Deuterated organic compound and uses thereof

Abstract

Provided is Compound A, described herein, its preparation, its use as a pharmaceutical, and pharmaceutical compositions comprising it. Compound A is useful, for instance, in modulating dopamine and serotonin neurotransmission and treating disorders that may benefit from the same, such as schizophrenia and depression.

Description

Attorney Docket No. EGL-13-PCTDEUTERATED ORGANIC COMPOUND AND USES THEREOF

[0001] This application claims priority to U.S. Provisional Application No. 63 / 729,291 filed December 6, 2024, which is hereby incorporated by reference in its entirety.FIELD

[0002] Provided is Compound A, described below, its preparation, its use as a pharmaceutical, and pharmaceutical compositions comprising it. Compound A is useful, for instance, in modulating dopamine and serotonin neurotransmission and treating disorders that may benefit from the same, such as schizophrenia and depression.BACKGROUND

[0003] Dopamine is involved in a variety of central nervous system functions, including voluntary movement, feeding, affect, reward, sleep, attention, working memory, and learning. Serotonin also is involved in a variety of central nervous system functions, including mood, cognition, reward, learning, memory, and various physiological processes. Accordingly, dopaminergic and / or serotonergic dysfunction can lead to diseases such as schizophrenia and depression.

[0004] When released from presynaptic terminals, dopamine activates members of a family of G protein-coupled dopamine receptors D1-D5. Dopamine receptors (D1-D5) are divided into two groups, the Dl-like (DI and D5) and the D2-like (D2, D3, and D4). Activation of Dl-like receptors activates adenylyl cyclase and increases cAMP levels. D2-like receptors are inhibitory. Activation of D2-like receptors inhibits activation of adenylyl cyclase.

[0005] Dl-like receptors are found postsynaptically on dopamine-receptive cells, while D2-like dopamine receptors are expressed both postsynaptically on dopamine target cells and presynaptically on dopaminergic neurons.

[0006] Fourteen serotonin receptor subtypes, grouped into sub-families, mediate effects of serotonin (5-HT). The 5-HT1A receptor subtype, a major receptor subtype, exists as presynaptic autoreceptor in serotonin neurons in the raphe nuclei and as postsynaptic heteroreceptors in the prefrontal cortex, hippocampus, septum, and hypothalamus. Signaling mechanisms of 5-HT1AAttorney Docket No. EGL-13-PCT receptors in the raphe nuclei may be different from 5-HT1 A receptors in other brain regions. Activation of 5-HT1A postsynaptic receptors can elicit increased dopamine release. The 5-HT2A receptor subtype is enriched in cortex and is linked to phosphatidylinositol turnover and also modulates dopamine release. 5-HT2A receptor antagonists have antipsychotic properties, while 5-HT2A receptor agonism is thought to be associated with cognition-enhancing and hallucinogenic properties. The hallucinogenic effects of lysergic diethylamide (LSD) and psilocybin are thought to arise from their 5-HT2A receptor agonism. 5-HT2A agonism has also been reported to promote neural plasticity and reduce depression.

[0007] Antipsychotics are used to manage psychosis, in particular schizophrenia. A hallmark of antipsychotics is D2 receptor antagonism. D2 receptor antagonism is effective in reducing positive symptoms of schizophrenia (for instance, hallucinations and delusions), but often also produces extrapy rami dal side effects, including parkinsonism, akathisia, and tardive dyskinesia, increases prolactin, and may exacerbate negative symptoms of schizophrenia (for instance, loss of interest and motivation in life and activities, social withdrawal, and anhedonia). A key feature of atypical antipsychotics is D2 receptor antagonism in combination with 5-HT2A receptor antagonism, which may explain their enhanced efficacy and reduced extrapyramidal motor side effects (EPS) compared to typical antipsychotics. Many psychotic patients also suffer from depression, which may be left untreated by current medications. However, some atypical antipsychotics are used adjunctively to serotonergic antidepressants to improve response in major depressive disorder.

[0008] Because imbalances in dopamine and serotonin can lead to a variety of disorders and current medications may not be able to effectively modulate levels of both, new compounds that can modulate dopamine and serotonin neurotransmission are needed, as are methods of treating diseases that involve imbalances in dopamine and serotonin.BRIEF SUMMARY

[0009] Provided is Compound A:Attorney Docket No. EGL-13-PCTCompound A, in free or salt form, wherein the compound is substantially free of its (S,S) enantiomer.

[0010] Further provided are pharmaceutical compositions comprising Compound A, processes for preparing Compound A, and pharmaceutical uses of Compound A, for instance, as an anti- anhedonic agent and to treat schizophrenia, depression, and post-traumatic stress disorder.

[0011] Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.DETAILED DESCRIPTION

[0012] The following description of the preferred embodiment s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.

[0013] In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.

[0014] D2- and D3- receptors are expressed both postsynaptically on dopamine target cells and presynaptically on dopamine neurons. Dopamine receptors are mainly located on non-dopamine neurons. Dopamine receptors on dopamine neurons are called autoreceptors. Autoreceptors contribute to regulating dopamine neuron activity and controlling the synthesis, release, and uptake of dopamine.Attorney Docket No. EGL-13-PCT

[0015] Presynaptic D2-like dopamine autoreceptors regulate dopamine release. A low dose of a D2-like receptor antagonist may preferentially block presynaptic autoreceptors and increase dopamine release, while a high dose may block postsynaptic receptors and decrease dopamine neurotransmission. Relatively high occupancy of D2-like receptors has been associated with antipsychotic effects, while lower occupancy has been associated with antidepressant effects.

[0016] Anhedonia is a core symptom of major depressive disorder (MDD) and is associated with inadequate response to approved selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) and psychotherapy (e.g., cognitive behavioral therapy (CBT)) and neurostimulation (e.g., transcranial magnetic stimulation (TMS)). There remains a need for effective treatment of MDD characterized by anhedonia. Despite a range of available therapies, up to 50% of people suffering from MDD fail to respond to treatments, and only about 30% of patients fully recover after receiving currently available antidepressants and treatment outcomes are even poorer for MDD individuals with anhedonia.

[0017] Depletion of dopamine / catecholamines induces symptoms of depression and anhedonia. Increasing dopamine neurotransmission can alleviate symptoms of depression and anhedonia. However, while a high dose of a dopamine D2 / D3 agonist may activate dopamine post-synaptic receptors, it can also be poorly tolerated (e.g., nausea / vomiting). Low dose of a dopamine D2 / D3 receptor antagonist may preferentially block pre-synaptic dopamine autoreceptors and increase dopamine release without being poorly tolerated.

