Deuterated organic compounds and uses thereof

Abstract

This application provides compounds of Formula I described herein, methods for their preparation, their use as pharmaceuticals, pharmaceutical compositions comprising them, and intermediates used in their preparation. Compounds of Formula I 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.

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.

[0002] field This application provides compounds of Formula I as described below, methods for their preparation, their use as pharmaceuticals, pharmaceutical compositions comprising them, and intermediates used in their preparation. Compounds of Formula I 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.

[0003] background 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 illnesses 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 on postsynaptic dopamine receptor cells, while D2-like dopamine receptors are expressed on postsynaptic dopamine target cells and presynaptic dopaminergic neurons.

[0006] Fourteen serotonin receptor subtypes, classified into subfamilies, mediate the effects of serotonin (5-HT). The 5-HT1A receptor subtype is a major subtype, existing as a presynaptic autoreceptor in serotonin neurons of the raphe nuclei and as a postsynaptic heteroreceptor in the prefrontal cortex, hippocampus, septum, and hypothalamus. The signal transduction mechanism of 5-HT1A receptors in the raphe nuclei may differ from that in other brain regions. Activation of the 5-HT1A postsynaptic receptor can lead to increased dopamine release. The 5-HT2A receptor subtype is enriched in the cortex and is involved in phosphatidylinositol conversion, and also regulates dopamine release. 5-HT2A receptor antagonists have 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 thought to originate from their 5-HT2A receptor agonistic effects. It was also reported that 5-HT2A agonism promotes neuroplasticity and reduces depression.

[0007] Antipsychotics are used to manage psychosis, particularly schizophrenia. A hallmark of antipsychotics is D2 receptor antagonism. D2 receptor antagonism effectively reduces the positive symptoms of schizophrenia (e.g., hallucinations and delusions), but often also produces extrapyramidal side effects, including Parkinson's disease, akathisia, and tardive dyskinesia, increases prolactin levels, and can exacerbate the negative symptoms of schizophrenia (e.g., loss of interest and motivation in life and activities, social withdrawal, and anhedonia). A key characteristic 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 may be untreatable with current medications. However, some atypical antipsychotics are used in conjunction with serotonergic antidepressants to improve responses to major depressive disorder.

[0008] Because an imbalance between dopamine and serotonin 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 an imbalance of dopamine and serotonin.

[0009] Brief Overview This application provides compounds of formula X: Formula X, In a compound in which six or more hydrogens are replaced by deuterium (i.e., the deuterium abundance at six or more hydrogen positions is significantly higher than the native deuterium abundance at those positions), the compound is in the form of a free or pharmaceutically acceptable salt.

[0010] This application further provides pharmaceutical compositions comprising compounds of formula X, methods for preparing compounds of formula X, and pharmaceutical uses of compounds of formula X, for example, as an anhedrin and for treating schizophrenia, depression, and post-traumatic stress disorder.

[0011] For example, this application provides compounds of formula I: Formula I, in: R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Independently selected from H and D; and among them At least one of R1, R2, and R3 is D; And R9, R 10 R 11 R 12 and R 13 At least one of them is D; The compound is in free or salt form.

[0012] This application also provides pharmaceutical compositions comprising compounds of formula I, methods for preparing compounds of formula I, and pharmaceutical uses of compounds of formula I, such as as anhedrinogens and for treating 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 although preferred embodiments of the invention have been pointed out, the detailed description and specific examples are intended for illustrative purposes only and are not intended to limit the scope of the invention.

[0014] Brief description of the attached diagram Figure 1 The mean plasma concentrations (ng / ml) of cis(R,R)nemopride and compound (D13) of Example 11 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 (D13) of Example 11 in rats when administered as a single PO dose of 0.5 mg / kg are shown.

[0016] Figure 3 The mean plasma and brain concentrations (ng / ml) of compound (D13) of Example 11 in rats were shown when administered as a single PO dose of 0.5 mg / kg.

[0017] Figure 4 The mean plasma and brain concentrations (ng / ml) of compound (D13) of Example 11 in rats were shown when administered at a single PO dose of 5 mg / kg.

[0018] Detailed description The following description of preferred embodiments is merely exemplary in nature and is by no means intended to limit the invention, its application, or use.

[0019] In the event of any conflict between the definitions in this disclosure and the definitions in the cited references, this disclosure shall prevail.

[0020] D2- and D3- receptors are expressed on 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.

[0021] 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. Relatively high D2-like receptor occupancy is associated with antipsychotic effects, while lower occupancy is associated with antidepressant effects.

[0022] Anhedonia is a core symptom of major depressive disorder (MDD) and is associated with inadequate response to approved selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), as well as psychotherapy (e.g., cognitive behavioral therapy (CBT)) and neurostimulation (e.g., transcranial magnetic stimulation (TMS)). Effective treatment for MDD characterized by anhedonia remains necessary. 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 antidepressants; the outcomes are even worse for individuals with MDD who have anhedonia.

[0023] Dopamine / catecholamine depletion induces symptoms of depression and anhedonia. Increasing dopamine neurotransmission can alleviate these symptoms. However, while high doses of dopamine D2 / D3 agonists 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 poor tolerance.

[0024] Besides MDD, anhedonia also plays a role in bipolar disorder, schizophrenia, post-traumatic stress disorder, and substance use disorder. Despite its role in multiple conditions, there are currently no approved medications to treat anhedonia.

[0025] Decreased serotonergic activity is associated with anxiety and depression. Increased serotonin neurotransmission can alleviate symptoms of anxiety and depression and may help with anxiety-related depression.

[0026] The IUPAC name for nemoprazole is (±)-cis- N 1-(1-Benzyl-2-methylpyrrolidone-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide. Nemopride is described in U.S. Patent No. 4,210,660 as a potent central nervous system depressant, particularly a potent antipsychotic.

[0027] 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 of nemopride for schizophrenia is 9 to 36 mg, administered orally in divided doses after a meal. The dose can be increased up to 60 mg daily.

[0028] The nemopride prescribing information indicates that when 3 mg and 6 mg of nemopride are administered orally to healthy adults, the elimination half-life is 2.3 to 4.5 hours. Nemopride metabolites in urine are caused by debenzylation and N-demethylation. See the Emilace package insert.

[0029] In addition to acting as a dopamine D2 / D3 / D4 receptor antagonist, nemopride is also a 5-HT1A agonist. Furthermore, nemopride has been reported to bind to 5-HT2A receptors; however, the inventors are unaware of any publications reporting its functional effects at this receptor. Nevertheless, as an antipsychotic, nemopride is expected to be a 5-HT2A receptor antagonist because a key characteristic of atypical antipsychotics is a combination of D2 receptor antagonism and either 5-HT2A receptor antagonism or inverse agonism.

[0030] When drugs (especially those with multiple biological targets) are used as a mixture of stereoisomers, it is impossible to predict the properties of each stereoisomer (e.g., biological targets, pharmacokinetics).

[0031] The compounds of formulas X and I disclosed herein are D2 receptor antagonists and 5-HT2A agonists. Surprisingly, the deuterated compound (D13) of Example 11 (also shown as 34 in Example 1) exhibits a higher 5-HT2A agonist activity than its non-deuterated analogue (see Example 3, Table 5). The deuterated compound (D13) of Example 11 is also a 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—R-remopride, S-remopride, R-sulpiride, R-sulfopride, and S-suflopride—did not even bind to the 5-HT2A receptor in vitro (competing with labeled ketansrin for assay).

[0032] As noted above, the combination of dopamine receptor antagonism and serotonin (5-HT1A and 5-HT2A) receptor agonism is a unique activity signature that allows for differential modulation of dopamine and serotonin neurotransmission compared to other D2 receptor antagonists. For example, D2 postsynaptic receptor antagonism reduces psychosis, particularly schizophrenia, by decreasing 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 increased prolactin levels. However, 5-HT1A agonism may limit those high-dose D2 antagonist-related side effects, thus providing an intrinsic safety profile for the compound when used at high doses as an antipsychotic. 5-HT1A agonism also provides anxiolytic effects. Furthermore, as potent 5-HT2A agonists, the deuterated compounds disclosed herein exhibit enhanced antidepressant effects, as seen in psychedelic antidepressants, such as rapid and sustained anti-anxiety effects. Moreover, the combination of D2 antagonism and 5-HT2A agonism can modulate the hallucinogenic effect of 5-HT2A.

[0033] Therefore, as D2 antagonists and 5-HT2A agonists, compounds of formula X and formula I can provide psychedelic-like antidepressant effects at low doses (e.g., lower than those of nemopride used to treat schizophrenia), and also have intrinsic protection against 5-HT2A-mediated hallucinations. Additionally, as D2 antagonists and 5-HT1A agonists, compounds of formula X and formula I can act as antipsychotics at high doses, but have intrinsic protection against the side effects associated with high-dose D2 antagonists.

[0034] Unexpectedly, 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 agonist activity relative to D2 antagonist activity. Data show that the deuterated compound (D13) of Example 11 disclosed herein exhibits weaker D2L antagonism and stronger 5-HT2A agonist activity compared to the non-deuterated analog. Furthermore, data indicate that the deuterated compound (D13) of Example 11 disclosed herein is also a stronger 5-HT2A agonist than the compound (A2) of Example 1 in International Publication No. WO 2023 / 130117. These differences result in a more balanced 5HT2A:D2L ratio for the deuterated compound (D13) of Example 11 (see Table 6). The different activity spectra of these compounds on two targets (dopamine and serotonin receptors) may allow the compounds to target different patient groups and be particularly beneficial to these patient groups.

[0035] The pharmacokinetics of the deuterated compounds disclosed herein are beneficial, for example, as follows: brain enrichment compared to plasma levels; brain:plasma exposure supporting once-daily dosing; and prolonged brain enrichment compared to plasma levels, which allows for higher and more sustained receptor occupancy, while requiring lower dosing frequency and potentially associated with fewer peripheral side effects. Nemopride requires multiple daily dosings.

[0036] 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 compound (D13) of Example 11 are similar (see Example 4). However, despite the similar plasma pharmacokinetics, Example 4 shows that compounds of formula X and I (D13) have enriched and maintained brain levels compared to their non-deuterated analogs. For example, Figure 2 Compared to cis(R,R)nemopride, D13 showed higher brain levels at all time points. D13 also exhibited prolonged brain enrichment compared to plasma levels of the compound (see [link to article]). Figure 3 and Figure 4 Brain: Plasma exposure supports once-daily administration of both compounds. Brain-level enrichment and prolonged brain enrichment are beneficial characteristics compared to plasma levels, achieving higher and more sustained receptor occupancy while requiring less frequent dosing and potentially associated with fewer peripheral side effects. The receptor occupancy levels provided by D13 can be maintained within the desired range with a convenient dosing regimen. In contrast, as mentioned above, nemopride requires multiple daily dosings.

