Deuterated organic compounds and uses thereof

Abstract

Provided herein are compounds of formula I, their preparation methods, their use as medicines, and pharmaceutical compositions containing them and intermediates used in their preparation.The compounds of formula I are useful, for example, for modulating dopamine and serotonin neurotransmission, and for treating disorders that may benefit from them, for example, schizophrenia and depression.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 296,134, filed January 3, 2022, U.S. Provisional Patent Application No. 63 / 345,007, filed May 23, 2022, and U.S. Provisional Patent Application No. 63 / 384,992, filed November 25, 2022, the entire contents of each of which are incorporated herein by reference.

[0002] Provided herein are compounds of formula I, methods for their preparation, their use as pharmaceuticals, pharmaceutical compositions containing them, and intermediates used in their preparation. Compounds of formula I are useful, for example, in modulating dopamine and serotonin neurotransmission, and in treating disorders that may benefit therefrom, such as schizophrenia and depression. [Background technology]

[0003] Dopamine is involved in various central nervous system functions, such as voluntary movement, feeding, emotion, reward, sleep, attention, working memory and learning. Serotonin is also involved in various central nervous system functions, such as mood, cognition, reward, learning, memory and various physiological processes. Thus, dopaminergic and / or serotonergic dysfunction may lead to disorders such as schizophrenia and depression.

[0004] When dopamine is released from the presynaptic terminal, it activates members of the G protein-coupled dopamine receptor D1-D5 family. The dopamine receptors (D1-D5) are divided into two groups: D1-like receptors (D1 and D5) and D2-like receptors (D2, D3 and D4). Activation of D1-like receptors activates adenyl cyclase and increases cAMP levels. D2-like receptors are inhibitory. Activation of D2-like receptors inhibits activation of adenyl cyclase.

[0005] D1-like receptors are present postsynaptically on dopamine receptor cells, whereas D2-like dopamine receptors are expressed both postsynaptically on dopamine target cells and presynaptically on dopaminergic neurons.

[0006] There are 14 subtypes of serotonin receptors, classified into subfamilies, that mediate the actions of serotonin (5-HT). The major receptor subtype, the 5-HT1A receptor subtype, is present on serotonin neurons in the raphe nuclei as presynaptic autoreceptors and in the prefrontal cortex, hippocampus, septum, and hypothalamus as postsynaptic heteroreceptors. The signaling mechanisms of 5-HT1A receptors in the raphe nuclei may differ from those of 5-HT1A receptors in other brain regions. Activation of 5-HT1A postsynaptic receptors can cause an increase in dopamine release. The 5-HT2A receptor subtype is abundant in the cortex, where it is associated with phosphatidylinositol turnover and also regulates dopamine release. 5-HT2A receptor antagonists are believed to have psychotic properties, while 5-HT2A receptor agonism is associated with cognitive enhancing and hallucinogenic properties. The hallucinogenic effects of lysergic acid diethylamide (LSD) and psilocybin are thought to arise from their 5-HT2A receptor agonism, which has also been reported to promote neuroplasticity and reduce depression.

[0007] Antipsychotics are used to treat psychosis, especially schizophrenia. A characteristic of antipsychotics is D2 receptor antagonism. D2 receptor antagonism is effective in reducing the positive symptoms of schizophrenia (e.g., hallucinations and delusions), but it can produce extrapyramidal side effects such as parkinsonism, akathisia, and tardive dyskinesia, and often increases prolactin levels, which can worsen the negative symptoms of schizophrenia (e.g., loss of interest and motivation for life and activities, social withdrawal, and anhedonia). The main characteristic of atypical antipsychotics is that they combine D2 receptor antagonism with 5-HT2A receptor antagonism, which is thought to be the reason for their enhanced efficacy and reduced extrapyramidal motor side effects (EPS) compared to typical antipsychotics. Many patients with psychosis also suffer from depression, which may remain untreated with current medications. However, some atypical antipsychotics are used as adjuncts to serotonergic antidepressants to improve response in major depressive disorder.

[0008] Because an imbalance between dopamine and serotonin can lead to a variety of disorders and current pharmaceuticals may not be able to effectively regulate levels of both, new compounds that can regulate dopamine and serotonin neurotransmission are needed, as well as methods for treating diseases involving an imbalance between dopamine and serotonin. Summary of the Invention

[0009] Compounds of formula I: [ka] [In the formula, R1, R2, R3, R4 and R5 are independently selected from H and D; At least one of R1, R2 and R3 is D. The compound of formula (1) is provided.

[0010] Additionally provided are pharmaceutical compositions comprising compounds of formula I, processes for preparing compounds of formula I, and medical uses of compounds of formula I, such as anti-anhedonic agents and for treating schizophrenia and depression.

[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. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows the disposition of cis(R,R) nemonapride in human hepatocytes.

[0013] [Diagram 2] FIG. 2 shows the disappearance of compound (A2) of Example 1 in human hepatocytes.

[0014] [Diagram 3] FIG. 3 shows the plasma concentrations (ng / ml) of cis (R,R) nemonapride and the compound of Example 1 (A2) following a single 0.5 mg / kg PO dose in rats.

[0015] [Figure 4] FIG. 4 shows the prolonged enrichment in the brain compared to plasma levels of compound of Example 1 (A2) following a single 0.5 mg / kg PO dose in rats.

[0016] [Diagram 5] FIG. 4 shows the prolonged enrichment in the brain compared to plasma levels of compound of Example 1 (A2) following a single PO dose of 5 mg / kg in rats.

[0017] [Figure 6]FIG. 6 shows the mean brain concentrations (ng / ml) of cis (R,R) nemonapride and the compound of Example 1 (A2) in rats administered a single 0.5 mg / kg PO dose.

[0018] [Figure 7] FIG. 7 shows the mean plasma concentrations (ng / ml) of cis(R,R) nemonapride and the compound of Example 1 (A2) following a single oral dose of 2.5 mg / kg in rats.

[0019] [Figure 8] FIG. 8 shows the prolongation of brain enrichment in rats following a single oral dose of 2.5 mg / kg of compound (A2) of Example 1, compared with plasma levels.

[0020] [Figure 9] FIG. 9 shows the mean brain concentrations (ng / ml) of cis (R,R) nemonapride and the compound of Example 1 (A2) following a single oral dose of 2.5 mg / kg to rats.

[0021] [Figure 10] FIG. 10 shows the D2 receptor occupancy of cis(R,R) nemonapride and the compound of Example 1 (A2) when orally administered to rats at a dose of 2.5 mg / kg.

[0022] [Figure 11] FIG. 11 shows the mean plasma and brain concentrations (ng / ml) of cis(R,R) nemonapride following a single oral dose of 2.5 mg / kg to rats.

[0023] [Figure 12A] FIG. 12A shows the response bias in a probabilistic reward task when the compound of Example 1 (A2) was administered to rats at doses of 0.5 mg / kg, 1 mg / kg, and 2.5 mg / kg.

[0024] [Figure 12B] FIG. 12B shows the discrimination in a probabilistic reward task when the compound of Example 1 (A2) was administered to rats at doses of 0.5 mg / kg, 1 mg / kg, and 2.5 mg / kg.

[0025] [Figure 13] FIG. 13 shows the pharmacokinetics:pharmacodynamics model of compound (A2) of Example 1 at 1 mg / kg oral administration.

[0026] Detailed Description The following description of the preferred embodiment is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.

[0027] In the event of a discrepancy between a definition in this disclosure and a definition in a cited reference, the present disclosure controls.

[0028] D2- and D3-receptors are expressed both postsynaptically on dopamine target cells and presynaptically on dopamine neurons. Dopamine receptors are mainly present on non-dopamine neurons. Dopamine receptors on dopamine neurons are called autoreceptors. Autoreceptors contribute to the regulation of dopamine neuron activity and control the synthesis, release and uptake of dopamine.

[0029] Presynaptic D2-like dopamine autoreceptors regulate dopamine release. Low doses of D2-like receptor antagonists may preferentially block presynaptic autoreceptors and increase dopamine release, whereas high doses of D2-like receptor antagonists may block postsynaptic receptors and decrease dopamine neurotransmission. Relatively high occupancy of D2-like receptors is associated with antipsychotic effects, whereas low occupancy is associated with antidepressant effects.

[0030] Anhedonia is a core symptom of major depressive disorder (MDD) and is associated with poor response to approved selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), as well as psychotherapy (e.g., cognitive behavioral therapy (CBT)) and neurostimulation techniques (e.g., transcranial magnetic stimulation (TMS)). There remains a need for effective treatments for MDD characterized by anhedonia. Despite the availability of a variety of therapies, up to 50% of people suffering from MDD do not respond to treatment, only about 30% of patients fully recover even with currently available antidepressants, and treatment outcomes for MDD individuals with anhedonia are even worse.

[0031] Dopamine / catecholamine depletion causes symptoms of depression and anhedonia. Increasing dopamine neurotransmission can reduce symptoms of depression and anhedonia. However, high doses of dopamine D2 / D3 agonists may activate dopamine postsynaptic receptors, but are also poorly tolerated (e.g., nausea / vomiting). Low doses of dopamine D2 / D3 receptor antagonists may preferentially block presynaptic dopamine autoreceptors and increase dopamine release without poorer tolerance.

[0032] In addition to MDD, anhedonia has also been implicated in bipolar disorder, schizophrenia, post-traumatic stress disorder and substance use disorders. Despite its involvement in many disorders, there are no approved medications to treat anhedonia.

[0033] Decreased serotonergic activity is involved in anxiety and depression, and increasing serotonin neurotransmission may reduce symptoms of anxiety and depression and may be useful for treating anxiety-related depression.

[0034] The IUPAC name for nemonapride is (±)-cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide. Nemonapride is described in U.S. Patent 4,210,660 as a potent central nervous system depressant, particularly as a potent antipsychotic.

[0035] Nemonapride is a dopamine D2 / D3 / D4 receptor antagonist. Nemonapride is approved in Japan and South Korea for the treatment of schizophrenia. Nemonapride is supplied in 3 mg and 10 mg tablets. The approved daily dose of nemonapride for schizophrenia is 9 to 36 mg orally taken in divided doses after meals. The dose can be increased to 60 mg daily.

[0036] Nemonapride's prescribing information indicates that the elimination half-life of nemonapride is 2.3-4.5 hours following oral administration of 3 mg and 6 mg doses to healthy adults. Urinary metabolites of nemonapride result from debenzylation and N-demethylation. See Emirace package insert.

[0037] Nemonapride is a 5-HT1A agonist in addition to being a dopamine D2 / D3 / D4 receptor antagonist.In addition, nemonapride has been reported to bind to the 5-HT2A receptor, but the inventors are not aware of any publications that report functional effects at that receptor.However, since the main characteristic of atypical antipsychotics is D2 receptor antagonism combined with 5-HT2A receptor antagonism or inverse agonism, it is expected that, as an antipsychotic, nemonapride is a 5-HT2A receptor antagonist.

