Arylcyclohexylamine derivatives and their use in treatment of psychiatric disorders

Abstract

To provide arylcyclohexylamine compounds and their use in the treatment of psychiatric disorders.SOLUTION: There are provided arylcyclohexylamine compounds and compositions of a single enantiomer or enantiomerically enriched mixtures of arylcyclohexylamine having significantly higher oral bioavailability, higher antidepressant potency, and / or greater therapeutic index between antidepressant effects and side effects, compared to ketamine.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 093,830, filed Dec. 26, 2019; U.S. Provisional Application No. 63 / 037,044, filed Jun. 10, 2020; and U.S. Provisional Patent Application No. 63 / 093,830, filed Oct. 20, 2020, each of which is hereby incorporated by reference in its entirety.

Background Art

[0002] Approximately one-third of patients with major depressive disorder (MDD) are unable to achieve symptom remission even after multiple treatments with several known classes of antidepressants, including selective serotonin reuptake inhibitors (SSRI) (Rush et al., 2006). This high prevalence of treatment-resistant depression (TRD) highlights the need for new and more effective drug therapies for depression that target novel mechanisms and / or patient populations. In recent years, ketamine, a drug that has been used for many years as a dissociative anesthetic, has received significant attention for its secondary use as a rapid-acting antidepressant with established efficacy even in patients with TRD (Zarate et al., 2006; Berman et al., 2000). The antidepressant effect of this drug is also notable in that it persists for several days or weeks after a single dose. Importantly, the S enantiomer of ketamine (S-ket) has recently been approved by the U.S. Food and Drug Administration for the treatment of depression.

[0003] Unfortunately, the potent dissociative anesthetic effects of ketamine and S-ket have made these drugs attractive to recreational drug users, and restricting their use to an environment under the direct supervision of healthcare providers limits the broad clinical utility of these compounds. Given that the main molecular target of ketamine is the N-methyl-D-aspartic acid receptor (NMDAR) and that inhibition of this target is responsible for the anesthetic effects of the drug, there have been many proposals that inhibition of this target is also responsible for the antidepressant effects of ketamine. Such a mechanism suggests that the antidepressant and dissociative effects of ketamine may not be separable at the mechanistic level. However, a lot of diverse evidence has cast doubt on this hypothesis (Aleksandrova et al., 2017). First, the R enantiomer of ketamine (R-ket) has been found to be more effective as an antidepressant than S-ket and to have a longer duration of action in rodent models, despite the fact that R-ket has a weaker binding affinity for NMDAR than S-ket (Zhang et al., 2014). Similarly, the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) induces antidepressant effects in rodent models but binds only weakly to NMDAR and has been shown not to associate with this receptor in vivo at the dose levels that induce antidepressant effects (Zanos et al., 2016; Lumsden et al., 2019; Morris et al., 2017). Thus, both R-ket and HNK may be able to induce antidepressant effects while limiting the dissociative effects of ketamine.

[0004] However, other methods that have been proposed to attenuate the dissociative effects of ketamine, such as targeting the NR2B subunit of NMDAR or utilizing compounds with low trapping properties, have ended up with insufficient results. For example, many such structurally different NMDAR antagonists (e.g., memantine, MK-0657, and lanicemine) reduce dissociation in some cases but have been shown to be less effective and / or have a shorter duration of action than ketamine in the treatment of depression (Zanos et al. 2016; Qu et al. 2017; Cerecor 2019; Kadriu et al. 2019; Lepow et al. 2017). Similarly, agonists with high affinity for NMDAR (e.g., MK-801) or agonists that target another binding site of the channel (e.g., rapastinel) have also ended in failure (Yang et al. 2016; Al Idrus 2019). Therefore, the exact molecular mechanism underlying the antidepressant effects of ketamine remains poorly understood, and other yet-to-be-identified targets may be involved. Furthermore, the magnitude of the antidepressant effects of NMDAR modulators and their accompanying dissociative effects is generally highly unpredictable. At the same time, these findings present the intriguing possibility that the antidepressant effects of ketamine may actually be separable from its dissociative anesthetic effects.

[0005] In addition to its dissociative side effects, the use of ketamine for the treatment of depression is further limited by the poor oral bioavailability of the drug (Clements et al. 1982). Thus, for the treatment of MDD, ketamine is used almost exclusively via the intravenous (i.v.) route. The practical challenges of i.v. administration further heighten the need to use ketamine under the supervision of a healthcare provider in a clinical or hospital setting. Thus, the inability to use ketamine via the oral route of administration is a significant drawback that limits the widespread application of the drug and increases the healthcare costs associated with its use. Other NMDAR antagonists that are orally bioavailable have been developed, but none have reached the market to date, and the robust clinical efficacy of ketamine as an antidepressant has not been demonstrated. Thus, there remains a significant need for a novel class of antidepressants in the ketamine family that have robust efficacy, reduced dissociative side effects, and increased oral bioavailability. A drug that retains the antidepressant activity of ketamine while reducing its dissociative effects and further increasing oral bioavailability would provide a treatment option that is easier to administer and potentially feasible for at-home use due to the reduction in its dissociative effects and the associated reduced potential for abuse.

Prior Art Documents

Non-Patent Documents

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Summary of the Invention

Means for Solving the Problems

[0007] The present disclosure provides, at least in part, an arylcyclohexylamine compound having significantly higher oral bioavailability, higher antidepressant efficacy, and / or a higher therapeutic index between antidepressant action and side effects compared to ketamine, and a composition of a single enantiomer or an enantiomerically enriched mixture of arylcyclohexylamine.

[0008] For example, the present disclosure provides compounds having increased oral bioavailability by having structural components that result in increased resistance to hepatic metabolism, for example, as compared to ketamine. This can be confirmed, for example, by the increased stability of such compounds in rodent and human liver microsome preparations. Importantly, despite such increased oral bioavailability, the disclosed compounds retain a substantially short half-life, in contrast to the more typical observation that clearance may slow down as hepatic stability increases. A short half-life may be desirable because the therapeutic efficacy of such compounds may not depend on the persistence of receptor occupancy. Instead, the pulsatile engagement of NMDAR (or other) signaling induces a therapeutic effect that persists much longer (days or weeks) than the drug's elimination (hours), thereby limiting overall exposure and potentially reducing the duration of dissociative or other negative side effects. Further, in some embodiments, compounds are provided herein that have increased antidepressant efficacy as a secondary effect of increased exposure while retaining the high brain permeability of ketamine, particularly after oral dosing. Such compounds may be more potent as antidepressants even if their in vitro affinity for NMDAR is similar to or lower than that of ketamine. Further, the compounds provided herein displace radioligands from membranes containing NMDAR isolated from rat cortex 3As a result of the NMDAR binding affinity of about 1-5 μM determined by the replacement of MK-801, an increase in the therapeutic index between the antidepressant effect and dissociative side effects may be shown. In certain embodiments, this affinity range, perhaps due to the rapid off-rate kinetics of such compounds, may be useful in maintaining the balance between antidepressant efficacy and side effects. For example, compounds having a very high affinity (<1 μM) for NMDAR, such as racemic ketamine and S-ket, show significant dissociative effects that limit their use to environments monitored by physicians and increase their tendency for abuse. Furthermore, high affinity for NMDAR may also reduce the therapeutic efficacy in depression (e.g., both MK-801 and S-ket appear to be weaker and have a shorter duration of antidepressant effect than racemic ketamine and R-ket having lower affinity). In contrast, compounds with very low affinity (>5 μm) for NMDAR may lose their antidepressant efficacy even when the dose is appropriately adjusted considering such lower affinity. Furthermore, even if effective, the very high doses required for such low-potency compounds may exacerbate toxicological issues or lead to undesirable off-target introductions (due to reduced selectivity for other weakly binding partners).

[0009] In one aspect, the general structure (I):

[0010] [Chemical formula]

[0011] (wherein R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, and a moiety of general formula (II), When R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cyclo-C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, D represents a deuterium-enriched H site, provided that one or more of R2 and R3 are different from H, or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyls or interrupted by one or more additional nitrogen or oxygen atoms, When R1 is the moiety of general formula (II):

[0012] [Chemical formula]

[0013] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, provided that one or more of R2 and R3 are different from H, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyls or interrupted by one or more additional nitrogen or oxygen atoms, R6, R7, R8, R9, and R10 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, -C(=O)NR17R18, where R11, R12, R13, R14, R15, R16, R17, and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, provided that one or more of R6-R10 is different from H, or provided that when R6 is Cl and R7-R10 are H, or when R7 is Cl, R6, R8-R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or provided that when R7 is OH, R6, R8-R10 are H, and R2 or R3 is H, the other of R2 or R3 is linear or branched C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or provided that when R6, R7, or R8 is OMe and the others of R6-R10 are each H and R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, When R1 is selected from thiazole, thiophene, and pyridine, each optionally and in some cases, is substituted with one or more OH, halogen (selected from F, Cl, Br, I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26, and R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O) alkyl, C(=O) aryl, C(=O) heteroaryl, R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, and the ring is optionally and in some cases, substituted with one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) Compounds having the same are provided herein.

[0014] In some embodiments, the compounds provided herein have the general structure (Ia):

[0015]

Chemical formula

[0016] (wherein R2 and R3 are independently selected from H, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, provided that one or more of R2 and R3 are different from H, or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, or R2 and R3, together with the nitrogen ring to which they are attached, form a C3-C9 cycloheteroalkyl ring, said ring being optionally and in some cases substituted by one or more C1-C10 alkyl, or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0017] In some embodiments, the compounds provided herein have the general formula (Ib):

[0018]

Chemical formula

[0019] (wherein R3 is C1-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5; R4 is C2-C10 alkylene; R5 is selected from H and C1-C10 alkyl; R6, R7, R8, R9, and R10 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, -C(=O)NR17R18; R11, R12, R13, R14, R15, R16, R17, and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, provided that one or more of R6-R10 are different from H, or when R6 is Cl and R7-R10 are H, or when R7 is Cl and R6, R8-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or when R7 is OH and R6, R8-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or when R6, R7, or R8 is OMe and the others of R6-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5) has

[0020] In some embodiments, the compounds provided herein have the general structure (I), where R1 is selected from thiazole, thiophene, pyridine, each optionally and in some cases substituted with one or more OH, halogen (selected from F, Cl, Br, I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26, and R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring optionally and in some cases substituted with one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0021] In some embodiments, the compounds provided herein have the general structure (Ia):

[0022]

Chemical formula

[0023] (wherein R2 and R3 are independently selected from H, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, provided that at least one of R2 and R3 is different from H) and have.

[0024] In some embodiments, the compounds provided herein have the general structure (Ia):

[0025]

Chemical formula

[0026] (wherein R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) have.

[0027] In some embodiments, the compounds provided herein have the general structure (Ia):

[0028]

Chemical formula

[0029] (wherein R2 and R3 together with the nitrogen ring to which they are attached form a C3-C9 cycloheteroalkyl ring, which ring is optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0030] In some embodiments, the compounds provided herein have the general structure (Ia):

[0031]

Chemical formula

[0032] (wherein R2 is H, and R3 is selected from branched or cyclo C3 alkyl, C4-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) have.

[0033] In some embodiments, the compounds provided herein have the general structure (Ia):

[0034]

Chemical formula

[0035] (wherein R2 and R3 are independently selected from C2-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) and have

[0036] In some embodiments, the compounds provided herein have the general structure (Ia):

[0037]

Chemical formula

[0038] (wherein R2 and R3 together with the nitrogen ring to which they are attached form a C3-C6 cycloheteroalkyl ring, which ring is optionally substituted by one or more C1-C2 alkyls or interrupted by one or more additional nitrogen or oxygen atoms) and have

[0039] In some embodiments, the compounds provided herein have the general structure (Ib):

[0040]

Chemical formula

[0041] (wherein one or more of R6, R7, R8, R9 and R10 is OH, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, provided that when R7 is OH and R6, R8-R10 are H, R3 is C3-C10 alkyl) has

[0042] In some embodiments, the compounds provided herein have the general structure (Ib):

[0043]

Chemical formula

[0044] (wherein one or more of R6, R7, R8, R9 and R10 is halogen (selected from F, Cl, Br, I), R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, provided that when R6 is Cl and R7-R10 are H, or when R7 is Cl and R6, R8-R10 are H, R3 is C3-C10 alkyl) has

[0045] In some embodiments, the compounds provided herein have the general structure (Ib):

[0046]

Chemical formula

[0047] (wherein one or more of R6, R7, R8, R9 and R10 is OMe, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, provided that when R6, R7 or R8 is OMe and the others of R6-R10 are H, R3 is C3-C10 alkyl) has.

[0048] In some embodiments, the compounds provided herein have the general structure (Ib):

[0049]

Chemical formula

[0050] (wherein one or more of R6, R7, R8, R9 and R10 are F, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) has.

[0051] In some embodiments, the compounds provided herein have the general structure (Ib):

[0052]

Chemical formula

[0053] (wherein one or more of R6, R7, R8, R9 and R10 are Me, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) has.

[0054] In some embodiments, the compounds provided herein have the general structure (Ib):

[0055]

Chemical formula

[0056] (In the formula, one or more of R6, R7, R8, R9 and R10 are OH, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, R5 is selected from H and C1-C5 alkyl, provided that when R7 is OH and R6, R8-R10 are H, R3 is C3-C5 alkyl) has

[0057] In some embodiments, the compounds provided herein have the general structure (Ib):

[0058] [Chemical formula]

[0059] (In the formula, one or more of R6, R7, R8, R9 and R10 are OMe, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, R5 is selected from H and C1-C5 alkyl, provided that when R6, R7 or R8 is OMe and the others of R6-R10 are H, R3 is C3-C5 alkyl) has

[0060] In some embodiments, the compounds provided herein have the general structure (Ib):

[0061] [Chemical formula]

[0062] (In the formula, one or more of R6, R7, R8, R9 and R10 are F, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, R5 is selected from H and C1-C5 alkyl) has

[0063] In some embodiments, the compounds provided herein have the general structure (Ib):

[0064] [Chemical formula]

[0065] (wherein one or more of R6, R7, R8, R9 and R10 is Me, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) have

[0066] In some embodiments, the compounds provided herein have the general structure (Ic):

[0067] [Chemical formula]

[0068] (wherein one or more of R6, R7, R8, R9 and R10 is OH, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, which ring is optionally substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have

[0069] In some embodiments, the compounds provided herein have the general structure (Ic):

[0070] [Chemical formula]

[0071] (wherein one or more of R6, R7, R8, R9 and R10 is OMe, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) has

[0072] In some embodiments, the compounds provided herein have the general structure (Ic):

[0073]

Chemical formula

[0074] (wherein one or more of R6, R7, R8, R9 and R10 is F, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) has

[0075] In some embodiments, the compounds provided herein have the general structure (Ic):

[0076]

Chemical formula

[0077] (wherein one or more of R6, R7, R8, R9 and R10 are Me, and R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have

[0078] In some embodiments, the compounds provided herein

[0079]

Chemical formula

[0080]

Chemical formula

[0081] are selected from, or are a pharmaceutically acceptable salt or ester thereof.

[0082] In some embodiments, the compounds provided herein

[0083]

Chemical formula

[0084] are selected from.

[0085] In another aspect, carrier and structure:

[0086]

Chemical formula

[0087] (wherein D represents a deuterium-enriched H site) A composition comprising a compound having the same is provided herein.

[0088] In some embodiments, each D represents a deuterium-enriched H site, and the level of deuterium at each deuterium-enriched H site of the compound is from 0.02% to 100%. In some embodiments, each D represents a deuterium-enriched H site, and the level of deuterium at each deuterium-enriched H site of the compound is from 20% to 100%, from 50% to 100%, from 70% to 100%, from 90% to 100%, from 97% to 100%, or from 99% to 100%.

[0089] In another aspect, the general structure (III):

[0090]

Chemical formula

[0091] (wherein R31 and R32 are each H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39wherein R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring optionally being substituted by one or more linear or branched C1-C10 alkyls or interrupted by one or more additional nitrogen or oxygen atoms; R27, R28, R29, and R30 are each independently selected from H, linear or branched C1-C10 alkyl, F, or R27 and R28 or R29 and R30 together with the carbon atom to which they are attached form a cycloalkyl ring or together with the carbon and one or more heteroatoms to which they are attached form a cycloheteroalkyl ring; R33, R34, R35, R36, and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -SR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47; R40, R41, R42, R43, R44, R45, R46, and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, provided that at least one of R27, R28, R29, or R30 is different from H, or when one of R27 and R28 is Me and the other is H, R32 is C2-C10 alkyl, C2-C10 haloalkyl, or -R 38 -O-R 39 wherein) Compounds having the same are provided herein.

[0092] In some embodiments, the compounds provided herein have the general structure (III):

[0093]

Chemical formula

[0094] (wherein, R31 and R32 are each H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39 ; R38 is C2-C10 alkylene; R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally and in some cases substituted by one or more linear or branched C1-C2 alkyl, or interrupted by one or more additional nitrogen or oxygen atoms; R27 and R28 are fluorine; R29 and R30 are H; R33, R34, R35, R36 and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47; and R40, R41, R42, R43, R44, R45, R46 and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl) have.

[0095] In some embodiments, the compounds provided herein have the general structure (III):

[0096] [Chemical formula]

[0097] (wherein, R31 and R32 are each H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39wherein R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring optionally and in some cases being substituted by one or more straight-chain or branched C1-C2 alkyl, or interrupted by one or more additional nitrogen or oxygen atoms, R27 and R28 together with the carbon and oxygen atoms to which they are attached form an oxetane ring, R29 and R30 are H, and R33, R34, R35, R36 and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, and R40, R41, R42, R43, R44, R45, R46 and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl) have

[0098] In some embodiments, the compounds provided herein are

[0099]

Chemical formula

[0100] selected from

[0101] In another aspect, pharmaceutical compositions comprising one or more compounds are provided herein. In some embodiments, the compositions described herein (e.g., pharmaceutical compositions) are oral compositions.

[0102] In another aspect, there is provided a method of treating depression, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, generally of structure (IV):

[0103] [Chemical Formula]

[0104] [wherein, R48 is phenyl, thiazole, thiophene, pyridine, or general formula (V);

[0105] [Chemical Formula]

[0106] (wherein, R51, R52, R53, R54, and R55 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1-C10 alkyl, R49 and R50 are each independently selected from H and C1-C10 alkyl, or R49 and R50, together with the nitrogen atom to which they are attached, optionally and in some cases form a C3-C9 cycloheteroalkyl ring optionally substituted with one or more C1-C10 alkyl, provided that when R51 is Cl, R52-R55 are H, and R49 or R50 is H, the other of R49 or R50 is C2-C10 alkyl) and are selected from the group consisting of) A method is provided herein that includes the step of administering a compound of to a subject.

[0107] In some embodiments, the compounds provided herein are

[0108] [Chemical Formula]

[0109] selected from.

[0110] In some embodiments, the compounds provided herein are

[0111]

Chem.

[0112] selected from

[0113] In another aspect, a method of treating depression, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, generally

[0114]

Chem.

[0115] including the step of administering a compound of to the subject is provided herein.

[0116] In another aspect, general structure (VI):

[0117]

Chem.

[0118] (wherein R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of general formula (VII), when R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, D represents a deuterium-enriched H site, and at least one of R2 and R3 is other than H, or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring, which ring is optionally and in some cases substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms, When R1 is a moiety of general formula (VII):

[0119]

Chemical formula

[0120] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, and at least one of R2 and R3 is other than H, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring, which ring is optionally and in some cases substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms, R6, R7, R8, R9 and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, -C(=O)NR17R18, where R11, R12, R13, R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl, at least one of R6-R10 is other than H, and neither R6 nor R10 is halogen, provided that when R7 is Cl, R6, R8-R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or provided that when R7 is OH, R6, R8-R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5, or provided that when R6, R7, or R8 is OMe, the others of R6-R10 are each H, and R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, When R1 is selected from thiazole, thiophene, and pyridine, each optionally and in some cases, is substituted with one or more OH, halogen (selected from F, Cl, Br, I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26, and R19, R20, R21, R22, R23, R24, R25 and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O) alkyl, C(=O) aryl, C(=O) heteroaryl, R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, and the ring is optionally and in some cases substituted with one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) A composition comprising a compound having or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is richer in the compound than its opposite enantiomer is provided herein.

[0121] In another aspect, carrier and structure:

[0122]

Chemical formula

[0123] (wherein D represents a deuterium-enriched H site) A composition comprising a compound having, wherein the composition is richer in the compound than its opposite enantiomer is provided herein.

[0124] In another aspect, general structure (VIII):

[0125] [Chemical formula]

[0126] (wherein R31 and R32 are independently H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39 selected from, R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32, together with the nitrogen atom to which they are attached, form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more linear or branched C1-C10 alkyls in some cases, or interrupted by one or more additional nitrogen or oxygen atoms, R27, R28, R29, R30 are each independently selected from H, linear or branched C1-C10 alkyl, F, and at least one of R27, R28, R29, or R30 is other than H, or R27 and R28, or R29 and R30, together with the carbon atom to which they are attached, form a cycloalkyl ring, or together with the carbon to which they are attached and one or more heteroatoms form a cycloheteroalkyl ring, R33, R34, R35, R36 and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, and R40, R41, R42, R43, R44, R45, R46 and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O) alkyl, C(=O) aryl, C(=O) heteroaryl, However, when one of R27 and R28 is Me, the other of R27 and R28 is H, R29 to R30 and R33 to R37 are each H, and one of R31 or R32 is H, the other of R31 or R32 is C2 - C10 alkyl, C2 - C10 haloalkyl or -R 38 -O-R 39 ) A composition comprising a compound having the formula, or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is richer in the compound than its opposite enantiomer is provided herein.

[0127] In another aspect, a method of treating depression, dysthymia, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, generally of structure (IX):

[0128] [Chemical formula]

[0129] [wherein, R48 is phenyl, thiazole, thiophene, pyridine, or general formula (X);

[0130] [Chemical formula] (wherein, R51 and R55 are independently selected from H, OH, OMe, C1 - C10 alkyl, R52, R53, and R54 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1 - C10 alkyl, R49 and R50 are each independently selected from H and C1 - C10 alkyl, or R49 and R50 together with the nitrogen atom to which they are attached optionally and in some cases form a C3 - C9 cycloheteroalkyl ring optionally substituted with one or more C1 - C10 alkyl) selected from the group consisting of parts of) A method is provided herein that includes administering to a subject a compound, or a pharmaceutically acceptable salt or ester of the compound, wherein the compound is enriched relative to its opposite enantiomer.

[0131] In another aspect, a method of treating depression, dysthymia, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, generally the compound:

[0132]

Chemical formula

[0133] A method is provided herein that includes administering to a subject.

[0134] In another aspect, general structure (XI):

[0135]

Chemical formula

[0136] (wherein R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of general formula (XII), When R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cyclo C3 alkyl, C4 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, where R4 is C2 - C10 alkylene and R5 is selected from H and C1 - C10 alkyl, D represents a deuterium-enriched H site, and at least one of R2 and R3 is other than H, or R2 and R3 are independently selected from C2 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, where R4 is C2 - C10 alkylene and R5 is selected from H and C1 - C10 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring, which ring is optionally and optionally substituted by one or more C1-C10 alkyls or interrupted by one or more additional nitrogen or oxygen atoms. When R1 is a moiety of general formula (XII):

[0137]

Chemical formula

[0138] then R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, and at least one of R2 and R3 is other than H, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring, which ring is optionally and optionally substituted by one or more C1-C10 alkyls or interrupted by one or more additional nitrogen or oxygen atoms. R6, R7, R8, R9 and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, -C(=O)NR17R18, where R11, R12, R13, R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl, and at least one of R6-R10 is other than H, and neither R6 nor R10 is halogen. However, when R7 is Cl, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5, or However, when R7 is OH, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5, or However, when R6, R7, or R8 is OMe, the others of R6 - R10 are each H, and R2 or R3 is H, the other of R2 or R3 is C3 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5, When R1 is selected from thiazole, thiophene, and pyridine, optionally and in some cases, it is substituted with one or more OH, halogen (selected from F, Cl, Br, I), -OR19, C1 - C10 alkyl, C2 - C10 alkenyl, C2 - C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26, where R19, R20, R21, R22, R23, R24, R25 and R26 are each independently selected from H, C1 - C10 alkyl, C2 - C10 alkenyl, C2 - C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, R2 and R3 are independently selected from H, C1 - C10 alkyl, C2 - C10 haloalkyl, C2 - C10 alkenyl, C2 - C10 alkynyl, -R4 - O - R5, where R4 is C2 - C10 alkylene and R5 is selected from H and C1 - C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3 - C9 cycloheteroalkyl ring, and said ring is optionally and in some cases substituted with one or more C1 - C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) A composition comprising a compound having the same, or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is richer in the compound than its opposite enantiomer is provided herein.

[0139] In another aspect, carrier and structure:

[0140]

Chemical formula

[0141] (wherein D represents a deuterium-enriched H site) A composition comprising a compound having the same, wherein the composition is richer in the compound than its opposite enantiomer is provided herein.

[0142] In another aspect, general structure (XIII):

[0143]

Chemical formula

[0144] (wherein R31 and R32 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39 wherein R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, which ring is optionally and in some cases substituted by one or more linear or branched C1-C10 alkyl, or interrupted by one or more additional nitrogen or oxygen atoms, R27, R28, R29, R30 are each independently selected from H, linear or branched C1-C10 alkyl, F, and at least one of R27, R28, R29 or R30 is other than H, or

[0145] R27 and R28, or R29 and R30, together with the carbon atom to which they are attached, form a cycloalkyl ring, or together with the carbon and one or more heteroatoms to which they are attached, form a cycloheteroalkyl ring, R33, R34, R35, R36 and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, and R40, R41, R42, R43, R44, R45, R46 and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, provided that when one of R27 and R28 is Me and the other is H, and R29-R30 and R33-R37 are each H, and R31 or R32 is H, the other of R31 or R32 is C2-C10 alkyl, C2-C10 haloalkyl or -R 38 -O-R 39 ) a compound having

[0146] or a composition comprising a pharmaceutically acceptable salt or ester of the compound, wherein the composition is richer in the compound than its opposite enantiomer is provided herein. In another aspect, a method of treating depression, dysthymia, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, generally of structure (XIV):

[0147]

Chemical formula

[0148] [wherein, R48 is phenyl, thiazole, thiophene, pyridine, or general formula (XV);

[0149]

Chem.

[0150] (wherein R51 and R55 are independently selected from H, OH, OMe, C1-C10 alkyl, R52, R53, and R54 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1-C10 alkyl, R49 and R50 are each independently selected from H and C1-C10 alkyl, or R49 and R50 together with the nitrogen atom to which they are attached optionally form, in some cases, a C3-C9 cycloheteroalkyl ring substituted with one or more C1-C10 alkyls) selected from the group consisting of the moieties of) administering to a subject a compound, or a pharmaceutically acceptable salt or ester of the compound, wherein the compound is enriched relative to its opposite enantiomer, are provided herein.

[0151] In another aspect, a method of treating depression, dysthymia, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, generally the compound:

[0152]

Chem.

[0153] administering to a subject a compound, or a pharmaceutically acceptable salt or ester of the compound, wherein the compound is enriched relative to its opposite enantiomer, are provided herein.

[0154] In another aspect, the general structure (XVI):

[0155]

Chem.

[0156] (wherein R56 and R57, together with the nitrogen atom to which they are attached, form a monocyclic or bicyclic C3-C8 cycloheteroalkyl ring, said ring being optionally and in some cases substituted by one or more C1-C3 alkyl, F, OH, OMe or =O, and optionally and in some cases interrupted by one or more additional nitrogen or oxygen atoms, R58, R59, R60, R61 and R62 are each independently H, OH, halogen (selected from F, Cl, Br, I), -OR63, -O-C(=O)R64, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR65R66, -NH-C(=O)R67, -SR68, -SO2R69, -CO2R70, -C(=O)NR71R72, and R63, R64, R65, R66, R67, R68, R69, R70, R71 and R72 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, provided that when R56 and R57, together with the nitrogen atom to which they are attached, form an unsubstituted piperidine ring, at least one of R58, R59, R60, R61 and R62 is other than H) Compounds having the same, or pharmaceutically acceptable salts or esters thereof, are provided herein.

[0157] In another aspect, general structure (XVII):

[0158]

Chemical formula

[0159] (wherein R73 and R74, together with the nitrogen atom to which they are attached, form an azetidine ring, said ring being optionally and in some cases substituted by one or more C1-C3 alkyl, F, OH or OMe, R75, R76, R77, R78, and R79 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR80, -O-C(=O)R81, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR82R83, -NH-C(=O)R84, -SR85, -SO2R86, -CO2R87, -C(=O)NR88R89, and R80, R81, R82, R83, R84, R85, R86, R87, R88, and R89 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl) Compounds having , or pharmaceutically acceptable salts or esters thereof are provided herein.

[0160] In another aspect, a method of treating depression, dysthymia, mood disorder, anxiety disorder, or substance use disorder and any symptoms or disorders associated therewith in a subject in need thereof, the method comprising administering to the subject a compound generally disclosed herein is provided herein.

[0161] In another aspect, a method of treating depression or dysthymia in a subject in need thereof, the method comprising administering to the subject a compound generally disclosed herein is provided herein.

[0162] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of this specification. However, the invention, together with its objects, features, and these advantages, will be best understood from the following detailed description when read in conjunction with the accompanying drawings, which are briefly described below with respect to both the construction and the method of operation. It will be understood that the elements shown in the drawings are not necessarily drawn to scale for the sake of brevity and clarity of illustration. For example, the dimensions of some elements may be exaggerated relative to other elements for clarity. Further, reference numerals may be repeated between the drawings to indicate corresponding or similar elements where appropriate.

