 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.

Anesthesia / Sedation

[0102] The compounds described herein can be used in a method described herein, for example to induce anesthesia or sedation. Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug which alone provides the correct combination of effects, or occasionally with a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achieve very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience.

[0103] Sedation is the reduction of irritability or agitation by administration of a pharmacological agent, generally to facilitate a medical procedure or diagnostic procedure.

[0104] Sedation and analgesia include a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[0105] Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are typically unaffected.

[0106] Moderate sedation/analgesia (conscious sedation) is a drug-induced depression of consciousness during which the patient responds purposefully to verbal command, either alone or accompanied by light tactile stimulation. No interventions are usually necessary to maintain a patent airway. Spontaneous ventilation is typically adequate. Cardiovascular function is usually maintained. [0107] Deep sedation/analgesia is a drug-induced depression of consciousness during which the patient cannot be easily aroused, but responds purposefully (not a reflex withdrawal from a painful stimulus) following repeated or painful stimulation. Independent ^{^} eflon ^{^} yla function may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

[0108] General anesthesia is a drug-induced loss of consciousness during which the patient is not arousable, even to painful stimuli. The ability to maintain independent ^{^} eflon ^{^} yla function is often impaired and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

[0109] Sedation in the intensive care unit (ICU) allows the depression of patients’ awareness of the environment and reduction of their response to external stimulation. It can play a role in the care of the critically ill patient, and encompasses a wide spectrum of symptom control that will vary between patients, and among individuals throughout the course of their illnesses. Heavy sedation in critical care has been used to facilitate endotracheal tube tolerance and ventilator synchronization, often with neuromuscular blocking agents.

[0110] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for a prolonged period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1 month, 2 months). Long-term sedation agents may have long duration of action. Sedation agents in the ICU may have short elimination half-life.

Procedural sedation and analgesia, also referred to as conscious sedation, is a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows a subject to tolerate unpleasant procedures while maintaining cardiorespiratory function. [0111] “Subject” and “patient” are used interchangeably. A subject may be a non-human animal such as a non-human primate (e.g., a monkey, chimpanzee), a farm animal (e.g, a horse, cow, pig, chicken, or sheep), a laboratory animal (e.g, a rat or mouse), or a companion animal (e.g, dog, cat, guinea pig or rabbit). In one aspect, the subject is a human.

[0112] The disclosed compounds may be administered by different routes including, but not limited to, intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or transmucosal administration. For systemic administration, oral administration is preferred. For oral administration, for example, the disclosed compounds may be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. These formulations may be designed for immediate release of the drug or they may be designed for a controlled release of the drug.

[0113] The term "effective amount" or “therapeutically effective amount” refers to the amount of the compound sufficient to elicit the desired biological response, e.g., to treat the depression. As will be appreciated by those of ordinary skill in this art, the therapeutically effective amount of the compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the depression being treated, the mode of administration, and the age, weight, health, and condition of the subject. A therapeutically effective amount encompasses therapeutic and prophylactic treatment.

[0114] In one aspect, the therapeutically effective amount refers to a dosage of the compound of the present disclosure that is between 0.01 - 100 mg/kg body weight/day. Dosing (e.g., oral dosing) may include from one to five oral doses per day administered either morning, afternoon, or night and with or without food. For example, in one aspect, the compound of the invnetion, or a pharmaceutically acceptable salt thereof, or composition comprising the compound of the present disclosure may be taken once daily (e.g., once a day at night) or daily over two doses. Amounts may vary, but can be 10 mg to 100 mg of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, taken once daily; 10 mg to 100 mg of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, taken once daily at night; or 10 mg to 100 mg of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, taken daily over two doses. In one aspect, the amount of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, administered is such that a steady state concentration of the compound is achieved. In one aspect, the steady state concentration is from 1 to 500 ng/ml e.g., from 1 to 100 ng/ml, from 1 to 25 ng/ml, from 25 to 50 ng/ml, from 50 to 100 ng/ml, from 100 ng/ml to 200 ng/ml, from 200 ng/ml to 300 ng/ml, from 300 ng/ml to 400 ng/ml, or from 400 ng/ml to 500 ng/ml. The disclosed compounds and their pharmaceutically acceptable salts, which are active when given orally, may be formulated as syrups or other liquid compositions, tablets, capsules, and lozenges. A syrup or liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier such as, for example, ethanol, peanut oil, olive oil, glycerin or water with or without a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be utilized. For example, aqueous gums, celluloses, silicates or oils may be used to form a soft gelatin capsule shell.