[0037] Compounds that regulate dopamine and serotonin neurotransmission can be used to treat conditions involving dopamine and serotonin signaling pathways, such as those involving D2, D3, D4, 5-HT1A, and / or 5-HT2A receptors.

[0038] 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.

[0039] This application provides compounds of formula X: Formula X, In a compound in which six or more hydrogens are replaced by deuterium (i.e., the deuterium abundance at six or more hydrogen positions is significantly higher than the native deuterium abundance at those positions), the compound is in the form of a free or pharmaceutically acceptable salt.

[0040] This application further provides pharmaceutical compositions comprising compounds of formula X, methods for preparing compounds of formula X, and pharmaceutical uses of compounds of formula X, for example, as an anhedrin and for treating schizophrenia, depression, and post-traumatic stress disorder.

[0041] For example, this application provides compounds of formula I: Formula I, in: R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Independently selected from H and D; and among them At least one of R1, R2, and R3 is D; And R9, R 10 R 11 R 12 and R 13 At least one of them is D; The compound is in free or salt form.

[0042] This application further provides compounds of formula I as follows: 1.1 Formula I, wherein the compound is in a pharmaceutically acceptable salt form.

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

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

[0045] 1.4 Any one of Equation I or 1.1-1.3, where R4, R5 and R6 are each D.

[0046] 1.5 Equation I or any one of 1.1-1.4, where R7 and R8 are D.

[0047] 1.6 Equation I or any one of 1.1-1.5, where R9, R 10 R 11 R 12 and R 13 Each is D.

[0048] 1.7 Any one of Equation I or 1.1-1.6, where R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Each is D.

[0049] 1.8 Formula I or any one of 1.1-1.7, wherein the compound is: , The compound is in free or salt form, for example, in free or pharmaceutically acceptable salt form, for example, in free form.

[0050] 1.9 Equation I or any of 1.1-1.8, wherein the designation of deuterium (i.e., D) at a position means that the position has a significantly greater natural abundance of deuterium than that at the position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope exists at a natural isotopic abundance.

[0051] 1.10 The compound of Formula I or any of 1.1-1.9, wherein the compound in free or salt form (e.g., a pharmaceutically acceptable salt form) has greater than 50%, such as 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% of deuterium (i.e., D) at one or more positions designated as deuterium (i.e., D). For example, the compound of Formula I or any of 1.1-1.9, wherein the compound in free or salt form (e.g., a pharmaceutically acceptable salt form) has greater than 50%, such as 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% of deuterium (i.e., D) at each position designated as deuterium (i.e., D).

[0052] 1.11 Formula I or any one of 1.1-1.10, wherein the compound is substantially stereoisomerically pure. For example, the compound has a stereoisomeric excess of greater than 90%, such as equal to or greater than 95%, such as equal to or greater than 96%, such as equal to or greater than 97%, such as equal to or greater than 98%, such as equal to or greater than 99%. For example, the compound is substantially diastereomeric and / or enantiomerically pure, such as the compound being substantially diastereomeric and enantiomerically pure.

[0053] 1.12 Formula I or any one of 1.1-1.11, wherein said compound is substantially diastereomeric pure. For example, said compound has a diastereomeric excess of greater than 90%, such as equal to or greater than 95%, such as equal to or greater than 96%, such as equal to or greater than 97%, such as equal to or greater than 98%, such as equal to or greater than 99%.

[0054] 1.13 Formula I or any one of 1.1-1.12, wherein the compound is substantially enantiomerically pure. For example, the compound has an enantiomeric excess of greater than 90%, such as equal to or greater than 95%, such as equal to or greater than 96%, such as equal to or greater than 97%, such as equal to or greater than 98%, such as equal to or greater than 99%.

[0055] 1.14 Formula I or any one of 1.1-1.13, wherein the compound has the stereochemical configuration shown in Formula I.

[0056] 1.15 Formula I or any one of 1.1-1.14, wherein the compound is contained in a pharmaceutical composition having a pharmaceutically acceptable carrier. For example, Formula I or any one of 1.1-1.14, wherein an effective amount of the compound is contained in a pharmaceutical composition having a pharmaceutically acceptable carrier.

[0057] This application further provides a pharmaceutical composition comprising a compound of formula X in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier.

[0058] This application further provides a pharmaceutical composition (composition 1) comprising a compound of formula I (e.g., any one of formulas 1.1-1.15): Formula I, in: R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Independently selected from H and D; and among them At least one of R1, R2, and R3 is D; And R9, R 10 R 11 R 12 and R 13 At least one of them is D; The compound is in free or pharmaceutically acceptable salt form.

[0059] This application also provides the following composition 1: 1.1 Composition 1, wherein the composition comprises a pharmaceutically acceptable carrier.

[0060] 1.2 Composition 1 or 1.1, wherein the composition comprises a compound in the form of a free or pharmaceutically acceptable salt, the compound being described as in Formula I or any of 1.1-1.15 (see above).

[0061] 1.3 Composition 1, 1.1, or 1.2, wherein the compound is in a free form.

[0062] 1.4 Composition 1 or any one of 1.1-1.3, wherein the compound of formula I is: , The compound is in a free or pharmaceutically acceptable salt form, for example, in a free form.

[0063] 1.5 Composition 1 or any one of 1.1-1.4, wherein the designation of deuterium (i.e., D) at a position means that the position has a significantly greater natural abundance of deuterium than that at the 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 a natural isotopic abundance.

[0064] 1.6 Composition 1 or any of 1.1-1.5, wherein the compound of Formula I in its free or pharmaceutically acceptable salt form has greater than 50%, such as greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99% deuterium (i.e., D) at one or more positions designated as deuterium (i.e., D). For example, composition 1 or any of 1.1-1.5, wherein the compound of Formula I in its free or pharmaceutically acceptable salt form has greater than 50%, such as greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99% deuterium (i.e., D) at each position designated as deuterium (i.e., D).

[0065] 1.7 Composition 1 or any one of 1.1-1.6, wherein the composition is an oral or parenteral dosage form, such as an oral dosage form, such as a tablet, capsule, solution, or suspension, such as a capsule or tablet.

[0066] 1.8 Composition 1 or any one of 1.1-1.7, wherein the composition comprises a therapeutically effective amount of a compound of formula I in a free or pharmaceutically acceptable salt form, for example, a therapeutically effective amount of a compound of formula I in a 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 a free or pharmaceutically acceptable salt form for any method disclosed herein.

[0067] 1.9 Composition 1 or any one of 1.1-1.8, wherein the composition is substantially free of any other stereoisomers of Formula I. For example, composition 1 or any one of 1.1-1.8, wherein the composition is substantially free of any other diastereomeric and / or enantiomeric forms of Formula I, for example, wherein the composition is substantially free of any other diastereomeric and enantiomeric forms of Formula I.

[0068] 1.10 Composition 1 or any one of 1.1-1.9, 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.

[0069] 1.11 Composition 1 or any one of 1.1-1.10, 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.

[0070] 1.12 Composition 1 or any one of 1.1-1.11, 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.

[0071] 1.13 Composition 1 or any one of 1.1-1.12, wherein the compound has a stereochemical configuration as shown in Formula I.

[0072] 1.14 Composition 1 or any one of 1.1-1.13, wherein the composition comprises 1-60 mg of a compound of formula I in a free or pharmaceutically acceptable salt form. For example, composition 1 or any one of 1.1-1.13, wherein the composition comprises 1-10 mg, for example 1-9 mg (e.g., 1-8 mg), of a compound of formula I in a free or pharmaceutically acceptable salt form. For example, composition 1 or any one of 1.1-1.13, wherein the composition comprises 3 mg or 10 mg of a compound of formula I in a free or pharmaceutically acceptable salt form. For example, composition 1 or any one of 1.1-1.13, wherein the composition comprises 1 mg to less than 3 mg (e.g., 2 mg), of a compound of formula I in a free or pharmaceutically acceptable salt form.

[0073] 1.15 Composition 1 or any one of 1.1-1.14, wherein the composition is administered once, twice, or three times daily. For example, composition 1 or any one of 1.1-1.14, wherein the composition is administered once daily.

[0074] This application further provides a method for preventing or treating 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 X in a free or pharmaceutically acceptable salt form, or a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula I or 1.1-1.15), or a pharmaceutical composition comprising a compound of formula X in a free or pharmaceutically acceptable salt form, or a pharmaceutical composition comprising a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., formula 1.15 or composition 1 or any one of 1.1-1.15). This application further provides a method for preventing or treating central nervous system disorders (e.g., brain disorders) that benefit from D2 receptor antagonism, D3 receptor antagonism, D4 receptor antagonism, 5-HT1A receptor agonism, and / or 5-HT2A receptor agonism in patients (e.g., humans) in need, wherein the method comprises administering to the patient a compound of formula X in a free or pharmaceutically acceptable salt form, or a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula I or 1.1-1.15), or a pharmaceutical composition comprising a compound of formula X in a free or pharmaceutically acceptable salt form, or a pharmaceutical composition comprising a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., formula 1.15 or composition 1 or 1.1-1.15). For example, this application provides the method described below.

[0075] This application further provides a method for enhancing neural plasticity in a patient (e.g., a person) in need, wherein the method comprises administering to the patient a compound of formula X in a free or pharmaceutically acceptable salt form, or a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula I or 1.1-1.15), or a pharmaceutical composition comprising a compound of formula X in a free or pharmaceutically acceptable salt form, or a pharmaceutical composition comprising a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., formula 1.15 or composition 1 or any one of 1.1-1.15). For example, this application provides a method for enhancing neuroplasticity to improve the rehabilitation of patients with brain injuries (e.g., humans) in need, such as improving rehabilitation after stroke or traumatic brain injury, wherein the method comprises administering to the patient a compound of formula X in a free or pharmaceutically acceptable salt form, or a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula I or 1.1-1.15), or a pharmaceutical composition comprising a compound of formula X, or a pharmaceutical composition comprising a compound of formula I in a free or pharmaceutically acceptable salt form (e.g., any one of formula 1.15 or composition 1 or 1.1-1.15).