Brief Description of the Drawings

[0163]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Mode for Carrying Out the Invention

[0164] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0165] In one aspect, the general structure (I):

[0166]

Chemical formula

[0167] (wherein, R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, and the moiety of general formula (II), when R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, D represents a deuterium-enriched H site, provided that one or more of R2 and R3 are different from H, or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring, and the ring is optionally substituted by one or more C1-C10 alkyls in some cases, or interrupted by one or more additional nitrogen or oxygen atoms, when R1 is the moiety of general formula (II):

[0168]

Chemical formula

[0169] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, provided that one or more of R2 and R3 are different from H, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring, and the ring is optionally substituted by one or more C1-C10 alkyls in some cases, or interrupted by one or more additional nitrogen or oxygen atoms, R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, -C(=O)NR17R18, where R11, R12, R13, R14, R15, R16, R17, and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl, provided that one or more of R6-R10 is different from H, or provided that when R6 is Cl and R7-R10 are H, or when R7 is Cl, R6, R8-R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or provided that when R7 is OH, R6, R8-R10 are H, and R2 or R3 is H, the other of R2 or R3 is linear or branched C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or provided that when R6, R7, or R8 is OMe and the others of R6-R10 are each H and R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, When R1 is selected from thiazole, thiophene, and pyridine, optionally and in each case, it is substituted by one or more OH, halogen (selected from F, Cl, Br, I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26, and R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O) alkyl, C(=O) aryl, C(=O) heteroaryl, R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring, and the ring is optionally and in each case substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) Compounds having the same are provided herein.

[0170] In some embodiments, the compounds provided herein have the general structure (Ia):

[0171]

Chemical formula

[0172] (wherein, R2 and R3 are independently selected from H, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, provided that one or more of R2 and R3 are different from H, or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, or R2 and R3, together with the nitrogen ring to which they are attached, form a C3-C9 cycloheteroalkyl ring, and the ring is optionally and in some cases substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0173] In some embodiments, the compounds provided herein have the general structure (Ib):

[0174]

Chemical formula

[0175] (wherein, R3 is C1-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5; R4 is C2-C10 alkylene; R5 is selected from H and C1-C10 alkyl; R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, -C(=O)NR17R18; R11, R12, R13, R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, provided that one or more of R6-R10 are different from H, or when R6 is Cl and R7-R10 are H, or when R7 is Cl and R6, R8-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or when R7 is OH and R6, R8-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or when R6, R7 or R8 is OMe and the others of R6-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5) has

[0176] In some embodiments, the compounds provided herein have the general structure (I), wherein R1 is selected from thiazole, thiophene, pyridine, each optionally and in some cases, substituted with one or more OH, halogen (selected from F, Cl, Br, I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26, and R19, R20, R21, R22, R23, R24, R25 and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring optionally and in some cases substituted with one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0177] In some embodiments, the compounds provided herein have the general structure (Ia):

[0178]

Chemical formula

[0179] (wherein R2 and R3 are independently selected from H, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, provided that at least one of R2 and R3 is different from H) and have.

[0180] In some embodiments, the compounds provided herein have the general structure (Ia):

[0181]

Chemical formula

[0182] (wherein R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) and have.

[0183] In some embodiments, the compounds provided herein have the general structure (Ia):

[0184]

Chemical formula

[0185] (wherein R2 and R3 together with the nitrogen ring to which they are attached form a C3-C9 cycloheteroalkyl ring, which ring is optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) and have.

[0186] In some embodiments, the compounds provided herein have the general structure (Ia):

[0187]

Chemical formula

[0188] (wherein R2 is H, and R3 is selected from branched or cyclo C3 alkyl, C4-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) and have.

[0189] In some embodiments, the compounds provided herein have the general structure (Ia):

[0190] [ka]

[0191] (wherein R2 and R3 are independently selected from C2-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl). has.

[0192] In some embodiments, the compounds provided herein have the general structure (Ia):

[0193] [ka]

[0194] wherein R2 and R3 together with the nitrogen ring to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. has.

[0195] In some embodiments, the compounds provided herein have the general structure (Ib):

[0196] [ka]

[0197] (In the formula, one or more of R6, R7, R8, R9 and R10 are OH, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, provided that when R7 is OH and R6, R8-R10 are H, R3 is C3-C10 alkyl) has

[0198] In some embodiments, the compounds provided herein have the general structure (Ib):

[0199]

Chemical formula

[0200] (In the formula, one or more of R6, R7, R8, R9 and R10 are halogen (selected from F, Cl, Br, I), R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, provided that when R6 is Cl and R7-R10 are H, or when R7 is Cl and R6, R8-R10 are H, R3 is C3-C10 alkyl) has

[0201] In some embodiments, the compounds provided herein have the general structure (Ib):

[0202]

Chemical formula

[0203] (In the formula, one or more of R6, R7, R8, R9 and R10 are OMe, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, provided that when R6, R7 or R8 is OMe and the others of R6-R10 are H, R3 is C3-C10 alkyl) has.

[0204] In some embodiments, the compounds provided herein have the general structure (Ib):

[0205]

Chemical formula

[0206] (wherein one or more of R6, R7, R8, R9 and R10 are F, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) has.

[0207] In some embodiments, the compounds provided herein have the general structure (Ib):

[0208]

Chemical formula

[0209] (wherein one or more of R6, R7, R8, R9 and R10 are Me, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) has.

[0210] In some embodiments, the compounds provided herein have the general structure (Ib):

[0211]

Chemical formula

[0212] (In the formula, one or more of R6, R7, R8, R9, and R10 are OH, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, R5 is selected from H and C1-C5 alkyl, provided that when R7 is OH and R6, R8-R10 are H, R3 is C3-C5 alkyl) has

[0213] In some embodiments, the compounds provided herein have the general structure (Ib):

[0214]

Chemical formula

[0215] (In the formula, one or more of R6, R7, R8, R9, and R10 are OMe, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, R5 is selected from H and C1-C5 alkyl, provided that when R6, R7, or R8 is OMe and the others of R6-R10 are H, R3 is C3-C5 alkyl) has

[0216] In some embodiments, the compounds provided herein have the general structure (Ib):

[0217]

Chemical formula

[0218] (In the formula, one or more of R6, R7, R8, R9, and R10 are F, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) has

[0219] In some embodiments, the compounds provided herein have the general structure (Ib):

[0220] [Chemical formula]

[0221] (wherein one or more of R6, R7, R8, R9 and R10 is Me, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) have

[0222] In some embodiments, the compounds provided herein have the general structure (Ic):

[0223] [Chemical formula]

[0224] (wherein one or more of R6, R7, R8, R9 and R10 is OH, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, which ring is optionally substituted by one or more C1-C2 alkyls or interrupted by one or more additional nitrogen or oxygen atoms) have

[0225] In some embodiments, the compounds provided herein have the general structure (Ic):

[0226] [Chemical formula]

[0227] (In the formula, one or more of R6, R7, R8, R9 and R10 are OMe, and R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, R5 is selected from H and C1-C5 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C6 cycloheteroalkyl ring, and the ring is optionally and in some cases substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0228] In some embodiments, the compounds provided herein have the general structure (Ic):

[0229]

Chemical formula

[0230] (In the formula, one or more of R6, R7, R8, R9 and R10 are F, and R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, R5 is selected from H and C1-C5 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C6 cycloheteroalkyl ring, and the ring is optionally and in some cases substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0231] In some embodiments, the compounds provided herein have the general structure (Ic):

[0232]

Chemical formula

[0233] (wherein one or more of R6, R7, R8, R9 and R10 are Me, and R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have

[0234] In some embodiments, the compounds provided herein are

[0235]

Chemical formula

[0236]

Chemical formula

[0237] selected from

[0238] In some embodiments, the compounds provided herein are

[0239]

Chemical formula

[0240] selected from

[0241] In another aspect, carrier and structure:

[0242]

Chemical formula

[0243] (wherein D represents a deuterium-enriched H site) Compositions are provided herein that include a compound having

[0244] In some embodiments, each D represents a deuterium-enriched H site, and the level of deuterium at each deuterium-enriched H site of the compound is from 0.02% to 100%. In some embodiments, each D represents a deuterium-enriched H site, and the level of deuterium at each deuterium-enriched H site of the compound is from 20% to 100%, from 50% to 100%, from 70% to 100%, from 90% to 100%, from 97% to 100%, or from 99% to 100%.

[0245] In another aspect, the general structure (III):

[0246]

Chemical formula

[0247] (wherein R31 and R32 are each H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39wherein R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally and in some cases substituted by one or more linear or branched C1-C10 alkyl, or interrupted by one or more additional nitrogen or oxygen atoms, R27, R28, R29, R30 are each independently selected from H, linear or branched C1-C10 alkyl, F, or R27 and R28 or R29 and R30 together with the carbon atom to which they are attached form a cycloalkyl ring, or together with the carbon and one or more heteroatoms to which they are attached form a cycloheteroalkyl ring, R33, R34, R35, R36 and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -SR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, R40, R41, R42, R43, R44, R45, R46 and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, provided that at least one of R27, R28, R29 or R30 is different from H, or when one of R27 and R28 is Me and the other is H, R32 is C2-C10 alkyl, C2-C10 haloalkyl, or -R 38 -O-R 39 wherein) Compounds having the same are provided herein.

[0248] In some embodiments, the compounds provided herein have the general structure (III):

[0249]

Chemical formula

[0250] (wherein, R31 and R32 are each H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39 wherein R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally and in some cases substituted by one or more linear or branched C1-C2 alkyl, or interrupted by one or more additional nitrogen or oxygen atoms, R27 and R28 are fluorine, R29 and R30 are H, and R33, R34, R35, R36 and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, and R40, R41, R42, R43, R44, R45, R46 and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl) have.

[0251] In some embodiments, the compounds provided herein have the general structure (III):

[0252]

Chemical formula

[0253] (wherein, R31 and R32 are each H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39wherein R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally and in some cases substituted by one or more linear or branched C1-C2 alkyl, or interrupted by one or more additional nitrogen or oxygen atoms, R27 and R28 together with the carbon and oxygen atoms to which they are attached form an oxetane ring, R29 and R30 are H, and R33, R34, R35, R36 and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, and R40, R41, R42, R43, R44, R45, R46 and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl) has.

[0254] In some embodiments, the compounds provided herein are

[0255]

Chemical formula

[0256] selected from.

[0257] In another aspect, a method of treating depression, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, generally having the structure (IV):

[0258]

Chemical formula

[0259] [wherein, R48 is phenyl, thiazole, thiophene, pyridine, or general formula (V);

[0260] [Chemical formula]

[0261] (wherein, R51, R52, R53, R54 and R55 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1-C10 alkyl, R49 and R50 are each independently selected from H and C1-C10 alkyl, or R49 and R50, together with the nitrogen atom to which they are attached, optionally form a C3-C9 cycloheteroalkyl ring optionally substituted with one or more C1-C10 alkyl, provided that when R51 is Cl, R52-R55 are H, and R49 or R50 is H, the other of R49 or R50 is C2-C10 alkyl) selected from the group consisting of the moiety of) A method is provided herein that includes a step of administering to a subject a compound of).

[0262] In some embodiments, the compounds provided herein are

[0263] [Chemical formula]

[0264] selected from.

[0265] In some embodiments, the compounds provided herein are

[0266] [Chemical formula]

[0267] is selected from.

[0268] In another aspect, a method of treating depression, mood disorder, anxiety disorder, or substance use disorder and any symptoms or disorders associated therewith in a subject in need thereof, generally,

[0269] [Chemical formula]

[0270] A method is provided herein that includes the step of administering a compound to a subject.

[0271] In another aspect, general structure (VI):

[0272] [Chemical formula]

[0273] (wherein R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, and a moiety of general formula (VII), when R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cyclo C3 alkyl, C4 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, R4 is C2 - C10 alkylene, R5 is selected from H and C1 - C10 alkyl, D represents a deuterium-enriched H site, and at least one of R2 and R3 is other than H, or R2 and R3 are independently selected from C2 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, R4 is C2 - C10 alkylene, and R5 is selected from H and C1 - C10 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring, which ring is optionally and optionally substituted by one or more C1-C10 alkyls or interrupted by one or more additional nitrogen or oxygen atoms, when R1 is of the general formula (VII):

[0274]

Chemical formula

[0275] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, and at least one of R2 and R3 is other than H, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring, which ring is optionally and optionally substituted by one or more C1-C10 alkyls or interrupted by one or more additional nitrogen or oxygen atoms, R6, R7, R8, R9 and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, -C(=O)NR17R18, where R11, R12, R13, R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl, and at least one of R6-R10 is other than H and neither R6 nor R10 is halogen, However, when R7 is Cl, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5, or However, when R7 is OH, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 - C10 alkyl, C2 - C10 haloalkyl or -R4 - O - R5, or However, when R6, R7, or R8 is OMe, the others of R6 - R10 are each H, and R2 or R3 is H, the other of R2 or R3 is C3 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5, When R1 is selected from thiazole, thiophene, and pyridine, each is optionally and in some cases substituted with one or more of OH, halogen (selected from F, Cl, Br, I), -OR19, C1 - C10 alkyl, C2 - C10 alkenyl, C2 - C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26, and R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1 - C10 alkyl, C2 - C10 alkenyl, C2 - C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, R2 and R3 are independently selected from H, C1 - C10 alkyl, C2 - C10 haloalkyl, C2 - C10 alkenyl, C2 - C10 alkynyl, -R4 - O - R5, R4 is C2 - C10 alkylene, R5 is selected from H and C1 - C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3 - C9 cycloheteroalkyl ring, and the ring is optionally and in some cases substituted with one or more C1 - C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) A composition comprising a compound having, or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is richer in the compound than its opposite enantiomer is provided herein.

[0276] In some embodiments, the compound has the general structure (VIa):

[0277]

Chemical formula

[0278] (wherein R2 and R3 are independently selected from H, branched or cyclo C3 alkyl, C4 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, R4 is C2 - C10 alkylene, R5 is selected from H and C1 - C10 alkyl, and at least one of R2 and R3 is other than H, or R2 and R3 are independently selected from C2 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, R4 is C2 - C10 alkylene, R5 is selected from H and C1 - C10 alkyl, or R2 and R3 together with the nitrogen ring to which they are attached form a C3 - C9 cycloheteroalkyl ring, which ring is optionally substituted by one or more C1 - C10 alkyls or interrupted by one or more additional nitrogen or oxygen atoms) has.

[0279] In some embodiments, the compound has the general structure (VIb):

[0280]

Chemical formula

[0281] (wherein R3 is C1 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5, R4 is C2 - C10 alkylene, R5 is selected from H and C1 - C10 alkyl, R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, -C(=O)NR17R18, where R11, R12, R13, R14, R15, R16, R17, and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O) alkyl, C(=O) aryl, C(=O) heteroaryl. At least one of R6-R10 is other than H, and neither R6 nor R10 is halogen. However, when R7 is Cl and R6, R8-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or However, when R7 is OH and R6, R8-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or However, when R6, R7, or R8 is OMe and the others of R6-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5. has.

[0282] In some embodiments, the compound has the general structure (VI):

[0283]

Chemical formula

[0284] (wherein, R1 is selected from thiazole, thiophene and pyridine, and each is optionally and in some cases substituted with one or more OH, halogen (selected from F, Cl, Br, I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26, and R19, R20, R21, R22, R23, R24, R25 and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O) alkyl, C(=O) aryl, C(=O) heteroaryl, R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, and the ring is optionally and in some cases substituted with one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0285] In some embodiments, the compound has the general structure (VIa):

[0286]

Chemical formula

[0287] (wherein, R2 and R3 are independently selected from H, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, and at least one of R2 and R3 is other than H) have.

[0288] In some embodiments, the compound has the general structure (VIa):

[0289]

Chemical formula

[0290] (wherein R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) has.

[0291] In some embodiments, the compound has the general structure (VIa):

[0292]

Chemical formula

[0293] (wherein R2 and R3 together with the nitrogen ring to which they are attached form a C3-C9 cycloheteroalkyl ring, and the ring is optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) has.

[0294] In some embodiments, the compound has the general structure (VIa):

[0295]

Chemical formula

[0296] (wherein R2 is H, and R3 is selected from branched or cyclo C3 alkyl, C4-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) has.

[0297] In some embodiments, the compound has the general structure (VIa):

[0298] [Chemical Formula]

[0299] (wherein R2 and R3 are independently selected from C2-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) and has

[0300] In some embodiments, the compound has the general structure (VIa):

[0301] [Chemical Formula]

[0302] (wherein R2 and R3 together with the nitrogen ring to which they are attached form a C3-C6 cycloheteroalkyl ring, and the ring is optionally substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) and has

[0303] In some embodiments, the compound has the general structure (VIb):

[0304] [Chemical Formula]

[0305] (wherein one or more of R6, R7, R8, R9 and R10 is OH, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl, However, when R7 is OH, and R6, R8 to R10 are H, R3 is C3 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5) has

[0306] In some embodiments, the compound has the general structure (VIb):

[0307] [Chemical formula]

[0308] (wherein one or more of R7, R8, and R9 are halogen (selected from F, Cl, Br, I), R3 is selected from C1 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, R4 is C2 - C10 alkylene, R5 is selected from H and C1 - C10 alkyl, However, when R7 is Cl, and R6, R8 to R10 are H, R3 is C3 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5) has

[0309] In some embodiments, the compound has the general structure (VIb):

[0310] [Chemical formula]

[0311] (wherein one or more of R6, R7, R8, R9 and R10 are OMe, R3 is selected from C1 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, R4 is C2 - C10 alkylene, R5 is selected from H and C1 - C10 alkyl, However, when R6, R7 or R8 is OMe, and the others of R6 to R10 are H, R3 is C3 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5) has

[0312] In some embodiments, the compound has the general structure (VIb):

[0313] [Chemical formula]

[0314] (wherein one or more of R7, R8, and R9 are F, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) and has the following structure.

[0315] In some embodiments, the compound has the general structure (VIb):

[0316] [Chemical formula]

[0317] (wherein one or more of R6, R7, R8, R9, and R10 are Me, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) and has the following structure.

[0318] In some embodiments, the compound has the general structure (VIb):

[0319] [Chemical formula]

[0320] (wherein one or more of R6, R7, R8, R9, and R10 are OH, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl, However, when R7 is OH and R6, R8 to R10 are H, R3 is C3 - C5 alkyl, C2 - C5 fluoroalkyl, or -R4 - O - R5) has

[0321] In some embodiments, the compound has the general structure (VIb):

[0322]

Chemical formula

[0323] (wherein one or more of R6, R7, R8, R9 and R10 are OMe, R3 is selected from C1 - C5 alkyl, C2 - C5 fluoroalkyl, -R4 - O - R5, R4 is C2 - C5 alkylene, R5 is selected from H and C1 - C5 alkyl, However, when R6, R7 or R8 is OMe and the others of R6 - R10 are H, R3 is C3 - C5 alkyl, C2 - C5 fluoroalkyl, or -R4 - O - R5) has

[0324] In some embodiments, the compound has the general structure (VIb):

[0325]

Chemical formula

[0326] (wherein one or more of R7, R8, or R9 are F, R3 is selected from C1 - C5 alkyl, C2 - C5 fluoroalkyl, -R4 - O - R5, R4 is C2 - C5 alkylene, R5 is selected from H and C1 - C5 alkyl) has

[0327] In some embodiments, the compound has the general structure (VIb):

[0328]

Chemical formula

[0329] (wherein one or more of R6, R7, R8, R9 and R10 is Me, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) has.

[0330] In some embodiments, the compound has the general structure (VIc):

[0331]

Chemical formula

[0332] (wherein one or more of R6, R7, R8, R9 and R10 is OH, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, which ring is optionally substituted by one or more C1-C2 alkyls or interrupted by one or more additional nitrogen or oxygen atoms) has.

[0333] In some embodiments, the compound has the general structure (VIc):

[0334]

Chemical formula

[0335] (wherein one or more of R6, R7, R8, R9 and R10 is OMe, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, where R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, which ring is optionally and optionally substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0336] In some embodiments, the compound has the general structure (VIc):

[0337]

Chemical formula

[0338] (wherein one or more of R7, R8, and R9 are F, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, where R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, which ring is optionally and optionally substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0339] In some embodiments, the compound has the general structure (VIc):

[0340]

Chemical formula

[0341] (wherein one or more of R6, R7, R8, R9 and R10 are Me, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, where R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C6 cycloheteroalkyl ring, which ring is optionally and in some cases substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0342] In some embodiments, the compound is:

[0343]

Chemical formula

[0344]

Chemical formula

[0345] selected from.

[0346] In some embodiments, the compound is:

[0347]

Chemical formula

[0348] selected from.

[0349] In another aspect, the carrier and structure:

[0350]

Chemical formula

[0351] (where D represents a deuterium-enriched H site) Compositions are provided herein that include a compound having, wherein the composition is enriched in the compound relative to its opposite enantiomer.

[0352] In some embodiments, each D represents a deuterium-enriched H site, and the level of deuterium at each deuterium-enriched H site of the compound is from 0.02% to 100%.

[0353] In some embodiments, each D represents a deuterium-enriched H site, and the level of deuterium at each deuterium-enriched H site of the compound is from 20% to 100%, from 50% to 100%, from 70% to 100%, from 90% to 100%, from 97% to 100%, or from 99% to 100%.

[0354] In another aspect, general structure (VIII):

[0355]

Chemical formula

[0356] (wherein R31 and R32 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39 R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more linear or branched C1-C10 alkyls or interrupted by one or more additional nitrogen or oxygen atoms, R27, R28, R29, R30 are each independently selected from H, linear or branched C1-C10 alkyl, F, and at least one of R27, R28, R29 or R30 is other than H, or R27 and R28, or R29 and R30, together with the carbon atom to which they are attached, form a cycloalkyl ring, or together with the carbon and one or more heteroatoms to which they are attached, form a cycloheteroalkyl ring, R33, R34, R35, R36 and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, and R40, R41, R42, R43, R44, R45, R46 and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O) alkyl, C(=O) aryl, C(=O) heteroaryl, provided that when one of R27 and R28 is Me and the other is H, and R29-R30 and R33-R37 are each H, and one of R31 or R32 is H, the other of R31 or R32 is C2-C10 alkyl, C2-C10 haloalkyl or -R 38 -O-R 39 ) A composition comprising a compound having the formula, or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in the compound compared to its opposite enantiomer, is provided herein.

[0357] In some embodiments, the compound has the general structure (VIII):

[0358]

Chemical formula

[0359] (wherein R31 and R32 are independently H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39selected from, R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32, together with the nitrogen atom to which they are attached, form a C3-C6 cycloheteroalkyl ring, and said ring is optionally and optionally substituted by one or more linear or branched C1-C2 alkyl, or interrupted by one or more additional nitrogen or oxygen atoms, R27 and R28 are fluorine, R29 and R30 are H, R33, R34, R35, R36 and R37 are each independently H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, and R40, R41, R42, R43, R44, R45, R46 and R47 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl) have.

[0360] In some embodiments, the compound has the general structure (VIII):

[0361]

Chemical formula

[0362] (wherein R31 and R32 are independently H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39 selected from, R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32, together with the nitrogen atom to which they are attached, form a C3-C6 cycloheteroalkyl ring, which ring is optionally and optionally substituted by one or more linear or branched C1-C2 alkyls or interrupted by one or more additional nitrogen or oxygen atoms. R27 and R28, together with the carbon and oxygen atoms to which they are attached, form an oxetane ring. R29 and R30 are H. R33, R34, R35, R36 and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, where R40, R41, R42, R43, R44, R45, R46 and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl). have.

[0363] In some embodiments, the compound is

[0364]

Chemical Structure

[0365]

Chemical Structure

[0366] selected from.

[0367] In some embodiments, the compound is

[0368]

Chemical Structure

[0369] is selected from.

[0370] In some embodiments, the optical purity of the compound is >5%, >25%, >50%, >75%, >90%, >95%, >97%, >98%, or >99%.

[0371] In another aspect, a method of treating depression, dysthymia, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, the structure (IX):

[0372] [Chemical formula]

[0373] [wherein R48 is phenyl, thiazole, thiophene, pyridine, or general formula (X);

[0374] [Chemical formula] (wherein R51 and R55 are independently selected from H, OH, OMe, C1-C10 alkyl, R52, R53, and R54 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1-C10 alkyl, R49 and R50 are each independently selected from H and C1-C10 alkyl, or R49 and R50, together with the nitrogen atom to which they are attached, optionally and in some cases, form a C3-C9 cycloheteroalkyl ring substituted with one or more C1-C10 alkyls) selected from the group consisting of the moieties of) administering a composition comprising a compound of or a pharmaceutically acceptable salt or ester of the compound to a subject, wherein the compound is enriched over its opposite enantiomer, is provided herein.

[0375] In some embodiments, the compound is

[0376] [Chemical Formula]

[0377] selected from

[0378] In some embodiments, the compound has the structure:

[0379] [Chemical Formula]

[0380] and has

[0381] In some embodiments, the disorder to be treated in the subject is depression or anxiety - depression. In some embodiments, the composition is administered orally.

[0382] In another aspect, a method for treating depression, anxiety - depression, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, the method comprising administering to the subject a composition comprising a compound:

[0383] [Chemical Formula]

[0384] or a pharmaceutically acceptable salt or ester of the compound, wherein the compound is enriched relative to its enantiomeric mirror image, is provided herein.

[0385] In another aspect, the general structure (XI):

[0386] [Chemical Formula]

[0387] (wherein, R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, and the moiety of general formula (XII), when R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cyclo C3 alkyl, C4 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, R4 is C2 - C10 alkylene, R5 is selected from H and C1 - C10 alkyl, D represents a deuterium - enriched H site, and at least one of R2 and R3 is other than H, or R2 and R3 are independently selected from C2 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, R4 is C2 - C10 alkylene, R5 is selected from H and C1 - C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3 - C9 cycloheteroalkyl ring, and the ring is optionally substituted by one or more C1 - C10 alkyls in some cases, or interrupted by one or more additional nitrogen or oxygen atoms, when R1 is the moiety of general formula (XII):

[0388]

Chemical formula

[0389] is the moiety of, R2 and R3 are independently selected from H, C1 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, R4 is C2 - C10 alkylene, R5 is selected from H and C1 - C10 alkyl, and at least one of R2 and R3 is other than H, or R2 and R3 together with the nitrogen atom to which they are attached form a C3 - C9 cycloheteroalkyl ring, and the ring is optionally substituted by one or more C1 - C10 alkyls in some cases, or interrupted by one or more additional nitrogen or oxygen atoms, R6, R7, R8, R9 and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, -C(=O)NR17R18, where R11, R12, R13, R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl, at least one of R6-R10 is other than H, and neither R6 nor R10 is halogen. However, when R7 is Cl, R6, R8-R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or However, when R7 is OH, R6, R8-R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or However, when R6, R7, or R8 is OMe, the others of R6-R10 are each H, and R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, When R1 is selected from thiazole, thiophene, and pyridine, each optionally and in some cases, is substituted with one or more OH, halogen (selected from F, Cl, Br, I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26, and R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O) alkyl, C(=O) aryl, C(=O) heteroaryl. R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, and the ring is optionally and in some cases substituted with one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) A composition comprising a compound having the formula, or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is richer in the compound than its opposite enantiomer is provided herein.

[0390] In some embodiments, the compound has the general structure (XIa):

[0391]

Chemical formula

[0392] (wherein R2 and R3 are independently selected from H, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, R5 is selected from H and C1-C10 alkyl, and at least one of R2 and R3 is other than H, or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl, or R2 and R3, together with the nitrogen ring to which they are attached, form a C3-C9 cycloheteroalkyl ring, which ring is optionally and in some cases substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) having.

[0393] In some embodiments, the compound has the general structure (XIb):

[0394]

Chemical formula

[0395] (wherein R3 is C1-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl, R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, -C(=O)NR17R18, where R11, R12, R13, R14, R15, R16, R17, and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O) alkyl, C(=O) aryl, C(=O) heteroaryl. At least one of R6-R10 is other than H, and neither R6 nor R10 is halogen. However, when R7 is Cl and R6, R8-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or However, when R7 is OH and R6, R8-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, or However, when R6, R7, or R8 is OMe and the others of R6-R10 are H, R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5. has.

[0396] In some embodiments, the compound has the general structure (XI):

[0397]

Chemical formula

[0398] (wherein, R1 is selected from thiazole, thiophene and pyridine, and each is optionally and in some cases substituted with one or more OH, halogen (selected from F, Cl, Br, I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26, and R19, R20, R21, R22, R23, R24, R25 and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, which ring is optionally and in some cases substituted with one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0399] In some embodiments, the compound has the general structure (XIa):

[0400]

Chemical formula

[0401] (wherein, R2 and R3 are independently selected from H, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, and at least one of R2 and R3 is other than H) have.

[0402] In some embodiments, the compound has the general structure (XIa):

[0403]

Chem.

[0404] (wherein R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) and has

[0405] In some embodiments, the compound has the general structure (XIa):

[0406]

Chem.

[0407] (wherein R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) and has

[0408] In some embodiments, the compound has the general structure (XIa):

[0409]

Chem.

[0410] (wherein R2 is H, and R3 is selected from branched or cyclo C3 alkyl, C4-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) and has

[0411] In some embodiments, the compound has the general structure (XIa):

[0412]

Chem.

[0413] (wherein R2 and R3 are independently selected from C2-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) and has

[0414] In some embodiments, the compound has the general structure (XIa):

[0415]

Chem.

[0416] (wherein R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, which ring is optionally substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) and has

[0417] In some embodiments, the compound has the general structure (XIb):

[0418]

Chem.

[0419] (wherein one or more of R6, R7, R8, R9 and R10 are OH, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl, However, when R7 is OH, and R6, R8 to R10 are H, R3 is C3 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5) has

[0420] In some embodiments, the compound has the general structure (XIb):

[0421]

Chemical formula

[0422] [wherein one or more of R7, R8, and R9 are halogen (selected from F, Cl, Br, I), R3 is selected from C1 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, R4 is C2 - C10 alkylene, and R5 is selected from H and C1 - C10 alkyl, however, when R7 is Cl, and R6, R8 to R10 are H, R3 is C3 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5)] has

[0423] In some embodiments, the compound has the general structure (XIb):

[0424]

Chemical formula

[0425] (wherein one or more of R6, R7, R8, R9 and R10 are OMe, R3 is selected from C1 - C10 alkyl, C2 - C10 haloalkyl, -R4 - O - R5, R4 is C2 - C10 alkylene, and R5 is selected from H and C1 - C10 alkyl, however, when R6, R7 or R8 is OMe, and the others of R6 to R10 are H, R3 is C3 - C10 alkyl, C2 - C10 haloalkyl, or -R4 - O - R5)] has

[0426] In some embodiments, the compound has the general structure (XIb):

[0427]

Chemical formula

[0428] (wherein one or more of R7, R8, and R9 is F, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) and has the following structure.)