[0038] 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 will have, especially for drugs with multiple biological targets.

[0039] The compounds of formula I disclosed herein are D2 / D3 / D4 receptor antagonists, 5-HT1A agonists and 5-HT2A partial agonists. The deuterated compound of Example 1 shows higher 5-HT2A agonism than its non-deuterated analogue (see Example 3). D2 / D3 / D4 receptor antagonism combined with 5-HT1A and 5-HT2A agonism is a unique activity profile that may allow for differential regulation of dopamine and serotonin neurotransmission compared to other D2 / D3 / D4 receptor antagonists. Other substituted benzamides tested, R-remoxipride, S-remoxipride, R-sulpiride, R-sulfopride and S-sulfopride, do not even bind to 5-HT2A receptors in vitro (labeled-Ketansrin competition assay).

[0040] As mentioned above, D2 / D3 / D4 receptor antagonism combined with 5-HT1A and 5-HT2A agonism is a unique activity profile that may allow for differential modulation of dopamine and serotonin neurotransmission compared to other D2 / D3 / D4 receptor antagonists. For example, D2 / D3 / D4 postsynaptic receptor antagonism reduces psychosis, particularly in schizophrenia, by lowering dopamine neurotransmission. High doses targeting 60% or more receptor occupancy may be associated with D2 antagonist-mediated side effects, such as extrapyramidal motor side effects (EPS) and increased prolactin. However, 5-HT1A agonism may limit the side effects associated with these high doses of D2 antagonists, thus providing a compound with built-in safety features when used at high doses as an antipsychotic. Partial 5-HT1A agonism also provides anxiolytic activity. Furthermore, as partial 5-HT2A agonists, the deuterated compounds disclosed herein may exhibit enhanced antidepressant effects, such as rapid and long-lasting anxiolytic effects, as seen with psychedelic antidepressants, while the hallucinogenic and fear / anxiety effects may be less pronounced than with full 5-HT2A agonists, and may block the hallucinogenic effects of 5-HT2A through D2 antagonism.

[0041] Thus, as a D2 / D3 antagonist and 5-HT2A partial agonist, the compound of formula I can provide psychedelic-like antidepressant efficacy at low doses (e.g., lower doses than those of nemonapride used to treat schizophrenia), and also has built-in protection against 5-HT2A-mediated hallucinations and no fear / anxiety.Furthermore, as a D2 / D3 antagonist and 5-HT1A agonist, the compound of formula I can act as an antipsychotic at high doses, but also has built-in protection against side effects associated with high doses of D2 antagonists.

[0042] The pharmacokinetics of the deuterated compounds disclosed herein are instructive. N-[(2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R)nemonapride) and the deuterated compound (A2) of Example 1 have similar plasma pharmacokinetics (see Example 5). However, despite the similar plasma pharmacokinetics, Examples 5 and 6 show that the compound of formula I (the deuterated compound of Example 1) has brain level enrichment and retention compared to its non-deuterated analog, with higher receptor occupancy levels at 1 hour, 2 hours, 8 hours and 24 hours. For example, Figures 6 and 9 show that at 8 hours, the brain levels of the compound (A2) of Example 1 are similar to the highest measured levels of cis(R,R)nemonapride, which occurs at a shorter time. The deuterated compound of Example 1 also shows extended brain enrichment compared to the plasma levels of the compound. Brain:plasma exposure supports once-daily dosing. The enrichment in brain levels, high receptor occupancy levels, and extended enrichment in brain compared to plasma levels are beneficial features that allow for higher and more sustained receptor occupancy with less frequent dosing, which may be associated with fewer peripheral side effects. Furthermore, the receptor occupancy curves of the deuterated compound of Example 1 (see FIG. 10) show a more gradual change between peaks and valleys (flatter curve) compared to its non-deuterated analog, which should provide more consistent and stable levels of dopamine and serotonin neurotransmission. Receptor occupancy levels can be maintained in the desired range with a convenient dosing regime. In contrast, nemonapride is taken multiple times per day.

[0043] Compounds that are D2 / D3 / D4 receptor antagonists, 5-HT1A receptor agonists and 5-HT2A receptor partial agonists modulate dopamine and serotonin neurotransmission and are therefore useful for treating disorders involving the dopamine and serotonin signaling pathways, e.g., disorders involving the D2, D3, D4, 5-HT1A and / or 5-HT2A receptors.

[0044] Compounds of formula I: [ka] [In the formula, R1, R2, R3, R4 and R5 are independently selected from H and D; At least one of R1, R2 and R3 is D. The compound of formula (1) is provided.

[0045] Additionally, there is provided a compound of formula I: 1.1 A compound of formula I in the form of a pharma- ceutically acceptable salt. 1.2 A compound of formula I in free form. 1.3 A compound of any of formulas I, 1.1 or 1.2, wherein R1, R2 and R3 are D. 1.4 A compound of any of formulae I or 1.1-1.3, wherein R4 and R5 are D. 1.5 A compound of any of formulae I or 1.1-1.4, wherein R1, R2, R3, R4 and R5 are each D. 1.6 Compounds of any of formula I or 1.1 to 1.5, in free form or in salt form, e.g., in free form or in pharma- ceutically acceptable salt form, e.g., in free form [ka] Compound.

[0046] 1.7 Compounds of any of formulas I or 1.1-1.6, wherein the designation of deuterium (i.e., D) at a position means significantly more than the 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%). Atoms not designated as a particular isotope are present in natural isotopic abundance.

[0047] 1.8 Compounds of any of Formula I or 1.1-1.7, in free or salt form (e.g., a pharma- ceutically acceptable salt form), having greater than 50%, 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% deuterium (i.e., D) incorporation at one or more positions (e.g., all positions) designated as deuterium (i.e., D). For example, any compound of Formula I or 1.1-1.7, in free or salt form (e.g., a pharma- ceutically acceptable salt form), having greater than 50%, 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% deuterium (i.e., D) incorporation at each position designated as deuterium (i.e., D).

[0048] 1.9 Substantially stereomerically pure compounds of formula I or any of 1.1-1.8, e.g., compounds of formula I or any of 1.1-1.8 having a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess of equal to or greater than 95%, e.g., a stereoisomeric excess of equal to or greater than 96%, e.g., a stereoisomeric excess of equal to or greater than 97%, e.g., a stereoisomeric excess of equal to or greater than 98%, e.g., a stereoisomeric excess of equal to or greater than 99%, e.g., a substantially diastereomerically and / or enantiomerically pure compound, e.g., a substantially diastereomerically and enantiomerically pure compound of formula I or any of 1.1-1.8.

[0049] 1.10 Substantially diastereomerically pure compounds of formula I or any of 1.1-1.9, e.g., compounds of formula I or any of 1.1-1.9 having a diastereomeric excess of greater than 90%, for example, a diastereomeric excess of greater than or equal to 95%, for example, a diastereomeric excess of greater than or equal to 96%, for example, a diastereomeric excess of greater than or equal to 97%, for example, a diastereomeric excess of greater than or equal to 98%, for example, a diastereomeric excess of greater than or equal to 99%.

[0050] 1.11 Substantially enantiomerically pure compounds of formula I or any of 1.1-1.10, e.g., compounds of formula I or any of 1.1-1.10 having an enantiomeric excess of greater than 90%, for example, an enantiomeric excess of greater than or equal to 95%, for example, an enantiomeric excess of greater than or equal to 96%, for example, an enantiomeric excess of greater than or equal to 97%, for example, an enantiomeric excess of greater than or equal to 98%, for example, an enantiomeric excess of greater than or equal to 99%.

[0051] 1.12 A compound of any of formula I or 1.1-1.11, having the stereochemical configuration shown in formula I.

[0052] 1.13 A compound of Formula I or any of 1.1-1.12, present in a pharmaceutical composition with a pharma- ceutically acceptable carrier, e.g., a compound of Formula I or any of 1.1-1.12, present in a pharmaceutical composition with a pharma- ceutically acceptable carrier, e.g., an effective amount of the compound is present in a pharmaceutical composition with a pharma- ceutically acceptable carrier.

[0053] Additionally, compounds of formula I (e.g., any of formulas 1.1-1.3), in free form or in pharma- ceutically acceptable salt form: [ka] [In the formula, R1, R2, R3, R4 and R5 are independently selected from H and D; At least one of R1, R2 and R3 is D. A pharmaceutical composition (Composition 1) is provided comprising the compound of formula (I).

[0054] Additionally, there is provided a composition 1 as follows: 1.1 Composition 1 comprising a pharma- ceutically acceptable carrier. 1.2 Composition 1 or 1.1 comprising a compound according to any of Formula I or 1.1-1.13 (see above), in free form or in a pharma- ceutically acceptable salt form. 1.3 Any of compositions 1, 1.1 or 1.2, wherein the compound is in free form. 1.4 The compounds of formula I may be in free form or in the form of a pharma- ceutically acceptable salt, e.g. [ka] Any of compositions 1 or 1.1 to 1.3,

[0055] 1.5 The designation of deuterium (i.e., D) at a position means that the position contains significantly more than the 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%). Atoms not designated as a particular isotope are present in their natural isotopic abundance.

[0056] 1.6 Any of compositions 1 or 1.1-1.5, wherein the compound of formula I, in free or pharma- ceutically acceptable salt form, has greater than 50%, 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% deuterium (i.e., D) incorporation at one or more positions (e.g., all positions) designated as deuterium (i.e., D). For example, any of compositions 1 or 1.1-1.5, wherein the compound of formula I, in free or pharma-ceutically acceptable salt form, has greater than 50%, 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% deuterium incorporation at each position designated as deuterium (i.e., D).

[0057] 1.7 An oral dosage form or a parenteral dosage form, e.g., an oral dosage form, e.g., a tablet, capsule, solution, or suspension, e.g., any of Compositions 1 or 1.1-1.6, which is a capsule or tablet.

[0058] 1.8 Any of Compositions 1 or 1.1-1.7 comprising a therapeutically effective amount of a compound of Formula I, in free form or in a pharma- ceutically acceptable salt form, for the prevention or treatment of a disorder disclosed herein, e.g., a therapeutically effective amount of a compound of Formula I, in free form or in a pharma- ceutically acceptable salt form, for use in any of the methods disclosed herein.

[0059] 1.9 Compositions 1 or any of 1.1-1.8, substantially free of any other stereoisomeric forms of Formula I. For example, any of compositions 1 or 1.1-1.8, substantially free of any other diastereomeric and / or enantiomeric forms of Formula I, for example, substantially free of any other diastereomeric and enantiomeric forms of Formula I.

[0060] 1.10 Composition 1 or any of 1.1-1.9 comprising less than 10% w / w (weight / weight) of any other stereoisomeric form of formula I, such as less than 5% w / w of any other stereoisomeric form of formula I, such as less than 4% w / w of any stereoisomer of formula I, such as less than 3% w / w of any other stereoisomeric form of formula I, such as less than 2% w / w of any other stereoisomeric form of formula I, such as less than 1% w / w of any other stereoisomeric form of formula I.