[0018] Besides MDD, anhedonia also plays a role in bipolar disorder, schizophrenia, post- traumatic stress disorder, and substance use disorder. Despite its role in many disorders, there are no approved medications to treat anhedonia.

[0019] Decreased serotonergic activity has been implicated in anxiety and depression. Increasing serotonin neurotransmission may alleviate symptoms of anxiety and depression and be helpful for anxious depression.

[0020] The TUPAC name of nemonapride is (±)-cA-A-(l-Benzyl-2-methylpyrrolidin-3-yl)-5- chloro-2-methoxy-4-methylaminobenzamide.

[0021] Nemonapride is a dopamine D2 / D3 / D4 receptor antagonist. Nemonapride is approved in Japan and South Korea for treatment of schizophrenia. Nemonapride is supplied as 3 mg and 10 mg tablets. The approved daily dose of nemonapride for schizophrenia is 9 to 36 mg given orally in divided doses after meals. The dose can be increased up to 60 mg daily.Attorney Docket No. EGL-13-PCT

[0022] The nemonapride prescribing information indicates that the elimination half-life when nemonapride 3 mg and 6 mg was administered orally to healthy adults was 2.3 to 4.5 hours. Urinary metabolites of nemonapride result from debenzylation and N-demethylation. See Emilace package insert.

[0023] In addition to being a dopamine D2 / D3 / D4 receptor antagonist, nemonapride is also a 5- HT1A agonist. Further, nemonapride has been reported to bind to 5-HT2A receptors. As an antipsychotic, it may be expected that nemonapride is a 5-HT2A receptor antagonist because a key feature of atypical antipsychotics is D2 receptor antagonism in combination with 5-HT2A receptor antagonism or inverse agonism.

[0024] When a drug is used as a mixture of stereoisomers, it is not possible to predict what properties (e.g., biological target, pharmacokinetics) each stereoisomer has, especially a drug that has multiple biological targets.

[0025] Compound A disclosed herein is a D2 receptor antagonist and 5-HT2A agonist. Surprisingly, Compound A shows higher 5-HT2A agonism than its non-deuterated analog (see Example 2, Table 4). D2 receptor antagonism in combination with 5-HT2A agonism is a unique pharmacological activity profde, which may allow for differential modulation of dopamine and serotonin neurotransmission compared to other D2 receptor antagonists. Other substituted benzamides tested - R-remoxipride, S-remoxipride, R-sulpiride, R-sulfopride, and S-suflopride - do not even bind to the 5-HT2A receptor in vitro (labeled-Ketanserin competition assay).

[0026] As noted above, D2 receptor antagonism in combination with 5-HT2A agonism is a unique activity profile, which may allow for different modulation of dopamine and serotonin neurotransmission compared to other D2 receptor antagonists. For instance, D2 postsynaptic receptor antagonism reduces psychosis, particularly in schizophrenia, by reducing dopamine neurotransmission. High doses that target > 80% receptor occupancy may be associated with D2 antagonist mediated side effects such as extrapyramidal motor side effects (EPS) and increased prolactin. Further, as a 5-HT2A agonist, Compound A disclosed herein may show additional antidepressant effects as seen with psychedelic antidepressants, for instance, rapid and long- lasting and with anxiolytic effects. Furthermore, D2 antagonism in combination with 5-HT2A agonism may modulate 5-HT2A agonism related potential hallucinogenic effects.Attorney Docket No. EGL-13-PCT

[0027] Thus, as a D2 antagonist and 5-HT2A agonist, Compound A may provide psychedeliclike antidepressant efficacy at low doses (e.g., doses lower than those of nemonapride used to treat schizophrenia), but also have built-in protection against 5-HT2A mediated hallucinations.

[0028] Surprisingly, different deuteration patterns of N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3- yl]-5-chloro-2-methoxy-4-(methylamino)benzamide result in distinct activity profiles, particularly with respect to 5-HT2A agonism relative to D2 antagonism. Data indicates that Compound A disclosed herein shows weaker D2L antagonism and stronger 5-HT2A agonism compared to its non-deuterated analog. In addition, data indicates that Compound A is also a stronger 5-HT2A agonist than the compound of Example 1 (A2) in International Publication No. WO 2023 / 130117. The differences result in a more balanced 5-HT2A:D2L ratio (see Table 6) for Compound A. The distinct activity profile of Compound A to two targets (dopamine and serotonin receptors) may allow the compound to be targeted to and particularly beneficial in different patient populations.

[0029] Pharmacokinetics of Compound A disclosed herein are beneficial, for instance, showing one or more of the following: enriched brain levels compared to plasma levels; brain:plasma exposure supporting once-daily dosing; and extended brain enrichment compared to plasma levels, which may allow for higher and more sustained receptor occupancy with less frequent dosing and may be associated with fewer peripheral side effects. Nemonapride is taken in multiple doses per day.

[0030] A compound that is a D2 receptor antagonist and 5-HT2A receptor agonist modulates dopamine and serotonin neurotransmission and is therefore useful in treating disorders involving dopamine and serotonin signaling pathways, for instance, disorders involving dopamine and / or 5-HT2A receptors.

[0031] Provided is Compound A:Attorney Docket No. EGL-13-PCTCompound A, in free or salt form, wherein the compound is substantially free of its (S,S) enantiomer.

[0032] Further provided is Compound A as follows:A.1 Compound A, wherein the compound is in pharmaceutically acceptable salt form.A.2 Compound A, wherein the compound is in free form.A.3 Compound A, A.l, or A.2, wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance.A.4 Any of Compound A or A.1-A.3, wherein the compound, in free or salt form (e.g., pharmaceutically acceptable salt form), has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.A.5 Any of Compound A or A.1-A.4, wherein the compound is substantially stereoisomerically pure. For instance, wherein the compound has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excessAttorney Docket No. EGL-13-PCT equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%. For instance, wherein the compound is substantially diastereomerically and / or enantiomerically pure, e.g., wherein the compound is substantially diastereomerically and enantiomerically pure.A.6 Any of Compound A or A.1-A.5, wherein the compound is substantially diastereomerically pure. For instance, wherein the compound has a diastereomeric excess of greater than 90%, e.g., a diastereomeric excess equal to or greater than 95%, e g., a diastereomeric excess equal to or greater than 96%, e.g., a diastereomeric excess equal to or greater than 97%, e.g., a diastereomeric excess equal to or greater than 98%, e.g., a diastereomeric excess equal to or greater than 99%.A.7 Any of Compound A or A.1-A.6, wherein the compound is substantially enantiomerically pure. For instance, wherein the compound has an enantiomeric excess of greater than 90%, e.g., an enantiomeric excess equal to or greater than 95%, e.g., an enantiomeric excess equal to or greater than 96%, e.g., an enantiomeric excess equal to or greater than 97%, e.g., an enantiomeric excess equal to or greater than 98%, e.g., an enantiomeric excess equal to or greater than 99%.A.8 Any of Compound A or A.1-A.7, wherein the compound has the stereochemical configuration as shown in Compound A.A.9 Any of Compound A or A.1-A.8, wherein the compound is in a pharmaceutical composition with a pharmaceutically acceptable carrier. For instance, any of Compound A or A.1-A.8, wherein an effective amount of the compound is in a pharmaceutical composition with a pharmaceutically acceptable carrier.