[0429] In some embodiments, the compound has the general structure (XIb):

[0430]

Chemical formula

[0431] (wherein one or more of R6, R7, R8, R9, and R10 is Me, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl) and has the following structure.)

[0432] In some embodiments, the compound has the general structure (XIb):

[0433]

Chemical formula

[0434] (wherein one or more of R6, R7, R8, R9, and R10 is OH, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl, However, when R7 is OH and R6, R8 to R10 are H, R3 is C3-C5 alkyl, C2-C5 fluoroalkyl, or -R4-O-R5) has

[0435] In some embodiments, the compound has the general structure (XIb):

[0436]

Chemical formula

[0437] (wherein one or more of R6, R7, R8, R9 and R10 are OMe, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl, However, when R6, R7 or R8 is OMe and the others of R6-R10 are H, R3 is C3-C5 alkyl, C2-C5 fluoroalkyl, or -R4-O-R5) has

[0438] In some embodiments, the compound has the general structure (XIb):

[0439]

Chemical formula

[0440] (wherein one or more of R7, R8, or R9 are F, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) has

[0441] In some embodiments, the compound has the general structure (XIb):

[0442]

Chemical formula

[0443] (wherein one or more of R6, R7, R8, R9 and R10 is Me, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl) has.

[0444] In some embodiments, the compound has the general structure (XIc):

[0445]

Chemical formula

[0446] (wherein one or more of R6, R7, R8, R9 and R10 is OH, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, and the ring is optionally substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) has.

[0447] In some embodiments, the compound has the general structure (XIc):

[0448]

Chemical formula

[0449] (wherein one or more of R6, R7, R8, R9 and R10 is OMe, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, where R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, which ring is optionally and in some cases substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0450] In some embodiments, the compound has the general structure (XIc):

[0451]

Chemical formula

[0452] (wherein one or more of R7, R8, and R9 are F, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, where R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, which ring is optionally and in some cases substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0453] In some embodiments, the compound has the general structure (XIc):

[0454]

Chemical formula

[0455] (wherein one or more of R6, R7, R8, R9 and R10 are Me, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5, where R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a C3-C6 cycloheteroalkyl ring, which ring is optionally and in some cases substituted by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms) have.

[0456] In some embodiments, the compound is

[0457]

Chemical formula

[0458]

Chemical formula

[0459]

Chemical formula

[0460] selected from.

[0461] In some embodiments, the compound is

[0462]

Chemical formula

[0463] selected from.

[0464] In another aspect, the carrier and structure:

[0465]

Chemical formula

[0466] (wherein D represents a deuterium-enriched H site) A composition comprising a compound having the formula, the composition being richer in the compound than its opposite enantiomer, is provided herein.

[0467] In some embodiments, each D represents a deuterium-enriched H site, and the level of deuterium at each deuterium-enriched H site of the compound is from 0.02% to 100%.

[0468] In some embodiments, each D represents a deuterium-enriched H site, and the level of deuterium at each deuterium-enriched H site of the compound is from 20% to 100%, from 50% to 100%, from 70% to 100%, from 90% to 100%, from 97% to 100%, or from 99% to 100%.

[0469] In another aspect, the general structure (XIII):

[0470] [Chemical formula]

[0471] (wherein R31 and R32 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39 R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, which ring is optionally substituted by one or more linear or branched C1-C10 alkyls or interrupted by one or more additional nitrogen or oxygen atoms, R27, R28, R29, R30 are each independently selected from H, linear or branched C1-C10 alkyl, F, and at least one of R27, R28, R29 or R30 is other than H, or R27 and R28, or R29 and R30, together with the carbon atom to which they are attached, form a cycloalkyl ring, or together with the carbon and one or more heteroatoms to which they are attached, form a cycloheteroalkyl ring, R33, R34, R35, R36 and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, where R40, R41, R42, R43, R44, R45, R46 and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O) alkyl, C(=O) aryl, C(=O) heteroaryl, provided that when one of R27 and R28 is Me and the other is H, and R29-R30 and R33-R37 are each H, and one of R31 or R32 is H, the other of R31 or R32 is C2-C10 alkyl, C2-C10 haloalkyl or -R 38 -O-R 39 (wherein) A composition comprising a compound having the formula, or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is richer in the compound than its opposite enantiomer is provided herein.

[0472] In some embodiments, the compound has the general structure (XIII):

[0473]

Chemical formula

[0474] (wherein R31 and R32 are independently H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39selected from, R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32, together with the nitrogen atom to which they are attached, form a C3-C6 cycloheteroalkyl ring, which ring is optionally and optionally substituted by one or more linear or branched C1-C2 alkyl, or interrupted by one or more additional nitrogen or oxygen atoms, R27 and R28 are fluorine, R29 and R30 are H, R33, R34, R35, R36 and R37 are each independently H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, and R40, R41, R42, R43, R44, R45, R46 and R47 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O) alkyl, C(=O) aryl, C(=O) heteroaryl) having.

[0475] In some embodiments, the compound has the general structure (XIII):

[0476]

Chemical formula

[0477] (wherein R31 and R32 are independently H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -O-R 39 selected from, R38 is C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32, together with the nitrogen atom to which they are attached, form a C3-C6 cycloheteroalkyl ring, and said ring is optionally and in some cases substituted by one or more linear or branched C1-C2 alkyls, or interrupted by one or more additional nitrogen or oxygen atoms, R27 and R28, together with the carbon and oxygen atoms to which they are attached, form an oxetane ring, R29 and R30 are H, R33, R34, R35, R36 and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR41R42, -SR43, -SO2R44, -CO2R45, -C(=O)NR46R47, and R40, R41, R42, R43, R44, R45, R46 and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl) have

[0478] In some embodiments, the compound is

[0479]

Chemical Structure

[0480]

Chemical Structure

[0481] selected from

[0482] In some embodiments, the compound is

[0483]

Chemical Structure

[0484] is selected from.

[0485] In some embodiments, the optical purity of the compound is >5%, >25%, >50%, >75%, >90%, >95%, >97%, >98%, or >99%.

[0486] In some embodiments, the compositions disclosed herein are pharmaceutical compositions.

[0487] In some embodiments, the disclosed compositions are oral compositions.

[0488] In another aspect, a method of treating depression, dysthymia, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, comprising structure (XIV):

[0489]

Chemical formula

[0490] [wherein, R48 is phenyl, thiazole, thiophene, pyridine, or general formula (XV);

[0491]

Chemical formula

[0492] (wherein, R51 and R55 are independently selected from H, OH, OMe, C1-C10 alkyl, R52, R53 and R54 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1-C10 alkyl, R49 and R50 are each independently selected from H and C1-C10 alkyl, or R49 and R50, together with the nitrogen atom to which they are attached, optionally and in some cases form a C3-C9 cycloheteroalkyl ring optionally substituted with one or more C1-C10 alkyl) selected from the group consisting of] administering to a subject a composition comprising a compound, or a pharmaceutically acceptable salt or ester of the compound, wherein the compound is enriched relative to its opposite enantiomer, is provided herein.

[0493] In some embodiments, the compound is

[0494]

Chemical formula

[0495] selected from

[0496] In some embodiments, the compound has the structure:

[0497]

Chemical formula

[0498] having

[0499] In some embodiments, the compound has the structure:

[0500]

Chemical formula

[0501] having

[0502] In some embodiments, the disorder to be treated in the subject is depression or dysthymia.

[0503] In some embodiments, the composition is administered orally.

[0504] In another aspect, a method of treating depression, dysthymia, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, the compound:

[0505] [Chem.]

[0506] Also provided herein is a method comprising administering to a subject a composition comprising a compound or a pharmaceutically acceptable salt or ester thereof, wherein the compound is enriched relative to its opposite enantiomer.

[0507] In another aspect, general structure (XVI):

[0508] [Chem.]

[0509] (wherein R56 and R57 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic C3-C8 cycloheteroalkyl ring, said ring being optionally and in some cases substituted by one or more C1-C3 alkyl, F, OH, OMe or =O, and optionally and in some cases interrupted by one or more additional nitrogen or oxygen atoms, R58, R59, R60, R61 and R62 are each independently H, OH, halogen (selected from F, Cl, Br, I), -OR63, -O-C(=O)R64, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR65R66, -NH-C(=O)R67, -SR68, -SO2R69, -CO2R70, -C(=O)NR71R72, and R63, R64, R65, R66, R67, R68, R69, R70, R71 and R72 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, provided that when R56 and R57 together with the nitrogen atom to which they are attached form an unsubstituted piperidine ring, at least one of R58, R59, R60, R61 and R62 is other than H) Compounds having the same, or pharmaceutically acceptable salts or esters thereof, are provided herein.

[0510] In some embodiments, R56 and R57 together with the nitrogen atom to which they are attached form a piperidine ring, said ring optionally and in some cases being substituted by one or more C1-C3 alkyl, F, OH, OMe, or =O, R58, R59, R60, R61 and R62 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR63, -O-C(=O)R64, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR65R66, -NH-C(=O)R67, -SR68, -SO2R69, -CO2R70, -C(=O)NR71R72, and R63, R64, R65, R66, R67, R68, R69, R70, R71 and R72 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, Provided that when R56 and R57 together with the nitrogen atom to which they are attached form an unsubstituted piperidine ring, at least one of R58, R59, R60, R61 and R62 is other than H, a compound, or a pharmaceutically acceptable salt or ester thereof.

[0511] In some embodiments, R56 and R57 together with the nitrogen atom to which they are attached form a pyrrolidine ring, said ring optionally and in some cases being substituted by one or more C1-C3 alkyl, F, OH, OMe, or =O, R58, R59, R60, R61 and R62 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR63, -O-C(=O)R64, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR65R66, -NH-C(=O)R67, -SR68, -SO2R69, -CO2R70, -C(=O)NR71R72, where R63, R64, R65, R66, R67, R68, R69, R70, R71 and R72 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, a compound, or a pharmaceutically acceptable salt or ester thereof.

[0512] In some embodiments, R56 and R57 together with the nitrogen atom to which they are attached form an azetidine ring, which ring is optionally substituted, in some cases, by one or more C1-C3 alkyl, F, OH, OMe, or =O. R58, R59, R60, R61 and R62 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR63, -O-C(=O)R64, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR65R66, -NH-C(=O)R67, -SR68, -SO2R69, -CO2R70, -C(=O)NR71R72, where R63, R64, R65, R66, R67, R68, R69, R70, R71 and R72 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, a compound, or a pharmaceutically acceptable salt or ester thereof.

[0513] In some embodiments, R56 and R57 together with the nitrogen atom to which they are attached form an azetidine ring, which ring is optionally substituted, in some cases, by one or more C1-C3 alkyl or F. R58, R59, R60, R61 and R62 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR63, -O-C(=O)R64, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, CN, CF3, OCF3, NO2, -NR65R66, -NH-C(=O)R67, -SR68, -SO2R69, -CO2R70, -C(=O)NR71R72, where R63, R64, R65, R66, R67, R68, R69, R70, R71 and R72 are each independently selected from H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, or a compound, or a pharmaceutically acceptable salt or ester thereof.

[0514] In some embodiments, the compound is

[0515]

Chemical Structure

[0516] selected from, or a pharmaceutically acceptable salt or ester thereof, and / or a specific S- or R-isomer thereof.

[0517] In some embodiments, the compound has the structure:

[0518]

Chemical Structure

[0519] or a pharmaceutically acceptable salt thereof.

[0520] In another aspect, the general structure (XVII):

[0521]

Chemical Structure

[0522] (wherein, R73 and R74 together with the nitrogen atom to which they are attached form an azetidine ring, said ring being optionally and optionally substituted by one or more C1-C3 alkyl, F, OH or OMe, R75, R76, R77, R78 and R79 are each independently H, OH, halogen (selected from F, Cl, Br, I), -OR80, -O-C(=O)R81, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR82R83, -NH-C(=O)R84, -SR85, -SO2R86, -CO2R87, -C(=O)NR88R89, and R80, R81, R82, R83, R84, R85, R86, R87, R88, and R89 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl) A compound having the formula, or a pharmaceutically acceptable salt or ester thereof, is provided herein.

[0523] In some embodiments, the compound is

[0524]

Chemical formula

[0525] selected from, or a pharmaceutically acceptable salt or ester thereof, and / or a specific S- or R-isomer thereof.

[0526] In another aspect,

[0527]

Chemical formula

[0528] An isolated, substantially enantiomerically pure compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, is provided herein.

[0529] In another aspect, [Chemical formula]

[0530] There is provided herein an enantiomeric compound represented by [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the enantiomeric compound is present in an enantiomeric mixture having at least 90%, at least 95%, or at least 99% of the enantiomeric compound.

[0531] In another aspect, [Chemical formula]

[0532] There is provided herein a compound selected from [Chemical formula].

[0533] In some embodiments, the compound is

[0534] [Chemical formula]

[0535] selected from [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0536] In some embodiments, the compound is

[0537] [Chemical formula]

[0538] as follows.

[0539] In another aspect,

[0540] [Chemical formula]

[0541] A composition comprising a mixture of enantiomers of a compound selected from the group consisting of, wherein the mixture of enantiomers has a significantly greater amount of the enantiomer having a lower binding affinity at the MK-801 site of the NMDA receptor, is provided herein.

[0542] In some embodiments, the compound is

[0543]

Chemical formula

[0544] selected from the group consisting of.

[0545] In another aspect,

[0546]

Chemical formula

[0547] A composition comprising a mixture of enantiomers of a compound selected from the group consisting of, wherein the mixture of enantiomers has a significantly greater amount of the enantiomer having a higher binding affinity at the MK-801 site of the NMDA receptor, is provided herein.

[0548] In another aspect, a method of treating depression, dysthymia, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound disclosed herein is provided herein.

[0549] In some embodiments, the compound is

[0550]

Chemical formula

[0551] selected from the group consisting of.

[0552] In another aspect, a method of treating depression, dysthymia, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, comprising administering to the subject in need thereof

[0553]

Chem.

[0554]

Chem.

[0555] an effective amount of a composition comprising an isolated, substantially enantiomerically pure compound or a pharmaceutically acceptable salt thereof selected from the group consisting of

[0556] In another aspect, a method of treating depression, dysthymia, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, comprising administering to the subject in need thereof

[0557]

Chem.

[0558]

[0559] In some embodiments, the compound is

[0560]

Chem.

[0561] selected from the group consisting of

[0562] In another aspect,

[0563] [Chemical formula]

[0564] an isolated, substantially enantiomerically pure compound represented by to or a pharmaceutically acceptable salt thereof is provided herein.

[0565] In another aspect, a method of treating depression, depressive anxiety, mood disorder, anxiety disorder, or substance use disorder and any associated symptoms or disorders in a subject in need thereof, the method comprising administering to the subject in need thereof

[0566] [Chemical formula]

[0567] an effective amount of a composition comprising an isolated, substantially enantiomerically pure compound represented by to or a pharmaceutically acceptable salt thereof is provided herein.

[0568] In another aspect, a method of treating depression or depressive anxiety in a subject in need thereof, the method comprising administering to the subject in need thereof

[0569] [Chemical formula]

[0570] an effective amount of an isolated, substantially enantiomerically pure compound represented by to or a pharmaceutically acceptable salt thereof is provided herein.

[0571] In another aspect,

[0572] [Chemical formula]

[0573] Compounds selected from or pharmaceutically acceptable salts thereof are provided herein.

[0574] In another aspect, provided herein is a method of treating depression or depressive disorder in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound disclosed herein.

[0575] In some embodiments, the compound is administered orally.

[0576] Provided herein is a method of treating a mental disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition disclosed herein. The mental disorders contemplated may include depressive disorders, such as major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, severe mood dysregulation, substance / medication-induced depressive disorder, and depressive disorder due to another medical condition.

[0577] Also provided herein are compounds, methods and compositions useful for the treatment of patients suffering from treatment-resistant depression, such as depressive disorders that do not respond and / or have not responded to an appropriate course of at least one, or at least two other antidepressant compounds or therapies. As used herein, "depressive disorder" includes treatment-resistant depression.

[0578] In some embodiments, the compounds, methods and compositions may be used for the treatment of mental disorders including bipolar disorder and related disorders, such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorders, and bipolar disorder and related disorders due to another medical condition.

[0579] In some embodiments, the compounds, methods, and compositions can be used to treat mental disorders including substance-related disorders, e.g., to prevent substance use cravings, reduce substance use cravings, and / or promote cessation or abstinence of substance use. Substance use disorders include the abuse of psychoactive compounds such as alcohol, caffeine, cannabis, inhalants, opioids, sedatives, hypnotics, anti-anxiety agents, stimulants, nicotine, and tobacco. As used herein, "substance" or "substances" are potentially addictive psychoactive compounds such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anti-anxiety agents, stimulants, nicotine, and tobacco. For example, the methods and compositions may be used to promote smoking cessation or opioid use cessation.

[0580] In some embodiments, the compounds, methods, and compositions may be used to treat mental disorders including anxiety disorders, e.g., separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, and anxiety disorder due to another medical condition.

[0581] In some embodiments, the compounds, methods, and compositions may be used to treat mental disorders including obsessive-compulsive disorder and related disorders, e.g., obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), skin picking disorder, substance / medication-induced obsessive-compulsive disorder and related disorders, and obsessive-compulsive disorder and related disorders due to another medical condition.

[0582] In some embodiments, the compounds, methods, and compositions may be used to treat mental disorders including trauma- and stressor-related disorders, e.g., reactive attachment disorder, disinhibited social engagement disorder, posttraumatic stress disorder, acute stress disorder, and adjustment disorder.

[0583] In some embodiments, the compounds, methods, and compositions may be used to treat mental disorders including feeding and eating disorders, e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, and avoidant / restrictive food intake disorder.

[0584] In some embodiments, the compounds, methods, and compositions may be used to treat mental disorders including neurocognitive disorders such as delirium, major neurocognitive disorder, mild neurocognitive disorder, major or mild neurocognitive disorder due to Alzheimer's disease, major or mild frontotemporal neurocognitive disorder, major or mild neurocognitive disorder with Lewy bodies, major or mild vascular neurocognitive disorder, major or mild neurocognitive disorder due to traumatic brain injury, major or mild neurocognitive disorder due to substance / medication-induced, major or mild neurocognitive disorder due to HIV infection, major or mild neurocognitive disorder due to prion disease, major or mild neurocognitive disorder due to Parkinson's disease, major or mild neurocognitive disorder due to Huntington's disease, major or mild neurocognitive disorder due to another medical condition, and major or mild neurocognitive disorder due to multiple etiologies.

[0585] In some embodiments, the compounds, methods, and compositions may be used to treat mental disorders including neurodevelopmental disorders such as autism spectrum disorder, attention deficit / hyperactivity disorder, stereotypical movement disorder, tic disorder, Tourette disorder, persistent (chronic) motor tic disorder or vocal tic disorder, and provisional tic disorder.

[0586] In some embodiments, the compounds, methods, and compositions may be used to treat mental disorders including personality disorders such as borderline personality disorder.

[0587] In some embodiments, the compounds, methods, and compositions may be used to treat mental disorders including sexual dysfunctions such as delayed ejaculation, erectile disorder, female orgasm disorder, female sexual interest / arousal disorder, genito-pelvic pain / penetration disorder, male hypoactive sexual desire disorder, premature ejaculation, and substance / medication-induced sexual dysfunction.

[0588] In some embodiments, the compounds, methods, and compositions may be used to treat mental disorders including gender dysphoria, such as gender dysphoria.

[0589] The terms "effective amount" or "therapeutically effective amount" refer to an amount of a compound, material, composition, pharmaceutical, or other material that, among other things, achieves certain pharmacological and / or physiological effects, or results in a desired pharmacological and / or physiological effect, such as a reduction, inhibition, or reversal of one or more of the underlying pathophysiological mechanisms underlying neurological dysfunction, modulation of dopamine levels or signaling, modulation of serotonin levels or signaling, modulation of norepinephrine levels or signaling, modulation of glutamate or GABA levels or signaling, modulation of synaptic connectivity or neurogenesis in certain brain regions, or a combination thereof, including, but not limited to, reduction in the frequency or severity of sadness or somnolence, depressive mood, anxiety or feelings of sadness, decreased interest in all or almost all activities, significant increase or decrease in appetite leading to weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness, feelings of helplessness, lack of concentration, and reduction in the frequency or severity of recurrent thoughts of death or suicide.

[0590] The term "therapeutic index", as used in connection with any compound and the associated therapeutic effects and side effects, refers to the ratio of the dose of the compound required to induce a particular negative side effect to the dose of the compound required to induce a desired therapeutic effect. For example, in the case of racemic ketamine, antidepressant therapeutic effects and dissociative side effects occur at similar doses, and thus the therapeutic index of this compound in this context is approximately 1:1. In contrast, the compounds disclosed herein may have an improved therapeutic index, such as 3:1, such that a three-fold higher dose is required to induce dissociative side effects relative to the dose required for the antidepressant therapeutic effect.

[0591] In some embodiments, the method comprises treating a mental disorder by administering to a subject in need thereof a pharmaceutical composition comprising from about 0.01 mg to about 400 mg of a compound disclosed herein. In some embodiments, the dosage may be in the range of, for example, about 0.1 - 300 mg, 0.1 - 250 mg, 0.1 - 200 mg, 0.1 - 150 mg, 0.1 - 100 mg, 0.1 - 75 mg, 0.1 - 50 mg, 0.1 - 25 mg, 0.1 - 20 mg, 0.1 - 15 mg, 0.1 - 10 mg, 0.1 - 5 mg, 0.1 - 1 mg, 10 - 300 mg, 10 - 250 mg, 10 - 200 mg, 10 - 150 mg, 10 - 100 mg, 10 - 50 mg, 10 - 25 mg, 10 - 15 mg, 20 - 300 mg, 20 - 250 mg, 20 - 200 mg, 20 - 150 mg, 20 - 100 mg, 20 - 50 mg, 50 - 300 mg, 50 - 250 mg, 50 - 200 mg, 50 - 150 mg, 50 - 100 mg, 100 - 300 mg, 100 - 250 mg, 100 - 200 mg, and examples of dosages include, for example, about 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, and 400 mg.

[0592] In some embodiments, the dosage amount may include an amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, for example, in the range of about 1 mg to 200 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10 mg, and specific examples of the dosage amount are 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, and 200 mg.

[0593] Typically, the dosage amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once, twice, three times, or four times a day, every other day, every three days, once a week, or once a month. In some embodiments, the dosage amount is, for example, about 1 to 400 mg / day, or 1 to 300 mg / day, or 1 to 250 mg / day, or 1 to 200 mg / day, for example, 300 mg / day, 250 mg / day, 200 mg / day, 150 mg / day, 100 mg / day, 75 mg / day, 50 mg / day, 25 mg / day, 20 mg / day, 10 mg / day, 5 mg / day, or 1 mg / day.

[0594] In some embodiments, a parenteral or inhalable pharmaceutical composition, e.g., a spray or mist of a compound of the invention or a pharmaceutically acceptable salt thereof, contains a concentration of from about 0.005 mg / mL to about 500 mg / mL. In some embodiments, the composition contains a compound or a pharmaceutically acceptable salt thereof disclosed herein at a concentration of, e.g., from about 0.05 mg / mL to about 50 mg / mL, from about 0.05 mg / mL to about 100 mg / mL, from about 0.005 mg / mL to about 500 mg / mL, from about 0.1 mg / mL to about 50 mg / mL, from about 0.1 mg / mL to about 10 mg / mL, from about 0.05 mg / mL to about 25 mg / mL, from about 0.05 mg / mL to about 10 mg / mL, from about 0.05 mg / mL to about 5 mg / mL, or from about 0.05 mg / mL to about 1 mg / mL.

[0595] In some embodiments, the composition contains a compound or a pharmaceutically acceptable salt thereof disclosed herein at a concentration of, e.g., from about 0.05 mg / mL to about 15 mg / mL, from about 0.5 mg / mL to about 10 mg / mL, from about 0.25 mg / mL to about 5 mg / mL, from about 0.5 mg / mL to about 7 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 15 mg / mL, from about 5 mg / mL to about 25 mg / mL, from about 5 mg / mL to 50 mg / mL, or from about 10 mg / mL to 100 mg / mL. In some embodiments, the pharmaceutical composition is formulated as a total volume of, e.g., about 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

[0596] Typically, the dosage may be administered to a subject once, twice, three times, or four times a day, every other day, every three days, twice a week, once a week, twice a month, or once a month. In some embodiments, the compounds disclosed herein are administered to a subject once in the morning or once in the evening. In some embodiments, the compounds disclosed herein are administered to a subject once in the morning and once in the evening. In some embodiments, what is disclosed herein is administered to a subject three times a day (e.g., at breakfast, lunch, and dinner) at a dose of, e.g., 50 mg / dose (e.g., 150 mg / day).

[0597] In some embodiments, the compounds disclosed herein are administered to a subject at a dose of 25 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to a subject at a dose of 50 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to a subject at a dose of 75 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to a subject at a dose of 100 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to a subject at a dose of 150 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to a subject at a dose of 200 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to a subject at a dose of 250 mg / day in one or more doses.

[0598] In some embodiments, the dosage of the compounds disclosed herein is 0.01 - 100 mg / kg, 0.5 - 50 mg / kg, 0.5 - 10 mg / kg or 25 - 50 mg / kg once, twice, three times or four times a day. For example, in some embodiments, the dosage is 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 1 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg once, twice, three times, or four times a day. In some embodiments, the subject is administered a total daily dose of 0.01 mg to 500 mg of the compounds disclosed herein once, twice, three times, or four times a day. In some embodiments, the total amount administered to the subject within 24 hours is, for example, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg. In some embodiments, the subject may be started at a low dose and the dosage increased. In some embodiments, the subject may be started at a high dose and the dosage decreased.

[0599] In some embodiments, the compounds or compositions disclosed herein are administered to a patient under the supervision of a healthcare provider.

[0600] In some embodiments, the compounds or compositions disclosed herein are administered to a patient under the supervision of a healthcare provider at a clinic specializing in the provision of psychotropic treatment.

[0601] In some embodiments, the compounds or compositions disclosed herein are administered to a patient at a dose intended to induce a psychedelic experience in the subject under the supervision of a healthcare provider.

[0602] In some embodiments, administration to the patient under the supervision of a healthcare provider is performed periodically to maintain a therapeutic effect in the patient, for example, every 3 days, twice a week, once a week, twice a month, once a month, three times a year, twice a year, or once a year.

[0603] In some embodiments, the compounds or compositions disclosed herein are administered by the patient himself or herself at home or otherwise at a location away from the supervision of a healthcare provider.

[0604] In some embodiments, self - administration by the patient is performed periodically to maintain a therapeutic effect in the patient, for example, daily, every other day, every 3 days, twice a week, once a week, twice a month, or once a month.

[0605] In some embodiments, the compounds or compositions disclosed herein may be administered at specified intervals. For example, during treatment, the patient may be administered the compound or composition at intervals of, for example, once a year, every 6 months, every 90 days, every 60 days, every 30 days, every 14 days, every 7 days, every 3 days, every 24 hours, every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, every 3 hours, every 2.5 hours, every 2.25 hours, every 2 hours, every 1.75 hours, every 1.5 hours, every 1.25 hours, every 1 hour, every 0.75 hours, every 0.5 hours, or every 0.25 hours.

[0606] In some embodiments, the compounds disclosed herein are in the form of their pharmaceutically acceptable salts.

[0607] In some embodiments, the pharmaceutical composition comprises one or more of the compounds disclosed herein.

[0608] In some embodiments, salts of the compounds disclosed herein are used in any of the methods, uses or compositions.

[0609] In some embodiments, pharmaceutically acceptable salts of the compounds disclosed herein are used in any of the methods, uses or compositions.

[0610] In some embodiments, esters of the compounds disclosed herein are used in any of the methods, uses or compositions.

[0611] Any of the compounds disclosed herein can be used in any of the disclosed methods, uses or compositions.

[0612] Any of the compounds used in the disclosed methods, uses or compositions can be replaced with any other compound disclosed herein.

[0613] Any of the disclosed general compounds can be used in any of the disclosed methods, uses or compositions.

[0614] As used herein, the terms “about” or “approximately” mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within three standard deviations, or higher than three standard deviations, according to the practice in the art. Alternatively, “about” can mean within a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Alternatively, especially with respect to biological systems or processes, the term can mean within an order of magnitude of a value, e.g., within fivefold or within twofold. In this specification, “about” and “approximately” are used interchangeably.

[0615] In the context of the present invention, the term "thiazole" refers to a moiety having the structure

[0616]

Chem.

[0617] and it should be understood that its connection to the backbone of the compounds disclosed herein is via any carbon atom of the ring.

[0618] In the context of the present invention, the term "thiophene" refers to a moiety having the structure

[0619]

Chem.

[0620] and it should be understood that its connection to the backbone of the compounds disclosed herein is via any carbon atom of the ring.

[0621] In the context of the present disclosure, the term "pyridine" refers to a moiety having the structure

[0622]

Chem.

[0623] and it should be understood that its connection to the backbone of the compounds disclosed herein is via any carbon atom of the ring.

[0624] In the context of the present disclosure, the term "alkyl" should be understood to refer to a straight-chain, branched, or, where possible, cyclo-hydrocarbon chain containing the indicated number of carbon atoms, where all bonds connecting the atoms are sigma bonds.

[0625] In the context of the present invention, the term "alkenyl" should be understood to refer to a straight-chain, branched, or, where possible, cyclo-hydrocarbon chain containing the indicated number of carbon atoms, where at least one bond between two carbons of the chain is a double (π) bond.

[0626] In the context of the present invention, the term "alkynyl" should be understood to refer to a straight-chain, branched, or, where possible, cyclo-hydrocarbon chain containing the indicated number of carbon atoms, where at least one bond connecting two carbon atoms of the chain is a triple bond.

[0627] In the context of the present invention, the term "aryl" should be understood to refer to a C5-C10 aromatic system having one or more rings.

