Deuterated organic compound and application thereof

Abstract

Provided are compounds of Formula I and Formula II as described herein, processes for their preparation, their use as medicaments, pharmaceutical compositions comprising them, and intermediates for their preparation. Compounds of Formula I and Formula II are useful, for example, to modulate dopamine and serotonin neurotransmission, and to treat conditions from which they may benefit, such as schizophrenia and depression.

Description

[0001] This application claims priority to U.S. Provisional Application No. 63 / 511,685, filed July 2, 2023; U.S. Provisional Application No. 63 / 511,847, filed July 3, 2023; U.S. Provisional Application No. 63 / 511,849, filed July 3, 2023; U.S. Provisional Application No. 63 / 511,852, filed July 3, 2023; U.S. Provisional Application No. 63 / 511,853, filed July 3, 2023; U.S. Provisional Application No. 63 / 511,855, filed July 3, 2023; and U.S. Provisional Application No. 63 / 512,064, filed July 5, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] Compounds of Formulas I and II are provided, along with their preparation methods, their use as pharmaceuticals, pharmaceutical compositions comprising them, and intermediates for their preparation. The compounds of Formulas I and II can be used, for example, to regulate dopamine and serotonin neurotransmission and to treat conditions from which they may benefit, such as schizophrenia and depression. Background Technology

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

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

[0005] D1-like receptors are present in postsynaptic dopamine receptor cells, while D2-like dopamine receptors are expressed in both postsynaptic dopamine target cells and presynaptic dopaminergic neurons.

[0006] Fourteen serotonin receptor subtypes, classified into different subfamilies, mediate the effects of serotonin (5-HT). The 5-HT1A receptor subtype is a major subtype, present as a presynaptic autoreceptor in serotonin neurons of the raphe nuclei and as a postsynaptic heterogeneous receptor in the prefrontal cortex, hippocampus, septum, and hypothalamus. The signaling mechanism of 5-HT1A receptors in the raphe nuclei may differ from that in other brain regions. Activation of the 5-HT1A postsynaptic receptor triggers increased dopamine release. The 5-HT2A receptor subtype is enriched in the cortex, associated with phosphatidylinositol conversion, and also regulates dopamine release. 5-HT2A receptor antagonists possess antipsychotic properties, while 5-HT2A receptor agonists are thought to be associated with cognitive enhancement and hallucinogenic properties. The hallucinogenic effects of lysergic acid diethylamide (LSD) and psilocybin are believed to originate from their 5-HT2A receptor agonistic effects. It has also been reported that 5-HT2A agonism can promote neuroplasticity and reduce depression.

[0007] Antipsychotics are used to manage psychosis, particularly schizophrenia. Antipsychotics are characterized by D2 receptor antagonism. D2 receptor antagonism is effective in reducing the positive symptoms of schizophrenia (e.g., hallucinations and delusions), but it often also produces extrapyramidal side effects, including Parkinson's disease, akathisia, and tardive dyskinesia, increases prolactin levels, and may exacerbate the negative symptoms of schizophrenia (e.g., loss of interest and motivation in life and activities, social withdrawal, and anhedonia). A key feature of atypical antipsychotics is the combination of D2 receptor antagonism and 5-HT2A receptor antagonism, which explains their enhanced efficacy and reduced extrapyramidal motor side effects (EPS) compared to typical antipsychotics. Many patients with psychosis also suffer from depression, which current medications may not be able to treat. However, some atypical antipsychotics are used as adjuncts to serotonergic antidepressants to improve responses to major depressive disorder.

[0008] Because dopamine and serotonin imbalances can lead to a variety of conditions, and current medications may not be able to effectively regulate the levels of both, there is a need for new compounds that can regulate dopamine and serotonin neurotransmission, as well as methods to treat diseases involving dopamine and serotonin imbalances. Summary of the Invention

[0009] A compound of formula I is provided: Formula I, in: R1, R2, R3, R4, and R5 are independently selected from H and D; and At least one of R1, R2, R3, R4, and R5 is D; The compound is in free form or salt form.

[0010] Further, pharmaceutical compositions comprising Formula I compounds, methods for preparing Formula I compounds, and pharmaceutical uses of Formula I compounds, such as as an anhedrinogen and for the treatment of schizophrenia, depression, and post-traumatic stress disorder, are provided.

[0011] Provide a compound of formula II: Formula II, in: R6, R7, and R8 are independently selected from H and D; and At least one of R6, R7 and R8 is D; The compound is in free form or salt form. The compound is substantially free of its (S,S) enantiomer.

[0012] Further, pharmaceutical compositions comprising compound II, methods for preparing compound II, and pharmaceutical uses of compound II are provided, such as as an anhedrin and for the treatment of schizophrenia, depression, and post-traumatic stress disorder.

[0013] Other applicable areas of the invention will become apparent from the detailed description provided below. It should be understood that while these detailed descriptions and specific examples point to preferred embodiments of the invention, they are for illustrative purposes only and are not intended to limit the scope of the invention. Attached Figure Description

[0014] Figure 1 The mean plasma concentrations (ng / ml) of cis(R,R)nemopride and compound (10) of Example 1 in rats when administered as a single PO dose of 0.5 mg / kg are shown.

[0015] Figure 2 The mean brain concentrations (ng / ml) of cis(R,R)nemopride and compound (10) of Example 1 in rats when administered as a single PO dose of 0.5 mg / kg are shown.

[0016] Figure 3 The mean plasma concentrations (ng / ml) of cis(R,R)nemopride and compound (18) of Example 2 in rats when administered as a single PO dose of 0.5 mg / kg are shown.

[0017] Figure 4 The mean brain concentrations (ng / ml) of cis(R,R)nemopride and compound (18) of Example 2 in rats when administered at a single PO dose of 0.5 mg / kg are shown.

[0018] Figure 5 The mean plasma and brain concentrations (ng / ml) of compound (10) from Example 1 in rats were shown when administered as a single PO dose of 0.5 mg / kg.

[0019] Figure 6 The mean plasma and brain concentrations (ng / ml) of compound (18) in Example 2 in rats were shown when administered as a single PO dose of 0.5 mg / kg.

[0020] Figure 7 This shows the effect of administration of Example 1 (10) and Example 1 (A2) from International Publication No. WO2023 / 130117 on dopamine in the nucleus accumbens of free-moving SD rats (%).

[0021] Figure 8 This shows the effect of administration of Example 1 (10) and Example 1 (A2) from International Publication No. WO2023 / 130117 on dopamine in the prefrontal cortex of free-moving SD rats (%). Detailed Implementation

[0022] The following description of preferred embodiments is merely exemplary in nature and is in no way intended to limit the invention, its application, or its use.

[0023] If there is any conflict between the definitions in this disclosure and the definitions in the cited references, the definitions in this disclosure shall prevail.

[0024] D2 and D3 receptors are expressed on both postsynaptic dopamine target cells and presynaptic dopamine neurons. Dopamine receptors are primarily located on non-dopamine neurons. Dopamine receptors on dopamine neurons are called autoreceptors. Autoreceptors help regulate dopamine neuronal activity and control the synthesis, release, and uptake of dopamine.

[0025] Presynaptic D2-like dopamine autoreceptors regulate dopamine release. Low doses of D2-like receptor antagonists preferentially block presynaptic autoreceptors and increase dopamine release, while high doses block postsynaptic receptors and reduce dopamine neurotransmission. A relatively high occupancy rate of D2-like receptors is associated with antipsychotic effects, while a relatively low occupancy rate is associated with antidepressant effects.

[0026] Anhedonia is a core symptom of major depressive disorder (MDD) and is associated with poor responses to approved selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), psychotherapy (e.g., cognitive behavioral therapy (CBT)), and neurostimulation (e.g., transcranial magnetic stimulation (TMS)). Effective treatment for MDD characterized by anhedonia remains in need. Despite a range of available therapies, up to 50% of people with MDD do not respond to treatment, and only about 30% of patients achieve complete recovery with currently available antidepressant medications; the outcomes are even worse for individuals with anhedonia-specific MDD.

[0027] Depletion of dopamine / catecholamines can induce symptoms of depression and anhedonia. Increasing dopamine neurotransmission can alleviate these symptoms. However, while high doses of dopamine D2 / D3 agonists can activate postsynaptic dopamine receptors, they may also be poorly tolerated (e.g., nausea / vomiting). Low doses of dopamine D2 / D3 receptor antagonists preferentially block presynaptic dopamine autoreceptors and increase dopamine release without the problem of poor tolerability.

[0028] Besides MDD, anhedonia also plays a role in bipolar disorder, schizophrenia, post-traumatic stress disorder, and substance use disorder. Despite its role in many conditions, there are currently no approved medications for treating anhedonia.

[0029] Decreased serotonergic activity is associated with anxiety and depression. Increasing serotonin neurotransmission can alleviate anxiety and depressive symptoms and is helpful for anxiety-related depression.

[0030] The IUPAC name for nemoprazole is (±)-cis- N -(1-Benzyl-2-methylpyrrolidone-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide. U.S. Patent No. 4,210,660 describes nemopride as a potent central nervous system depressant, and in particular a potent antipsychotic.

[0031] Nemopride is a dopamine D2 / D3 / D4 receptor antagonist. Nemopride is approved in Japan and South Korea for the treatment of schizophrenia. Nemopride is available in 3 mg and 10 mg tablets. The approved daily dose for schizophrenia is 9 to 36 mg, administered orally in divided doses after meals. The dose can be increased to 60 mg daily.

[0032] Prescribing information for nemopride indicates that its elimination half-life is 2.3 to 4.5 hours when administered orally to healthy adults at doses of 3 mg and 6 mg. Urinary metabolites of nemopride are produced by debenzylation and N-demethylation. See the Emilace product information leaflet.

[0033] Nemopride is not only a dopamine D2 / D3 / D4 receptor antagonist but also a 5-HT1A agonist. Furthermore, nemopride has been reported to bind to 5-HT2A receptors; however, the inventors have not found any publications reporting its functional effects on this receptor. Nevertheless, as an antipsychotic, nemopride shows promise as a 5-HT2A receptor antagonist because a key characteristic of atypical antipsychotics is the combination of D2 receptor antagonism with or inversely agonistic 5-HT2A receptor antagonism.

[0034] When drugs are used in the form of a mixture of stereoisomers, especially for drugs with multiple biological targets, it is impossible to predict what characteristics each stereoisomer will have (e.g., biological targets, pharmacokinetics).

[0035] The compounds of Formula I and Formula II disclosed herein are D2 receptor antagonists and 5-HT2A agonists. Surprisingly, the deuterated compounds of Examples 1 and 2 exhibited higher 5-HT2A agonist activity than their non-deuterated analogs (see Example 4, Table 5). The deuterated compound (10) of Example 1 is also a 5-HT1A agonist, and the deuterated compound (18) of Example 2 is also a partial 5-HT1A agonist. The combination of D2 receptor antagonism with 5-HT1A and 5-HT2A agonism (especially potent 5-HT2A agonism) constitutes a unique pharmacological activity spectrum that allows for differential modulation of dopamine and serotonin neurotransmission compared to other D2 receptor antagonists. Other substituted benzamides tested, namely R-remopride, S-remopride, R-sulpiride, R-sulfopride, and S-suflopride, did not even bind to the 5-HT2A receptor in vitro (labeled ketocelin competition assay).

[0036] As described above, the combination of D2 receptor antagonism with 5-HT1A and 5-HT2A agonism constitutes a unique activity spectrum, potentially allowing for different modulations of dopamine and serotonin neurotransmission compared to other D2 receptor antagonists. For example, D2 postsynaptic receptor antagonism alleviates psychosis, particularly schizophrenia, by reducing dopamine neurotransmission. High doses targeting ≥60% receptor occupancy may be associated with D2 antagonist-mediated side effects, such as extrapyramidal motor side effects (EPS) and elevated prolactin levels. However, 5-HT1A agonism may limit those side effects associated with high-dose D2 antagonism, thus providing an intrinsic safety profile for these compounds when used at high doses as antipsychotics. 5-HT1A agonism also provides anxiolytic effects. Furthermore, as potent 5-HT2A agonists, the deuterated compounds disclosed herein may exhibit enhanced antidepressant effects similar to those of hallucinogenic antidepressants, such as rapid and sustained action, and possess anxiolytic activity. Meanwhile, the combination of D2 antagonism and 5-HT2A agonism may modulate the hallucinogenic effects of 5-HT2A.