[0061] 1.11 Any of compositions 1 or 1.1-1.10 comprising less than 10% w / w of any other diastereomeric form of formula I, such as less than 5% w / w of any other diastereomeric form of formula I, such as less than 4% w / w of any other diastereomeric form of formula I, such as less than 3% w / w of any other diastereomeric form of formula I, such as less than 2% w / w of any other diastereomeric form of formula I, such as less than 1% w / w of any other diastereomeric form of formula I.

[0062] 1.12 Any of compositions 1 or 1.1-1.11 comprising less than 10% w / w of any other enantiomeric form of formula I, such as less than 5% w / w of any other enantiomeric form of formula I, such as less than 4% w / w of any other enantiomeric form of formula I, such as less than 3% w / w of any other enantiomeric form of formula I, such as less than 2% w / w of any other enantiomeric form of formula I, such as less than 1% w / w of any other enantiomeric form of formula I.

[0063] 1.13 Any of compositions 1 or 1.1-1.12, wherein the compound has the stereochemical configuration shown in Formula I.

[0064] 1.14 Any of compositions 1 or 1.1 to 1.13 comprising 1 to 60 mg of a compound of formula I. For example, any of compositions 1 or 1.1 to 1.13 comprising 1 to 10 mg, for example 1 to 9 mg (for example 1 to 8 mg), of a compound of formula I. For example, any of compositions 1 or 1.1 to 1.13 comprising 3 mg or 10 mg of a compound of formula I. For example, any of compositions 1 or 1.1 to 1.13 comprising 1 mg to less than 3 mg (for example 2 mg) of a compound of formula I.

[0065] 1.15 Composition 1 or any of 1.1-1.14, which is for administration once daily, twice daily, or three times daily. For example, Composition 1 or any of 1.1-1.14, which is for administration once daily.

[0066] Further provided is a method of preventing or treating a central nervous system disorder (e.g., a brain disorder), for example a central nervous system disorder (e.g., a brain disorder) that would benefit from modulation of dopamine and / or serotonin transmission, in a patient in need of such prevention or treatment, comprising administering to the patient a compound of formula I (e.g., any of formulas I or 1.1-1.13 (see above)), in free form or in a pharma- ceutically acceptable salt form, or a pharmaceutical composition comprising a compound of formula I (e.g., formula 1.13, or any of compositions 1 or 1.1-1.15 (see above)), in free form or in a pharma- ceutically acceptable salt form, or a compound of formula Ia or Compound A (see below), in free form or in a pharma- ceutically acceptable salt form. Further provided is a method of preventing or treating a central nervous system disorder (e.g., brain disorder) that would benefit from D2 receptor antagonism, D3 receptor antagonism, D4 receptor antagonism, 5-HT1A receptor agonism (e.g., 5-HT1A receptor partial) and / or 5-HT2A receptor agonism (e.g., 5-HT2A receptor partial agonism) in a patient in need of such prevention or treatment, comprising administering to the patient a compound of Formula I (e.g., Formula I or 1.1), in free form or in pharma- ceutical acceptable salt form. To 1.13 (see above)), or a pharmaceutical composition comprising a compound of formula I in free form or in pharma- ceutical acceptable salt form (e.g., any of formulas 1.13, or compositions 1 or 1.1 to 1.15 (see above)), or a compound of formula Ia or compound A (see below), in free form or in pharma- ceutical acceptable salt form, or a pharmaceutical composition comprising a compound of formula Ia or compound A (see below), in free form or in pharma- ceutical acceptable salt form. For example, the following methods are provided:

[0067] A method of treating or preventing a disorder (e.g., a brain disorder) in a patient in need of such treatment or prevention (Method 1), comprising administering to a patient a compound of Formula Ia: [ka] [In the formula, It has cis stereochemistry at two stereocenters, indicated by asterisks in the diagram, R1, R2, R3, R4 and R5 are independently selected from H and D. The method includes administering an effective amount of a compound of the formula:

[0068] Additionally, a method 1 is provided as follows: 1.1 Method 1 comprising administering (±)-cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide (i.e., nemonapride) in free form or in a pharma- ceutically acceptable salt form, wherein (±)-cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide exhibits no optical rotation in chloroform. For example, method 1, comprising administering the free form of (±)-cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide (i.e., nemonapride), wherein (±)-cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide exhibits no optical rotation in chloroform.

[0069] 1.2 Compound A in free form or in the form of a pharma- ceutically acceptable salt: [ka] Method 1, comprising administering an effective amount of. For example, the effective amount of compound A in free form or in pharma- ceutically acceptable salt form has a stereoisomeric excess of more than 90%, for example, a stereoisomeric excess of equal to or greater than 95%, for example, a stereoisomeric excess of equal to or greater than 96%, for example, a stereoisomeric excess of equal to or greater than 97%, for example, a stereoisomeric excess of equal to or greater than 98%, for example, a stereoisomeric excess of equal to or greater than 99%. For example, the effective amount of compound A in free form or in pharma-ceutically acceptable salt form is substantially diastereomerically and / or enantiomerically pure, for example, the effective amount of compound A in free form or in pharma-ceutically acceptable salt form is substantially diastereomerically and enantiomerically pure. Method 1, for example, wherein the effective amount of compound A, in free form or in pharma- ceutically acceptable salt form, has a diastereomeric and / or enantiomeric excess of greater than 90%, such as a diastereomeric and / or enantiomeric excess of equal to or greater than 95%, for example a diastereomeric and / or enantiomeric excess of equal to or greater than 96%, for example a diastereomeric and / or enantiomeric excess of equal to or greater than 97%, for example a diastereomeric and / or enantiomeric excess of equal to or greater than 98%, for example a diastereomeric and / or enantiomeric excess of equal to or greater than 99%. Method 1, for example, wherein the effective amount of compound A, in free form or in pharma- ceutically acceptable salt form, has a diastereomeric and enantiomeric excess of greater than 90%, for example, a diastereomeric and enantiomeric excess of equal to or greater than 95%, for example, a diastereomeric and enantiomeric excess of equal to or greater than 96%, for example, a diastereomeric and enantiomeric excess of equal to or greater than 97%, for example, a diastereomeric and enantiomeric excess of equal to or greater than 98%, for example, a diastereomeric and enantiomeric excess of equal to or greater than 99%.

[0070] 1.3 Formula I, in free form or in pharma- ceutically acceptable salt form: [ka] [In the formula, R1, R2, R3, R4 and R5 are independently selected from H and D; At least one of R1, R2 and R3 is D. Method 1, comprising administering a compound of formula (I) to a subject.

[0071] 1.4 Method 1.3, wherein R1, R2, R3, R4 and R5 are D.

[0072] 1.5 Method 1.3 or 1.4 comprising administering to the patient a compound of formula I, in free form or in a pharma- ceutically acceptable salt form, as described in any of formula I or 1.1-1.13 (see above). For example, method 1.3 or 1.4 comprising administering to the patient a pharmaceutical composition comprising a compound of formula I, in free form or in a pharma- ceutically acceptable salt form, as described in any of composition I or 1.1-1.15 (see above).

[0073] 1.6 Any of methods 1.3-1.5, wherein the effective amount of the compound of formula I, in free form or in pharma- ceutically acceptable salt form, has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess of greater than or equal to 95%, e.g., a stereoisomeric excess of greater than or equal to 96%, e.g., a stereoisomeric excess of greater than or equal to 97%, e.g., a stereoisomeric excess of greater than or equal to 98%, e.g., a stereoisomeric excess of greater than or equal to 99%. For example, any of methods 1.3-1.5, wherein the effective amount of the compound of formula I, in free form or in pharma-ceutically acceptable salt form, is substantially diastereomerically and / or enantiomerically pure, e.g., the effective amount of the compound of formula I, in free form or in pharma-ceutically acceptable salt form, is substantially diastereomerically and / or enantiomerically pure. For example, any of Methods 1.3-1.5, wherein the effective amount of the compound of Formula I, in free form or in pharma- ceutically acceptable salt form, has a diastereomeric and / or enantiomeric excess of greater than 90%, e.g., a diastereomeric and / or enantiomeric excess of greater than or equal to 95%, a diastereomeric excess of greater than or equal to 96%, a diastereomeric excess of greater than or equal to 97%, e.g., a diastereomeric excess of greater than or equal to 98%, e.g., a diastereomeric excess of greater than or equal to 99%. For example, any of Methods 1.3-1.5, wherein the effective amount of the compound of formula I, in free form or in pharma- ceutically acceptable salt form, has a diastereomeric and enantiomeric excess of greater than 90%, for example, a diastereomeric and enantiomeric excess of greater than or equal to 95%, for example, a diastereomeric and enantiomeric excess of greater than or equal to 96%, for example, a diastereomeric and enantiomeric excess of greater than or equal to 97%, for example, a diastereomeric and enantiomeric excess of greater than or equal to 98%, for example, a diastereomeric and enantiomeric excess of greater than or equal to 99%.

[0074] 1.7 Any of methods 1 or 1.1-1.6, wherein the compound is in free form.

[0075] 1.8 Compound B in free form or in pharma- ceutically acceptable salt form, e.g., in free form: [ka] Method 1.3, comprising administering an effective amount of

[0076] 1.9 Method 1.8, wherein the effective amount of compound B in free form or in pharma- ceutically acceptable salt form has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess of greater than or equal to 95%, e.g., a stereoisomeric excess of greater than or equal to 96%, e.g., a stereoisomeric excess of greater than or equal to 97%, e.g., a stereoisomeric excess of greater than or equal to 98%, e.g., a stereoisomeric excess of greater than or equal to 99%. For example, method 1.8, wherein the effective amount of compound B in free form or in pharma- ceutically acceptable salt form is substantially diastereomerically and / or enantiomerically pure, e.g., the effective amount of compound B in free form or in pharma- ceutically acceptable salt form is substantially diastereomerically and enantiomerically pure. Method 1.8, for example, wherein the effective amount of Compound B, in free form or in a pharma- ceutically acceptable salt form, has a diastereomeric and / or enantiomeric excess of greater than 90%, for example, a diastereomeric and / or enantiomeric excess of greater than or equal to 95%, for example, a diastereomeric and / or enantiomeric excess of greater than or equal to 96%, for example, a diastereomeric and / or enantiomeric excess of greater than or equal to 97%, for example, a diastereomeric and / or enantiomeric excess of greater than or equal to 98%, for example, a diastereomeric and / or enantiomeric excess of greater than or equal to 99%. Method 1.8, for example, wherein the effective amount of Compound B, in free form or in pharma- ceutically acceptable salt form, has a diastereomeric and enantiomeric excess of greater than 90%, for example, a diastereomeric and enantiomeric excess of equal to or greater than 95%, for example, a diastereomeric and enantiomeric excess of equal to or greater than 96%, for example, a diastereomeric and enantiomeric excess of equal to or greater than 97%, for example, a diastereomeric and enantiomeric excess of equal to or greater than 98%, for example, a diastereomeric and enantiomeric excess of equal to or greater than 99%.

