WO2023130117A1 - Deuterated organic compounds and uses thereof - Google Patents

Deuterated organic compounds and uses thereof Download PDF

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Publication number
WO2023130117A1
WO2023130117A1 PCT/US2023/010050 US2023010050W WO2023130117A1 WO 2023130117 A1 WO2023130117 A1 WO 2023130117A1 US 2023010050 W US2023010050 W US 2023010050W WO 2023130117 A1 WO2023130117 A1 WO 2023130117A1
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WIPO (PCT)
Prior art keywords
compound
disorder
formula
free
pharmaceutically acceptable
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PCT/US2023/010050
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French (fr)
Inventor
Krishna VADODARIA
Kimberly Vanover
Jordi SERRATS
Vikram SUDARSAN
David Garvey
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Engrail Therapeutics Inc
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Engrail Therapeutics Inc
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Priority to AU2023204432A priority Critical patent/AU2023204432A1/en
Priority to US18/726,550 priority patent/US20250091990A1/en
Priority to KR1020247025927A priority patent/KR20240132476A/en
Priority to JP2024561730A priority patent/JP2025501410A/en
Priority to CA3242751A priority patent/CA3242751A1/en
Priority to IL314019A priority patent/IL314019A/en
Application filed by Engrail Therapeutics Inc filed Critical Engrail Therapeutics Inc
Priority to CN202380024878.6A priority patent/CN118804910A/en
Priority to EP23735187.9A priority patent/EP4460490A1/en
Publication of WO2023130117A1 publication Critical patent/WO2023130117A1/en
Priority to MX2024008372A priority patent/MX2024008372A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds

Definitions

  • Dopamine is involved in a variety of central nervous system functions, including voluntary movement, feeding, affect, reward, sleep, attention, working memory, and learning. Serotonin also is involved in a variety of central nervous system functions, including mood, cognition, reward, learning, memory, and various physiological processes. Accordingly, dopaminergic and/or serotonergic dysfunction can lead to diseases such as schizophrenia and depression.
  • dopamine When released from presynaptic terminals, dopamine activates members of a family of G protein-coupled dopamine receptors D1-D5.
  • Dopamine receptors (D1-D5) are divided into two groups, the DI -like (DI and D5) and the D2-like (D2, D3, and D4).
  • DI -like receptors activates adenylyl cyclase and increases cAMP levels.
  • D2-like receptors are inhibitory.
  • Activation of D2-like receptors inhibits activation of adenylyl cyclase.
  • DI -like receptors are found postsynaptically on dopamine-receptive cells, while
  • D2-like dopamine receptors are expressed both postsynaptically on dopamine target cells and presynaptically on dopaminergic neurons.
  • serotonin receptor subtypes Fourteen serotonin receptor subtypes, grouped into sub-families, mediate effects of serotonin (5-HT).
  • the 5-HT1 A receptor subtype a major receptor subtype, exists as presynaptic autoreceptor in serotonin neurons in the raphe nuclei and as postsynaptic heteroreceptors in the prefrontal cortex, hippocampus, septum, and hypothalamus. Signaling mechanisms of 5-HT1 A receptors in the raphe nuclei may be different from 5-HT1 A receptors in other brain regions.
  • 5-HT1 A postsynaptic receptors can elicit increased dopamine release.
  • the 5-HT2A receptor subtype is enriched in cortex and is linked to phosphatidylinositol turnover and also modulates dopamine release.
  • 5-HT2A receptor antagonists have antipsychotic properties, while 5-HT2A receptor agonism is thought to be associated with cognition-enhancing and hallucinogenic properties. The hallucinogenic effects of lysergic diethylamide (LSD) and psilocybin are thought to arise from their 5-HT2A receptor agonism.
  • 5-HT2A agonism has also been reported to promote neural plasticity and reduce depression.
  • Antipsychotics are used to manage psychosis, in particular schizophrenia.
  • a hallmark of antipsychotics is D2 receptor antagonism.
  • D2 receptor antagonism is effective in reducing positive symptoms of schizophrenia (for instance, hallucinations and delusions), but often also produces extrapy rami dal side effects, including parkinsonism, akathisia, and tardive dyskinesia, increases prolactin, and may exacerbate negative symptoms of schizophrenia (for instance, loss of interest and motivation in life and activities, social withdrawal, and anhedonia).
  • a key feature of atypical antipsychotics is D2 receptor antagonism in combination with 5-HT2A receptor antagonism, which may explain their enhanced efficacy and reduced extrapy rami dal motor side effects (EPS) compared to typical antipsychotics.
  • EPS extrapy rami dal motor side effects
  • Many psychotic patients also suffer from depression, which may be left untreated by current medications.
  • some atypical antipsychotics are used adjunctively to serotonergic antidepressants to improve response in major depressive disorder.
  • Ri, R2, R3, R4, and R5 are independently selected from H and D; and at least one of Ri, R2, and R3 is D; in free or salt form.
  • compositions comprising compounds of Formula I, processes for preparing compounds of Formula I, and pharmaceutical uses of compounds of Formula I, for instance, as an anti-anhedonic agent and to treat schizophrenia and depression.
  • Figure 1 shows disappearance of cis (R,R) nemonapride in human hepatocytes.
  • Figure 2 shows disappearance of the compound of Example 1 (A2) in human hepatocytes.
  • Figure 3 shows plasma concentration (ng/ml) in rats of cis (R,R) nemonapride and the compound of Example 1 (A2) following a single PO dose of 0.5 mg/kg.
  • Figure 4 shows extended brain enrichment of the compound of Example 1 (A2) in rats following a single PO dose of 0.5 mg/kg compared to plasma levels.
  • Figure 5 shows extended brain enrichment of the compound of Example 1 (A2) in rats following a single PO dose of 5 mg/kg compared to plasma levels.
  • Figure 6 shows average brain concentration (ng/ml) in rats of cis (R,R) nemonapride and the compound of Example 1 (A2) when administered at a single PO dose of 0.5 mg/kg.
  • Figure 7 shows average plasma concentration (ng/ml) in rats of cis (R,R) nemonapride and the compound of Example 1 (A2) following single oral administration of 2.5 mg/kg.
  • Figure 8 shows extended brain enrichment of the compound of Example 1 (A2) in rats following a single oral administration of 2.5 mg/kg compared to plasma levels.
  • Figure 9 shows average brain concentration (ng/ml) of cis (R,R) nemonapride and the compound of Example 1 (A2) following a single oral administration of 2.5 mg/kg to rats.
  • Figure 10 shows D2 receptor occupancy of cis (R,R) nemonapride and the compound of Example 1 (A2) when administered orally at a dose of 2.5 mg/kg to rats.
  • Figure 11 shows average plasma and brain concentrations (ng/ml) of cis (R,R) nemonapride following a single oral administration of 2.5 mg/kg to rats.
  • Figure 12A shows response bias in probabilistic reward task for the compound of Example 1 (A2) when administered at doses of 0.5, 1, and 2.5 mg/kg to rats.
  • Figure 12B shows discriminability in the probabilistic reward task for the compound of Example 1 (A2) when administered at doses of 0.5, 1, and 2.5 mg/kg to rats.
  • Figure 13 shows a pharmacokinetic:pharmacodynamic model for the compound of Example 1 (A2) for an oral 1 mg/kg oral dose.
  • D2- and D3- receptors are expressed both postsynaptically on dopamine target cells and presynaptically on dopamine neurons.
  • Dopamine receptors are mainly located on nondopamine neurons.
  • Dopamine receptors on dopamine neurons are called autoreceptors.
  • autoreceptors contribute to regulating dopamine neuron activity and controlling the synthesis, release, and uptake of dopamine.
  • Presynaptic D2-like dopamine autoreceptors regulate dopamine release.
  • a low dose of a D2-like receptor antagonist may preferentially block presynaptic autoreceptors and increase dopamine release, while a high dose may block postsynaptic receptors and decrease dopamine neurotransmission.
  • Relatively high occupancy of D2-like receptors has been associated with antipsychotic effects, while lower occupancy has been associated with antidepressant effects.
  • Anhedonia is a core symptom of major depressive disorder (MDD) and is associated with inadequate response to approved selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) and psychotherapy (e.g., cognitive behavioral therapy (CBT)) and neurostimulation (e.g., transcranial magnetic stimulation (TMS)).
  • SSRIs selective serotonin reuptake inhibitors
  • SNRIs serotonin norepinephrine reuptake inhibitors
  • TMS transcranial magnetic stimulation
  • dopamine/catecholamines induces symptoms of depression and anhedonia. Increasing dopamine neurotransmission can alleviate symptoms of depression and anhedonia.
  • a dopamine D2/D3 agonist may activate dopamine post-synaptic receptors, it can also be poorly tolerated (e.g., nausea/vomiting).
  • Low dose of a dopamine D2/D3 receptor antagonist may preferentially block pre-synaptic dopamine autoreceptors and increase dopamine release without being poorly tolerated.
  • anhedonia also plays a role in bipolar disorder, schizophrenia, post-traumatic stress disorder, and substance use disorder. Despite its role in many disorders, there are no approved medications to treat anhedonia.
  • nemonapride is ( ⁇ )-cA-7V-(l-Benzyl-2-methylpyrrolidin-3- yl)-5-chloro-2-methoxy-4-methylaminobenzamide.
  • Nemonapride is described in U.S. Patent No. 4,210,660 as a strong central nervous system depressant, in particular a strong antipsychotic.
  • Nemonapride is a dopamine D2/D3/D4 receptor antagonist.
  • Nemonapride is approved in Japan and South Korea for treatment of schizophrenia. Nemonapride is supplied as 3 mg and 10 mg tablets.
  • the approved daily dose of nemonapride for schizophrenia is 9 to 36 mg given orally in divided doses after meals. The dose can be increased up to 60 mg daily.
  • the nemonapride prescribing information indicates that the elimination half-life when nemonapride 3 mg and 6 mg was administered orally to healthy adults was 2.3 to 4.5 hours.
  • Urinary metabolites of nemonapride result from debenzylation and N-demethylation. See Emilace package insert.
  • nemonapride In addition to being a dopamine D2/D3/D4 receptor antagonist, nemonapride is also a 5-HT1 A agonist. Further, nemonapride has been reported to bind to 5-HT2A receptors, however, the inventors are not aware of any publication that reports its functional effect at that receptor. Yet, as an antipsychotic, it may be expected that nemonapride is a 5-HT2A receptor antagonist because a key feature of atypical antipsychotics is D2 receptor antagonism in combination with 5-HT2A receptor antagonism or inverse agonism.
  • 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 analog (see Example 3).
  • D2/D3/D4 receptor antagonism in combination with 5-HT1 A and 5-HT2A agonism is a unique activity profile, which may allow for different modulation of dopamine and serotonin neurotransmission compared to other D2/D3/D4 receptor antagonists.
  • D2/D3/D4 receptor antagonism in combination with 5-HT1 A and 5-HT2A agonism is a unique activity profile, which may allow for different modulation of dopamine and serotonin neurotransmission compared to other D2/D3/D4 receptor antagonists.
  • D2/D3/D4 postsynaptic receptor antagonism reduces psychosis, particularly in schizophrenia, by reducing dopamine neurotransmission.
  • High doses that target > 60% receptor occupancy may be associated with D2 antagonist mediated side effects such as extrapy rami dal motor side effects (EPS) and increased prolactin.
  • EPS extrapy rami dal motor side effects
  • 5-HT1 A agonism may limit those high dose D2 antagonist related side effects, thus providing the compounds with a built-in safety feature when used at high dose as an antipsychotic.
  • Partial 5-HT1 A agonism also provides anxiolytic effects.
  • deuterated compounds disclosed herein may show enhanced antidepressant effects as seen with psychedelic antidepressants, for instance, rapid and long-lasting and with anxiolytic effects, yet at the same time hallucinogenic and fear/anxiety effects may not be as pronounced as with a full 5-HT2A agonist.
  • D2 antagonism may also block 5-HT2A hallucinogenic effects.
  • compounds of Formula I may provide psychedelic-like antidepressant efficacy at low doses (e.g., doses lower than those of nemonapride used to treat schizophrenia), but also have built-in protection against 5-HT2A mediated hallucinations and without fear/anxiety.
  • compounds of Formula I may act as antipsychotics at high doses, but have built-in protection against high dose D2 antagonist related side effects.
  • Example 5 Plasma pharmacokinetics of N-[(2R,3R)-l-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 Example 5). However, despite similar plasma pharmacokinetics, Examples 5 and 6 show that a compound of Formula I (the deuterated compound of Example 1) has enriched and retained brain levels compared to its non-deuterated analog and higher receptor occupancy levels at 1, 2, 8, and 24 hours.
  • Figures 6 and 9 show that at 8 hours, brain levels of the compound of Example 1 (A2) are similar to the highest levels of cis (R,R) nemonapride measured, which occur at shorter time.
  • the deuterated compound of Example 1 also shows extended brain enrichment compared to plasma levels of the compound.
  • the braimplasma exposure supports once-daily dosing. Enriched brain levels, higher receptor occupancy levels, and extended brain enrichment compared to plasma levels are beneficial features that allows for higher and more sustained receptor occupancy with less frequent dosing and may be associated with fewer peripheral side effects.
  • the receptor occupancy curve of the deuterated compound of Example 1 exhibits more moderate changes between peaks and troughs (a 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 a desired range with a convenient dosing regime.
  • nemonapride is taken in multiple doses per day.
  • Compounds that are D2/D3/D4 receptor antagonists, 5-HT1 A receptor agonists, and 5-HT2A receptor partial agonists modulate dopamine and serotonin neurotransmission and are therefore useful in treating disorders involving dopamine and serotonin signaling pathways, for instance, disorders involving D2, D3, D4, 5-HT1 A, and/or 5-HT2A receptors.
  • Ri, R2, R3, R4, and R5 are independently selected from H and D; and at least one of Ri, R2, and R3 is D; in free or salt form.
  • any of Formula I or 1.1-1.7 wherein the compound, in free or salt form (e.g., pharmaceutically acceptable salt form), has greater than 50% incorporation of deuterium (i.e., D) at one or more positions (e.g., at all positions) designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
  • any of Formula I or 1.1-1.7 wherein the compound, in free or salt form (e.g., pharmaceutically acceptable salt form), has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
  • Any of Formula I or 1.1-1.8, wherein the compound is substantially stereoisomerically pure.
  • the compound has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%.
  • the compound is substantially diastereomerically and/or enantiomerically pure, e.g., wherein the compound is substantially diastereomerically and enantiomerically pure.
  • any of Formula I or 1.1-1.9 wherein the compound is substantially diastereomerically pure.
  • the compound has a diastereomeric excess of greater than 90%, e.g., a diastereomeric excess equal to or greater than 95%, e.g., a diastereomeric excess equal to or greater than 96%, e.g., a diastereomeric excess equal to or greater than 97%, e.g., a diastereomeric excess equal to or greater than 98%, e.g., a diastereomeric excess equal to or greater than 99%.
  • the compound has an enantiomeric excess of greater than 90%, e.g., an enantiomeric excess equal to or greater than 95%, e.g., an enantiomeric excess equal to or greater than 96%, e.g., an enantiomeric excess equal to or greater than 97%, e.g., an enantiomeric excess equal to or greater than 98%, e.g., an enantiomeric excess equal to or greater than 99%.
  • any of Formula I or 1.1-1.12, wherein the compound is in a pharmaceutical composition with a pharmaceutically acceptable carrier for instance, any of Formula I or 1.1-1.12, wherein an effective amount of the compound is in a pharmaceutical composition with a pharmaceutically acceptable carrier.
  • composition 1 comprising a compound of Formula I (e.g., any of Formula 1.1-1.13):
  • Ri, R2, R3, R4, and R5 are independently selected from H and D; and at least one of Ri, R2, and R3 is D; in free or pharmaceutically acceptable salt form.