[0037] Therefore, as D2 antagonists and 5-HT2A agonists, compounds of formula I and II can provide hallucinogenic-like antidepressant efficacy at low doses (e.g., below the dose of nemopride used to treat schizophrenia), while possessing intrinsic protection against 5-HT2A-mediated hallucinations. Furthermore, as D2 antagonists and 5-HT1A agonists, compounds of formula I and II can be used as antipsychotics at high doses, but possess intrinsic protection against the side effects associated with high-dose D2 antagonists.

[0038] Surprisingly, different deuteration modes of N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide lead to different activity profiles, particularly regarding 5-HT2A agonism relative to D2 antagonism. Data indicate that the deuterated compounds of Examples 1 (10) and 2 (18) disclosed herein exhibit weaker D2L antagonism and stronger 5-HT2A agonism compared to their non-deuterated analogs. Furthermore, data suggest that the deuterated compounds of Examples 1 (10) and 2 (18) disclosed herein are also stronger 5-HT2A agonists than compound (A2) of Example 1 in International Publication No. WO2023 / 130117. These differences result in a more balanced 5HT2A:D2L ratio for the deuterated compounds of Examples 1 (10) and 2 (18) (see Table 6). The different activity profiles of these compounds at two targets (dopamine and serotonin receptors) may allow the compounds to target different patient groups and be particularly beneficial to these patient groups.

[0039] The pharmacokinetics of the deuterated compounds disclosed herein are beneficial. The plasma pharmacokinetics of N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R)nemopride) and the deuterated compounds of Examples 1 (10) and 2 (18) are similar (see Example 5). However, despite the similar plasma pharmacokinetics, Example 5 shows that the compounds of Formula I and II (the deuterated compounds of Examples 1 (10) and 2 (18)) have enriched and maintained brain levels compared to their non-deuterated analogues. For example, Figure 2 and 4 Compared to cis(R,R)nemopride, the compounds of Examples 1 (10) and 2 (18) showed higher brain levels at all time points. The deuterated compounds of Examples 1 (10) and 2 (18) also exhibited prolonged brain enrichment compared to plasma levels (see [link to original text]). Figure 5 and Figure 6 Brain: Plasma exposure supports once-daily administration of both compounds. Brain-level enrichment and prolonged brain enrichment are beneficial features compared to plasma levels, allowing for higher and more sustained receptor occupancy with lower dosing frequency and potentially fewer peripheral side effects. The receptor occupancy levels provided by the deuterated compounds of Examples 1 (10) and 2 (18) can be maintained within the desired range with convenient dosing regimens. In contrast, nemopride requires multiple daily dosings.

[0040] Compounds that act as D2 receptor antagonists, 5-HT1A receptor agonists, and 5-HT2A receptor agonists regulate dopamine and serotonin neurotransmission and can therefore be used to treat conditions involving dopamine and serotonin signaling pathways, such as conditions involving dopamine, 5-HT1A, and / or 5-HT2A receptors.

[0041] A compound of formula I is provided: Formula I, in: R1, R2, R3, R4, and R5 are independently selected from H and D; and At least one of R1, R2, R3, R4, and R5 is D; The compound is in free form or salt form.

[0042] Further, compounds of formula I are provided: 1.1 Formula I, wherein the compound is in a pharmaceutically acceptable salt form.

[0043] Formula 1.2, wherein the compound is in free form.

[0044] 1.3 Any one of Equation I, 1.1 or 1.2, where R1, R2, R3, R4 and R5 are each D.

[0045] 1.4 Formula I or any one of 1.1-1.3, wherein the compound is: , The compound is in free form or salt form, for example, in free form or in a pharmaceutically acceptable salt form, for example, in free form.

[0046] 1.5 Equation I or any one of 1.1-1.4, wherein the labeling of a position as deuterium (i.e., D) indicates that the deuterium abundance at that position is significantly greater than the natural abundance 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 labeled as a specific isotope exists at its natural isotopic abundance.

[0047] 1.6 A compound of Formula I or any of 1.1-1.5, wherein the compound is in free or salt form (e.g., a pharmaceutically acceptable salt form) and has a deuterium (i.e., D) incorporation of more than 50% at one or more positions labeled as deuterium (i.e., D) (e.g., at all positions), for example, more than 60%, or more than 70%, or more than 80%, or more than 90%, or more than 95%, or more than 96%, or more than 97%, or more than 98%, or more than 99%. For example, a compound of Formula I or any of 1.1-1.5, wherein the compound is in free or salt form (e.g., a pharmaceutically acceptable salt form) and has a deuterium (i.e., D) incorporation of more than 50% at each position labeled as deuterium (i.e., D), for example, more than 60%, or more than 70%, or more than 80%, or more than 90%, or more than 95%, or more than 96%, or more than 97%, or more than 98%, or more than 99%.

[0048] 1.7 Formula I or any one of 1.1-1.6, wherein the compound is substantially stereoisomerically pure. For example, wherein the stereoisomer excess of the compound is greater than 90%, for example, the stereoisomer excess is equal to or greater than 95%, for example, the stereoisomer excess is equal to or greater than 96%, for example, the stereoisomer excess is equal to or greater than 97%, for example, the stereoisomer excess is equal to or greater than 98%, for example, the stereoisomer excess is equal to or greater than 99%. For example, wherein the compound is substantially diastereomerically pure and / or enantiomerically pure, for example, wherein the compound is substantially diastereomerically pure and enantiomerically pure.

[0049] 1.8 Formula I or any one of 1.1-1.7, wherein the compound is substantially diastereomer-pure. For example, wherein the diastereomer excess of the compound is greater than 90%, for example, the diastereomer excess is equal to or greater than 95%, for example, the diastereomer excess is equal to or greater than 96%, for example, the diastereomer excess is equal to or greater than 97%, for example, the diastereomer excess is equal to or greater than 98%, for example, the diastereomer excess is equal to or greater than 99%.

[0050] 1.9 Formula I or any one of 1.1-1.8, wherein the compound is substantially enantiomerically pure. For example, wherein the enantiomeric excess of the compound is greater than 90%, for example, an enantiomeric excess equal to or greater than 95%, for example, an enantiomeric excess equal to or greater than 96%, for example, an enantiomeric excess equal to or greater than 97%, for example, an enantiomeric excess equal to or greater than 98%, for example, an enantiomeric excess equal to or greater than 99%.

[0051] 1.10 Formula I or any one of 1.1-1.9, wherein the compound has the stereochemical configuration shown in Formula I.

[0052] 1.11 Formula I or any one of 1.1-1.10, wherein the compound is in a pharmaceutical composition containing a pharmaceutically acceptable carrier. For example, Formula I or any one of 1.1-1.10, wherein an effective amount of the compound is in a pharmaceutical composition containing a pharmaceutically acceptable carrier.

[0053] A compound of formula II is also provided: Formula II, in: R6, R7, and R8 are independently selected from H and D; and At least one of R6, R7 and R8 is D; The compound is in free form or salt form. The compound is substantially free of its (S,S) enantiomer.

[0054] 2.1 Formula II, wherein the compound is in a pharmaceutically acceptable salt form.

[0055] 2.2 Formula II, wherein the compound is in free form.

[0056] 2.3 Any one of Equation II, 2.1 or 2.2, where R6, R7 and R8 are each D.

[0057] 2.4 Formula II or any one of 2.1-2.3, wherein the compound is: , The compound is in free form or salt form, for example, in free form or in a pharmaceutically acceptable salt form, for example, in free form.

[0058] 2.5 Equation II or any one of 2.1-2.4, wherein the labeling of a position as deuterium (i.e., D) indicates that the deuterium abundance at that position is significantly greater than the natural abundance 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 labeled as a specific isotope exists at its natural isotopic abundance.

[0059] 2.6 A compound of Formula II or any one of 2.1-2.5, wherein the compound is in free form or in salt form (e.g., a pharmaceutically acceptable salt form) and has a deuterium (i.e., D) incorporation of more than 50% at one or more positions labeled as deuterium (i.e., D) (e.g., at all positions), for example, more than 60%, or more than 70%, or more than 80%, or more than 90%, or more than 95%, or more than 96%, or more than 97%, or more than 98%, or more than 99%. For example, a compound of Formula II or any one of 2.1-2.5, wherein the compound is in free form or in salt form (e.g., a pharmaceutically acceptable salt form) and has a deuterium (i.e., D) incorporation of more than 50% at each position labeled as deuterium (i.e., D), for example, more than 60%, or more than 70%, or more than 80%, or more than 90%, or more than 95%, or more than 96%, or more than 97%, or more than 98%, or more than 99%.

[0060] 2.7 Formula II or any one of 2.1-2.6, wherein the compound is substantially stereoisomerically pure. For example, wherein the stereoisomer excess of the compound is greater than 90%, for example, the stereoisomer excess is equal to or greater than 95%, for example, the stereoisomer excess is equal to or greater than 96%, for example, the stereoisomer excess is equal to or greater than 97%, for example, the stereoisomer excess is equal to or greater than 98%, for example, the stereoisomer excess is equal to or greater than 99%. For example, wherein the compound is substantially diastereomerically pure and / or enantiomerically pure, for example, wherein the compound is substantially diastereomerically pure and enantiomerically pure.

[0061] 2.8 Formula II or any one of 2.1-2.7, wherein the compound is substantially diastereomer-pure. For example, wherein the diastereomer excess of the compound is greater than 90%, for example, the diastereomer excess is equal to or greater than 95%, for example, the diastereomer excess is equal to or greater than 96%, for example, the diastereomer excess is equal to or greater than 97%, for example, the diastereomer excess is equal to or greater than 98%, for example, the diastereomer excess is equal to or greater than 99%.

[0062] 2.9 Formula II or any one of 2.1-2.8, wherein the compound is substantially enantiomerically pure. For example, wherein the enantiomer excess of the compound is greater than 90%, for example, an enantiomer excess equal to or greater than 95%, for example, an enantiomer excess equal to or greater than 96%, for example, an enantiomer excess equal to or greater than 97%, for example, an enantiomer excess equal to or greater than 98%, for example, an enantiomer excess equal to or greater than 99%.

[0063] 2.10 Formula II or any one of 2.1-2.9, wherein the compound has the stereochemical configuration shown in Formula II.

[0064] 2.11 Formula II or any one of 2.1-2.10, wherein the compound is in a pharmaceutical composition containing a pharmaceutically acceptable carrier. For example, Formula II or any one of 2.1-2.10, wherein an effective amount of the compound is in a pharmaceutical composition containing a pharmaceutically acceptable carrier.

[0065] A pharmaceutical composition (composition 1) is further provided, comprising a compound of formula I (e.g., any one of formulas 1.1-1.11): Formula I, in: R1, R2, R3, R4, and R5 are independently selected from H and D; and At least one of R1, R2, R3, R4, and R5 is D; The compound is in free form or salt form.

[0066] A pharmaceutical composition (composition 2) is further provided, comprising a compound of formula II (e.g., any one of formulas 2.1-2.11): Formula II, in: R6, R7, and R8 are independently selected from H and D; and At least one of R6, R7 and R8 is D; The compound is in free form or salt form. The compound is substantially free of its (S,S) enantiomer.

[0067] Composition 1 and Composition 2 are further provided as follows: 1.1 Composition 1 or Composition 2, wherein the composition comprises a pharmaceutically acceptable carrier.

[0068] 1.2 Composition 1, Composition 2, or 1.1, wherein the composition comprises a compound in free or pharmaceutically acceptable salt form as described in any one of Formula I or 1.1-1.11. Alternatively, Composition 1, Composition 2, or 1.1, wherein the composition comprises a compound in free or pharmaceutically acceptable salt form as described in any one of Formula II or 2.1-2.11.

[0069] 1.3 Any one of composition 1, composition 2, 1.1 or 1.2, wherein the compound is in a free form.

[0070] 1.4 Composition 1, Composition 2, or any one of 1.1-1.3, wherein the compound of formula I is: , It exists in free or pharmaceutically acceptable salt form, for example, in free form.

[0071] 1.5 Composition 1, Composition 2, or any one of 1.1-1.3, wherein the compound of formula II is: It exists in free or pharmaceutically acceptable salt form, for example, in free form.

[0072] 1.6 Composition 1, Composition 2, or any of 1.1-1.5, wherein the designation of deuterium (i.e., D) at a certain position indicates that the deuterium abundance at that position is significantly greater than the natural abundance 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 specific isotope is present at the natural isotopic abundance.