[0077] 1.10 Any of Methods 1 or 1.3-1.9, where the designation of deuterium (i.e., D) at a position means that the position has significantly more than the 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%). Atoms not designated as a particular isotope are present in their natural isotopic abundance.

[0078] 1.11 Any of Methods 1 or 1.3-1.10, wherein the compound in free form or in pharma- ceutically acceptable salt form has greater than 50% deuterium (i.e., D) commitment, 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% deuterium (i.e., D) commitment, at one or more positions (e.g., all positions) designated as deuterium (i.e., D). For example, any of Methods 1 or 1.3-1.10, wherein the compound in free form or in pharma- ceutically acceptable salt form has greater than 50% deuterium (i.e., D) incorporation, 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% deuterium (i.e., D) incorporation, at each position designated as deuterium (i.e., D).

[0079] 1.12 Any of methods 1 or 1.1-1.11, wherein the disorder is a brain disorder. For example, any of methods 1 or 1.1-1.11, wherein the disorder is a neuropsychiatric condition in which anhedonia is prominent.

[0080] 1.13 Any of methods 1 or 1.1 to 1.12, where the disorder is an affective (mood) disorder or an anxiety disorder.

[0081] 1.14 Any of methods 1 or 1.1-1.13, wherein the disorder is depression (e.g., depression associated with anhedonia), anxiety disorder, psychosis (e.g., psychosis of a neurodegenerative condition, e.g., Alzheimer's disease, Parkinson's disease, or psychosis in dementia (e.g., dementia-associated psychosis)), schizophrenia, schizoaffective disorder, post-traumatic stress disorder (PTSD), attention-deficit / hyperactivity disorder (ADHD), Tourette's 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 combined features), or migraine. For example, any of methods 1 or 1.1-1.13, wherein the anxiety disorder is panic disorder, social anxiety disorder, phobia, or generalized anxiety disorder. Alternatively, any of Methods 1 or 1.1-1.13, preventing or treating behavioral and psychological symptoms of dementia, including agitation, depression, anxiety, apathy, and / or psychosis.

[0082] 1.15 Any of methods 1 or 1.1-1.14, wherein the disorder is anhedonia or depression associated with anhedonia, suicidal ideation, anxiety depression, inflammatory depression, treatment resistant depression, dysthymia, bipolar depression, psychotic depression or post-psychotic depression. For example, any of methods 1 or 1.1-1.14, wherein the disorder is anxiety depression. Or, for example, any of methods 1 or 1.1-1.14, wherein the disorder is melancholic depression.

[0083] 1.16 Method 1 or any of 1.1-1.15, wherein the disorder is major depressive disorder. 1.17 The disorder is a substance use disorder, either method 1 or 1.1–1.14.

[0084] 1.18 Preventing or treating negative symptoms of schizophrenia, any of Method 1 or 1.1-1.14. Alternatively, improving cognition in schizophrenia, any of Method 1 or 1.1-1.14.

[0085] 1.19 Any of Methods 1 or 1.1-1.11, wherein the compound, in free form or in a pharma- ceutically acceptable salt form, is administered as an antiemetic agent.

[0086] 1.20 Any of Methods 1 or 1.1-1.19 comprising administering 9-60 mg of the compound in free form or in pharma- ceutically acceptable salt form per day (i.e., a total daily dose of 9-60 mg of the compound in free form or in pharma- ceutically acceptable salt form). For example, any of Methods 1 or 1.1-1.19 comprising administering 9-36 mg of the compound in free form or in pharma- ceutically acceptable salt form per day (i.e., a total daily dose of 9-36 mg of the compound in free form or in pharma- ceutically acceptable salt form).

[0087] 1.21 Any of Methods 1 or 1.1-1.20, comprising, for example, administering a compound in free form or in a pharma- ceutically acceptable salt form in an amount that provides a D2 / D3 receptor occupancy of 55% to 80% as measured by positron emission tomography. Any of Methods 1 or 1.1-1.20, comprising, for example, administering a compound in free form or in a pharma- ceutically acceptable salt form in an amount that provides a D2 / D3 receptor occupancy of about 65% as measured by positron emission tomography. Alternatively, any of Methods 1 or 1.1-1.20, comprising, for example, administering a compound in free form or in a pharma- ceutically acceptable salt form in an amount that provides a D2 / D3 receptor occupancy of about 60% as measured by positron emission tomography.

[0088] 1.22 Method 1.20 or 1.21, wherein the disorder is psychosis (e.g., a neurodegenerative condition such as Alzheimer's disease, Parkinson's disease, and dementia psychosis (e.g., dementia associated psychosis)), schizophrenia, schizoaffective disorder, or a bipolar disorder (e.g., bipolar mania).

[0089] 1.23 Method 1.20 or 1.21 for preventing or treating negative symptoms of schizophrenia. Alternatively, Method 1.20 or 1.21 for improving cognition in schizophrenia.

[0090] 1.24 Any of Methods 1 or 1.1 to 1.19 comprising administering 1 to 9 mg (e.g., 1 to 8 mg, e.g., 1.5 to 6 mg) of the compound in free form or in a pharma- ceutically acceptable salt form per day (i.e., a total daily dose of 1 to 9 mg, e.g., a total daily dose of 1 to 8 mg, e.g., a total daily dose of 1.5 to 6 mg) of the compound in free form or in a pharma-ceutically acceptable salt form. For example, any of Methods 1 or 1.1 to 1.19 comprising administering 1 to 8 mg of the compound in free form or in a pharma-ceutically acceptable salt form per day (i.e., a total daily dose of 1 to 8 mg of the compound in free form or in a pharma-ceutically acceptable salt form). For example, any of Methods 1 or 1.1 to 1.19 comprising administering 1 to 3 mg of the compound in free form or in a pharma-ceutically acceptable salt form per day (i.e., a total daily dose of 1 to 3 mg of the compound in free form or in a pharma-ceutically acceptable salt form). For example, any of Methods 1 or 1.1-1.19, comprising administering less than 3 mg (e.g., 2 mg per day) of the compound in free form or in a pharma- ceutically acceptable salt form (i.e., a total daily dose of 1 mg to less than 3 mg of the compound in free form or in a pharma- ceutically acceptable salt form).

[0091] 1.25 Any of Methods 1, 1.1-1.19 or 1.24 comprising administering the compound in free form or in a pharma- ceutically acceptable salt form in an amount that provides a D2 / D3 receptor occupancy of 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%) as determined by positron emission tomography. Alternatively, any of Methods 1, 1.1-1.19 or 1.24 comprising administering the compound in free form or in a pharma-ceutically acceptable salt form in an amount that provides a D2 / D3 receptor occupancy of 40% or less (e.g., about 40%), e.g., less than 40%, as determined by positron emission tomography.

[0092] 1.26 Method 1.24 or 1.25, wherein the disorder is depression (e.g., depression associated with anhedonia), anxiety disorder, post-traumatic stress disorder (PTSD), attention-deficit / hyperactivity disorder (ADHD), Tourette's syndrome, anorexia nervosa, bulimia nervosa, binge eating disorder, body dysmorphic disorder, obsessive-compulsive disorder, addiction, bipolar disorder, bipolar disorder with mixed features, or migraine. For example, Method 1.24 or 1.25, wherein the anxiety disorder is panic disorder, social anxiety disorder, phobia, or generalized anxiety disorder.

[0093] 1.27 Any of methods 1.24-1.26, wherein the disorder is anhedonia or depression associated with anhedonia, suicidal ideation, anxiety depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression. For example, any of methods 1.24-1.26, wherein the disorder is anxiety depression.

[0094] 1.28 Any of methods 1.24 to 1.27, wherein the disorder is major depressive disorder. 1.29 The disorder is a substance use disorder, Method 1.24 or 1.25.

[0095] 1.30 Any of Methods 1 or 1.1-1.29 comprising administering a pharmaceutical composition comprising the compound in free form or a pharma- ceutically acceptable salt form, e.g., any of Methods 1 or 1.1-1.29 comprising administering Formula 1.13, or any of Compositions 1 or 1.1-1.15 (see above).

[0096] 1.31 Any of Methods 1 or 1.1-1.30 comprising administering a compound of formula I, in free form or in a pharma- ceutically acceptable salt form, once a day, twice a day, or three times a day, e.g., once a day. For example, any of Methods 1 or 1.1-1.30 comprising administering a pharmaceutical composition comprising a compound of formula I, in free form or in a pharma- ceutically acceptable salt form, once a day, twice a day, or three times a day, e.g., once a day.

[0097] 1.32 Any of Methods 1 or 1.1-1.31 comprising administering a compound of formula I, in free form or in a pharma- ceutically acceptable salt form, once a day, twice a day, or three times a day, e.g., once a day. For example, any of Methods 1 or 1.1-1.31 comprising administering a pharmaceutical composition comprising a compound of formula I, in free form or in a pharma- ceutically acceptable salt form, once a day, twice a day, or three times a day, e.g., once a day.

[0098] 1.33 Any of Methods 1 or 1.1-1.32 comprising administering Compound B, in free form or in a pharma- ceutically acceptable salt form, once a day, twice a day, or three times a day, e.g., once a day. For example, any of Methods 1 or 1.1-1.32 comprising administering Compound B, in free form or in a pharma- ceutically acceptable salt form, once a day, twice a day, or three times a day, e.g., once a day.

[0099] Further provided is a compound of Formula I (e.g., any of Formulas 1.1-1.13) or a pharmaceutical composition (e.g., Formula 1.13, or Composition 1 or any of 1.1-1.15) disclosed herein for use in any of Methods 1 or 1.1-1.33 (see above).

[0100] Further provided is the use of a compound of Formula I (e.g., any of Formulas 1.1-1.13) or a pharmaceutical composition (e.g., Formula 1.13, or Composition 1 or any of 1.1-1.15) disclosed herein in any of Methods 1 or 1.1-1.33 (see above).

[0101] There is further provided the use of a compound of Formula I (e.g., any of Formulas 1.1-1.13) in the manufacture of a medicament (e.g., Formula 1.13, or Composition 1 or any of 1.1-1.15) for use in any of Methods 1 or 1.1-1.33 (see above).

[0102] Further provided are intermediate compounds of Formula II and Formula III, each in free form or in salt (eg, pharma- ceutically acceptable salt) form.