  • Composition 1 as follows:
  • composition 1 wherein the composition comprises a pharmaceutically acceptable carrier.
  • composition 1 or 1.1 wherein the composition comprises the compound, in free or pharmaceutically acceptable salt form, as described in any of Formula I or 1.1- 1.13 vide supra.
  • Composition 1 or 1.1-1.3 wherein the compound of Formula I is: in free or pharmaceutically acceptable salt form, e.g., in free form.
  • composition 1 or 1.1-1.4 wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance.
  • composition 1 or 1.1-1.5 wherein the compound of Formula I, in free or pharmaceutically acceptable salt form, has greater than 50% incorporation of deuterium (i.e., D) at one or more positions (e.g., at all positions) designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
  • deuterium i.e., D
  • any of Composition 1 or 1.1-1.5 wherein the compound of Formula I, in free or pharmaceutically acceptable salt form, has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
  • Any of Composition 1 or 1.1-1.6 wherein the composition is in oral or parenteral dosage form, e.g., oral dosage form, for instance, a tablet, capsule, solution, or suspension, for instance, a capsule or tablet.
  • composition 1 or 1.1-1.7 wherein the composition comprises a therapeutically effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, e.g., a therapeutically effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, for the prophylaxis or treatment of a disorder disclosed herein, e.g., a therapeutically effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, for use in any of the methods disclosed herein.
  • composition 1 or 1.1-1.9 wherein the composition comprises less than 10% w/w (weight/weight) of any other stereoisomeric form of Formula I, e.g., less than 5% w/w of any other stereoisomeric form of Formula I, e.g., less than 4% w/w of any other stereoisomeric form of Formula I, e.g., less than 3% w/w of any other stereoisomeric form of Formula I, e.g., less than 2% w/w of any other stereoisomeric form of Formula I, e.g., less than 1% w/w of any other stereoisomeric form of Formula I.
  • composition 1 or 1.1-1.10 wherein the composition comprises less than 10% w/w of any other diastereomeric form of Formula I, e.g., less than 5% w/w of any other diastereomeric form of Formula I, e.g., less than 4% w/w of any other diastereomeric form of Formula I, e.g., less than 3% w/w of any other diastereomeric form of Formula I, e.g., less than 2% w/w of any other diastereomeric form of Formula I, e.g., less than 1% w/w of any other diastereomeric form of Formula I.
  • composition 1 or 1.1-1.11 wherein the composition comprises less than 10% w/w of any other enantiomeric form of Formula I, e.g., less than 5% w/w of any other enantiomeric form of Formula I, e.g., less than 4% w/w of any other enantiomeric form of Formula I, e.g., less than 3% w/w of any other enantiomeric form of Formula I, e.g., less than 2% w/w of any other enantiomeric form of Formula I, e.g., less than 1% w/w of any other enantiomeric form of Formula I.
  • Any of Composition 1 or 1.1-1.13, wherein the composition comprises 1-60 mg of the compound of Formula I.
  • any of Composition 1 or 1.1-1.13, wherein the composition comprises 1-10 mg, e.g., 1-9 mg (e.g., 1-8 mg) of the compound of Formula I.
  • any of Composition 1 or 1.1-1.13, wherein the composition comprises 3 mg or 10 mg of the compound of Formula I.
  • 1.15 Any of Composition 1 or 1.1-1.14, wherein the composition is for once, twice, or three times daily dosing.
  • any of Composition 1 or 1.1-1.14, wherein the composition is for once daily dosing.
  • a central nervous system disorder e.g., a brain disorder
  • a central nervous system disorder e.g., a brain disorder
  • the method comprises administering to the patient a compound of Formula I, in free or pharmaceutically acceptable salt form (e.g., any of Formula I or 1.1-1.13 vide supra), or a pharmaceutical composition comprising a compound of Formula I, in free or pharmaceutically acceptable salt form (e.g., Formula 1.13 or any of Composition 1 or 1.1-1.15 vide supra), or a compound of Formula la or Compound A, in free or pharmaceutically acceptable salt form (vide infra), or a pharmaceutical composition comprising a compound of Formula la or Compound A, in free or pharmaceutically acceptable salt form (vide infra).
  • a central nervous system disorder e.g., a brain disorder
  • a central nervous system disorder e.g., a brain disorder
  • D2 receptor antagonism e.g., D3 receptor antagonism, D4 receptor antagonism
  • 5-HT1 A receptor agonism e.g., 5-HT1 A receptor partial agonism
  • 5-HT2A receptor agonism e.g., 5-HT2A receptor partial agonism
  • the method comprises administering to the patient a compound of Formula I, in free or pharmaceutically acceptable salt form (e.g., any of Formula I or 1.1-1.13 vide supra), or a pharmaceutical composition comprising a compound of Formula I, in free or pharmaceutically acceptable salt form (e.g., Formula 1.13 or any of Composition 1 or 1.1-1.15 vide supra), or a compound of Formula la or Compound A, in free or pharmaceutically acceptable salt form (vide infra), or a pharmaceutical composition comprising a compound of Formula la or Compound A, in free or pharmaceutically acceptable salt
  • Method 1 for treatment or prophylaxis of a disorder (e.g., a brain disorder) in a patient in need thereof, wherein the method comprises administering to the patient an effective amount of a compound of Formula la:
  • Ri, R2, R3, R4, and R5 are independently selected from H and D; in free or pharmaceutically acceptable salt form.
  • Method 1 wherein the method comprises administering ( ⁇ )-cz -7V-(l-Benzyl-2- methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide (i.e., nemonapride), in free or pharmaceutically acceptable salt form, wherein ( ⁇ )-cis- 7V-(l-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide does not show optical rotation in chloroform.
  • the method comprises administering ( ⁇ )-cz -7V-(l-Benzyl-2- methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide (i.e., nemonapride), in free form, wherein ( ⁇ )-cz.s-A-( l -Benzyl-2-methylpyrrolidin-3- yl)-5-chloro-2-methoxy-4-methylaminobenzamide does not show optical rotation in chloroform.
  • Method 1 wherein the method comprises administering an effective amount of Compound A:
  • Compound A in free or pharmaceutically acceptable salt form.
  • the effective amount of Compound A, in free or pharmaceutically acceptable salt form has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%.
  • the effective amount of Compound A, in free or pharmaceutically acceptable salt form is substantially diastereomerically and/or enantiomerically pure, e.g., wherein the effective amount of Compound A, in free or pharmaceutically acceptable salt form, is substantially diastereomerically and enantiomerically pure.
  • the effective amount of compound A, in free or pharmaceutically acceptable salt form has a diastereomeric and/or enantiomeric excess of greater than 90%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 99%.
  • the effective amount of compound A, in free or pharmaceutically acceptable salt form has a diastereomeric and enantiomeric excess of greater than 90%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 99%.
  • Method 1 wherein the method comprises administering a compound of Formula I:
  • Ri, R2, R3, R4, and R5 are independently selected from H and D; and at least one of Ri, R2, and R3 is D; in free or pharmaceutically acceptable salt form.
  • Method 1.3 or 1.4, wherein the method comprises administering to the patient a pharmaceutical composition comprising a compound of Formula I, in free or pharmaceutically acceptable salt form, as described in any of Composition I or 1.1-1.15 vide supra.
  • any of Method 1.3-1.5 wherein the effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%.
  • the effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form is substantially diastereomerically and/or enantiomerically pure, e.g., wherein the effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, is substantially diastereomerically and enantiomerically pure.
  • the effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form has a diastereomeric and/or enantiomeric excess of greater than 90%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 95%, a diastereomeric and/or enantiomeric excess equal to or greater than 96%, a diastereomeric and/or enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 99%.
  • the effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form has a diastereomeric and enantiomeric excess of greater than 90%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 99%. Any of Method 1 or 1.1-1.6, wherein the compound is in free form. Method 1.3, wherein the method comprises administering an effective amount of Compound B:
  • Method 1.8 wherein the effective amount of Compound B, in free or pharmaceutically acceptable salt form, has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%.
  • the effective amount of Compound B, in free or pharmaceutically acceptable salt form is substantially diastereomerically and/or enantiomerically pure, e.g., wherein the effective amount of Compound B, in free or pharmaceutically acceptable salt form, is substantially diastereomerically and enantiomerically pure.
  • the effective amount of compound B, in free or pharmaceutically acceptable salt form has a diastereomeric and/or enantiomeric excess of greater than 90%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 99%.
  • the effective amount of compound B, in free or pharmaceutically acceptable salt form has a diastereomeric and enantiomeric excess of greater than 90%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 99%.
  • Method 1 or 1.3-1.10 wherein the compound, in free or pharmaceutically acceptable salt form, has greater than 50% incorporation of deuterium (i.e., D) at one or more positions (e.g., at all positions) designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
  • deuterium i.e., D
  • any of Method 1 or 1.3-1.10 wherein the compound, in free or pharmaceutically acceptable salt form, has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
  • Any of Method 1 or 1.1-1.11, wherein the disorder is a brain disorder.
  • any of Method 1 or 1.1-1.11, wherein the disorder is a neuropsychiatric condition in which anhedonia is prominent.
  • Method 1 or 1.1-1.12 wherein the disorder is an affective (mood) disorder or an anxiety disorder.
  • the disorder is depression (e.g., depression associated with anhedonia), an anxiety disorder, psychosis (e.g., psychosis in neurodegenerative conditions, such as psychosis in Alzheimer’s disease, Parkinson’s disease, or dementia (e.g., dementia-related psychosis)), schizophrenia, schizoaffective disorder, post-traumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder (including bipolar depression, bipolar mania, and bipolar disorder with mixed features), or a migraine.
  • depression e.g., depression associated with anhedonia
  • psychosis e.g., psychosis in neurodegenerative conditions, such as psychosis in Alzheimer
  • any of Method 1 or 1.1-1.13, wherein the anxiety disorder is panic disorder, social anxiety disorder, a phobia, or generalized anxiety disorder.
  • any of Method 1 or 1.1-1.13, wherein the method is prophylaxis or treatment of behavioral and psychological symptoms of dementia including agitation, depression, anxiety, apathy, and/or psychosis.
  • Any of Method 1 or 1.1-1.14, wherein the disorder is anhedonia or depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression.
  • any of Method 1 or 1.1-1.14, wherein the disorder is anxious depression.
  • Method 1 or 1.1-1.14 wherein the disorder is melancholic depression. Any of Method 1 or 1.1-1.15, wherein the disorder is maj or depressive disorder. Any of Method 1 or 1.1-1.14, wherein the disorder is a substance use disorder. Any of Method 1 or 1.1-1.14, wherein the method is prophylaxis or treatment of negative symptoms of schizophrenia. Or, any of Method 1 or 1.1-1.14, wherein the method is improving cognition in schizophrenia. Any of Method 1 or 1.1-1.11, wherein the compound, in free or pharmaceutically acceptable salt form, is administered as an anti-emetic.
  • Method 1 or 1.1-1.19 wherein the method comprises administering 9-60 mg a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 9-60 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form).
  • the method comprises administering 9-36 mg a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 9-36 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form).
  • the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides 55%-80% D2/D3 receptor occupancy, e.g., as measured by positron emission tomography.
  • the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides about 65% D2/D3 receptor occupancy, e.g., as measured by positron emission tomography.
  • the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides about 60% D2/D3 receptor occupancy, e.g., as measured by positron emission tomography.
  • Method 1.20 or 1.21 wherein the disorder is psychosis (e.g., psychosis in neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease, and dementia (e.g., dementia-related psychosis)), schizophrenia, schizoaffective disorder, or bipolar disorder (e.g., bipolar mania).
  • Method 1.20 or 1.21 wherein the method is prophylaxis or treatment of negative symptoms of schizophrenia. Or, Method 1.20 or 1.21, wherein the method is improving cognition in schizophrenia. Any of Method 1 or 1.1-1.19, wherein the method comprises administering 1-9 mg (e.g., 1-8 mg, e.g., 1.5-6 mg) a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 1-9 mg total daily dose, e.g., 1-8 mg total daily dose, e.g., 1.5-6 mg total daily dose, of the compound, in free or pharmaceutically acceptable salt form).
  • 1-9 mg e.g., 1-8 mg, e.g., 1.5-6 mg
  • any of Method 1 or 1.1-1.19 wherein the method comprises administering 1 mg to less than 3 mg a day (e.g., 2 mg a day) of the compound, in free or pharmaceutically acceptable salt form (i.e., 1 mg to less than 3 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form).
  • 1 mg to less than 3 mg a day e.g., 2 mg a day
  • free or pharmaceutically acceptable salt form i.e., 1 mg to less than 3 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form.
  • Method 1, 1.1-1.19, or 1.24 wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides 10%-60% (e.g., 40%-60% or, e.g., 10%-55%, e.g., 10%-50%, e.g., 30%- 50% or, e.g., 15%-50%, e.g., 15%-45%, e.g., 20%-40%, e.g., 10%-30%) D2/D3 receptor occupancy, e.g., as measured by positron emission tomography.
  • 10%-60% e.g., 40%-60% or, e.g., 10%-55%, e.g., 10%-50%, e.g., 30%- 50% or, e.g., 15%-50%, e.g., 15%-45%, e.g., 20%-40%, e.g., 10%-30%
  • D2/D3 receptor occupancy e.g., as measured by positron emission tomography.
  • any of Method 1, 1.1-1.19, or 1.24 wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides ⁇ 40% (e.g., about 40%), e.g., ⁇ 40% D2/D3 receptor occupancy, e.g., as measured by positron emission tomography.
  • ⁇ 40% e.g., about 40%
  • D2/D3 receptor occupancy e.g., as measured by positron emission tomography.
  • Method 1.24 or 1.25 wherein the disorder is depression (e.g., depression associated with anhedonia), an anxiety disorder, post-traumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder, bipolar disorder with mixed features, or a migraine.
  • depression e.g., depression associated with anhedonia
  • PTSD post-traumatic stress disorder
  • ADHD attention-deficit/hyperactivity disorder
  • Tourette syndrome anorexia nervosa
  • bulimia nervosa binge-eating disorder
  • body dysmorphic disorder obsessive compulsive disorder
  • addiction e.g., bipolar disorder, bipolar disorder with mixed features
  • bipolar disorder e.g., depression associated with anhedonia
  • PTSD post-traumatic stress disorder
  • ADHD attention
  • Method 1.24-1.26 wherein the disorder is anhedonia or depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression. For instance, wherein the disorder is anxious depression. Any of Method 1.24-1.27, wherein the disorder is major depressive disorder. Method 1.24 or 1.25, wherein the disorder is a substance use disorder. Any of Method 1 or 1.1-1.29, wherein the method comprises administering a pharmaceutical composition comprising the compound, in free or pharmaceutically acceptable salt form. For instance, any of Method 1 or 1.1-1.29, wherein the method comprises administering Formula 1.13 or any of Composition 1 or 1.1-1.15 vide supra.
  • Method 1 or 1.1-1.30 wherein the method comprises administering the compound of Formula la, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day.
  • the method comprises administering the compound of Formula la, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day.
  • Method 1 or 1.1-1.31 wherein the method comprises administering the compound of Formula I, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day.
  • Method 1 or 1.1-1.31 wherein the method comprises administering the compound of Formula I, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day.
  • the method comprises administering a pharmaceutical composition comprising the compound of Formula I, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day.
  • Method 1 or 1.1-1.32 wherein the method comprises administering Compound B, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day.
  • the method comprises administering a pharmaceutical composition comprising Compound B, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day.
  • a compound of Formula I e.g., any of Formula 1.1-1.13 or a pharmaceutical composition disclosed herein (e.g., Formula 1.13 or any of Composition 1 or 1.1- 1.15) for use in any of Method 1 or 1.1-1.33 vide supra.