[0628] In the context of the present disclosure, the term "heteroaryl" should be understood to refer to an aromatic ring system in which at least one carbon atom is replaced by a heteroatom selected from O, N, S.

[0629] In the context of the present disclosure, the term "alkylene" should be understood to refer to a straight-chain, branched, or, where possible, cyclo-hydrocarbon chain containing the indicated number of carbon atoms, where all bonds connecting the atoms are sigma bonds, where two hydrogen atoms are removed, and thus it is possible to connect with two open sigma bonds (valences).

[0630] In the context of the present disclosure, the term "heteroalkyl" should be understood to refer to a straight-chain, branched, or, where possible, cyclo-hydrocarbon chain containing the indicated number of carbon atoms, where the chain is interrupted by at least one heteroatom (selected from O, N, S), and all bonds connecting the atoms are sigma bonds. For example, azetidine is an example of a C3 cycloheteroalkyl, pyrrolidine is an example of a C4 cycloheteroalkyl, piperidine is an example of a C5 cycloheteroalkyl, and morpholine is an example of a C4 cycloheteroalkyl.

[0631] In the context of the present disclosure, the term "haloalkyl" should be understood to refer to a straight-chain, branched, or, where possible, cyclo-hydrocarbon chain containing the indicated number of carbon atoms, where all bonds connecting the atoms are sigma bonds and at least one of the hydrogen atoms on the chain is replaced by a halogen atom selected from F, Cl, Br, and I.

[0632] The compounds disclosed herein can contain at least one asymmetric center. These centers are designated by the symbols "R" or "S" depending on the arrangement of the substituents around the chiral atom. Unless otherwise indicated in the structural formula, it should be understood that the present invention encompasses all stereochemical isomeric forms including diastereomers, enantiomers, and epimeric forms, as well as d-isomers and l-isomers, and mixtures thereof. The individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or a mixture of enantiomeric products can be prepared and then converted into a mixture of diastereomers, followed by separation or recrystallization, etc. Separation, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other suitable method known in the art can be used. Specific stereochemical starting compounds are commercially available or can be prepared and resolved by techniques known in the art. Further, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and suitable mixtures thereof. Additionally, the compounds can exist as tautomers, and all tautomeric isomers are provided by the present invention. Furthermore, the compounds disclosed herein can exist not only in the unsolvated form but also in the solvated form with pharmaceutically acceptable solvents such as water and ethanol. Generally, the solvated forms are considered to be equivalent to the unsolvated forms.

[0633] In some embodiments, the compositions disclosed herein may be enriched in a particular enantiomer of any of the compounds disclosed herein with respect to the corresponding opposite enantiomers of that compound such that the mixture is not racemic. In such cases, the mixture of enantiomers is understood to have an enantiomeric excess and optical purity of >0%. The enantiomeric excess or optical purity of the enantiomer mixture may be >0%, >5%, >25%, >50%, >75%, >90%, >95%, >97%, >98%, or >99%. The enantiomeric excess or optical purity of the enantiomer mixture may be 5 - 100%, 25 - 100%, 50 - 100%, 75 - 100%, 90 - 100%, 95 - 100%, 97 - 100%, 98 - 100%, or 99 - 100%. Thus, for example, compositions are contemplated herein that include the S enantiomer of a compound that is substantially free of the R enantiomer, or the R enantiomer of a compound that is substantially free of the S enantiomer. Further, when a named compound contains more than one chiral center, the scope of the present disclosure includes compositions that include mixtures of various ratios between diastereomers, and compositions that include one or more diastereomers that are substantially free of one or more other diastereomers. "Substantially free of" means that the composition contains less than 50%, 25%, 15%, 10%, 8%, 5%, 3%, 2%, or 1% of the minor enantiomer or diastereomer.

[0634] For the sake of clarity, in the context of the present disclosure, as defined by wedge and dash notation, a chemical structure of a compound depicted in a particular stereochemical orientation at any particular chiral center is intended to represent the specified stereoisomer of the compound in substantially pure form, or a mixture enriched in the stereoisomer having the specified stereochemical orientation at the defined chiral centers over the stereoisomer having the opposite orientation at said chiral center.

[0635] The present disclosure also may include any salts of the compounds disclosed herein above and below, including any pharmaceutically acceptable salts, where the compounds disclosed herein have a net charge (either positive or negative), and at least one counterion (having a counter negative or positive charge) is added thereto to form said salt. As used herein, the phrase "pharmaceutically acceptable salt" means a salt of a compound disclosed herein that is safe and effective for pharmaceutical use in mammals, and has the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds disclosed herein. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Certain compounds disclosed herein can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. A review of pharmaceutically acceptable salts is provided in BERGE et al., 66 J. PHARM. SCI. 1-19 (1977), which is incorporated herein by reference.

[0636] The present invention also contemplates inclusion of all isotopes of atoms present on the compounds disclosed herein. Isotopes include atoms having the same atomic number but different mass numbers. General examples include, but are not limited to, isotopes of hydrogen including tritium and deuterium. Isotopes of carbon include 13 C and 14 C.

[0637] Any notation of carbon in the structures throughout this application, when used without further notation, 12 C, 13 C or 14 C etc. is intended to represent all isotopes of carbon. Further, 13 C or 14 Any compound containing C may have the structure of any of the compounds disclosed herein in detail.

[0638] Also, any notation of hydrogen in the structures throughout this application, when used without further notation, 1 H, 2 H or 3 H etc. is intended to represent all isotopes of hydrogen. Further, 2 H or 3 Any compound containing H may have the structure of any of the compounds disclosed herein in detail.

[0639] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically labeled reagents in place of the unlabeled reagents utilized.

[0640] In some embodiments, each D in the chemical structure represents a deuterium-enriched H site, and the level of deuterium at each deuterium-enriched H site of the compound is from 0.02% to 100%.

[0641] In some embodiments, each D in the chemical structure represents a deuterium-enriched H site, and the level of deuterium at each deuterium-enriched H site of the compound is 20 - 100%, 50 - 100%, 70 - 100%, 90 - 100%, 95 - 100%, 97 - 100%, or 99 - 100%.

[0642] It is understood that the substituents and substitution patterns on the compounds used in the method of the present invention may be selected by those skilled in the art in order to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art from readily available starting materials. When a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure is obtained.

[0643] When selecting the compounds used in the method of the present invention, those skilled in the art will recognize that the various substituents, namely R1, R2, etc., should be selected in accordance with the well-known principles of chemical structure connectivity.

[0644] As used herein, the term "treatment" means the management and care of a patient for the purpose of combating a disease, disorder or condition. This term is intended to include delaying the progression of a disease, disorder or condition, alleviating or reducing symptoms and complications, and / or curing or eliminating a disease, disorder or condition. The patient to be treated is preferably a mammal, particularly a human.

[0645] Accordingly, the present disclosure also relates to pharmaceutical compositions comprising a pharmaceutically acceptable adjuvant and a compound as defined hereinabove and below, optionally admixed with other therapeutic agents. The adjuvant must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to its recipient.

[0646] Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration or administration via an implant. The compositions can be prepared by any method well known in the art of pharmacy.

[0647] Such a method involves the step of associating the compound or its combination used in the present invention with any auxiliary agent. Auxiliary agents, also called excipients, include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and wetting agents. Such auxiliary agents are suitably selected with respect to the intended form and route of administration and in accordance with conventional pharmaceutical practices.

[0648] Pharmaceutical compositions suitable for oral administration may be presented as individual dosage units, such as pills, tablets, dragees or capsules, or as powders or granules, or as solutions or suspensions. The active ingredient may also be presented as a bolus or paste. The composition may further be processed into suppositories or enemas for rectal administration.

[0649] Tablets can contain an active ingredient compound and suitable binders, lubricants, disintegrants, colorants, flavoring agents, flow inducing agents, and melting agents. Gelatin capsules can contain an active ingredient compound and powdery carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Compressed tablets can be prepared using similar diluents. Compressed tablets can be sugar-coated or film-coated to mask unpleasant tastes and protect the tablets from the atmosphere, or enteric-coated to selectively disintegrate in the digestive tract. For example, when orally administered in the dosage unit form of tablets or capsules, the active drug ingredient can be combined with orally non-toxic pharmaceutically acceptable inert carriers such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0650] When administered orally in liquid dosage form, the oral drug component is combined with any oral non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable oils, alcohols or other organic solvents containing esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-foaming granules, and foaming preparations reconstituted from foaming granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickening agents, and melting agents. Liquid dosage forms for oral administration may contain coloring agents and flavoring agents to enhance patient acceptability.

[0651] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile solutions. Generally, water, suitable oils, physiological saline, aqueous solutions of glucose (dextrose) and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Parenteral solutions preferably contain water-soluble salts of the active ingredient, suitable stabilizers, and, if necessary, buffering substances. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizers. Also, citric acid and its salts, and sodium EDTA are used. Further, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. The composition may be presented in unit dose or multi-dose containers, for example, sealed vials and ampoules, and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as water, before use. In the case of transdermal administration, for example, gels, patches or sprays may be contemplated. For example, compositions or formulations suitable for pulmonary administration by nasal inhalation include fine dusts or mists that can be generated by metered-dose pressurized aerosols, nebulizers or inhalers. Parenteral and intravenous forms can also contain minerals and other materials to be compatible with the type of selected injection or delivery system.

[0652] The compounds used in the methods of the present disclosure can also be administered in the form of liposomal delivery systems such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from various phospholipids such as cholesterol, stearylamine, or phosphatidylcholine. The compounds can be administered as components of tissue-targeted emulsions.

[0653] The compounds used in the methods of the present disclosure can also be conjugated to soluble polymers as targeted drug carriers or as prodrugs. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Further, the compounds may be conjugated to biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0654] The pharmaceutical compositions herein may have an immediate release, delayed release, sustained release, or modified release profile. In some embodiments, pharmaceutical compositions having different drug release profiles can be combined to create a biphasic or triphasic release profile. For example, the pharmaceutical composition may have an immediate release profile and a sustained release profile. In some embodiments, the pharmaceutical composition may have a sustained release and a delayed release profile. Such compositions may be provided as pulsatile formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc.

[0655] The pharmaceutical compositions herein may be provided with an abuse deterrent function by techniques known in the art, such as by making tablets that are difficult to crush or dissolve in water.

[0656] The present invention further comprises a pharmaceutical composition as described above, in combination with a packaging material comprising instructions for use of the composition for use as described above.

[0657] The exact dosage and administration regimen of the composition will necessarily depend on the type and magnitude of the therapeutic or nutritional effect to be achieved, and may vary depending on factors such as the particular compound, formulation, route of administration, or the age and condition of the individual subject to whom the composition is administered.

[0658] Furthermore, in some embodiments, the pharmaceutical compositions disclosed herein may comprise a single enantiomer, diastereomer, or structural isomer of a compound disclosed herein. In other embodiments, the pharmaceutical compositions disclosed herein may comprise a mixture of at least one single enantiomer, diastereomer, or structural isomer of a compound disclosed herein and any other enantiomer, diastereomer, or structural isomer of a compound disclosed herein. In further embodiments, the mixture is a racemic mixture. In other embodiments, the mixture is a non-racemic mixture (wherein one enantiomer or diastereomer is enriched in the non-racemic mixture).

[0659] The compounds used in the methods of the present disclosure may be administered in a variety of forms including those detailed herein. Treatment with the compounds may be a component of combination therapy or adjuvant therapy, i.e., a subject or patient in need of a drug is treated or administered another drug for a disease together with one or more of the compounds of the present invention. This combination therapy may be sequential therapy in which the patient is first treated with one drug and then with another drug, or the two drugs may be administered simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage form utilized.

[0660] Each embodiment disclosed in this specification is intended to be applicable to each of the other disclosed embodiments. Accordingly, all combinations of the various elements described herein are within the scope of the present disclosure.

[0661] It can be understood that the stereochemical designation (e.g., the R- and S-configurations of the specific compounds provided below) may be different, for example, when determined by X-ray crystallography.

Example

[0662] Preparation and Characterization of Compounds 35 and 37 General Considerations. Reagents and solvents were obtained from commercial sources and used without further purification (including anhydrous solvents) unless otherwise stated. Reactions were monitored by TLC using a solvent mixture appropriate for each reaction. All column chromatography was performed on silica gel (40 - 63 μm). Preparative TLC was carried out on glass plates coated with a 1 mm silica layer. Nuclear magnetic resonance spectra were recorded on a Bruker 400 or 500 MHz instrument. Chemical shifts are reported as δ values in ppm relative to CDCl3 ( 1 1H NMR = 7.26 and 13 13C NMR = 77.16), MeOD ( 1 1H NMR = 3.31 and 13 13C NMR = 49.00), or DMSO-d6 ( 1 1H NMR = 2.50 and 13 13C NMR = 39.52). Multiplicities are indicated as follows: s (singlet); d (doublet); t (triplet); p (quintet); dd (doublet of doublets); ddd (doublet of doublets of doublets); dddd (doublet of doublets of doublets of doublets); td (doublet of triplets); dt (triplet of doublets); m (multiplet); br (broad). All carbon peaks are rounded to one decimal place, except when such rounding causes two adjacent peaks to become identical; in these cases, two digits are retained.

[0663]

Chemical Formula

[0664] Cyclopentyl(2-fluorophenyl)methanone (79). To anhydrous THF (90 mL) under argon, cyclopentylmagnesium bromide (2 M in Et2O; 30.00 mL, 60.00 mmol), 2-fluorobenzonitrile (5.43 mL, 6.06 g, 50.00 mmol), and CuBr·SMe2 (206 mg, 1.00 mmol) were added, and the mixture was stirred at room temperature for 16 h. Note: When CuBr·SMe2 was added, the mixture turned from yellow to black and gas evolution occurred. At this point, water (20 mL) and 15% m / m H2SO4 aqueous solution (100 mL) were added, and the mixture was stirred for 1 h. Then, the reaction mixture was extracted with hexane (3 × 50 mL), and the combined organics were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give ketone 79 as a yellowish-brown oil (9.54 g, 99%) containing trace impurities. 1 H NMR (500 MHz, CDCl3) δ 7.79 (td, J = 7.6, 1.9 Hz, 1H), 7.48 (dddd, J = 9.0, 7.1, 5.0, 1.9 Hz, 1H), 7.21 (td, J = 7.6, 1.1 Hz, 1H), 7.11 (ddd, J = 11.2, 8.3, 1.0 Hz, 1H), 3.69 - 3.58 (m, 1H), 1.98 - 1.82 (m, 4H), 1.75 - 1.55 (m, 4H); 13 C NMR (126 MHz, CDCl3) δ 202.0 (d, J C-F = 3.8 Hz), 161.5 (d, J C-F = 253.8 Hz), 134.0 (d, J C-F = 9.0 Hz), 130.9 (d, J C-F = 2.9 Hz), 126.5 (d, J C-F = 13.1 Hz), 124.5 (d, J C-F = 3.3 Hz), 116.7 (d, J C-F = 24.0 Hz), 51.2 (d, J C-F = 5.9 Hz), 29.4, 26.2.

[0665] (1-Bromocyclopentyl)(2-fluorophenyl)methanone (80). A solution of compound 79 (9.52 g, 49.52 mmol) in CCl4 (50 mL) at 0 °C was added dropwise with a solution of Br2 (2.66 mL, 8.31 g, 52.00 mmol) in CCl4 (50 mL) in small portions over 20 minutes. At the end of the addition, the mixture was allowed to warm to room temperature and stirred for 60 minutes. The reaction mixture was then diluted with CH2Cl2 (100 mL) and washed with saturated aqueous Na2S2O3 (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give bromoketone 80 as a yellow-orange oil (12.94 g, 96%) containing trace impurities. 1 H NMR (500 MHz, CDCl3) δ 7.76 (td, J = 7.4, 1.8 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.19 (td, J = 7.6, 1.1 Hz, 1H), 7.12 (ddd, J = 10.3, 8.3, 1.0 Hz, 1H), 2.46 - 2.33 (m, 4H), 2.10 - 1.99 (m, 2H), 1.89 - 1.79 (m, 2H); 13 C NMR (126 MHz, CDCl3) δ 196.9, 159.4 (d, J C-F = 252.1 Hz), 132.8 (d, J C-F = 8.5 Hz), 130.3 (d, J C-F = 2.8 Hz), 126.8 (d, J C-F = 15.0 Hz), 123.9 (d, J C-F = 3.6 Hz), 116.5 (d, J C-F = 22.2 Hz), 73.9, 40.5 (d, J C-F = 2.1 Hz), 23.4.

[0666] 1 - ((2 - Fluorophenyl)(methylimino)methyl)cyclopentan - 1 - ol (81). Liquid methylamine was freshly prepared as follows. Solid methylamine HCl (150 g) was added dropwise with 50% m / m aqueous NaOH solution (200 g), and the generated gas was passed through a drying tube containing NaOH pellets and condensed in a flask. This was cooled to -78 °C, and a cooler containing dry ice / acetone was attached to the top. After adding all the NaOH solution, the neutralization reaction product was heated to 80 °C to continue gas generation. When the required amount of liquid methylamine was collected, the reaction was carried out as follows. Compound 80 (12.89 g, 47.54 mmol) and liquid methylamine (50 mL) were combined under argon at -78 °C (Note: The bromoketone was too viscous to be stirred at this temperature and had to be warmed), and the resulting mixture was warmed to the boiling point of methylamine (-6 °C) and stirred with a spatula until all the bromoketone was dissolved. Then the solution was cooled back to -78 °C and stirred for 20 minutes, then stirred at -6 °C for an additional 40 minutes. Then all the methylamine was carefully removed by boiling with a heat gun, and the resulting residue was dried in vacuo to give a sticky orange solid. This material was triturated with Et2O (100 mL), filtered, and the filter cake was washed with Et2O (2 × 50 mL). The combined filtrates were concentrated in vacuo to give imine 81 as an oily orange solid (10.32 g, 98%) containing trace impurities. 1 H NMR (500 MHz, CDCl3) δ 7.38 (dddd, J = 8.3, 7.3, 5.4, 1.8 Hz, 1H), 7.20 (td, J = 7.5, 1.1 Hz, 1H), 7.13 (ddd, J = 9.3, 8.3, 1.0 Hz, 1H), 7.03 (ddd, J = 7.4, 6.7, 1.8 Hz, 1H), 5.50 (br s, 1H), 3.01 (s, 3H), 1.97 - 1.83 (m, 3H), 1.74 - 1.62 (m, 3H), 1.62 - 1.49 (m, 2H); 13 C NMR (126 MHz, CDCl3) δ 171.3, 158.4 (d, J C-F= 246.3 Hz), 130.8 (d, J C-F = 7.8 Hz), 129.3 (d, J C-F = 4.4 Hz), 124.3 (d, J C-F = 3.5 Hz), 122.5 (d, J C-F = 19.5 Hz), 116.0 (d, J C-F = 21.9 Hz), 84.2, 39.8, 38.2 and 38.0 (conformational isomers), 24.0 and 23.7 (conformational isomers).

[0667] 2-(2-Fluorophenyl)-2-(methylamino)cyclohexan-1-one (35rac). Compound 81 (10.20 g, 46.10 mmol) was dissolved in decalin (80 mL), and the mixture was refluxed under argon. After 1 hour of reflux (dark brown / black solution, slow conversion by TLC), PdCl2 (245 mg, 1.38 mmol) was added, and reflux was continued for an additional 2.5 hours. The reaction mixture was cooled to room temperature, diluted with Et2O (150 mL), and extracted with 2% m / m aqueous HCl (150 mL) and water (2 × 100 mL). The combined acidic aqueous extracts were washed with hexane (100 mL) and Et2O (100 mL), basified with 25% m / m aqueous NaOH, and extracted with Et2O (3 × 100 mL). The combined organics were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give a very dark brown oil (6.69 g). This material was purified by column chromatography (8:2 hexane:EtOAc + 2% Et3N, 1 column volume → 7:3 hexane:EtOAc + 2% Et3N, 4 column volumes) to give a dark brown oil (4.56 g) still containing impurities. This material was further purified by additional column chromatography (1:1 hexane:EtOAc, 2 column volumes → 3:7 hexane:EtOAc, 3 column volumes → EtOAc, 1 column volume) to give racemic 35 (35rac) as a viscous light brown oil, which slowly crystallized to a waxy solid (3.40 g, 33%). This material was converted to the HCl salt as follows. Free base 35rac (3.40 g, 15.37 mmol) was dissolved in Et2O (100 mL), and 2.0 M HCl in Et2O (11.53 mL, 23.06 mmol) was added with stirring at room temperature. The resulting precipitate was collected by filtration, washed with Et2O (3×), and dried to give 35rac HCl as a powdery white solid (3.98 g, quantitative recovery). Free base: 11H NMR (400 MHz, CDCl3) δ 7.40 (td, J = 7.8, 1.8 Hz, 1H), 7.29 (dddd, J = 8.1, 7.1, 5.1, 1.8 Hz, 1H), 7.19 (td, J = 7.5, 1.3 Hz, 1H), 7.04 (ddd, J = 11.5, 8.1, 1.3 Hz, 1H), 2.79 - 2.68 (m, 1H), 2.54 - 2.37 (m, 2H), 2.11 (s, 3H), 2.07 (s, 1H), 1.99 - 1.89 (m, 1H), 1.86 - 1.62 (m, 4H); 13 13C NMR (101 MHz, CDCl3) δ 210.1, 161.2 (d, J C-F = 246.9 Hz), 129.5 (d, J C-F = 8.8 Hz), 128.9 (d, J C-F = 5.0 Hz), 127.3 (d, J C-F = 13.0 Hz), 124.3 (d, J C-F = 3.2 Hz), 116.4 (d, J C-F = 22.9 Hz), 68.5 (d, J C-F = 2.2 Hz), 39.5, 38.4, 29.4, 28.6, 22.1; HCl salt: 11H NMR (400 MHz, DMSO-d6) δ 10.29 (br s, 1H), 9.46 (br s, 1H), 7.85 (td, J = 8.0, 1.7 Hz, 1H), 7.64 (dddd, J = 8.6, 7.2, 5.3, 1.6 Hz, 1H), 7.45 (td, J = 7.7, 1.3 Hz, 1H), 7.39 (ddd, J = 12.0, 8.3, 1.2 Hz, 1H), 3.28 (dd, J = 13.9, 2.9 Hz, 1H), 2.47 - 2.37 (m, 2H), 2.07 - 1.93 (m, 2H), 1.79 (dt, J = 13.9, 3.2 Hz, 1H), 1.68 - 1.52 (m, 1H), 1.45 (qt, J = 13.4, 3.5 Hz, 1H); 13 13C NMR (101 MHz, DMSO-d6) δ 205.5, 160.7 (d, J C-F = 247.6 Hz), 133.2 (d, J C-F = 9.0 Hz), 130.9 (d, J C-F = 2.9 Hz), 125.7 (d, J C-F = 3.0 Hz), 118.2 (d, J C-F = 11.8 Hz), 116.8 (d, J C-F = 22.7 Hz), 68.7, 38.6 (d, J C-F = 1.8 Hz), 34.5, 28.3, 27.2, 21.1.

[0668] Chiral separation of 35 enantiomers (35R and 35S). The enantiomers of compound 35 were separated by crystallization of the diastereomeric hydrogen tartrate salts formed with L-(+)- and D-(-)-tartaric acid. Free base 35rac (1.02 g, 4.61 mmol) was combined with L-(+)-tartaric acid (692 mg, 4.61 mmol) and water (2.75 mL), and the mixture was gently warmed until a clear brown solution was obtained and then allowed to stand at room temperature. After 16 hours and then several hours in an acetone chamber (for vapor diffusion), crystals had not yet formed. Therefore, acetone (5.5 mL) was added to the solution, and the entire mixture immediately crystallized as a dense mass. The resulting crystals were collected by filtration, washed with a minimal amount of ice-cold 2:1 acetone:water (2×, some crystals dissolved) and ice-cold acetone (2×), and dried to give crystal 1 (white needles, 344 mg, hydrogen L-tartrate, approximately 80:20 R:S). Crystal 1 was dissolved in water (1.5 mL) and placed in an acetone chamber (for vapor diffusion). After 84 hours, the total volume of the solution was approximately 10 - 12 mL (estimated approximately 6:1 acetone:water), and densely packed fine needle-like crystals were formed. These were collected by filtration, washed with acetone at room temperature (2×), and dried to give crystal 2 (fine white needles, 176 mg, hydrogen L-tartrate, R enantiomer, >95% e.e.). Over several hours, additional crystals were formed in the filtrate from crystal 2. These were collected after standing overnight, washed with acetone at room temperature (2×), and dried to give crystal 3 (fine white needles, 37.6 mg, hydrogen L-tartrate, R enantiomer, >95% e.e.). The concentrated filtrate from crystals 1 and 3 (sticky off-white foam, 1.48 g) was dissolved in water (1.5 mL), acetone (3.0 mL) was added, and the mixture was seeded with crystal 3. After 2 hours at room temperature, the resulting crystals were collected by filtration, washed with acetone at room temperature (4×), and dried to give crystal 4 (white needles, 690 mg, hydrogen L-tartrate, 48:52 R:S). The concentrated filtrate from crystal 4 (white foam, 796 mg, hydrogen L-tartrate, 39:61 R:S) was enriched in the S enantiomer and converted back to the free base (nearly colorless waxy solid, 425 mg, 1.92 mmol).The amount of this free base (419 mg, 1.89 mmol) was combined with D-(-)-tartaric acid (284 mg, 1.89 mmol) and water (1.13 mL), and the mixture was gently warmed until a clear brown solution was obtained. After cooling to room temperature, acetone (3.39 mL) was added, the mixture was allowed to stand for 2 hours, and then placed in an acetone chamber (for vapor diffusion) for 24 hours. At this point, rosettes of blade-shaped crystals were formed, which appeared to be different polymorphs. These were collected by filtration, washed with ice-cold 3:1 acetone:H2O (1×) and acetone at room temperature (2×), and dried to give Crystal 5 (white crystals, 311 mg, hydrogen D-tartrate, 46.5:53.5 R:S), but the enrichment in the S enantiomer was surprisingly decreased, which might be due to crystallization as different polymorphs. However, fine needles immediately formed in the filtrate of Crystal 5, which appeared to be the same polymorph as in the previous crystallization. These were collected by filtration, washed with acetone at room temperature (3×), and dried to give Crystal 6 (fine white needles, 159 mg, hydrogen D-tartrate, S enantiomer, >95% e.e.). Additional fine needles immediately formed in the filtrate of Crystal 6. These were collected by filtration, washed with acetone at room temperature (3×), and dried to give Crystal 7 (fine white needles, 54.8 mg, hydrogen D-tartrate, S enantiomer, >95% e.e.). Crystal 5 was dissolved in water (1.0 mL) and placed in an acetone chamber (for vapor diffusion) over the weekend. After that, since crystals were still forming, the solution was seeded with Crystal 6. Crystals began to form within 30 minutes, and after standing at room temperature for 2 hours, these were collected by filtration, washed with acetone at room temperature (3×), and dried to give Crystal 8 (fine white needles, 150 mg, hydrogen D-tartrate, 33:77 R:S). The e.e. of all crystal harvests was determined by chiral HPLC (Daicel Chiralcel AD column, 4.6 mm ID, 97:3 hexane:iPrOH + 0.30% Et2NH, 1 mL / min, sample concentration of 4 mg / mL, injection volume of 20 μL; 35R t. R = 12.7 min, 35S t RDetermined by HPLC (retention time = 11.7 minutes). Hydrogen tartrate (identical for both R and S enantiomers): 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (td, J = 7.8, 1.8 Hz, 1H), 7.37 (tdd, J = 7.5, 5.2, 1.8 Hz, 1H), 7.25 (td, J = 7.6, 1.3 Hz, 1H), 7.16 (ddd, J = 11.8, 8.2, 1.3 Hz, 1H), 4.20 (s, 2H), 2.54 (td, J = 9.2, 4.7 Hz, 1H), 2.42 - 2.35 (m, 1H), 2.31 - 2.24 (m, 1H), 2.02 (s, 3H), 1.96 - 1.86 (m, 1H), 1.86 - 1.72 (m, 3H), 1.59 - 1.50 (m, 1H); 1 H NMR (500 MHz, methanol-d4) δ 7.76 (td, J = 7.9, 1.7 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.47 (td, J = 7.7, 1.2 Hz, 1H), 7.32 (ddd, J = 11.8, 8.3, 1.2 Hz, 1H), 4.40 (s, 2H), 3.27 - 3.20 (m, 1H), 2.55 - 2.49 (m, 2H), 2.36 (s, 3H), 2.15 - 2.07 (m, 1H), 1.96 - 1.85 (m, 2H), 1.83 - 1.65 (m, 2H).

[0669] (R)-2-(2-Fluorophenyl)-2-(methylamino)cyclohexan-1-one (35R). t R = 12.7 minutes (Daicel Chiralcel AD column, 4.6 mm ID, 97:3 hexane:iPrOH + 0.30% Et2NH, 1 mL / min, sample concentration 4 mg / mL, injection volume 20 μL).

[0670] (S)-2-(2-Fluorophenyl)-2-(methylamino)cyclohexan-1-one (35S). t R= 11.7 minutes (Daicel Chiralcel AD column, 4.6 mm ID, 97:3 hexane:iPrOH + 0.30% Et2NH, 1 mL / min, sample concentration of 4 mg / mL, injection volume of 20 μL).

[0671] Assignment of the absolute configuration of the 35 enantiomers (35R and 35S). Crystals of X-ray quality were grown as follows. An amount of Crystal 2 (20.5 mg, 0.055 mmol) was dissolved in water (10 mL), basified with 5% m / m aqueous NaOH, and extracted with Et2O (3 × 10 mL). The combined organics were washed with water (2 × 5 mL) and brine (5 mL), dried over Na2SO4, and concentrated to obtain the corresponding free base (11.6 mg, 0.052 mmol). This material was divided into two vials (5.8 mg each, 0.026 mmol), and (1S)-(+)-camphorsulfonic acid (6.1 mg, 0.026 mmol; (+)-CSA) was added to one vial and (1R)-(-)-camphorsulfonic acid (6.1 mg, 0.026 mmol; (-)-CSA) was added to the other. Water (0.2 mL) was also added to each vial, and the mixtures were gently warmed, stirred to homogenize, and then concentrated in vacuo to obtain the diastereomeric camphorsulfonates. These salts were dissolved in the minimum amount of toluene, and the solutions were allowed to slowly evaporate at room temperature in 4 mL vials with the lids slightly open. Under these conditions, crystals of acceptable quality for structure assignment by single crystal X-ray diffraction were obtained from the (-)-CSA salt. The absolute configuration was assigned by both anomalous dispersion and reference to the known configuration of the (-)-CSA counterion, showing that Crystal 2 has the R configuration (R factor = 0.0387). The crystallographic parameters are shown in Table 1, and an illustration of the determined crystal structure is shown in Figure 1. Once the absolute configuration of Crystal 2 was known, the configuration and e.e. of the other harvests of the crystals could be determined by chiral HPLC as described above.