[0103] For example, a compound of Formula II, in free form or in salt (e.g., pharma- ceutically acceptable salt) form: [ka] [In the formula, R 31 , R 32 and R 33 is independently selected from H and D; X is OH or a leaving group; R 31 , R 32 and R 33 at least one of them is D] Further provided is a compound of the formula:

[0104] Additionally, there is provided a compound of formula II: 2.1 A compound of formula II in a pharma- ceutically acceptable salt form. 2.2 Formula II or 2.1 [wherein R 31 , R 32 and R 33 is D] compound. 2.3 A compound of any of formulas II, 2.1 or 2.2, where X is OH. 2.4 A compound of any of formulas II, 2.1 or 2.2, where X is a leaving group (e.g., an activated ester, e.g., an O-acylisourea, or a halide). For example, a compound of any of formulas II, 2.1 or 2.2, where the compound of formula II is reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. 2.5 The compounds may be in free form or in salt (e.g., pharma- ceutically acceptable salt) form, e.g., in free form [ka] A compound of any of formula II or 2.1-2.3,

[0105] Also included are compounds of formula III, in free form or in salt (e.g., pharma- ceutically acceptable salt) form: [ka] [In the formula, R 34 and R 35 is D] Further provided is a compound of the formula:

[0106] Additionally, there is provided a compound of formula III: 3.1 A compound of formula III in a pharma- ceutically acceptable salt form. 3.2 The compounds may be in free form or in salt (e.g., pharma- ceutically acceptable salt) form, e.g., [ka] A compound of any of formula III or 3.1,

[0107] Further provided is a method (Method 1) of synthesizing a compound of Formula I (eg, any of Formulas 1.1-1.13), in free form or in salt (eg, pharma- ceutically acceptable salt) form.

[0108] Further provided is the following method 1: 1.1 Method 1, comprising reacting a compound of formula II (e.g., any of formulas 2.1-2.5) with a compound of formula III (e.g., any of formulas 3.1-3.2).

[0109] 1.2 Method 1 or 1.1 carried out in the presence of an amine (eg triethylamine, for example triethylamine and dimethylformamide).

[0110] 1.3 Methods 1, 1.1 or 1.2 carried out in an organic solvent (eg, dimethylformamide).

[0111] 1.4 Method 1 or any of 1.1-1.3 carried out using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and hydroxybenzotriazole. For example, Method 1 or any of 1.1-1.3 carried out using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydroxybenzotriazole, triethylamine and dimethylformamide.

[0112] 1.5 Compounds of formula IIa, in free form or in salt (e.g., pharma- ceutically acceptable salt) form: [ka] [In the formula, R 31 , R 32 and R 33 is independently selected from H and D; R 31 , R 32 and R 33 at least one of them is D] with an activating agent (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide).

[0113] 1.6 Formula IIb, in free form or in salt (e.g., pharma- ceutically acceptable salt) form: [ka] [In the formula, R 31 , R 32 and R 33 is independently selected from H and D; R 31 , R 32 and R 33 at least one of them is D] to form the compound of formula 1.5. 1.7 Method 1.6, where the compound of formula IIb is formed in situ.

[0114] In the compounds disclosed herein, a hydrogen atom position of a structure is considered to be replaced by deuterium when the abundance of deuterium is enriched at that position.Since the natural abundance of deuterium is about 0.02%, a compound is "enriched" in deuterium at a particular position when the frequency of deuterium incorporation at that position is greater than 0.02%.Thus, in the deuterated compounds disclosed herein, any position designated as deuterium (i.e., D) can be enriched in deuterium at a level of more than 0.1%, or more than 0.5%, or more than 1%, or more than 5%, for example, more than 50%, or more than 60%, or more than 70%, or more than 80%, or more than 90%, or more than 95%, or more than 96%, or more than 97%, or more than 98%, or more than 99%.In the compounds disclosed herein, atoms that are not designated as a specific isotope are present at their natural isotopic abundance.

[0115] The compounds disclosed herein, for example, any of Formula I (e.g., any of Formulas 1.1-1.13), Formula Ia, Formula II (e.g., any of Formulas 2.1-2.5), Formula III (e.g., any of Formulas 3.1-3.2), Formula IIa, Formula IIb, Compound A, and Compound B, may exist in free form or in salt form, for example, as an acid addition salt. As used herein, unless otherwise specified, phrases such as "compound of formula" are understood to encompass the compound in any form, for example, in free form or in acid addition salt form, or, if the compound contains an acidic substituent, in base addition salt form. Since the compounds of Formula I (e.g., any of Formulas 1.1-1.13), Formula Ia, Compound A, and Compound B are intended for use as pharmaceuticals, pharma- ceutically acceptable salts are preferred. Salts that are not suitable for pharmaceutical use may be useful, for example, in the isolation or purification of the free compounds of Formula I or Formula Ia or their pharma- ceutically acceptable salts, and therefore are also included.

[0116] Isolation or purification of stereoisomers of any of the compounds disclosed herein, in free form or in pharma- ceutically acceptable salt form, such as Formula I (e.g., any of Formulas 1.1-1.13), Formula Ia, Formula II (e.g., any of Formulas 2.1-2.5), Formula III (e.g., any of Formulas 3.1-3.2), Formula IIa, Formula IIb, Compound A, and Compound B, can be accomplished by conventional methods known in the art, such as column purification, preparative thin layer chromatography, preparative HPLC, trituration, simulated moving bed, and the like.

[0117] Pure stereoisomeric forms of the compounds and intermediates disclosed herein are isomers that are 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 with a stereoisomeric excess of more than 90% (i.e., more than 90% of one isomer and less than 10% of the other possible isomers). The terms "substantially diastereomerically pure" and "substantially enantiomerically pure" should be understood in a similar manner, but in that case, the diastereomeric excess and enantiomeric excess of the substance in question, respectively, should be considered.

[0118] The compounds disclosed herein, for example, any of Formula I (e.g., any of Formulas 1.1-1.13), Formula Ia, Formula II (e.g., any of Formulas 2.1-2.5), Formula III (e.g., any of Formulas 3.1-3.2), Formula IIa, Formula IIb, Compound A, and Compound B, either in free or pharma- ceutically acceptable salt form, can be prepared by using methods as described and exemplified herein, and methods analogous thereto, as well as methods known in the chemical arts. Such methods include, but are not limited to, the methods described below. The starting materials for these processes, if not commercially available, can be prepared by procedures selected from the chemical arts, using techniques analogous or similar to the synthesis of known compounds.

[0119] Pharmaceutically acceptable salts of any of Formula I (e.g., any of Formulas 1.1-1.13), Formula Ia, Formula II (e.g., any of Formulas 2.1-2.5), Formula III (e.g., any of Formulas 3.1-3.2), Formula IIa, Formula IIb, Compound A, and Compound B can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free base form of these compounds with a stoichiometric amount of the appropriate acid in a suitable solvent.

[0120] In methods of treatment, the term "effective amount" is intended to encompass a therapeutically effective amount for treating a particular disease or disorder.

[0121] Dosages employed in practicing the present invention will, of course, vary depending on, for example, the particular disease or condition being treated, the particular compound used, the mode of administration, and the therapy desired.

[0122] The compounds disclosed herein, e.g., any compound of Formula I (e.g., any of Formulas 1.1-1.13), Formula Ia, Compound A, or Compound B, either in free form or in a pharma- ceutically acceptable salt form, can be administered by any suitable route, including orally, parenterally, or transdermally, but are preferably administered orally.

[0123] Pharmaceutical compositions comprising the compounds disclosed herein, e.g., any of the compounds of Formula I (e.g., any of Formulas 1.1-1.13, or any of Compositions 1 or 1.1-1.15), Formula Ia, Compound A, or Compound B, either in free form or in pharma- ceutically acceptable salt form, can be prepared using conventional diluents or excipients and techniques known in the galenic art. Oral dosage forms can thus include tablets, capsules, solutions, suspensions, and the like. EXAMPLES

[0124] Abbreviation s AcOH = acetic acid Boc = tert-butyloxycarbonyl DIAD = diisopropyl azodicarboxylate DCM = dichloromethane DMAP = 4-dimethylaminopyridine DMF = Dimethylformamide EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc or EA = ethyl acetate h=time(s) HOBt = hydroxybenzotriazole MeOH = methanol MsCl = methanesulfonyl chloride rt (or RT) = room temperature TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran

[0125] Example 1 A2: Synthesis of 5-chloro-N-((2R,3R)-1-(dideutero(phenyl)methyl)-2-methylpyrrolidin-3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide [ka] Compound 15: tert-Butyl (R)-2-methyl-3,5-dioxopyrrolidine-1-carboxylate [ka]

[0126] To a stirred solution of Boc-L-alanine (500 g, 2.64 mol), Meldrum's acid (400 g, 2.78 mol) and DMAP (388 g, 3.18 mol) in CHCl (5 L) under nitrogen at 0° C., EDCI (608 g, 3.18 mol) is added. The resulting solution is then warmed to room temperature (rt) and stirred for 16 h. Quenched with water (1.5 L), the organic phase is washed with a cold solution of 5% KHSO (3 Lx3), water (3 Lx1) and brine, dried over anhydrous MgSO and concentrated to give a residue. EtOAc (4 L) is added and the reaction mixture is refluxed for 2 h. The solution is concentrated and the residue is stirred in EtOAc (1 L) at −10° C. for 2 h, filtered and the filter cake is collected to give the title compound as a white solid (150 g, 27% yield). The mother liquor is refluxed for a further 2 h, then stirred in EA at −10° C. and filtered to give the title compound (40 g) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 4.45 (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] +

[0127] Compound 16: tert-Butyl (2R,3R)-3-hydroxy-2-methyl-5-oxopyrrolidine-1-carboxylate [ka]

[0128] To a stirred solution of compound 15 (40 g, 187.6 mmol) in DCM (400 mL) is added AcOH (200 mL) at 0° C., followed by NaBH4 (21.3 g, 562.8 mmol) in three portions. The resulting solution is then warmed to room temperature and stirred for 16 h. The reaction mixture is quenched with 5% NaHCO3 at 0° C. It is extracted with DCM (200 mL×3). The organic layers are combined and washed with 5% NaHCO3 solution. The organic phase is dried over anhydrous MgSO4 and concentrated to give a residue which is stirred in isopropyl ether and filtered to give the title compound 16 (24 g, 59.4% yield). 1 H NMR (400 MHz, CDCl3) δ 4.53-4.47 (m, 1H), 4.29-4.22 (m, 1H), 2.75-2.55 (m, 2H), 1.53 (s, 9H), 1.31(d, J = 6.8 Hz, 3H). MS m / z (ESI): 160 [M+H-56] +

[0129] Compound 17: tert-Butyl (2R,3R)-3-hydroxy-2-methylpyrrolidine-1-carboxylate [ka]

[0130] To a solution of compound 16 (87 g, 405 mmol) in dry THF (1 L) is added a solution of BH3-SMe2 (600 mL, 1200 mmol) at 0 °C and stirred at 0 °C for 30 min. The mixture is then refluxed for 4 h. The resulting mixture is cooled and quenched with saturated NH4Cl at 0 °C. It is then extracted with EtOAc (1 L x 3). The organic phase is dried over anhydrous MgSO4 and concentrated to give compound 17 (70 g, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ 5.11(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] +