[0115] Alternatively, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and subcutaneous. For injection, the compounds encompassed by Structure I may be formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil. In addition, the disclosed compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.

[0116] The amounts of various compounds encompassed by Structure I to be administered can be determined by standard procedures taking into account factors such as the compound ICso, EC50, the biological half-life of the compound, the age, size and weight of the subject, and the disease or disorder associated with the subject. The importance of these and other factors to be considered are known to those of ordinary skill in the art.

[0117] Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses may have to be administered.

[0118] The composition may be in unit dosage form. For oral application, for example, a tablet or capsule may be administered; for nasal application, a metered aerosol dose may be administered; for transdermal application, a topical formulation or patch may be administered; and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the subject may administer a unit dose irrespective of weight or for a general weight range, rather than on a per kilogram body weight basis.

[0119] The compounds of the present disclosure can be prepared according to the methods described herein. Further details are provided by International Patent Publication Nos. 2005/105822 and 2016/164763, the contents of which are hereby incorporated by reference in their entirety.

[0120] Key Deuterated reagents commercially available to enable chemistry: (CD₃)₃SOI; CD₃OD, NaOD, D₂O and deuterated imidazoles.

n =0, 2, or 3 n =0, 2, or 3

Evaluation of Metabolic Stability

[0121] Microsomal Assay : Human liver microsomes (20 mg/mL) are obtained from Xenotech,

LLC (Lenexa, KS). b-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl₂), and dimethyl sulfoxide (DMSO) are purchased from Sigma- Aldrich.

[0122] Determination of Metabolic Stability: 7.5 mM stock solutions of test compounds are prepared in DMSO. The 7.5 mM stock solutions are diluted to 12.5-50 mM in acetonitrile (ACN). The 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl₂. The diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate. A 10 μL aliquot of the 12.5-50 mM test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution. The final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25-1.0 μM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl₂. The reaction mixtures are incubated at 37 °C, and 50 μL aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 μL of ice-cold ACN with internal standard to stop the reactions. The plates are stored at 4 °C for 20 minutes after which 100 μL of water is added to the wells of the plate before centrifugation to pellet precipitated proteins. Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio- systems API 4000 mass spectrometer. The same procedure is followed for the non-deuterated counterpart of the compound of the present disclosure and the positive control, 7-ethoxycoumarin (1 μM). Testing is done in triplicate.

[0123] Data analysis: The in vitro ti/2S for test compounds are calculated from the slopes of the linear regression of % parent remaining (In) vs incubation time relationship. in vitro t _½ = 0.693/k k = -[slope of linear regression of % parent remaining (In) vs incubation time]

Data analysis is performed using Microsoft Excel Software.

[0124] The invention is further described by the following numbered embodiments:

1. A method of treating depression in a patient in need thereof comprising orally administering a daily dose of about 5 mg to about 120 mg of a deuterated derivative of Compound 1:

or a pharmaceutically acceptable salt thereof, wherein the depression is selected from the group consisting of major depressive disorder, major depressive disorder with suicidal risk, clinical depression, postnatal or postpartum depression, treatment resistant postpartum depression, perimenopausal depression, menopausal depression, child and adolescent depression, premenstrual dysphoric disorder (PMDD), atypical depression, melancholic depression, Psychotic Major Depression (PMD), catatonic depression, Seasonal Affective Disorder (SAD), persistent depressive disorder (dysthymia), double depression, Depressive Personality Disorder (DPD), Recurrent Brief Depression (RBD), minor depressive disorder, bipolar disorder or manic depressive disorder, bipolar depression with suicidal risk, post-traumatic stress disorders, depression caused by chronic medical conditions, depressive disorder due to another medical condition, treatment-resistant depression, refractory depression, substance/medication induced depressive disorder, depression with anxiety, suicidality, suicidal ideation, or suicidal behavior. la. The method of embodiment 1, wherein the deuterated derivative of Compound 1 is selected from the group consisting of:

pharmaceutically acceptable salt thereof.