  • R 3 i , R 32 , and R 33 are independently selected from H and D;
  • X is OH or a leaving group; and at least one of R 3 I, R 32 , and R 33 are D; in free or salt (e.g., pharmaceutically acceptable salt) form.
  • X is a leaving group
  • R34 and R35 are D; in free or salt (e.g., pharmaceutically acceptable salt) form.
  • Process 1 wherein the process comprises reacting a compound of Formula II (e.g., any of Formula 2.1-2.5) with a compound of Formula III (e.g., any of Formula 3.1-3.2).
  • a compound of Formula II e.g., any of Formula 2.1-2.5
  • a compound of Formula III e.g., any of Formula 3.1-3.2
  • Process 1 or 1.1-1.3 any of Process 1 or 1.1-1.3, wherein the process occurs with l-ethyl-3-(3- dimethylaminopropyl)carbodiimide and hydroxybenzotriazole.
  • R 3 i , R 32 , and R 33 are independently selected from H and D and at least one of R 3 I, R 32 , and R 33 is D, in free or salt (e.g., pharmaceutically acceptable salt) form, with an activating agent (e.g., l-ethyl-3-(3- dimethylaminopropyl)carbodiimide).
  • an activating agent e.g., l-ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • R 3 i , R 32 , and R 33 are independently selected from H and D and at least one of R 3 I, R 32 , and R 33 is D, in free or salt (e.g., pharmaceutically acceptable salt) form.
  • a hydrogen atom position of a structure is considered substituted with deuterium when the abundance of deuterium at that position is enriched.
  • the natural abundance of deuterium is about 0.02%, so a compound is “enriched” with deuterium at a specific position when the frequency of incorporation of deuterium at that position exceeds 0.02%.
  • any position designated as deuterium may be enriched with deuterium at a level of greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%, such as, greater than 50%, or greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
  • any atom not designated as a particular isotope is present at natural isotopic abundance.
  • Formula Ila, Formula lib, Compound A, and Compound B may exist in free or salt form, e.g., as acid addition salts.
  • language such as “compound of formula” is to be understood as embracing the compound in any form, for example free or acid addition salt form, or where the compound contains an acidic substituent, in base addition salt form.
  • Compounds of Formula I e.g., any of Formula 1.1-1.13
  • Formula la, Compound A, and Compound B are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free compounds of Formula I or Formula la or their pharmaceutically acceptable salts, so therefore are also included.
  • Formula III e.g., any of 3.1-3.2
  • Formula Ila e.g., any of 3.1-3.2
  • Formula lib e.g., Compound A, and Compound B, any in free or pharmaceutically acceptable salt form
  • column purification e.g., column purification, preparative thin layer chromatography, preparative HPLC, trituration, simulated moving beds, and the like.
  • stereoisomeric forms of the compounds and intermediates disclosed herein are isomers substantially free of other enantiomeric and diastereomeric forms of the same basic molecular structure of said compounds or intermediates.
  • “Substantially stereoisomerically pure” includes compounds or intermediates having a stereoisomeric excess of greater than 90% (i.e., more than 90% of one isomer and less than 10% of any other possible isomer).
  • the terms “substantially diastereomerically pure” and “substantially enantiomerically pure” should be understood in a similar way, but then having regard to the diastereomeric excess and enantiomeric excess, respectively, of the material in question.
  • Compounds disclosed herein e.g., any of Formula I (e.g., any of Formula 1.1- 1.13), Formula la, Formula II (e.g., any of Formula 2.1-2.5), Formula III (e.g., any of 3.1-3.2), Formula Ila, Formula lib, Compound A, and Compound B, any in free or pharmaceutically acceptable salt form, may be made by using the methods as described and exemplified herein and by methods similar thereto and by methods known in the chemical art. Such methods include, but are not limited to, those described below. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques that are similar to or analogous to the synthesis of known compounds.
  • such salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in an appropriate solvent.
  • the word “effective amount” is intended to encompass a therapeutically effective amount to treat a specific disease or disorder.
  • Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular compound used, the mode of administration, and the therapy desired.
  • Compounds disclosed herein e.g., any of Formula I (e.g., any of Formula 1.1- 1.13), Formula la, Compound A, or Compound B, any in free or pharmaceutically acceptable salt form, may be administered by any suitable route, including orally, parenterally, or transdermally, but are preferably administered orally.
  • compositions comprising compounds disclosed herein, e.g., any of Formula I (e.g., any of Formula 1.1-1.13 or any of Composition 1 or 1.1-1.15), Formula la, Compound A, or Compound B, any in free or pharmaceutically acceptable salt form, may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.
  • Boc tert-butyloxy carbonyl
  • DIAD diisopropyl azodi carb oxy late
  • DMF dimethylformamide
  • EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • HOBt hydroxybenzotriazole
  • Receptor accession numbers, cellular background, and reference compounds are listed in Table 1.
  • Example 1 The compound from Example 1 (A2) is tested for radioligand binding competition activity at human Dopamine D2S, D3, and D4.4 and Serotonin 5-HT1 A, 5-HT2A, and 5-HT7A receptors and results are provided in Table 2.
  • SPA 35 S-GTPgS experiments are conducted with membrane preparations.
  • IP-One and cAMP HTRF assays are conducted with recombinant cell lines.
  • Receptor accession numbers, cellular background, and reference compounds are listed in Table 3.
  • Example 1 The compound from Example 1 (A2) is tested for antagonist activity at human Dopamine D2S, D3, and D4.4 receptors, for agonist activity at human Serotonin 5-HT1 A receptor, for agonist and antagonist activity at human Serotonin 5-HT2A receptor, and for antagonist activity at human Serotonin 5-HT7A receptor. Results are in Tables 4 and 5.
  • Agonist activity of test compounds is expressed as a percentage of the activity of the reference agonist at its ECioo concentration.
  • Antagonist activity of the test compound is expressed as a percentage of the inhibition of reference agonist activity at its EC «o concentration.
  • the deuterated compound of Example 1 is a D2/D3/D4 antagonist, 5-HT1 A agonist, and 5-HT2A partial agonist.
  • Example 4 In vitro metabolism [0092] Study compounds are investigated in pooled cryopreserved human (mixed gender) hepatocytes. The incubations are performed using 5 pM initial concentration and sampling at 0, 60, and 120 minute time points. The samples are analyzed using UPLC-QE- orbitrap-MS. Incubation volume: 300 pl in 48-well plate. Number of cells: 1 million viable cells/ml. Test compound: 5 pM (stock solution in DMSO). Incubation medium: pH 7.4, Bioreclamation IVT in vitro KHB medium. Shaking: 600 rpm. Time points: 0, 60, and 120 minutes with and without cells. Temperature: 37 °C. Sampling volume: 60 pl. DMSO content in incubation: 0.5%. Termination of incubations: 2-fold volume of 75% acetonitrile. Control: verapamil disappearance rate.
  • Sample preparation for hepatocyte samples Samples are centrifuged for 20 min at 2272 x g at room temperature and pipetted to a UPLC-plate for analysis.
  • Test compounds are the deuterated compound of Example 1 (A2) and N- [(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis (R,R) nemonapride).
  • Rats are surgically cannulated with femoral artery catheter for blood collection. Approximate weight of rats is 250-350 g. Water is provided ad libitum. Fasting overnight prior to oral dose. Food available 4 h post dose.
  • Dose formulations are 0.5% aqueous methylcellulose (4000 cps) with 0.1% TweenTM80 for PO administration. Once prepared, the suspension is vortexed/homogenized and continuously stirred until administration. Dose concentration: 0.1 mg/mL for 0.5 mg/kg dose and 1 mg/mL for 5 mg/kg dose. Route of administration: oral gavage. Dose volume: 5 mL/kg. Serial bleed: 200 p,L per time point. Terminal bleed: 500 p,L.
  • Plasma samples are obtained via an automated sampling system in tubes containing potassium EDTA anticoagulant up to 24 h post dose. Plasma is obtained by centrifugation and snap frozen on dry ice within 30 minutes after collection. Aliquots of each dose formulation are taken, diluted appropriately, and analyzed at the same time with plasma samples by LC-MS/MS.
  • Plasma harvested from blood samples
  • brain tissues homogenized and processed
  • Plasma is harvested from blood via centrifugation within 30 minutes of sample collection.
  • Brain tissue is collected after animals undergo perfusion to remove residual cardiovascular blood.
  • Dose solutions, plasma (harvested from blood), and brain tissues (homogenized and processed) are stored at -20 °C until analysis.
  • Plasma samples are thawed at room temperature before adding an organic solvent containing an internal standard to precipitate proteins.
  • Brain samples are thawed and homogenized in water (3-4 volumes) and aliquots of homogenates analyzed by LC/MS/MS.
  • Results are shown in Figures 3-6.
  • Plasma pharmacokinetics between N-[(2R,3R)-l-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 Figure 3, see also Figure 7).
  • the deuterated compound of Example 1 has enriched brain levels compared to N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4- (methylamino)benzamide (cis (R,R) nemonapride) (see Figure 6, both administered at a single PO dose of 0.5 mg/kg).
  • This study is to determine receptor occupancy at central D2 receptors following oral administration of the deuterated compound of Example 1 (A2) at various time points (1, 2, 4, 8, and 24 hours) and the positive comparator, olanzapine (10 mg/kg, po) using [ 3 H]racl opride and rat striatal membranes. Liquid scintillation counting is used to quantify radioactivity.
  • mice are dosed orally with either vehicle, a single dose (2.5 mg/kg) of the deuterated compound of Example 1 (A2), N-[(2R,3R)-l-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).
  • Vehicle is 0.5% methylcellulose.
  • a post-mortem blood sample (approx. 5 ml) is taken by cardiac puncture and placed into KZEDTA tubes.
  • the post-mortem blood samples are gently inverted, centrifuged (1900 g for 5 minutes at 4°C), and 1 ml of plasma from taken for PK determination. All plasma samples are frozen and stored at -80°C.
  • the striata is homogenised individually in ice-cold 50 mM Tris, pH 7.4, 120 mM NaCl, 5 mM KC1, 2 mM CaCl 2 , 1 mM MgCl 2 , and 10 pM pargyline using a tight-fitting homogeniser equivalent to 6.25 mg wet weight of tissue/ml and used immediately in the binding assay.
  • Striatal homogenates 400 pl, equivalent to 2.5 mg wet weight tissue/tube are incubated with 50 pl of 1.6 nM [ 3 H]raclopride and either 50 pl assay buffer (total binding) or 50 pl of 1 pM (-)sulpiride (to define non-specific binding) for 30 minutes at 23°C.
  • the assay buffer consists of 50 mM Tris, pH 7.4, 120 mM NaCl, 5 mM KC1, 2 mM CaCl 2 , ImM MgCl 2 , and 10 pM pargyline.
  • the wash buffer consists of 50 mM Tris, pH 7.4. There are two tubes for the determination of total binding and two tubes for the determination of non-specific binding.
  • Membrane bound radioactivity is recovered by filtration under vacuum through filters, presoaked in 0.5% polyethylenimine (PEI) using a cell harvester. Filters are rapidly washed with ice-cold buffer and radioactivity determined by liquid scintillation counting.
  • PEI polyethylenimine
  • a value for specific binding is generated by the subtraction of mean nonspecific binding (dpm) from mean total binding (dpm) for each animal.
  • the deuterated compound of Example 1 has enriched and retained brain levels compared to N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4- (methylamino)benzamide (cis (R,R) nemonapride) (see Figure 9) (single oral administration of 2.5 mg/kg of each compound).
  • the deuterated compound of Example 1 has higher receptor occupancy levels at Ih, 2h, 8h, and 24h compared to N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3- yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis (R,R) nemonapride) (see Figure 10).
  • the Probabilistic Reward Task uses visual discrimination methodology to quantify reward responsiveness to both identify deficits and characterize drug-induced improvements.
  • Groups of rats are trained on the touchscreen-based PRT and exposed to asymmetrical probabilistic contingencies to generate response biases to the richly rewarded stimulus (Pizzagalli, D. et al., Biological Psychiatry, 2005, 57, 319-327; Kangas, B. et al., Translational Psychiatry, 2020, 10(l):285; Wooldridge, L. et al., International Journal of Neuropsychopharmacology, 2021, 24, 409-418).
  • subjects are tested with vehicle and three doses of the deuterated compound of Example 1 (A2).
  • the receptacle is mounted 3 cm above the floor bars and centered on the left-hand inside wall. Both touchscreen and fluid reservoir are easily accessible to the subject.
  • a speaker bar (NQ576AT, Hewlett- Packard, Palo Alto, CA) mounted above the touchscreen is used to emit audible feedback. All experimental events and data collection are programmed in E-Prime Professional 2.0 (Psychology Software Tools, Inc., Sharpsburg, PA). Procedure
  • Modified response-shaping techniques are used to train rats to engage with the touchscreen (Kangas, B. et al., Journal of Neuroscience Methods, 2012, 209, 331-336).
  • a 5x5 cm blue square on a black background is presented in different sections of the touchscreen (left, right or center), with the proviso that its lower edge always is 10 cm above the floor bars. This requires the rat to rear on its hind legs to reach the screen and make a touchscreen response with its paw.
  • Each response is reinforced with 0.1 mL of 30% sweetened condensed milk and the delivery is paired with an 880 ms yellow screen flash and 440 Hz tone and followed by a 5-sec intertrial interval (ITI) blackout period.
  • ITI 5-sec intertrial interval
  • Discrete trials begin with concurrent presentation of a white line presented 5 cm above left and right response boxes.
  • the width of the line is always 7 cm, but the length of the line is either 30 cm or 15 cm and varies in a quasi-random fashion across 100-trial sessions (50 trials of each length).
  • Response box designation is counter-balanced across subjects.
  • a correct response is reinforced as described above and is followed by a 5 sec ITI, whereas an incorrect response immediately results in a 5 sec ITI.
  • a correction procedure Karlin, B.
  • an acute drug testing protocol is arranged that includes intermittent maintenance sessions in which correct responses on all trials are reinforced, control sessions in which 3: 1 (60%:20%) rich/lean probabilistic contingencies are arranged and, no more than once per week, a drug testing session in which vehicle or a dose of the deuterated compound of Example 1 (A2) (0.5, 1, or 2.5 mg/kg) is tested by administering it orally, 4-5 hr prior to a 3 : 1 (60%:20%) probabilistic session.
  • Doses of the deuterated compound of Example 1 (A2) are tested in a mixed order across subjects using a Latin Square design. Vehicle and all doses of the deuterated compound of Example 1 (A2) are tested in all subjects.
  • High bias values are produced by high numbers of correct responses during rich trials and incorrect responses during lean trials, which increase the log b numerator.
  • High discriminability values are produced by high numbers of correct responses during both rich and lean trials, which increase the log d numerator. (0.5 is added to all parameters to avoid instances where no errors are made on a given trial type, which would make log transformation impossible.) All data (log Z>, log d, accuracy, reaction time) are subject to repeated measures analysis of variance (ANOVA). Drugs
  • Example 1 The deuterated compound of Example 1 (A2) is dissolved in a 0.5% methylcellulose solution. Drug doses are administered orally 4-5 hr prior to the experimental session.
  • the deuterated compound of Example 1 enhances reward response bias (log Z>) significantly at 1 mg/kg.
  • the deuterated compound of Example 1 enhances discriminability significantly at 0.5 mg/kg and 2.5 mg/kg, with a trend at 1 mg/kg.
  • the Conditioned Avoidance Response (CAR) Test is an animal model screening for antipsychotic drugs.
  • Example 1 The deuterated compound of Example 1 (A2) (1, 5, 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 test.
  • DOI 3 mg/kg is dissolved in saline and administered IP at a dose volume of 1 ml/kg (10 minutes prior to test).