[0033] Further provided is a pharmaceutical composition (Composition 1) comprising Compound A (e.g., any of Formula A.1-A.9):Attorney Docket No. EGL-13-PCTCompound A, in free or pharmaceutically acceptable salt form, wherein the compound is substantially free of its (S,S) enantiomer.

[0034] Further provided is Composition 1 as follows:1.1 Composition 1, wherein the composition comprises a pharmaceutically acceptable carrier.1.2 Composition 1 or 1.1, wherein the composition comprises the compound, in free or pharmaceutically acceptable salt form, as described in any Formula A.1-A.9 vide supra.1.3 Any of Composition 1, 1.1, or 1.2, wherein the compound is in free form.1.4 Any of Composition 1 or 1.1-1.3, wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance.1.5 Any of Composition 1 or 1. 1-1.4, wherein Compound A, in free or pharmaceutically acceptable salt form, has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.Attorney Docket No. EGL-13-PCT Any of Composition 1 or 1.1-1.5, wherein the composition is in oral or parenteral dosage form, e.g., oral dosage form, for instance, a tablet, capsule, solution, or suspension, for instance, a capsule or tablet. Any of Composition 1 or 1.1-1.6, wherein the composition comprises a therapeutically effective amount of Compound A, in free or pharmaceutically acceptable salt form, e.g., a therapeutically effective amount of Compound A, in free or pharmaceutically acceptable salt form, for the prophylaxis or treatment of a disorder disclosed herein, e.g., a therapeutically effective amount of Compound A, in free or pharmaceutically acceptable salt form, for use in any of the methods disclosed herein. Any of Composition 1 or 1. 1-1.7, wherein the composition is substantially free of any other stereoisomeric form of Compound A. For instance, any of Composition 1 or 1.1 -1.7, wherein the composition is substantially free of any other diastereomeric and / or enantiomeric form of Compound A, e.g., wherein the composition is substantially free of any other diastereomeric and enantiomeric form of Compound A. Any of Composition 1 or 1.1-1.8, wherein the composition comprises less than 10% w / w (weight / weight) of any other stereoisomeric form of Compound A, e.g., less than 5% w / w of any other stereoisomeric form of Compound A, e.g., less than 4% w / w of any other stereoisomeric form of Compound A, e.g., less than 3% w / w of any other stereoisomeric form of Compound A, e.g., less than 2% w / w of any other stereoisomeric form of Compound A, e.g., less than 1% w / w of any other stereoisomeric form of Compound A. Any of Composition 1 or 1.1 -1.9, wherein the composition comprises less than 10% w / w of any other diastereomeric form of Compound A, e.g., less than 5% w / w of any other diastereomeric form of Compound A, e.g., less than 4% w / w of any other diastereomeric form of Compound A, e.g., less than 3% w / w of any other diastereomeric form of Compound A, e.g., less than 2% w / w of any other diastereomeric form of Compound A, e.g., less than 1% w / w of any other diastereomeric form of Compound A.Attorney Docket No. EGL-13-PCT1.11 Any of Composition 1 or 1.1-1.10, wherein the composition comprises less than 10% w / w of any other enantiomeric form of Compound A, e.g., less than 5% w / w of any other enantiomeric form of Compound A, e.g., less than 4% w / w of any other enantiomeric form of Compound A, e.g., less than 3% w / w of any other enantiomeric form of Compound A, e.g., less than 2% w / w of any other enantiomeric form of Compound A, e.g., less than 1% w / w of any other enantiomeric form of Compound A.1.12 Any of Composition 1 or 1.1-1.11, wherein the compound has the stereochemical configuration as shown in Compound A.1.13 Any of Composition 1 or 1.1-1.12, wherein the composition comprises 1-60 mg of Compound A, in free or pharmaceutically acceptable salt form. For instance, any of Composition 1 or 1.1-1.12, wherein the composition comprises 1-10 mg, e.g., 1-9 mg (e.g., 1-8 mg) of Compound A, in free or pharmaceutically acceptable salt form. For instance, any of Composition 1 or 1.1-1.12, wherein the composition comprises 3 mg or 10 mg of Compound A, in free or pharmaceutically acceptable salt form. For instance, any of Composition 1 or 1.1- 1.12, wherein the composition comprises 1 mg to less than 3 mg (e.g., 2 mg) of Compound A, in free or pharmaceutically acceptable salt form.1.14 Any of Composition 1 or 1.1-1.13, wherein the composition is for once, twice, or three times daily dosing. For instance, any of Composition 1 or 1.1-1.13, wherein the composition is for once daily dosing.

[0035] Further provided are methods of prophylaxis or treatment of a central nervous system disorder (e.g., a brain disorder), for instance, a central nervous system disorder (e.g., a brain disorder) that benefits from modulating dopamine and / or serotonin transmission, in a patient (e.g., a human) in need thereof, wherein the method comprises administering to the patient Compound A, in free or pharmaceutically acceptable salt form (e.g., any of Formula A.1-A.9 vide supra) or a pharmaceutical composition comprising Compound A, in free or pharmaceutically acceptable salt form (e.g., Formula A.9 or any of Composition 1 or 1.1-1.14 vide supra). Further provided are methods of prophylaxis or treatment of a central nervous system disorder (e.g., a brain disorder) that benefits from D2 receptor antagonism, D3 receptor antagonism, D4 receptor antagonism, and / or 5-HT2A receptor agonism in a patient (e.g., aAttorney Docket No. EGL-13-PCT human) in need thereof, wherein the method comprises administering to the patient Compound A, in free or pharmaceutically acceptable salt form (e.g., any of Formula A.1-A.9 vide supra) or a pharmaceutical composition comprising Compound A, in free or pharmaceutically acceptable salt form (e.g., Formula A.9 or any of Composition 1 or 1.1-1.14 vide supra). For instance, provided are methods as described below.