[0073] 1.7 Composition 1 or any one of 1.1-1.6, wherein the Formula I compound, in free or pharmaceutically acceptable salt form, has a deuterium (i.e., D) incorporation of greater than 50% at one or more positions labeled as deuterium (i.e., D) (e.g., at all positions), for example, 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 example, composition 1 or any one of 1.1-1.6, wherein the Formula I compound, in free or pharmaceutically acceptable salt form, has a deuterium (i.e., D) incorporation of greater than 50% at each position labeled as deuterium (i.e., D), for example, 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%. Alternatively, composition 2 or any of 1.1-1.6, wherein the compound of formula II, in the form of a free or pharmaceutically acceptable salt, has a deuterium (i.e., D) incorporation of greater than 50% at one or more positions labeled as deuterium (i.e., D) (e.g., at all positions), for example, 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 example, composition 2 or any of 1.1-1.6, wherein the compound of formula II, in the form of a free or pharmaceutically acceptable salt, has a deuterium (i.e., D) incorporation of greater than 50% at each position labeled as deuterium (i.e., D), for example, 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%.

[0074] 1.8 Composition 1, Composition 2, or any one of 1.1-1.7, wherein the composition is an oral or parenteral dosage form, such as an oral dosage form, for example, a tablet, capsule, solution, or suspension, such as a capsule or tablet.

[0075] 1.9 Composition 1 or any one of 1.1-1.8, wherein the composition comprises a therapeutically effective amount of a compound of formula I in its free or pharmaceutically acceptable salt form, for example, a therapeutically effective amount of a compound of formula I in its free or pharmaceutically acceptable salt form for the prevention or treatment of the conditions disclosed herein, for example, a therapeutically effective amount of a compound of formula I in its free or pharmaceutically acceptable salt form used in any of the methods disclosed herein. Alternatively, composition 2 or any one of 1.1-1.8, wherein the composition comprises a therapeutically effective amount of a compound of formula II in its free or pharmaceutically acceptable salt form, for example, a therapeutically effective amount of a compound of formula II in its free or pharmaceutically acceptable salt form for the prevention or treatment of the conditions disclosed herein, for example, a therapeutically effective amount of a compound of formula II in its free or pharmaceutically acceptable salt form used in any of the methods disclosed herein.

[0076] 1.10 Composition 1 or any one of 1.1-1.9, wherein the composition is substantially free of any other stereoisomers of Formula I. For example, composition 1 or any one of 1.1-1.9, wherein the composition is substantially free of any other diastereomeric and / or enantiomers of Formula I, for example, wherein the composition is substantially free of any other diastereomeric and enantiomers of Formula I. Or, composition 2 or any one of 1.1-1.9, wherein the composition is substantially free of any other stereoisomers of Formula II. For example, composition 2 or any one of 1.1-1.9, wherein the composition is substantially free of any other diastereomeric and / or enantiomers of Formula II, for example, wherein the composition is substantially free of any other diastereomeric and enantiomers of Formula II.

[0077] 1.11 Composition 1 or any one of 1.1-1.10, wherein the composition comprises less than 10% w / w (weight / weight) of any other stereoisomer of Formula I, for example, less than 5% w / w of any other stereoisomer of Formula I, for example, less than 4% w / w of any other stereoisomer of Formula I, for example, less than 3% w / w of any other stereoisomer of Formula I, for example, less than 2% w / w of any other stereoisomer of Formula I, for example, less than 1% w / w of any other stereoisomer of Formula I. Alternatively, composition 2 or any one of 1.1-1.10, wherein the composition comprises less than 10% w / w (weight / weight) of any other stereoisomer of formula II, for example, less than 5% w / w of any other stereoisomer of formula II, for example, less than 4% w / w of any other stereoisomer of formula II, for example, less than 3% w / w of any other stereoisomer of formula II, for example, less than 2% w / w of any other stereoisomer of formula II, for example, less than 1% w / w of any other stereoisomer of formula II.

[0078] 1.12 Composition 1 or any one of 1.1-1.11, wherein the composition comprises less than 10% w / w of any other diastereomeric form of Formula I, for example, less than 5% w / w of any other diastereomeric form of Formula I, for example, less than 4% w / w of any other diastereomeric form of Formula I, for example, less than 3% w / w of any other diastereomeric form of Formula I, for example, less than 2% w / w of any other diastereomeric form of Formula I, for example, less than 1% w / w of any other diastereomeric form of Formula I. Alternatively, composition 2 or any one of 1.1-1.11, wherein the composition comprises less than 10% w / w of any other diastereomeric form of formula II, for example, less than 5% w / w of any other diastereomeric form of formula II, for example, less than 4% w / w of any other diastereomeric form of formula II, for example, less than 3% w / w of any other diastereomeric form of formula II, for example, less than 2% w / w of any other diastereomeric form of formula II, for example, less than 1% w / w of any other diastereomeric form of formula II.

[0079] 1.13 Composition 1 or any one of 1.1-1.12, wherein the composition comprises less than 10% w / w of any other enantiomer of Formula I, for example, less than 5% w / w of any other enantiomer of Formula I, for example, less than 4% w / w of any other enantiomer of Formula I, for example, less than 3% w / w of any other enantiomer of Formula I, for example, less than 2% w / w of any other enantiomer of Formula I, for example, less than 1% w / w of any other enantiomer of Formula I. Alternatively, composition 2 or any one of 1.1-1.12, wherein the composition comprises less than 10% w / w of any other enantiomer of formula II, for example, less than 5% w / w of any other enantiomer of formula II, for example, less than 4% w / w of any other enantiomer of formula II, for example, less than 3% w / w of any other enantiomer of formula II, for example, less than 2% w / w of any other enantiomer of formula II, for example, less than 1% w / w of any other enantiomer of formula II.

[0080] 1.14 Composition 1 or any one of 1.1-1.13, wherein the compound has a stereochemical configuration as shown in Formula I. Or, composition 2 or any one of 1.1-1.13, wherein the compound has a stereochemical configuration as shown in Formula II.

[0081] 1.15 Composition 1 or any one of 1.1-1.14, wherein the composition comprises 1-60 mg of a Formula I compound in free or pharmaceutically acceptable salt form. For example, composition 1 or any one of 1.1-1.14, wherein the composition comprises 1-10 mg, for example, 1-9 mg (e.g., 1-8 mg) of a Formula I compound in free or pharmaceutically acceptable salt form. For example, composition 1 or any one of 1.1-1.14, wherein the composition comprises 3 mg or 10 mg of a Formula I compound in free or pharmaceutically acceptable salt form. For example, composition 1 or any one of 1.1-1.14, wherein the composition comprises 1 mg to less than 3 mg (e.g., 2 mg) of a Formula I compound in free or pharmaceutically acceptable salt form. Alternatively, composition 2 or any one of 1.1-1.14, wherein the composition comprises 1-60 mg of a Formula II compound in free or pharmaceutically acceptable salt form. For example, composition 2 or any one of 1.1-1.14, wherein the composition comprises 1-10 mg, for example, 1-9 mg (e.g., 1-8 mg) of a compound of formula II in free or pharmaceutically acceptable salt form. For example, composition 2 or any one of 1.1-1.14, wherein the composition comprises 3 mg or 10 mg of a compound of formula II in free or pharmaceutically acceptable salt form. For example, composition 2 or any one of 1.1-1.14, wherein the composition comprises 1 mg to less than 3 mg (e.g., 2 mg) of a compound of formula II in free or pharmaceutically acceptable salt form.

[0082] 1.16 Composition 1, Composition 2, or any one of 1.1-1.15, wherein the composition is for administration once, twice, or three times daily. For example, composition 1, composition 2, or any one of 1.1-1.15, wherein the composition is for administration once daily.

[0083] Further, methods are provided for the prevention or treatment of central nervous system disorders (e.g., brain disorders) in patients (e.g., humans) who benefit from the regulation of dopamine and / or serotonin transmission, wherein the method comprises administering to the patient a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula I above or 1.1-1.11), or a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula II above or 2.1-2.11), or a pharmaceutical composition comprising a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula 1.11 above or composition 1 or 1.1-1.16), or a pharmaceutical composition comprising a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula 2.11 above or composition 2 or 1.1-1.16). Further, a method is provided for the prevention or treatment of central nervous system disorders (e.g., brain disorders) in patients (e.g., humans) who benefit from D2 receptor antagonism, D3 receptor antagonism, D4 receptor antagonism, 5-HT1A receptor agonism (e.g., partial agonism of 5-HT1A receptors), and / or 5-HT2A receptor agonism, wherein the method comprises administering to the patient a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula I above or 1.1-1.11), or a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula II above or 2.1-2.11), or a pharmaceutical composition comprising a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula 1.11 above or composition 1 or 1.1-1.16), or a pharmaceutical composition comprising a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula 2.11 above or composition 2 or 1.1-1.16). For example, the following method is provided.

[0084] Further, a method for enhancing the neuroplasticity of a patient (e.g., a human) in need is provided, wherein the method comprises administering to the patient a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula I above or 1.1-1.11), or a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula II above or 2.1-2.11), or a pharmaceutical composition comprising a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula 1.11 above or composition 1 or 1.1-1.16), or a pharmaceutical composition comprising a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula 2.11 above or composition 2 or 1.1-1.16). For example, methods are provided to enhance neuroplasticity to improve the rehabilitation of patients with brain injuries (e.g., people) in need, such as improving rehabilitation after stroke or traumatic brain injury, wherein the method comprises administering to the patient a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula I above or 1.1-1.11), or a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula II above or 2.1-2.11), or a pharmaceutical composition comprising a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula 1.11 above or composition 1 or 1.1-1.16), or a pharmaceutical composition comprising a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula 2.11 above or composition 2 or 1.1-1.16).

[0085] A method (method 1) is provided for treating or preventing a condition (e.g., a brain condition) in a patient (e.g., a person) in need, wherein the method comprises administering an effective amount of a compound of formula I to the patient: Formula I, in: R1, R2, R3, R4, and R5 are independently selected from H and D; and At least one of R1, R2, R3, R4, and R5 is D; The compound is in free form or salt form.

[0086] A method (method 2) is also provided for treating or preventing a condition (e.g., a brain condition) in a patient (e.g., a person) in need, wherein the method comprises administering an effective amount of a compound of formula II to the patient: Formula II, in: R6, R7, and R8 are independently selected from H and D; and At least one of R6, R7 and R8 is D; The compound is in free form or salt form. The compound is substantially free of its (S,S) enantiomer.

[0087] The following methods 1 and 2 are further provided: 1.1 Method 1, wherein the method comprises administering to a patient a compound of formula I in free or pharmaceutically acceptable salt form, as described in Formula I above or any one of 1.1-1.11. For example, Method 1, wherein the method comprises administering to a patient a pharmaceutical composition comprising a compound of formula I in free or pharmaceutically acceptable salt form, as described in Formula 1.11 above or Composition 1 or any one of 1.1-1.16.

[0088] 1.2 Method 2, wherein the method comprises administering to a patient a compound of formula II in a free or pharmaceutically acceptable salt form, as described in Formula II above or any one of 2.1-2.11. For example, Method 2, wherein the method comprises administering to a patient a pharmaceutical composition comprising a compound of formula II in a free or pharmaceutically acceptable salt form, as described in Formula 2.11 above or Composition 2 or any one of 1.1-1.16.

[0089] 1.3 Method 1 or 1.1, wherein the effective amount of the stereoisomer of the Formula I compound in its free or pharmaceutically acceptable salt form has an excess value greater than 90%, for example, an excess value equal to or greater than 95%, for example, an excess value equal to or greater than 96%, for example, an excess value equal to or greater than 97%, for example, an excess value equal to or greater than 98%, for example, an excess value equal to or greater than 99%. For example, wherein the effective amount of the Formula I compound in its free or pharmaceutically acceptable salt form is substantially diastereomerically pure and / or enantiomerically pure, for example, wherein the effective amount of the Formula I compound in its free or pharmaceutically acceptable salt form is substantially diastereomerically pure and enantiomerically pure. For example, the excess of diastereomers and / or enantiomers of Formula I compound in the form of free or pharmaceutically acceptable salts is greater than 90%, for example, an excess of diastereomers and / or enantiomers equal to or greater than 95%, an excess of diastereomers and / or enantiomers equal to or greater than 96%, an excess of diastereomers and / or enantiomers equal to or greater than 97%, for example, an excess of diastereomers and / or enantiomers equal to or greater than 98%, for example, an excess of diastereomers and / or enantiomers equal to or greater than 99%. For example, the excess of diastereomers and enantiomers of Formula I compound in the form of free or pharmaceutically acceptable salts is greater than 90%, for example, the excess of diastereomers and enantiomers is equal to or greater than 95%, for example, the excess of diastereomers and enantiomers is equal to or greater than 96%, for example, the excess of diastereomers and enantiomers is equal to or greater than 97%, for example, the excess of diastereomers and enantiomers is equal to or greater than 98%, for example, the excess of diastereomers and enantiomers is equal to or greater than 99%.