[0076] This application provides any of the following methods 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 to the patient an effective amount of a compound of formula X in a free or pharmaceutically acceptable salt form.

[0077] This application provides a method (method 1) 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, R5, R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Independently selected from H and D; and among them At least one of R1, R2, and R3 is D; And R9, R 10 R 11 R 12 and R 13 At least one of them is D; The compound is in free or pharmaceutically acceptable salt form.

[0078] This application further provides the following method 1: 1.1 Method 1, wherein the method comprises administering to the patient a compound of Formula I in its free or pharmaceutically acceptable salt form, as described in Formula I above or any one of 1.1-1.15. For example, Method 1, wherein the method comprises administering to the patient a pharmaceutical composition comprising a compound of Formula I in its free or pharmaceutically acceptable salt form, as described in Formula 1.15 above or Composition 1 or any one of 1.1-1.15.

[0079] 1.2 Method 1 or 1.1, wherein the effective amount of the compound of formula I in its free or pharmaceutically acceptable salt form has a stereoisomeric excess of greater than 90%, for example, equal to or greater than 95%, equal to or greater than 96%, equal to or greater than 97%, equal to or greater than 98%, or equal to or greater than 99%. For example, wherein the effective amount of the compound of formula I in its free or pharmaceutically acceptable salt form is substantially diastereomeric and / or enantiomerically pure, for example, wherein the effective amount of the compound of formula I in its free or pharmaceutically acceptable salt form is substantially diastereomeric and enantiomerically pure. For example, the effective amount of the compound of formula I in its free or pharmaceutically acceptable salt form has a diastereomeric and / or enantiomeric excess of greater than 90%, such as equal to or greater than 95%, equal to or greater than 96%, equal to or greater than 97%, equal to or greater than 98%, or equal to or greater than 99%. For example, the effective amount of the compound of formula I in its free or pharmaceutically acceptable salt form has an excess of more than 90% diastereomers and enantiomers, such as equal to or greater than 95% diastereomers and enantiomers, such as equal to or greater than 96% diastereomers and enantiomers, such as equal to or greater than 97% diastereomers and enantiomers, such as equal to or greater than 98% diastereomers and enantiomers, such as equal to or greater than 99% diastereomers and enantiomers.

[0080] 1.3 Any one of Method 1, 1.1 or 1.2, wherein the compound is in free form.

[0081] 1.4 Method 1 or any one of 1.1-1.3, wherein said 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.

[0082] 1.5 Method 1.4, wherein the effective amount of compound A in its free or pharmaceutically acceptable salt form has a stereoisomer excess of greater than 90%, for example, equal to or greater than 95%, equal to or greater than 96%, equal to or greater than 97%, equal to or greater than 98%, or 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 diastereomeric and / or enantiomerically pure. For example, the effective amount of compound A in its free or pharmaceutically acceptable salt form has an excess of more than 90% diastereomers and / or enantiomers, such as equal to or greater than 95% diastereomers and / or enantiomers, such as equal to or greater than 96% diastereomers and / or enantiomers, such as equal to or greater than 97% diastereomers and / or enantiomers, such as equal to or greater than 98% diastereomers and / or enantiomers, such as equal to or greater than 99% diastereomers and / or enantiomers. For example, the effective amount of compound A in its free or pharmaceutically acceptable salt form has an excess of more than 90% of diastereomers and enantiomers, such as equal to or greater than 95% of diastereomers and enantiomers, such as equal to or greater than 96% of diastereomers and enantiomers, such as equal to or greater than 97% of diastereomers and enantiomers, such as equal to or greater than 98% of diastereomers and enantiomers, such as equal to or greater than 99% of diastereomers and enantiomers.

[0083] 1.6 Method 1 or any of 1.3-1.5, wherein the designation of deuterium (i.e., D) at a position means that the position has a significantly greater natural abundance of deuterium than that at the 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 a natural isotopic abundance.

[0084] 1.7 Method 1 or any of 1.1-1.6, wherein an effective amount of the compound in its free or pharmaceutically acceptable salt form is incorporated with greater than 50%, 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% deuterium (i.e., D) at one or more positions designated as deuterium (i.e., D). For example, Method 1 or any of 1.1-1.6, wherein an effective amount of the compound in its free or pharmaceutically acceptable salt form is incorporated with greater than 50%, 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% deuterium (i.e., D) at each position designated as deuterium (i.e., D).

[0085] 1.8 Method 1 or any of 1.1-1.7, wherein the condition is a brain condition. For example, Method 1 or any of 1.1-1.7, wherein the condition is a neuropsychiatric condition in which anhedonia is significant.

[0086] 1.9 Method 1 or any of 1.1-1.8, wherein the condition is an affective (emotional) disorder or an anxiety disorder.

[0087] 1.10 Method 1 or any one of 1.1-1.9, wherein the condition is depression (e.g., anhedonia-associated depression), anxiety disorder, psychosis (e.g., psychosis in neurodegenerative disorders 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, binge eating disorder, somatic 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 or any one of 1.1-1.9, wherein the anxiety disorder is panic disorder, social anxiety disorder, phobia, or generalized anxiety disorder. Or, Method 1 or any one of 1.1-1.9, wherein the method prevents or treats behavioral and psychological symptoms of dementia, including agitation, depression, anxiety, emotional blunting, and / or psychosis. For example, method 1 or any of 1.1-1.9, wherein the method is used to prevent or treat post-traumatic stress disorder (PTSD), for example, to treat post-traumatic stress disorder (PTSD).

[0088] 1.11 Method 1 or any of 1.1-1.10, wherein the condition is anhedonia or anhedonia-associated depression, suicidal ideation, anxiety-related depression, inflammatory depression, treatment-resistant depression, dysphoric depression, bipolar depression, psychotic depression, or post-psychotic depression. For example, Method 1 or any of 1.1-1.10, wherein the condition is anxiety-related depression. Or, for example, Method 1 or any of 1.1-1.10, wherein the condition is melancholic depression.

[0089] 1.12 Method 1 or any one of 1.1-1.11, wherein the condition is major depressive disorder.

[0090] 1.13 Method 1 or any of 1.1-1.10, wherein the condition is a substance use disorder.

[0091] 1.14 Method 1 or any one of 1.1-1.10, wherein said method prevents or treats negative symptoms of schizophrenia. Or, Method 1 or any one of 1.1-1.10, wherein said method improves cognition of schizophrenia.

[0092] 1.15 Method 1 or any one of 1.1-1.10, wherein said 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 or any one of 1.1-1.10, wherein said method is used to improve cognition in major depressive disorder.

[0093] 1.6 Method 1 or any of 1.1-1.7, wherein the compound is administered as an antiemetic in its free or pharmaceutically acceptable salt form.

[0094] 1.17 Method 1 or any one of 1.1-1.16, wherein the method comprises administering 9-60 mg of the compound in its free or pharmaceutically acceptable salt form daily (i.e., 9-60 mg of the compound in its free or pharmaceutically acceptable salt form as a total daily dose). For example, Method 1 or any one of 1.1-1.16, wherein the method comprises administering 9-36 mg of the compound in its free or pharmaceutically acceptable salt form daily (i.e., 9-36 mg of the compound in its free or pharmaceutically acceptable salt form as a total daily dose).

[0095] 1.18 Method 1 or any one of 1.1-1.17, wherein said method comprises administering a compound in a free or pharmaceutically acceptable salt form that provides 55%-80% D2 / D3 receptor occupancy, for example, as measured by positron emission tomography. For example, said method comprises administering a compound in a free or pharmaceutically acceptable salt form that provides approximately 65% ​​D2 / D3 receptor occupancy, for example, as measured by positron emission tomography. Or, for example, said method comprises administering a compound in a free or pharmaceutically acceptable salt form that provides approximately 60% D2 / D3 receptor occupancy, for example, as measured by positron emission tomography.

[0096] 1.19 Method 1.17 or 1.18, wherein the condition is a psychosis (e.g., a psychosis among 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).

[0097] 1.20 Method 1.17 or 1.18, wherein said method prevents or treats negative symptoms of schizophrenia. Or, method 1.17 or 1.18, wherein said method improves cognition of schizophrenia.

[0098] 1.21 Method 1 or any one of 1.1-1.16, wherein the method comprises administering 1-9 mg (e.g., 1-8 mg, e.g., 1.5-6 mg) of a compound in a 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). For example, any one of Method 1 or 1.1-1.16, wherein the method comprises administering 1-8 mg of a compound in a free or pharmaceutically acceptable salt form daily (i.e., a total daily dose of 1-8 mg). For example, any one of Method 1 or 1.1-1.16, wherein the method comprises administering 1-3 mg of a compound in a free or pharmaceutically acceptable salt form daily (i.e., a total daily dose of 1-3 mg). For example, any of method 1 or 1.1-1.16, 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., 1 mg to less than 3 mg of a total daily dose of a compound in free or pharmaceutically acceptable salt form).

[0099] 1.22 Any one of Method 1, 1.1-1.16, or 1.21, wherein said method comprises administering an amount of a compound in a free or pharmaceutically acceptable salt form that provides 10%-60% (e.g., 40%-60%, or e.g., 10%-55%, 10%-50%, 30%-50%, or 15%-50%, 15%-45%, 20%-40%, 10%-30%) D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography. Alternatively, for example, any one of Method 1, 1.1-1.16, or 1.21, wherein said method comprises administering an amount of a compound in a free or pharmaceutically acceptable salt form that provides ≤40% (e.g., about 40%), e.g., <40% D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography.

[0100] 1.23 Method 1.21 or 1.22, wherein the condition is depression (e.g., anhedonia-associated 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, bipolar disorder with mixed features, or migraine. For example, Method 1.21 or 1.22, wherein the anxiety disorder is panic disorder, social anxiety disorder, phobia, or generalized anxiety disorder. Or, for example, Method 1.21 or 1.22, wherein the condition is post-traumatic stress disorder.

[0101] 1.24 Any of methods 1.21-1.23, wherein the condition is anhedonia or anhedonia-associated depression, suicidal ideation, anxiety depression, inflammatory depression, treatment-resistant depression, dysphoric depression, bipolar depression, psychotic depression, or post-psychotic depression. For example, the condition is anxiety depression.

[0102] 1.25 Any of methods 1.21-1.24, wherein the condition is major depressive disorder.

[0103] 1.26 Method 1.21 or 1.22, wherein the condition described is a substance use disorder.