[0131] Compound 18: [ka]

[0132] To a cold solution of compound 17 (15.74 g, 78.2 mmol), 4-nitrobenzoic acid (13.72 g, 82.1 mmol) and PPh3 (16.42 g, 62.6 mmol) in dry THF (250 ml) is added DIAD (16.6 g, 82.1 mmol) at 0° C. for 30 min. The reaction mixture is warmed to room temperature for 16 h. The resulting mixture is cooled and quenched with water. The mixture is extracted with EtOAc (200 ml×3), dried over anhydrous MgSO4, and then concentrated. The residue is purified by silica gel chromatography to give compound 18 (24.7 g, 90.1% yield). 1 H NMR (400 MHz, CDCl3) δ 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] +

[0133] Compound 19: (2R,3S)-2-Methylpyrrolidin-3-yl 4-nitrobenzoate [ka]

[0134] 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 h, then concentrated to give compound 19 (16.7 g, 100% yield). LCMS: M+1=251

[0135] Compound 20: (2R,3S)-1-benzoyl-2-methylpyrrolidin-3-yl 4-nitrobenzoate [ka]

[0136] To a solution of compound 19 (16.7 g, 66.8 mmol) in toluene (520 ml) is added 2N NaOH (520 ml, 104 mmol), followed by benzoyl chloride (9.6 g, 66.8 mmol) in toluene (200 ml) at 0° C. The mixture is separated and the aqueous phase is extracted with DCM (250 ml×3). The organic phases are combined, dried over MgSO4, and concentrated to give compound 20 (21.3 g, 90% yield). LCMS: M+1=355

[0137] Compound 21: ((2R,3S)-3-Hydroxy-2-methylpyrrolidin-1-yl)(phenyl)methanone [ka]

[0138] To a stirred solution of compound 20 (21.3 g, 60.1 mmol) in MeOH (400 mL) is added 6N NaOH (11 mL, 66 mmol). The reaction mixture is stirred for 40 min and concentrated under reduced pressure. The residue is diluted with DCM (200 mL) and water (100 mL). The aqueous phase is extracted with DCM (250 ml x 3). The organic phase is dried over MgSO4 and concentrated to give a residue which is treated with petroleum ether (10 ml) and EtOAc (2 ml) to give the title compound 21 (9.85 g, 79.8% yield). LCMS: M+1=206

[0139] Compound 22: (2R,3S)-2-Methyl-1-(phenylmethyl-d2)pyrrolidin-3-ol [ka]

[0140] To a stirred solution of compound 21 (3 g, 14.6 mmol) in dry THF (50 mL) is added lithium aluminum deuteride (614 mg, 14.6 mmol) slowly in portions at -15°C. The reaction mixture is then warmed and stirred at room temperature for 18 h. The mixture is cooled to 0°C and quenched with 20% aqueous KOH (3.5 mL). The mixture is filtered and the precipitate is washed with diethyl ether. The organic phases are combined, dried over Na2SO4, and concentrated to give a residue that is purified by silica gel chromatography to give the title compound 22 (2.68 g, 95% yield). LCMS: M+1=194

[0141] Compound 23: (2R,3R)-3-azido-2-methyl-1-(phenylmethyl-d2)pyrrolidine [ka]

[0142] To a stirred solution of compound 22 (1.5 g, 7.8 mmol), DMAP (2.36 g, 0.78 mmol) and Et3N (95 mg, 23.4 mmol) in dry CHCl2 at 0 °C, MsCl (1.8 g, 15.62 mmol) is added. The reaction mixture is stirred at room temperature for 3 h, then quenched with saturated aqueous NaHCO3 and the aqueous phase is extracted with CHCl3 (30 mLx3). The organic phases are combined, washed with brine and dried over anhydrous Na2SO4. The organic phase is concentrated under reduced pressure, the residue is diluted with DMF (40 mL) and NaN3 (1.65 g, 23.4 mmol) is added. The reaction mixture is stirred at 80 °C for 16 h. Quenched with water and extracted with EtOAc (100 mlx3). The organic phase is dried over MgSO4 and concentrated to give a residue which is purified by silica gel column chromatography to give the title compound 23 (1.7 g, 99% yield). LCMS: M+1=219

[0143] Compound 24: [ka]

[0144] A mixture of compound 23 (1.36 g, 6.2 mmol) and 10% Pd / C (151 mg) in MeOH (50 mL) is stirred under H2 for 18 h. The reaction mixture is filtered and the solvent is evaporated under reduced pressure to give compound 24 (1.12 g, 93% yield). LCMS: M+1=193

[0145] Compound 11: Methyl 4-(tert-butoxycarbonylamino)-5-chloro-2-methoxybenzoate [ka]

[0146] To a mixture of methyl 4-amino-5-chloro-2-methoxybenzoate (5 g, 23.2 mmol), DMAP (1.4 g, 11.7 mmol) and triethylamine (13.2 mL) in THF (175 mL), Boc2O (5.6 g, 25.5 mmol) is added and the reaction mixture is stirred at 38° C. for 6 h. Concentration gives a residue which is purified by silica gel column chromatography to give compound 11 (4.4 g, 60% yield). 1 H NMR (400 MHz, CDCl3) δ 8.71(s, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 1.49 (s, 9H). MS m / z (ESI): 316 [M+H-56] +

[0147] Compound 12: Methyl 4-(tert-butoxycarbonyl(trideuteromethyl)amino)-5-chloro-2-methoxybenzoate [ka]

[0148] To a solution of compound 11 (1.96 g, 6.2 mmol) in dry DMF (40 mL) is added NaH (370 mg, 9.3 mmol) and the reaction is stirred at room temperature for 30 min, then CD3I (1.8 g, 12.4 mmol) is added and the reaction is stirred at room temperature for 3 h. The reaction is cooled to 0° C. and quenched with saturated aqueous NH4Cl. Extract with EtOAc (100 mL) and wash the organic phase with water, brine and dry over anhydrous Na2SO4. The organic phase is concentrated under reduced pressure and the residue is purified by silica gel column chromatography to give the title compound 12 (2.02 g, 97.6% yield). NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 6.85 (s, 1H), 3.90 (s, 6H), 1.36 (s, 9H). MS m / z (ESI): 277 [M+H-56] +

[0149] Compound 13: 4-(tert-butoxycarbonyl(trideuteromethyl)amino)-5-chloro-2-methoxybenzoic acid [ka]

[0150] To a solution of compound 12 (1.68 g, 5.1 mmol) in THF (65 mL) and water (20 mL), LiOH·H2O (844 mg, 20 mmol) is added and the mixture is stirred for 12 h. The reaction is acidified to pH=3 with 1N HCl, then extracted with EtOAc (50 mL×3), the organic phases are combined, washed with brine and dried over anhydrous Na2SO4. The organic phase is concentrated under reduced pressure and the residue is purified by silica gel column chromatography to give the title compound 13 (1.46 g, 90% yield). 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(s, 1H), 6.96 (s, 1H), 4.08 (s, 3H), 1.39 (s, 9H). MS m / z (ESI): 263 [M+H-56] +

[0151] Compound 14: 5-Chloro-2-methoxy-4-(trideuteromethylamino)benzoic acid [ka]

[0152] A mixture of compound 13 (1.44 g, 4.5 mmol) and TFA (12 mL) in CH2Cl2 (25 mL) is stirred at room temperature for 1 h. The reaction mixture is concentrated to give compound 14 (0.73 g, 73.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.61(s, 1H), 6.20 (s, 1H), 6.18 (s, 1H), 3.83 (s, 3H). MS m / z (ESI): 219 [M+H] +

[0153] A2: 5-chloro-N-((2R,3R)-1-(dideutero(phenyl)methyl)-2-methylpyrrolidine 3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide [ka]

[0154] A mixture of compound 24 (100 mg, 0.52 mmol), compound 14 (114 mg, 0.52 mmol), HOBt (105 mg, 0.78 mmol), EDCI (150 mg, 0.78 mmol) and TEA (158 mg, 1.56 mmol) in dry DMF (2 ml) is stirred at room temperature for 16 h. The resulting mixture is quenched with water, extracted with EtOAc (15 mLx3), washed with brine, dried over anhydrous MgSO4 and concentrated to give a residue which is purified by silica gel chromatography to give compound A2 (85 mg, 41.5% yield). 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 8.00 (s, 1H), 7.52-7.35 (m, 5H), 6.13 (s, 1H), 4.69 (s, 2H), 4.00 (s, 3H), 2.97 (s, 1H), 2.63 (s, 1H), 2.21-2.05 (m, 2H), 1.59 (s, 1H), 1.13 (s, 3H). MS m / z (ESI): 393 [M+H] +

[0155] Example 2 - Radioligand binding competition activity against recombinant human dopamine and serotonin receptors using filtration binding assays Radioligand binding experiments are performed using membrane preparations. Accession numbers of receptors, cell backgrounds, and reference compounds are shown in Table 1.

[0156] [Table 1]

[0157] Compound (A2) of Example 1 was tested for radioligand binding competition activity at human dopamine D2S, D3, D4.4 receptors and serotonin 5-HT1A, 5-HT2A, 5-HT7A receptors, and the results are shown in Table 2.

[0158] [Table 2]

[0159] Example 3 - Agonist or antagonist activity at recombinant human dopamine and serotonin receptors using IPOne HTRF, cAMP HTRF and GTPγS assays SPA 35 S-GTPgS experiments are performed using membrane preparations. IP-One and cAMP HTRF assays are performed using recombinant cell lines. The receptor accession numbers, cell backgrounds, and reference compounds are shown in Table 3.

[0160] [Table 3]

[0161] Compound (A2) of Example 1 is tested for antagonist activity at human dopamine D2S, D3 and D4.4 receptors, agonist activity at human serotonin 5-HT1A receptors, agonist and antagonist activity at human serotonin 5-HT2A receptors, and antagonist activity at human serotonin 5-HT7A receptors.The results are shown in Table 4 and Table 5.

[0162] The agonist activity of the test compounds was determined by the EC 100 The activity of the test compound is expressed as a percentage of the activity of the reference agonist at the concentration. 80 The concentrations are expressed as percentage of inhibition of the reference agonist activity.

[0163] [Table 4]

[0164] [Table 5]

[0165] As indicated above, the deuterated compound of Example 1 is a D2 / D3 / D4 antagonist, a 5-HT1A agonist and a 5-HT2A partial agonist.

[0166] Example 4 - In vitro metabolism Test compounds were studied with pooled human cryopreserved hepatocytes (mixed sex). Incubations are performed at an initial concentration of 5 μM, with sampling at 0, 60 and 120 min. Samples are analyzed using UPLC-QE-orbitrap-MS. Incubation volume: 300 μl in 48-well plates. Cell count: 1 million viable cells / ml. Test compound: 5 μM (stock solution in DMSO). Incubation medium: pH 7.4, Bioreclamation IVT in vitro KHB medium. Shaking: 600 rpm. Time points: 0, 60 and 120 min (with and without cells). Temperature: 37° C. Sampling volume: 60 μl. DMSO content during incubation: 0.5%. End of incubation: 2x volume of 75% acetonitrile. Control: verapamil disappearance.