[0090] 1.4 Method 2 or 1.2, wherein the effective amount of the stereoisomer of the compound of formula II in its free or pharmaceutically acceptable salt form has an excess value greater than 90%, for example, an excess value equal to or greater than 95%, for example, an excess value equal to or greater than 96%, for example, an excess value equal to or greater than 97%, for example, an excess value equal to or greater than 98%, for example, an excess value equal to or greater than 99%. For example, wherein the effective amount of the compound of formula II in its free or pharmaceutically acceptable salt form is substantially diastereomerically pure and / or enantiomerically pure, for example, wherein the effective amount of the compound of formula II in its free or pharmaceutically acceptable salt form is substantially diastereomerically pure and enantiomerically pure. For example, the excess of diastereomers and / or enantiomers of the effective amount of the compound of formula II in the form of a free or pharmaceutically acceptable salt is greater than 90%, for example, the excess of diastereomers and / or enantiomers is equal to or greater than 95%, the excess of diastereomers and / or enantiomers is equal to or greater than 96%, the excess of diastereomers and / or enantiomers is equal to or greater than 97%, for example, the excess of diastereomers and / or enantiomers is equal to or greater than 98%, for example, the excess of diastereomers and / or enantiomers is equal to or greater than 99%. For example, the excess of diastereomers and enantiomers of the effective amount of the compound of formula II in the form of free or pharmaceutically acceptable salts is greater than 90%, for example, the excess of diastereomers and enantiomers is equal to or greater than 95%, for example, the excess of diastereomers and enantiomers is equal to or greater than 96%, for example, the excess of diastereomers and enantiomers is equal to or greater than 97%, for example, the excess of diastereomers and enantiomers is equal to or greater than 98%, for example, the excess of diastereomers and enantiomers is equal to or greater than 99%.

[0091] 1.5 Method 1, 2 or any one of 1.1-1.4, wherein the compound is in free form.

[0092] 1.6 Any one of methods 1, 1.1, 1.3, or 1.5, wherein the method comprises administering an effective amount of compound A: Compound A, The compound is in a free or pharmaceutically acceptable salt form, for example, in a free form.

[0093] 1.7 Method 1.6, wherein the effective amount of compound A in its free or pharmaceutically acceptable salt form has a stereoisomer excess value greater than 90%, for example, a stereoisomer excess value equal to or greater than 95%, for example, a stereoisomer excess value equal to or greater than 96%, for example, a stereoisomer excess value equal to or greater than 97%, for example, a stereoisomer excess value equal to or greater than 98%, for example, a stereoisomer excess value equal to or greater than 99%. For example, wherein the effective amount of compound A in its free or pharmaceutically acceptable salt form is substantially diastereomerically pure and / or enantiomerically pure, for example, wherein the effective amount of compound A in its free or pharmaceutically acceptable salt form is substantially diastereomerically pure and enantiomerically pure. For example, the excess of an effective amount of compound A in its free or pharmaceutically acceptable salt form, including diastereomers and / or enantiomers, is greater than 90%, for example, equal to or greater than 95%, for example, equal to or greater than 96%, for example, equal to or greater than 97%, for example, equal to or greater than 98%, for example, equal to or greater than 99%. For example, the excess of diastereomers and enantiomers of compound A in the form of free or pharmaceutically acceptable salts is greater than 90%, for example, the excess of diastereomers and enantiomers is equal to or greater than 95%, for example, the excess of diastereomers and enantiomers is equal to or greater than 96%, for example, the excess of diastereomers and enantiomers is equal to or greater than 97%, for example, the excess of diastereomers and enantiomers is equal to or greater than 98%, for example, the excess of diastereomers and enantiomers is equal to or greater than 99%.

[0094] 1.8 Any one of method 2, 1.2, 1.4 or 1.5, wherein the method comprises administering an effective amount of compound B: Compound B, The compound is in a free or pharmaceutically acceptable salt form, for example, in a free form.

[0095] 1.9 Method 1.8, wherein the effective amount of compound B in its free or pharmaceutically acceptable salt form has a stereoisomer excess value greater than 90%, for example, a stereoisomer excess value equal to or greater than 95%, for example, a stereoisomer excess value equal to or greater than 96%, for example, a stereoisomer excess value equal to or greater than 97%, for example, a stereoisomer excess value equal to or greater than 98%, for example, a stereoisomer excess value equal to or greater than 99%. For example, wherein the effective amount of compound B in its free or pharmaceutically acceptable salt form is substantially diastereomerically pure and / or enantiomerically pure, for example, wherein the effective amount of compound B in its free or pharmaceutically acceptable salt form is substantially diastereomerically pure and enantiomerically pure. For example, the excess of an effective amount of compound B in its free or pharmaceutically acceptable salt form, including diastereomers and / or enantiomers, is greater than 90%, for example, equal to or greater than 95%, for example, equal to or greater than 96%, for example, equal to or greater than 97%, for example, equal to or greater than 98%, for example, equal to or greater than 99%. For example, the excess of diastereomers and enantiomers of compound B in the form of free or pharmaceutically acceptable salts is greater than 90%, for example, the excess of diastereomers and enantiomers is equal to or greater than 95%, for example, the excess of diastereomers and enantiomers is equal to or greater than 96%, for example, the excess of diastereomers and enantiomers is equal to or greater than 97%, for example, the excess of diastereomers and enantiomers is equal to or greater than 98%, for example, the excess of diastereomers and enantiomers is equal to or greater than 99%.

[0096] 1.10 Method 1, 2, or any of 1.1-1.9, wherein a deuterium (i.e., D) label at a position indicates that the deuterium abundance at that position is significantly greater than the natural abundance 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 labeled as a specific isotope exists at its natural isotopic abundance.

[0097] 1.11 Method 1, 2, or any one of 1.1-1.10, wherein an effective amount of the compound in its free or pharmaceutically acceptable salt form has a deuterium (i.e., D) incorporation greater than 50% at one or more positions labeled as deuterium (i.e., D) (e.g., at all positions), for example, 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 example, Method 1, 2, or any one of 1.1-1.10, wherein an effective amount of the compound in its free or pharmaceutically acceptable salt form has a deuterium (i.e., D) incorporation greater than 50% at each position labeled as deuterium (i.e., D), for example, 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%.

[0098] 1.12 Method 1, 2, or any one of 1.1-1.11, wherein the condition is a brain condition. For example, Method 1, 2, or any one of 1.1-1.11, wherein the condition is a neuropsychiatric disorder characterized primarily by anhedonia.

[0099] 1.13 Method 1, 2 or any one of 1.1-1.12, wherein the condition is an affective (emotional) disorder or an anxiety disorder.

[0100] 1.14 Method 1, 2, or any one of 1.1-1.13, wherein the condition is depression (e.g., depression associated with anhedonia), anxiety disorder, psychosis (e.g., psychosis in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, or psychosis in 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, bulimia disorder, body dysmorphic disorder, obsessive-compulsive disorder, addiction, bipolar disorder (including bipolar depression, bipolar mania, and bipolar disorder with mixed features), or migraine. For example, Method 1, 2, or any one of 1.1-1.13, wherein the anxiety disorder is panic disorder, social anxiety disorder, phobia, or generalized anxiety disorder. Alternatively, any of methods 1, 2, or 1.1-1.13, wherein the method is used to prevent or treat behavioral and psychological symptoms of dementia, including agitation, depression, anxiety, apathy, and / or psychosis. For example, any of methods 1, 2, or 1.1-1.13, wherein the method is used to prevent or treat post-traumatic stress disorder (PTSD), such as treating post-traumatic stress disorder (PTSD).

[0101] 1.15 Method 1, 2, or any one of 1.1-1.14, wherein the condition is anhedonia or anhedonia-related depression, suicidal ideation, anxiety depression, inflammatory depression, treatment-resistant depression, dysphoric depression, bipolar depression, psychotic depression, or post-psychotic depression. For example, Method 1, 2, or any one of 1.1-1.14, wherein the condition is anxiety depression. Or, for example, Method 1, 2, or any one of 1.1-1.14, wherein the condition is melancholic depression.

[0102] 1.16 Method 1, 2 or any one of 1.1-1.15, wherein the condition described is major depressive disorder.

[0103] 1.17 Method 1, 2 or any one of 1.1-1.14, wherein the condition is a substance use disorder.

[0104] 1.18 Method 1, 2, or any one of 1.1-1.14, wherein the method is used to prevent or treat negative symptoms of schizophrenia. Alternatively, Method 1, 2, or any one of 1.1-1.14, wherein the method is used to improve cognition in schizophrenia.

[0105] 1.19 Method 1, 2, or any one of 1.1-1.14, wherein the method is used to improve cognition, for example, to improve cognitive impairment, such as cognitive impairment in schizophrenia, depression, or dementia. For example, Method 1, 2, or any one of 1.1-1.14, wherein the method is used to improve cognition in major depressive disorder.

[0106] 1.20 The compound, in the form of a free or pharmaceutically acceptable salt, is administered as an antiemetic.

[0107] 1.21 Method 1, 2, or any one of 1.1-1.20, wherein the method comprises administering 9-60 mg of the compound in its free or pharmaceutically acceptable salt form daily (i.e., a total daily dose of 9-60 mg of the compound in its free or pharmaceutically acceptable salt form). For example, Method 1, 2, or any one of 1.1-1.20, wherein the method comprises administering 9-36 mg of the compound in its free or pharmaceutically acceptable salt form daily (i.e., a total daily dose of 9-36 mg of the compound in its free or pharmaceutically acceptable salt form).

[0108] 1.22 Method 1, 2, or any one of 1.1-1.21, wherein the method comprises administering an amount of a compound in a free or pharmaceutically acceptable salt form, the compound providing 55%-80% D2 / D3 receptor occupancy, for example, as measured by positron emission tomography. For example, wherein the method comprises administering an amount of a compound in a free or pharmaceutically acceptable salt form, the compound providing approximately 65% ​​D2 / D3 receptor occupancy, for example, as measured by positron emission tomography. Or, for example, wherein the method comprises administering an amount of a compound in a free or pharmaceutically acceptable salt form, the compound providing approximately 60% D2 / D3 receptor occupancy, for example, as measured by positron emission tomography.

[0109] 1.23 Method 1.21 or 1.22, wherein the condition is a psychosis (e.g., a 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).

[0110] 1.24 Method 1.21 or 1.22, wherein the method is used to prevent or treat negative symptoms of schizophrenia. Alternatively, method 1.21 or 1.22, wherein the method is used to improve cognition in schizophrenia.

[0111] 1.25 Method 1, 2, or any one of 1.1-1.20, wherein the method comprises administering 1-9 mg (e.g., 1-8 mg, e.g., 1.5-6 mg) of a compound in free or pharmaceutically acceptable salt form daily (i.e., a total daily dose of 1-9 mg, e.g., a total daily dose of 1-8 mg, e.g., a total daily dose of 1.5-6 mg of a compound in free or pharmaceutically acceptable salt form). For example, any one of Method 1, 2, or 1.1-1.20, wherein the method comprises administering 1-8 mg of a compound in free or pharmaceutically acceptable salt form daily (i.e., a total daily dose of 1-8 mg of a compound in free or pharmaceutically acceptable salt form). For example, any one of Method 1, 2, or 1.1-1.20, wherein the method comprises administering 1-3 mg of a compound in free or pharmaceutically acceptable salt form daily (i.e., a total daily dose of 1-3 mg of a compound in free or pharmaceutically acceptable salt form). For example, any one of methods 1, 2 or 1.1-1.20, wherein the method comprises administering 1 mg to less than 3 mg (e.g., 2 mg daily) of a compound in free or pharmaceutically acceptable salt form (i.e., a total daily dose of 1 mg to less than 3 mg of a compound in free or pharmaceutically acceptable salt form).

[0112] 1.26 Any one of methods 1, 2, 1.1-1.20 or 1.25, wherein the method comprises administering an amount of a compound in a free or pharmaceutically acceptable salt form, the compound providing a D2 / D3 receptor occupancy of 10%-60% (e.g., 40%-60%, or e.g., 10%-55%, 10%-50%, 30%-50%, or 15%-50%, 15%-45%, 20%-40%, 10%-30%), e.g., as measured by positron emission tomography. Alternatively, for example, any one of methods 1, 2, 1.1-1.20 or 1.25, wherein the method comprises administering an amount of a compound in a free or pharmaceutically acceptable salt form, the compound providing a D2 / D3 receptor occupancy of ≤40% (e.g., about 40%), e.g., <40%, as measured by positron emission tomography.