[0036] Further provided are methods of enhancing neural plasticity in a patient (e.g., a human) in need thereof, wherein the method comprises administering to the patient Compound A, in free or pharmaceutically acceptable salt form (e.g., any of Formula A.1-A.9 vide supra) or a pharmaceutical composition comprising Compound A, in free or pharmaceutically acceptable salt form (e.g., Formula A.9 or any of Composition 1 or 1.1-1.14 vide supra). For instance, provided are methods of enhancing neural plasticity to improve recovery in a patient (e.g., a human) in need thereof with a brain injury, e.g., to improve recovery following a stroke or traumatic brain injury, wherein the method comprises administering to the patient Compound A, in free or pharmaceutically acceptable salt form (e.g., any of Formula A.1-A.9 vide supra) or a pharmaceutical composition comprising Compound A, in free or pharmaceutically acceptable salt form (e.g., Formula A.9 or any of Composition 1 or 1.1-1.14 vide supra).

[0037] Provided is a method (Method 1) for treatment or prophylaxis of a disorder (e.g., a brain disorder) in a patient (e.g., a human) in need thereof, wherein the method comprises administering to the patient an effective amount of Compound A:Compound A, in free or pharmaceutically acceptable salt form, wherein the effective amount of the compound is substantially free of its (S,S) enantiomer.Attorney Docket No. EGL-13-PCT

[0038] Further provided are Method 1 as follows:1.1 Method 1, wherein the method comprises administering to the patient Compound A, in free or pharmaceutically acceptable salt form, as described in any of Formula A.1-A.9 vide supra. For instance, Method 1, wherein the method comprises administering to the patient a pharmaceutical composition comprising Compound A, in free or pharmaceutically acceptable salt form, as described in any of Formula A.9 or Composition 1 or 1.1-1.14 vide supra.1.2 Method 1 or 1.1, wherein the effective amount of Compound A, in free or pharmaceutically acceptable salt form, has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e g., a stereoisomeric excess equal to or greater than 99%. For instance, wherein the effective amount of Compound A, in free or pharmaceutically acceptable salt form, is substantially diastereomerically and / or enantiomerically pure, e.g., wherein the effective amount of Compound A, in free or pharmaceutically acceptable salt form, is substantially diastereomerically and enantiomerically pure. For instance, wherein the effective amount of Compound A, in free or pharmaceutically acceptable salt form, has a diastereomeric and / or enantiomeric excess of greater than 90%, e.g., a diastereomeric and / or enantiomeric excess equal to or greater than 95%, a diastereomeric and / or enantiomeric excess equal to or greater than 96%, a diastereomeric and / or enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and / or enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and / or enantiomeric excess equal to or greater than 99%. For instance, wherein the effective amount of Compound A, in free or pharmaceutically acceptable salt form, has a diastereomeric and enantiomeric excess of greater than 90%, e g., a diastereomeric and enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 97%, e.g., aAttorney Docket No. EGL-13-PCT diastereomeric and enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 99%. Any of Method 1, 1.1, or 1.2, wherein the compound is in free form. Any of Method 1 or 1.1-1.3, wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance. Any of Method 1 or 1.1 -1.4, wherein the effective amount of the compound, in free or pharmaceutically acceptable salt form, has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. Any of Method 1 or 1.1-1.5, wherein the disorder is a brain disorder. For instance, any of Method 1 or 1.1-1.5, wherein the disorder is a neuropsychiatric condition in which anhedonia is prominent. Any of Method 1 or 1.1-1.6, wherein the disorder is an affective (mood) disorder or an anxiety disorder. Any of Method 1 or 1.1-1.7, wherein the disorder is depression (e.g., depression associated with anhedonia), an anxiety disorder, psychosis (e.g., psychosis in neurodegenerative conditions, such as psychosis in Alzheimer’s disease, Parkinson’s disease, or dementia (e.g., dementia-related psychosis)), schizophrenia, schizoaffective disorder, post-traumatic stress disorder (PTSD), attention-deficit / hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder (including bipolar depression, bipolar mania, and bipolar disorder with mixed features), or a migraine. For instance, any of Method 1 or 1.1-1.7, wherein the anxiety disorder is panic disorder, social anxiety disorder, a phobia, or generalized anxiety disorder. Or, any of Method 1 or 1.1-1.7, wherein the method is prophylaxis orAttorney Docket No. EGL-13-PCT treatment of behavioral and psychological symptoms of dementia including agitation, depression, anxiety, apathy, and / or psychosis. For instance, any of Method 1 or 1.1-1.7, wherein the method is prophylaxis or treatment of post- traumatic stress disorder (PTSD), e.g., treatment of post-traumatic stress disorder (PTSD). Any of Method 1 or 1.1-1.8, wherein the disorder is anhedonia or depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression. For instance, any of Method 1 or 1.1-1.8, wherein the disorder is anxious depression. Or, for instance any of Method 1 or 1.1-1.8, wherein the disorder is melancholic depression. Any of Method 1 or 1.1-1.9, wherein the disorder is major depressive disorder. Any ofMethod 1 or 1.1-1.8, wherein the disorder is a substance use disorder. Any ofMethod 1 or 1.1-1.8, wherein the method is prophylaxis or treatment of negative symptoms of schizophrenia. Or, any ofMethod 1 or 1.1-1.8, wherein the method is improving cognition in schizophrenia. Any ofMethod 1 or 1.1-1.8, wherein the method is improving cognition, e.g., in cognitive impairment, e.g., cognitive impairment in schizophrenia, depression, or dementia. For instance, any ofMethod 1 or 1.1-1.8, wherein the method is improving cognition in major depressive disorder. Any ofMethod 1 or 1.1-1.5, wherein the compound, in free or pharmaceutically acceptable salt form, is administered as an anti-emetic. Any ofMethod 1 or 1.1-1.14, wherein the method comprises administering 9-60 mg a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 9-60 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form). For instance, any ofMethod 1 or 1.1-1.14, wherein the method comprises administering 9-36 mg a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 9-36 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form). Any ofMethod 1 or 1.1-1.15, wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, thatAttorney Docket No. EGL-13-PCT provides 55%-80% D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography. For instance, wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides about 65% D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography. Or, for instance, wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides about 60% D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography. Method 1.15 or 1.16, wherein the disorder is psychosis (e.g., psychosis in neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease, and dementia (e.g., dementia-related psychosis)), schizophrenia, schizoaffective disorder, or bipolar disorder (e.g., bipolar mania). Method 1.15 or 1.16, wherein the method is prophylaxis or treatment of negative symptoms of schizophrenia. Or, Method 1.15 or 1.16, wherein the method is improving cognition in schizophrenia. Any of Method 1 or 1.1-1.14, wherein the method comprises administering 1-9 mg (e.g., 1-8 mg, e.g., 1.5-6 mg) a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 1-9 mg total daily dose, e.g., 1-8 mg total daily dose, e.g., 1.5-6 mg total daily dose, of the compound, in free or pharmaceutically acceptable salt form). For instance, any of Method 1 or 1.1-1.14, wherein the method comprises administering 1-8 mg a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 1-8 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form). For instance, any of Method 1 or 1.1-1.14, wherein the method comprises administering 1-3 mg a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 1-3 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form). For instance, any of Method 1 or 1.1-1.14, wherein the method comprises administering 1 mg to less than 3 mg a day (e.g., 2 mg a day) of the compound, in free or pharmaceutically acceptable salt form (i.e., 1 mg to less than 3 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form).Attorney Docket No. EGL-13-PCT Any of Method 1, 1.1-1.14, or 1.19, wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides 10%-60% (e.g., 40%-60% or, e.g., 10%-55%, e.g., 10%-50%, e.g., 30%- 50% or, e.g., 15%-50%, e.g., 15%-45%, e.g., 20%-40%, e.g., 10%-30%) D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography. Or, for instance, any of Method 1, 1.1-1.14, or 1.19, wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides < 40% (e.g., about 40%), e g., < 40% D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography. Method 1.19 or 1.20, wherein the disorder is depression (e.g., depression associated with anhedonia), an anxiety disorder, post-traumatic stress disorder (PTSD), attend on-deficit / hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder, bipolar disorder with mixed features, or a migraine. For instance, Method 1.19 or 1.20, wherein the anxiety disorder is panic disorder, social anxiety disorder, a phobia, or generalized anxiety disorder. Or, for instance, Method 1.19 or 1.20, wherein the disorder is post-traumatic stress disorder. Any of Method 1.19-1.21, wherein the disorder is anhedonia or depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression. For instance, wherein the disorder is anxious depression. Any of Method 1.19-1.22, wherein the disorder is major depressive disorder. Any of Method 1.19-1.21, wherein the disorder is a substance use disorder. Any of Method 1 or 1.1-1.24, wherein the method comprises administering a pharmaceutical composition comprising the compound, in free or pharmaceutically acceptable salt form. For instance, any of Method 1 or 1.1-1.24, wherein the method comprises administering Formula A.9 or any of Composition 1 or 1.1-1.14 vide supra.Attorney Docket No. EGL-13-PCT1.26 Any of Method 1 or 1.1-1.25, wherein the method comprises administering Compound A, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day. For instance, any of Method 1 or 1.1-1.25, wherein the method comprises administering a pharmaceutical composition comprising Compound A, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day.1.27 Also provided are any of Methods 1 or 1.1-1.26 to promote or enhance neural plasticity in a patient (e g., a human) in need thereof, wherein the method comprises administering to the patient Compound A, in free or pharmaceutically acceptable salt form (e.g., any of Formula A.1-A.9 vide supra) or a pharmaceutical composition comprising Compound A, in free or pharmaceutically acceptable salt form (e.g., Formula A.9 or any of Composition 1 or 1.1-1.14 vide supra). For instance, provided are methods of promoting or enhancing neural plasticity to improve recovery in a patient (e.g., a human) in need thereof with a brain injury, e.g., to improve recovery following a stroke or traumatic brain injury, wherein the method comprises administering to the patient Compound A, in free or pharmaceutically acceptable salt form (e.g., any of Formula A.1-A.9 vide supra) or a pharmaceutical composition comprising Compound A, in free or pharmaceutically acceptable salt form (e.g., Formula A.9 or any of Composition 1 or 1.1-1.14 vide supra).