[0167] Sample preparation for hepatocyte samples: Samples are centrifuged at 2272 x g for 20 minutes at room temperature and pipetted onto a UPLC plate for analysis.

[0168] The data are shown in Figures 1 and 2 and in the table below. In Figures 1 and 2, the dashed lines indicate the absence of cells and the solid lines indicate the presence of cells.

[0169] [Table 6]

[0170] [Table 7]

[0171] Example 5 - In vivo pharmacokinetics Group A of male Sprague-Dawley (SD) rats is dosed (oral) with test compound at 0.5 mg / kg and 5 mg / kg (N=3 / dose level). Blood samples are taken at 5 min, 10 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after dosing. After blood sampling at 24 h, animals are perfused with brain tissue before harvesting.

[0172] Male Sprague-Dawley (SD) rats in group B were dosed (oral) with test compound at 0.5 mg / kg and 5 mg / kg (N=9 rats / dose level). At the designated time points (1 hour, 4 hours, and 8 hours), three animals from each dose group were bled and cerebral perfused before samples were taken.

[0173] The test compounds were the deuterated compound (A2) of Example 1 and N-[(2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R) nemonapride).

[0174] A femoral artery catheter was surgically placed in the rats to collect blood. The rats weighed approximately 250-350g. Water was available ad libitum. They were fasted overnight before oral administration. Food was allowed to be consumed 4 hours after administration.

[0175] The dosage formulation was 0.5% aqueous methylcellulose (4000 cps) with 0.1% Tween. TM 80 plus 100% ethanol for PO administration. Once prepared, vortex / homogenize suspension and continue stirring until dosing. Dosing Concentrations: 0.1 mg / mL for 0.5 mg / kg dose and 1 mg / mL for 5 mg / kg dose. Route of Administration: oral gavage. Dosing Volume: 5 mL / kg. Serial bleed: 200 μL at each time point. Terminal bleed: 500 μL.

[0176] Blood samples will be obtained via an automated sampling system in tubes containing potassium EDTA anticoagulant for up to 24 hours post-dose. Plasma will be obtained by centrifugation and frozen on dry ice within 30 minutes of collection. Aliquots of each dose formulation will be taken, appropriately diluted, and analyzed by LC-MS / MS simultaneously with the plasma samples.

[0177] Plasma (obtained from blood samples) and brain tissue (homogenized and processed) are analyzed by LC / MS / MS. Plasma is harvested from the blood via centrifugation within 30 minutes of sample collection. Brain tissue is harvested after the animals are perfused to remove any blood remaining in the cardiovascular system.

[0178] Dosing solutions, plasma (collected from blood), and brain tissue (homogenized and processed) are stored at -20°C until analysis.

[0179] After thawing the plasma samples at room temperature, proteins are precipitated by the addition of an organic solvent containing an internal standard.

[0180] Thaw the brain samples, homogenize in water (3-4 volumes), and analyze an aliquot of the homogenate by LC / MS / MS.

[0181] The results are shown in Figures 3 to 6. The plasma pharmacokinetics of N-[(2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R) nemonapride) and the deuterated compound of Example 1 (A2) are similar (see FIG. 3, also see FIG. 7). In FIG. 3, the data for cis(R,R) nemonapride are shown as a dashed line and the average (N=3) data for the deuterated compound of Example 1 (A2) are shown as a solid line.

[0182] The prolonged brain concentration of compound (A2) of Example 1 after single PO administration of 0.5 mg / kg and 5 mg / kg in rats is shown in Figures 4 and 5, respectively, in comparison with plasma levels. In each figure, the mean brain concentration (ng / ml) is shown as a dashed line, and the mean plasma concentration (ng / ml) is shown as a solid line. While the plasma concentration decreases, the brain concentration increases (see Figure 5, also see Figure 8).

[0183] Deuterated compound (A2) of Example 1 is enriched in brain levels compared to N-[(2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R) nemonapride) (see FIG. 6, both at a single PO dose of 0.5 mg / kg). A comparison of brain to plasma ratios of N-[(2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R) nemonapride) and deuterated compound (A2) of Example 1 is shown in Table 8 (both at a single PO dose of 0.5 mg / kg).

[0184] [Table 8]

[0185] Example 6 - Ex vivo radioligand binding in membrane preparations to determine the time course of receptor occupancy at central D2 receptors This exam is 3 The aim of the study was to determine receptor occupancy at central D2 receptors following oral administration of the deuterated compound of Example 1 (A2) and the positive comparator olanzapine (10 mg / kg, po) at various time points (1 hr, 2 hr, 4 hr, 8 hr and 24 hr) using [H]raclopride and rat striatal membranes. Liquid scintillation counting was used to quantitate radioactivity.

[0186] animal Thirty-five male Sprague-Dawley rats were fed standard pelleted diet and filtered water ad libitum.

[0187] Drug treatment On the day of the test, animals are orally administered either vehicle, deuterated compound (A2) of Example 1, N-[(2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R) nemonapride) (2.5 mg / kg), or olanzapine (10 mg / kg, po). Rats are sacrificed 1 hour (N=5), 2 hours (N=5), 4 hours (N=5), 8 hours (N=5), and 24 hours (N=5) after drug administration, or 1 hour after vehicle and olanzapine administration (N=5 for vehicle, N=5 for olanzapine). The vehicle is 0.5% methylcellulose.

[0188] Pharmacokinetics Postmortem blood samples (approximately 5 ml) are taken by cardiac puncture and placed into K / EDTA tubes. Postmortem blood samples are gently inverted, centrifuged (1900 g for 5 min at 4° C.), and 1 ml of plasma is removed for PK determination. All plasma samples are frozen and stored at −80° C.

[0189] Whole brains are removed, washed with saline, and blotted dry. Left and right striatum are dissected, weighed, and frozen on dry ice. Striata from each hemisphere are frozen separately. Tissues are wrapped in aluminum foil, bagged, and stored at -20°C until the day of assay.

[0190] [ 3 H]raclopride binding Preparation of homogenates Striata are individually homogenized in ice-cold 50 mM Tris, pH 7.4, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, and 10 μM pargyline using a press-fit homogenizer equivalent to 6.25 mg wet weight of tissue / ml and used immediately for binding assays.

[0191] Assay Striatal homogenates (400 μl, equivalent to 2.5 mg wet weight tissue / tube) were diluted with 50 μl of 1.6 nM [ 3Incubate with [H]raclopride and 50 μl of assay buffer (total binding) or 50 μl of 1 μM (-)sulpiride (to define nonspecific binding) for 30 min at 23°C. Assay buffer consists of 50 mM Tris, pH 7.4, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2 and 10 μM pargyline. Wash buffer consists of 50 mM Tris, pH 7.4. Two tubes for total binding and two for nonspecific binding.

[0192] Membrane-bound radioactivity is recovered by filtration under vacuum through filters presoaked in 0.5% polyethyleneimine (PEI) using a cell harvester. Filters are rapidly washed with ice-cold buffer and radioactivity is measured by liquid scintillation counting.

[0193] Data analysis Values ​​for specific binding (dpm) are obtained by subtracting the mean non-specific binding (dpm) from the mean total binding (dpm) for each animal.

[0194] The results are shown in Figures 7 to 11. The plasma pharmacokinetics of N-[(2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R) nemonapride) and the deuterated compound (A2) of Example 1 are similar (see FIG. 7, also see FIG. 3). In FIG. 7, the average data for cis(R,R) nemonapride data is shown as a dashed line and the average data for the deuterated compound (A2) of Example 1 is shown as a solid line (each compound was administered orally at a single dose of 2.5 mg / kg).

[0195] The prolongation of brain concentrations relative to plasma levels of compound (A2) of Example 1 following a single oral dose of 2.5 mg / kg in rats is shown in Figure 8. In Figure 8, the mean brain concentration (ng / ml) is shown by the dashed line and the mean plasma concentration (ng / ml) is shown by the solid line.

[0196] Deuterated compound (A2) of Example 1 is enriched and maintained in the brain compared to N-[(2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R) nemonapride) (see FIG. 9) (each compound was administered orally at a single dose of 2.5 mg / kg). A comparison of the brain to plasma ratios of N-[(2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R) nemonapride) and deuterated compound (A2) of Example 1 is shown in Table 9 (each compound was administered orally at a single dose of 2.5 mg / kg).

[0197] [Table 9]

[0198] Additionally, the deuterated compound (A2) of Example 1 exhibits higher receptor occupancy levels at 1 h, 2 h, 8 h and 24 h compared to N-[(2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R) nemonapride) (see FIG. 10).

[0199] Example 7 - Touchscreen-Based Probabilistic Reward Task for Rats The Probabilistic Reward Task (PRT) uses visual discrimination methodology to quantify reward responsiveness, identify deficits and characterize drug-induced improvements. Groups of rats are trained on the touchscreen-based PRT and exposed to asymmetric probabilistic contingencies to generate response tendencies toward enriched rewarding stimuli (Pizzagalli, D. et al., Biological Psychiatry, 2005, 57, 319-327; Kangas, B. et al., Translational Psychiatry, 2020, 10(1):285; Wooldridge, L. et al., International Journal of Neuropsychopharmacology, 2021, 24, 409-418). Subjects are then tested with vehicle and three doses of the deuterated compound of Example 1 (A2).

[0200] method subject Male Sprague Dawley rats were used in this study. Device Details and a schematic of the rodent haptic experimental chamber can be found in Kangas, B. et al., Behavioural Pharmacology, 2017, 28, 623-629. Briefly, a custom-made Plexiglas chamber (25x30x35cm) is placed inside a sound- and light-attenuating enclosure (40x60x45cm). A 17-inch touchscreen (1739L, ELO TouchSystems, Menlo Park, CA) is mounted on the right-hand interior wall of the enclosure. An infusion pump (PHM-100-5, Med Associates, St. Albans, VT), located outside the enclosure, is used to deliver sweetened condensed milk into a shallow reservoir in a custom-designed aluminum receptacle. The receptacle is mounted 3cm above the floor bar, centered on the left-hand interior wall. Both the touchscreen and the fluid reservoir are positioned to be easily accessible to the subject. A speaker bar (NQ576AT, Hewlett-Packard, Palo Alto, CA) mounted above the touchscreen was used to provide audio feedback. All experimental events and data collection were programmed with E-Prime Professional 2.0 (Psychology Software Tools, Inc.).