  • Acute oral administration of the deuterated compound of Example 1 (A2) (1, 5, and 10 mg/kg) shows no significant increase in the number of headshakes compared to vehicle.
  • DOI (3 mg/kg) significantly increases headshake responses in the rats following acute i.p. injection.
  • Example 1 The deuterated compound of Example 1 (A2) (1, 5, 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 test.
  • DOI 3 mg/kg
  • IP IP
  • Ketanserin (1 mg/kg) is dissolved in saline and injected IP 30 minutes prior to DOI at a dose volume of 1 mg/kg.

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Abstract

Provided are compounds of Formula I, described herein, processes for their preparation, their use as pharmaceuticals, and pharmaceutical compositions comprising them and intermediates used in their preparation. Compounds of Formula I are useful, for instance, in modulating dopamine and serotonin neurotransmission and treating disorders that may benefit from the same, such as schizophrenia and depression.

Description

DEUTERATED ORGANIC
COMPOUNDS AND USES THEREOF
[0001] This application claims priority to U.S. Provisional Application No. 63/296,134 filed January 3, 2022, U.S. Provisional Application No. 63/345,007 filed May 23, 2022, and U.S. Provisional Application No. 63/384,992 filed November 25, 2022, the contents of each of which are hereby incorporated by reference in their entireties.
FIELD
[0002] Provided are compounds of Formula I, described below, processes for their preparation, their use as pharmaceuticals, and pharmaceutical compositions comprising them and intermediates used in their preparation. Compounds of Formula I are useful, for instance, in modulating dopamine and serotonin neurotransmission and treating disorders that may benefit from the same, such as schizophrenia and depression.
BACKGROUND
[0003] Dopamine is involved in a variety of central nervous system functions, including voluntary movement, feeding, affect, reward, sleep, attention, working memory, and learning. Serotonin also is involved in a variety of central nervous system functions, including mood, cognition, reward, learning, memory, and various physiological processes. Accordingly, dopaminergic and/or serotonergic dysfunction can lead to diseases such as schizophrenia and depression.
[0004] When released from presynaptic terminals, dopamine activates members of a family of G protein-coupled dopamine receptors D1-D5. Dopamine receptors (D1-D5) are divided into two groups, the DI -like (DI and D5) and the D2-like (D2, D3, and D4). Activation of DI -like receptors activates adenylyl cyclase and increases cAMP levels. D2-like receptors are inhibitory. Activation of D2-like receptors inhibits activation of adenylyl cyclase.
[0005] DI -like receptors are found postsynaptically on dopamine-receptive cells, while
D2-like dopamine receptors are expressed both postsynaptically on dopamine target cells and presynaptically on dopaminergic neurons. [0006] Fourteen serotonin receptor subtypes, grouped into sub-families, mediate effects of serotonin (5-HT). The 5-HT1 A receptor subtype, a major receptor subtype, exists as presynaptic autoreceptor in serotonin neurons in the raphe nuclei and as postsynaptic heteroreceptors in the prefrontal cortex, hippocampus, septum, and hypothalamus. Signaling mechanisms of 5-HT1 A receptors in the raphe nuclei may be different from 5-HT1 A receptors in other brain regions. Activation of 5-HT1 A postsynaptic receptors can elicit increased dopamine release. The 5-HT2A receptor subtype is enriched in cortex and is linked to phosphatidylinositol turnover and also modulates dopamine release. 5-HT2A receptor antagonists have antipsychotic properties, while 5-HT2A receptor agonism is thought to be associated with cognition-enhancing and hallucinogenic properties. The hallucinogenic effects of lysergic diethylamide (LSD) and psilocybin are thought to arise from their 5-HT2A receptor agonism. 5-HT2A agonism has also been reported to promote neural plasticity and reduce depression.
[0007] Antipsychotics are used to manage psychosis, in particular schizophrenia. A hallmark of antipsychotics is D2 receptor antagonism. D2 receptor antagonism is effective in reducing positive symptoms of schizophrenia (for instance, hallucinations and delusions), but often also produces extrapy rami dal side effects, including parkinsonism, akathisia, and tardive dyskinesia, increases prolactin, and may exacerbate negative symptoms of schizophrenia (for instance, loss of interest and motivation in life and activities, social withdrawal, and anhedonia). A key feature of atypical antipsychotics is D2 receptor antagonism in combination with 5-HT2A receptor antagonism, which may explain their enhanced efficacy and reduced extrapy rami dal motor side effects (EPS) compared to typical antipsychotics. Many psychotic patients also suffer from depression, which may be left untreated by current medications. However, some atypical antipsychotics are used adjunctively to serotonergic antidepressants to improve response in major depressive disorder.
[0008] Because imbalances in dopamine and serotonin can lead to a variety of disorders and current medications may not be able to effectively modulate levels of both, new compounds that can modulate dopamine and serotonin neurotransmission are needed, as are methods of treating diseases that involve imbalances in dopamine and serotonin.
BRIEF SUMMARY [0009] Provided is a compound of Formula I:
Figure imgf000005_0001
Formula I, wherein:
Ri, R2, R3, R4, and R5 are independently selected from H and D; and at least one of Ri, R2, and R3 is D; in free or salt form.
[0010] Further provided are pharmaceutical compositions comprising compounds of Formula I, processes for preparing compounds of Formula I, and pharmaceutical uses of compounds of Formula I, for instance, as an anti-anhedonic agent and to treat 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 shows disappearance of cis (R,R) nemonapride in human hepatocytes.
[0013] Figure 2 shows disappearance of the compound of Example 1 (A2) in human hepatocytes.
[0014] Figure 3 shows plasma concentration (ng/ml) in rats of cis (R,R) nemonapride and the compound of Example 1 (A2) following a single PO dose of 0.5 mg/kg.
[0015] Figure 4 shows extended brain enrichment of the compound of Example 1 (A2) in rats following a single PO dose of 0.5 mg/kg compared to plasma levels. [0016] Figure 5 shows extended brain enrichment of the compound of Example 1 (A2) in rats following a single PO dose of 5 mg/kg compared to plasma levels.
[0017] Figure 6 shows average brain concentration (ng/ml) in rats of cis (R,R) nemonapride and the compound of Example 1 (A2) when administered at a single PO dose of 0.5 mg/kg.
[0018] Figure 7 shows average plasma concentration (ng/ml) in rats of cis (R,R) nemonapride and the compound of Example 1 (A2) following single oral administration of 2.5 mg/kg.
[0019] Figure 8 shows extended brain enrichment of the compound of Example 1 (A2) in rats following a single oral administration of 2.5 mg/kg compared to plasma levels.
[0020] Figure 9 shows average brain concentration (ng/ml) of cis (R,R) nemonapride and the compound of Example 1 (A2) following a single oral administration of 2.5 mg/kg to rats.
[0021] Figure 10 shows D2 receptor occupancy of cis (R,R) nemonapride and the compound of Example 1 (A2) when administered orally at a dose of 2.5 mg/kg to rats.
[0022] Figure 11 shows average plasma and brain concentrations (ng/ml) of cis (R,R) nemonapride following a single oral administration of 2.5 mg/kg to rats.
[0023] Figure 12A shows response bias in probabilistic reward task for the compound of Example 1 (A2) when administered at doses of 0.5, 1, and 2.5 mg/kg to rats.
[0024] Figure 12B shows discriminability in the probabilistic reward task for the compound of Example 1 (A2) when administered at doses of 0.5, 1, and 2.5 mg/kg to rats.
[0025] Figure 13 shows a pharmacokinetic:pharmacodynamic model for the compound of Example 1 (A2) for an oral 1 mg/kg oral dose.
DETAILED DESCRIPTION
[0026] The following description of the preferred embodiment s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.
[0027] In the event of a conflict in a definition in the present disclosure and that of 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 located on nondopamine neurons. Dopamine receptors on dopamine neurons are called autoreceptors. Autoreceptors contribute to regulating dopamine neuron activity and controlling the synthesis, release, and uptake of dopamine.
[0029] Presynaptic D2-like dopamine autoreceptors regulate dopamine release. A low dose of a D2-like receptor antagonist may preferentially block presynaptic autoreceptors and increase dopamine release, while a high dose may block postsynaptic receptors and decrease dopamine neurotransmission. Relatively high occupancy of D2-like receptors has been associated with antipsychotic effects, while lower occupancy has been associated with antidepressant effects.
[0030] Anhedonia is a core symptom of major depressive disorder (MDD) and is associated with inadequate response to approved selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) and psychotherapy (e.g., cognitive behavioral therapy (CBT)) and neurostimulation (e.g., transcranial magnetic stimulation (TMS)). There remains a need for effective treatment of MDD characterized by anhedonia. Despite a range of available therapies, up to 50% of people suffering from MDD fail to respond to treatments, and only about 30% of patients fully recover after receiving currently available antidepressants and treatment outcomes are even poorer for MDD individuals with anhedonia. [0031] Depletion of dopamine/catecholamines induces symptoms of depression and anhedonia. Increasing dopamine neurotransmission can alleviate symptoms of depression and anhedonia. However, while a high dose of a dopamine D2/D3 agonist may activate dopamine post-synaptic receptors, it can also be poorly tolerated (e.g., nausea/vomiting). Low dose of a dopamine D2/D3 receptor antagonist may preferentially block pre-synaptic dopamine autoreceptors and increase dopamine release without being poorly tolerated.
[0032] Besides MDD, anhedonia also plays a role in bipolar disorder, schizophrenia, post-traumatic stress disorder, and substance use disorder. Despite its role in many disorders, there are no approved medications to treat anhedonia.
[0033] Decreased serotonergic activity has been implicated in anxiety and depression. Increasing serotonin neurotransmission may alleviate symptoms of anxiety and depression and be helpful for anxious depression.
[0034] The IUPAC name of nemonapride is (±)-cA-7V-(l-Benzyl-2-methylpyrrolidin-3- yl)-5-chloro-2-methoxy-4-methylaminobenzamide. Nemonapride is described in U.S. Patent No. 4,210,660 as a strong central nervous system depressant, in particular a strong antipsychotic. [0035] Nemonapride is a dopamine D2/D3/D4 receptor antagonist. Nemonapride is approved in Japan and South Korea for treatment of schizophrenia. Nemonapride is supplied as 3 mg and 10 mg tablets. The approved daily dose of nemonapride for schizophrenia is 9 to 36 mg given orally in divided doses after meals. The dose can be increased up to 60 mg daily.
[0036] The nemonapride prescribing information indicates that the elimination half-life when nemonapride 3 mg and 6 mg was administered orally to healthy adults was 2.3 to 4.5 hours. Urinary metabolites of nemonapride result from debenzylation and N-demethylation. See Emilace package insert.
[0037] In addition to being a dopamine D2/D3/D4 receptor antagonist, nemonapride is also a 5-HT1 A agonist. Further, nemonapride has been reported to bind to 5-HT2A receptors, however, the inventors are not aware of any publication that reports its functional effect at that receptor. Yet, as an antipsychotic, it may be expected that nemonapride is a 5-HT2A receptor antagonist because a key feature of atypical antipsychotics is D2 receptor antagonism in combination with 5-HT2A receptor antagonism or inverse agonism.
[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 has, especially a drug that has multiple biological targets.
[0039] 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 analog (see Example 3). D2/D3/D4 receptor antagonism in combination with 5-HT1 A and 5-HT2A agonism is a unique activity profile, which may allow for different modulation 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-suflopride - do not even bind to the 5-HT2A receptor in vitro (labeled-Ketansrin competition assay).
[0040] As noted above, D2/D3/D4 receptor antagonism in combination with 5-HT1 A and 5-HT2A agonism is a unique activity profile, which may allow for different modulation of dopamine and serotonin neurotransmission compared to other D2/D3/D4 receptor antagonists. For instance, D2/D3/D4 postsynaptic receptor antagonism reduces psychosis, particularly in schizophrenia, by reducing dopamine neurotransmission. High doses that target > 60% receptor occupancy may be associated with D2 antagonist mediated side effects such as extrapy rami dal motor side effects (EPS) and increased prolactin. However, 5-HT1 A agonism may limit those high dose D2 antagonist related side effects, thus providing the compounds with a built-in safety feature when used at high dose as an antipsychotic. Partial 5-HT1 A agonism also provides anxiolytic effects. Further, as partial 5-HT2A agonists, deuterated compounds disclosed herein may show enhanced antidepressant effects as seen with psychedelic antidepressants, for instance, rapid and long-lasting and with anxiolytic effects, yet at the same time hallucinogenic and fear/anxiety effects may not be as pronounced as with a full 5-HT2A agonist. And, D2 antagonism may also block 5-HT2A hallucinogenic effects.
[0041] Thus, as D2/D3 antagonists and 5-HT2A partial agonists, compounds of Formula I may provide psychedelic-like antidepressant efficacy at low doses (e.g., doses lower than those of nemonapride used to treat schizophrenia), but also have built-in protection against 5-HT2A mediated hallucinations and without fear/anxiety. Further, as D2/D3 antagonists and 5-HT1 A agonists, compounds of Formula I may act as antipsychotics at high doses, but have built-in protection against high dose D2 antagonist related side effects.
[0042] Pharmacokinetics of deuterated compounds disclosed herein are beneficial.
Plasma pharmacokinetics of N-[(2R,3R)-l-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 Example 5). However, despite similar plasma pharmacokinetics, Examples 5 and 6 show that a compound of Formula I (the deuterated compound of Example 1) has enriched and retained brain levels compared to its non-deuterated analog and higher receptor occupancy levels at 1, 2, 8, and 24 hours. For instance, Figures 6 and 9 show that at 8 hours, brain levels of the compound of Example 1 (A2) are similar to the highest levels of cis (R,R) nemonapride measured, which occur at shorter time. The deuterated compound of Example 1 also shows extended brain enrichment compared to plasma levels of the compound. The braimplasma exposure supports once-daily dosing. Enriched brain levels, higher receptor occupancy levels, and extended brain enrichment compared to plasma levels are beneficial features that allows for higher and more sustained receptor occupancy with less frequent dosing and may be associated with fewer peripheral side effects. Further, the receptor occupancy curve of the deuterated compound of Example 1 (see Figure 10) exhibits more moderate changes between peaks and troughs (a 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 a desired range with a convenient dosing regime. In contrast, nemonapride is taken in multiple doses per day.
[0043] Compounds that are D2/D3/D4 receptor antagonists, 5-HT1 A receptor agonists, and 5-HT2A receptor partial agonists modulate dopamine and serotonin neurotransmission and are therefore useful in treating disorders involving dopamine and serotonin signaling pathways, for instance, disorders involving D2, D3, D4, 5-HT1 A, and/or 5-HT2A receptors.
[0044] Provided is a compound of Formula I:
Figure imgf000010_0001
Formula I, wherein:
Ri, R2, R3, R4, and R5 are independently selected from H and D; and at least one of Ri, R2, and R3 is D; in free or salt form.
[0045] Further provided are compounds of Formula I as follows:
1.1 Formula I, wherein the compound is in pharmaceutically acceptable salt form.
1.2 Formula I, wherein the compound is in free form.
1.3 Any of Formula I, 1.1, or 1.2, wherein Ri, R2, and R3 are D.
1.4 Any of Formula I or 1.1-1.3, wherein R4 and R5 are D.
1.5 Any of Formula I or 1.1-1.4, wherein each of Ri, R2, R3, R4, and R5 are D.
1.6 Any of Formula I or 1.1-1.5, wherein the compound is:
Figure imgf000011_0001
in free or salt form, e.g., in free or pharmaceutically acceptable salt form, e.g., in free form. Any of Formula I or 1.1-1.6, wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance. Any of Formula I or 1.1-1.7, wherein the compound, in free or salt form (e.g., pharmaceutically acceptable salt form), has greater than 50% incorporation of deuterium (i.e., D) at one or more positions (e.g., at all positions) designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. For instance, any of Formula I or 1.1-1.7, wherein the compound, in free or salt form (e.g., pharmaceutically acceptable salt form), has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. Any of Formula I or 1.1-1.8, wherein the compound is substantially stereoisomerically pure. For instance, wherein the compound has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%. For instance, wherein the compound is substantially diastereomerically and/or enantiomerically pure, e.g., wherein the compound is substantially diastereomerically and enantiomerically pure.