[0039] Further provided is Compound A (e.g., any of Formula A.1-A.9) or a pharmaceutical composition disclosed herein (e.g., Formula A.9 or any of Composition 1 or 1.1-1.14) for use in any of Method 1 or 1.1-1.27 vide supra.

[0040] Further provided is use of Compound A (e.g., any of Formula A.1-A.9) or a pharmaceutical composition disclosed herein (e.g., Formula A.9 or any of Composition 1 or 1.1- 1.14) in any of Method 1 or 1.1-1.27 vide supra.

[0041] Further provided is use of Compound A (e.g., any of Formula A.1-A.9) in the manufacture of a medicament (e.g., Formula A.9 or any of Composition 1 or 1.1-1.14) for use in any of Method 1 or 1.1-1.27 vide supra.

[0042] For compounds disclosed herein, a hydrogen atom position of a structure is considered substituted with deuterium when the abundance of deuterium at that position is enriched. TheAttorney Docket No. EGL-13-PCT natural abundance of deuterium is about 0.02%, so a compound is “enriched” with deuterium at a specific position when the frequency of incorporation of deuterium at that position exceeds 0.02%. Therefore, for deuterated compounds disclosed herein, any position designated as deuterium (i.e., D) may be enriched with deuterium at a level of greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%, such as, greater than 50%, or greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. For compounds disclosed herein, any atom not designated as a particular isotope is present at natural isotopic abundance.

[0043] Compound A may exist in free or salt form, e.g., as an acid addition salt. As used herein, unless otherwise indicated, language such as “compound of formula” is to be understood as embracing the compound in any form, for example free or acid addition salt form, or where the compound contains an acidic substituent, in base addition salt form. Compound A is intended for use as a pharmaceutical, therefore a pharmaceutically acceptable salt is preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of Compound A in free form or for its pharmaceutically acceptable salts, so therefore are also included.

[0044] Isolation or purification of Compound A, in free or pharmaceutically acceptable salt form, may be achieved by conventional methods known in the art, e.g., column purification, preparative thin layer chromatography, preparative HPLC, trituration, simulated moving beds, and the like.

[0045] Pure stereoisomeric forms of Compound A and intermediates disclosed herein are isomers substantially free of other enantiomeric and diastereomeric forms of the same basic molecular structure of said compounds or intermediates. “Substantially stereoisomerically pure” includes compounds or intermediates having a stereoisomeric excess of greater than 90% (i.e., more than 90% of one stereoisomer and less than 10% of any other possible stereoisomer). The terms “substantially diastereomerically pure” and “substantially enantiomerically pure” should be understood in a similar way, but then having regard to the diastereomeric excess and enantiomeric excess, respectively, of the material in question.

[0046] Compound A, in free or pharmaceutically acceptable salt form, may be made by using the methods as described and exemplified herein and by methods similar thereto and by methodsAttorney Docket No. EGL-13-PCT known in the chemical art. Such methods include, but are not limited to, those described below. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques that are similar to or analogous to the synthesis of known compounds.