[0113] 1.27 Method 1.25 or 1.26, wherein the condition is depression (e.g., anhedonia-related depression), 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, mixed-feature bipolar disorder, or migraine. For example, Method 1.25 or 1.26, wherein the anxiety disorder is panic disorder, social anxiety disorder, phobia, or generalized anxiety disorder. Or, for example, Method 1.25 or 1.26, wherein the condition is post-traumatic stress disorder.

[0114] 1.28 Any one of methods 1.25-1.27, wherein the condition is anhedonia or anhedonia-related depression, suicidal ideation, anxiety depression, inflammatory depression, treatment-resistant depression, dysphoric depression, bipolar depression, psychotic depression, or post-psychotic depression. For example, the condition described is anxiety depression.

[0115] 1.29 Any one of methods 1.25-1.28, wherein the condition described is major depressive disorder.

[0116] Method 1.30, or 1.25 or 1.26, wherein the condition described is a substance use disorder.

[0117] 1.31 Any of method 1, 2, or 1.1-1.30, wherein the method comprises administering a pharmaceutical composition comprising a compound in free or pharmaceutically acceptable salt form. For example, any of method 1, 2, or 1.1-1.30, wherein the method comprises administering a compound of formula 1.11 or 2.11, or any of composition 1, 2, or 1.1-1.16.

[0118] 1.32 Method 1, 2, or any one of 1.1-1.31, wherein the method comprises administering a compound of formula I in its free or pharmaceutically acceptable salt form, or a compound of formula II in its free or pharmaceutically acceptable salt form, once, twice, or three times daily, for example, once daily. For example, Method 1, 2, or any one of 1.1-1.31, wherein the method comprises administering a pharmaceutical composition comprising a compound of formula I in its free or pharmaceutically acceptable salt form, or a pharmaceutical composition comprising a compound of formula II in its free or pharmaceutically acceptable salt form, once, twice, or three times daily, for example, once daily.

[0119] 1.33 Method 1, 2 or any one of 1.1-1.32, wherein the method comprises administering compound A or compound B in free or pharmaceutically acceptable salt form once, twice or three times daily, for example once daily.

[0120] 1.34 also provides methods 1, 2, or any one of 1.1-1.33 to promote or enhance neuroplasticity in a patient (e.g., a person) in need, wherein the method comprises administering to the patient a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula I above or 1.1-1.11), or a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula II above or 2.1-2.11), or a pharmaceutical composition comprising a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula 1.11 above or composition 1 or 1.1-1.16), or a pharmaceutical composition comprising a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula 2.11 above or composition 2 or 1.1-1.16). For example, methods are provided to promote or enhance neuroplasticity to improve the rehabilitation of patients with brain injuries (e.g., people) in need, such as improving rehabilitation after stroke or traumatic brain injury, wherein the method comprises administering to the patient a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula I above or 1.1-1.11), or a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula II above or 2.1-2.11), or a pharmaceutical composition comprising a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula 1.11 above or composition 1 or 1.1-1.16), or a pharmaceutical composition comprising a compound of formula II in a free or pharmaceutically acceptable salt form (e.g., any one of formula 2.11 above or composition 2 or 1.1-1.16).

[0121] Further, a compound of formula I (e.g., any one of formulas 1.1-1.11) or a pharmaceutical composition disclosed herein (e.g., formula 1.11 or composition 1 or any one of 1.1-1.16) is provided for use in method 1 or any one of 1.1-1.34 described above.

[0122] Further provided is a compound of formula II (e.g., any one of formulas 2.1-2.11) or a pharmaceutical composition disclosed herein (e.g., formula 2.11 or composition 2 or any one of 1.1-1.15) for use in method 2 above or any one of 1.1-1.34.

[0123] Further, the use of a compound of formula I (e.g., any one of formulas 1.1-1.11) or a pharmaceutical composition disclosed herein (e.g., formula 1.11 or composition 1 or any one of 1.1-1.16) in any one of methods 1 or 1.1-1.34 above is provided.

[0124] Further, the use of a compound of formula II (e.g., any one of formulas 2.1-2.11) or a pharmaceutical composition disclosed herein (e.g., formula 2.11 or composition 2 or any one of 1.1-1.16) in any one of the preceding methods 2 or 1.1-1.34 is provided.

[0125] Further, the use of a compound of formula I (e.g., any one of formulas 1.1-1.11) in the preparation of a medicament (e.g., formula 1.11 or composition 1 or any one of 1.1-1.16) for use in methods 1 or 1.1-1.34 described above.

[0126] Further, the use of a compound of formula II (e.g., any one of formulas 2.1-2.11) in the preparation of a medicament (e.g., formula 2.11 or composition 2 or any one of 1.1-1.16) for use in method 2 or any one of 1.1-1.34 described above.

[0127] Further intermediate compounds of formulas III and IV are provided, each in free form or in salt form (e.g., pharmaceutically acceptable salt).

[0128] For example, a compound of formula III is further provided: Formula III, in: R 31 R 32 R 33 R 34 and R 35 Independently selected from H and D; and R 31 R 32 R33 R 34 and R 35 At least one of them is D; The compound is in free form or salt form.

[0129] Further, the following compound of formula III is provided: 3.1 Formula III, wherein the compound is in a pharmaceutically acceptable salt form.

[0130] 3.2 Equation III or 3.1, where R 31 R 32 R 33 R 34 and R 35 Each is D.

[0131] 3.3 Formula III, 3.1, or 3.2, wherein the compound is: , It exists in free or salt form (e.g., a pharmaceutically acceptable salt), for example, in free form.

[0132] Furthermore, a compound of formula IV is provided: Formula IV, in: X is OH or a leaving group; PG is an H or amine protecting group (e.g., an ester that forms a carbamate with the attached nitrogen, such as tert-butoxycarbonyl or benzyloxycarbonyl, such as tert-butoxycarbonyl); R 36 R 37 and R 38 Independently selected from H and D; and R 36 R 37 and R 38 At least one of them is D; The compound is in free form or salt form.

[0133] Further, compounds of formula IV are provided: 4.1 Formula IV, wherein the compound is in a pharmaceutically acceptable salt form.

[0134] 4.2 Equation IV or 4.1, where R 36 R 37 and R 38 Each is D.

[0135] 4.3 Formula IV, 4.1, or 4.2, wherein the compound is: , It exists in free or salt form (e.g., a pharmaceutically acceptable salt), for example, in free form.

[0136] 4.4 Formula IV or any one of 4.1-4.3, wherein the compound is: , It exists in free or salt form (e.g., a pharmaceutically acceptable salt), for example, in free form.

[0137] 4.5 Equation IV or any one of 4.1-4.4, where X is OH.

[0138] 4.6 Formula IV or any one of 4.1-4.4, wherein X is a leaving group (e.g., an activated ester, such as an O-acylisourea, or a halide). For example, any one of Formula IV or 4.1-4.4, wherein the compound is: .

[0139] A method (method 1) is further provided for synthesizing a compound of formula I (e.g., any one of formulas 1.1-1.11) in its free form or in the form of a salt (e.g., a pharmaceutically acceptable salt).

[0140] The following method 1 is further provided: 1.1 Method 1, wherein the method comprises reacting a compound of formula III (e.g., any one of formulas 3.1-3.3) with a compound of formula V: Formula V, in: Y is an H or amine protecting group (e.g., an ester that forms a carbamate with the attached nitrogen, such as tert-butoxycarbonyl or benzyloxycarbonyl, such as tert-butoxycarbonyl), and Z is OH or a leaving group. The compound is in free form or in a pharmaceutically acceptable salt form.

[0141] 1.2 Method 1 or 1.1, where Y is H.

[0142] 1.3 Method 1 or 1.1, wherein Y is an amine protecting group. For example, Method 1 or 1.1, wherein Y is a tert-butyloxycarbonyl group.

[0143] 1.4 Method 1 or any one of 1.1-1.3, where Z is OH.

[0144] 1.5 Method 1 or any one of 1.1-1.4, wherein compound V is: , It exists in free or salt form (e.g., a pharmaceutically acceptable salt), for example, in free form.

[0145] 1.6 Method 1 or any one of 1.1-1.3, wherein Z is a leaving group (e.g., an activated ester, such as an O-acylisourea, or a halide).

[0146] 1.7 Any one of Method 1, 1.1-1.3, or 1.6, wherein compound V is: .

[0147] 1.8 Method 1 or any one of 1.1-1.7, wherein the method is carried out in the presence of an amine (e.g., triethylamine, such as triethylamine and dimethylformamide or dimethylacetamide).

[0148] 1.9 Method 1 or any one of 1.1-1.8, wherein the method is carried out in an organic solvent (e.g., triethylamine and dimethylacetamide).

[0149] 1.10 Method 1 or any one of 1.1-1.9, wherein the method is carried out using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and hydroxybenzotriazole. For example, any one of the methods, wherein the method is carried out using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydroxybenzotriazole, triethylamine, and dimethylacetamide or dimethylformamide.

[0150] 1.11 Method 1 or any one of 1.1-1.10, wherein the method comprises making the following compound: Reaction with activators (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), Optionally, the product is formed in situ.

[0151] 1.12 Method 1 or any one of 1.1-1.11, wherein the method further comprises removing the amine protecting group, for example under acidic or basic conditions, such as optionally in ethyl acetate with hydrochloric acid.

[0152] 1.13 Method 1 or any one of 1.1-1.12, wherein the method further comprises isolating the compound of formula I in free form or in the form of a salt (e.g., a pharmaceutically acceptable salt) (e.g., any one of formulas 1.1-1.11).

[0153] A method (method 2) is further provided for synthesizing a compound of formula II (e.g., any one of formulas 2.1-2.11) in its free form or in the form of a salt (e.g., a pharmaceutically acceptable salt).

[0154] The following method 2 is further provided: 2.1 Method 2, wherein the method comprises reacting a compound of formula IV (e.g., any one of formulas 4.1-4.6) with the following compounds: .

[0155] 2.2 Method 2 or 2.1, wherein the method is carried out in the presence of an amine (e.g., triethylamine, such as triethylamine and dimethylformamide or dimethylacetamide).

[0156] 2.3 Method 2, 2.1 or 2.2, wherein the method is carried out in an organic solvent (e.g., triethylamine and dimethylacetamide).

[0157] 2.4 Method 1 or any one of 2.1-2.3, wherein the method is carried out using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and hydroxybenzotriazole. For example, any one of the methods, wherein the method is carried out using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydroxybenzotriazole, triethylamine, and dimethylacetamide or dimethylformamide.

[0158] 2.5 Method 2 or any one of 2.1-2.4, wherein the method comprises preparing the following compound: Reaction with activators (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), Optionally, the product is formed in situ.

[0159] 2.6 Method 2 or any one of 2.1-2.5, wherein the method further comprises removing the amine protecting group, for example under acidic or basic conditions, such as optionally in ethyl acetate with hydrochloric acid.

[0160] 2.7 Method 2 or any one of 2.1-2.6, wherein the method further comprises isolating the compound of formula II in free form or in the form of a salt (e.g., a pharmaceutically acceptable salt) (e.g., any one of formulas 2.1-2.11).

[0161] For the compounds disclosed herein, a hydrogen atom position in the structure is considered to be deuterated when the deuterium abundance is enriched at that position. The natural abundance of deuterium is approximately 0.02%, therefore, when the deuterium doping frequency at a specific position exceeds 0.02%, the compound is considered "enriched" at that position. Thus, for the deuterated compounds disclosed herein, the deuterium enrichment level at any position labeled as deuterium (i.e., D) can be 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 the compounds disclosed herein, any atom not labeled with a specific isotope exists at its natural isotopic abundance.

[0162] The compounds disclosed herein, such as any one of Formulas I (e.g., any one of Formulas 1.1-1.11), II (e.g., any one of Formulas 2.1-2.11), III (e.g., any one of Formulas 3.1-3.3), IV (e.g., any one of Formulas 4.1-4.6), V, compound A, and compound B, may exist in free or salt form, for example, as an acid addition salt. As used herein, unless otherwise stated, language such as “compound of formula…” should be understood to include the compound in any form, such as in free or acid addition salt form, or, when the compound contains an acidic substituent, in a base addition salt form. Formulas I (e.g., any one of Formulas 1.1-1.11), II (e.g., any one of Formulas 2.1-2.11), compound A, and compound B are intended for use as pharmaceuticals, and therefore pharmaceutically acceptable salts are preferred. Salts unsuitable for pharmaceutical use may be used, for example, to isolate or purify free compounds of formula I or II, or their pharmaceutically acceptable salts, and are therefore included.