1.10 Any of Formula I or 1.1-1.9, wherein the compound is substantially diastereomerically pure. For instance, wherein the compound has a diastereomeric excess of greater than 90%, e.g., a diastereomeric excess equal to or greater than 95%, e.g., a diastereomeric excess equal to or greater than 96%, e.g., a diastereomeric excess equal to or greater than 97%, e.g., a diastereomeric excess equal to or greater than 98%, e.g., a diastereomeric excess equal to or greater than 99%.
1.11 Any of Formula I or 1.1-1.10, wherein the compound is substantially enantiomerically pure. For instance, wherein the compound has an enantiomeric excess of greater than 90%, e.g., an enantiomeric excess equal to or greater than 95%, e.g., an enantiomeric excess equal to or greater than 96%, e.g., an enantiomeric excess equal to or greater than 97%, e.g., an enantiomeric excess equal to or greater than 98%, e.g., an enantiomeric excess equal to or greater than 99%.
1.12 Any of Formula I or 1.1-1.11, wherein the compound has the stereochemical configuration as shown in Formula I.
1.13 Any of Formula I or 1.1-1.12, wherein the compound is in a pharmaceutical composition with a pharmaceutically acceptable carrier. For instance, any of Formula I or 1.1-1.12, wherein an effective amount of the compound is in a pharmaceutical composition with a pharmaceutically acceptable carrier.
[0046] Further provided is a pharmaceutical composition (Composition 1) comprising a compound of Formula I (e.g., any of Formula 1.1-1.13):
Figure imgf000013_0001
Formula I, wherein:
Ri, R2, R3, R4, and R5 are independently selected from H and D; and at least one of Ri, R2, and R3 is D; in free or pharmaceutically acceptable salt form.
[0047] Further provided is Composition 1 as follows:
1.1 Composition 1, wherein the composition comprises a pharmaceutically acceptable carrier.
1.2 Composition 1 or 1.1, wherein the composition comprises the compound, in free or pharmaceutically acceptable salt form, as described in any of Formula I or 1.1- 1.13 vide supra.
1.3 Any of Composition 1, 1.1, or 1.2, wherein the compound is in free form.
1.4 Any of Composition 1 or 1.1-1.3, wherein the compound of Formula I is:
Figure imgf000013_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
1.5 Any of Composition 1 or 1.1-1.4, wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance. Any of Composition 1 or 1.1-1.5, wherein the compound of Formula I, in free or pharmaceutically acceptable salt form, has greater than 50% incorporation of deuterium (i.e., D) at one or more positions (e.g., at all positions) designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. For instance, any of Composition 1 or 1.1-1.5, wherein the compound of Formula I, in free or pharmaceutically acceptable salt form, has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. Any of Composition 1 or 1.1-1.6, wherein the composition is in oral or parenteral dosage form, e.g., oral dosage form, for instance, a tablet, capsule, solution, or suspension, for instance, a capsule or tablet. Any of Composition 1 or 1.1-1.7, wherein the composition comprises a therapeutically effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, e.g., a therapeutically effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, for the prophylaxis or treatment of a disorder disclosed herein, e.g., a therapeutically effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, for use in any of the methods disclosed herein. Any of Composition 1 or 1.1-1.8, wherein the composition is substantially free of any other stereoisomeric form of Formula I. For instance, any of Composition 1 or 1.1-1.8, wherein the composition is substantially free of any other diastereomeric and/or enantiomeric form of Formula I, e.g., wherein the composition is substantially free of any other diastereomeric and enantiomeric form of Formula I. Any of Composition 1 or 1.1-1.9, wherein the composition comprises less than 10% w/w (weight/weight) of any other stereoisomeric form of Formula I, e.g., less than 5% w/w of any other stereoisomeric form of Formula I, e.g., less than 4% w/w of any other stereoisomeric form of Formula I, e.g., less than 3% w/w of any other stereoisomeric form of Formula I, e.g., less than 2% w/w of any other stereoisomeric form of Formula I, e.g., less than 1% w/w of any other stereoisomeric form of Formula I. Any of Composition 1 or 1.1-1.10, wherein the composition comprises less than 10% w/w of any other diastereomeric form of Formula I, e.g., less than 5% w/w of any other diastereomeric form of Formula I, e.g., less than 4% w/w of any other diastereomeric form of Formula I, e.g., less than 3% w/w of any other diastereomeric form of Formula I, e.g., less than 2% w/w of any other diastereomeric form of Formula I, e.g., less than 1% w/w of any other diastereomeric form of Formula I. Any of Composition 1 or 1.1-1.11, wherein the composition comprises less than 10% w/w of any other enantiomeric form of Formula I, e.g., less than 5% w/w of any other enantiomeric form of Formula I, e.g., less than 4% w/w of any other enantiomeric form of Formula I, e.g., less than 3% w/w of any other enantiomeric form of Formula I, e.g., less than 2% w/w of any other enantiomeric form of Formula I, e.g., less than 1% w/w of any other enantiomeric form of Formula I. Any of Composition 1 or 1.1-1.12, wherein the compound has the stereochemical configuration as shown in Formula I. Any of Composition 1 or 1.1-1.13, wherein the composition comprises 1-60 mg of the compound of Formula I. For instance, any of Composition 1 or 1.1-1.13, wherein the composition comprises 1-10 mg, e.g., 1-9 mg (e.g., 1-8 mg) of the compound of Formula I. For instance, any of Composition 1 or 1.1-1.13, wherein the composition comprises 3 mg or 10 mg of the compound of Formula I. For instance, any of Composition 1 or 1.1-1.13, wherein the composition comprises 1 mg to less than 3 mg (e.g., 2 mg) of the compound of Formula I. 1.15 Any of Composition 1 or 1.1-1.14, wherein the composition is for once, twice, or three times daily dosing. For instance, any of Composition 1 or 1.1-1.14, wherein the composition is for once daily dosing.
[0048] Further provided are methods of prophylaxis or treatment of a central nervous system disorder (e.g., a brain disorder), for instance, a central nervous system disorder (e.g., a brain disorder) that benefits from modulating dopamine and/or serotonin transmission, in a patient in need thereof, wherein the method comprises administering to the patient a compound of Formula I, in free or pharmaceutically acceptable salt form (e.g., any of Formula I or 1.1-1.13 vide supra), or a pharmaceutical composition comprising a compound of Formula I, in free or pharmaceutically acceptable salt form (e.g., Formula 1.13 or any of Composition 1 or 1.1-1.15 vide supra), or a compound of Formula la or Compound A, in free or pharmaceutically acceptable salt form (vide infra), or a pharmaceutical composition comprising a compound of Formula la or Compound A, in free or pharmaceutically acceptable salt form (vide infra). Further provided are methods of prophylaxis or treatment of a central nervous system disorder (e.g., a brain disorder) that benefits from D2 receptor antagonism, D3 receptor antagonism, D4 receptor antagonism, 5-HT1 A receptor agonism (e.g., 5-HT1 A receptor partial agonism), and/or 5-HT2A receptor agonism (e.g., 5-HT2A receptor partial agonism) in a patient in need thereof, wherein the method comprises administering to the patient a compound of Formula I, in free or pharmaceutically acceptable salt form (e.g., any of Formula I or 1.1-1.13 vide supra), or a pharmaceutical composition comprising a compound of Formula I, in free or pharmaceutically acceptable salt form (e.g., Formula 1.13 or any of Composition 1 or 1.1-1.15 vide supra), or a compound of Formula la or Compound A, in free or pharmaceutically acceptable salt form (vide infra), or a pharmaceutical composition comprising a compound of Formula la or Compound A, in free or pharmaceutically acceptable salt form (vide infra). For instance, provided are methods as described below.
[0049] Provided is a method (Method 1) for treatment or prophylaxis of a disorder (e.g., a brain disorder) in a patient in need thereof, wherein the method comprises administering to the patient an effective amount of a compound of Formula la:
Figure imgf000017_0001
Formula la, wherein: the compound of Formula la has cis stereochemistry at the two stereocenters marked with asterisks in the drawing,
Ri, R2, R3, R4, and R5 are independently selected from H and D; in free or pharmaceutically acceptable salt form.
[0050] Further provided is Method 1 as follows:
1.1 Method 1, wherein the method comprises administering (±)-cz -7V-(l-Benzyl-2- methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide (i.e., nemonapride), in free or pharmaceutically acceptable salt form, wherein (±)-cis- 7V-(l-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide does not show optical rotation in chloroform. For instance, wherein the method comprises administering (±)-cz -7V-(l-Benzyl-2- methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide (i.e., nemonapride), in free form, wherein (±)-cz.s-A-( l -Benzyl-2-methylpyrrolidin-3- yl)-5-chloro-2-methoxy-4-methylaminobenzamide does not show optical rotation in chloroform.
1.2 Method 1, wherein the method comprises administering an effective amount of Compound A:
Figure imgf000018_0001
Compound A, in free or pharmaceutically acceptable salt form. For instance, wherein the effective amount of Compound A, in free or pharmaceutically acceptable salt form, has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%. For instance, wherein the effective amount of Compound A, in free or pharmaceutically acceptable salt form, is substantially diastereomerically and/or enantiomerically pure, e.g., wherein the effective amount of Compound A, in free or pharmaceutically acceptable salt form, is substantially diastereomerically and enantiomerically pure. For instance, wherein the effective amount of compound A, in free or pharmaceutically acceptable salt form, has a diastereomeric and/or enantiomeric excess of greater than 90%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 99%. For instance, wherein the effective amount of compound A, in free or pharmaceutically acceptable salt form, has a diastereomeric and enantiomeric excess of greater than 90%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 99%. Method 1, wherein the method comprises administering a compound of Formula I:
Figure imgf000019_0001
Formula I, wherein:
Ri, R2, R3, R4, and R5 are independently selected from H and D; and at least one of Ri, R2, and R3 is D; in free or pharmaceutically acceptable salt form. Method 1.3, wherein Ri, R2, R3, R4, and R5 are D. Method 1.3 or 1.4, wherein the method comprises administering to the patient a compound of Formula I, in free or pharmaceutically acceptable salt form, as described in any of Formula I or 1.1-1.13 vide supra. For instance, Method 1.3 or 1.4, wherein the method comprises administering to the patient a pharmaceutical composition comprising a compound of Formula I, in free or pharmaceutically acceptable salt form, as described in any of Composition I or 1.1-1.15 vide supra. Any of Method 1.3-1.5, wherein the effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%. For instance, wherein the effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, is substantially diastereomerically and/or enantiomerically pure, e.g., wherein the effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, is substantially diastereomerically and enantiomerically pure. For instance, wherein the effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, has a diastereomeric and/or enantiomeric excess of greater than 90%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 95%, a diastereomeric and/or enantiomeric excess equal to or greater than 96%, a diastereomeric and/or enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 99%. For instance, wherein the effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form, has a diastereomeric and enantiomeric excess of greater than 90%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 99%. Any of Method 1 or 1.1-1.6, wherein the compound is in free form. Method 1.3, wherein the method comprises administering an effective amount of Compound B:
Figure imgf000020_0001
Compound B, in free or pharmaceutically acceptable salt form, e.g., in free form. Method 1.8, wherein the effective amount of Compound B, in free or pharmaceutically acceptable salt form, has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%. For instance, wherein the effective amount of Compound B, in free or pharmaceutically acceptable salt form, is substantially diastereomerically and/or enantiomerically pure, e.g., wherein the effective amount of Compound B, in free or pharmaceutically acceptable salt form, is substantially diastereomerically and enantiomerically pure. For instance, wherein the effective amount of compound B, in free or pharmaceutically acceptable salt form, has a diastereomeric and/or enantiomeric excess of greater than 90%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and/or enantiomeric excess equal to or greater than 99%. For instance, wherein the effective amount of compound B, in free or pharmaceutically acceptable salt form, has a diastereomeric and enantiomeric excess of greater than 90%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 99%. Any of Method 1 or 1.3-1.9, wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance. Any of Method 1 or 1.3-1.10, wherein the compound, in free or pharmaceutically acceptable salt form, has greater than 50% incorporation of deuterium (i.e., D) at one or more positions (e.g., at all positions) designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. For instance, any of Method 1 or 1.3-1.10, wherein the compound, in free or pharmaceutically acceptable salt form, has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. Any of Method 1 or 1.1-1.11, wherein the disorder is a brain disorder. For instance, any of Method 1 or 1.1-1.11, wherein the disorder is a neuropsychiatric condition in which anhedonia is prominent. Any of Method 1 or 1.1-1.12, wherein the disorder is an affective (mood) disorder or an anxiety disorder. Any of Method 1 or 1.1-1.13, wherein the disorder is depression (e.g., depression associated with anhedonia), an anxiety disorder, psychosis (e.g., psychosis in neurodegenerative conditions, such as psychosis in Alzheimer’s disease, Parkinson’s disease, or dementia (e.g., dementia-related psychosis)), schizophrenia, schizoaffective disorder, post-traumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder (including bipolar depression, bipolar mania, and bipolar disorder with mixed features), or a migraine. For instance, any of Method 1 or 1.1-1.13, wherein the anxiety disorder is panic disorder, social anxiety disorder, a phobia, or generalized anxiety disorder. Or, any of Method 1 or 1.1-1.13, wherein the method is prophylaxis or treatment of behavioral and psychological symptoms of dementia including agitation, depression, anxiety, apathy, and/or psychosis. Any of Method 1 or 1.1-1.14, wherein the disorder is anhedonia or depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression. For instance, any of Method 1 or 1.1-1.14, wherein the disorder is anxious depression. Or, for instance any of Method 1 or 1.1-1.14, wherein the disorder is melancholic depression. Any of Method 1 or 1.1-1.15, wherein the disorder is maj or depressive disorder. Any of Method 1 or 1.1-1.14, wherein the disorder is a substance use disorder. Any of Method 1 or 1.1-1.14, wherein the method is prophylaxis or treatment of negative symptoms of schizophrenia. Or, any of Method 1 or 1.1-1.14, wherein the method is improving cognition in schizophrenia. Any of Method 1 or 1.1-1.11, wherein the compound, in free or pharmaceutically acceptable salt form, is administered as an anti-emetic. Any of Method 1 or 1.1-1.19, wherein the method comprises administering 9-60 mg a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 9-60 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form). For instance, any of Method 1 or 1.1-1.19, wherein the method comprises administering 9-36 mg a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 9-36 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form). Any of Method 1 or 1.1-1.20, wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides 55%-80% D2/D3 receptor occupancy, e.g., as measured by positron emission tomography. For instance, wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides about 65% D2/D3 receptor occupancy, e.g., as measured by positron emission tomography. Or, for instance, wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides about 60% D2/D3 receptor occupancy, e.g., as measured by positron emission tomography. Method 1.20 or 1.21, wherein the disorder is psychosis (e.g., psychosis in neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease, and dementia (e.g., dementia-related psychosis)), schizophrenia, schizoaffective disorder, or bipolar disorder (e.g., bipolar mania). Method 1.20 or 1.21, wherein the method is prophylaxis or treatment of negative symptoms of schizophrenia. Or, Method 1.20 or 1.21, wherein the method is improving cognition in schizophrenia. Any of Method 1 or 1.1-1.19, wherein the method comprises administering 1-9 mg (e.g., 1-8 mg, e.g., 1.5-6 mg) a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 1-9 mg total daily dose, e.g., 1-8 mg total daily dose, e.g., 1.5-6 mg total daily dose, of the compound, in free or pharmaceutically acceptable salt form). For instance, any of Method 1 or 1.1-1.19, wherein the method comprises administering 1-8 mg a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 1-8 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form). For instance, any of Method 1 or 1.1-1.19, wherein the method comprises administering 1-3 mg a day of the compound, in free or pharmaceutically acceptable salt form (i.e., 1-3 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form). For instance, any of Method 1 or 1.1-1.19, wherein the method comprises administering 1 mg to less than 3 mg a day (e.g., 2 mg a day) of the compound, in free or pharmaceutically acceptable salt form (i.e., 1 mg to less than 3 mg total daily dose of the compound, in free or pharmaceutically acceptable salt form). Any of Method 1, 1.1-1.19, or 1.24, wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides 10%-60% (e.g., 40%-60% or, e.g., 10%-55%, e.g., 10%-50%, e.g., 30%- 50% or, e.g., 15%-50%, e.g., 15%-45%, e.g., 20%-40%, e.g., 10%-30%) D2/D3 receptor occupancy, e.g., as measured by positron emission tomography. Or, for instance, any of Method 1, 1.1-1.19, or 1.24, wherein the method comprises administering an amount of the compound, in free or pharmaceutically acceptable salt form, that provides < 40% (e.g., about 40%), e.g., < 40% D2/D3 receptor occupancy, e.g., as measured by positron emission tomography. Method 1.24 or 1.25, wherein the disorder is depression (e.g., depression associated with anhedonia), an anxiety disorder, post-traumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder, bipolar disorder with mixed features, or a migraine. For instance, Method 1.24 or 1.25, wherein the anxiety disorder is panic disorder, social anxiety disorder, a phobia, or generalized anxiety disorder. Any of Method 1.24-1.26, wherein the disorder is anhedonia or depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression. For instance, wherein the disorder is anxious depression. Any of Method 1.24-1.27, wherein the disorder is major depressive disorder. Method 1.24 or 1.25, wherein the disorder is a substance use disorder. Any of Method 1 or 1.1-1.29, wherein the method comprises administering a pharmaceutical composition comprising the compound, in free or pharmaceutically acceptable salt form. For instance, any of Method 1 or 1.1-1.29, wherein the method comprises administering Formula 1.13 or any of Composition 1 or 1.1-1.15 vide supra. Any of Method 1 or 1.1-1.30, wherein the method comprises administering the compound of Formula la, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day. For instance, any of Method 1 or 1.1-
1.30, wherein the method comprises administering a pharmaceutical composition comprising the compound of Formula la, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day. Any of Method 1 or 1.1-1.31, wherein the method comprises administering the compound of Formula I, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day. For instance, any of Method 1 or 1.1-
1.31, wherein the method comprises administering a pharmaceutical composition comprising the compound of Formula I, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day.