[0047] Pharmaceutically acceptable salts of Compound A may be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.Generally, such salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in an appropriate solvent.

[0048] For methods of treatment, the word “effective amount” is intended to encompass a therapeutically effective amount to treat a specific disease or disorder.

[0049] Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular compound used, the mode of administration, and the therapy desired.

[0050] Compound A, in free or pharmaceutically acceptable salt form, may be administered by any suitable route, including orally, parenterally, or transdermally, but are preferably administered orally.

[0051] Pharmaceutical compositions comprising Compound A, in free or pharmaceutically acceptable salt form, may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.

[0052] “Patient” as used herein includes human and non-human (i.e., animal). In some embodiments, the patient is human.EXAMPLESAbbreviationsAcOH = acetic acidBoc = tert-butyloxy carbonylDI AD = di isopropyl azodi carb oxy lateDCM = dichloromethaneDMA or DMAc = dimethylacetamideDMAP = 4-dimethylaminopyridineAttorney Docket No. EGL-13-PCTDMF = dimethylformamideEDCI = l-ethyl-3-(3-dimethylaminopropyl)carbodiimideEtOAc or EA = ethyl acetate h = hour(s)HOBt = hydroxybenzotriazoleMeOH = methanol min = minute(s)MsCl = methanesulfonyl chloride rt (or RT or r.t.) = room temperatureTEA = triethylamineTFA = trifluoroacetic acidTHF = tetrahydrofuranExample 1Step 1SM-1 1

[0053] A solution of SM-1 (2.0 g, 9.5 mmol) in dry THF (20 m ) is dropwise added to a stirring solution of LiAlD4 (0.6 g, 14.3 mmol) in dry THF (20 mb) at 0 °C under nitrogen atmosphere.The reaction is allowed to warm to room temperature and stirred at the same temperature over 16 h. On completion, it is cooled to 0 °C and quenched with 10% aqueous NaOH (0.6 mb) and H2O (1.2 mb). The suspension is filtered. The filtrate is concentrated to give crude 1 (2.0 g crude, 99% yield) as a yellow oil.

[0054] Synthesis of SM-1 (also referred to as 21) is described in Example 9.Step 2Attorney Docket No. EGL-13-PCT

[0055] To a stirred solution of 1 (2.0 g, 10.1 mmol) in EtiN (2.0 g, 20.2 mmol) and DCM (20 mL) at 0 °C is added MsCl (1.6 g, 14 mmol). The reaction mixture is stirred at rt for 2 h, then quenched with saturated aqueous NaHCOa (x 2) and the aqueous layer extracted with DCM. The combined organic phase is washed with brine. The organic phase is dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give 2 (2.8 g, 100% yield) as a yellow oil. Step 3

[0056] To a stirred solution of 2 (2.8 g, 10.1 mmol) in DMF (30 mL) is added NaNa (2 g, 30.2 mmol). The reaction mixture is stirred for 18 h at 80 °C. It is quenched with water and extracted with EtOAc (x 2). The organic phase is washed with brine and dried over Na2SO4. The organic phase is concentrated. The residue containing 3 with DMF is used directly for next step (2.3 g,99% yield).Step 4Attorney Docket No. EGL-13-PCT

[0057] A mixture of 3 (2.3 g, 10.1 mmol) and 10% Pd / C (0.6 g) in MeOH (150 mL) is stirred under H2 (atmospheric pressure) over 18 h at rt. The reaction mixture is filtered, the solvent evaporated, and it is diluted with EtOAc (3 mL). HC1 (4 mol / L in EtOAc) (3.0 mL) is added to the solution. The reaction mixture is stirred at rt for 1 h and then filtered to give 4 (0.96 g, 41% yield) as a pink oil.Step 5

[0058] A mixture of SM-2 (1.3 g, 4.1 mmol), EtaN (1.2 g, 12.3 mmol), and DMAc (10 mL) is stirred at rt for 0.5 h. Then 4 (0.96 g, 4.1 mmol), HOBt (0.7 g, 4.9 mmol), and EDO (0.9 g, 4.9 mmol) are added and the reaction mixture is stirred at rt for 3.5 h. The resulting mixture is quenched with water and extracted with EtOAc (x 3), washed with brine, dried (Na2SO4), and concentrated to give 5 (0.9 g, 44% yield) as a brown oil.Step 6

[0059] To a stirred solution of 5 (0.9 g, 1.8 mmol) in EtOAc (30 mL) is added HC1 (4 mol / L in EtOAc) (30 mL) at rt and stirred for 1 h. The reaction mixture is concentrated and the residue is diluted with EtOAc (2 L) and basified by addition of saturated NaHCOa to pH~8. The organic layer is separated and washed with brine, dried over Na2SO4, and concentrated. The residue is purified by flash column chromatography (0~5% methanol in DCM) to give 6 (Compound A) as a solid. 'H NMR (400 MHz, DMSO-t / 6) 5 7.92 (d, J= 8.8 Hz, 1H), 7.74 (s, 1H), 6.26 (s, 1H), 6.12-6.09 (m, 1H), 4.42-4.40 (m, 1H), 3.98 (s, 3H), 2.85-2.81 (m, 4H), 2.59-2.54 (m, 1H), 2.13- 2.06 (m, 2H), 1.54-1.49 (m, 1H), 1.00 (d, J= 6.4 Hz, 3H).Attorney Docket No. EGL-13-PCTExample 2 - Binding Competition and Agonist or Antagonist Activity on Recombinant Human D2L, D2S, 5-HT1A, and 5-HT2A Receptors using cAMP HTRF, IPOne HTRF, and Filtration Binding Assays

[0060] Radioligand binding experiments are conducted with membrane preparations.

[0061] IPOne and cAMP assays are conducted with recombinant cell lines. Receptors, accession numbers, and cellular background are shown in Table 1 and Table 2.Table 1. Cell lines - functionalTable 2. Cell lines - binding

[0062] Compounds are tested for agonist activity at the human 5-HT2A receptor and for antagonist activity at the human D2L and D2S receptors at ten concentrations in duplicate.

[0063] Compounds are tested for radioligand binding competition activity at the human 5-HT2A and D2L receptors at ten concentrations in duplicate.

[0064] Agonist activity of test compounds is expressed as a percentage of the activity of the reference agonist at its ECioo concentration. Antagonist activity of the test compound is expressed as a percentage of the inhibition of reference agonist activity at its ECso concentration.

[0065] Binding of test compounds is expressed as a percentage of the residual binding of the radioligand.