[0672]

Table 1

[0673] (2-Aminophenyl)(cyclopentyl)methanone (89). Under argon, to a solution of 2-aminobenzonitrile (4.73 g, 40.00 mmol) in anhydrous THF (15 mL) at 0 °C was added cyclopentylmagnesium bromide (2 M in Et2O; 60.00 mL, 120.00 mmol). After adding approximately 1 / 3 of the Grignard reagent over 5 minutes, a thick yellow precipitate formed and the mixture became difficult to stir. Additional anhydrous THF (45 mL) was added in an attempt to reduce the viscosity and improve stirring, but this had little effect. Therefore, the remaining 2 / 3 of the Grignard reagent was added over 5 minutes, and the mixture was manually stirred during addition to mix as completely as possible, then allowed to warm to room temperature. Once at room temperature, additional anhydrous THF (40 mL) was added and the mixture was stirred further, resulting in the thick pale yellow slurry thinning sufficiently to allow stirring. After stirring at room temperature for 3 hours, the reaction was poured into a mixture of ice (150 g) and 10% aqueous HCl (100 mL), and the resulting biphasic yellow solution was allowed to stand with occasional mixing until TLC showed complete hydrolysis of the imine intermediate. The hydrolyzed mixture was basified to pH 7 - 8 with solid NaHCO3 and extracted with Et2O (3 × 100 mL). The combined organics were washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give a yellow oil that slowly crystallized to a waxy yellow solid (7.37 g). This material was purified by column chromatography (9:1 hexane:EtOAc) to give pure amino ketone 89 as a waxy lemon yellow solid (6.72 g, 89%). 1 H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 6.69 - 6.61 (m, 2H), 6.27 (br s, 2H), 3.72 (p, J = 8.0 Hz, 1H), 1.97 - 1.86 (m, 4H), 1.80 - 1.70 (m, 2H), 1.70 - 1.60 (m, 2H); 1313C NMR (126 MHz, CDCl3) δ 205.6, 150.8, 134.0, 131.5, 118.0, 117.5, 115.8, 46.8, 30.5, 26.5.

[0674] Cyclopentyl(2-iodophenyl)methanone (90). Under argon, to a solution of amino ketone 89 (6.68 g, 35.30 mmol) in CH3CN (141 mL) was added p-toluenesulfonic acid monohydrate (20.14 g, 105.9 mmol), and the yellow solution was cooled to 0 °C. A solution of NaNO2 (4.87 g, 70.60 mmol) and KI (14.65 g, 88.26 mmol) in water (21 mL) was added dropwise in small portions (ca. 1 mL / min) over about 30 min while maintaining the temperature at <5 °C. Foaming was observed during the addition, and the mixture rapidly became dark orange-brown, then almost black (difficult to stir at this stage), then dark orange-brown again. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 2 h. At this point, TLC indicated that the mixture was still mostly starting material and no further progress had occurred, so the reaction was quenched. The mixture was poured into water (200 mL), saturated aqueous NaHCO3 (50 mL) and saturated aqueous Na2S2O3 (50 mL) were added, and the mixture was extracted with Et2O (3 × 100 mL). The combined organics were washed with water (50 mL), 5% aqueous HCl (50 mL), water (2 × 50 mL), saturated aqueous NaHCO3 (25 mL), and brine (25 mL), dried over Na2SO4, and concentrated in vacuo to give a yellow-orange oil (7.70 g). This material was purified by column chromatography (40:1 hexane:Et2O, 2 column volumes → 30:1 hexane:Et2O, 3 column volumes → 5:1 hexane:Et2O, 2 column volumes) to give the residual starting material 89 as a waxy yellow solid (3.96 g, 59%) and the iodo ketone 90 as a yellow oil (3.42 g, 32%). 11H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.9 Hz, 1H), 7.39 (td, J = 7.5, 1.1 Hz, 1H), 7.32 (dd, J = 7.6, 1.8 Hz, 1H), 7.10 (td, J = 7.6, 1.8 Hz, 1H), 3.54 (p, J = 7.9 Hz, 1H), 2.00 - 1.81 (m, 4H), 1.81 - 1.68 (m, 2H), 1.68 - 1.56 (m, 2H); 13 13C NMR (101 MHz, CDCl3) δ 207.8, 145.7, 140.4, 131.3, 128.0, 127.8, 91.6, 50.5, 29.7, 26.3.

[0675] (1-Bromocyclopentyl)(2-iodophenyl)methanone (91). A solution of iodo ketone 90 (1.71 g, 5.70 mmol) in CCl4 (5.8 mL) at 0 °C was added dropwise with a solution of Br2 (0.307 mL, 957 mg, 5.99 mmol) in CCl4 (5.8 mL) in small portions over 20 min. At the end of the addition, the mixture was allowed to warm to room temperature and stirred for 40 min. The reaction mixture was then diluted with CH2Cl2 (20 mL) and washed with saturated aqueous Na2S2O3 (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give compound 91 as a yellow oil (2.14 g, 99%). 1 1H NMR (500 MHz, CDCl3) δ 7.89 (dd, J = 7.9, 1.1 Hz, 1H), 7.70 (dd, J = 7.7, 1.7 Hz, 1H), 7.38 (td, J = 7.6, 1.1 Hz, 1H), 7.12 (td, J = 7.7, 1.6 Hz, 1H), 2.46 - 2.30 (m, 4H), 2.11 - 2.00 (m, 2H), 1.93 - 1.83 (m, 2H); 1313C NMR (101 MHz, CDCl3) δ 201.1, 144.7, 140.0, 131.1, 127.8, 127.7, 92.3, 73.5, 41.0, 23.4.

[0676] 2-(2-Iodophenyl)-2-(methylamino)cyclohexan-1-one (37rac). Liquid methylamine was freshly prepared as follows. Solid methylamine HCl (30 g) was added dropwise with 50% m / m aqueous NaOH solution (40 g), and the generated gas was passed through a drying tube containing NaOH pellets and condensed into a flask equipped with a cooler containing dry ice / acetone at the top. Once the required amount of liquid methylamine was collected, the reaction was carried out as follows. Compound 91 (2.12 g, 5.59 mmol) and liquid methylamine (4.5 mL) were combined under argon at -10 °C, and the resulting mixture was stirred for 1 hour. Then, all of the methylamine was carefully removed by boiling, and the obtained residue was dried in vacuo to give a pale yellow solid (2.40 g). This material was triturated with Et2O (10 mL), filtered, and the filter cake was washed with Et2O (2 × 5 mL). The combined filtrates were concentrated in vacuo to give crude 1-((2-iodophenyl)(methylimino)methyl)cyclopentan-1-ol as a waxy yellow solid (1.78 g). An amount (1.76 g) of this material was dissolved in decalin (9.5 mL), and the yellow solution was refluxed under argon for 2 hours. Then, the reaction mixture (dark brown at this time) was cooled to room temperature, diluted with Et2O (20 mL), and extracted with 2% aqueous HCl solution (20 mL) and water (2 × 20 mL). The combined aqueous extracts were washed with hexane (20 mL) and Et2O (20 mL), basified to pH 9 - 10 with aqueous NaOH solution, and extracted with Et2O (3 × 20 mL). The combined organics were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give a viscous yellow oil (690 mg). This material was purified by column chromatography (8:2 hexane:EtOAc, 4 column volumes → 7:3 hexane:EtOAc, 4 column volumes) to yield an almost colorless oil, which slowly crystallized into an off-white solid (0.31 g) still containing impurities.This material was further purified by additional column chromatography (20:1 hexane:EtOAc + 2% Et3N, 2 column volumes → 9:1 hexane:EtOAc + 2% Et3N, 2 column volumes → 5.67:1 hexane:EtOAc + 2% Et3N, 2 column volumes) to afford racemic 37 (37rac) as a nearly colorless oil, which slowly crystallized to a waxy white solid (267 mg, 15% over two steps). This material was converted to the HCl salt as follows. Free base 37rac (267 mg, 0.811 mmol) was dissolved in Et2O (5 mL), and 2.0 M HCl in Et2O (0.61 mL, 1.22 mmol) was added with stirring at room temperature. The mixture was concentrated in vacuo, and the resulting solid was triturated with hexane. The mixture was concentrated again to afford 37rac HCl as a powdery off-white solid (281 mg, 95% recovery). Free base:. 1 H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 7.8 Hz, 1H), 7.52 (dd, J = 7.9, 1.7 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 6.94 (td, J = 7.6, 1.7 Hz, 1H), 2.76 - 2.66 (m, 1H), 2.54 - 2.44 (m, 2H), 2.18 - 2.08 (m, 2H), 2.07 (s, 3H), 1.94 - 1.84 (m, 1H), 1.83 - 1.75 (m, 3H); 13 C NMR (126 MHz, CDCl3) δ 207.6, 142.5, 142.2, 129.8, 128.9, 127.9, 98.3, 72.2, 39.9, 38.9, 29.3, 26.9, 21.7; HCl salt: 11H NMR (500 MHz, DMSO-d6) δ 9.89 (br s, 1H), 8.84 (br s, 1H), 8.12 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 3.43 - 3.29 (putative m, 1H; hidden by H2O peak as shown by COSY), 2.65 - 2.53 (m, 2H), 2.25 (s, 3H), 2.09 - 1.99 (m, 1H), 1.88 (td, J = 13.7, 3.4 Hz, 1H), 1.77 (br d, J = 13.9 Hz, 1H), 1.74 - 1.64 (m, 1H), 1.55 - 1.42 (m, 1H).

Example

[0677] Preparation of Compounds 14S and 14R

[0678]

Chem.

[0679] Step 1: Preparation of (S)-2-(methylamino)-2-phenylcyclohexan-1-one (14S) and (R)-2-(methylamino)-2-phenylcyclohexan-1-one (14R) A solution of 2-(methylamino)-2-phenylcyclohexan-1-one hydrochloride (1.4 g, 1.97 mmol) (14 rac) stirred at room temperature in dry methanol (20 mL) was treated with NaOH (0.25 g, 6.26 mmol), and the reaction mixture was stirred for 30 minutes. The mixture was filtered and the filtrate was concentrated in vacuo. After evaporation, the residue was separated by chiral chromatography using a 250×20 mm, 5 μm Chiralpak AD-H column eluting with 90 - 5 - 5 hexane - IPA - MeOH at a flow rate of 12 mL / min. The samples were combined to afford the product free base, which was acidified with HCl in dioxane and concentrated to give the HCl salt, providing the following. 0.475 g of ENT-1 2-(methylamino)-2-phenylcyclohexan-1-one hydrochloride, tR = 18.150 min (for the free base) (assigned here as the S isomer, 14S); m / z [M+H] + 204.0; 1 H NMR (DMSO-d6, 400 MHz) (HCl): δ (ppm) 9.98 (s, 1H), 9.34 (s, 1H), 7.55 (m, 3H), 7.42 (d, J = 7.1 Hz, 2H), 3.17 (d, J = 13.1 Hz, 1H), 2.40 (m, 1H), 2.30 (m, 1H), 2.12 (m, 1H), 2.10 (s, 3H), 1.97 (m, 1H), 1.86 (m, 1H), 1.59 (m, 2H); And 0.470 g of ENT-2 2-(methylamino)-2-phenylcyclohexan-1-one hydrochloride, tR = 27.830 min (for the free base) (assigned here as the R isomer, 14R); m / z [M+H] + 204.1; 11H NMR (DMSO-d6, 400 MHz) (HCl): δ (ppm) 10.00 (s, 1H), 9.34 (s, 1H), 7.54 (m, 3H), 7.41 (d, J = 6.9 Hz, 2H), 3.15 (d, J = 13.8 Hz, 1H), 2.39 (m, 1H), 2.29 (m, 1H), 2.14 (m, 1H), 2.12 (s, 3H), 1.96 (m, 1H), 1.85 (m, 1H), 1.60 (m, 2H).

Example

[0680] Preparation of Compounds 29R and 29S

[0681]

Chem.

[0682] Step 1: Preparation of a 0.8 M solution of cyclopentylmagnesium bromide in THF To a stirred solution of bromocyclopentane (83 g, 560 mmol) in THF (700 mL) was added a catalytic amount of iodine and ethyl iodide. Magnesium turnings (17.5 g, 672 mmol) were added and the reaction mixture was refluxed with stirring for 5 h and then cooled to room temperature to give cyclopentylmagnesium bromide in THF, which was used directly in the next step.

[0683] Step 2: Preparation of cyclopentyl(phenyl)methanol A solution of benzaldehyde (40.3 g, 380 mmol) in THF (200 mL) was added dropwise to a solution of cyclopentylmagnesium bromide in THF (0.8 M, 700 mL, 560 mmol, 1.5 equiv) at room temperature. The reaction mixture was stirred at room temperature overnight. The mixture was cooled in an ice-water bath and then treated dropwise with a solution of NH4Cl (50 g) in water (500 mL). The resulting mixture was extracted with ethyl acetate (3 × 400 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel (500 g of SiO2 / 25 g of reaction mixture, hexane / MTBE 20 / 1 → 1 / 1) gave 27 g of cyclopentyl(phenyl)methanol (40% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.35 - 7.19 (m, 5H), 4.39 (d, J = 8.4 Hz, 1H), 2.21 (h, J = 8.2 Hz, 1H), 1.93 - 1.81 (m, 1H), 1.71 - 1.41 (m, 5H), 1.36 (dtd, J = 11.4, 7.4, 3.7 Hz, 1H), 1.14 (dq, J = 12.4, 8.1 Hz, 1H).

[0684] Step 3: Preparation of cyclopentyl(phenyl)methanone A solution of cyclopentyl(phenyl)methanol (27 g, 153 mmol) in dry dichloromethane (250 mL) was stirred, cooled in an ice-water bath, and treated with Dess-Martin periodinane (DMP, 97.5 g, 230 mmol). The reaction mixture was stirred at room temperature overnight, diluted with an aqueous solution of sodium bicarbonate (75 g, 500 mL), and extracted twice with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel (100 g of SiO2 / 10 g of reaction mixture, hexane / DCM 10 / 1) gave 17 g of cyclopentyl(phenyl)methanone (59% yield). 11H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 7.7 Hz, 2H), 7.62 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 1.94 - 1.82 (m, 2H), 1.75 (q, J = 6.8 Hz, 2H), 1.71 - 1.56 (m, 4H).

[0685] Step 4: Preparation of (1-bromocyclopentyl)(phenyl)methanone A solution of cyclopentyl(phenyl)methanone (17 g, 90 mmol) in a mixture of dry ethyl acetate (75 mL) and dry CHCl3 (75 mL) was added copper(II) bromide (60 g, 270 mmol), and the reaction mixture was stirred overnight under reflux. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give 22 g of (1-bromocyclopentyl)(phenyl)methanone (yield 96.6%), which was used in the next step without further purification.

[0686] Step 5: Preparation of 1-(((2-methoxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride To a solution of (1-bromocyclopentyl)(phenyl)methanone (22 g, 86.9 mmol) in dry methanol (220 mL) was added 2-methoxyethylamine (19.6 g, 260.7 mmol), and the reaction mixture was stirred at room temperature for 48 h. The mixture was evaporated under reduced pressure and diluted with water (300 mL) and ethyl acetate (300 mL). The separated organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 16 g of 1-(((2-methoxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol. The compound was stirred in dioxane (1 M), treated with HCl / dioxane (1.05 equiv), and then evaporated under reduced pressure to give 1-(((2-methoxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride. 11H NMR (500 MHz, chloroform-d) δ 7.98 (dd, J = 7.6, 1.9 Hz, 1H), 7.50 - 7.31 (m, 3H), 7.05 (dt, J = 5.8, 1.7 Hz, 1H), 3.57 (td, J = 6.0, 2.6 Hz, 1H), 3.35 - 3.22 (m, 3H), 2.43 - 2.32 (m, 1H), 2.09 - 1.97 (m, 1H), 1.89 (dddd, J = 22.6, 10.8, 5.5, 2.8 Hz, 4H), 1.65 (ddt, J = 11.1, 5.6, 2.7 Hz, 1H), 1.52 (ddt, J = 7.8, 5.3, 2.9 Hz, 1H).

[0687] Step 6: Preparation of 2-((2-methoxyethyl)amino)-2-phenylcyclohexan-1-one (29rac) Heated to 200 °C in an oil bath and stirred, 1-(((2-methoxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride was added portionwise to Dowtherm (90 mL, 294 mmol). The reaction mixture was heated at 180 °C for 15 minutes, cooled to room temperature, and diluted with CHCl3 (250 mL) and water (150 mL). The separated aqueous layer was washed with CHCl3 (2 × 200 mL) and evaporated under reduced pressure. The residue was recrystallized (5 mL of EtOH + a few drops of MeOH per 1 g of crude product) to give 3.2 g of 2-((2-methoxyethyl)amino)-2-phenylcyclohexan-1-one hydrochloride (29 rac). m / z [M+H] + 248.3; 1 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.39 (s, 2H), 7.46 (m, 3H), 7.39 (m, J = 7.0 Hz, 2H), 3.44 (m, 2H), 3.34 (m, 1H), 3.19 (s, 3H), 3.01 (m, 1H), 2.41 (m, 2H), 2.31 (m, 1H), 2.12 (m, 1H), 1.90 (m, 1H), 1.82 (m, 1H), 1.64 (q, J = 12.4, 12.3, 12.3 Hz, 1H), 1.51 (q, J = 12.4, 12.4, 12.3 Hz, 1H).

[0688] Step 7: Preparation of (R)-2-((2-methoxyethyl)amino)-2-phenylcyclohexan-1-one (29R) and (S)-2-((2-methoxyethyl)amino)-2-phenylcyclohexan-1-one (29S) The HCl salt of 29rac was basified with an aqueous solution of NaHCO3, extracted with CH2Cl2, and the organic extract was concentrated to produce the free base (850 mg). This substance was separated into enantiomers by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH, B%: 17%; multiple injection process with an interval of 1.2 minutes between injections) to obtain ENT-1, RT = 1.080 minutes (241 mg) (assigned here as the S isomer, 29S) and ENT-2, RT = 1.236 minutes (184 mg) (assigned here as the R isomer, 29R). The retention times were determined using the following chiral analysis method: column: Chiralpak OD-3, 100 × 4.6 mm I.D., 3 μm; mobile phase: A: CO2, B: EtOH (0.1% IPAm, v / v); gradient: (time (min) / A% / B%), (0.0 / 95 / 5, 0.5 / 95 / 5, 2.0 / 60 / 40, 3.0 / 60 / 40, 3.6 / 95 / 5, 4.0 / 95 / 5); flow rate: 3.4 mL / min; column temperature: 35 °C; ABPR: 1800 psi.

Example

[0689] Preparation of Compounds 30R and 30S

[0690]

Chem.

[0691] Step 1: Preparation of 1-(((2-hydroxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride A solution of (1-bromocyclopentyl)(phenyl)methanone (17 g, 67.15 mmol) in dry methanol (170 mL) was added to 2-aminoethanol (12.3 g, 201.45 mmol), and the reaction mixture was stirred at room temperature for 48 h. Upon completion, the mixture was evaporated under reduced pressure, diluted with water (300 mL), and extracted with ethyl acetate (300 mL). The separated organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 8 g of 1-(((3-hydroxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol. This substance was stirred in dioxane (1 M) and treated with HCl / dioxane (1.05 equiv), and evaporated under reduced pressure to give 1-(((3-hydroxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride. 1 H NMR (400 MHz, DMSO-d6) δ 7.58 - 7.50 (m, 2H), 7.27 (dd, J = 8.3, 6.3 Hz, 3H), 4.37 (s, 1H), 3.48 (td, J = 7.4, 3.1 Hz, 2H), 3.17 (s, 1H), 2.40 (d, J=9.2 Hz, 1H), 1.71 - 1.62 (m, 2H), 1.59 (d, J=7.2 Hz, 2H), 1.58 - 1.46 (m, 2H), 1.25 (d, J=10.5 Hz, 2H).

[0692] Step 2: 2-((2-Hydroxyethyl)amino)-2-phenylcyclohexan-1-one (30 rac) Preparation of Heated to 200 °C in an oil bath and stirred, 1-(((3-hydroxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride was added portionwise to Dowtherm (70 mL, 228.7 mmol). The reaction mixture was heated to 180 °C for 15 minutes, cooled to room temperature, and diluted with CHCl3 (200 mL) and water (120 mL). The aqueous layer was washed with CHCl3 (2 × 150 mL) and evaporated under reduced pressure. The residue was recrystallized (5 mL of EtOH + a few drops of ACN per 1 g of crude product) to give 2.7 g of 2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one hydrochloride (30 rac). 1 H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 7.7 Hz, 2H), 7.43 - 7.32 (m, 3H), 7.32 - 7.23 (m, 2H), 5.41 (t, J = 3.7 Hz, 1H), 3.91 (dd, J = 10.7, 3.8 Hz, 1H), 3.85 - 3.73 (m, 2H), 2.94 - 2.81 (m, 1H), 2.64 (dd, J = 13.7, 3.0 Hz, 1H), 2.21 - 2.06 (m, 2H), 1.94 (dt, J = 12.6, 3.4 Hz, 2H), 1.86 - 1.68 (m, 2H), 1.53 - 1.47 (m, 1H), 1.31 - 1.18 (m, 1H).

[0693] Step 3: Preparation of (R)-2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one (30R) and (S)-2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one (30S) A solution of 2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one hydrochloride (1.7 g, 2 mmol) in dry methanol (20 mL) was treated with NaOH (0.3 g, 7 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was then filtered, and the filtrate was concentrated in vacuo. The residue after evaporation was separated on a 250×20 mm, 5 μm Chiralpak AD-H column eluting with 99-1 hexane-IPA at a flow rate of 15 mL / min. The samples were separated and combined to give the product free base. These were treated with 10% HCl (5 mL) in dioxane in dioxane and evaporated to dryness to give the following. ENT-1 2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one hydrochloride 0.268 g, tR = 9.953 min (for the free base) (assigned here as the R isomer, 30R); m / z [M+H] + 216.2; 1 H NMR (DMSO-d6, 400 MHz) (HCl): δ (ppm) 10.27 (s, 1H), 9.95 (s, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.44 (t, 2H), 7.38 (t, J = 5.8 Hz, 1H), 5.67 (br s, 1H), 4.01 (d, J = 13.3 Hz, 1H), 3.93 (t, J = 14.0, 14.0 Hz, 1H), 3.09 (d, J = 15.6 Hz, 1H), 2.73 (m, 1H), 2.39 (m, 1H), 2.14 (m, 5H), 1.56 (m, 1H), 0.95 (m, 1H); and ENT-2 2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one hydrochloride 0.288 g, tR = 12.382 min (for the free base) (assigned here as the S isomer, 30S); m / z [M+H] + 216.2; 11H NMR (DMSO-d6, 400 MHz) (HCl): δ (ppm) 10.24 (s, 1H), 9.97 (s, 1H), 7.58 (d, J = 7.3 Hz, 2H), 7.46 (t, J = 7.5, 7.5 Hz, 2H), 7.39 (t, J = 7.6, 7.6 Hz, 1H), 5.67 (br s, 1H), 4.02 (d, J = 15.3 Hz, 1H), 3.93 (t, J = 12.6, 12.6 Hz, 1H), 3.09 (d, J = 16.4 Hz, 1H), 2.73 (m, 1H), 2.39 (m, 1H), 2.14 (m, 5H), 1.55 (m, 1H), 0.96 (m, 1H).

Example

[0694] Preparation of Compounds 38R and 38S

[0695]

Chem.

[0696] Step 1: Preparation of cyclopentyl(o-tolyl)methanol A solution of 2-methylbenzaldehyde (37 g, 380 mmol) in THF (200 mL) was added dropwise to a THF solution of cyclopentylmagnesium bromide (0.8 M, 700 mL, 560 mmol, 1.5 equiv). The reaction mixture was stirred overnight at room temperature. The mixture was cooled in an ice-water bath and treated dropwise with a solution of NH4Cl (50 g) in water (500 mL). The resulting mixture was extracted with ethyl acetate (3 × 400 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel (500 g of SiO2 / 25 g of reaction mixture, hexane / MTBE 20 / 1 → 1 / 1) gave 25 g of cyclopentyl(o-tolyl)methanol (yield 39.5%). 11H NMR (500 MHz, chloroform-d) δ 7.46 - 7.40 (m, 1H), 7.26 - 7.19 (m, 1H), 7.16 (ddt, J = 10.4, 5.6, 2.7 Hz, 2H), 4.72 (dd, J=8.2, 2.2 Hz, 1H), 2.45 (s, 3H), 2.29 (dt, J = 8.0, 6.0 Hz, 2H), 1.89 (dtt, J = 10.9, 8.4, 5.6 Hz, 1H), 1.78 - 1.68 (m, 1H), 1.68 - 1.60 (m, 2H), 1.60 - 1.43 (m, 3H), 1.24 - 1.13 (m, 1H).

[0697] Step 2: Preparation of cyclopentyl(o-tolyl)methanone To a solution of cyclopentyl(o-tolyl)methanol (25 g, 150 mmol) in dry dichloromethane (250 mL) cooled in an ice bath was added Dess-Martin periodinane (DMP, 97.5 g, 230 mmol). The reaction mixture was stirred overnight at room temperature, diluted with an aqueous solution of sodium bicarbonate (75 g, 500 mL), and extracted twice with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel (100 g of SiO2 / 10 g of reaction mixture, hexane / DCM 10 / 1) gave 16 g of cyclopentyl(o-tolyl)methanone (60% yield).

[0698] Step 3: Preparation of (1-bromocyclopentyl)(o-tolyl)methanone To a solution of cyclopentyl(o-tolyl)methanone (16 g, 90 mmol) in a mixture of dry ethyl acetate (75 mL) and dry CHCl3 (75 mL) was added copper(II) bromide (57 g, 257 mmol), and the reaction mixture was stirred overnight under reflux. The mixture was cooled, filtered, and the filtrate was concentrated in vacuo to give 20 g of (1-bromocyclopentyl)(o-tolyl)methanone (96% yield), which was used in the next step without further purification. 11H NMR (400 MHz, chloroform-d) δ 7.74 (d, J = 7.7 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.27 - 7.14 (m, 2H), 2.36 (m, 7H), 2.05 (tt, J = 9.6, 5.3 Hz, 2H), 1.81 (q, J = 7.6 Hz, 2H).

[0699] Step 4: Preparation of 1-((methylimino)(o-tolyl)methyl)cyclopentan-1-ol hydrochloride (1-Bromocyclopentyl)(o-tolyl)methanone (15 g, 56.14 mmol) and a solution of methylamine in methanol (150 mL) were stirred at room temperature for 48 h. When complete, the mixture was evaporated under reduced pressure and the residue was diluted with water (300 mL) and ethyl acetate (300 mL). The separated organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 9.5 g of 1-((methylimino)(o-tolyl)methyl)cyclopentan-1-ol. This material in dioxane (1 M) was treated with HCl / dioxane (1.05 equiv) and evaporated under reduced pressure to give 11.1 g of 1-((methylimino)(o-tolyl)methyl)cyclopentan-1-ol hydrochloride. 1 1H NMR (500 MHz, chloroform-d) δ 7.26 (d, J = 4.0 Hz, 3H), 6.95 (s, 1H), 2.95 (s, 3H), 2.14 (s, 3H), 1.91 (s, 2H), 1.86 (s, 1H), 1.81 (s, 1H), 1.67 (s, 3H), 1.25 (s, 1H).

[0700] Step 5: Preparation of 2-(methylamino)-2-(o-tolyl)cyclohexan-1-one (38rac) Heated to 200 °C in an oil bath and stirred, Dowtherm (70 mL, 228.7 mmol) was added portionwise with 1-((methylimino)(o-tolyl)methyl)cyclopentan-1-ol hydrochloride. The reaction mixture was heated at 180 °C for 15 minutes, cooled to room temperature, and diluted with CHCl3 (250 mL) and water (150 mL). The aqueous layer was washed with CHCl3 (2 × 200 mL) and evaporated under reduced pressure. The residue was recrystallized (5 mL of EtOH and a few drops of ACN per 1 g of crude product) to afford 2.7 g of 2-(methylamino)-2-(o-tolyl)cyclohexan-1-one hydrochloride (38 rac). 1 H NMR (400 MHz, chloroform-d) δ 7.45 (dd, J = 7.5, 1.7 Hz, 1H), 7.21 (dtd, J = 14.5, 7.2, 2.3 Hz, 2H), 7.14 (dd, J = 7.3, 1.8 Hz, 1H), 3.05 (dd, J = 15.2, 4.1 Hz, 1H), 2.37 (dd, J = 7.9, 3.1 Hz, 1H), 2.13 (s, 3H), 2.04 (s, 3H), 2.01 - 1.96 (m, 1H), 1.83 - 1.70 (m, 3H), 1.54 (dq, J = 14.2, 4.7 Hz, 1H).