2. The method of embodiment 1 or la, wherein the depression is major depressive disorder (MDD).

3. The method of embodiment 2, wherein the MDD patient is a patient with insomnia.

4. The method of any one of embodiments 1-3, wherein major depressive disorder is severe major depressive disorder.

5. The method of any one of embodiments 1-4, wherein prior to said treatment, the patient’s total Hamilton Depression Rating Scale (HAM-D) value is at least 22.

6. The method of embodiment 1, wherein the depression is treatment resistant depression.

7. The method of any one of embodiments 1-6, wherein about 15 mg to about 120 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered per day. 8. The method of any one of embodiments 1-7, wherein about 15 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

9. The method of any one of embodiments 1-7, wherein about 15 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day.

10. The method of any one of embodiments 1-7, wherein about 30 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

11. The method of any one of embodiments 1-7, wherein about 30 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day.

12. The method of any one of embodiments 1-7, wherein about 60 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

12(a). The method of any one of embodiments 1-7, wherein about 30 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day.

12(b). The method of any one of embodiments 1-7, wherein about 80 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

12(c). The method of any one of embodiments 1-7, wherein about 40 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day.

12(d). The method of any one of embodiments 1-7, wherein about 100 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day. 12(e). The method of any one of embodiments 1-7, wherein about 50 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day.

12(f). The method of any one of embodiments 1-7, wherein about 120 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

12(g). The method of any one of embodiments 1-7, wherein about 60 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day.

13. The method of any one of embodiments 1-12, wherein said administering is for about 2 weeks, about 4 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 24 weeks or about 50 weeks.

14. The method of any one of embodiments 1-6 and 13, wherein the administering comprises:

(a) administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for at least one week at an initial daily dose and

(b) administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for at least one week at a maintenance daily dose, wherein the initial daily dose is greater than the maintenance daily dose.

15. The method of any one of embodiments 1-14, further comprising titrating the dose of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for at least one week until a steady state is achieved in the patient.

16. The method of any one of embodiments 1-15, wherein after said administering for a period of at least 1 week, the patient experiences a substantial reduction in depression compared to prior to said administering.

17. The method of any one of embodiments 1-16, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of depression that is characterized by an at least two point decline in total Hamilton Depression Rating Scale (HAM-D) value. 18. The method of embodiment 17, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of depression that is characterized by an at least 50% reduction in HAM-D value.

19. The method of embodiment 17, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of depression that is characterized by an at least one category change in HAM-D severity classification.

20. The method of embodiment 17, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of depression that is characterized by HAM-D remission.

21. The method of any one of embodiments 1-16, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of depression that is characterized by an at least two point decline in Montgomery Asberg Depression Rating Scale (MADRS) value.

22. The method of embodiment 21, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of depression that is characterized by an at least 50% reduction in MADRS value.

23. The method of embodiment 21, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of depression that is characterized by MADRS remission.

24. The method of any one of embodiments 1-16, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of anxiety that is characterized by an at least two point decline in total Hamilton Rating Scale for anxiety (HAM- A) value.

25. The method of embodiment 24, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of anxiety that is characterized by an at least 50% reduction in HAM-A value.

26. The method of embodiment 24, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of anxiety that is characterized by an at least one category change in HAM-A severity classification.

27. The method of any one of embodiments 1-16, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of depression that is characterized by at least one point decline in one or more of the Clinical Global Impression (CGI) sub scale scores, wherein the CGI subscales are selected from Severity of Illness Subscale (CGI-S) or Global Improvement Subscale (CGI-I).