[0066] Data is in Tables 3-5.Table 3. Functional AssaysAttorney Docket No. EGL-13-PCTa. (±)-cA-A-(l-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide b. N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4- (methylamino)benzamide c. Average of numbers in parentheses.d.Table 4. Top % Inhibition or Activation at maximal concentrationa. (±)-cA-A-(l-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide b. N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide c. Average of numbers in parentheses.Table 5. BindingAttorney Docket No. EGL-13-PCTa. (±)-cA-A-(l-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide b. N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(m ethyl ami no)b enzami de c. Average of numbers in parentheses.

[0067] As shown above, Compound A is a D2 antagonist and 5-HT2A agonist.Table 6.a. N-[(2R, 3R)-1 -benzyl -2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(m ethyl ami no)b enzami deExample 3 - In vivo pharmacokinetics

[0068] Group A rats are dosed (by PO) with test compound. Blood samples are obtained at 5, 10, and 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Following blood collection at 24 hours, brain perfusion is performed on the animals before harvesting brain tissues.

[0069] Group B rats are dosed (by PO) with test compound. At designated timepoints (1, 4, and 8 hours), three animals from each dose group undergo blood draw followed by brain perfusion before samples are collected.

[0070] Test compound is Compound A.

[0071] Plasma (harvested from blood samples) and brain tissues (homogenized and processed) are analyzed by LC / MS / MS. Plasma is harvested from blood via centrifugation. Brain tissue is collected after animals undergo perfusion to remove residual cardiovascular blood.Attorney Docket No. EGL-13-PCTExample 4 - Ex Vivo Radioligand Binding in Membrane Preparations to Determine Time- Course of Receptor Occupancy at Central D2 Receptors

[0072] This study is to determine receptor occupancy at central D2 receptors following oral administration of Compound A at various time points (e.g., 1, 2, 4, 8, and 24 hours) and the positive comparator, olanzapine (10 mg / kg, po) using [3H]raclopride and rat striatal membranes. Liquid scintillation counting is used to quantify radioactivity.Animals

[0073] Rats.Drug Treatment

[0074] On day of test, animals are dosed orally with either vehicle, a single dose of Compound A or olanzapine. Rats are sacrificed at specified time points, e.g., 1, 2, 4, 8, and 24 hours after drug administration or 1 hour after vehicle and olanzapine administration.Pharmacokinetics

[0075] A post-mortem blood sample is taken by cardiac puncture. Plasma is taken for PK determination.

[0076] Whole brains are removed, rinsed with saline, and blot dried. The left striatum and right striatum is dissected out and weighed before being frozen on dry ice.Homogenate Preparation

[0077] The striata is homogenised individually.Assay

[0078] Striatal homogenates are incubated with [3H]racl opride. Radioactivity is determined by liquid scintillation counting.Example 5 - Touchscreen-Based Rat Probabilistic Reward Task

[0079] The Probabilistic Reward Task (PRT) uses visual discrimination methodology to quantify reward responsiveness to both identify deficits and characterize drug-induced improvements. Groups of rats are trained on the touchscreen-based PRT and exposed to asymmetrical probabilistic contingencies to generate response biases to the richly rewarded stimulus (Pizzagalli, D. et al., Biological Psychiatry, 2005, 57, 319-327; Kangas, B. et al., Translational Psychiatry, 2020, 10(l):285; Wooldridge, L. et al., International Journal of Neuropsychopharmacology, 2021, 24, 409-418). Next, subjects are tested with vehicle or Compound A.Attorney Docket No. EGL-13-PCT

[0080] Details and schematics of the rodent touch-sensitive experimental chamber and methods can be found in Kangas, B. et al., Behavioural Pharmacology, 2017, 28, 623-629.Example 6 - Conditioned Avoidance Response

[0081] Rats are used. Risperidone (0.5 mg / kg; Sigma Aldrich) is dissolved in 10% DMSO in water and injected i.p. at a dose volume of 1 mg / kg 30 minutes prior to test. Compound A is administered orally prior to test.

[0082] The Conditioned Avoidance Response (CAR) Test is an animal model screening for antipsychotic drugs.Example 7 - Headshake Response

[0083] Rats are used. Compound A is administered orally.

[0084] Animals are administered vehicle, DOI, or test compound and returned to their holding cage for the appropriate pretreatment time, following which headshakes are recorded. The headshake response is a rapid, rhythmic shaking of the head in a radial motion.Example 8 - DOI-Induced Headshake Response

[0085] Rats are used. Compound A is administered orally. DOI is administered IP. Ketanserin (1 mg / kg) is injected IP.

[0086] Animals are administered vehicle, ketanserin, or test compound and returned to their holding cage for the appropriate pretreatment time. Rats are then injected with DOI and headshakes are recorded 10 minutes after DOI injection for 10 minutes. The headshake response is a rapid, rhythmic shaking of the head in a radial motion.Example 9 - Synthesis of Starting Material for Example 1Compound 15: tert-butyl (R)-2-methyl-3,5-dioxopyrrolidine-l-carboxylateAttorney Docket No. EGL-13-PCT

[0087] To a stirred solution of Boc-D-alanine (500 g, 2.64 mol), Meldrum’s acid (400 g, 2.78 mol) and DMAP (388 g, 3.18 mol) in CH2CI2 (5 L) is added EDCI (608 g, 3.18 mol) under nitrogen at 0 °C. The resulting solution is then allowed to warm up to room temperature (rt) and stirred over 16 h. It is quenched with water (1.5 L), the organic phase is washed with a cold solution of 5% KHSO4 (3 L x 3), water (3 L x 1), and brine, then dried over anhydrous MgSCU, and concentrated to give the residue. EtOAc (4 L) is added and the reaction mixture is refluxed for 2 hours. The solution is concentrated and the residue is stirred in EtOAc (500 L) at -15 °C for 2 h, then filtered, and the filter cake is collected to give the title compound as a white solid (150 g, 27% yield). The mother liquid is further refluxed for 2 hours then stirred in EA at -10 °C and filtered to give the title compound (40 g) as a white solid. 'H NMR (400 MHz, CDCI3): 84.45 (q, J= 6.8 Hz, 1H), 3.22 (s, 2H), 1.57 (s, 9H), 1.51 (d, J= 6.8 Hz, 3H). MS m / z (ESI): 158 [M+H-56]+sCompound 16: tert-butyl (2R,3R)-3-hydroxy-2-methyl-5-oxopyrrolidine-l-carboxylate15 16