1.33 Any of Method 1 or 1.1-1.32, wherein the method comprises administering Compound B, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day. For instance, any of Method 1 or 1.1-1.32, wherein the method comprises administering a pharmaceutical composition comprising Compound B, in free or pharmaceutically acceptable salt form, once, twice, or three times a day, e.g., once a day.
[0051] Further provided is a compound of Formula I (e.g., any of Formula 1.1-1.13) or a pharmaceutical composition disclosed herein (e.g., Formula 1.13 or any of Composition 1 or 1.1- 1.15) for use in any of Method 1 or 1.1-1.33 vide supra.
[0052] Further provided is use of a compound of Formula I (e.g., any of Formula 1.1- 1.13) or a pharmaceutical composition disclosed herein (e.g., Formula 1.13 or any of Composition 1 or 1.1-1.15) in any of Method 1 or 1.1-1.33 vide supra.
[0053] Further provided is use of a compound of Formula I (e.g., any of Formula 1.1- 1.13) in the manufacture of a medicament (e.g., Formula 1.13 or any of Composition 1 or 1.1- 1.15) for use in any of Method 1 or 1.1-1.33 vide supra.
[0054] Further provided are intermediate compounds of Formula II and Formula III, each in free or salt (e.g., pharmaceutically acceptable salt) form.
[0055] For instance, further provided is a compound of Formula II:
Figure imgf000026_0001
Formula II, wherein R3 i, R32, and R33 are independently selected from H and D;
X is OH or a leaving group; and at least one of R3I, R32, and R33 are D; in free or salt (e.g., pharmaceutically acceptable salt) form. [0056] Further provided are compounds of Formula II as follows:
2.1 Formula II, wherein the compound is in pharmaceutically acceptable salt form.
2.2 Formula II or 2.1, wherein R31, R32, and R33 are D.
2.3 Any of Formula II, 2.1, or 2.2, wherein X is OH.
2.4 Any of Formula II, 2.1, or 2.2, wherein X is a leaving group (e.g., an activated ester, e.g., an O-acylisourea, or a halide). For instance, any of Formula II, 2.1, or 2.2, wherein the compound of Formula II is reacted with l-ethyl-3-(3- dimethylaminopropyl)carbodiimide.
2.5 Any of Formula II or 2.1-2.3, wherein the compound is:
Figure imgf000027_0001
in free or salt (e.g., pharmaceutically acceptable salt) form, e.g., in free form.
[0057] Also further provided is a compound of Formula III:
Figure imgf000027_0002
wherein:
R34 and R35 are D; in free or salt (e.g., pharmaceutically acceptable salt) form.
[0058] Further provided are compounds of Formula III as follows:
3.1 Formula III, wherein the compound is in pharmaceutically acceptable salt form.
3.2 Any of Formula III or 3.1, wherein the compound is:
Figure imgf000028_0001
in free or salt (e.g., pharmaceutically acceptable salt) form, e.g., in free form. [0059] Further provided is a process (Process 1) for synthesizing a compound of Formula I (e.g., any of Formula 1.1-1.13), in free or salt (e.g., pharmaceutically acceptable salt) form.
[0060] Further provided is Process 1 as follows:
1.1 Process 1, wherein the process comprises reacting a compound of Formula II (e.g., any of Formula 2.1-2.5) with a compound of Formula III (e.g., any of Formula 3.1-3.2).
1.2 Process 1 or 1.1, wherein the process occurs in the presence of an amine (e.g., tri ethylamine, e.g., tri ethylamine and dimethylformamide).
1.3 Process 1, 1.1, or 1.2, wherein the process occurs in an organic solvent (e.g., dimethylformamide).
1.4 Any of Process 1 or 1.1-1.3, wherein the process occurs with l-ethyl-3-(3- dimethylaminopropyl)carbodiimide and hydroxybenzotriazole. For instance, any process wherein the process occurs with l-ethyl-3-(3- dimethylaminopropyl)carbodiimide, hydroxybenzotriazole, triethylamine, and dimethylformamide.
1.5 Any of Process 1 or 1.1-1.4, wherein the process comprises reacting a compound of Formula Ila:
Figure imgf000028_0002
Formula Ila, wherein R3 i, R32, and R33 are independently selected from H and D and at least one of R3I, R32, and R33 is D, in free or salt (e.g., pharmaceutically acceptable salt) form, with an activating agent (e.g., l-ethyl-3-(3- dimethylaminopropyl)carbodiimide).
1.6 Process 1.5, wherein the process forms a compound of Formula lib :
Figure imgf000029_0001
Formula lib, wherein R3 i, R32, and R33 are independently selected from H and D and at least one of R3I, R32, and R33 is D, in free or salt (e.g., pharmaceutically acceptable salt) form.
1.7 Process 1.6, wherein the compound of Formula lib is formed in situ.
[0061] For compounds disclosed herein, a hydrogen atom position of a structure is considered substituted with deuterium when the abundance of deuterium at that position is enriched. The natural abundance of deuterium is about 0.02%, so a compound is “enriched” with deuterium at a specific position when the frequency of incorporation of deuterium at that position exceeds 0.02%. Therefore, for deuterated compounds disclosed herein, any position designated as deuterium (i.e., D) may be enriched with deuterium at a level of greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%, such as, greater than 50%, or greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. For compounds disclosed herein, any atom not designated as a particular isotope is present at natural isotopic abundance. [0062] Compounds disclosed herein, e.g., any of Formula I (e.g., any of Formula 1.1- 1.13), Formula la, Formula II (e.g., any of Formula 2.1-2.5), Formula III (e.g., any of Formula
3.1-3.2), Formula Ila, Formula lib, Compound A, and Compound B, may exist in free or salt form, e.g., as acid addition salts. As used herein, unless otherwise indicated, language such as “compound of formula” is to be understood as embracing the compound in any form, for example free or acid addition salt form, or where the compound contains an acidic substituent, in base addition salt form. Compounds of Formula I (e.g., any of Formula 1.1-1.13), Formula la, Compound A, and Compound B are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free compounds of Formula I or Formula la or their pharmaceutically acceptable salts, so therefore are also included.
[0063] Isolation or purification of the stereoisomers of compounds disclosed herein, for instance, Formula I (e.g., any of Formula 1.1-1.13), Formula la, Formula II (e.g., any of Formula
2.1-2.5), Formula III (e.g., any of 3.1-3.2), Formula Ila, Formula lib, Compound A, and Compound B, any in free or pharmaceutically acceptable salt form, may be achieved by conventional methods known in the art, e.g., column purification, preparative thin layer chromatography, preparative HPLC, trituration, simulated moving beds, and the like.
[0064] Pure stereoisomeric forms of the compounds and intermediates disclosed herein are isomers substantially free of other enantiomeric and diastereomeric forms of the same basic molecular structure of said compounds or intermediates. “Substantially stereoisomerically pure” includes compounds or intermediates having a stereoisomeric excess of greater than 90% (i.e., more than 90% of one isomer and less than 10% of any other possible isomer). The terms “substantially diastereomerically pure” and “substantially enantiomerically pure” should be understood in a similar way, but then having regard to the diastereomeric excess and enantiomeric excess, respectively, of the material in question.
[0065] Compounds disclosed herein, e.g., any of Formula I (e.g., any of Formula 1.1- 1.13), Formula la, Formula II (e.g., any of Formula 2.1-2.5), Formula III (e.g., any of 3.1-3.2), Formula Ila, Formula lib, Compound A, and Compound B, any in free or pharmaceutically acceptable salt form, may be made by using the methods as described and exemplified herein and by methods similar thereto and by methods known in the chemical art. Such methods include, but are not limited to, those described below. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques that are similar to or analogous to the synthesis of known compounds.
[0066] Pharmaceutically acceptable salts of any of Formula I (e.g., any of Formula 1.1- 1.13), Formula la, Formula II (e.g., any of Formula 2.1-2.5), Formula III (e.g., any of 3.1-3.2), Formula Ila, Formula lib, Compound A, and Compound B, may be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in an appropriate solvent.
[0067] For methods of treatment, the word “effective amount” is intended to encompass a therapeutically effective amount to treat a specific disease or disorder.
[0068] Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular compound used, the mode of administration, and the therapy desired.
[0069] Compounds disclosed herein, e.g., any of Formula I (e.g., any of Formula 1.1- 1.13), Formula la, Compound A, or Compound B, any in free or pharmaceutically acceptable salt form, may be administered by any suitable route, including orally, parenterally, or transdermally, but are preferably administered orally.
[0070] Pharmaceutical compositions comprising compounds disclosed herein, e.g., any of Formula I (e.g., any of Formula 1.1-1.13 or any of Composition 1 or 1.1-1.15), Formula la, Compound A, or Compound B, any in free or pharmaceutically acceptable salt form, may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.
EXAMPLES
Abbreviations
AcOH = acetic acid
Boc = tert-butyloxy carbonyl
DIAD = diisopropyl azodi carb oxy late
DCM = dichloromethane
DMAP = 4-dimethylaminopyridine
DMF = dimethylformamide EDCI = l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
EtO Ac or EA = ethyl acetate h = hour(s)
HOBt = hydroxybenzotriazole
MeOH = methanol
MsCl = methanesulfonyl chloride rt (or RT) = room temperature
TEA = triethylamine
TFA = trifluoroacetic acid
THF = tetrahydrofuran
Example 1
Synthesis of A2: 5-Chloro-/V-((21?,3^)-l-(dideutero(phenyl)methyl)-2-methylpyrrolidin-
3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide
Figure imgf000032_0001
Compound 15: tert-butyl (R)-2-methyl-3,5-dioxopyrrolidine-l-carboxylate
Figure imgf000032_0002
[0071] 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 CH2CI2 (5 L) is added EDCI (608 g, 3.18 mol) under nitrogen at 0 °C. The resulting solution is then allowed to warm up to room temperature (rt) and stirred over 16 h. It is quenched with water (1.5 L), the organic phase is washed with a cold solution of 5% KHSO4 (3 L x 3), water (3 L x 1), and brine, then dried over anhydrous MgSCE, and concentrated to give the residue. EtOAc (4 L) is added and the reaction mixture is refluxed for 2 hours. The solution is concentrated and the residue is stirred in EtOAc (1 L) at -10 °C for 2 h, then filtered, and the filter cake is collected to give the title compound as a white solid (150 g, 27% yield). The mother liquid is further refluxed for 2 hours then stirred in EA at -10 °C and filtered to give the title compound (40 g) as a white solid. ’H NMR (400 MHz, CDCI3) 6 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]+
Compound 16: tert-butyl (2R,3R)-3-hydroxy-2-methyl-5-oxopyrrolidine-l-carboxylate
Figure imgf000033_0001
[0072] To a stirred solution of compound 15 (40 g, 187.6 mmol) in DCM (400 ml) is added AcOH (200 mL) at 0 °C, then NaBH4 (21.3 g, 562.8 mmol) is added in three portions. The resulting solution is then allowed to warm up to room temperature and stirred over 16 h. The reaction mixture is quenched with 5% NaHCCf at 0 °C. It is extracted with DCM (200 mL x 3).