[0201] procedure initial training Rats are trained to engage with the touchscreen using a modified response-shaping technique (Kangas, B. et al., Journal of Neuroscience Methods, 2012, 209, 331-336). A 5 × 5 cm blue square on a black background is presented on different parts of the touchscreen (left, right, center), except that the bottom edge is always 10 cm above the floor bar. This requires the rat to approach the screen with its hind paws and make a touchscreen response with its forepaws. Each response is reinforced with 0.1 mL of 30% sweetened condensed milk, delivery of which is paired with an 880 ms yellow screen flash and a 440 Hz tone, followed by a 5 s intertrial interval (ITI) blackout period. After responses are reliably observed with latencies of less than 5 s after stimulus presentation, line-length discrimination training begins.

[0202] Line length identification training An individual trial begins with the simultaneous presentation of a white line 5 cm above the left and right response boxes. The width of the line is always 7 cm, but the length of the line is 30 cm or 15 cm, varying quasi-randomly over 100 test segments (50 trials at each length). Subjects are trained to respond to the left or right response box depending on the length of the white line (i.e., long line = respond to the left, short line = respond to the right, or vice versa). Response box assignment is counterbalanced across subjects. Correct responses are reinforced as above, followed by a 5-s ITI, whereas incorrect responses are immediately followed by a 5-s ITI. A correction procedure (Kangas, B.et al., Journal of the Experimental Analysis of Behavior, 2008, 90, 103-112) is implemented during initial discrimination training, where each incorrect trial is repeated until a correct response is obtained, and then stopped when the number of repetitions of each trial type for the entire session is less than 5. Discrimination sessions are continued uncorrected until accuracy for both line lengths exceeds 75% for three consecutive sessions.

[0203] Probabilistic Reward Task Following line length discrimination training, a stochastic reinforcement schedule was introduced. Based on the human task protocol, a 3:1 rich / lean stochastic schedule was arranged such that 60% of correct responses to one of the line lengths (e.g., long line = rich alternative) were rewarded and 20% of correct responses to the other line length (e.g., short line = lean alternative). Rich / lean line assignments were counterbalanced across subjects, and 50 trials of each trial type were presented in a quasi-random sequence. These stochastic contingencies were assessed over five consecutive sessions before drug testing began.

[0204] PRT Drug Test After the stochastic contingencies are established, an acute drug testing protocol is instituted that includes intermittent maintenance sessions in which correct responses on all trials are reinforced, control sessions in which 3:1 (60%:20%) rich / lean stochastic contingencies are arranged, and drug test sessions no more than once a week (a dose of vehicle or deuterated compound (A2) of Example 1 (0.5 mg / kg, 1 mg / kg or 2.5 mg / kg) is tested by orally administering it 4-5 hours before the 3:1 (60%:20%) stochastic session). Doses of deuterated compound (A2) of Example 1 are tested in a mixed order across subjects using a Latin square design. All doses of vehicle and deuterated compound (A2) of Example 1 are tested in all subjects.

[0205] Data analysis The implementation of probabilistic contingencies yields two main dependent measures, response bias and task discrimination, which can be quantified by examining the number of correct and incorrect responses on rich and lean trial types, respectively, using the log b and log d formulas derived from signal detection theory (Kangas, B. et al., Journal of the Experimental Analysis of Behavior, 2008, 90, 103-112; Luc O. et al., Perspectives on Behavior Science, 2021, 44 (4), 517-540; McCarthy, D., Signal Detection: Mechanisms, Models, and Applications (eds Nevin, J. et al.), Behavioral Detection Theory: Some Implications for Applied Human Research, 1991 (Erlbaum, New Jersey)).

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[0206] High bias values ​​result from more correct responses on rich trials and more incorrect responses on lean trials, increasing the log b numerator. High discrimination results from more correct responses on both rich and lean trials, increasing the log d numerator. (0.5 is added to all parameters to avoid cases where no errors are made on some trial types, making log transformation impossible.) All data (log b, log d, accuracy, reaction times) were subjected to repeated measures analysis of variance (ANOVA).

[0207] Drugs Dissolve the deuterated compound (A2) from Example 1 in a 0.5% methylcellulose solution. Administer the drug orally 4-5 h before the experimental session.

[0208] Results and Discussion As shown in FIG. 12A, the deuterated compound of Example 1 (A2) significantly enhances the reward response bias (log b) at 1 mg / kg.

[0209] As shown in FIG. 12B, the deuterated compound (A2) of Example 1 significantly improved discrimination at 0.5 mg / kg and 2.5 mg / kg, and a similar tendency was observed at 1 mg / kg.

[0210] The data demonstrate that a dose of the deuterated compound of Example 1 (A2) that targets low D2RO but not high D2RO significantly increases reward responsiveness.

[0211] No catalepsy was observed at the doses tested.

[0212] The data show that low doses of the deuterated compound of Example 1 (A2) can reduce anhedonia without inducing extrapyramidal side effects.

[0213] In the data, D 2 / 3 It has been suggested that when receptor occupancy is approximately 40-60%, an antihedonic effect is achieved, when it is approximately 65-80%, an antipsychotic effect is achieved, and when it exceeds 80%, catalepsy occurs.

[0214] Example 8 - Conditioned avoidance response Adult male Wistar rats are used. Risperidone (0.5 mg / kg; Sigma Aldrich) is dissolved in 10% DMSO in water and injected ip at a dose volume of 1 mg / kg 30 minutes before testing. Deuterated compound (A2) of Example 1 (0.5 mg / kg, 2.5 mg / kg, 5 mg / kg) is formulated in 0.5% methylcellulose in water and orally administered at a dose of 1 mg / kg 4 hours before testing.

[0215] The conditioned avoidance response (CAR) test is an animal model screen for antipsychotic drugs.

[0216] Dunnett's post hoc analysis revealed that risperidone (0.5 mg / kg) and deuterated compound (A2) of Example 1 (2.5 mg / kg and 5 mg / kg) significantly reduced the percentage and number of avoidance responses compared to vehicle.

[0217] Dunnett's post-hoc analysis revealed that risperidone (0.5 mg / kg) increased escape failures compared to vehicle. The deuterated compound of Example 1 (A2) had no significant treatment effect on this measure at any dose.

[0218] Rats acutely treated with deuterated compound (A2) of Example 1 (2.5 and 5 mg / kg) show a reduction in the rate and percentage of avoidance responses indicating potential antipsychotic activity. Deuterated compound (A2) of Example 1 shows no effect on escape failure at any dose.

[0219] Example 9 - Headshake Response Adult male Sprague Dawley rats are used. Deuterated compound (A2) of Example 1 (1 mg / kg, 5 mg / kg and 10 mg / kg) is formulated in 0.5% methylcellulose solution and administered orally (PO) at a dose volume of 1 ml / kg 4 hours before testing. DOI (3 mg / kg) is dissolved in saline and administered orally at 1 ml / kg 10 minutes before testing.

[0220] Animals are administered vehicle, DOI, or test compound and returned to their home cages for the appropriate pretreatment time (10 min for DOI, 4 h for deuterated compound (A2) of Example 1) before recording headshakes for 10 min using a video camera. Headshake responses are rapid rhythmic radial head shaking. Data are analyzed by ANOVA with post-hoc analysis where appropriate.

[0221] Dunnett's post-hoc analysis showed that DOI significantly increased the number of head shakes compared to vehicle. The deuterated compound of Example 1 (A2) did not significantly affect this measure at any dose.

[0222] Acute oral administration of deuterated compound (A2) of Example 1 (1 mg / kg, 5 mg / kg, and 10 mg / kg) does not show a significant increase in the number of head shakes compared to vehicle. DOI (3 mg / kg) significantly increases head shake responses after acute ip injection in rats.

[0223] Example 10 - DOI-induced head shake response Adult male Sprague Dawley rats are used. Deuterated compound (A2) of Example 1 (1 mg / kg, 5 mg / kg and 10 mg / kg) is formulated in 0.5% methylcellulose solution and administered orally (PO) at a dose volume of 1 ml / kg 4 hours prior to testing. DOI (3 mg / kg) is dissolved in saline and administered IP (10 minutes prior to testing) at a dose volume of 1 ml / kg. Ketanserin (1 mg / kg) is dissolved in saline and injected IP at a dose volume of 1 mg / kg 30 minutes prior to DOI.

[0224] Animals are administered vehicle, ketanserin or test compound and returned to their home cages for the appropriate pretreatment time (4 hours for the deuterated compound (A2) of Example 1, 30 minutes for ketanserin). Rats are then injected with DOI and head shaking is recorded by video camera for 10 minutes after DOI injection. The head shaking response is a rapid rhythmic shaking of the head in a radial direction. Data are analyzed by ANOVA with post-hoc analysis as appropriate.

[0225] Dunnett's post hoc analysis showed that DOI significantly increased the number of head shakes compared to vehicle. Ketanserin and deuterated compound (A2) of Example 1 (1 mg / kg, 5 mg / kg, and 10 mg / kg) significantly attenuated the head shake response induced by DOI.

[0226] Acute oral administration of deuterated compound (A2) of Example 1 (1 mg / kg, 5 mg / kg, and 10 mg / kg) reduces DOI-induced head shaking compared to vehicle. Ketanserin (1 mg / kg) also reduces the number of DOI-induced head shaking responses after acute ip injection.

Claims

1. Formula I, in free or salt form: 【Chemistry 1】 [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from H and D; R 1 , R 2 and R 3 at least one of them is D] Compound.

2. 2. The compound of claim 1 in free form.

3. R 1 , R 2 and R 3 The compound according to claim 1 or 2, wherein is D.

4. R 1 , R 2 , R 3 , R 4 and R 5 and each is D.

5. The compound may be in free or salt form. 【Chemistry 2】 The compound according to any one of claims 1 to 4,

6. 6. The compound of any one of claims 1 to 5, wherein the compound in free form or in a pharma- ceutically acceptable salt form has greater than 90% deuterium incorporation at one or more positions designated as deuterium.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, in free form or in a pharma- ceutically acceptable salt form, and a pharma- ceutically acceptable carrier.

8. A method of treating a brain disorder in a patient in need thereof, comprising administering to said patient a compound according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7, in free form or in a pharma- ceutical acceptable salt form.

9. 9. The method of claim 8, wherein the disorder is an affective disorder or an anxiety disorder.

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

11. 11. The method of claim 10, wherein the anxiety disorder is a panic disorder, social anxiety disorder, a phobia or generalized anxiety disorder.

12. 9. The method of claim 8, wherein the disorder is anhedonia, depression associated with anhedonia, suicidal ideation, anxiety depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression or post-psychotic depression.

13. 9. The method of claim 8, wherein the disorder is anxiety depression.

14. 9. The method of claim 8, wherein the disorder is melancholic depression.

15. 9. The method of claim 8, wherein the disorder is major depressive disorder.

16. 9. The method of claim 8, wherein the disorder is a substance use disorder.

17. A compound according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7, in free form or in a pharma- ceutically acceptable salt form, for use in the treatment of a brain disorder.

18. 13. Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for treating a brain disorder.

19. The use according to claim 17 or 18, wherein the brain disorder is one according to any one of claims 9 to 16.

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