[0088] To a stirred solution of compound 15 (40 g, 187.6 mmol) in DCM (400 ml) is added AcOH (200 mL) at 0 °C, then NaBH4 (21.3 g, 562.8 mmol) is added in three portions. The resulting solution is then allowed to warm up to room temperature and stirred over 16 h. The reaction mixture is quenched with 5% NaHCCE at 0 °C. It is extracted with DCM (200 mL x 3). The combined organic layer is washed with 5% NaHCCh solution. The organic phase is dried over anhydrous MgSCL and concentrated to give the residue that is stirred in isopropyl ether and filtered to give the title compound 16 (24 g, 59.4% yield). 'H NMR (400 MHz, CDCI3): 84.53- 4.47 (m, 1H), 4.29-4.22 (m, 1H), 2.75-2.55 (m, 2H), 1.53 (s, 9H), 1.3 l(d, J= 6.8 Hz, 3H). MS m / z (ESI): 160 [M+H-56]+Compound 17: tert-butyl (2R,3R)-3-hydroxy-2-methylpyrrolidine-l-carboxylateAttorney Docket No. EGL-13-PCT

[0089] To a solution of compound 16 (87 g, 405 mmol) in dry THF (1 L) is added a solution of BHa-SMe? (600 mL, 1200 mmol) at 0 °C and it is stirred for 30 min at 0 °C. Then the mixture is refluxed for 4 h. The resulting mixture is cooled and quenched with saturated NH4CI at 0 °C. It is then extracted with EtOAc (1 L x 3). The organic phases are dried over anhydrous MgSO4 and concentrated to give compound 17 (70 g, 86% yield). 'H NMR (400 MHz, DMSO-d6): 5 5.1 l(s, 1H), 4.19-4.10 (m, 1H), 3.83-3.63 (m, 1H), 3.22-2.89 (m, 2H), 1.87-1.54 (m, 2H), 1.38 (s, 9H), 0.85 (d, J= 6.8 Hz, 3H). MS m / z (ESI): 146 [M+H-56]+Compound 18: (2R,3S)-tert-butyl 2-methyl-3-(4-nitrobenzoyloxy)pyrrolidine-l-carboxylate

[0090] To a cold solution of compound 17 (15.74 g, 78.2 mmol), 4-nitrobenzoic acid (13.72 g, 82.1 mmol), and PPhs (16.42 g, 62.6 mmol) in dry THF (250 ml) is added DIAD (16.6 g, 82.1 mmol) for 30 minutes at 0 °C. The reaction mixture is allowed to warm room temperature for 16 h. The resulting mixture is cooled and quenched with water. The mixture is extracted with EtOAc (200 ml x 3), dried over anhydrous MgSCh, and then concentrated. The residue is purified by silica gel chromatography to afford the compound 18 (24.7 g, 90.1% yield). 'H NMRAttorney Docket No. EGL-13-PCT(400 MHz, CDCI3): 8 8.31-8.17 (m, 4H), 5.20 (d, J= 4 Hz, 1H), 4.17-3.86 (m, 1H), 3.59-3.46(m, 2H), 2.35-2.11 (m, 2H) 1.48 (s, 9H), 1.28 (d, J= 6.8 Hz, 3H). MS m / z (ESI): 295 [M+H-56]+Compound 19: (2R,3S)-2-methylpyrrolidin-3-yl 4-nitrobenzoate

[0091] A mixture of compound 18 (23.4 g, 66.8 mmol) and TFA (120 mL) in DCM (240 mL) is stirred at room temperature for 1 and then it is concentrated to give compound 19 (16.7 g, 100% yield). LCMS: M+ 1=251Compound 20: (2R,3S)-2-methyl-l-(pentadeuterobenzoyl)pyrrolidin-3-yl 4-nitrobenzoate

[0092] To a solution of the HC1 salt of 19 and 1.4 equivalents of benzoyl chloride-ds in DCM is added 4.4 equivalents of EtiN at 0 °C. The reaction mixture is allowed to warm r.t. and stirred for 16 h. Upon completion, the reaction mixture is washed with water (2 times), and concentrated to give 20 (crude).Compound 21 (SM-1 in Example 1): ((2R,3S)-3-hydroxy-2-methylpyrrolidin-l- yl)(pentadeuterophenyl) methanoneAttorney Docket No. EGL-13-PCT

[0093] To a stirred solution of 20 in MeOH / FEO (1: 1) is added 1.2 equivalents of NaOH. The reaction mixture is stirred for 2 h and then concentrated under reduced pressure. The residue is diluted with water, extracted with DCM (5 times). The organic phase is concentrated to give 21 (SM-1 in Example 1) (crude).

Claims

Attorney Docket No. EGL-13-PCTWhat is claimed:Compound A, in free or salt form, wherein the compound is substantially free of its (S,S) enantiomer.

2. The compound according to claim 1, wherein the compound is in pharmaceutically acceptable salt form.

3. The compound according to claim 1, wherein the compound is in free form.

4. The compound according to any one of claims 1-3, wherein the compound, in free or pharmaceutically acceptable salt form, has greater than 90% incorporation of deuterium at each designated as deuterium.

5. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound according to any one of claims 1-4, in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier.

6. A method for treatment of a brain disorder in a patient in need thereof, wherein the method comprises administering to the patient a compound according to any one of claims 1-Attorney Docket No. EGL-13-PCT4, in free or pharmaceutically acceptable salt form, or the pharmaceutical composition according to claim 5.

7. The method according to claim 6, wherein the disorder is an affective disorder or an anxiety disorder.

8. The method according to claim 7, wherein the disorder is depression, an anxiety disorder, psychosis, schizophrenia, schizoaffective disorder, post-traumatic stress disorder (PTSD), attention-deficit / hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder, or a migraine.

9. The method according to claim 6, wherein the anxiety disorder is panic disorder, social anxiety disorder, a phobia, or generalized anxiety disorder.

10. The method according to claim 6, wherein the disorder is anhedonia, depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post- psychotic depression.

11. The method according to claim 6, wherein the disorder is anxious depression.

12. The method according to claim 6, wherein the disorder is melancholic depression.

13. The method according to claim 6, wherein the disorder is major depressive disorder.

14. The method according to claim 6, wherein the disorder is a substance use disorder.Attorney Docket No. EGL-13-PCT15. The method according to claim 6, wherein the disorder is post-traumatic stress disorder (PTSD).

16. The compound according to any one of claims 1-4, in free or pharmaceutically acceptable salt form, or the pharmaceutical composition according to claim 5, for use in the treatment of a brain disorder.

17. Use of a compound according to any one of claims 1-4 in the manufacture of a medicament for treatment of a brain disorder.

18. The use according to claim 16 or 17, wherein the brain disorder is as recited in any of claims 7-15.

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