[0104] 1.27 Method 1 or any one of 1.1-1.26, wherein said method comprises administering a pharmaceutical composition comprising a compound in its free or pharmaceutically acceptable salt form. For example, Method 1 or any one of 1.1-1.26, wherein said method comprises administering Formula 1.15 or Composition 1 or any one of 1.1-1.15 (see above).

[0105] 1.28 Method 1 or any one of 1.1-1.27, wherein the method comprises administering a compound of formula I in its free or pharmaceutically acceptable salt form once, twice, or three times daily (e.g., once daily). For example, Method 1 or any one of 1.1-1.27, wherein the method comprises administering a pharmaceutical composition comprising a compound of formula I in its free or pharmaceutically acceptable salt form once, twice, or three times daily (e.g., once daily).

[0106] 1.29 Method 1 or any one of 1.1-1.28, wherein the method comprises administering compound A in its free or pharmaceutically acceptable salt form once, twice, or three times daily (e.g., once daily).

[0107] 1.30 This application also provides method 1 or any one of 1.1-1.29 to promote or enhance neuroplasticity in a patient (e.g., a human) in need, wherein said method comprises administering to said patient a compound of formula I in free or pharmaceutically acceptable salt form (e.g., any one of formula I above or 1.1-1.15), or a pharmaceutical composition comprising a compound of formula I in free or pharmaceutically acceptable salt form (e.g., formula 1.15 above or composition 1 or any one of 1.1-1.15). For example, this application provides a method for promoting or enhancing neuroplasticity to improve the rehabilitation of patients with brain injuries (e.g., humans) 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 free or pharmaceutically acceptable salt form (e.g., any one of formula I above or 1.1-1.15), or a pharmaceutical composition comprising a compound of formula I in free or pharmaceutically acceptable salt form (e.g., formula 1.15 above or composition 1 or any one of 1.1-1.15).

[0108] This application also provides compounds of formula X or formula I (e.g., any of formulas 1.1-1.15) or pharmaceutical compositions disclosed herein (e.g., formula 1.15 or composition 1 or any of 1.1-1.15) for use in method 1 or any of 1.1-1.30 (see above).

[0109] This application also provides the use of a compound of formula X or formula I (e.g., any of formulas 1.1-1.15) or a pharmaceutical composition disclosed herein (e.g., formula 1.15 or composition 1 or any of 1.1-1.15) in method 1 or any of 1.1-1.30 (see above).

[0110] This application also provides the use of a compound of formula X or formula I (e.g., any of formulas 1.1-1.15) in the preparation of a medicament (e.g., formula 1.15 or composition 1 or any of 1.1-1.15) for use in method 1 or any of 1.1-1.30 (see above).

[0111] This application also provides intermediate compounds of Formulas II and III, each in free or salt (e.g., pharmaceutically acceptable salt) form.

[0112] For example, this application also provides compounds of formula II: Formula II, in: R 31 R 32 R 33 R 34 R 35 R 36 and R 37 Independently selected from H and D; and R 33 R 34 R 35 R 36 and R 37 At least one of them is D; The compound is in free or salt form. Optionally, the compounds described herein are substantially free of their (S,S) enantiomers.

[0113] This application further provides compounds of formula II as follows: 2.1 Formula II, wherein the compound is in a pharmaceutically acceptable salt form.

[0114] 2.2 Equation II or 2.1, where R 31 and R 32 The answer is D.

[0115] 2.3 Any one of Equations II, 2.1, or 2.2, where R 33 R 34 R 35 R 36 and R 37 Each is D.

[0116] 2.4 Equation II or any one of 2.1-2.3, where R 31 R 32 R 33 R 34 R 35 R 36 and R 37 Each is D.

[0117] 2.5 Formula II or any one of 2.1-2.4, wherein said compound is: , The compound is in free or salt (e.g., a pharmaceutically acceptable salt) form, for example, in free form.

[0118] This application also provides compounds of formula III: Formula III, 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 38 R 39 R 40 R 41 R 42 and R 43 Independently selected from H and D; and R 38 R 39 and R 40 At least one of them is D; The compound is in free or salt form.

[0119] This application further provides compounds of formula III as follows: 3.1 Formula III, wherein the compound is in a pharmaceutically acceptable salt form.

[0120] 3.2 Equation III or 3.1, where R 38 R 39 and R 40 Each is D.

[0121] 3.3 Any one of Equations III, 3.1, or 3.2, where R 41 R 42 and R 43 Each is D.

[0122] 3.4 Equation III or any one of 3.1-3.3, where R 38 R 39 R 40 R 41 R 42 and R 43 Each is D.

[0123] 3.5 Formula III or any one of 3.1-3.4, wherein said compound is: , The compound is in free or salt (e.g., a pharmaceutically acceptable salt) form, for example, in free form.

[0124] 3.6 Formula III or any one of 3.1-3.5, wherein said compound is: , The compound is in free or salt (e.g., a pharmaceutically acceptable salt) form, for example, in free form.

[0125] 3.7 Any one of Formula III or 3.1-3.5, where X is OH.

[0126] 3.8 Formula III or any one of 3.1-3.5, wherein X is a leaving group (e.g., an activated ester, such as an O-acylisourea, or a halide). For example, Formula III or any one of 3.1-3.5, wherein said compound is: .

[0127] This application further provides a method (method 1) for synthesizing compounds of formula I in free or salt (e.g., pharmaceutically acceptable salt) form.

[0128] This application further provides the following method 1: 1.1 Method 1, wherein the method comprises reacting a compound of formula II (e.g., any one of formulas 2.1-2.5) with a compound of formula III (e.g., any one of formulas 3.1-3.8).

[0129] 1.2 Method 1 or 1.1, wherein the method is carried out in the presence of an amine (e.g., triethylamine, dimethylformamide and / or dimethylacetamide).

[0130] 1.3 Method 1, 1.1 or 1.2, wherein the method is carried out in an organic solvent (e.g., dimethylformamide, triethylamine and / or dimethylacetamide).

[0131] 1.4 Method 1 or any one of 1.1-1.3, wherein the method is carried out using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and hydroxybenzotriazole. For example, any method wherein the method is carried out using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydroxybenzotriazole, triethylamine, and dimethylformamide and / or dimethylacetamide.

[0132] 1.5 Method 1 or any one of 1.1-1.4, wherein said method comprises taking a compound of formula IIIa in free or salt (e.g., a pharmaceutically acceptable salt) form: Formula IIIa, Where PG is an H or amine protecting group (e.g., H); and R 38 R 39 R 40 R 41 R 42 and R 43 Independently selected from H and D, and R 38 R 39 and R 40 At least one of them is D, which reacts with an activator (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide).

[0133] 1.6 Method 1.5, wherein the method forms a compound of formula IIIb: Formula IIIb, Where PG is an H or amine protecting group (e.g., H); and R 38 R 39 R 40 R 41 R 42 and R 43 Independently selected from H and D, and R 38 R 39 and R 40 At least one of them is D, and the compound is in free or salt form (e.g., a pharmaceutically acceptable salt).

[0134] 1.7 Method 1.6, wherein the compound of formula IIIb is formed in situ.

[0135] 1.8 Any of Method 1 or 1.1-1.7, further comprising, for example, removing the amine protecting group with hydrochloric acid in ethyl acetate under acidic or basic conditions, for example, optionally.

[0136] 1.9 Any of Method 1 or 1.1-1.8, wherein the method further comprises isolating the compound of Formula I in free or salt (e.g., pharmaceutically acceptable salt) form (e.g., any of Formula 1.1-1.15).

[0137] For the compounds disclosed herein, a hydrogen atom position is considered to be substituted with deuterium when the abundance of deuterium at that position is enriched. The natural abundance of deuterium is approximately 0.02%, therefore, when the frequency of deuterium incorporation at a specific position exceeds 0.02%, the compound is considered to be "enriched" with deuterium at that position. Thus, for the deuterated compounds disclosed herein, any position designated as deuterium (i.e., D) can be enriched with levels 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 designated as a specific isotope exists at its natural isotopic abundance.

[0138] The compounds disclosed herein, such as any one of Formula X, Formula I (e.g., any one of Formulas 1.1-1.15), Formula II (e.g., any one of Formulas 2.1-2.5), Formula III (e.g., any one of Formulas 3.1-3.8), and any one of Compound A, may exist in free or salt form, for example, as an acid addition salt. As used herein, unless otherwise specified, the language such as “compound of formula…” should be understood to cover any form of compound, for example, in free or acid addition salt form, or in which the compound contains an acidic substituent, or in a base addition salt form. Compounds of Formula X, compounds of Formula I (e.g., any one of Formulas 1.1-1.15), and Compound A are intended for use as pharmaceuticals, and therefore pharmaceutically acceptable salts are preferred. Salts unsuitable for pharmaceutical use may be included, for example, for the isolation or purification of free compounds of Formula X, compounds of Formula I (e.g., any one of Formulas 1.1-1.15), or Compound A, or their pharmaceutically acceptable salts.

[0139] The separation or purification of stereoisomers of compounds disclosed herein in free or pharmaceutically acceptable salt forms (e.g., any one of formulas X, I (e.g., any one of formulas 1.1-1.15), II (e.g., any one of formulas 2.1-2.5), III (e.g., any one of formulas 3.1-3.8), and compound A) can all be achieved by conventional methods known in the art, such as column purification, preparative thin-layer chromatography, preparative HPLC, grinding, and simulated moving bed methods.

[0140] The pure stereoisomers of the compounds and intermediates disclosed herein are isomers of other enantiomers and diastereomeric forms that substantially lack the same basic molecular structure of the compound or intermediate. "Substantially stereoisomerically pure" includes compounds or intermediates with a stereoisomer excess of greater than 90% (i.e., more than 90% of one stereoisomer and less than 10% of any other possible stereoisomers). The terms "substantially diastereomeric pure" and "substantially enantiomerically pure" should be understood in a similar manner, but subsequently, diastereomeric and enantiomeric excesses of the material under discussion should be taken into account, respectively.

[0141] The compounds disclosed herein in free or pharmaceutically acceptable salt form, such as any of formulas X, I (e.g., any one of formulas 1.1-1.15), II (e.g., any one of formulas 2.1-2.5), III (e.g., any one of formulas 3.1-3.8), and compound A, can be prepared by means of methods as described and exemplified herein, as well as similar methods and methods known in the field of chemistry. Such methods include, but are not limited to, those described below. If not commercially available, the starting materials used in these methods can be prepared using techniques similar to or analogous to the synthesis of known compounds by procedures selected from the field of chemistry.