[0163] The separation or purification of any of the compounds disclosed herein in free or pharmaceutically acceptable salt form, such as Formula I (e.g., any one of Formulas 1.1-1.11), Formula II (e.g., any one of Formulas 2.1-2.11), Formula III (e.g., any one of Formulas 3.1-3.3), Formula IV (e.g., any one of Formulas 4.1-4.6), Formula V, Compound A, and Compound B, of their stereoisomers can be achieved by conventional methods known in the art, such as column purification, preparative thin-layer chromatography, preparative HPLC, grinding, simulated moving bed methods, etc.

[0164] The pure stereoisomers of the compounds and intermediates disclosed herein are isomers of other enantiomers and diastereomers that substantially lack the same basic molecular structure of the compound or intermediate. "Substantially stereoisomerically pure" includes compounds or intermediates with a stereoisomer excess greater than 90% (i.e., more than 90% of one stereoisomer and less than 10% of any other possible stereoisomers). The terms "substantially diastereomerically pure" and "substantially enantiomerically pure" should be understood in a similar manner, but with separate consideration for diastereomer and enantiomer excesses of the substance.

[0165] Compounds disclosed herein in free or pharmaceutically acceptable salt form, such as any of Formula I (e.g., any one of Formulas 1.1-1.11), Formula II (e.g., any one of Formulas 2.1-2.11), Formula III (e.g., any one of Formulas 3.1-3.3), Formula IV (e.g., any one of Formulas 4.1-4.6), Formula V, Compound A, and Compound B, can be prepared using the methods described and illustrated herein, similar methods, and methods known in the field of chemistry. Such methods include, but are not limited to, those described below. If no commercially available product is available, the starting materials for these methods can be prepared using techniques similar to or close to the synthesis of known compounds, selected from methods in the field of chemistry.

[0166] Pharmaceutically acceptable salts of Formula I (e.g., any one of Formulas 1.1-1.11), Formula II (e.g., any one of Formulas 2.1-2.11), Formula III (e.g., any one of Formulas 3.1-3.3), Formula IV (e.g., any one of Formulas 4.1-4.6), Formula V, Compound A, and Compound B can be synthesized by conventional chemical methods from parent compounds containing basic or acidic groups. Generally, such salts can be prepared by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid in a suitable solvent.

[0167] For treatment methods, the term "effective amount" is intended to cover the effective amount of treatment used to treat a specific disease or disorder.

[0168] Of course, the dosage used in implementing this invention will vary depending on, for example, the specific disease or condition to be treated, the specific compound used, the method of administration, and the desired therapy.

[0169] The compounds disclosed herein, in free or pharmaceutically acceptable salt form, such as any one of Formula I (e.g., any one of Formulas 1.1-1.11), Formula II (e.g., any one of Formulas 2.1-2.11), Compound A, and Compound B, may be administered by any suitable route, including oral, parenteral, or transdermal, but oral administration is preferred.

[0170] Pharmaceutical compositions comprising any of the compounds disclosed herein in free or pharmaceutically acceptable salt form (e.g., any of Formula I (e.g., any of Formulas 1.1-1.11 or Composition 1 or 1.1-1.16), any of Formula II (e.g., any of Formulas 2.1-2.11 or Composition 2 or 1.1-1.16), compound A, or compound B) can be prepared using conventional diluents or excipients and techniques known in the pharmaceutical field. Therefore, oral dosage forms may include tablets, capsules, solutions, suspensions, etc.

[0171] As used herein, the term "patient" includes both human and non-human (i.e., animal) individuals. In some implementations, the patient is a human.

[0172] Example abbreviation AcOH = Acetic acid Boc = tert-Butoxycarbonyl DIAD = diisopropyl azodicarbonate DCM = dichloromethane DMA or DMAc = dimethylacetamide DMAP = 4-Dimethylaminopyridine DMF = dimethylformamide EDCI = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc or EA = Ethyl acetate h = hours HOBt = Hydroxybenzotriazole MeOH = Methanol min = minutes MsCl = Methanesulfonyl chloride rt (or RT or rt) = room temperature TEA = Triethylamine TFA = Trifluoroacetic acid THF = Tetrahydrofuran Example 1 Synthesis of 5-chloro- N -((2 R ,3 R )-1-((pentadeuterated phenyl)methyl)-2-methylpyrrolidone-3-yl)-2-methoxy-4-(methylamino)benzamide Step 1 Et3N (12.7 g, 125 mmol) was added to a solution of 1 (8.0 g, 27.9 mmol) and benzoyl chloride-d5 (5.56 g, 38.2 mmol) in dichloromethane (160 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete, the reaction mixture was washed with water (90 mL × 2) and concentrated to give 2 (8.75 g crude product) as a white solid.

[0173] Step 2 Sodium hydroxide (1.14 g, 28.38 mmol) was added to a stirred methanol / water (43 mL / 43 mL) solution of 2. The reaction mixture was stirred for 2 hours, followed by concentration under reduced pressure. The residue was diluted with water (60 mL) and extracted with dichloromethane (60 mL × 5). The organic phase was concentrated to give 3 (4.7 g, crude product) as a white solid.

[0174] Step 3 Under a nitrogen atmosphere, at 0–10 °C, a solution of 3 (4.7 g, 22.35 mmol) in anhydrous tetrahydrofuran (47 mL) was added dropwise to a stirred solution of LiAlH4 (2.1 g, 55.88 mmol) in anhydrous tetrahydrofuran (47 mL). After stirring at 0–10 °C for 45 minutes, the reaction mixture was brought to room temperature and stirred at this temperature for more than 16 hours. After the reaction was complete, the reaction mixture was cooled to 0 °C and quenched successively with 20% potassium hydroxide aqueous solution (3.3 mL) and water (6.6 mL). The suspension was extracted with dichloromethane (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 4 (5.0 g, crude product), a yellow oil.

[0175] Step 4 At 0 °C, methanesulfonyl chloride (4.4 g, 38.21 mmol) was added to a solution of compound 4 (5.0 g, 25.47 mmol) and triethylamine (5.15 g, 50.94 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 3 hours, then quenched with saturated NaHCO3 aqueous solution (50 mL × 2), and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic phases were washed with brine (50 mL). The organic phase was concentrated under reduced pressure to give compound 5 (6.3 g, crude), a yellow oil.

[0176] Step 5 Sodium azide (4.5 g, 68.9 mmol) was added to a stirred solution of compound 5 (6.3 g, 22.96 mmol) in 63 mL of DMF at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (70 mL × 2). The organic phase was washed with brine (60 mL). The organic phase was concentrated, and then methanol (60 mL × 2) was added and concentrated to approximately 60 mL. The methanol solution of compound 6 was used directly in the next step of the reaction.

[0177] Step 6 A mixture of 6 and 10% palladium on carbon (0.6 g) in methanol (60 mL) was stirred for 24 hours at room temperature under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered, the solvent was evaporated, and the residue was diluted with ethyl acetate (10 mL). An ethyl acetate solution of HCl (4 mol / L in ethyl acetate, 6 mL, 24 mmol) was added to this solution, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered to give 7 (0.7 g) as a yellow solid.

[0178] Step 7 Compound 8 (500 mg, 1.6 mmol) was added to a solution of Et3N (320 mg, 3.17 mmol) and DMA (10 mL) under stirring, along with compound 7 (371 mg, 1.9 mmol), HOBt (321 mg, 2.4 mmol), and EDCI (454 mg, 2.4 mmol). The mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 3), washed with brine (50 mL × 1), and dried over anhydrous sodium sulfate. The organic phase was concentrated to give compound 9 (700 mg, 90% yield) as a brown oil.

[0179] Step 8 Compound 9 (700 mg, 1.4 mmol) was dissolved in an ethyl acetate solution of HCl (4 mol / L in ethyl acetate, 10 mL, 40.0 mmol), and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (25 mL) and extracted with water (25 mL × 2). The combined aqueous phases were alkalized to pH 11 with sodium hydroxide, extracted with ethyl acetate (25 mL × 3), and the combined organic phases were washed with brine (25 mL × 1) and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by column chromatography (40 g silica gel; eluent: 0-100% ethyl acetate in n-hexane) to give compound 10 (370 mg, 65% yield) as a light gray solid. 1 H NMR (400 MHz, DMSO- d 6) δ 7.93 (d, J = 8.8 Hz, 1H), 7.74(s, 1H), 6.26 (s, 1H), 6.14–6.06 (m, 1H), 4.48– 4.37 (m, 1H), 3.98 (s, 3H), 3.95 (s, 1H), 3.18 (d, J = 13.2 Hz, 1H), 2.85 (d, J = 4.8 Hz, 3H), 2.81–2.79 (m,1H), 2.64–2.53 (m, 1H), 2.16–2.04 (m, 2H), 1.57–1.48 (m, 1H), 1.00 (d, J = 6.3Hz, 3H). Calculated LC-MS (ESI) m / z value C 21 H 21 D5ClN3O2 (M+H) + 392.9, measured value 393.3.

[0180] Example 2 Synthesis: 5-chloro- N -((2 R ,3 R 1-((phenyl)methyl)-2-methylpyrrolidone-3-yl)-2-trideuterated methoxy-4-(methylamino)benzamide Step 1 Under nitrogen protection, a solution of 50 mL of anhydrous tetrahydrofuran containing compound 11 (5.0 g, 24.36 mmol) was added dropwise to a solution of 50 mL of anhydrous tetrahydrofuran containing LiAlH4 (1.58 g, 41.41 mmol) under stirring at 0–10 °C. After stirring at 0–10 °C for 45 minutes, the reaction mixture was brought to room temperature and stirred at this temperature for more than 16 hours. After the reaction was complete, the reaction mixture was cooled to 0 °C and quenched successively with 2.7 mL of 20% potassium hydroxide aqueous solution and 5.4 mL of water. The suspension was extracted with dichloromethane (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 12 (5.1 g crude product, 100% yield) as a yellow oil.

[0181] Step 2 At 0 °C, methanesulfonyl chloride (3.7 g, 52.3 mmol) was added to a solution of dichloromethane (51 mL) containing compound 12 (5.1 g, 26.7 mmol) and Et3N (5.4 g, 53.4 mmol) under stirring. The reaction mixture was stirred at room temperature for 3 hours, then quenched with saturated NaHCO3 aqueous solution (50 mL × 2), and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic phases were washed with brine (50 mL). The organic phase was concentrated under reduced pressure to give compound 13 (7.0 g, crude product) as a yellow oil.

[0182] Step 3 Sodium azide (5.1 g, 78 mmol) was added to a DMF (70 mL) solution of compound 13 (7.0 g, 26 mmol) under stirring at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (70 mL × 2). The organic phase was washed with brine (70 mL). The organic phase was concentrated to approximately 1 L, and then methanol (70 mL × 2) was added and concentrated to approximately 70 mL. The methanol solution of compound 14 was used directly in the next reaction step.

[0183] Step 4 A mixture of 14% and 10% Pd / C (0.7 g) was dissolved in MeOH (70 mL) and stirred for 24 hours at room temperature under a hydrogen atmosphere (at normal pressure). The reaction mixture was filtered, the solvent was evaporated, and then diluted with EtOAc (70 mL). HCl (4 mol / L EtOAc solution) (6 mL, 24 mmol) was added to the solution. The reaction mixture was stirred for 1 hour at room temperature and then filtered to give 15% (1.92 g) as a yellow solid.

[0184] Step 5 To a solution of 16 (433 mg, 1.3 mmol) under stirring, 15 (308 mg, 1.6 mmol), HOBt (273 mg, 2.0 mmol), and EDCI (387 mg, 2.02 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), washed with brine (50 mL × 1), and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by column chromatography (silica gel, 40 g; 0–10% methanol / dichloromethane) to give 17 (450 mg, 71% yield) as a brown oil.

[0185] Step 6 Add HCl solution (4 mol / L, in ethyl acetate) (10 mL, 40.0 mmol) to the stirred 17 (450 mg, 0.9 mmol). Stir the reaction mixture at room temperature for 2 hours. Concentrate the reaction mixture, dilute the residue with ethyl acetate (25 mL), and extract with water (25 mL × 2). Combine the aqueous phases, alkalinize to pH approximately 11 with sodium hydroxide, extract with ethyl acetate (25 mL × 3), wash the combined organic phases with brine (25 mL × 1), and dry with anhydrous sodium sulfate. Concentrate the organic phase, and purify the residue by column chromatography (silica gel, 40 g; 0-100% ethyl acetate / hexane) to give 18 (210 mg, 58% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 7.94 (d, J= 8.8 Hz, 1H), 7.74 (s, 1H),7.37–7.29 (m, 4H), 7.27–7.21 (m, 1H), 6.25 (s, 1H), 6.17–6.05 (m, 1H), 4.49–4.35 (m, 1H), 3.96 (d, J = 13.2 Hz, 1H), 3.18 (d, J = 13.2 Hz, 1H), 2.84 (d, J =4.8 Hz, 3H), 2.83–2.77 (m, 1H), 2.60–2.55 (m, 1H), 2.17–2.06 (m, 2H), 1.56–1.46 (m, 1H), 1.00 (d, J = 6.2 Hz, 3H). Calculated LC-MS (ESI) m / z value C 21 H 23 D3ClN3O2 (M+H) + 391.1, measured value 391.1.