28. The method of any one of embodiments 1-16, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of depression that is characterized by at least about a 10%, 20%, or 30% improvement in Symptoms of Depression Questionnaire (SDQ) total scale score or in any of the respective subscales of SDQ-1, SDQ-2, SDQ-3, SDQ-4 and SDQ-5.

29. The method of any one of embodiments 1-16, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of depression that is characterized by an at least one point decline in Pittsburgh Sleep Quality Index (PSQI) Global score.

30. The method of any one of embodiments 1-29, wherein the patient is an MDD patient with insomnia.

31. The method of embodiment 30, wherein after said administering for a period of at least 1 week, the patient experiences a substantial reduction in insomnia compared to prior to said administering.

32. The method of embodiment 31, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of insomnia that is characterized by at least about a 30% decline in wake time after sleep onset (WASO) compared to prior to the treatment.

33. The method of embodiment 31, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of insomnia that is characterized by at least about a 30% increase in Total Sleep Time (TST) compared to prior to the treatment.

34. The method of embodiment 31, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of insomnia that is characterized by at least about a 30% increase in sleep efficiency (SE) compared to prior to the treatment.

35. The method of embodiment 31, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of insomnia that is characterized by at least about a 30% decrease in latency to persistent sleep (LPS) compared to prior to the treatment.

36. The method of embodiment 31, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of insomnia characterized by at least a one point decline in Global Pittsburgh Sleep Quality Index (PSQI) score compared to prior to the treatment. 37. The method of embodiment 31, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of insomnia that is characterized by at least a one point increase in Epworth Sleepiness Scale value compared to prior to the treatment.

38. The method of embodiment 31, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of insomnia that is characterized by at least a one point decrease in Insomnia Severity Index scale value compared to prior to the treatment.

39. The method of embodiment 31, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of insomnia that is characterized by at least about a 10% improvement in total Leeds Sleep Evaluation Questionnaire value compared to prior to the treatment.

40. The method of embodiment 31, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of insomnia that is characterized by at least a one point decrease in total Athens Insomnia Scale value compared to prior to the treatment.

41. The method of embodiment 31, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of insomnia that is characterized by a one point decrease in total Sleep Quality Index value compared to prior to the treatment.

42. The method of any one of embodiments 1-41, wherein the deuterated derivative of Compound l is a pharmaceutically acceptable salt.

43. The method of any one of embodiments 1 -42, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, citrate, malate, mesylate, phosphate, and tartrate.

44. The method of any one of embodiments 1-43, wherein the administration to a patient in need thereof provides a mean steady state blood plasma AUC (0-24) hours from about 500 to about 2500 ng*h/ml of the deuterated derivative of Compound 1.

45. The method of any one of embodiments 1-43, wherein the administration to a patient in need thereof provides a mean steady state blood plasma Cmax from about 25 ng/mL to about 600 ng/ml of the deuterated derivative of Compound 1. 46. The method of any one of embodiments 1-43, wherein the administration to a patient in need thereof provides a mean steady state blood plasma Cmax that does not exceed 600 ng/ml of the deuterated derivative of Compound 1.

47. The method of any one of embodiments 1-46, wherein the composition is an oral dosage form.

48. The method of any one of embodiments 1-47, wherein the deuterated derivative of Compound 1 is in the form of an extended release oral dosage form.

49. The method of any one of embodiments 1-48, further comprising administering one or more additional antidepressants.

50. The method of embodiment 49, wherein the additional antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mirtazapine bupropion, lamotrigine and atypical antipsychotics.

51. The method of embodiment 50, wherein the selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, escitalopram, citalopram, sertraline, and paroxetine.

52. The method of embodiment 50, wherein the serotonin norepinephrine reuptake inhibitor is selected from the group consisting of venlafaxine and duloxetine.

53. The method of embodiment 50, wherein the serotonin tricyclic antidepressant is selected from the group consisting of amitriptyline, imipramine, and nortriptyline.

54. The method of embodiment 50, wherein the monoamine oxidase inhibitor is selected from the group consisting of phenelzine and tranylcypromine.