The combined organic layer is washed with 5% NaHCCf solution. The organic phase is dried over anhydrous MgSCL and concentrated to give the residue that is stirred in isopropyl ether and filtered to give the title compound 16 (24 g, 59.4% yield). 'H NMR (400 MHz, CDCf) 6 4.53- 4.47 (m, 1H), 4.29-4.22 (m, 1H), 2.75-2.55 (m, 2H), 1.53 (s, 9H), 1.3 l(d, J= 6.8 Hz, 3H). MS m/z (ESI): 160 [M+H-56]+
Compound 17: tert-butyl (2R,3R)-3-hydroxy-2-methylpyrrolidine-l-carboxylate
Figure imgf000033_0002
[0073] 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 it is stirred for 30 min at 0 °C. Then the mixture is refluxed for 4 h. The resulting mixture is cooled and quenched with saturated NH4C1 at 0 °C. It is then extracted with EtOAc (1 L x 3). The organic phases are dried over anhydrous MgSCE and concentrated to give compound 17 (70 g, 86% yield). 'H N R (400 MHz, DMSO- d6) 8 5.1 l(s, 1H), 4.19-4.10 (m, 1H), 3.83-3.63 (m, 1H), 3.22-2.89 (m, 2H), 1.87-1.54 (m, 2H), 1.38 (s, 9H), 0.85 (d, J= 6.8 Hz, 3H). MS m/z (ESI): 146 [M+H-56]+
Compound 18:
Figure imgf000034_0001
[0074] 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) for 30 minutes at 0 °C. The reaction mixture is allowed to warm room temperature for 16 h. The resulting mixture is cooled and quenched with water. The mixture is extracted with EtOAc (200 ml x 3), dried over anhydrous MgSO4, and then concentrated. The residue is purified by silica gel chromatography to afford the compound 18 (24.7 g, 90.1% yield). ’H NMR (400 MHz, CDCh) 6 8.31-8.17 (m, 4H), 5.20 (d, J= 4 Hz, 1H), 4.17-3.86 (m, 1H), 3.59-3.46 (m, 2H), 2.35-2.11 (m, 2H) 1.48 (s, 9H), 1.28 (d, J= 6.8 Hz, 3H). MS m/z (ESI): 295 [M+H-56]+
Compound 19: (2R,3S)-2-methylpyrrolidin-3-yl 4-nitrobenzoate
Figure imgf000034_0002
18 19
[0075] A mixture of compound 18 (23.4 g, 66.8 mmol) and TFA (120 mL) in DCM (240 mL) is stirred at room temperature for 1 and then it is concentrated to give compound 19 (16.7 g, 100% yield). LCMS: M+l=251 Compound 20: (2R,3S)-l-benzoyl-2-methylpyrrolidin-3-yl 4-nitrobenzoate
Figure imgf000035_0001
[0076] To a solution of compound 19 (16.7 g, 66.8 mmol) in toluene (520 ml) is added 2N NaOH (520 ml, 104 mmol), then benzoyl chloride (9.6 g, 66.8 mmol) in toluene (200 ml) is added at 0 °C. The mixture is separated and the aqueous phase is extracted with DCM (250 ml x 3). The combined organic phase is dried over MgSCri and concentrated to give compound 20 (21.3g, 90% yield). LCMS: M+l=355
Compound 21: ((2R,3S)-3-hydroxy-2-methylpyrrolidin-l-yl)(phenyl)methanone
Figure imgf000035_0002
20 21
[0077] 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 minutes 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 the residue that is treated with petroleum ether (10 ml) and EtOAc (2 ml) to afford the title compound 21 (9.85 g, 79.8% yield). LCMS: M+l=206
Compound 22: (2R,3S)-2-methyl-l-(phenylmethyl-d2)pyrrolidin-3-ol
Figure imgf000036_0001
[0078] To a stirred solution of compound 21 (3 g, 14.6 mmol) in dry THF (50 mL) is slowly added lithium aluminum deuteride (614 mg, 14.6 mmol) 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 washed with diethyl ether. The combined organic phases are dried over Na2SO4 and concentrated to give the residue that is purified by silica gel chromatography to afford the title compound 22 (2.68 g, 95% yield). LCMS: M+l=194
Compound 23: (2R,3R)-3-azido-2-methyl-l-(phenylmethyl-d2)pyrrolidine
Figure imgf000036_0002
22 23
[0079] To a stirred solution of compound 22 (1.5 g, 7.8 mmol), DMAP (2.36 g, 0.78 mmol), and EtsN (95 mg, 23.4 mmol) in dry CH2CI2 at 0 °C is added MsCl (1.8 g, 15.62 mmol). The reaction mixture is stirred for 3 h at room temperature, then quenched with saturated aqueous NaHCCh, and the aqueous layer extracted with CHCI3 (30 mL x 3). The combined organic phase is washed with brine and dried over anhydrous Na2SO4. The organic phase is concentrated under reduced pressure and the residue is diluted with DMF (40 ml) and NaNs (1.65 g, 23.4 mmol) is added. The reaction mixture is stirred for 16 h at 80 °C. It is quenched with water, extracted with EtOAc (100 ml x 3). The organic phase is dried over MgSCL and concentrated to give the residue that is purified by silica gel column chromatography to afford the title compound 23 (1.7 g, 99% yield). LCMS: M+l=219
Compound 24:
Figure imgf000037_0001
[0080] A mixture of compound 23 (1.36 g, 6.2 mmol) and 10% of Pd/C (151 mg) in MeOH (50 mL) is stirred under H2 for 18 hours. The reaction mixture is filtered and the solvent evaporated under reduced pressure to afford the compound 24 (1.12 g, 93% yield). LCMS: M+l=193
Compound 11: Methyl 4-(tert-butoxycarbonylamino)-5-chloro-2-methoxybenzoate
Figure imgf000037_0002
11
[0081] 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) is added Boc2O (5.6 g, 25.5 mmol) and the reaction mixture is stirred at 38 °C for 6 h. It is concentrated to give the residue that is purified by silica gel column chromatography to afford the compound 11 (4.4 g,
60% yield). XH NMR (400 MHz, CDC13) 6 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]+
Compound 12: Methyl 4-(tert-butoxycarbonyl(trideuteromethyl)amino)-5-chloro-2- methoxybenzoate
Figure imgf000037_0003
11 12
[0082] 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 minutes, 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 NH4C1. It is extracted with EtOAc (100 mL) and the organic phase is washed with water, brine, and dried over anhydrous Na2SO4. The organic phase is concentrated under reduced pressure and the residue purified by silica gel column chromatography to afford the title compound 12 (2.02 g, 97.6% yield). NMR (400 MHz, CDCh) 8 7.86 (s, 1H), 6.85 (s, 1H), 3.90 (s, 6H), 1.36 (s, 9H). MS m/z (ESI): 277 [M+H-56]+
Compound 13: 4-(tert-Butoxycarbonyl(trideuteromethyl)amino)-5-chloro-2- methoxybenzoic acid
Figure imgf000038_0001
12 13
[0083] To a solution of compound 12 (1.68 g, 5.1 mmol) in THF (65 mL) and water (20 mL) is added LiOH*H2O (844 mg, 20 mmol) and the mixture is stirred for 12 h. The reaction is acidified to pH = 3 with IN HC1 and then is extracted with EtOAc (50 mL x 3) and the combined organic phases are 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 afford the title compound 13. (1.46 g, 90% yield). *HNMR (400 MHz, CDCI3) 6 8.23 (s, 1H), 6.96 (s, 1H), 4.08 (s, 3H), 1.39 (s, 9H). MS m/z (ESI): 263 [M+H-56]+
Compound 14: 5-Chloro-2-methoxy-4-(trideuteromethylamino)benzoic acid
Figure imgf000038_0002
13 14
[0084] A mixture of compound 13 (1.44g, 4.5mmol) and TFA (12 mL) in CH2CI2 (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). *HNMR (400 MHz, DMSO-d6) 8 7.61(s, 1H), 6.20 (s, 1H), 6.18 (s, 1H), 3.83 (s, 3H). MS m/z (ESI): 219 [M+H]+ A2: 5-Chloro-/V-((21?,3^)-l-(dideutero(phenyl)methyl)-2-methylpyrrolidin-
3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide
Figure imgf000039_0001
[0085] 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 and extracted with EtOAc (15 mL x 3), washed with brine, dried over anhydrous MgSCE, and concentrated to give the residue which is purified by silica gel chromatography to afford compound A2 (85mg, 41.5% yield). ’H NMR (400 MHz, CDC13) 8 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]+
Example 2 - Radioligand Binding Competition Activity on Recombinant Human Dopamine and Serotonin Receptors Using Filtration Binding Assays
[0086] Radioligand binding experiments are conducted with membrane preparations.
Receptor accession numbers, cellular background, and reference compounds are listed in Table 1.
Table 1.
Figure imgf000039_0002
[0087] The compound from Example 1 (A2) is tested for radioligand binding competition activity at human Dopamine D2S, D3, and D4.4 and Serotonin 5-HT1 A, 5-HT2A, and 5-HT7A receptors and results are provided in Table 2.
Table 2. Binding
Figure imgf000040_0001
a. (±)-cz -A-(l-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide b. N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4- (methylamino)benzamide c. Average of numbers in parentheses.
Example 3 - Agonist or Antagonist Activity on Recombinant Human Dopamine and
Serotonin Receptors Using IPOne HTRF, cAMP HTRF, and GTPyS Assays
[0088] SPA 35S-GTPgS experiments are conducted with membrane preparations. IP-One and cAMP HTRF assays are conducted with recombinant cell lines. Receptor accession numbers, cellular background, and reference compounds are listed in Table 3.
Table 3.
Figure imgf000040_0002
[0089] The compound from Example 1 (A2) is tested for antagonist activity at human Dopamine D2S, D3, and D4.4 receptors, for agonist activity at human Serotonin 5-HT1 A receptor, for agonist and antagonist activity at human Serotonin 5-HT2A receptor, and for antagonist activity at human Serotonin 5-HT7A receptor. Results are in Tables 4 and 5.
[0090] Agonist activity of test compounds is expressed as a percentage of the activity of the reference agonist at its ECioo concentration. Antagonist activity of the test compound is expressed as a percentage of the inhibition of reference agonist activity at its EC«o concentration.
Table 4. Functional Assays
Figure imgf000041_0001
a. (±)-cz -A-(l-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide b. N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4- (methylamino)benzamide c. Average of numbers in parentheses.
Table 5.
Figure imgf000042_0001
a. Top % Inhibition or Activation at maximal concentration b. (±)-cz -A-(l-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide c. N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-
(methylamino)benzamide d. Average of numbers in parentheses.
[0091] As shown above, the deuterated compound of Example 1 is a D2/D3/D4 antagonist, 5-HT1 A agonist, and 5-HT2A partial agonist.
Example 4 - In vitro metabolism [0092] Study compounds are investigated in pooled cryopreserved human (mixed gender) hepatocytes. The incubations are performed using 5 pM initial concentration and sampling at 0, 60, and 120 minute time points. The samples are analyzed using UPLC-QE- orbitrap-MS. Incubation volume: 300 pl in 48-well plate. Number of cells: 1 million viable cells/ml. Test compound: 5 pM (stock solution in DMSO). Incubation medium: pH 7.4, Bioreclamation IVT in vitro KHB medium. Shaking: 600 rpm. Time points: 0, 60, and 120 minutes with and without cells. Temperature: 37 °C. Sampling volume: 60 pl. DMSO content in incubation: 0.5%. Termination of incubations: 2-fold volume of 75% acetonitrile. Control: verapamil disappearance rate.
[0093] Sample preparation for hepatocyte samples: Samples are centrifuged for 20 min at 2272 x g at room temperature and pipetted to a UPLC-plate for analysis.
[0094] Data are shown in Figures 1 and 2 and in the tables below. In both Figures 1 and 2, the dashed line is without cells and the solid line is with cells.
Table 6.
Figure imgf000043_0001
Table 7.
Figure imgf000043_0002
Example 5 - In vivo pharmacokinetics
[0095] Group A male Sprague-Dawley (SD) rats are dosed (by PO) with test compounds at 0.5 mg/kg and 5 mg/kg (N=3 animals/dose level). Blood samples are obtained at 5, 10, and 30 minutes and 1, 2, 4, 8, and 24 hours after dosing. Following blood collection at 24 hours, brain perfusion is performed on the animals before harvesting brain tissues. [0096] Group B male Sprague-Dawley (SD) rats are dosed (by PO) with test compounds at 0.5 mg/kg and 5 mg/kg (N=9 animals/dose level). At designated timepoints (1, 4, and 8 hours), three animals from each dose group undergo blood draw followed by brain perfusion before samples are collected.
[0097] Test compounds are the deuterated compound of Example 1 (A2) and N- [(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis (R,R) nemonapride).
[0098] Rats are surgically cannulated with femoral artery catheter for blood collection. Approximate weight of rats is 250-350 g. Water is provided ad libitum. Fasting overnight prior to oral dose. Food available 4 h post dose.
[0099] Dose formulations are 0.5% aqueous methylcellulose (4000 cps) with 0.1% Tween™80 for PO administration. Once prepared, the suspension is vortexed/homogenized and continuously stirred until administration. Dose concentration: 0.1 mg/mL for 0.5 mg/kg dose and 1 mg/mL for 5 mg/kg dose. Route of administration: oral gavage. Dose volume: 5 mL/kg. Serial bleed: 200 p,L per time point. Terminal bleed: 500 p,L.
[00100] Blood samples are obtained via an automated sampling system in tubes containing potassium EDTA anticoagulant up to 24 h post dose. Plasma is obtained by centrifugation and snap frozen on dry ice within 30 minutes after collection. Aliquots of each dose formulation are taken, diluted appropriately, and analyzed at the same time with plasma samples by LC-MS/MS.
[00101] Plasma (harvested from blood samples) and brain tissues (homogenized and processed) are analyzed by LC/MS/MS. Plasma is harvested from blood via centrifugation within 30 minutes of sample collection. Brain tissue is collected after animals undergo perfusion to remove residual cardiovascular blood.
[00102] Dose solutions, plasma (harvested from blood), and brain tissues (homogenized and processed) are stored at -20 °C until analysis.
[00103] Plasma samples are thawed at room temperature before adding an organic solvent containing an internal standard to precipitate proteins.
[00104] Brain samples are thawed and homogenized in water (3-4 volumes) and aliquots of homogenates analyzed by LC/MS/MS.
[00105] Results are shown in Figures 3-6. [00106] Plasma pharmacokinetics between N-[(2R,3R)-l-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 Figure 3, see also Figure 7). In Figure 3, cis (R,R) nemonapride data is shown as the dashed line and average (N=3) data for the deuterated compound of Example 1 (A2) is shown as the solid line.
[00107] The extended brain enrichment of the compound of Example 1 (A2) in rats following single PO doses of 0.5 mg/kg and 5 mg/kg compared to plasma levels is shown in Figure 4 and Figure 5, respectively. In each figure, average brain concentration (ng/ml) is shown as the dashed line and average plasma concentration (ng/ml) is shown as the solid line. While plasma concentrations decrease, brain concentrations increase (see Figure 5, see also Figure 8). [00108] The deuterated compound of Example 1 (A2) has enriched brain levels compared to N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4- (methylamino)benzamide (cis (R,R) nemonapride) (see Figure 6, both administered at a single PO dose of 0.5 mg/kg). A comparison of brain to plasma ratios for N-[(2R,3R)-l-benzyl-2- methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis (R,R) nemonapride) and the deuterated compound of Example 1 (A2) is in Table 8 (both administered at a single PO dose of 0.5 mg/kg).
Table 8.
Figure imgf000045_0001
Example 6 - Ex Vivo Radioligand Binding in Membrane Preparations to Determine Time- Course of Receptor Occupancy at Central D2 Receptors
[00109] This study is to determine receptor occupancy at central D2 receptors following oral administration of the deuterated compound of Example 1 (A2) at various time points (1, 2, 4, 8, and 24 hours) and the positive comparator, olanzapine (10 mg/kg, po) using [3H]racl opride and rat striatal membranes. Liquid scintillation counting is used to quantify radioactivity.
Animals [00110] Thirty -five male Sprague-Dawley rats. Standard pelleted diet and filtered water is available ad libitum.
Drug Treatment
[00111] On day of test, animals are dosed orally with either vehicle, a single dose (2.5 mg/kg) of the deuterated compound of Example 1 (A2), N-[(2R,3R)-l-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 at 1 (N=5 rats), 2 (N=5 rats), 4 (N=5 rats), 8 (N=5 rats), and 24 (N=5 rats) hours after drug administration or 1 hour after vehicle and olanzapine administration (N=5 rats for vehicle and N=5 rats for olanzapine). Vehicle is 0.5% methylcellulose.
Pharmacokinetics
[00112] A post-mortem blood sample (approx. 5 ml) is taken by cardiac puncture and placed into KZEDTA tubes. The post-mortem blood samples are gently inverted, centrifuged (1900 g for 5 minutes at 4°C), and 1 ml of plasma from taken for PK determination. All plasma samples are frozen and stored at -80°C.
[00113] Whole brains are removed, rinsed with saline, and blot dried. The left striatum and right striatum is dissected out and weighed before being frozen on dry ice. The striata from each hemisphere are frozen separately. The tissue is wrapped in aluminum foil, placed in bags, and stored at -20°C until the day of the assay.