[0186] Example 3: Determination of radioligand competitive binding activity of recombinant human dopamine and serotonin receptors using a filtration binding assay Radioligand binding assays were performed using membrane formulations. Receptor accession numbers, cell backgrounds, and reference compounds are listed in Table 1.

[0187] Table 1.

[0188] Radioligand competitive binding activity tests were performed on the compounds of Example 1 (10) and Example 2 (18) on human D2L, D2S, 5-HT1A and 5-HT2A receptors, and the results are provided in Table 2.

[0189] Table 2. Combination

[0190] a. (±)-cis- N -(1-Benzyl-2-methylpyrrolidone-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide, b. N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide c. The average of the numbers in parentheses. d. .

[0191] Example 4: Determination of agonist or antagonist activity of recombinant human dopamine and serotonin receptors using IPOne HTRF and cAMP HTRF assays SPA 35 The S-GTPgS assay was performed using a membrane formulation. The IP-One and cAMP HTRF assays were performed using recombinant cell lines. Receptor accession numbers, cell backgrounds, and reference compounds are listed in Table 3.

[0192] Table 3.

[0193] The compounds from Examples 1 (10) and 2 (18) were subjected to antagonist activity tests for human D2L, D2S, D3, and D4.4 receptors and agonist activity tests for human 5-HT1A and 5-HT2A receptors. The results are shown in Tables 4-6.

[0194] The agonist activity of the test compound is compared with that of the reference agonist in its EC50. 100 Activity is expressed as a percentage of concentration. The antagonist activity of the test compound is expressed as a percentage of the reference agonist at its EC50. 80 The percentage of inhibition of activity at a given concentration is expressed as a percentage.

[0195] Table 4. Functional Tests

[0196] a. (±)-cis- N -(1-Benzyl-2-methylpyrrolidone-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide, b. N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide c. The average of the numbers in parentheses.

[0197] Table 5.

[0198] a. The highest percentage of inhibition or activation at the maximum concentration. b. (±)-cis- N -(1-Benzyl-2-methylpyrrolidone-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide, c. N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide d. The average of the numbers in parentheses.

[0199] As shown above, the deuterated compounds of Examples 1 (10) and 2 (18) are D2 antagonists and 5-HT2A agonists. The deuterated compound of Example 1 (10) is a strong 5-HT1A agonist. The deuterated compound of Example 2 (18) is a partial 5-HT1A agonist.

[0200] Table 6.

[0201] a. N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide.

[0202] Example 5: In vivo pharmacokinetics Group A male SD rats (via PO) were administered the test compound at 0.5 mg / kg and 5 mg / kg (N=3 animals / dose level). Blood samples were collected at 5, 10, and 30 minutes and at 1, 2, 4, 8, and 24 hours after administration. After blood collection at 24 hours, the animals underwent cerebral perfusion, and brain tissue was then obtained.

[0203] Male SD rats in group B (via PO) were administered the test compound at 0.5 mg / kg and 5 mg / kg (N=9 animals / dose level). At specified time points (1, 4, and 8 hours), blood was collected from three animals in each dose group, followed by cerebral perfusion, and then samples were collected.

[0204] The test compounds were the deuterated compounds of Examples 1 (10) and 2 (18) and N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R)nemopride).

[0205] Blood was collected from rats by surgical cannulation of the femoral artery. The rats weighed approximately 250-350 g. Free access to water was provided. The rats were fasted overnight before oral administration. They could eat 4 hours after administration.

[0206] The dosage form for PO administration is containing 0.1% Tween TM 80% aqueous solution of 0.5% methylcellulose (4000 cps). Once prepared, vortex / homogenize the suspension and continue stirring until administration. Dosage concentration: 0.5 mg / kg is a dose of 0.1 mg / mL, 5 mg / kg is a dose of 1 mg / mL. Route of administration: oral gavage. Dosage volume: 5 mL / kg.

[0207] Within 24 hours of drug administration, blood samples were collected using an automated sampling system into tubes containing potassium EDTA as an anticoagulant. Plasma was obtained by centrifugation within 30 minutes of collection and then rapidly frozen on dry ice. Aliquots of each dosage were appropriately diluted and analyzed simultaneously with the plasma samples by LC-MS / MS.

[0208] Plasma (obtained from blood samples) and brain tissue (homogenized and processed) were analyzed by LC / MS / MS. Plasma was obtained from the blood by centrifugation within 30 minutes of sample collection. Brain tissue was collected after perfusion of the animals to remove residual cardiovascular blood.

[0209] The drug solution, plasma (obtained from blood), and brain tissue (homogenized and processed) were stored at -20°C until analysis.

[0210] The plasma sample was thawed at room temperature, and then an organic solvent containing an internal standard was added to precipitate the protein.

[0211] The brain samples were thawed, homogenized in water (3-4 times the volume), and the aliquots of the homogenate were analyzed by LC / MS / MS.

[0212] The results are as follows Figure 1-6 As shown.

[0213] N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R)nemopride) has similar plasma pharmacokinetics to the deuterated compounds of Examples 1 (10) and 2 (18) (see [link to relevant documentation]). Figure 1 See also Figure 3 ).exist Figure 1 and 3 In the figures, data for cis(R,R)nemopride are shown in solid lines, while data for the deuterated compounds of Examples 1 (10) and 2 (18) are shown in dashed lines.

[0214] The deuterated compounds of Examples 1 (10) and 2 (18), after a single PO administration of 0.5 mg / kg, showed prolonged brain accumulation in rats as follows: Figure 5 and Figure 6 As shown in the figure. In each figure, the mean brain concentration (ng / ml) is shown as a dashed line, and the mean plasma concentration (ng / ml) is shown as a solid line.

[0215] Compared to N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R)nemopride), the deuterated compounds of Examples 1 (10) and 2 (18) exhibited enriched brain levels (see Figure 2 and4 All of them were administered at a single PO dose of 0.5 mg / kg. The brain-to-plasma ratios of N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R)nemopride) and the deuterated compounds of Examples 1 (10) and 2 (18) are compared in Table 7 (all of them were administered at a single PO dose of 0.5 mg / kg).

[0216] Table 7.

[0217] Table 8. Plasma concentration (ng / ml) relative to time

[0218] Table 9. Brain concentration over time (ng / ml)

[0219] Example 6: Time progression of isolated radioligand binding in membrane formulations to determine receptor occupancy at central D2 receptors. This study uses [ 3 [H] Raldoliprid and rat striatal membranes were used to determine the receptor occupancy at central D2 receptors of the deuterated compounds of Examples 1 (10) and 2 (18) at different time points (e.g., 1, 2, 4, 8, and 24 hours) after oral administration, as well as the positive control olanzapine (10 mg / kg, orally). Radioactivity was quantified using liquid scintillation counting.

[0220] animal Rats.

[0221] Drug treatment On the day of testing, animals were orally administered a single dose of the mediator, the deuterated compound of Example 1 (10) and Example 2 (18), or olanzapine. Rats were sacrificed at specified time points, such as 1, 2, 4, 8 and 24 hours after administration, or 1 hour after administration of the mediator and olanzapine.

[0222] Pharmacokinetics Blood samples were obtained after death via cardiac puncture. Plasma was collected for pharmacokinetic (PK) testing.

[0223] Remove the entire brain, rinse with saline solution, and pat dry. Dissect and weigh the left and right striatums, then freeze them on dry ice.

[0224] Homogenization preparation The striatum was homogenized separately.

[0225] test Homogenize the striatum with [ 3 Incubate with [H] raldilopeptide. Determine radioactivity by liquid scintillation counting.

[0226] Example 7: Touchscreen-based probabilistic reward task for rats The Probabilistic Reward Task (PRT) uses visual discrimination methods to quantify reward responsiveness, identify deficiencies, and characterize drug-induced improvements. Rats were grouped and trained on a touchscreen-based PRT and exposed to asymmetric probabilistic random events to develop a response bias to high-reward stimuli (Pizzagalli, D. et al., Biological Psychiatry, 2005, 57, 319-327; Kangas, B. et al., Translational Psychiatry, 2020, 10(1):285; Wooldridge, L. et al., International Journal of Neuropsychopharmacology, 2021, 24, 409-418). Subjects were then tested with either the mediator or the deuterated compounds of Examples 1 (10) and 2 (18).

[0227] For details, diagrams, and methods of the rodent touch sensitivity test chamber, please refer to Kangas, B. et al., Behavioural Pharmacology, 2017, 28, 623-629.

[0228] Example 8: Conditioned Avoidance Response Rats were used. Risperidone (0.5 mg / kg; Sigma Aldrich) was dissolved in 10% DMSO aqueous solution and administered intraperitoneally (ip) 30 minutes before the test at a volume of 1 mg / kg. The deuterated compounds of Examples 1 (10) and 2 (18) were administered orally before the test.

[0229] The Conditioned Avoidance Response (CAR) test is an animal model for screening antipsychotic drugs.

[0230] Example 9: Head shaking response Rat. The deuterated compounds of Examples 1 (10) and 2 (18) were administered orally.

[0231] Animals were given the medium, DOI, or test compound and then returned to their cages for a pretreatment period of an appropriate time, after which head shaking was recorded. Head shaking is a rapid, rhythmic swaying of the head in a radial pattern. Data were analyzed using ANOVA and subsequently post-analyzed when appropriate.

[0232] Example 10: DOI-induced head-shaking response Rats were used. The deuterated compounds of Examples 1 (10) and 2 (18) were administered orally. DOI was administered via IP. Ketoserine (1 mg / kg) was administered via IP injection.

[0233] Animals were administered the vector, ketoselin, or the test compound and then returned to their cages for a pretreatment period of appropriate duration. Rats were then injected with a DOI (Disposable Oral Injection), and head shaking was recorded 10 minutes after injection and continued for 10 minutes. Head shaking was defined as rapid, rhythmic radiating head movements. Data were analyzed using ANOVA and subsequently post-analyzed when appropriate.

[0234] Example 11: Synthesis of starting materials for Examples 1 and 2 Intermediate 15: (R)-2-methyl-3,5-dioxopyrrolidine-1-carboxylic acid tert-butyl ester Under nitrogen atmosphere and at 0 °C, EDCI (608 g, 3.18 mol) was added to a solution of Boc-D-alanine (500 g, 2.64 mol), McFarland acid (400 g, 2.78 mol), and DMAP (388 g, 3.18 mol) in dichloromethane (5 L). The resulting solution was slowly heated to room temperature (rt), and the reaction mixture was stirred for 16 h. The reaction was quenched with water (1.5 L), and the organic phase was washed successively with cold 5% potassium hydrogen sulfate solution (3 L × 3), water (3 L × 1), and brine. After drying with anhydrous MgSO4, the solution was concentrated to give the residue. Ethyl acetate (4 L) was added, and the reaction mixture was refluxed for 2 h. The solution was concentrated, and the residue was stirred with ethyl acetate (500 mL) at -15 °C for 2 h, followed by filtration. The filter cake was collected to give the title compound as a white solid (150 g, 27% yield). The mother liquor was refluxed for another 2 hours, then stirred in ethyl acetate at -10 °C, filtered, and the title compound (40 g) was obtained as a white solid. 1 H NMR (400 MHz, CDCl3) δ 4.45 (q, J = 6.8 Hz, 1H), 3.22 (s,2H), 1.57 (s, 9H), 1.51 (d, J = 6.8 Hz, 3H). MS m / z (ESI): 158 [M+H-56] + .