55. The method of embodiment 50, wherein the atypical antipsychotic is selected from the group consisting of lurasidone, aripiprazole, risperidone, olanzapine, quetiapine, ziprasidone, clozapine, iloperidone, paliperidone, asenapine and olanzapine/fluoxetine.

56. A method of treating a mood or affective disorder in a patient in need thereof comprising orally administering a daily dose of about 5 mg to about 120 mg of a deuterated derivative of Compound 1:

or a pharmaceutically acceptable salt thereof, wherein the mood or affective disorder is selected from the group consisting of perimenopause, menopause, generalized anxiety disorder, panic disorder, social anxiety disorder, acute stress disorder, post-traumatic stress disorder, specific phobia, and selective mutism.

56a. The method of embodiment 56, wherein the deuterated derivative of Compound 1 is selected from the group consisting of:

pharmaceutically acceptable salt thereof.

57. The method of embodiment 56 or 56a, wherein the mood or affective disorder is acute stress disorder.

58. The method of embodiment 56 or 56a, wherein the mood or affective disorder is post- traumatic stress disorder. 59. The method of any one of embodiments 1-6 and 14-58, wherein about 20 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

60. The method of any one of embodiments 1-6 and 14-58, wherein about 20 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day.

61. The method of any one of embodiments 1-6 and 14-58, wherein about 25 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

62. The method of any one of embodiments 1-6 and 14-58, wherein about 25 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day.

63. The method of any one of embodiments 1-6 and 14-58, wherein about 35 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

64. The method of any one of embodiments 1-6 and 14-58, wherein about 40 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

65. The method of any one of embodiments 1-6 and 14-58, wherein about 45 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

66. The method of any one of embodiments 1-6 and 14-58, wherein about 50 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

67. The method of any one of embodiments 1-6 and 14-58, wherein about 55 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day. 68. The method of any one of embodiments 1-6 and 14-58, wherein about 60 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

69. The method of any one of embodiments 1-6 and 14-58, wherein about 65 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

70. The method of any one of embodiments 1-6 and 14-58, wherein about 70 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

71. The method of any one of embodiments 1-6 and 14-58, wherein about 75 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

72. The method of any one of embodiments 1-6 and 14-58, wherein about 80 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

73. The method of any one of embodiments 1-6 and 14-58, wherein about 85 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

74. The method of any one of embodiments 1-6 and 14-58, wherein about 90 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

75. The method of any one of embodiments 1-6 and 14-58, wherein about 95 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

76. The method of any one of embodiments 1-6 and 14-58, wherein about 100 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day. 76(a) The method of any one of embodiments 1-6 and 14-58, wherein about 15 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

77. A method of treating a substance addiction disorder comprising administering to a patient in need thereof a therapeutically effective amount of a deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof.

77a. The method of embodiment 77, wherein the deuterated derivative of Compound 1 is selected from the group consisting of:

pharmaceutically acceptable salt thereof.

78. The method of embodiment 77 or 77a, wherein the substance addiction disorder is an opioid use disorder.

79. The method of embodiment 77 or 77a, wherein the substance addiction disorder is a cocaine use disorder.

80. The method of embodiment 77 or 77a, wherein the substance addiction disorder is alcohol use disorder.

81. The method of embodiment 77 or 77a, wherein the substance addiction disorder is benzodiazepine use disorder.

82. The method of any one of embodiments 78-81, wherein after the administering, the patient experiences a substantial reduction in substance addiction disorder compared to prior to said administering. 83. The method of embodiment 78, wherein after the administering, the patient experiences a reduction of opioid use disorder that is characterized by abstinence to opioid use during the period of deuterated derivative of Compound 1 administration.

84. The method of embodiment 78 or 83, wherein after the administering, the patient experiences a reduction of opioid use disorder that is characterized by a statistically significant decrease in the percentage of opioid-free weeks in the deuterated derivative of Compound 1 treated group compared to a placebo treated group during the period of deuterated derivative of Compound 1 administration.

85. The method of any one of claims 78 and 83-84, wherein after the administering, the patient experiences a reduction of opioid use disorder that is characterized by substantial improvement in craving assessment compared to prior to the treatment.