[0142] Pharmaceutically acceptable salts of any of Formula X, Formula I (e.g., any one of Formulas 1.1-1.15), Formula II (e.g., any one of Formulas 2.1-2.5), Formula III (e.g., any one of Formulas 3.1-3.8), and Compound A can be synthesized by conventional chemical methods from parent compounds containing basic or acidic moieties. 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.

[0143] Regarding treatment methods, the term "effective dose" is intended to encompass the effective dose for treating a specific disease or condition.

[0144] The dosage used to implement this invention will, of course, vary depending on, for example, the specific disease or condition to be treated, the specific compound used, the mode of administration, and the desired therapy.

[0145] The compounds disclosed herein, in free or pharmaceutically acceptable salt form, such as any of formula X, formula I (e.g., any one of formulas 1.1-1.15), and compound A, may be administered by any suitable route, including oral, parenteral, or transdermal, but preferably orally.

[0146] Pharmaceutical compositions comprising compounds in free or pharmaceutically acceptable salt form disclosed herein (e.g., any of formula X, formula I (e.g., any of formulas 1.1-1.15 or composition 1 or any of 1.1-1.15) or compound A) can be prepared using conventional diluents or excipients and techniques known in the medical field. Therefore, oral dosage forms may include tablets, capsules, solutions, suspensions, etc.

[0147] As used herein, the term "patient" includes both humans and non-humans (i.e., animals). In some implementations, the patient is a human.

[0148] Example abbreviation AcOH = Acetic acid Boc = tert-Butoxycarbonyl DIAD = diisopropyl azodicarbonate DCM = dichloromethane DMA or DMAc = dimethylacetamide DMAP = 4-Dimethylaminopyridine DPPA = Diphenylphosphoazide DMF = dimethylformamide EDCI or EDC = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc or EA = Ethyl acetate h = hours HATU = Azabenzotriazole tetramethylurea hexafluorophosphate 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: 5-chloro- N -((2 R ,3 R )-1-(dideuterated(pentadeuterated phenyl)methyl)-2-methylpyrrolidone-3-yl)-2-trideuterated methoxy-4-(trideuterated methylamino)benzamide Compound 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 stirred solution of Boc-D-alanine (500 g, 2.64 mol), Miescherichia coli (400 g, 2.78 mol), and DMAP (388 g, 3.18 mol) in CH2Cl2 (5 L). The resulting solution was then warmed to room temperature (rt) and stirred for 16 h. It was quenched with water (1.5 L), and the organic phase was washed with a cold solution of 5% KHSO4 (3 L × 3), water (3 L × 1), and brine, then dried over anhydrous MgSO4 and concentrated to give a residue. EtOAc (4 L) was added, and the reaction mixture was refluxed for 2 h. The solution was concentrated, and the residue was stirred in EtOAc (500 L) at -15 °C for 2 h, then filtered, and the filter cake was collected to give the title compound as a white solid (150 g, 27% yield). The mother liquor was further refluxed for 2 hours, then stirred and filtered in EA at -10°C to obtain the title compound (40 g) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 4.45 (q, J =6.8 Hz, 1H), 3.22 (s, 2H), 1.57 (s, 9H), 1.51 (d, J =6.8 Hz, 3H). MS m / z (ESI): 158 [M+H-56] + . Compound 16: (2R,3R)-3-hydroxy-2-methyl-5-oxopyrrolidine-1-carboxylic acid tert-butyl ester At 0 °C, 200 mL of AcOH was added to a stirred solution of compound 15 (40 g, 187.6 mmol) in 400 mL of DCM, followed by three portions of NaBH4 (21.3 g, 562.8 mmol). The resulting solution was then warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with 5% NaHCO3 at 0 °C. It was extracted with DCM (200 mL × 3). The combined organic layers were washed with 5% NaHCO3 solution. The organic phase was dried over anhydrous MgSO4 and concentrated to give a residue, which was stirred in isopropyl ether and filtered to give title compound 16 (24 g, 59.4% yield). 1H 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] + . Compound 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 a dry THF (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 at 0 °C and quenched with saturated NH4Cl. It was then extracted with EtOAc (1 L × 3). The organic phase was dried over anhydrous MgSO4 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] + . Compound 18: (2R,3S)-2-methyl-3-(4-nitrobenzoyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester DIAD (16.6 g, 82.1 mmol) was added to a cold solution of compound 17 (15.74 g, 78.2 mmol), 4-nitrobenzoic acid (13.72 g, 82.1 mmol), and PPh3 (16.42 g, 62.6 mmol) in dried THF (250 ml) over 30 minutes at 0 °C. The reaction mixture was warmed to room temperature for 16 hours. The resulting mixture was cooled and quenched with water. The mixture was extracted with EtOAc (200 ml × 3), dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography to give compound 18 (24.7 g, 90.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.31-8.17 (m,4H), 5.20 (d, J =4 Hz, 1H), 4.17-3.86 (m, 1H), 3.59-3.46 (m, 2H), 2.35-2.11 (m,2H) 1.48 (s, 9H), 1.28 (d, J =6.8 Hz, 3H). MS m / z (ESI): 295 [M+H-56] + . Compound 19: (2R,3S)-2-methylpyrrolidone-3-yl-4-nitrobenzene ester The mixture of compound 18 (23.4 g, 66.8 mmol) and TFA (120 mL) in DCM (240 mL) was stirred at room temperature for 1 hour, then concentrated to give compound 19 (16.7 g, 100% yield). LCMS: M+1 = 251. Compound 20: (2R,3S)-2-methyl-1-(pentadeuterylbenzoyl)pyrrolidine-3-yl-4-nitrobenzene ester At 0 °C, 4.4 equivalents of Et3N were added to a DCM solution of 19 HCl salt and 1.4 equivalents of benzoyl chloride-d5. The reaction mixture was heated to room temperature and stirred for 16 h. After the reaction was complete, the reaction mixture was washed twice with water and concentrated to give 20 (crude product).

[0149] Compound 21: ((2R,3S)-3-hydroxy-2-methylpyrrolidone-1-yl)(pentadeuterated phenyl) methyl ketone 1.2 equivalents of NaOH were added to a 20 mL MeOH / H₂O (1:1) stirred solution. The reaction mixture was stirred for 2 h and then concentrated under reduced pressure. The residue was diluted with water and extracted with DCM (5 times). The organic phase was concentrated to give 21 (crude product).

[0150] Compound 22: (2R,3S)-1-(dideuterated(pentadeuteratedphenyl)methyl)-2-methylpyrrolidine-3-ol Under a nitrogen atmosphere at 0–10 °C, a dry THF solution of 21 was added dropwise to a 40 mL solution of 2.5 equivalents of LiAlD4 in dry THF. After stirring at 0–10 °C for 45 min, the reaction was heated to room temperature and stirred at the same temperature for 16 h. After the reaction was complete, it was cooled to 0 °C and quenched with 20% KOH aqueous solution and H2O. The suspension was extracted twice with DCM. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain 22.

[0151] Compound 23: (2R,3S)-1-(dideuterated (pentadeuterated phenyl)methyl)-2-methylpyrrolidine-3-ylmethanesulfonate At 0 °C, 1.5 equivalents of MsCl (methanesulfonyl chloride) were added to a stirred solution of 22 and 2 equivalents of Et3N in DCM. The reaction mixture was stirred at rt for 3 h, then quenched twice with a saturated NaHCO3 aqueous solution, and the aqueous layer was extracted with DCM. The combined organic phases were washed with brine. The organic phase was concentrated under reduced pressure to give 23.

[0152] Compound 24: (2R,3R)-3-azido-1-(dideuterated(pentadeuteratedphenyl)methyl)-2-methylpyrrolidine At rt, 3 equivalents of NaN3 were added to a 23% DMF stirred solution. The reaction mixture was stirred at 80°C for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (twice). The organic phase was washed with brine. The organic phase was concentrated to approximately 1 mL, and then MeOH was added and concentrated. The 24% MeOH solution was used directly for the next step.

[0153] Compound 25: (2R,3R)-1-(dideuterated(pentadeuteratedphenyl)methyl)-2-methylpyrrolidine-3-amine The mixture of 24 and 10% Pd / C in MeOH was stirred for 24 h at rt and H2 (atm). The reaction mixture was filtered, the solvent was evaporated, and diluted with EtOAc. HCl (4 mol / L in EtOAc) was added to the solution. The reaction mixture was stirred at rt for 1 h and then filtered to obtain 25.

[0154] Compound 27: A DMF (90 mL) solution of 26 (9.00 g, 49.2 mmol), CD3I (17.81 g, 122.9 mmol), and K2CO3 (16.98 g, 122.9 mmol) was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum to give 27 (6.32 g, 59.20% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.88 (d, J=1.6Hz, 1H), 7.87-7.85 (m, 2H). Compound 28: 10% Pd-C (100 mg) was added to a methanol (65 mL) solution of 27 (6.32 g, 29.1 mmol). The reaction mixture was stirred at room temperature for 1 hour under hydrogen (50 psi). The reaction was monitored by TLC. The mixture was filtered and concentrated under vacuum to give 28 (4.10 g, 75.26% yield) as a white solid. LC-MS (ESI) m / z calculated values ​​(M+H) + 187.9, measured value 187.1. Compound 29: NCS (0.85 g, 14.9 mmol) was added to a CH3CN (41 mL) solution of 28 (4.10 g, 21.9 mmol). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to rt and concentrated under vacuum. The resulting residue was purified with a 1:1 hexane / EtOAc solution to give 29 (2.46 g, 50.68%) as a brown solid. LC-MS (ESI) m / z (M+H) + 221.9, measured value 221.1. Compound 30: At 0 °C, t-BuONa (1.60 g, 16.7 mmol) was added to 29 (2.46 g, 11.1 mmol) of DCM (80 mL). Then, Boc₂O (2.42 g, 11.1 mmol) was added dropwise to the mixture. The reaction was stirred at 25 °C for 16 hours. The mixture was concentrated under vacuum to obtain a residue, which was purified by silica gel chromatography (10-50% EtOAc / petroleum ether) to give 30 (1.83 g) as a yellow solid.

[0155] Compound 31: One equivalent of NaH was added to a 30 mL dry DMF solution, and the resulting solution was stirred at room temperature for 30 minutes. Then, 1.5 equivalents of CD3I were added, and the mixture was stirred at room temperature for 3 hours. The reaction was cooled to 0 °C, quenched with a saturated aqueous NH4Cl solution, and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by rapid column chromatography to give 31 mL.