[0701] Step 6: Preparation of (R)-2-(methylamino)-2-(o-tolyl)cyclohexan-1-one (38R) and (S)-2-(methylamino)-2-(o-tolyl)cyclohexan-1-one (38S) A solution of 2-(methylamino)-2-(o-tolyl)cyclohexan-1-one hydrochloride (1.4 g, 2 mmol) in dry methanol (20 mL) was treated with NaOH (0.3 g, 7 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was then filtered, and the filtrate was concentrated in vacuo to afford the free base. The residue after evaporation was separated on a 250×20 mm, 5 μm Chiralcel OJ-H column eluting with 95:2.5:2.5 hexane-IPA-MeOH at a flow rate of 15 mL / min. The samples were separated and combined to afford the product free base. The free base obtained was dissolved in dioxane, treated with 10% HCl (5 mL) in dioxane, and then evaporated to dryness to afford the following. ENT-1 2-(methylamino)-2-(o-tolyl)cyclohexan-1-one hydrochloride 0.494 g, tR = 11.012 min (for the free base) (assigned here as the S isomer, 38S); m / z [M+H] + 218.2; 1 H NMR (DMSO-d6, 400 MHz) (HCl): δ (ppm) 9.65 (s, 1H), 8.95 (s, 1H), 7.67 (m, 1H), 7.39 (m, 2H), 7.30 (m, 1H), 3.33 (m, 1H), 2.41 (m, 1H), 2.31 (m, 1H), 2.15 (s, 3H), 2.09 (s, 3H), 1.98 (m, 1H), 1.83 (t, J = 13.6, 13.6 Hz, 1H), 1.76 (d, J = 12.7 Hz, 1H), 1.59 (m, 2H); and ENT-2 2-(methylamino)-2-(o-tolyl)cyclohexan-1-one hydrochloride 0.453 g; tR = 15.045 min (for the free base) (assigned here as the R isomer, 38R); m / z [M+H] + 218.2; 11H NMR (DMSO-d6, 400 MHz) (HCl): δ (ppm) 9.67 (s, 1H), 8.94 (s, 1H), 7.67 (m, 1H), 7.40 (m, 2H), 7.31 (m, 1H), 3.35 (m, 1H), 2.41 (m, 1H), 2.32 (m, 1H), 2.15 (s, 3H), 2.10 (s, 3H), 1.99 (m, 1H), 1.83 (t, J = 12.0, 12.0 Hz, 1H), 1.76 (d, J = 15.3 Hz, 1H), 1.59 (m, 2H).

Example

[0702] Preparation of Compounds 26R and 26S

[0703]

Chem.

[0704] Step 1: Preparation of 2-phenylcyclohexan-1-ol To a stirred solution of 7-oxabicyclo[4.1.0]heptane (107 g, 1090 mmol) in THF (1000 mL) was added CuI (20.76 g, 109 mmol). To the resulting mixture, cooled to 0 °C, was added dropwise a solution of phenylmagnesium bromide in THF (1500 mL, 1200 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was cooled to 0 °C and treated dropwise with a concentrated solution of NH4Cl (90 g, 1690 mmol) in water. The resulting mixture was evaporated to a total volume of 1500 mL and diluted with MTBE. The organic layer was separated and the aqueous layer was extracted with additional MTBE. The combined organic layers were washed three times with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 120 g of 2-phenylcyclohexan-1-ol (yield 62.5%). 11H NMR (400 MHz, chloroform-d) δ 7.32 (t, J = 7.5 Hz, 2H), 7.24 (dd, J = 7.6, 2.6 Hz, 3H), 3.65 (td, J = 10.0, 4.2 Hz, 1H), 2.41 (ddd, J = 13.1, 9.9, 3.4 Hz, 1H), 2.14 - 2.05 (m, 1H), 1.85 (dd, J = 12.2, 3.4 Hz, 2H), 1.79 - 1.70 (m, 1H), 1.59 - 1.27 (m, 6H).

[0705] Step 2: Preparation of 2-phenylcyclohexan-1-one To a stirred solution of 2-phenylcyclohexan-1-ol (120 g, 680 mmol) in dry dichloromethane (1500 mL) cooled in an ice bath was added Dess-Martin periodinane (DMP, 303 g, 715 mmol) portionwise. The reaction mixture was stirred at room temperature overnight, poured into a K2CO3 / ice mixture (250 g, 2000 mL), stirred for 30 minutes, and filtered. The filtrate was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was diluted with hexane, refluxed, and filtered. The filtrate was evaporated under reduced pressure to give 90 g of 2-phenylcyclohexan-1-one (69% yield). 1 1H NMR (400 MHz, chloroform-d) δ 7.34 - 7.22 (m, 3H), 7.12 (d, J = 7.0 Hz, 2H), 3.60 (d, J = 9.3 Hz, 1H), 2.50 (s, 1H), 2.46 (d, J = 7.6 Hz, 1H), 2.26 (s, 1H), 2.14 (s, 1H), 2.02 (d, J = 19.8 Hz, 2H), 1.82 (s, 2H).

[0706] Step 3: Preparation of 2-Nitro-2-phenylcyclohexan-1-one To a solution of 2-phenylcyclohexan-1-one (90 g, 470 mmol) in 1,2-dichloroethane (1200 mL) were added ammonium cerium(IV) nitrate (524 g, 956 mmol) and copper(II) acetate (17.3 g, 95 mmol). The reaction mixture was stirred at 60 °C overnight and then cooled to room temperature and filtered. The filtrate was washed twice with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give 90 g of 2-nitro-2-phenylcyclohexan-1-one (87% yield).

[0707] Step 4: Preparation of 2-Amino-2-phenylcyclohexan-1-one Hydrochloride To a solution of 2-nitro-2-phenylcyclohexan-1-one (90 g, 410 mmol) in acetic acid (1000 mL) was added zinc in four portions at 30-minute intervals (26.8 g, 410 mmol each). The reaction mixture was stirred at room temperature overnight, filtered, and the filtrate was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed four times with saturated aqueous Na2CO3, acidified with HCl in dioxane, and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel (MTBE:MeOH (50:1 → 1:4)) gave 16 g of 2-amino-2-phenylcyclohexan-1-one hydrochloride (71.1 mmol, 10.4% yield over two steps). 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 2H), 7.50 (dd, J = 9.2, 3.7 Hz, 2H), 7.48 - 7.35 (m, 3H), 2.48 (s, 1H), 2.43 - 2.25 (m, 2H), 2.15 (td, J = 13.9, 13.5, 4.2 Hz, 1H), 1.99 - 1.91 (m, 1H), 1.81 (d, J = 11.7 Hz, 1H), 1.59 (dt, J = 24.5, 8.6 Hz, 2H).

[0708] Step 5: Preparation of 2-Phenyl-2-(piperidin-1-yl)cyclohexan-1-one (26rac) To a solution of 2-amino-2-phenylcyclohexan-1-one hydrochloride (3.5 g, 15.5 mmol) in DMF, K2CO3 (6.4 g, 46.5 mmol) and 1,5-dibromopentane (2.11 mL, 15.5 mmol) were added. The reaction mixture was stirred at 80 °C overnight, cooled to room temperature, and poured into water. The aqueous layer was extracted 4 times with ethyl acetate. The combined organic layers were washed 5 times with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and HCl in dioxane (50 mL) was added dropwise. The resulting mixture was stirred for 15 minutes and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel (MTBE:MeOH (50:1→1:4)) gave 1.1 g of 2-phenyl-2-(piperidin-1-yl)cyclohexan-1-one hydrochloride (26rac) (yield 24.2%). 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.57 - 7.51 (m, 3H), 7.45 (br s, 2H), 3.42 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 13.7 Hz, 1H), 3.07 (d, J = 11.4 Hz, 1H), 2.67 (q, J = 11.1 Hz, 1H), 2.43 - 2.16 (m, 4H), 2.05 - 1.57 (m, 8H), 1.42 (m, 1H), 1.29 - 1.17 (m, 1H).

[0709] Step 6: Preparation of (R)-2-Phenyl-2-(piperidin-1-yl)cyclohexan-1-one (26R) and (S)-2-Phenyl-2-(piperidin-1-yl)cyclohexan-1-one (26S) A solution of 2-phenyl-2-(piperidin-1-yl)cyclohexan-1-one hydrochloride (1.1 g, 3.74 mmol) in dry methanol (20 mL) was treated with NaOH (0.15 g, 3.74 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was then filtered, and the filtrate was concentrated in vacuo to afford the free base. The residue was separated on a 250×20 mm, 5 μm Chiralcel OJ-H column eluting with hexane-IPA-MeOH 70-15-15 at a flow rate of 12 mL / min. The samples were combined to afford the product free base. The free base obtained was dissolved in dioxane and treated with 10% HCl (5 mL) in dioxane and evaporated to dryness to afford the following. 0.328 g of ENT-1 2-phenyl-2-(piperidin-1-yl)cyclohexan-1-one hydrochloride, tR = 9.303 min (for the free base) (assigned here as the S isomer, 26S); m / z [M+H] + 258.2; 1 H NMR (DMSO-d6, 500 MHz) (HCl): δ (ppm) 9.79 (s, 1H), 7.58 (m, 3H), 7.48 (m, 2H), 3.45 (d, J = 10.1 Hz, 1H), 3.27 (d, J = 12.0 Hz, 1H), 3.08 (d, J = 12.0 Hz, 1H), 2.72 (m, 1H), 2.42 (m, 2H), 2.30 (m, 2H), 2.05 - 1.57 (m, 8H), 1.47 (m, 1H), 1.27 (m, 1H); And 0.338 g of ENT-2 2-phenyl-2-(piperidin-1-yl)cyclohexan-1-one hydrochloride, tR = 12.153 min (for the free base) (assigned here as the R isomer, 26R); m / z [M+H] + 258.2; 11H NMR (DMSO-d6, 500 MHz): δ (ppm) 10.04 (s, 1H), 7.57 (m, 3H), 7.49 (m, 2H), 3.45 (d, J = 10.1 Hz, 1H), 3.28 (d, J = 13.6 Hz, 1H), 3.14 (d, J = 10.9 Hz, 1H), 2.70 (q, J = 10.9, 10.9, 10.0 Hz, 1H), 2.42 (m, 2H), 2.30 (m, 2H), 2.04 (q, J = 13.9, 13.9, 13.8 Hz, 1H), 1.93 - 1.57 (m, 7H), 1.43 (m, 1H), 1.25 (m, 1H).

Example

[0710] Preparation of Compounds 27R and 27S

[0711]

Chem.

[0712] Step 1: Preparation of 2-Phenyl-2-(pyrrolidin-1-yl)cyclohexan-1-one (27rac) To a solution of 2-amino-2-phenylcyclohexan-1-one (4 g, 17.7 mmol, hydrochloride) in DMF, K2CO3 (7.3 g, 53 mmol) and 1,4-dibromobutane (2.33 mL, 19.5 mmol) were added. The reaction mixture was stirred at 80 °C overnight, cooled to room temperature, and poured into water. The aqueous layer was extracted 4 times with ethyl acetate. The combined organic layers were washed 5 times with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and HCl in dioxane (50 mL) was added dropwise. The resulting mixture was stirred for 15 minutes and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel (MTBE:MeOH (50:1 → 1:4)) gave 1.5 g of 2-phenyl-2-(pyrrolidin-1-yl)cyclohexan-1-one hydrochloride (27rac) (yield 30.2%). m / z [M+H] + 244.2; 11H NMR (DMSO-d6, 400 MHz): δ (ppm) 11.26 (s, 1H), 7.54 (m, 5H), 3.06 (m, 5H), 2.32 (m, 3H), 1.80 (m, 7H), 1.47 (q, J=13.5, 12.8, 12.8 Hz, 1H).

[0713] Step 2: Preparation of (R)-2-Phenyl-2-(pyrrolidin-1-yl)cyclohexan-1-one (27R) and (S)-2-Phenyl-2-(pyrrolidin-1-yl)cyclohexan-1-one (27S) The HCl salt of 27rac was basified with an aqueous NaHCO3 solution and extracted with CH2Cl2, and the organic extract was concentrated to produce the free base (850 mg). This material was separated into enantiomers by SFC (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH, B%: 36%; multiple injection process with 3-minute intervals between injections) to obtain ENT-1, RT = 2.177 min (300 mg) (assigned here as the S isomer, 27S) and ENT-2, RT = 2.438 min (316 mg) (assigned here as the R isomer, 27R). The retention times were determined using the following chiral analytical method: column: Lux Cellulose-2, 100 × 4.6 mm I.D., 3 μm; mobile phase: A: CO2, B: MeOH (0.05% IPAm, v / v); gradient: (time (min) / A% / B%), (0.0 / 95 / 5, 0.5 / 95 / 5, 2.0 / 60 / 40, 3.0 / 60 / 40, 3.6 / 95 / 5, 4.0 / 95 / 5); flow rate: 3.4 mL / min; column temperature: 35 °C; ABPR: 1800 psi.

Example

[0714] Preparation of Compounds 19R and 19S

[0715]

Chem.

[0716] Step 1: Preparation of Cyclopentyl(3-fluorophenyl)methanol A solution of 3-fluorobenzaldehyde (39 g, 380 mmol) in THF (200 mL) was added dropwise to a solution of cyclopentylmagnesium bromide in THF (0.8 M, 700 mL, 560 mmol, 1.5 equiv). The reaction mixture was stirred overnight at room temperature. To the mixture cooled in an ice-water bath was added dropwise a solution of NH4Cl (50 g) in water (500 mL). The resulting mixture was extracted with ethyl acetate (3 × 400 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel (100 g of SiO2 / 10 g of reaction mixture, hexane / DCM 10 / 1) gave 23 g of cyclopentyl(3-fluorophenyl)methanol (yield 39.5%).

[0717] Step 2: Preparation of Cyclopentyl(3-fluorophenyl)methanone To a solution of cyclopentyl(3-fluorophenyl)methanol (23 g, 150 mmol) in dry dichloromethane (250 mL) cooled in an ice-water bath was added Dess-Martin periodinane (DMP, 97.5 g, 230 mmol). The reaction mixture was stirred overnight at room temperature, diluted with an aqueous solution of sodium bicarbonate (75 g, 500 mL), and extracted twice with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel (100 g of SiO2 / 10 g of reaction mixture, hexane / DCM 10 / 1) gave 16.5 g of cyclopentyl(3-fluorophenyl)methanone (yield 57.3%).

[0718] Step 3: Preparation of (1-Bromocyclopentyl)(3-fluorophenyl)methanone To a solution of cyclopentyl(3-fluorophenyl)methanone (16.5 g, 86 mmol) in a mixture of dry ethyl acetate (90 mL) and dry CHCl3 (90 mL) was added copper(II) bromide (58 g, 258 mmol), and the reaction mixture was stirred overnight under reflux. Upon completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give 21 g of (1-bromocyclopentyl)(3-fluorophenyl)methanone (yield 90%), which was used in the next step without further purification. 11H NMR (400 MHz, chloroform-d) δ 7.94 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 9.8 Hz, 1H), 7.41 (td, J = 7.9, 5.4 Hz, 1H), 7.23 (dd, J = 9.3, 7.0 Hz, 1H), 2.44 (dh, J = 21.7, 7.6, 6.9 Hz, 4H), 2.05 (q, J = 6.3, 5.5 Hz, 2H), 1.80 (q, J = 7.4 Hz, 2H).

[0719] Step 4: Preparation of 1-((3-Fluorophenyl)(methylimino)methyl)cyclopentan-1-ol Hydrochloride (1-Bromocyclopentyl)(3-fluorophenyl)methanone (21 g, 77.5 mmol) and a solution of methylamine in methanol (200 mL) were stirred at room temperature for 48 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (300 mL) and ethyl acetate (300 mL). The separated organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 14 g of 1-((3-fluorophenyl)(methylimino)methyl)cyclopentan-1-ol. This material in dioxane was diluted with HCl / dioxane and evaporated under reduced pressure to give 16.3 g of the hydrochloride salt.

[0720] Step 5: Preparation of 2-(3-Fluorophenyl)-2-(methylamino)cyclohexan-1-one (19rac) 16 g of 1-((3-fluorophenyl)(methylimino)methyl)cyclopentan-1-ol was added portionwise to Dowtherm (100 mL, 326.7 mmol) heated to 200 °C in an oil bath. The reaction mixture was heated to 180 °C for 15 min, cooled to room temperature and diluted with CHCl3 (250 mL) and water (150 mL). The aqueous layer was washed with CHCl3 (2 × 200 mL) and evaporated under reduced pressure. The residue was recrystallized (5 mL of EtOH and a few drops of MeOH per 1 g of crude product) to give 3.9 g of 2-(3-fluorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride (19rac). 11H NMR (500 MHz, DMSO-d6) 9.49 (s, 2H), 7.59 (q, J = 7.5 Hz, 1H), 7.37 (td, J = 8.5, 2.4 Hz, 1H), 7.32 (d, J = 10.0 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 3.14 (dd, J = 14.2, 3.1 Hz, 1H), 2.39 (d, J = 13.5 Hz, 1H), 2.36 - 2.26 (m, 1H), 2.21 - 2.12 (m, 1H), 2.11 (s, 3H), 1.95 (ddd, J = 12.6, 6.2, 3.1 Hz, 1H), 1.87 - 1.81 (m, 1H), 1.67 - 1.50 (m, 2H).

[0721] Step 6: Preparation of (R)-2-(3-Fluorophenyl)-2-(methylamino)cyclohexan-1-one (19R) and (S)-2-(3-Fluorophenyl)-2-(methylamino)cyclohexan-1-one (19S) A solution of 2-(3-fluorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride (1.9 g, 2.5 mmol) in dry methanol (20 mL) was treated with NaOH (0.35 g, 7.5 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was then filtered, and the filtrate was concentrated in vacuo to give the free base. The residue after evaporation was separated on a ChiralPak IA 250×20 mm, 5 μm column eluting with hexane-IPA-MeOH 90-5-5 at a flow rate of 12 mL / min. The samples were separated and combined to give the product free base. The free base obtained in dioxane was treated with 10% HCl (5 mL) in dioxane and evaporated to dryness to give the following. ENT-1 2-(3-fluorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride 0.406 g, tR = 14.233 min (for the free base) (assigned here as the S isomer, 19S); m / z [M+H] + 222.0; 11H NMR (DMSO-d6, 500 MHz) (HCl): δ (ppm) 9.94 (s, 1H), 9.44 (s, 1H), 7.60 (q, J = 7.6, 7.6, 7.5 Hz, 1H), 7.38 (t, J = 8.1, 8.1 Hz, 1H), 7.31 (d, J = 10.1 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 3.13 (d, J = 12.8 Hz, 1H), 2.40 (d, J = 13.2 Hz, 1H), 2.31 (m, 1H), 2.13 (s, 3H), 2.07 (m, 1H), 1.96 (m, 1H), 1.85 (d, J = 10.2 Hz, 1H), 1.59 (m, 2H); and 0.351 g of ENT-2 2-(3-fluorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride, tR = 18.439 (for the free base) (here assigned as the R isomer, 19R); m / z [M+H] + 222.0; 1 1H NMR (DMSO-d6, 500 MHz) (HCl): δ (ppm) 10.03 (s, 1H), 9.42 (s, 1H), 7.60 (q, J = 7.3, 7.3, 6.6 Hz, 1H), 7.38 (t, J = 8.3, 8.3 Hz, 1H), 7.31 (d, J = 10.2 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 3.14 (d, J = 13.7 Hz, 1H), 2.40 (d, J = 13.8 Hz, 1H), 2.31 (m, 1H), 2.11 (s, 3H), 2.11 (m, 1H), 1.96 (m, 1H), 1.85 (d, J = 10.7 Hz, 1H), 1.59 (m, 2H).

Example

[0722] Preparation of Compounds 88R and 88S

[0723]

Chem.

[0724] Step 1: 2-((Methyl-d 3 )amino)-2-phenylcyclohexan-1-one (88rac) Preparation To a solution of 2-amino-2-phenylcyclohexane-1-one hydrochloride (10 g, 44.3 mmol) in DMF, K2CO3 (18.37 g, 133 mmol) and CD3I (3.3 mL, 53 mmol) were added. The reaction mixture was stirred at 80 °C overnight, cooled to room temperature, and poured into water. The aqueous layer was extracted four times with ethyl acetate. The combined organic layers were washed five times with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and HCl in dioxane (50 mL) was added dropwise. The resulting mixture was stirred for 15 minutes and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel (MTBE:MeOH (50:1 → 1:4)) gave 1.7 g of 2-((methyl-d3)amino)-2-phenylcyclohexane-1-one as the hydrochloride (yield 15.8%). 1 H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 2H), 7.56 - 7.48 (m, 3H), 7.43 - 7.36 (m, 2H), 3.14 (dq, J = 13.9, 3.2 Hz, 1H), 2.40 - 2.34 (m, 1H), 2.32 - 2.25 (m, 1H), 2.12 (td, J = 13.4, 4.1 Hz, 1H), 1.95 (ddd, J = 12.8, 6.3, 3.3 Hz, 1H), 1.88 - 1.81 (m, 1H), 1.66 - 1.52 (m, 2H).

[0725] Step 2: Preparation of (S)-2-((Methyl-d 3 )amino)-2-phenylcyclohexan-1-one (88S) and (R)-2-((Methyl-d 3 )amino)-2-phenylcyclohexan-1-one (88R) To a solution of 2-((methyl-d3)amino)-2-phenylcyclohexan-1-one (1.7 g, 7 mmol, hydrochloride) in dry methanol (20 mL) was added NaOH (0.28 g, 7 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was then filtered, and the filtrate was concentrated in vacuo to give the free base. The residue after evaporation was separated on a ChiralPak AD 250×30 mm, 10 μm column eluting with hexane-IPA-MeOH 95-5-5 at a flow rate of 40 mL / min. The samples were separated and combined to give the product free base. The free base obtained in dioxane was treated with 10% HCl (5 mL) in dioxane and evaporated to dryness to give the following. 0.317 g of ENT-1 2-((methyl-d3)amino)-2-phenylcyclohexan-1-one hydrochloride, tR = 14.656 min (for the free base) (assigned here as the R isomer, 88R); m / z [M+H] + 207.1; 1 H NMR (DMSO-d6, 400 MHz) (HCl) δ (ppm) 10.00 (s, 1H), 9.34 (s, 1H), 7.56 (m, J = 6.6 Hz, 3H), 7.41 (d, J = 6.9 Hz, 2H), 3.16 (m, J = 13.8 Hz, 1H), 2.39 (d, J = 13.5 Hz, 1H), 2.28 (m, 1H), 2.14 (t, J = 13.1 Hz, 1H), 1.95 (m, 1H), 1.85 (d, J = 11.0 Hz, 1H), 1.59 (m, 2H) And 0.315 g of ENT-2 2-((methyl-d3)amino)-2-phenylcyclohexan-1-one hydrochloride, tR = 30.684 min (for the free base) (assigned here as the S isomer, 88S); m / z [M+H] + 207.2; 11H NMR (DMSO-d6, 400 MHz): δ (ppm) 10.01 (s, 1H), 9.34 (s, 1H), 7.54 (m, 3H), 7.41 (d, J = 7.5 Hz, 2H), 3.15 (d, J = 13.8 Hz, 1H), 2.39 (d, J = 13.6 Hz, 1H), 2.29 (m, 1H), 2.14 (t, J = 11.6, 11.6 Hz, 1H), 1.96 (m, 1H), 1.85 (d, J = 11.8 Hz, 1H), 1.61 (m, 2H).

Example

[0726] Preparation of Compounds 86S and 86R

[0727]

Chem.

[0728] Step 1: Preparation of 2-((2-Fluoroethyl)amino)-2-phenylcyclohexan-1-one (86rac) To a solution of 2-amino-2-phenylcyclohexan-1-one (9 g, 40 mmol, hydrochloride) in DMF, K2CO3 (16.5 g, 119.6 mmol) and 1-fluoro-2-iodoethane (4 mL, 47.9 mmol) were added. The reaction mixture was stirred at 80 °C overnight, cooled to room temperature, and poured into water. The aqueous layer was extracted 4 times with ethyl acetate. The combined organic layers were washed 5 times with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and HCl in dioxane (50 mL) was added dropwise. The resulting mixture was stirred for 15 minutes and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel (MTBE:MeOH (50:1 → 1:4)) gave 1.8 g of 2-((2-fluoroethyl)amino)-2-phenylcyclohexan-1-one as the hydrochloride (86rac) (yield 16.5%). 11H NMR (500 MHz, DMSO-d6) (free base) δ 7.35 (m, 2H), 7.25 (m, 3H), 4.37 (t, J = 5.1 Hz, 1H), 4.31 - 4.24 (m, 1H), 2.99 (dd, J = 14.5, 2.9 Hz, 1H), 2.41 (m, 4H), 1.89 - 1.74 (m, 5H).

[0729] Step 2: Preparation of (S)-2-((2-Fluoroethyl)amino)-2-phenylcyclohexan-1-one (86S) and (R)-2-((2-Fluoroethyl)amino)-2-phenylcyclohexan-1-one (86R) To a solution of 2-((2-fluoroethyl)amino)-2-phenylcyclohexan-1-one (1.8 g, 6.6 mmol, hydrochloride) in dry methanol (20 mL) was added NaOH (0.265 g, 6.6 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was then filtered, and the filtrate was concentrated in vacuo to produce the free base. The residue after evaporation was separated on a 250×20 mm, 5 μm Chiralpak AD-H hexane-IPA-MeOH 98-1-1 at a flow rate of 18 mL / min. The samples were separated and combined to give the product free base. The free base obtained in dioxane was treated with 10% HCl (5 mL) in dioxane and evaporated to dryness to give the following. 0.324 g of ENT-1 2-((2-fluoroethyl)amino)-2-phenylcyclohexan-1-one hydrochloride, tR = 14.667 min (for the free base) (assigned here as the R isomer, 86R); m / z [M+H] + 236.0; 1 1H NMR (DMSO-d6, 500 MHz) (HCl): δ (ppm) 9.77 (s, 1H), 9.57 (s, 1H), 7.55 (m, 3H), 7.44 (d, J = 6.3 Hz, 2H), 4.60 (d, J = 48.4 Hz, 2H), 3.17 (m, 1H), 2.89 (m, 1H), 2.74 (m, 1H), 2.38 (m, 2H), 2.15 (t, J = 12.4, 12.4 Hz, 1H), 1.95 (d, J = 14.8 Hz, 1H), 1.84 (d, J = 15.9 Hz, 1H), 1.62 (m, 1H), 1.51 (m, 1H); and 0.310 g of ENT-2 2-((2-fluoroethyl)amino)-2-phenylcyclohexan-1-one hydrochloride, tR = 16.727 min (for the free base) (here assigned as the S isomer, 86S); m / z [M+H] + 236.0; 1 H NMR (DMSO-d6, 500 MHz) (free base): δ (ppm) 7.36 (t, J = 7.6, 7.6 Hz, 2H), 7.27 (t, 1H), 7.23 (d, J = 8.1 Hz, 2H), 4.36 (m, 2H), 2.84 (d, J = 13.3 Hz, 1H), 2.39 (m, 4H), 1.95 (m, 1H), 1.83 (m, 2H), 1.72 (m, 2H).

Example

[0730] Preparation of Compounds 28R and 28S

[0731]

Chem.

[0732] Step 1: Preparation of 2-(Isopropylamino)-2-phenylcyclohexan-1-one (28rac) A mixture of 2-amino-2-phenyl-cyclohexan-1-one (4 g, 21.14 mmol, 1 equiv), 2-bromopropane (13.00 g, 105.68 mmol, 5 equiv), KI (701.71 mg, 4.23 mmol, 0.2 equiv), and K2CO3 (5.84 g, 42.27 mmol, 2 equiv) in MeCN (10 mL) was stirred at 100 °C for 12 h. The mixture was cooled, filtered, concentrated, and then purified by preparative HPLC (column: Agela DuraShell C18 250×70 mm, 10 μm; mobile phase: A: water (10 mM NH4HCO3); B: ACN; B%: 25% - 55%, 25 min) to give 2-(isopropylamino)-2-phenylcyclohexan-1-one (1 g, 4.32 mmol, 20.45% yield) (28rac) as a white solid.

[0733] Step 2: Preparation of (R)-2-(isopropylamino)-2-phenylcyclohexan-1-one (28R) and (S)-2-(isopropylamino)-2-phenylcyclohexan-1-one (28S) The racemate was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH, B%: 10%; multiple injection process with 5-minute intervals between injections) to obtain ENT-1 at 0.659 minutes (230 mg) as a white solid and ENT-2 at 1.111 minutes (250 mg) as a white solid. The retention times were determined using the following chiral analysis method: column: Chiralpak AD-3, 100 × 4.6 mm I.D., 3 μm; mobile phase: A: CO2 B: EtOH (0.05% IPAm, v / v); gradient: (time (min) / A% / B%), (0.0 / 95 / 5, 0.5 / 95 / 5, 2.0 / 60 / 40, 3.0 / 60 / 40, 3.6 / 95 / 5, 4.0 / 95 / 5); flow rate: 3.4 mL / min; column temperature: 35 °C; ABPR: 1800 psi.

[0734] ENT-1, RT = 0.659 minutes (assigned here as the R isomer, 28R); LCMS R T = 1.630 minutes; MS calculated value: 231.33, [M+H] + = 232.1; 1 H NMR (400 MHz, chloroform-d) δ = 7.41 - 7.34 (m, 2H), 7.31 - 7.25 (m, 3H), 2.96 (qd, J = 2.8, 13.6 Hz, 1H), 2.48 - 2.35 (m, 2H), 2.33 - 2.23 (m, 2H), 1.98 - 1.68 (m, 5H), 0.91 (d, J = 6.4 Hz, 3H), 0.75 (d, J = 6.4 Hz, 3H); 13 C NMR (101 MHz, chloroform -d) δ = 211.62, 139.76, 129.11, 127.76, 127.54, 70.56, 43.44, 39.97, 38.01, 28.04, 26.04, 25.35, 22.88; ENT-2, RT = 1.111 minutes (assigned here as the S isomer, 28S); LCMS R T = 1.636 minutes; MS calculated value: 231.33, [M+H]+ = 232.1; 1 1H NMR (400 MHz, chloroform-d) δ = 7.41 - 7.33 (m, 2H), 7.32 - 7.23 (m, 3H), 3.01 - 2.92 (m, 1H), 2.49 - 2.35 (m, 2H), 2.32 - 2.25 (m, 2H), 1.97 - 1.68 (m, 5H), 0.91 (d, J = 6.4 Hz, 3H), 0.75 (d, J = 6.4 Hz, 3H); 13 13C NMR (101 MHz, chloroform-d) δ = 211.62, 139.80, 129.09, 127.73, 127.52, 70.54, 43.39, 39.97, 38.04, 28.03, 26.08, 25.36, 22.88.