86. The method of any one of claims 78 and 83-85, wherein after the administering, the patient experiences a reduction of opioid use disorder that is characterized by a statistically significant change in retention assessment compared to a placebo treated group.

87. The method of any one of claims 78 and 83-86, wherein after the administering, the patient experiences a reduction of opioid use disorder that is characterized by a significant statistical difference in the mean change in number of days of retention in the deuterated derivative of Compound 1 treatment group relative to placebo.

88. The method of any one of claims 78-87, wherein the the deuterated derivative of Compound 1 is administered as an adjunctive to methadone; buprenorphine; buprenorphine and naloxone; naltrexone, benzodiazepine, lofexidine, medically supervised withdrawal (detoxification), residential rehabilitation treatment, mutual help groups or outpatient substance use disorder services (e.g., counseling or medication for addiction), or combinations thereof.

89. A method of treating major depressive disorder (MDD) in a patient in need thereof comprising orally administering a daily dose of from about 30 mg to about 120 mg of a deuterated derivative Compound 1 :

or a pharmaceutically acceptable salt thereof to a patient in need thereof to treat MDD.

89a. The method of embodiment 77, wherein the deuterated derivative of Compound 1 is selected from the group consisting of:

pharmaceutically acceptable salt thereof.

90. The method of embodiment 89 or 89a, wherein prior to said treatment, the patient’s total Hamilton Depression Rating Scale (HAM-D) value is at least 22.

91. The method of any one of embodiments 89-90, wherein about 45 mg to about 80 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

92. The method of any one of embodiments 89-90, wherein about 45 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

93. The method of embodiment 90, wherein about 60 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

94. The method of any one of embodiments 89-90, wherein about 80 mg of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

95. The method of any one of embodiments 89-94, wherein the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily. 96. The method of any one of embodiments 89-95, wherein the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered at bedtime.

97. The method of any one of embodiments 89-96, wherein the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is administered without regard to meals.

98. The method of any one of embodiments 89-97, wherein the method comprises administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about twelve months, about 18 months, about 24 months, about 30 months or about 36 months.

99. The method of any one of embodiments 89-98, wherein the method comprises continuous administration of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof.

100. The method of embodiment 99, wherein the method comprises:

(a) administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for about 1 week and

(b) after the administration period (a) not administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for at least 3 weeks.

101. The method of embodiment 99, wherein the method comprises:

(a) administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for about 3 weeks and

(b) after the administration period (a) not administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for at least 3 weeks.

102. The method of embodiment 99, wherein the method comprises:

(a) administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for about 4 weeks and

(b) after the administration period (a) not administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for at least 3 weeks. 103. The method of any one of embodiments 89-98, wherein the method comprises intermittent administration of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof.

104. The method of embodiment 103, intermittent administration comprises:

(a) administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for a first administration period;

(b) after the first administration period (a), not administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for a cessation period;

(c) after the cessation period (b), administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for a second administration period.

105. The method of embodiment 103, wherein the intermittent administration comprises:

(a) administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for about 1 week;

(b) after the administration period (a) not administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for about 1 week; and

(c) after the cessation period (b) administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for about 1 week.

106. The method of embodiment 103, wherein the intermittent administration comprises:

(a) administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks;

(b) after the administration period (a) not administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks; and

(c) after the cessation period (b) administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks.

107. The method of any one of embodiments 103-106, further comprising administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for one or more additional cessation periods. 108. The method of any one of embodiments 103-107, further comprising administering the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for one or more additional administration periods.

109. The method of any one of embodiments 103-104 and 107-108, wherein the first administration period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

110. The method of any one of embodiments 103-104 and 107-109, wherein the cessation period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

111. The method of any one of embodiments 103-104 and 107-110, wherein, the second administration period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

112. The method of any one of embodiments 103-104 and 107-111, wherein the first administration period is about one week; the cessation period is about three weeks; and the second administration period is about one week.

113. The method of any one of embodiments 103-104 and 107-111, wherein the first administration period is about two weeks; the first cessation period is about two weeks; the second administration period is about one week; the second cessation period is about one week and the third administration period is about one week.