[0235] Intermediate 16: (2R,3R)-3-hydroxy-2-methyl-5-oxopyrrolidine-1-carboxylic acid tert-butyl ester At 0 °C, AcOH (200 mL) was added to a stirred solution of 15 (40 g, 187.6 mmol) in 400 mL of dichloromethane, followed by the addition of NaBH4 (21.3 g, 562.8 mmol) in three portions. The resulting solution was slowly brought to room temperature and stirred for at least 16 hours. The reaction mixture was quenched at 0 °C with 5% NaHCO3 solution and extracted with dichloromethane (200 mL × 3). The combined organic layers were washed with 5% NaHCO3 solution. The organic phase was dried over anhydrous magnesium sulfate, concentrated to obtain a residue, which was stirred in isopropyl ether and filtered to give title compound 16 (24 g, 59.4% yield). 1 H NMR (400 MHz, CDCl3) δ 4.53-4.47 (m, 1H), 4.29-4.22 (m, 1H), 2.75-2.55 (m, 2H), 1.53 (s,9H), 1.31(d, J = 6.8 Hz, 3H). MS m / z (ESI): 160 [M+H-56] + .

[0236] Intermediate 17: (2R,3R)-3-hydroxy-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester At 0 °C, a solution of BH3-SMe2 (600 mL, 1200 mmol) was added to an anhydrous tetrahydrofuran (1 L) solution of compound 16 (87 g, 405 mmol), and the mixture was stirred at 0 °C for 30 min. The mixture was then refluxed for 4 h. The resulting mixture was cooled and quenched with a saturated ammonium chloride solution at 0 °C. It was then extracted with ethyl acetate (1 L × 3). The organic phase was dried over anhydrous magnesium sulfate and concentrated to give compound 17 (70 g, 86% yield). 1 H NMR (400 MHz, DMSO-d6) δ 5.11(s,1H), 4.19-4.10 (m, 1H), 3.83-3.63 (m, 1H), 3.22-2.89 (m, 2H), 1.87-1.54 (m,2H), 1.38 (s, 9H), 0.85 (d, J = 6.8 Hz, 3H). MS m / z (ESI): 146 [M+H-56] + .

[0237] Intermediate 18 (intermediate used in synthesis): DIAD (16.6 g, 82.1 mmol) was added to a cooled 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 anhydrous tetrahydrofuran (250 mL). The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was then allowed to rise to room temperature for 16 h. The resulting mixture was cooled and quenched with water. The mixture was extracted with ethyl acetate (200 mL × 3), dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography to give intermediate 18 (24.7 g, 90.1% yield). 1 H NMR (400 MHz, CDCl3) δ8.31-8.17 (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] + .

[0238] Intermediate 19: 4-Nitrobenzoic acid (2R,3S)-2-methylpyrrolidone-3-yl ester The mixture of intermediate 18 (23.4 g, 66.8 mmol) and TFA (120 mL) in DCM (240 mL) was stirred at room temperature for 1 hour, followed by concentration to give compound 19 (16.7 g, 100% yield). LCMS: M+1 = 251.

[0239] Intermediate 20: 4-Nitrobenzoic acid (2R,3S)-1-benzoyl-2-methylpyrrolidine-3-yl ester To a toluene (520 mL) solution of compound 19 (16.7 g, 66.8 mmol), 520 mL of 2 N NaOH solution (104 mmol) was added, followed by a toluene (200 mL) solution of benzoyl chloride (9.6 g, 66.8 mmol) at 0 °C. The mixture was separated, and the aqueous phase was extracted with dichloromethane (250 mL × 3). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to give compound 20 (21.3 g, 90% yield). LCMS: M+1 = 355.

[0240] Intermediate 21: ((2R,3S)-3-hydroxy-2-methylpyrrolidone-1-yl)(phenyl)methyl ketone To a methanol (400 mL) solution of compound 20 (21.3 g, 60.1 mmol) under stirring, 11 mL of 6N NaOH solution (66 mmol) was added. The reaction mixture was stirred for 40 min and concentrated under reduced pressure. The residue was diluted with dichloromethane (200 mL) and water (100 mL), and the aqueous phase was extracted with dichloromethane (250 mL × 3). The organic phase was dried over magnesium sulfate and concentrated to give a residue, which was treated with petroleum ether (10 mL) and ethyl acetate (2 mL) to give intermediate 21 (9.85 g, 79.8% yield). LCMS: M+1 = 206.

[0241] Example 12: Synthesis of the starting materials of Example 1 Dissolve 22 (7.5 g, 59 mmol) in cold dichloromethane (200 mL, 0 °C). Add 3 drops of DMF and oxalyl chloride (118 mmol, added dropwise) to the solution. Raise the temperature to room temperature and stir for 3 hours. Remove the solvent under reduced pressure to give 23 (100% yield, 8.59 g).

[0242] Example 13: Microdialysis Experiment For the microdialysis experiment, male rats (n=8 per experiment) were surgically implanted with probes in the nucleus accumbens and prefrontal cortex. The rats were given at least 16 hours to recover, during which time the probes were continuously perfused with artificial cerebrospinal fluid.

[0243] Before administration of the test compound / solvent, microdialysis fluid was collected from conscious, freely moving rats at 30-minute intervals for a baseline period of 2 hours. Samples were collected for another 8 hours after administration of the test compound / solvent.

[0244] The test compounds were compound (10) of Example 1 and compound (A2) of International Publication No. WO 2023 / 130117.

[0245] The test compound was administered at 2.5 mg / kg in 0.5% methylcellulose (oral, gavage) + normal saline (ip). The solvent group was 0.5% methylcellulose (oral, gavage) + normal saline (ip).

[0246] Neurotransmitter detection and subsequent quantification in the samples were performed using HPLC coupled with an electrochemical detector. Data were logarithmically transformed, and statistical comparisons were conducted using Williams' test and multiple t-tests.

[0247] All microdialysis data were log-transformed. The baseline was defined as the geometric mean of the four samples prior to drug administration (collection times were -90, -60, -30, and 0 min). To handle extreme values, robust regression analysis using M-estimation and Huber weighting was employed, with default parameters using the treatment factor as the factor and log(baseline) as the covariate.

[0248] Data from the prefrontal cortex of one rat was excluded due to a continuous decline in levels during the experiment. Data from the nucleus accumbens of one rat could not be obtained. Dopamine levels from two rats were excluded due to outliers.

[0249] Analyze each time point separately, or by time interval and overall time period (0–2 hours, 0–4 hours, 0–8 hours after administration). For calculating hourly and 2-hourly averages, missing data were imputed using the geometric mean of the preceding and following values. Between-group comparisons with the solvent group were performed using Williams' test or multiple t-tests.

[0250] Compound (10) in Example 1 transiently reduced 5-HT levels in the nucleus accumbens (lasting up to 1.5 hours) without significantly altering 5-HT levels in the prefrontal cortex.

[0251] Dopamine-related results can be found Figure 7 and Figure 8 .

[0252] exist Figure 7 In the diagram, hollow circles represent 0.5% methylcellulose (5 ml / kg, oral) + physiological saline (2 ml / kg, ip), solid circles represent 0.5% methylcellulose (5 ml / kg, oral) + dextroamphetamine (0.3 mg / kg, ip), hollow squares represent Example 1 (A2) (2.5 mg / kg, oral) + physiological saline (ip) in International Publication No. WO2023 / 130117, and hollow triangles represent the compound described in Example 1 (10) (2.5 mg / kg, oral) + physiological saline (ip).

[0253] exist Figure 7 In the mean, the results were adjusted; n=6-8. SEM was calculated based on the residuals of the statistical model. Drug dosage was expressed as free alkali, and vertical arrows indicated the time points for drug administration. After logarithmic transformation, the data were analyzed using robust regression with log(baseline value) as a covariate. Williams' test was used to compare A2 with the solvent group, and multiple t-tests were used for comparisons with the solvent group. Multiple t-tests were also used to compare compound 10 with A2.

[0254] exist Figure 7 Among the groups, the significant differences between the 0.5% methylcellulose (5 ml / kg, oral) + dextroamphetamine group and the solvent group were: *p<0.05, **p<0.01, ***p<0.001. The significant differences between A2 and the solvent group were: †p<0.05, ††p<0.01, †††p<0.001. The significant differences between compound 10 and the solvent group were: #p<0.05, ##p<0.01, ###p<0.001.

[0255] like Figure 7 As shown, the compound of Example 1 (10) exhibited a significant and sustained increase in dopamine in the nucleus accumbens (for most of the 8-hour test period). The effect was similar to that of the deuterated compound (A2) of Example 1 in International Publication No. WO2023 / 130117.

[0256] exist Figure 8 In the diagram, hollow circles represent 0.5% methylcellulose (5 ml / kg, oral) + physiological saline (2 ml / kg, ip), solid circles represent 0.5% methylcellulose (5 ml / kg, oral) + dextroamphetamine (0.3 mg / kg, ip), hollow squares represent Example 1 (A2) (2.5 mg / kg, oral) + physiological saline (ip) in International Publication No. WO2023 / 130117, and hollow triangles represent the compound described in Example 1 (10) (2.5 mg / kg, oral) + physiological saline (ip).

[0257] exist Figure 8 In the mean, the results were adjusted; n=7-8. SEM was calculated based on the residuals of the statistical model. Drug dosage was expressed as free alkali, and vertical arrows indicated the time points for drug administration. After logarithmic transformation, the data were analyzed using robust regression with log(baseline value) as a covariate. Williams' test was used to compare A2 with the solvent group, and multiple t-tests were used for comparisons with the solvent group. Multiple t-tests were also used to compare compound 10 with A2.

[0258] exist Figure 8Among the groups treated, the significant differences between the 0.5% methylcellulose (5 ml / kg, oral) + dextroamphetamine group and the solvent group were: *p<0.05, **p<0.01, ***p<0.001. The significant differences between the 10 group and the solvent group were: #p<0.05, ##p<0.01, ###p<0.001. The significant differences between the 10 group and A2 group were: ^p<0.05, ^^p<0.01, ^^^p<0.001.

[0259] like Figure 8 As shown, compound 10 of Example 1 exhibited a significant and sustained (for most of the 8-hour test period) increase in dopamine in the prefrontal cortex, and was more potent than the deuterated compound (A2) of Example 1 in International Publication No. WO2023 / 130117. Compound 10 and A2 had the same number of deuterated substitutions, but at different substitution positions.

[0260] Data show that the compound of Example 1 (10) can enhance reward perception and cognition by increasing dopamine in the nucleus accumbens and prefrontal cortex.

Claims

1. Compounds of Formula I: Formula I, in: R1, R2, R3, R4, and R5 are independently selected from H and D; and At least one of R1, R2, R3, R4, and R5 is D; The compound is in free form or salt form.

2. Compounds of Formula II: Formula II, in: R6, R7, and R8 are independently selected from H and D; and At least one of R6, R7 and R8 is D; The compound is in free form or salt form. The compound is substantially free of its (S,S) enantiomer.

3. The compound according to claim 1 or 2, wherein the compound is in a free form.

4. The compound according to claim 1 or 3, wherein R1, R2, R3, R4 and R5 are each D.

5. The compound according to claim 2 or 3, wherein R6, R7 and R8 are each D.

6. The compound according to claim 1, 3 or 4, wherein the compound is: ， It exists in free form or as a salt.

7. The compound according to claim 2, 3 or 5, wherein the compound is: ， It exists in free form or as a salt.

8. The compound according to any one of claims 1-7, wherein the compound in the form of a free or pharmaceutically acceptable salt has a deuterium incorporation rate of more than 90% at one or more sites labeled as deuterium.

9. A pharmaceutical composition comprising a compound in free or pharmaceutically acceptable salt form according to any one of claims 1-8, and a pharmaceutically acceptable carrier.

10. A method of treating a patient with a brain condition, wherein the method comprises administering to the patient a compound in free or pharmaceutically acceptable salt form according to any one of claims 1-8, or a pharmaceutical composition according to claim 9.

11. The method of claim 10, wherein the condition is an affective disorder or anxiety disorder.

12. The method of claim 11, wherein the condition is depression, 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 migraine.

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

14. The method of claim 10, wherein the condition is anhedonia, anhedonia-related depression, suicidal ideation, anxiety depression, inflammatory depression, treatment-resistant depression, dysphoric depression, bipolar depression, psychotic depression, or post-psychotic depression.

15. The method of claim 10, wherein the condition is anxiety depression.

16. The method of claim 10, wherein the condition is depressive disorder.

17. The method of claim 10, wherein the condition is major depressive disorder.

18. The method of claim 10, wherein the condition is a substance use disorder.

19. The method of claim 10, wherein the condition is post-traumatic stress disorder (PTSD).

20. The compound in free or pharmaceutically acceptable salt form according to any one of claims 1-8, or the pharmaceutical composition according to claim 9, for the treatment of brain disorders.

21. Use of the compound according to any one of claims 1-8 in the preparation of a medicament for treating brain disorders.

22. The use according to claim 20 or 21, wherein the brain condition is as described in any one of claims 11-19.

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