Example

[0735] Preparation of Compounds 84R, 84S, 11R and 11S

[0736]

Chem.

[0737] Step 1: Preparation of 2-nitro-2-phenyl-cyclohexan-1-one A mixture of 2-phenylcyclohexan-1-one (15 g, 86.09 mmol, 1 equiv), CAN (94.39 g, 172.18 mmol, 85.81 mL, 2 equiv) and Cu(OAc)2 (3.13 g, 17.22 mmol, 0.2 equiv) in DCE (150 mL) was stirred at 85 °C for 12 h. When completed, the mixture was filtered and concentrated. The residue was purified by silica gel (PE:EA = 30:1) to give 2-nitro-2-phenyl-cyclohexan-1-one (10 g, 45.61 mmol, 52.98% yield) as a yellow oil. 11H NMR (400 MHz, chloroform -d) δ ppm 7.50 - 7.45 (m, 3H), 7.36 (dd, J = 2.8, 6.8 Hz, 2H), 3.08 (ddd, J = 3.2, 10.8, 14.4 Hz, 1H), 2.97 - 2.85 (m, 1H), 2.74 - 2.64 (m, 1H), 2.61 - 2.52 (m, 1H), 2.00 - 1.88 (m, 3H), 1.84 - 1.75 (m, 1H).

[0738] Step 2: Preparation of 2-amino-2-phenyl-cyclohexan-1-one (11rac) A mixture of 2 - nitro - 2 - phenyl - cyclohexan - 1 - one (10 g, 45.61 mmol, 1 equiv) and Zn (23.86 g, 364.90 mmol, 8 equiv) in AcOH (100 mL) was stirred at 20 °C for 12 h. When complete, the mixture was filtered and concentrated. The residue was dissolved in DCM, washed with saturated NaHCO3, H2O, and brine, dried over Na2SO4, filtered, and concentrated to give 2 - amino - 2 - phenyl - cyclohexan - 1 - one (7.5 g, 39.63 mmol, 86.88% yield) (11rac) as a brown oil. 1 1H NMR (400 MHz, chloroform -d) δ ppm 7.33 - 7.27 (m, 2H), 7.24 - 7.17 (m, 3H), 2.88 - 2.79 (m, 1H), 2.42 - 2.24 (m, 2H), 2.24 - 2.09 (m, 2H), 1.95 - 1.87 (m, 1H), 1.85 - 1.59 (m, 4H).

[0739] Step 3: Preparation of 2-(azetidin-1-yl)-2-phenyl-cyclohexan-1-one (84rac) A mixture of 2-amino-2-phenyl-cyclohexan-1-one (2 g, 10.57 mmol, 1 equiv), 1,3-dibromopropane (2.77 g, 13.74 mmol, 1.40 mL, 1.3 equiv), KI (526.28 mg, 3.17 mmol, 0.3 equiv), and K2CO3 (4.38 g, 31.70 mmol, 3 equiv) in MeCN (30 mL) was stirred at 100 °C for 12 h. The mixture was cooled, filtered, and concentrated. The residue was purified by preparative HPLC (column: Agela DuraShell C18 250×70 mm, 10 μm; mobile phase: A: water (10 mM NH4HCO3), B: ACN; B%: 25% - 55%, 20 min) to give 2-(azetidin-1-yl)-2-phenyl-cyclohexan-1-one (1 g, 4.36 mmol, 41.26% yield) (84rac) as a white solid.

[0740] Step 4: Preparation of (R)-2-(azetidin-1-yl)-2-phenylcyclohexan-1-one (84R) and (S)-2-(azetidin-1-yl)-2-phenylcyclohexan-1-one (84S) The racemate (84rac) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3H2O in ETOH; B%: 15%; multiple injection process) to give ENT-1 at 0.736 min (340 mg) as a white solid and ENT-2 at 0.831 min (370 mg) as a white solid. The retention times were determined using the following chiral analytical method: column: Chiralpak AD-3, 50×4.6 mm I.D., 3 μm; mobile phase: A: CO2 B: EtOH (0.05% IPAm, v / v); gradient: (time (min) / A% / B%), (0.0 / 95 / 5, 0.2 / 95 / 5, 1.2 / 50 / 50, 2.2 / 50 / 50, 2.6 / 95 / 5, 3.0 / 95 / 5); flow rate: 3.4 mL / min; column temperature: 35 °C; ABPR: 1800 psi.

[0741] ENT-1, RT = 0.736 min (assigned here as the R isomer, 84R); LCMS (R T = 1.534 min, MS calculated: 229.15, [M+H] + = 230.1); 11H NMR (400 MHz, chloroform-d) δ ppm 7.47 - 7.41 (m, 2H), 7.38 - 7.32 (m, 1H), 7.16 (d, J = 7.6 Hz, 2H), 3.29 (q, J = 7.2 Hz, 2H), 3.09 (q, J = 6.8 Hz, 2H), 2.64 (qd, J = 3.2, 14.0 Hz, 1H), 2.39 - 2.26 (m, 2H), 1.95 - 1.55 (m, 7H); 13 13C NMR (101 MHz, chloroform -d) δ ppm 212.19, 134.03, 128.54, 128.31, 128.21, 127.68, 72.74, 48.48, 40.57, 33.18, 28.09, 21.72, 17.39; ENT-2, RT = 0.831 min (assigned here as the S isomer, 84S); LCMS (R T = 1.529 min, MS cal.: 229.15, [M+H] + = 230.1); 1 1H NMR (400 MHz, chloroform-d) δ ppm 7.49 - 7.40 (m, 2H), 7.39 - 7.32 (m, 1H), 7.16 (d, J = 7.6 Hz, 2H), 3.30 (q, J = 6.8 Hz, 2H), 3.10 (q, J = 6.8 Hz, 2H), 2.65 (qd, J = 3.2, 14.0 Hz, 1H), 2.39 - 2.26 (m, 2H), 1.94 - 1.52 (m, 7H); 13 13C NMR (101 MHz, chloroform -d) δ ppm 212.17, 134.01, 128.54, 128.39, 128.21, 127.69, 72.75, 48.49, 40.57, 33.18, 28.09, 21.72, 17.39.

[0742] Step 5: Preparation of (S)-2-amino-2-phenyl-cyclohexan-1-one (11S) and (R)-2-amino-2-phenyl-cyclohexan-1-one (11R) Racemic 2-amino-2-phenyl-cyclohexan-1-one (11rac)Separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH]; B%: 42%; multiple injection process with an interval of 3.8 minutes during injection), 1.691 minutes (370 mg, 1.96 mmol) of ENT-1 was obtained as an off-white solid, and 2.135 minutes (340 mg, 1.80 mmol) of ENT-2 was obtained as an off-white solid. The retention times were determined using the following chiral analysis method: column: Chiralpak AD-3, 100 × 4.6 mm I.D., 3 μm; mobile phase: A: CO2, B: MeOH (0.05% IPAm, v / v); gradient: (time (min) / A% / B%), (0.0 / 95 / 5, 0.5 / 95 / 5, 2.0 / 60 / 40, 3.0 / 60 / 40, 3.6 / 95 / 5, 4.0 / 95 / 5); flow rate: 3.4 mL / min; column temperature: 35 °C; ABPR: 1800 psi.

[0743] ENT-1, RT = 1.691 min (assigned here as the S isomer, 11S); LCMS (R T = 1.360 min, MS calculated value: 189.12, [M+H] + = 190.1); 1 H NMR (400 MHz, chloroform -d) δ ppm 7.42 - 7.34 (m, 2H), 7.32 - 7.24 (m, 3H), 2.92 - 2.82 (m, 1H), 2.50 - 2.35 (m, 2H), 2.04 - 1.95 (m, 1H), 1.88 (s, 2H), 1.83 - 1.64 (m, 4H); 13 C NMR (101 MHz, chloroform-d) δ ppm 213.60, 141.87, 129.24, 127.68, 126.09, 66.49, 39.85, 39.48, 28.18, 22.69; ENT-2, RT = 2.135 min (assigned here as the R isomer, 11R); LCMS (R T = 1.387 min, MS calculated value: 189.12, [M+H] + = 190.1); 11H NMR (400 MHz, chloroform-d) δ ppm 7.41 - 7.36 (m, 2H), 7.32 - 7.25 (m, 3H), 2.92 - 2.82 (m, 1H), 2.51 - 2.35 (m, 2H), 2.04 - 1.95 (m, 1H), 1.87 (s, 2H), 1.83 - 1.67 (m, 4H); 13 13C NMR (101 MHz, chloroform -d) δ ppm 213.54, 141.89, 141.88, 129.24, 127.69, 126.10, 66.50, 39.85, 39.50, 28.18, 22.70.

Example

[0744] Preparation of Compounds 114S and 114R

[0745]

Chem.

[0746] Step 1: Preparation of 2-(o-tolyl)cyclohexan-1-ol A solution of 1-bromo-2-methyl-benzene (10 g, 58.47 mmol, 1 equiv) in THF (100 mL) was cooled to -70 °C. Then, n-BuLi (2.5 M, 27 mL, 1.15 equiv) was added. The mixture was stirred at -70 °C for 0.5 h, then 7-oxabicyclo[4.1.0]heptane (6.31 g, 64.31 mmol, 1.1 equiv) and BF3·Et2O (9.13 g, 64.31 mmol, 1.1 equiv) were added. The mixture was stirred at -70 °C for 1.5 h. When completed, the mixture was poured into saturated aqueous NH4Cl (100 ml) and extracted with EA (50 ml × 2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel (PE:EA = 50:1~5:1) to give 2-(o-tolyl)cyclohexan-1-ol (4 g, 21.02 mmol, yield 35.95%) as a colorless oil. 11H NMR (400 MHz, chloroform-d) δ = 7.28 - 7.24 (m, 1H), 7.23 - 7.08 (m, 3H), 3.82 - 3.73 (m, 1H), 2.83 - 2.72 (m, 1H), 2.37 (s, 3H), 2.14 (td, J = 4.4, 8.8 Hz, 1H), 1.91 - 1.85 (m, 1H), 1.84 - 1.74 (m, 2H), 1.48 - 1.32 (m, 4H).

[0747] Step 2: Preparation of 2-(o-tolyl)cyclohexan-1-one To a mixture of 2-(o-tolyl)cyclohexan-1-ol (3.5 g, 18.39 mmol, 1 equiv) in DCM (15 mL), Dess-Martin periodinane (DMP, 11.70 g, 27.59 mmol, 1.5 equiv) was added all at once at 0 °C under N2. The mixture was stirred at 25 °C for 12 h. The mixture was filtered, and the filtrate was washed with saturated aqueous Na2SO3, saturated aqueous Na2CO3, and brine, then dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel (PE:EA = 50:1~8:1) to give 2-(o-tolyl)cyclohexan-1-one (2.9 g, 15.40 mmol, 83.74% yield) as a colorless oil. 1 1H NMR (400 MHz, chloroform-d) δ = 7.26 - 7.13 (m, 4H), 3.86 - 3.77 (m, 1H), 2.62 - 2.48 (m, 2H), 2.33 - 2.21 (m, 5H), 2.10 - 2.05 (m, 2H), 1.94 - 1.80 (m, 2H).

[0748] Step 3: Preparation of 2-nitro-2-(o-tolyl)cyclohexan-1-one A mixture of 2-(o-tolyl)cyclohexanone (2.4 g, 12.75 mmol, 1 equiv), cerium(IV) ammonium nitrate (CAN, 13.98 g, 25.50 mmol, 2 equiv), and Cu(OAc)₂ (463 mg, 2.55 mmol, 0.2 equiv) in DCE (25 mL) was stirred at 85 °C for 12 h. The mixture was cooled, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 - 0 / 1) to give 2-nitro-2-(o-tolyl)cyclohexan-1-one (1.2 g, 5.14 mmol, 40.35% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.26 - 7.13 (m, 4H), 3.86 - 3.77 (m, 1H), 2.62 - 2.48 (m, 2H), 2.33 - 2.21 (m, 5H), 2.10 - 2.05 (m, 2H), 1.94 - 1.80 (m, 2H).

[0749] Step 4: Preparation of 2-amino-2-(o-tolyl)cyclohexan-1-one (114rac) A mixture of 2-nitro-2-(o-tolyl)cyclohexan-1-one (2 g, 8.57 mmol, 1 equiv) and Zn (3.92 g, 60.02 mmol, 7 equiv) in AcOH (25 mL) was stirred at 20 °C for 12 h. The mixture was filtered and concentrated. The residue was dissolved in DCM, washed with saturated aqueous NaHCO₃, H₂O, and brine, dried over Na₂SO₄, filtered, and concentrated to give 2-amino-2-(o-tolyl)cyclohexan-1-one (900 mg, 4.43 mmol, 51.64% yield) (114rac) as a brown oil.

[0750] Step 5: Preparation of (S)-2-amino-2-(o-tolyl)cyclohexan-1-one (114S) and (R)-2-amino-2-(o-tolyl)cyclohexan-1-one (114R) The racemate was separated by SFC (column: REGIS (s,s) WHELK-O1 (250 mm × 30 mm, 5 μm); mobile phase: A: CO2, B: 0.1% NH3H2O in IPA; B%: 15%, multiple injection process with 10-minute intervals during the run) to obtain ENT-1 at 1.591 minutes (260 mg, 1.28 mmol) as a yellow oil and ENT-2 at 1.906 minutes (330 mg, 1.62 mmol) as a yellow oil. The retention times were determined using the following chiral analytical method: column: (S,S)-WHELK-O1, 100 × 4.6 mm I.D., 3.5 μm; mobile phase: A: CO2, B: IPA (0.05% IPAm, v / v); gradient: (time (min) / A% / B%), (0.0 / 95 / 5, 0.5 / 95 / 5, 2.0 / 60 / 40, 3.0 / 60 / 40, 3.6 / 95 / 5, 4.0 / 95 / 5); flow rate: 3.4 mL / min; column temperature: 35 °C; ABPR: 1800 psi.

[0751] ENT-1, RT = 1.591 min (assigned here as the S isomer, 114S); LCMS (R T = 1.448 min, MS calculated: 203.13, [M+H] + = 204.1); 1 H NMR (400 MHz, chloroform-d) δ = 7.54 (d, J = 7.6 Hz, 1H), 7.27 - 7.11 (m, 3H), 2.89 (dd, J = 3.2, 14.4 Hz, 1H), 2.49 - 2.28 (m, 2H), 2.17 - 2.14 (m, 3H), 2.05 - 1.94 (m, 1H), 1.88 - 1.53 (m, 4H); 13 C NMR (101 MHz, chloroform-d) δ = 215.34, 139.36, 136.72, 132.76, 127.86, 126.72, 126.39, 67.52, 43.67, 39.72, 30.04, 22.90, 20.93; ENT-2, RT = 1.906 min (assigned here as the R isomer, 114R); LCMS (R T = 1.482 min, MS calculated: 203.13, [M+H] += 204.1); 1 1H NMR (400 MHz, chloroform-d) δ = 7.54 (d, J = 7.6 Hz, 1H), 7.27 - 7.11 (m, 3H), 2.89 (dd, J = 3.2, 14.4 Hz, 1H), 2.49 - 2.28 (m, 2H), 2.17 - 2.14 (m, 3H), 2.05 - 1.94 (m, 1H), 1.88 - 1.53 (m, 4H); 13 13C NMR (101 MHz, chloroform-d) δ = 215.34, 139.36, 136.72, 132.76, 127.86, 126.72, 126.39, 67.52, 43.67, 39.72, 30.04, 22.90, 20.93.

Example

[0752] Preparation of Compounds 31S and 31R

[0753]

Chem.

[0754] Step 1: Preparation of 2-morpholino-2-phenylcyclohexan-1-one (31rac) A mixture of 2-amino-2-phenyl-cyclohexane-1-one (2 g, 10.57 mmol, 1 equiv), 1-bromo-2-(2-bromoethoxy)ethane (7.35 g, 31.70 mmol, 3.97 mL, 3 equiv), K2CO3 (4.38 g, 31.70 mmol, 3 equiv), and KI (526 mg, 3.17 mmol, 0.3 equiv) in MeCN (50 mL) was stirred at 80 °C for 12 h. The mixture was cooled, filtered, and concentrated. The residue was purified by preparative HPLC (column: Agela DuraShell C18 250×70 mm, 10 μm; mobile phase: A: water (0.05% NH3H2O + 10 mM NH4HCO3), B: ACN; B%: 20% - 55%, 30 min) to give 2-morpholino-2-phenylcyclohexane-1-one (1.1 g, 4.24 mmol, 40.14% yield) as a white solid.

[0755] Step 2: Preparation of (S)-2-morpholino-2-phenylcyclohexan-1-one (31S) and (R)-2-morpholino-2-phenylcyclohexan-1-one (31R) The racemate was separated by SFC (column: REGIS (R,R) WHELK-O1 (250 mm × 25 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3H2O in IPA; B%: 38%, multiple injection process with 6-minute intervals between injections), and ENT-1 at 1.950 minutes (434 mg) was obtained as a white solid, and ENT-2 at 2.276 minutes (474 mg) was obtained as a white solid. The retention times were determined using the following chiral analysis method: column: (S,S)-WHELK-O1, 100 × 4.6 mm I.D., 3.5 μm; mobile phase: A: CO2, B: IPA (0.05% IPAm, v / v); gradient: (time (min) / A% / B%), (0.0 / 95 / 5, 0.5 / 95 / 5, 2.0 / 60 / 40, 3.0 / 60 / 40, 3.6 / 95 / 5, 4.0 / 95 / 5); flow rate: 3.4 mL / min; column temperature: 35 °C; ABPR: 1800 psi.

[0756] ENT-1, RT = 1.950 min (assigned here as the S isomer, 31S); LCMS (R T = 1.425 min, MS calculated value: 259.34, [M+H] + = 260.1); 1 1H NMR (400 MHz, chloroform-d) δ = 7.41 - 7.36 (m, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.28 - 7.24 (m, 2H), 3.73 - 3.63 (m, 4H), 2.59 - 2.42 (m, 4H), 2.41 - 2.31 (m, 3H), 2.23 (ddd, J = 3.6, 10.8, 14.0 Hz, 1H), 1.97 - 1.85 (m, 2H), 1.82 - 1.67 (m, 2H); 13 13C NMR (101 MHz, chloroform-d) δ = 211.12, 135.80, 128.59, 128.23, 127.66, 74.52, 67.57, 47.47, 40.84, 31.98, 28.24, 22.17; ENT-2, RT = 2.276 min; (assigned here as the R isomer, 31R); LCMS (R T = 1.439 min, MS calculated value: 259.34, [M+H] + = 260.1); 1 H NMR (400 MHz, chloroform-d) δ = 7.42 - 7.36 (m, 2H), 7.34 - 7.29 (m, 1H), 7.28 - 7.23 (m, 2H), 3.73 - 3.63 (m, 4H), 2.52 (br s, 1H), 2.59 - 2.42 (m, 1H), 2.40 - 2.30 (m, 3H), 2.28 - 2.18 (m, 1H), 1.97 - 1.85 (m, 2H), 1.82 - 1.66 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ = 211.12, 135.77, 128.59, 128.23, 127.67, 74.54, 67.55, 47.47, 40.85, 31.98, 28.24, 22.17.

Example

[0757] Preparation of Compounds 117rac and 18rac

[0758]

Chem.

[0759] Step 1: Preparation of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one A mixture of 2-(4-fluorophenyl)cyclohexan-1-one (5 g, 26.01 mmol, 1 equiv), cerium(IV) ammonium nitrate (CAN, 28.52 g, 52.02 mmol, 2 equiv), and Cu(OAc)₂ (945 mg, 5.20 mmol, 0.2 equiv) in DCE (50 mL) was stirred at 85 °C for 12 h. The mixture was cooled, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 - 0 / 1) to give 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (2.5 g, 10.54 mmol, 40.52% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.47 - 7.29 (m, 2H), 7.22 - 7.04 (m, 2H), 3.12 (ddd, J = 3.6, 10.0, 14.0 Hz, 1H), 2.86 - 2.76 (m, 1H), 2.75 - 2.62 (m, 1H), 2.61 - 2.47 (m, 1H), 2.08 - 1.86 (m, 3H), 1.80 (dt, J = 3.6, 9.2 Hz, 1H).

[0760] Step 2: Preparation of 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (117rac) A mixture of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (3 g, 12.65 mmol, 1 equiv) and Zn (19.85 g, 303.51 mmol, 24 equiv) in AcOH (25 mL) was stirred at 20 °C for 12 h. The mixture was cooled, filtered, and concentrated. The residue was dissolved in DCM, washed with saturated NaHCO₃, H₂O, and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel (PE:EA = 50:1 - 8:1) to give 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1.5 g, 7.24 mmol, 57.23% yield) (117 rac) as a brown oil. LCMS (R T = 1.336 min, MS calcd: 207.11, [M+H] + = 208.1) 11H NMR (400 MHz, chloroform-d) δ = 7.26 - 7.19 (m, 2H), 7.11 - 7.01 (m, 2H), 2.87 - 2.73 (m, 1H), 2.50 - 2.42 (m, 1H), 2.41 - 2.29 (m, 1H), 2.04 - 1.96 (m, 1H), 1.93 (s, 2H), 1.83 - 1.63 (m, 4H); 3 13C NMR (101 MHz, chloroform-d) δ = 213.28, 163.27, 160.82, 137.67, 137.63, 127.99, 127.91, 116.16, 115.95, 65.93, 39.71, 28.08, 22.61

[0761] Step 3: Preparation of 2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one (18rac) A mixture of 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1.3 g, 6.27 mmol, 1 equiv) and methyl trifluoromethanesulfonate (1.03 g, 6.27 mmol, 1 equiv) in hexafluoroisopropanol (HFIP, 130 mL) was stirred at 0 - 25 °C for 12 h under a N2 atmosphere. The mixture was filtered and concentrated. The residue was adjusted to pH = 7 with saturated Na2CO3 (20 ml). The aqueous phase was extracted with EA (50 mL × 2). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250×70 mm, 10 μm; mobile phase: A: water (0.05% NH3H2O), B: ACN; B%: 18% - 48%, 32 min) to give 2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one (590 mg, 4.02 mmol, 42.45% yield) (18rac) as a white solid. LCMS (R T = 1.415 min, MS calculated: 221.12, [M+H] + = 222.1); 11H NMR (400 MHz, chloroform-d) δ = 7.26 - 7.17 (m, 2H), 7.07 (br t, J = 8.4 Hz, 2H), 2.92 - 2.74 (m, 1H), 2.50 - 2.26 (m, 3H), 2.12 - 1.93 (m, 4H), 1.90 - 1.63 (m, 4H); 13 13C NMR (101 MHz, chloroform-d) δ = 211.15, 163.20, 160.75, 134.68, 134.65, 128.99, 128.91, 115.79, 115.58, 69.37, 39.70, 35.85, 28.87, 27.70, 22.21.

Example

[0762] Preparation of Compounds 118rac and 23rac

[0763]

Chem.

[0764] Step 1: Preparation of 2-(m-tolyl)cyclohexan-1-ol A mixture of 1-bromo-3-methyl-benzene (15 g, 87.70 mmol, 10.64 mL, 1 equiv) in THF (150 mL) was cooled to -70 °C. Then, n-BuLi (2.5 M, 38.59 mL, 1.1 equiv) was added. The mixture was stirred at -70 °C for 0.5 h, then 7-oxabicyclo[4.1.0]heptane (9.47 g, 96.47 mmol, 9.76 mL, 1.1 equiv) and BF3·Et2O (13.69 g, 96.47 mmol, 11.91 mL, 1.1 equiv) were added. The mixture was stirred at -70 °C for 1.5 h. The mixture was poured into saturated aqueous NH4Cl (200 ml) and extracted with EA (100 ml × 2). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel (PE:EA = 100:1~10:1) to give 2-(m-tolyl)cyclohexan-1-ol (13 g, 68.32 mmol, 77.9% yield) as a colorless oil. 11H NMR (400 MHz, chloroform-d) δ = 7.33 - 7.28 (m, 1H), 7.16 - 7.09 (m, 3H), 3.72 (dt, J = 4.0, 10.0 Hz, 1H), 2.50 - 2.44 (m, 1H), 2.41 (s, 3H), 2.22 - 2.14 (m, 1H), 1.92 (br d, J = 10.8 Hz, 2H), 1.83 (br d, J = 12.4 Hz, 1H), 1.61 - 1.36 (m, 4H).

[0765] Step 2: Preparation of 2-(m-tolyl)cyclohexan-1-one To a mixture of 2-(m-tolyl)cyclohexan-1-ol (13 g, 68.32 mmol, 1 equiv) in DCM (50 mL), Dess-Martin periodinane (43.47 g, 102.48 mmol, 31.73 mL, 1.5 equiv) was added portionwise at 0 °C (while maintaining the temperature at 0 °C during addition). The mixture was then stirred at 20 °C for 12 h. The mixture was filtered, and the filtrate was washed with saturated aqueous Na2SO3, saturated aqueous Na2CO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EA = 1:0~5:1) to give 2-(m-tolyl)cyclohexan-1-one (13 g, crude) as a white solid. 1 1H NMR (400 MHz, chloroform-d) δ 7.26 - 7.21 (m, 1H), 7.10 - 7.06 (m, 1H), 6.98 - 6.93 (m, 2H), 3.62 - 3.55 (m, 1H), 2.58 - 2.44 (m, 2H), 2.35 (s, 3H), 2.31 - 2.23 (m, 1H), 2.21 - 2.13 (m, 1H), 2.08 - 1.97 (m, 2H), 1.90 - 1.83 (m, 2H).

[0766] Step 3: Preparation of 2-(m-tolyl)-2-nitro-cyclohexan-1-one A mixture of 2-(m-tolyl)cyclohexan-1-one (11 g, 58.43 mmol, 1 equiv), cerium(IV) ammonium nitrate (CAN, 64.06 g, 116.86 mmol, 58.24 mL, 2 equiv), and Cu(OAc)₂ (2.12 g, 11.69 mmol, 0.2 equiv) in DCE (200 mL) was stirred at 85 °C for 12 h. The mixture was cooled, filtered, and the filter cake was washed with EtOAc (80 mL × 4). The filtrate was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (SiO₂, PE / EtOAc = 10 / 1) to afford 2-(m-tolyl)-2-nitro-cyclohexan-1-one (3 g, 12.86 mmol, 22.01% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.39 - 7.33 (m, 1H), 7.28 (br s, 1H), 7.18 - 7.13 (m, 2H), 3.06 (ddd, J = 3.2, 10.7, 14.3 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.74 - 2.64 (m, 1H), 2.62 - 2.52 (m, 1H), 2.40 (s, 3H), 1.99 - 1.88 (m, 3H), 1.78 (ddd, J = 3.6, 6.6, 10.4 Hz, 1H).

[0767] Step 4: Preparation of 2-amino-2-(m-tolyl)cyclohexan-1-one (118rac) To a mixture of 2-(m-tolyl)-2-nitro-cyclohexan-1-one (2.5 g, 10.72 mmol, 1 equiv) in AcOH (30 mL) was added Zn (16.82 g, 257.22 mmol, 24 equiv) over 1 h, and then the mixture was stirred at 20 °C for 12 h. When complete, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (10 ml), adjusted to pH = 8 with saturated Na₂CO₃, and extracted with DCM (10 mL × 2). The organic phase was dried over Na₂SO₄, filtered, and concentrated to give 2-amino-2-(m-tolyl)cyclohexan-1-one (1.90 g, 9.35 mmol, 87.21% yield) (118rac) as a yellow oil. LCMS (R T= 1.629 min, MS calculated value: 203.3, [M+H] + = 204.1); 1 H NMR (400 MHz, chloroform-d) δ = 7.30 - 7.27 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.09 - 7.05 (m, 2H), 2.91 - 2.83 (m, 1H), 2.49 - 2.41 (m, 2H), 2.36 (s, 3H), 2.07 - 1.94 (m, 1H), 1.80 - 1.650 (m, 4H); 13 C NMR (101 MHz, chloroform -d) δ = 213.83, 141.84, 139.01, 129.14, 128.46, 126.79, 123.08, 66.50, 39.94, 39.49, 28.24, 22.78, 21.57.

[0768] Step 5: Preparation of 2-(methylamino)-2-(m-tolyl)cyclohexan-1-one (23rac) To a mixture of 2-amino-2-(m-tolyl)cyclohexan-1-one (1.34 g, 6.59 mmol, 1 equiv) in hexafluoroisopropanol (HFIP, 140 mL), methyl trifluoromethanesulfonate (1.08 g, 6.59 mmol, 721.15 uL, 1 equiv) was added at 0 °C. The mixture was then stirred at 25 °C for 12 h under a N2 atmosphere. The mixture was filtered and concentrated. The residue was adjusted to pH = 7 with an aqueous Na2CO3 solution (30 mL). The aqueous phase was extracted with EA (100 mL × 2). The combined organic phases were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Agela DuraShell C18 250×70 mm, 10 μm; mobile phase: A: water (0.05% NH3H2O + 10 mM NH4HCO3), B: ACN; B%: 29% - 59%, 20 min) to give 2-(methylamino)-2-(m-tolyl)cyclohexan-1-one (742 mg, 3.41 mmol, 51.8% yield) (23rac) as a brown oil. LCMS (R T = 1.551 min, MS calculated value: 217.3, [M+H] += 218.1); 1 1H NMR (400 MHz, chloroform-d) δ = 7.28 - 7.19 (m, 1H), 7.11 - 6.95 (m, 3H), 2.86 (td, J = 2.4, 5.4 Hz, 1H), 2.43 - 2.30 (m, 2H), 2.34 (br s, 3H), 2.05 (s, 3H), 1.97 - 1.87 (m, 1H), 1.87 - 1.62 (m, 4H); 13 13C NMR (101 MHz, chloroform-d) δ = 211.63, 138.66, 138.55, 128.63, 128.30, 127.73, 124.18, 69.86, 39.88, 35.28, 28.94, 27.81, 22.34, 21.62.

Example

[0769] Preparation of Compounds 120rac and 119rac

[0770]

Chem.