[0156] Compound 32: 1.2 equivalents of LiOH were added to a THF:water (2:1) solution of 31, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC. The mixture was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (1-12% MeOH / DCM) to give 32.

[0157] Compound 33: To a stirred solution of 2 equivalents of Et3N and DMA, 1.2 equivalents of 25, 1.5 equivalents of HOBt, and 1.6 equivalents of EDCI were added. The reaction mixture was stirred at rt for 2 h. The resulting mixture was quenched with water, extracted with EtOAc (3 times), washed with brine (once), and dried over anhydrous Na2SO4. The organic phase was concentrated, and the residue was purified and concentrated by column chromatography (silica gel; 0-10% methanol / dichloromethane) to give 33.

[0158] Compound 34: The solution of 33 was stirred at rt for 2 h in excess HCl (4 mol / L in EtOAc). The reaction mixture was concentrated, and the residue was diluted with EtOAc and extracted twice with H2O. The aqueous phases were combined and alkalized to pH ~11 with sodium hydroxide, extracted three times with EtOAc, and the combined organic phases were washed with brine and dried over anhydrous Na2SO4. The organic phases were concentrated, and the residue was purified by column chromatography (silica gel, 0-100% EtOAc / hexane) to give 34.

[0159] Example 2 – Determination of radioligand binding competition activity on recombinant human dopamine and serotonin receptors using filtration binding Radioligand binding experiments were performed using membrane preparations. Receptor accession numbers, cell backgrounds, and reference compounds are listed in Table 1.

[0160] Table 1.

[0161] The radioligand competitive binding activity of compound (D13) from Example 11 (also shown as 34 in Example 1) was tested. The results are shown in Table 2.

[0162] Table 2. Combination

[0163] a. (±)-cis- N -(1-Benzyl-2-methylpyrrolidone-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide b. N-[(2R,3R)-1-benzyl-2-methylpyrrolid-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide c. The average of the values ​​in parentheses.

[0164] d. Example 3 – Determination of agonist or antagonist activity on recombinant human dopamine and serotonin receptors using IPOne HTRF, cAMP HTRF, and GTPγS SPA 35 S-GTPgS assays were performed using membrane preparations. 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.

[0165] Table 3.

[0166] The compound (D13) of Example 11 (also shown as 34 in Example 1) was tested for antagonist and agonist activities against human dopamine and serotonin receptors. The results are shown in Tables 4-6.

[0167] The agonist activity of the test compound is expressed as the reference agonist in its EC50 values. 100 Percentage of activity at a given concentration. The antagonistic activity of the tested compound is expressed as its EC50 value. 80 The percentage of inhibition of the reference agonist activity at a given concentration.

[0168] Table 4. Functional Measurement

[0169] a. (±)-cis- N -(1-Benzyl-2-methylpyrrolidone-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide b. N-[(2R,3R)-1-benzyl-2-methylpyrrolid-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide c. The average of the values ​​in parentheses.

[0170] Table 5.

[0171] 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-methylpyrrolid-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide d. The average of the values ​​in parentheses.

[0172] As shown above, the deuterated compound (D13) of Example 11 (also shown as 34 in Example 1) is a D2 antagonist and a 5-HT2A and 5-HT1A agonist.

[0173] Table 6.

[0174] a. N-[(2R,3R)-1-benzyl-2-methylpyrrolid-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide Example 4 – In vivo pharmacokinetics Group A rats were administered the test compound (via PO). Blood samples were obtained at 5, 10, and 30 minutes and at 1, 2, 4, 8, and 24 hours post-administration. After 24 hours of blood collection, the animals underwent cerebral perfusion, and brain tissue was then obtained.

[0175] Group B rats were administered the test compound (via PO). Blood samples were collected from three animals in each dose group at specified time points (1, 4, and 8 hours), followed by cerebral perfusion, and then samples were collected.

[0176] The test compound was the deuterated compound (D13) of Example 11 (also shown as 34 in Example 1).

[0177] Plasma (obtained from blood samples) and brain tissue (after homogenization and processing) were analyzed by LC / MS / MS. Plasma was obtained from the blood by centrifugation. Brain tissue was collected after the animals were perfused to remove residual cardiovascular blood.

[0178] Blood was collected from rats by surgical cannulation of the femoral artery. The rats weighed approximately 250-350 g. Water was provided without restriction. The rats were fasted overnight before oral administration. Food was available 4 hours after administration.

[0179] The dosage form is a 0.5% aqueous solution of methylcellulose (4000 cps) and a 0.1% Tween solution. TM 80°C for PO administration. Once prepared, vortex / homogenize the suspension and continuously stir until administration. Dosage concentrations: 0.1 mg / mL (for a 0.5 mg / kg dose) and 1 mg / mL (for a 5 mg / kg dose). Route of administration: tube feeding. Dosage volume: 5 mL / kg. Formulation is a suspension.

[0180] Blood samples were obtained via an automated sampling system in tubes containing potassium EDTA anticoagulant up to 24 hours post-administration. Plasma was obtained by centrifugation and flash-frozen on dry ice 30 minutes after collection. Aliquots of each dosage were taken, appropriately diluted, and analyzed simultaneously using plasma samples by LC-MS / MS.

[0181] Plasma (obtained from blood samples) and brain tissue (homogenized and processed) were analyzed by LC / MS / MS. Plasma was obtained from blood by centrifugation within 30 minutes of sample collection. Brain tissue was collected after the animal underwent perfusion to remove residual cardiovascular blood.

[0182] Dosage solutions, plasma (obtained from blood), and brain tissue (homogenized and processed) were stored at -20°C until analysis.

[0183] The plasma sample was thawed at room temperature before adding an organic solvent containing an internal standard to precipitate the protein.

[0184] The brain samples were thawed and homogenized in water (3-4 times the volume), and the aliquots of the homogenate were analyzed by LC / MS / MS.

[0185] The results are shown in Figure 1-4 middle.

[0186] The plasma pharmacokinetics of N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R)nemopride) are similar to those of the deuterated compound (D13) of Example 11 (see [link to relevant documentation]). Figure 1 ).exist Figure 1 In the figures, data for cis(R,R)nemopride are shown as solid lines, while data for the deuterated compound (D13) of Example 11 are shown as dashed lines.

[0187] The deuterated compound (D13) of Example 11, after a single PO administration of 0.5 mg / kg and 5 mg / kg, showed prolonged brain accumulation in rats as follows: Figure 3 and Figure 4 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.

[0188] Compared to N-[(2R,3R)-1-benzyl-2-methylpyrrolidone-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide (cis(R,R)nemopride), the deuterated compound (D13) of Example 11 exhibits enriched brain levels (see [link to example]). Figure 2 Both 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 compound (D13) of Example 11 are compared in Table 7 (both were administered at a single PO dose of 0.5 mg / kg).

[0189] Table 7.

[0190] Example 5 – Time progression of isolated radioligand binding in membrane preparations to determine receptor occupancy at central D2 receptors This study involved oral administration of the deuterated compound (34) of Example 1 and the positive control olanzapine (10 mg / kg, po) at various time points (e.g., 1, 2, 4, 8, and 24 hours), followed by […]. 3[H] Raldapride and rat striatal membranes were used to determine receptor occupancy at central D2 receptors. Liquid scintillation counting was used to quantify radioactivity.

[0191] animal Rats.

[0192] Drug treatment On the day of testing, animals were given a single oral dose of the mediator, the deuterated compound (34) of Example 1, or olanzapine. Rats were sacrificed at specified time points, for example, 1, 2, 4, 8, and 24 hours after administration, or 1 hour after administration of the mediator and olanzapine.

[0193] Pharmacokinetics Blood samples were obtained after death via cardiac puncture. Plasma was collected for pharmacokinetic (PK) testing.

[0194] 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.

[0195] Homogenization preparation The striatum was homogenized separately.

[0196] Measurement Homogenize the striatum with [ 3 Incubate with [H] raldilopeptide. Determine radioactivity by liquid scintillation counting.

[0197] Example 6 – A Probabilistic Reward Task for Rats Based on a Touchscreen The Probabilistic Reward Task (PRT) uses visual discrimination methods to quantify reward responsiveness, identify deficiencies, and characterize drug-induced improvements. Rats were trained on a touchscreen-based PRT and exposed to asymmetric probabilistic unexpected events to generate a biased response to rich 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 a medium or the deuterated compound (34) of Example 1.

[0198] 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.

[0199] Example 7 – Conditioned Avoidance Response Rats were used. Risperidone (0.5 mg / kg; Sigma Aldrich) was dissolved in water containing 10% DMSO and administered intraperitoneally (ip) 30 minutes before the test at a volume of 1 mg / kg. The deuterated compound (34) of Example 1 was administered orally before the test.

[0200] The Conditioned Avoidance Response (CAR) test is an animal model used to screen antipsychotic drugs.

[0201] Example 8 – Head Shaking Response Rat. The deuterated compound (34) of Example 1 was administered orally.

[0202] Animals were given the drug, DOI, or test compound and then returned to their cages for an appropriate pretreatment period. Head shaking was then recorded. Head shaking is a rapid, rhythmic swaying of the head in a radial pattern.

[0203] Example 9 – DOI-induced head-shaking response Rat were used. The deuterated compound (34) of Example 1 was administered orally. DOI was administered via intraperitoneal injection. Ketoserine (1 mg / kg) was administered via intraperitoneal injection.

[0204] The animal was administered the drug, ketoselin, or the test compound and then returned to its cage for an appropriate pretreatment period. The rat was then injected with the DOI, and head shaking was recorded 10 minutes after injection and continued for 10 minutes. The head shaking response was a rapid, rhythmic, radial head movement.

[0205] Example 10 – Synthesis of the starting materials of Example 1 Dissolve 22 (7.5 g, 59 mmol) in cold DCM (200 mL, 0 °C). Add 3 drops of DMF and oxalyl chloride (118 mmol, dropwise) to the solution. Heat the reaction to room temperature and stir for 3 hours. Remove the solvent under reduced pressure to give 23 (100% yield, 8.59 g).