114. The method of any one of embodiments 103-104 and 107-111, wherein intermittent administration period is about one month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about twelve months, about 18 months, about 24 months, about 30 months or about 36 months.

115. The method of any one of embodiments 89-114, further comprising titrating the dose of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof for at least one week until a maintenance dose is achieved in the patient.

116. The method of embodiment 115, wherein the initial dose of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is from about 15 mg to about 45 mg. 117. The method of any one of embodiments 115-116, wherein the maintenance dose of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is from about 45 mg to about 80 mg.

118. The method of any one of embodiments 115-117, wherein the initial dose is administered for one week and the maintenance dose is administered for at least one week.

119. The method of any of embodiments 89-98, wherein the method comprises:

(a) administering a loading dose of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof and

(b) administering a maintenance dose of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof.

120. The method of embodiment 119, wherein the loading dose is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days or about 14 days.

121. The method of embodiment of any one of embodiments 119-120, wherein the loading dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg.

122. The method of embodiment of any one of embodiments 115 and 119-121, wherein the maintenance dose is administered for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months, about 30 months, or about 36 months.

123. The method of embodiment of any one of embodiments 115 and 119-122, wherein the maintenance dose of the deuterated derivative of Compound 1 or a pharmaceutically acceptable salt thereof is about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg. 124. The method of embodiment of any one of embodiments 119-123, wherein the method further comprises a cessation period after administration of the loading dose and prior to administration of the maintenance dose.

125. The method of embodiment 124, wherein the cessation period is about one day, about two days, about three days, about four days, about five days, about six days, or about seven days.

126. The method of embodiment 124, wherein the cessation period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

127. The method of any one of embodiments 89-126, wherein the administering provides a mean steady state AUCo-24 of from about 600 ng_*h/mL to about 900 ng_*h

128. The method of any one of embodiments 89-127, wherein the administering provides a mean steady state Cmax of from about 25 ng/mL to about 600 ng/mL.

129. The method of any one of embodiments 89-128, wherein the administering provides a mean steady state Cmax of from about 125 ng/mL to about 250 ng/mL.

130. The method of any one of embodiments 89-129, wherein after the administering, the patient experiences a substantial reduction in depression compared to prior to said administering.

131. The method of any one of embodiments 89-130, wherein after the administering, the patient experiences a reduction of depression that is characterized by an at least ten point decline in total Hamilton Depression Rating Scale (HAM-D) value.

132. The method of embodiment 131, wherein after the administering, the patient experiences a reduction of depression that is characterized by an at least 50% reduction in HAM-D value.

133. The method of embodiment 131, wherein after the administering, the patient experiences a reduction of depression that is characterized by an at least one category change in HAM-D severity classification.

134. The method of embodiment 131, wherein after the administering, the patient experiences a reduction of depression that is characterized by HAM-D remission. 135. The method of any one of embodiments 89- 134, wherein after the administering, the patient experiences a reduction of depression that is characterized by an at least two point decline in Montgomery Asberg Depression Rating Scale (MADRS) value.

136. The method any one of embodiments 89-135, wherein after the administering, the patient experiences a reduction of depression that is characterized by an at least 50% reduction in MADRS value.

137. The method any one of embodiments 89-136, wherein after the administering, the patient experiences a reduction of depression that is characterized by MADRS remission.

138. The method of any one of embodiments 89-137, wherein after the administering, the patient experiences a reduction of depression that is characterized by at least one point decline in one or more of the Clinical Global Impression (CGI) subscale scores, wherein the CGI subscales are selected from Severity of Illness Subscale (CGI-S) or Global Improvement Subscale (CGI-I).

139. The method of any one of embodiments 89-138, wherein after the administering, the patient experiences a reduction of depression that is characterized by at least about a 10%, 20%, or 30% improvement in Symptoms of Depression Questionnaire (SDQ) total scale score or in any of the respective subscales of SDQ-1, SDQ-90, SDQ-3, SDQ-4 and SDQ-5.