[ HJRaclopnde Binding
Homogenate Preparation
[00114] The striata is homogenised individually in ice-cold 50 mM Tris, pH 7.4, 120 mM NaCl, 5 mM KC1, 2 mM CaCl2, 1 mM MgCl2, and 10 pM pargyline using a tight-fitting homogeniser equivalent to 6.25 mg wet weight of tissue/ml and used immediately in the binding assay.
Assay
[00115] Striatal homogenates (400 pl, equivalent to 2.5 mg wet weight tissue/tube) are incubated with 50 pl of 1.6 nM [3H]raclopride and either 50 pl assay buffer (total binding) or 50 pl of 1 pM (-)sulpiride (to define non-specific binding) for 30 minutes at 23°C. The assay buffer consists of 50 mM Tris, pH 7.4, 120 mM NaCl, 5 mM KC1, 2 mM CaCl2, ImM MgCl2, and 10 pM pargyline. The wash buffer consists of 50 mM Tris, pH 7.4. There are two tubes for the determination of total binding and two tubes for the determination of non-specific binding. [00116] Membrane bound radioactivity is recovered by filtration under vacuum through filters, presoaked in 0.5% polyethylenimine (PEI) using a cell harvester. Filters are rapidly washed with ice-cold buffer and radioactivity determined by liquid scintillation counting.
Data Analysis
[00117] A value for specific binding (dpm) is generated by the subtraction of mean nonspecific binding (dpm) from mean total binding (dpm) for each animal.
[00118] Results are shown in Figures 7-11.
[00119] Plasma pharmacokinetics between N-[(2R,3R)-l-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 Figure 7, see also Figure 3). In Figure 7, average data for cis (R,R) nemonapride data is shown as the dashed line and average data for the deuterated compound of Example 1 (A2) is shown as the solid line (single oral administration of 2.5 mg/kg of each compound).
[00120] The extended brain enrichment of the compound of Example 1 (A2) in rats following single oral administration of 2.5 mg/kg compared to plasma levels is shown in Figure 8. In Figure 8, average brain concentration (ng/ml) is shown as the dashed line and average plasma concentration (ng/ml) is shown as the solid line.
[00121] The deuterated compound of Example 1 (A2) has enriched and retained brain levels compared to N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4- (methylamino)benzamide (cis (R,R) nemonapride) (see Figure 9) (single oral administration of 2.5 mg/kg of each compound). A comparison of brain to plasma ratios for N-[(2R,3R)-l-benzyl- 2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis (R,R) nemonapride) and the deuterated compound of Example 1 (A2) is in Table 9 (single oral administration of 2.5 mg/kg of each compound).
Table 9.
Figure imgf000047_0001
Figure imgf000048_0001
[00122] In addition, the deuterated compound of Example 1 (A2) has higher receptor occupancy levels at Ih, 2h, 8h, and 24h compared to N-[(2R,3R)-l-benzyl-2-methylpyrrolidin-3- yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis (R,R) nemonapride) (see Figure 10).
Example 7 - Touchscreen-Based Rat Probabilistic Reward Task
[00123] The Probabilistic Reward Task (PRT) uses visual discrimination methodology to quantify reward responsiveness to both identify deficits and characterize drug-induced improvements. Groups of rats are trained on the touchscreen-based PRT and exposed to asymmetrical probabilistic contingencies to generate response biases to the richly rewarded stimulus (Pizzagalli, D. et al., Biological Psychiatry, 2005, 57, 319-327; Kangas, B. et al., Translational Psychiatry, 2020, 10(l):285; Wooldridge, L. et al., International Journal of Neuropsychopharmacology, 2021, 24, 409-418). Next, subjects are tested with vehicle and three doses of the deuterated compound of Example 1 (A2).
Methods
Subjects
[00124] Male Sprague Dawley rats are used in the present study.
Apparatus
[00125] Details and schematics of the rodent touch-sensitive experimental chamber can be found in Kangas, B. et al., Behavioural Pharmacology, 2017, 28, 623-629. Briefly, a custom- built Plexiglas chamber (25x30x35 cm) is situated in a sound- and light-attenuating enclosure (40x60x45 cm). A 17” touch-sensitive screen (1739L, ELO TouchSystems, Menlo Park, CA) comprises the inside right-hand wall of the enclosure. An infusion pump (PHM- 100-5, Med Associates, St. Albans, VT) outside the enclosure is used to deliver sweetened condensed milk solution into the shallow reservoir of a custom-designed aluminum receptacle. The receptacle is mounted 3 cm above the floor bars and centered on the left-hand inside wall. Both touchscreen and fluid reservoir are easily accessible to the subject. A speaker bar (NQ576AT, Hewlett- Packard, Palo Alto, CA) mounted above the touchscreen is used to emit audible feedback. All experimental events and data collection are programmed in E-Prime Professional 2.0 (Psychology Software Tools, Inc., Sharpsburg, PA). Procedure
Initial training
[00126] Modified response-shaping techniques are used to train rats to engage with the touchscreen (Kangas, B. et al., Journal of Neuroscience Methods, 2012, 209, 331-336). A 5x5 cm blue square on a black background is presented in different sections of the touchscreen (left, right or center), with the proviso that its lower edge always is 10 cm above the floor bars. This requires the rat to rear on its hind legs to reach the screen and make a touchscreen response with its paw. Each response is reinforced with 0.1 mL of 30% sweetened condensed milk and the delivery is paired with an 880 ms yellow screen flash and 440 Hz tone and followed by a 5-sec intertrial interval (ITI) blackout period. After responses are reliably observed with latencies <5 sec following stimulus presentation, line-length discrimination training commenced. Line-length discrimination training
[00127] Discrete trials begin with concurrent presentation of a white line presented 5 cm above left and right response boxes. The width of the line is always 7 cm, but the length of the line is either 30 cm or 15 cm and varies in a quasi-random fashion across 100-trial sessions (50 trials of each length). Subjects learn to respond to the left or right response box depending on the length of the white line (i.e., long line = respond left, short line = respond right, or vice versa). Response box designation is counter-balanced across subjects. A correct response is reinforced as described above and is followed by a 5 sec ITI, whereas an incorrect response immediately results in a 5 sec 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 - each incorrect trial is repeated until a correct response is made - and is discontinued after session-wide trial repeats are <5 in each trial type. Discrimination sessions continue without correction until accuracies for both line lengths are >75% correct for 3 consecutive sessions. Probabilistic Reward Task
[00128] Following line-length discrimination training, probabilistic reinforcement schedules are introduced. Based on the human task protocol, a 3: 1 rich/lean probabilistic schedule is arranged such that 60% of correct responses to one of the line lengths (e.g., long line = rich alternative) and 20% of correct responses to the other line length (e.g., short line = lean alternative) are rewarded. Rich/lean line assignment is counterbalanced across subjects and 50 trials of each trial type are presented in a quasi-random sequence. These probabilistic contingencies are assessed across 5 consecutive sessions prior to initiation of drug testing. PRT Drug Tests
[00129] Following the establishment of probabilistic contingencies, an acute drug testing protocol is arranged that includes intermittent maintenance sessions in which correct responses on all trials are reinforced, control sessions in which 3: 1 (60%:20%) rich/lean probabilistic contingencies are arranged and, no more than once per week, a drug testing session in which vehicle or a dose of the deuterated compound of Example 1 (A2) (0.5, 1, or 2.5 mg/kg) is tested by administering it orally, 4-5 hr prior to a 3 : 1 (60%:20%) probabilistic session. Doses of the deuterated compound of Example 1 (A2) are tested in a mixed order across subjects using a Latin Square design. Vehicle and all doses of the deuterated compound of Example 1 (A2) are tested in all subjects.
Data Analysis
[00130] The implementation of probabilistic contingencies yields two primary dependent measures: response bias and task discriminability. These can be quantified by examining the number of Correct and Incorrect responses in rich and lean trial types using, respectively, log b and log d equations 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)).
Figure imgf000050_0001
[00131] High bias values are produced by high numbers of correct responses during rich trials and incorrect responses during lean trials, which increase the log b numerator. High discriminability values are produced by high numbers of correct responses during both rich and lean trials, which increase the log d numerator. (0.5 is added to all parameters to avoid instances where no errors are made on a given trial type, which would make log transformation impossible.) All data (log Z>, log d, accuracy, reaction time) are subject to repeated measures analysis of variance (ANOVA). Drugs
[00132] The deuterated compound of Example 1 (A2) is dissolved in a 0.5% methylcellulose solution. Drug doses are administered orally 4-5 hr prior to the experimental session.
Results and Discussion
[00133] As shown in Figure 12A, the deuterated compound of Example 1 (A2) enhances reward response bias (log Z>) significantly at 1 mg/kg.
[00134] As shown in Figure 12B, the deuterated compound of Example 1 (A2) enhances discriminability significantly at 0.5 mg/kg and 2.5 mg/kg, with a trend at 1 mg/kg.
[00135] The data shows that a dose of the deuterated compound of Example 1 (A2) targeting low but not high D2 RO significantly increases reward responsiveness.
[00136] No catalepsy is observed at tested doses.
[00137] Data shows that the deuterated compound of Example 1 (A2) may reduce anhedonia at low doses without inducing extrapy rami dal side effects.
[00138] Data suggests that D2/3 receptor occupancy of about 40-60% provides anti- anhedonic effects, D2/3 receptor occupancy of about 65-80% provides antipsychotic effects, and catalepsy emerges above 80% receptor occupancy.
Example 8 - Conditioned Avoidance Response
[00139] Adult male Wistar rats are used. Risperidone (0.5 mg/kg; Sigma Aldrich) is dissolved in 10% DMSO in water and injected i.p. at a dose volume of 1 mg/kg 30 minutes prior to test. The deuterated compound of Example 1 (A2) (0.5, 2.5, and 5 mg/kg) is formulated in 0.5% methyl cellulose in water and administered orally at a dose volume of 1 mg/kg 4 hours prior to test.
[00140] The Conditioned Avoidance Response (CAR) Test is an animal model screening for antipsychotic drugs.
[00141] Dunnett’s post hoc analysis reveals that risperidone (0.5 mg/kg) and the deuterated compound of Example 1 (A2) (2.5 and 5 mg/kg) significantly decrease percent avoidance as well as the number of avoidance responses compared to vehicle.
[00142] Dunnett’s post hoc analysis reveals that risperidone (0.5 mg/kg) increases escape failures compared to vehicle. None of the doses of the deuterated compound of Example 1 (A2) have a significant treatment effect on this measure. [00143] Rats treated acutely with the deuterated compound of Example 1 (A2) (2.5 and 5 mg/kg) show decreased avoidance responses and percent avoidance indicating potential antipsychotic activity. None of the doses of the deuterated compound of Example 1 (A2) shows any effects on escape failures.
Example 9 - Headshake Response
[00144] Adult male Sprague Dawley rats are used. The deuterated compound of Example 1 (A2) (1, 5, 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 test. DOI (3 mg/kg) is dissolved in saline and administered IP at a dose volume of 1 ml/kg (10 minutes prior to test).
[00145] Animals are administered vehicle, DOI, or test compound and returned to their holding cage for the appropriate pretreatment time (10 minutes for DOI and 4 hours for the deuterated compound of Example 1 (A2)), following which headshakes are recorded for 10 minutes using video cameras. The headshake response is a rapid, rhythmic shaking of the head in a radial motion. Data are analyzed by ANOVA followed by post hoc analysis where appropriate. [00146] Dunnett’s post analysis finds that, compared to vehicle, DOI significantly increases the number of headshakes. None of the doses of the deuterated compound of Example 1 (A2) have any significant effect on this measure.
[00147] Acute oral administration of the deuterated compound of Example 1 (A2) (1, 5, and 10 mg/kg) shows no significant increase in the number of headshakes compared to vehicle. DOI (3 mg/kg) significantly increases headshake responses in the rats following acute i.p. injection.
Example 10 - DOI-Induced Headshake Response
[00148] Adult male Sprague Dawley rats are used. The deuterated compound of Example 1 (A2) (1, 5, 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 test. DOI (3 mg/kg) is dissolved in saline and administered IP at a dose volume of 1 ml/kg (10 minutes prior to test). Ketanserin (1 mg/kg) is dissolved in saline and injected IP 30 minutes prior to DOI at a dose volume of 1 mg/kg.
[00149] Animals are administered vehicle, ketanserin, or test compound and returned to their holding cage for the appropriate pretreatment time (4 hours for the deuterated compound of Example 1 (A2) and 30 minutes for ketanserin). Rats are then injected with DOI and headshakes are recorded 10 minutes after DOI injection for 10 minutes using video cameras. The headshake response is a rapid, rhythmic shaking of the head in a radial motion. Data is analyzed by ANOVA followed by post hoc analysis where appropriate.
[00150] Dunnett’s post analysis finds that, compared to vehicle, DOI significantly increases the number of headshakes. Ketanserin and the deuterated compound of Example 1 (A2) (1, 5, and 10 mg/kg) significantly attenuate DOI-indcued headshake responses.
[00151] Acute oral administration of the deuterated compound of Example 1 (A2) (1, 5, and 10 mg/kg) decreases DOI-induced headshakes compared to vehicle. Ketanserin (1 mg/kg) also decreases the number of headshake responses induced by DOI following acute i.p. injection.

Claims

CLAIMS What is claimed:
1. A compound of Formula I:
Figure imgf000054_0001
Formula I, wherein:
Ri, R2, R3, R4, and R5 are independently selected from H and D; and at least one of Ri, R2, and R3 is D; in free or salt form.
2. The compound according to claim 1, wherein the compound is in free form.
3. The compound according to claim 1 or 2, wherein Ri, R2, and R3 are D.
4. The compound according to any one of claims 1-3, wherein each of Ri, R2, R3, R4, and R5 are D.
5. The compound according to any one of claims 1-4, wherein the compound is:
Figure imgf000054_0002
in free or salt form.
52 The compound according to any one of claims 1-5, wherein the compound, in free or pharmaceutically acceptable salt form, has greater than 90% incorporation of deuterium at one or more positions designated as deuterium. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound according to any one of claims 1-6, in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier. A method for treatment of a brain disorder in a patient in need thereof, wherein the method comprises administering to the patient a compound according to any one of claims 1-6, in free or pharmaceutically acceptable salt form, or a pharmaceutical composition according to claim 7. The method according to claim 8, wherein the disorder is an affective disorder or an anxiety disorder. The method according to claim 8, wherein the disorder is depression, an anxiety disorder, psychosis, schizophrenia, schizoaffective disorder, post-traumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder, or a migraine. The method according to claim 10, wherein the anxiety disorder is panic disorder, social anxiety disorder, a phobia, or generalized anxiety disorder. The method according to claim 8, wherein the disorder is anhedonia, depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression. The method according to claim 8, wherein the disorder is anxious depression. The method according to claim 8, wherein the disorder is melancholic depression. The method according to claim 8, wherein the disorder is major depressive disorder. The method according to claim 8, wherein the disorder is a substance use disorder.
53 The compound according to any one of claims 1-6, in free or pharmaceutically acceptable salt form, or a pharmaceutical composition according to claim 7, for use in the treatment of a brain disorder. Use of a compound according to any one of claims 1-6 in the manufacture of a medicament for treatment of a brain disorder. The use according to claim 17 or 18, wherein the brain disorder is as recited in any of claims 9-16.
54
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104744333A (en) * 2013-12-26 2015-07-01 张云 Production method of nemonapride
US20190328745A1 (en) * 2013-12-03 2019-10-31 Intra-Cellular Therapies, Inc. Novel methods

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190328745A1 (en) * 2013-12-03 2019-10-31 Intra-Cellular Therapies, Inc. Novel methods
CN104744333A (en) * 2013-12-26 2015-07-01 张云 Production method of nemonapride

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE ANONYMOUS : "BRD-A66927094-001-01-7", XP093078500, retrieved from PUBCHEM *

Cited By (2)

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