[0206] Example 11 Synthesis: 5-chloro- N -((2 R ,3 R )-1-(dideuterated(pentadeuteratedphenyl)methyl)-2-methylpyrrolidone-3-yl)-2-trideuteratedmethoxy-4-(trideuteratedmethylamino)benzamide (D13) Int-3: Methyl 1-acetylcyclopropane-1-carboxylic acid ester At 0 °C, K₂CO₃ (178 g, 1.3 mol, 1.5 eq) and 1,2-dibromoethane (193.4 g, 1.0 mol, 1.2 eq) were added to a stirred solution of methyl 3-oxobutyrate (Int-1) (100 g, 0.9 mol, 1.0 eq) in CH₃CN (2000 mL, 20 V). The reaction mixture was stirred at 70 °C for 48 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered and washed with CH₃CN (500 mL). The filtrate was distilled under vacuum below 40 °C to give the crude product. The crude product was then distilled under vacuum at 120 °C, and the pure fraction of Int-3 (60 g, 49% yield) as a colorless liquid was collected. 1 H NMR (400 MHz, DMSO- d 6 ): δ 3.36 (s, 3H), 2.34 (s, 3H), 1.38-1.34 (m, 4H).

[0207] Int-5: (R)-2-methyl-1-(1-phenylethyl)-4,5-dihydro-1H-pyrrole-3-carboxylic acid methyl ester (R)-1-phenylethyl-1-amine (51.1 g, 0.4 mol, 1.0 eq) was added to a stirred solution of Int-3 (60 g, 0.4 mol, 1.0 eq) in toluene (600 mL, 10 V). The resulting reaction mixture was stirred at 115 °C for 48 h. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography. The product was eluted with 8-10% ethyl acetate / hexane to give Int-5 (35 g, crude product) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ7.45-7.34 (m, 2H), 7.30-7.20 (m, 3H), 4.96 (q, J =7.0, 6.8 Hz, 1H), 3.51 (s,3H), 3.48-3.36 (m, 1H), 3.06 (q, J =9.2, 1.6 Hz, 1H), 2.72-2.52 (m, 2H), 2.25(s, 3H), 1.49 (d, J=7.2 Hz, 3H). LCMS m / z: 246.2 (M+1).

[0208] Int-6 and 6a: 2-Methyl-1-((R)-1-phenylethyl)pyrrolidine-3-carboxylic acid methyl ester At 0 °C, AcOH (175 mL, 5 V) and NaBH4 (16.1 g, 0.4 mol, 3.0 eq) were added in portions to a stirred solution of Int-5 (35 g, 0.1 mol, 1.0 eq) in CH3CN (350 mL, 10 V). The reaction mixture was stirred at room temperature for 5 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was alkalized at 0 °C with saturated NaHCO3 solution and extracted with ethyl acetate (200 mL × 2). The organic layers were combined, dried over sodium sulfate, and concentrated under vacuum to give a mixture of 6 and 6A (18 g, crude product) as a brown, viscous oil. LCMS m / z: 248.33 (M+1).

[0209] Int-7: (2R,3R)-2-methyl-1-((R)-1-phenylethyl)pyrrolidine-3-carboxylic acid methyl ester The mixture of 6 and 6A (18 g, 0.07 mol, 1.0 eq) was stirred in hexane (90 mL, 5 V) and cooled to -78 °C, then stirred at -70 °C for 2 h. After 2 h, the mixture was filtered, and the solid was collected and dried under vacuum to give Int-7 (8.0 g, 23% yield in two steps) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.40-7.21 (m, 5H), 3.65-3.55 (m, 1H), 3.40-3.30 (m, 1H), 3.12-3.05 (m, 1H), 2.65-2.56 (m, 1H), 2.45-2.38 (m, 1H), 2.08-1.98 (m, 1H), 1.84-1.72 (m, 1H), 1.27 (d, J =6.8 Hz, 3H), 0.71 (d, J =6.4 Hz, 3H). LCMS m / z: 248.0 (M+1).

[0210] Int-8: (2R,3R)-2-methylpyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-methyl ester At room temperature and under a nitrogen atmosphere, 10% Pd / C (50% wet, 10% w / w) and (Boc)₂O (17.67 g, 80.97 mmol, 2.5 eq) were added to a stirred solution of Int-7 (8.0 g, 32.4 mmol, 1.0 eq) in MeOH:EtOAc (1:1, 80 mL, 10 V). The reaction mixture was degassed twice with nitrogen, followed by purging with hydrogen and then priming the autoclave with hydrogen at a pressure of 20 kg. The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate (200 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography. Int-8 was eluted with 10–12% ethyl acetate / hexane to give a brown, viscous oil (5.5 g, 70% yield). 1 HNMR (400 MHz, DMSO- d 6 ): δ 4.09-3.95 (m, 1H), 3.63 (s, 3H), 3.35-3.15 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.86 (m, 1H), 1.39 (s, 9H), 0.96 (d, J =6.4 Hz, 3H). LCMS m / z: 244.37 (M+1).

[0211] Int-9: (2R,3R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-3-carboxylic acid At 0 °C, LiOH·H₂O (4.5 g, 0.1 mol, 5.0 eq) was added to a methanol-water (1:1, 55 mL, 10 V) solution of Int-8 (5.5 g, 0.02 mol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. The reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was diluted with water (50 mL) and ethyl acetate (50 mL). The layers were separated, and the aqueous layer was acidified with 1 M HCl and extracted with ethyl acetate (2 × 100 mL). The organic layer was concentrated under vacuum to obtain Int-9 (5.2 g, crude product) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6): δ 12.45 (s, 1H), 4.10-3.95 (m, 1H), 3.40-3.27 (m, 1H), 3.22-3.01 (m, 2H), 2.15-2.00 (m, 1H), 1.97-1.82 (m, 1H), 1.39 (s, 9H), 1.01 (d, J =6.4 Hz, 3H). LCMS m / z: 228.3 (M-1).

[0212] Int-10: (2R,3R)-3-(((benzyloxy)carbonyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester TEA (6.1 mL, 0.05 mol, 2.0 eq) and DPPA (12.37 g, 0.05 mol, 2.0 eq) were added to a stirred solution of Int-9 (5.2 g, 0.02 mol, 1.0 eq) in toluene (52 mL, 10 V). The reaction mixture was heated to 90 °C for 2 h. After 2 h, the reaction mixture was cooled to 0 °C, and benzyl alcohol (4.8 g, 0.05 mol, 2.0 eq) was added. The temperature was raised to 90 °C and maintained for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by rapid column chromatography. Int-10 was eluted with 8–10% ethyl acetate / hexane (4.1 g, 54% yield) to give a brown, viscous oil. 1 HNMR (400 MHz, DMSO- d 6 ): δ 7.69-7.52 (m, 1H), 7.42-7.30 (m, 5H), 5.04 (s, 2H), 4.04-3.80 (m, 2H), 3.30-3.10 (m, 2H), 2.02-1.75 (m, 2H), 1.39 (s, 9H), 0.90(d, J =6.0 Hz, 3H). LCMS m / z: 335.4 (M+1).

[0213] Int-11: ((2R,3R)-2-methylpyrrolidone-3-yl)benzyl carbamate At 0 °C, TFA (4.0 mL, 1 V) was added to a stirred solution of Int-10 (4.0 g, 0.01 mol, 1.0 eq) in DCM. The reaction mixture was stirred at room temperature for 4 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and ground with heptane to obtain Int-11 (3.5 g, crude product) as a brown, viscous oil. The crude product was used in the next step without further purification. LCMS m / z: 234.6 (M+1).

[0214] Int-13: At 0 °C, HATU (9.1 g, 0.02 mol, 2.0 eq), benzoic acid-2,3,4,5,6-d5 (3.2 g, 0.01 mol, 1.0 eq), and DIPEA (5.5 mL, 0.03 mol, 3.0 eq) were added to a stirred solution of Int-11 (3.2 g, 0.01 mol, 1.0 eq) in THF (32 mL, 10 V). The reaction mixture was stirred at room temperature for 4 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with ice water (30 mL, 10 V) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by rapid column chromatography. Int-13 was eluted with 7–9% ethyl acetate / hexane (2.1 g, 45% yield) to give a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.63-7.52 (m, 1H),7.45-7.25 (m, 5H), 5.15-4.97 (m, 2H), 4.40-4.28 (m, 1H), 4.18-3.90 (m, 1H),3.65-3.45 (m, 1H), 3.30-3.15 (m, 1H), 2.02-1.75 (m, 2H), 1.10 (d, J =6.0 Hz,3H). LCMS m / z: 344.03 (M+1).

[0215] Int-14: ((2R,3R)-3-amino-2-methylpyrrolidone-1-yl)(phenyl-d5) methyl ketone 10% Pd / C (0.3 g, 10% w / w) was added to a stirred MeOH solution of Int-13 (2.1 g, 2.9 mmol, 1.0 eq) (20 mL, 10 V). The reaction mixture was stirred at room temperature for 16 h in the presence of H2 (20 kg). The reaction progress was monitored by TLC. The reaction mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under vacuum to give Int-14 (1.1 g, crude product) as a viscous oil. The crude product was used for the next step without further purification. LCMS m / z: 209.8 (M+1).

[0216] Int-15: (2R,3R)-2-methyl-1-((phenyl-d5)methyl-d2)pyrrolidine-3-amine At 0 °C, LiAlD4 (0.3 g, 7.9 mmol, 1.5 eq) was added fractionally to a stirred solution of Int-14 (1.1 g, 5.3 mmol, 1.0 eq) in THF (10 mL, 20 V). The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water at 0 °C. The reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give Int-15 (0.6 g, crude product) as a viscous oil. The crude product was used for the next step without further purification. LCMS (Method F) m / z: 198.0 (M+1).

[0217] Int-16: (2-chloro-5-(methoxy-d3)-4-(((2R,3R)-2-methyl-1-((phenyl-d5)methyl-d2)pyrrolidone-3-yl)carbamoyl)phenyl)(methyl-d3)tert-butyl carbamate At 0 °C, EDC-HCl (0.7 g, 3.7 mmol, 1.2 eq), HOBt (0.5 g, 3.7 mmol, 1.2 eq), TEA (1.2 mL, 9.1 mmol, 3.0 eq), and Int-15 (0.6 g, 3.0 mmol, 1.0 eq) were added to a stirred solution of Int-A (see Example 12) (0.98 g, 3.0 mmol, 1.0 eq) in THF (6 mL, 10 V). The reaction mixture was stirred at room temperature for 4 h. The reaction progress was monitored by TLC. The reaction mixture was diluted with cold water (30 mL, 10 V) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give Int-16 (0.400 g, 26.28% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.18 (d, J =6.8 Hz, 1H).7.77(s, 1H), 7.28 (s, 1H), 4.48-4.38 (m, 1H), 2.90-2.75 (m, 1H), 2.65-2.55 (m,1H), 2.20-2.02 (m, 2H), 1.65-1.50 (m, 1H), 1.32 (s, 9H), 1.20 (d, J =6.0 Hz,3H). LCMS m / z: 500.6 (M+1).