140. The method of any one of embodiments 89-139, wherein after the administering, the patient experiences a reduction of depression that is characterized by an at least one point decline in Pittsburgh Sleep Quality Index (PSQI) Global score.

141. The method of any one of embodiments 89-140, wherein the patient is an MDD patient with insomnia.

142. The method of embodiment 141, wherein after the administering, the patient experiences a substantial reduction in insomnia compared to prior to said administering.

143. The method of embodiment 142, wherein after the administering, the patient experiences a reduction of insomnia that is characterized by at least about a 30% decline in wake time after sleep onset (WASO) compared to prior to the treatment.

144. The method of embodiment 142, wherein after the administering, the patient experiences a reduction of insomnia that is characterized by at least about a 30% increase in Total Sleep Time (TST) compared to prior to the treatment. 145. The method of embodiment 142, wherein after the administering, the patient experiences a reduction of insomnia that is characterized by at least about a 30% increase in sleep efficiency (SE) compared to prior to the treatment.

146. The method of embodiment 142, wherein after the administering, the patient experiences a reduction of insomnia that is characterized by at least about a 30% decrease in latency to persistent sleep (LPS) compared to prior to the treatment.

147. The method of embodiment 142, wherein after the administering, the patient experiences a reduction of insomnia characterized by at least a one point decline in Global Pittsburgh Sleep Quality Index (PSQI) score compared to prior to the treatment.

148. The method of embodiment 142, wherein after the administering, the patient experiences a reduction of insomnia that is characterized by at least a one point increase in Epworth Sleepiness Scale value compared to prior to the treatment.

149. The method of embodiment 142, wherein after the administering, the patient experiences a reduction of insomnia that is characterized by at least a one point decrease in Insomnia Severity Index scale value compared to prior to the treatment.

150. The method of embodiment 142, wherein after the administering, the patient experiences a reduction of insomnia that is characterized by at least about a 10% improvement in total Leeds Sleep Evaluation Questionnaire value compared to prior to the treatment.

151. The method of embodiment 142, wherein after the administering, the patient experiences a reduction of insomnia that is characterized by at least a one point decrease in total Athens Insomnia Scale value compared to prior to the treatment.

152. The method of embodiment 142, wherein after the administering, the patient experiences a reduction of insomnia that is characterized by a one point decrease in total Sleep Quality Index value compared to prior to the treatment.

153. The method of any one of embodiments 89-152, wherein the deuterated derivative of Compound l is a pharmaceutically acceptable salt.

154. The method of embodiment 153, wherein the pharmaceutically acceptable salt is the citrate.

Claims

CLAIMS What is claimed is:

1. A deuterated deritivative of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, selected from the group consisting of:

pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising: i) the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutically acceptable carrier or diluent.

4. A method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein the subject is a human.

6. The method of claim 4 or 5, wherein the compound is administered in combination with another therapeutic agent.

7. A method for treating seizure in a subject, comprising administering to the subject an effective amount of the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof.

8. A method for treating epilepsy or status or status epilepticus in a subject, the method comprising administering to the subject the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the status epilepticus is convulsive status epilepticus (e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus) or non-convulsive status epilepticus, (e.g., generalized status epilepticus, complex partial status epilepticus).

10. A method for treating disorders related to GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof.

11. A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound claim 1 or 2, or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus.

13. The method of claim 12, wherein the compound is administered orally.

14. The method of claim 13, wherein the compound is administered intramuscularly.

15. The method of claim 11, wherein the subject is a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome.

16. The method of claim 11, wherein the CNS-related disorder is a sleep disorder, an eating disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus.

17. The method of claim 11, wherein the CNS-related disorder is depression.

18. The method of claim 17, wherein the depression is post-partum depression.

19. The method of claim 11, wherein the CNS-related disorder is tremor.

20. The method of claim 19, wherein the tremor is essential tremor.

21. The method of claim 11, wherein the CNS-related disorder is an eating disorder.

22. The method of claim 21, wherein the eating disorder is selected from the group consisting of anorexia nervosa, bulimia nervosa, binge-eating disorder, cachexia.