[0218] D13: 5-Chloro-2-(methoxy-d3)-N-((2R,3R)-2-methyl-1-((phenyl-d5)methyl-d2)pyrrolid-3-yl)-4-((methyl-d3)amino)benzamide At 0 °C, 0.8 mL of water containing 37% HCl (2 V) was added to a stirred solution of Int-16 (0.4 g, 0.8 mmol, 1.0 eq) in EtOAc. The reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure, the residue was alkalized with NaHCO3 solution (10 mL), and the aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the crude product. The crude product was purified by preparative chiral chromatography to give D13 (0.1 g, crude product) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d6 ): δ 7.94 (d, J =8.8 Hz, 1H).7.74(s, 1H), 6.26 (s, 1H), 6.08 (s, 1H), 4.50-4.35 (m, 1H), 2.83 (t, J =6.8 Hz, 1H), 2.59 (t, J =6.8 Hz, 1H), 2.19-2.02 (m, 2H), 1.58-1.48 (m, 1H), 1.02 (d, J =6.4 Hz, 3H). LCMS m / z: 401.6 (M+1). HPLC: 4.12 min, purity 99.8%. Chiral HPLC: 4.88 min, purity 99.8%.

[0219] Example 12: Synthesis: Int-A Synthesis of methyl 2-hydroxy-4-nitrobenzoate H₂SO₄ (20 mL, 2 V) was added dropwise to a stirred solution of 2-hydroxy-4-nitrobenzoic acid (10.0 g, 54.6 mmol, 1.0 eq) dissolved in MeOH (200 mL, 20 V) and cooled to 0 °C. The reaction mixture was then stirred at 80 °C for 16 h. The progress was observed by TLC. After the reaction was complete, the solvent was removed under vacuum, followed by alkalization with NaHCO₃ solution (100 mL) and extraction with ethyl acetate (100 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography. Methyl 2-hydroxy-4-nitrobenzoate was eluted with 6–8% ethyl acetate / hexane (9.0 g, yield 83.6%) to give a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.99 (s, 1H), 7.94 (d, J= 8.8 Hz, 1H), 7.75-7.70 (m, 2H), 3.89 (s, 3H).

[0220] Synthesis of methyl 2-(methoxy-d3)-4-nitrobenzoate K₂CO₃ (12.6 g, 91.4 mmol, 2.0 eq) was added to a stirred solution of methyl 2-hydroxy-4-nitrobenzene (9.0 g, 45.7 mmol, 1.0 eq) in DMF (90 mL, 10 V) cooled to 0 °C. The reaction mixture was stirred for 30 min, then CD₃I (13.2 g, 91.4 mmol, 2.0 eq) was added, and the reaction mixture was stirred at room temperature for 16 h. The progress was monitored by TLC. The reaction mixture was diluted with cold water and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give the crude product. The crude product was purified by rapid chromatography. The product was eluted with 5–8% ethyl acetate / hexane (8.3 g, yield 84.90%) to give a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.88-7.84 (m, 3H), 3.82 (s, 3H).

[0221] Synthesis of methyl 4-amino-2-(methoxy-d3)benzoate 10% Pd / C (0.830 g, 0.1 eq, w / w) was added to a stirred solution of methyl 2-(methoxy-d3)-4-nitrobenzoate (8.3 g, 45.7 mmol, 1.0 eq) in MeOH (83 mL, 10 V). The reaction mixture (20 kg) was stirred under H2 pressure. The process was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with MeOH (200 mL). The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 4-amino-2-(methoxy-d3)benzoate (6.2 g, 87% yield) as a grayish-white solid. The crude product was used for the next step without further purification. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.51 (d, J= 8.0 Hz, 1H), 6.20 (d, J= 2.0 Hz, 1H), 6.14 (dd, J= 6.8, 1.6Hz, 1H), 5.93 (s, 2H), 3.67 (s, 3H).

[0222] Synthesis of methyl 4-amino-5-chloro-2-(methoxy-d3)benzoate NCS (4.8 g, 35.9 mmol, 1.1 eq) was added to a CH3CN (90 mL, 10 V) stirred solution of methyl 4-amino-2-(methoxy-d3)benzoate (6.0 g, 32.6 mmol, 1.0 eq) cooled to 0 °C. The reaction mixture was stirred for 30 min, then iodomethane (9.2 g, 64.2 mmol, 2.0 eq) was added, and the reaction mixture was stirred at room temperature for 16 h. The progress was monitored by TLC. The reaction mixture was quenched with 30% NaHCO3 solution (30 mL) and extracted with ethyl acetate (80 mL × 2). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give the crude product. The crude product was purified by rapid chromatography. Methyl 4-amino-5-chloro-2-(methoxy-d3)benzoate was eluted with 4–6% (ethyl acetate / hexane) (3.2 g, 45% yield) to give a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.60 (s, 1H), 6.45 (s, 1H), 6.17 (s, 2H), 3.69 (s, 3H). LCMS m / z: 219.1 (M+1).

[0223] Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-5-chloro-2-(methoxy-d3)benzoate To a stirred solution of methyl 4-amino-5-chloro-2-(methoxy-d3)benzoate (3.2 g, 15 mmol, 1.0 eq) in THF (32 mL, 10 V) cooled to 0 °C, (Boc)₂O (4.9 g, 22.4 mmol, 1.5 eq), TEA (4.0 mL, 29.9 mmol, 2.0 eq), and DMAP (2.73 g, 22.42 mmol, 1.5 eq) were added. The reaction mixture was stirred at 70 °C for 3 h, followed by the addition of K₂CO₃ (13.2 g, 91.4 mmol, 2.0 eq) and MeOH (15 mL, 5 V). The reaction mixture was stirred at 50 °C for 16 h. The progress was monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give the crude product. The crude product was purified by rapid chromatography. The product was eluted with 4-6% (ethyl acetate / hexane) (2.5 g, yield 54%) to give a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6): δ 8.71 (s, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 3.77 (s, 3H), 1.49 (s, 9H). LCMS m / z: 319.4 (M+1).

[0224] Synthesis of methyl 4-((tert-butoxycarbonyl)(methyl-d3)amino)-5-chloro-2-(methoxy-d3)benzoate Under N2 and 0 °C, NaH (60% in mineral oil) (0.6 g, 15.7 mmol, 2.0 eq) was added to a stirred solution of methyl 4-((tert-butoxycarbonyl)amino)-5-chloro-2-(methoxy-d3)benzoate (2.5 g, 7.9 mmol, 1.0 eq) in DMF (25 mL, 10 V). The resulting mixture was stirred at 70 °C for 30 min. After 30 min, CD3I (2.6 g, 15.7 mmol, 2.0 eq) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product. The crude product was purified by rapid chromatography. The product was eluted with 5–7% (ethyl acetate / hexane) (1.8 g, 68% yield) to give a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.72 (s, 1H), 7.27 (s, 1H), 3.80 (s, 3H), 1.26 (s, 9H). LCMS m / z: 336.4 (M+1).

[0225] Synthesis of 4-((tert-butoxycarbonyl)(methyl-d3)amino)-5-chloro-2-(methoxy-d3)benzoic acid (Int-A) At 0 °C, H₂O (7.5 mL, 5 V) containing LiOH·H₂O (1.5 g, 0.009 mol, 2.0 eq) was added to a stirred solution of methyl 4-((tert-butoxycarbonyl)(methyl-d3)amino)-5-chloro-2-(methoxy-d3)benzoate (1.5 g, 0.005 mol, 1.0 eq) in THF (15 mL, 10 V). The resulting mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water (15 mL, 10 V) and extracted with ethyl acetate (50 mL × 2). The aqueous layer was then acidified with 1N HCl (15 mL) and extracted with DCM (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Int-A (1.2 g, quantitative yield). 1 H NMR (400 MHz, DMSO- d 6 ): δ 13.00 (s, 1H), 7.71 (s, 1H), 7.23 (s, 1H), 1.18 (s, 9H). LCMS m / z: 266.1 (M-56).

Claims

1. Compounds of Formula I: ， Formula I, in: R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Independently selected from H and D; and among them At least one of R1, R2, and R3 is D; And R9, R 10 R 11 R 12 and R 13 At least one of them is D; The compound is in free or salt form.

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

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

4. The compound according to any one of claims 1-3, wherein R1, R2 and R3 are each D.

5. The compound according to any one of claims 1-4, wherein R4, R5 and R6 are each D.

6. The compound according to any one of claims 1-5, wherein R7 and R8 are D.

7. The compound according to any one of claims 1-6, wherein R9, R 10 R 11 R 12 and R 13 Each is D.

8. The compound according to any one of claims 1-7, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Each is D.

9. The compound according to any one of claims 1-8, wherein the compound is: ， The compound is in free or salt form.

10. The compound according to any one of claims 1-9, wherein the compound in its free or pharmaceutically acceptable salt form has a deuterium incorporation of more than 90% at one or more sites designated as deuterium.

11. A pharmaceutical composition comprising a compound according to any one of claims 1-10 in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier.

12. A method for treating a brain condition in a patient in need, wherein the method comprises administering to the patient a compound in a free or pharmaceutically acceptable salt form according to any one of claims 1-10, or a pharmaceutical composition according to claim 11.

13. The method of claim 12, wherein the condition is an affective disorder or anxiety disorder.

14. The method of claim 12, 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.

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

16. The method of claim 12, wherein the condition is anhedonia, anhedonia-associated depression, suicidal ideation, anxiety depression, inflammatory depression, treatment-resistant depression, dysphoric depression, bipolar depression, psychotic depression, or post-psychotic depression.

17. The method of claim 12, wherein the condition is anxiety depression.

18. The method of claim 12, wherein the condition is depressive disorder.

19. The method of claim 12, wherein the condition is major depressive disorder.

20. The method of claim 12, wherein the condition is a substance use disorder.

21. The method of claim 12, wherein the condition is post-traumatic stress disorder (PTSD).

22. The compound of any one of claims 1-10, or the pharmaceutical composition of claim 11, in free or pharmaceutically acceptable salt form, for the treatment of brain disorders.

23. Use of the compound according to any one of claims 1-10 in the preparation of a medicament for treating brain disorders.

24. The use according to claim 22 or 23, wherein the brain condition is as described in any one of claims 13-21.

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