[0771] Step 1: Preparation of 2-(p-tolyl)cyclohexan-1-ol A solution of 1-bromo-4-methyl-benzene (15 g, 87.70 mmol, 10.79 mL, 1 equiv) in THF (200 mL) was cooled to -70 °C. Then, n-BuLi (2.5 M, 38.59 mL, 1.1 equiv) was added. The mixture was stirred at -70 °C for 0.5 h, then 7-oxabicyclo[4.1.0]heptane (9.47 g, 96.47 mmol, 9.76 mL, 1.1 equiv) and BF3·Et2O (13.69 g, 96.47 mmol, 11.91 mL, 1.1 equiv) were added. The mixture was stirred at -70 °C for 1.5 h. Upon completion, the reaction was quenched slowly with saturated aqueous NH4Cl solution (40 ml), then extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1, 5 / 1) to give 2-(p-tolyl)cyclohexan-1-ol (13 g, 68.32 mmol, 77.9% yield) as a white solid. 1 1H NMR (400 MHz, chloroform-d) δ = 7.18 - 7.13 (m, 4H), 3.69 - 3.61 (m, 1H), 2.44 - 2.37 (m, 1H), 2.35 (s, 3H), 2.16 - 2.09 (m, 1H), 1.91 - 1.82 (m, 2H), 1.80 - 1.73 (m, 1H), 1.55 - 1.31 (m, 4H).

[0772] Step 2: Preparation of 2-(p-tolyl)cyclohexan-1-one To a mixture of 2-(p-tolyl)cyclohexan-1-ol (13 g, 68.32 mmol, 1 equiv) in CH2Cl2 (50 mL), Dess-Martin periodinane (43.47 g, 102.48 mmol, 31.73 mL, 1.5 equiv) was added portionwise at 0 °C (while maintaining the temperature at 0 °C during addition) in several portions. The mixture was then stirred at 20 °C for 12 h. The mixture was filtered. The filtrate was washed with saturated aqueous Na2SO3, saturated aqueous Na2CO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EA = 50:1~5:1) to give 2-(p-tolyl)cyclohexan-1-one (12.01 g, 63.82 mmol, 93.41% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.20 - 7.13 (m, 2H), 7.08 - 7.02 (m, 2H), 3.63 - 3.55 (m, 1H), 2.58 - 2.42 (m, 2H), 2.35 (s, 3H), 2.32 - 2.23 (m, 1H), 2.20 - 2.12 (m, 1H), 2.08 - 1.98 (m, 2H), 1.90 - 1.81 (m, 2H).

[0773] Step 3: Preparation of 2-nitro-2-(p-tolyl)cyclohexan-1-one A mixture of 2-(p-tolyl)cyclohexan-1-one (11 g, 58.43 mmol, 1 equiv), cerium(IV) ammonium nitrate (CAN, 64.06 g, 116.86 mmol, 58.24 mL, 2 equiv), and Cu(OAc)2 (2.12 g, 11.69 mmol, 0.2 equiv) in DCE (150 mL) was stirred at 85 °C for 12 h. The reaction mixture was cooled, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0~0 / 1) to give 2-nitro-2-(p-tolyl)cyclohexan-1-one (5.98 g, 25.64 mmol, 43.88% yield) as a yellow oil. 11H NMR (400 MHz, chloroform-d) δ = 7.36 - 7.27 (m, 4H), 3.10 (ddd, J = 3.6, 10.9, 14.4 Hz, 1H), 2.99 - 2.89 (m, 1H), 2.76 - 2.65 (m, 1H), 2.65 - 2.54 (m, 1H), 2.44 (s, 3H), 2.05 - 1.92 (m, 3H), 1.86 - 1.73 (m, 1H).

[0774] Step 4: Preparation of 2-amino-2-(p-tolyl)cyclohexan-1-one (120rac) To a solution of 2-nitro-2-(p-tolyl)cyclohexan-1-one (4.98 g, 21.35 mmol, 1 equiv) in AcOH (40 mL) was added Zn (33.50 g, 512.38 mmol, 24 equiv) at 0 °C. The mixture was stirred at 25 °C for 12 h. Upon completion, the mixture was filtered and concentrated. The residue was adjusted to pH = 7 with aqueous Na2CO3 solution (150 mL). The aqueous phase was extracted with DCM (200 mL × 2), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0~0 / 1) to give 2-amino-2-(p-tolyl)cyclohexan-1-one (1.3 g, 6.40 mmol, 29.95% yield) (120 rac) as a yellow oil. LCMS (R T = 1.618 min, MS calcd: 203.3, [M+H] + = 204.1); 1 1H NMR (400 MHz, chloroform-d) δ = 7.14 (q, J = 8.4 Hz, 4H), 2.90 - 2.75 (m, 1H), 2.48 - 2.35 (m, 2H), 2.32 (s, 3H), 1.96 (br s, 3H), 1.83 - 1.52 (m, 4H); 13 13C NMR (101 MHz, chloroform-d) δ = 213.76, 138.92, 137.49, 129.93, 126.04, 66.28, 39.83, 39.53, 28.22, 22.76, 20.99.

[0775] Step 5: Preparation of 2-(methylamino)-2-(p-tolyl)cyclohexan-1-one (119rac) To a mixture of 2-amino-2-(p-tolyl)cyclohexan-1-one (583 mg, 2.87 mmol, 1 equiv) in hexafluoroisopropanol (HFIP, 60 mL), methyl trifluoromethanesulfonate (470.65 mg, 2.87 mmol, 313.76 uL, 1 equiv) was added at 0 °C. The mixture was then stirred at 25 °C for 12 h under a N2 atmosphere. The mixture was filtered and concentrated. The residue was adjusted to pH = 7 with saturated aqueous Na2CO3 solution (100 mL). The aqueous phase was extracted with EA (100 mL × 2). The combined organic phases were washed with brine (100 mL × 1), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250×70 mm, 10 μm; mobile phase: A: water (0.05% NH3H2O), B: ACN; B%: 10% - 45%, 35 min) to give 2-(methylamino)-2-(p-tolyl)cyclohexan-1-one (398.86 mg, 1.84 mmol, 64.00% yield) (119rac) as a yellow oil. LCMS (R T = 1.574 min, MS calculated value: 217.3, [M+H] + = 218.1); 1 H NMR (400 MHz, chloroform-d) δ = 7.21 - 7.17 (m, 2H), 7.16 - 7.10 (m, 2H), 2.92 - 2.83 (m, 1H), 2.44 - 2.36 (m, 2H), 2.35 (s, 3H), 2.04 (s, 3H), 2.01 - 1.91 (m, 1H), 1.86 - 1.68 (m, 4H); 13 C NMR (101 MHz, chloroform-d) δ = 211.35, 137.45, 129.60, 127.17, 69.80, 39.76, 35.30, 28.87, 27.78, 22.31, 21.04.

Example

[0776] Preparation of Compounds 25R and 25S

[0777] [Chem.]

[0778] Step 1: Preparation of 2-(diethylamino)-2-phenylcyclohexan-1-one (25rac) A mixture of 2-amino-2-phenyl-cyclohexan-1-one (5 g, 26.42 mmol, 1 equiv), iodoethane (20.60 g, 132.10 mmol, 10.57 mL, 5 equiv) and K2CO3 (10.95 g, 79.26 mmol, 3 equiv) in MeCN (50 mL) was stirred at 100 °C for 12 h. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (mobile phase: A: water (10 mM NH4HCO3), B: ACN; B%: 35% - 70%, 20 min) to give 2-(diethylamino)-2-phenylcyclohexan-1-one (3 g, 12.23 mmol, 46.28% yield) (25 rac) as a yellow oil. 1 H NMR (400 MHz, chloroform -d) δ = 7.32 - 7.16 (m, 5H), 2.60 - 2.51 (m, 1H), 2.47 (q, J = 7.2 Hz, 4H), 2.41 - 2.17 (m, 3H), 1.92 - 1.65 (m, 3H), 1.63 - 1.47 (m, 1H), 0.90 (t, J = 7.2 Hz, 6H).

[0779] Step 2: Preparation of (R)-2-(diethylamino)-2-phenylcyclohexanone (25R) and (S)-2-(diethylamino)-2-phenylcyclohexanone (25S) The racemate was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3H2O in IPA; B%: 11%, multiple injection process with 5-minute intervals between injections) to obtain ENT-1 at 1.103 minutes (343 mg) as a yellow oil and ENT-2 at 1.300 minutes (373 mg) as a yellow oil. The retention times were determined using the following chiral analysis method: column: Chiralcel OJ-3, 100 × 4.6 mm I.D., 3 μm; mobile phase: A: CO2 B: IPA (0.05% IPA m / v); gradient: (time (min) / A% / B%), (0.0 / 95 / 5, 0.5 / 95 / 5, 2.0 / 60 / 40, 3.0 / 60 / 40, 3.6 / 95 / 5, 4.0 / 95 / 5); flow rate: 3.4 mL / min; column temperature: 35 °C; ABPR: 1800 psi.

[0780] ENT-1, RT = 1.103 minutes (assigned here as the S isomer, 25S); LCMS (R T = 1.456 minutes, MS calculated value: 245.18, [M+H] + = 246.1); 1 1H NMR (400 MHz, chloroform-d) δ = 7.31 - 7.20 (m, 4H), 7.20 - 7.14 (m, 1H), 2.58 - 2.48 (m, 1H), 2.43 (q, J = 7.2 Hz, 4H), 2.37 - 2.14 (m, 3H), 1.91 - 1.63 (m, 3H), 1.60 - 1.48 (m, 1H), 0.93 - 0.79 (m, 6H); 13 13C NMR (101 MHz, chloroform-d) δ = 212.94, 139.77, 128.71, 128.04, 127.25, 45.89, 41.27, 35.08, 27.85, 22.46, 16.85; ENT-2, RT = 1.300 minutes (assigned here as the R isomer, 25R); LCMS (R T = 1.514 minutes, MS calculated value: 245.18, [M+H] + = 246.1); 11H NMR (400 MHz, chloroform-d) δ = 7.34 - 7.21 (m, 4H), 7.20 - 7.14 (m, 1H), 2.59 - 2.48 (m, 1H), 2.43 (q, J = 7.2 Hz, 4H), 2.36 - 2.13 (m, 3H), 1.92 - 1.62 (m, 3H), 1.60 - 1.48 (m, 1H), 0.96 - 0.80 (m, 6H); 13 13C NMR (101 MHz, chloroform-d) δ = 212.96, 139.77, 128.71, 128.04, 127.25, 45.89, 41.28, 35.09, 27.85, 22.46, 16.85.

Example

[0781] Preparation of Compound 128mix

[0782]

Chem.

[0783] Step 1: Preparation of 2-(2-methylazetidin-1-yl)-2-phenylcyclohexan-1-one (128mix) A mixture of 2-amino-2-phenyl-cyclohexane-1-one (200 mg, 1.06 mmol, 1 equiv), 1,3-dibromobutane (296.63 mg, 1.37 mmol, 1.3 equiv), KI (52.63 mg, 317.04 μmol, 0.3 equiv), and K2CO3 (438.16 mg, 3.17 mmol, 3 equiv) in MeCN (2 mL) was stirred at 100 °C for 12 h. The mixture was cooled, filtered, and concentrated. The residue was purified by preparative HPLC (mobile phase: A: water (0.05% NH3H2O + 10 mM NH4HCO3), B: ACN; B%: 25% - 55%, 8 min) to give 2-(2-methylazetidin-1-yl)-2-phenylcyclohexane-1-one (50 mg, 205.47 μmol, 19.44% yield) (128mix) as a yellow oil, which is a mixture of all four diastereomers. LCMS (R T = 1.542 min, MS calculated: 243.16, [M+H] += 244.1); 1 1H NMR (400 MHz, chloroform-d) (partial integration due to mixture of isomers) δ = 7.50 - 7.29 (m, 3H), 7.25 - 7.15 (m, 2H), 3.65 (br d, J = 4.8 Hz, 0.5H), 3.51 - 3.33 (m, 1H), 3.29 - 3.16 (m, 0.5H), 3.10 (br d, J = 6.0 Hz, 1H), 2.79 - 2.54 (m, 1H), 2.50 - 2.24 (m, 2H), 1.93 - 1.80 (m, 3H), 1.76 - 1.44 (m, 4H), 1.02 - 0.76 (m, 3H).

Example

[0784] Preparation of Compound 129rac

[0785]

Chem.

[0786] Step 1: Preparation of 2-(3-methylazetidin-1-yl)-2-phenyl-cyclohexan-1-one (129rac) A mixture of 2-amino-2-phenyl-cyclohexane-1-one (300 mg, 1.59 mmol, 1 equiv), 1,3-dibromo-2-methyl-propane (444.94 mg, 2.06 mmol, 1.3 equiv), KI (78.94 mg, 475.55 μmol, 0.3 equiv), and K2CO3 (657.24 mg, 4.76 mmol, 3 equiv) in MeCN (5 mL) was stirred at 100 °C for 12 h. The mixture was cooled, filtered, and concentrated. The residue was purified by preparative HPLC (mobile phase: A: water (10 mM NH4HCO3), B: ACN; B%: 30% - 50%, 8 min) to give 2-(3-methylazetidin-1-yl)-2-phenyl-cyclohexane-1-one (16 mg, 65.09 μmol, yield 4.11%, purity 99%) (129rac) as a white solid. LCMS (R T = 1.602 min, MS calculated: 243.16, [M+H] + = 244.1); 11H NMR (400 MHz, methanol-d4) δ = 7.55 - 7.47 (m, 2H), 7.46 - 7.40 (m, 1H), 7.27 - 7.18 (m, 2H), 3.56 - 3.48 (m, 1H), 3.31 - 3.26 (m, 1H), 2.92 - 2.84 (m, 1H), 2.81 - 2.69 (m, 2H), 2.47 - 2.21 (m, 3H), 1.99 - 1.91 (m, 1H), 1.84 - 1.55 (m, 4H), 0.84 (d, J = 6.8 Hz, 3H).

Example

[0787] Metabolic Stability in Human Liver Microsomes The disclosed compounds were tested for stability in human liver microsomes (HLM), and the results are summarized in Table 2. For some of the compounds, stability was tested under two microsomal incubation conditions, a condition with normal enzyme activity (low activity), and a condition with a higher enzyme load, longer incubation time, and lower compound concentration that was intended to increase metabolic instability (high activity). The disclosed compounds showed greater metabolic stability than ketamine under both conditions in this model.

[0788] Drug. The compounds were tested as racemates (designated by the "rac" name) or pure enantiomers (designated by the "R" or "S" name).

[0789] HLM stability (low activity). Pooled HLM (XenoTech H0630) from adult male and female donors was used. Microsomal incubations were performed in 96-well plates with five aliquots (one for each time point) of 40 μL each. The hepatic microsomal incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), glucose-6-phosphate (5.3 mM), and glucose-6-phosphate dehydrogenase (0.67 units / mL), and 0.42 mg of hepatic microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. The test compound (2 μM, final solvent concentration 1.6%) was incubated with microsomes at 37 °C with shaking at 100 rpm. Incubations were performed in duplicate. Five time points were analyzed over 40 minutes. The reaction was stopped by adding 12 volumes of 90% acetonitrile-water to the incubation aliquots, followed by centrifugation at 5500 rpm for 3 minutes to pellet the protein. The supernatant was analyzed for remaining parent compound using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method suitable for the purpose, with a reference sample of each analyte used for identity confirmation.

[0790] HLM Stability (Low Activity, Alternative Method). Pooled HLM (Corning 452117) from adult male and female donors was used. Microsomal incubations were performed in multiwell plates. The liver microsomal incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPH (1 mM), and 0.50 mg of liver microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.0%) were incubated with microsomes at 37 °C with constant shaking. Six time points were taken over 60 minutes, and 60 μL aliquots of the reaction mixture were withdrawn and analyzed at each time point. The reaction aliquots were stopped by adding 180 μL of cold (4 °C) acetonitrile containing 200 ng / mL of tolbutamide and 200 ng / mL of labetalol as internal standards (IS), followed by shaking for 10 minutes and then centrifuging at 4000 rpm for 20 minutes at 4 °C to pellet the protein. Supernatant samples (80 μL) were diluted with water (240 μL) and analyzed for the remaining parent compound using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method suitable for the purpose.

[0791] HLM stability (high activity). Pooled HLM (XenoTech H0630) from adult male and female donors was used. Microsomal incubations were performed in 96-well plates with five aliquots (one at each time point) of 40 μL each. The liver microsomal incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), glucose-6-phosphate (5.3 mM), and glucose-6-phosphate dehydrogenase (0.67 units / mL), and 1.0 mg of liver microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.6%) were incubated with microsomes at 37 °C with shaking at 100 rpm. Incubations were performed in duplicate. Five time points were analyzed over 60 minutes. The reaction was stopped by adding 12 volumes of 90% acetonitrile-water to the incubation aliquots, followed by centrifugation at 5500 rpm for 3 minutes to pellet the protein. The supernatant was analyzed for the remaining parent compound using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method suitable for the purpose, with a reference sample of each analyte used for identity confirmation.

[0792] Data analysis. The disappearance constant (k el ), half-life (t 1 / 2 ), and intrinsic clearance (Cl int ) were determined using linear regression analysis in a plot of ln(AUC) versus time.

[0793]

Table 2A

[0794]

Table 2B

[0795]

Table 2C

[0796]

Table 2D

[0797]

Table 2E

[0798]

Table 2F

[0799]

Table 2G

Examples

[0800] Metabolic Stability in Mouse Liver Microsomes The disclosed compounds were tested for stability in mouse liver microsomes (MLM), and the results are summarized in Table 3. Two microsome incubation conditions were used: a condition with normal enzyme activity (low activity) and a condition with a higher enzyme load (high activity) that was intended to increase metabolic instability. The disclosed compounds showed greater metabolic stability than ketamine under both conditions in this model.

[0801] Drugs. Compounds were tested as racemates (indicated by the “rac” name) or pure enantiomers (indicated by the “R” or “S” name).

[0802] MLM stability (low activity). Pooled MLM (XenoTech M1000) from male CD-1 mice was used. Microsomal incubations were performed in multi-well plates. The liver microsomal incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPH (1 mM), and 0.50 mg of liver microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.0%) were incubated with microsomes at 37 °C with constant shaking. Six time points were taken over 60 minutes, and 60 μL aliquots of the reaction mixture were withdrawn and analyzed at each time point. The reaction aliquots were stopped by adding 180 μL of cold (4 °C) acetonitrile containing 200 ng / mL of tolbutamide and 200 ng / mL of labetalol as internal standards (IS), followed by shaking for 10 minutes and then centrifuging at 4000 rpm for 20 minutes at 4 °C to precipitate the protein. Supernatant samples (80 μL) were diluted with water (240 μL) and analyzed for the remaining parent compound using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method suitable for the purpose.

[0803] MLM stability (high activity). Pooled MLM (XenoTech M3000) from male BALB / c mice was used. Microsomal incubations were performed in 96-well plates with five aliquots (one at each time point) of 40 μL each. The liver microsomal incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), glucose-6-phosphate (5.3 mM), and glucose-6-phosphate dehydrogenase (0.67 units / mL), and 1.0 mg of liver microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.6%) were incubated with microsomes at 37 °C with shaking at 100 rpm. Incubations were performed in duplicate. Five time points were analyzed over 60 minutes. The reaction was stopped by adding nine volumes of 90% acetonitrile-water to the incubation aliquots, followed by centrifugation at 5500 rpm for 3 minutes to pellet the protein. The supernatant was analyzed for remaining parent compound using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method suitable for the purpose, with a reference sample of each analyte used for identity confirmation.

[0804] Data analysis. The disappearance constant (k el ), half-life (t 1 / 2 ), and intrinsic clearance (Cl int ) were determined using linear regression analysis in a plot of ln(AUC) versus time.

[0805]

Table 3A

[0806]

Table 3B

[0807]

Table 3C

[0808]

Table 3D

[0809]

Table 3E

[0810]

Table 3F

Example

[0811] Metabolic Stability in Rat Liver Microsomes The stability of the disclosed compounds in rat liver microsomes (RLM) was tested and the results are summarized in Table 4. Two microsomal incubation conditions, a condition with normal enzyme activity (low activity), and a condition with a higher enzyme load (high activity) that was intended to increase metabolic instability were used variously. The disclosed compounds showed greater metabolic stability than ketamine under both conditions in this model. Furthermore, deuterated compounds 88R and 88S showed an increase in metabolic stability and a decrease in the formation of their respective metabolites 11R and 11S compared to their non-deuterated counterparts 14R and 14S (Table 4 and Figure 2). These effects on metabolism are more pronounced for the R isomer.

[0812] Drugs. Compounds were tested as racemates (indicated by the “rac” name) or pure enantiomers (indicated by the “R” or “S” name).

[0813] RLM stability (low activity). Pooled RLM (XenoTech R1000) from male Sprague Dawley rats was used. Microsome incubations were performed in multi-well plates. The liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPH (1 mM), and 0.50 mg of liver microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.0%) were incubated with microsomes at 37 °C with constant shaking. Six time points were taken over 60 minutes, and 60 μL aliquots of the reaction mixture were withdrawn and analyzed at each time point. The reaction aliquots were stopped by adding 180 μL of cold (4 °C) acetonitrile containing 200 ng / mL of tolbutamide and 200 ng / mL of labetalol as internal standards (IS), followed by shaking for 10 minutes and then centrifuging at 4000 rpm for 20 minutes at 4 °C to precipitate the protein. The supernatant sample (80 μL) was diluted with water (240 μL) and analyzed for the remaining parent compound using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method suitable for the purpose.

[0814] RLM stability (high activity). Pooled RLM from male Sprague Dawley rats (XenoTech R1000, lot number 1910100) was used. Microsomal incubations were performed in 96-well plates with five aliquots (one for each time point) of 40 μL each. The hepatic microsomal incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), glucose-6-phosphate (5.3 mM), and glucose-6-phosphate dehydrogenase (0.67 units / mL), and 1.0 mg of hepatic microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.6%) were incubated with microsomes at 37 °C with shaking at 100 rpm. Incubations were performed in duplicate. Five time points were analyzed over 60 minutes. The reaction was stopped by adding nine volumes of 90% acetonitrile-water to the incubation aliquots, followed by sedimentation of the protein by centrifugation at 5500 rpm for 3 minutes. The supernatant was analyzed for the remaining parent compound using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method suitable for the purpose, using a reference sample of each analyte for calibration and identity confirmation.

[0815] This condition was also used for experiments measuring the formation of metabolite 11R from compounds 14R and 88R, and the formation of metabolite 11S from compounds 14S and 88S. The concentrations of 11R and 11S formed during incubation were quantified using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method suitable for the purpose, using a reference sample of each analyte for calibration and identity confirmation.

[0816] Data analysis. The disappearance constant (k el ), half-life (t 1 / 2 ), and intrinsic clearance (Cl int ) were determined using linear regression analysis in a plot of ln(AUC) versus time.

[0817]

Table 4A

[0818]

Table 4B

[0819]

Table 4C

[0820]

Table 4D

[0821]

Table 4E

Example

[0822] Oral Bioavailability in Mice

[0823] In mice, the disclosed compounds showed improved absolute oral bioavailability (F), longer half-life (t 1 / 2 ), higher maximum concentration (C max ), and higher absolute exposure (quantified by area under the curve (AUC)) in both plasma (Table 5) and brain (Table 6) compared to ketamine.

[0824] Method A:

[0825] Animals. Male CD-1 mice were used in these studies. Animals were randomly assigned to treatment groups and fasted for 4 hours before dosing.

[0826] Drugs. The test compounds were dissolved in normal saline (ketamine) or deionized water (other compounds), and administered intravenously (iv) or orally (po) at a dose of 10 mg / kg (calculated based on the free base) and a volume of 5 mL / kg body weight. The compounds were tested as racemates (indicated by the "rac" name) or pure enantiomers (indicated by the "R" or "S" name).

[0827] Sample collection and bioanalysis. Blood samples were collected from the orbital sinus into microvessels containing K2EDTA under 2,2,2-tribromoethanol anesthesia (150 mg / kg, ip) at time points of 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (4 animals per time point). Immediately after blood collection, the mice were euthanized by cervical dislocation, and brain samples were collected at the same time points. All samples were processed immediately, snap-frozen, and stored at -70 °C until subsequent analysis. Plasma samples were separated by centrifugation of whole blood, and an aliquot (50 μL) was mixed with 200 μL of internal standard solution (400 ng / mL in 1:1 v / v CH3CN:MeOH). After mixing by pipetting and centrifuging at 6000 rpm for 4 minutes, 0.5 μL of each supernatant was analyzed for the drug using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method suitable for the purpose, with reference samples of each analyte used for calibration and identification. Brain samples (100 mg ± 1 mg in mass) were dispersed in 500 μL of internal standard solution (400 ng / mL in 4:1 v / v MeOH:water) using zirconium oxide beads (115 mg ± 5 mg) at speed 8 for 30 seconds in a Bullet Blender® homogenizer. After homogenization, the samples were centrifuged at 14,000 rpm for 4 minutes, and 0.5 μL of each supernatant was analyzed for the drug using an LC-MS / MS method suitable for the purpose, with reference samples of each analyte used for calibration and identification.

[0828] Data analysis. The drug concentration of samples below the lower limit of quantification (LLOQ) was designated as zero. Pharmacokinetic data analysis was performed using a non-compartmental, bolus injection or extravascular input analysis model in WinNonlin 5.2 (PharSight). Data points below the LLOQ were t1 / 2 Represented as missing values to improve the validity of the calculation.

[0829] Method B:

[0830] Animals. Male CD-1 mice were used in these studies. The animals were randomly assigned to treatment groups and fasted for 4 hours prior to oral administration.

[0831] Drugs. The test compounds were dissolved in a vehicle consisting of normal saline (compounds 19S and 88R), or a mixture of 5% v / v N-methyl-2-pyrrolidone, 5% v / v Solutol HS-15, and 90% v / v normal saline (compounds 11S, 11R, 114S, and 114R). They were then administered intravenously (iv) or orally (po) at a dose of 10 mg / kg (calculated based on the free base) and a volume of 5 mL / kg body weight. The compounds were tested as racemates (indicated by the "rac" designation) or pure enantiomers (indicated by the "R" or "S" designation).

[0832] Sample collection and bioanalysis. Blood samples (approx. 60 μL) were collected from the retro-orbital sinus at the time points of 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (4 animals per time point) under light isoflurane anesthesia (Surgivet®). Immediately after blood collection, plasma was recovered by centrifugation at 4000 rpm for 10 minutes at 4 °C, and the samples were stored at -70 ± 10 °C until bioanalysis. Following blood collection, the animals were sacrificed immediately, the abdominal vena cava was incised, and the whole body was perfused from the heart using 10 mL of normal saline, and brain samples were collected from all animals. After isolation, the brain samples were rinsed three times in ice-cold normal saline (each rinse was done using approximately 5 - 10 mL of normal saline in a disposable Petri dish for 5 - 10 seconds each) and dried with absorbent paper. The brain samples were homogenized using ice-cold phosphate-buffered saline (pH 7.4). The total homogenate volume was three times the tissue mass. All homogenates were stored at -70 ± 10 °C until bioanalysis. For bioanalysis, 25 μL aliquots of plasma / brain study samples or spiked plasma / brain calibration standards were added to individual pre-labeled microcentrifuge tubes, followed by the addition of 100 μL of internal standard solution (glypidide, 500 ng / mL in acetonitrile), and with the exception of those not filled in, 100 μL of acetonitrile was added. The samples were vortexed for 5 minutes and then centrifuged at 4000 rpm for 10 minutes at 4 °C. Following centrifugation, 100 μL of each clear supernatant was transferred to a 96-well plate and analyzed using an LC-MS / MS method suitable for the purpose, using reference samples of each analyte for calibration and identification.

[0833] Data analysis. Pharmacokinetic parameters were estimated using the non-compartmental analysis tool of Phoenix® WinNonlin software (Ver 8.0).

[0834]

Table 5A

[0835]

Table 5B

[0836]

Table 6A

[0837]

Table 6B

Example

[0838] Exposure after intraperitoneal administration in mice In mice, after intraperitoneal (ip) administration of compounds 14R and 14S at 3.16 mg / kg, values of maximum concentration (C max ) and absolute exposure (quantified by area under the curve (AUC)) were obtained in both plasma (Table 7) and brain (Table 8) that were comparable to or higher than those achieved by ketamine after a higher dose of 10 mg / kg. Thus, exposure to 14R and 14S is much higher than that of ketamine after ip administration when scaling for dose equivalence. Furthermore, exposure (AUC) to 14R was approximately 2-fold higher than that to 14S after the same dose, suggesting greater metabolic stability for the R isomer. Animals. Male CD-1 mice were used in these studies. Animals were randomly assigned to treatment groups and fasted for 4 hours prior to dosing.

[0839] Drugs. Test compounds (HCl salts) were dissolved in deionized water and administered intraperitoneally (ip) at the indicated doses (calculated based on the free base) and a volume of 5 mL / kg body weight. Compounds were tested as racemates (indicated by the “rac” designation) or pure enantiomers (indicated by the “R” or “S” designation) as shown.

[0840] Pharmacokinetics. Blood samples were collected from the orbital sinus into microvessels containing K2EDTA under 2,2,2-tribromoethanol anesthesia (150 mg / kg, ip) at time points of 0.083, 0.25, 0.5, 1, and 2 hours (ketamine, 4 animals per time point) or 0.083, 0.25, 0.5, 1, 2, 4, and 8 hours (14R and 14S, 4 animals per time point). Immediately after blood collection, the mice were euthanized by cervical dislocation and brain samples were collected at the same time points. All samples were immediately processed, snap-frozen, and stored at -70 °C until subsequent analysis. Plasma samples were separated from whole blood by centrifugation, and an aliquot (50 μL) was mixed with 200 μL of an internal standard solution (400 ng / mL in 1:1 v / v CH3CN:MeOH). After mixing by pipetting and centrifuging at 6000 rpm for 4 minutes, 0.5 μL of each supernatant was analyzed for the drug using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method suitable for the purpose, with reference samples of each analyte used for calibration and identification. Brain samples (200 mg ± 1 mg in mass) were dispersed in 800 μL of an internal standard solution (400 ng / mL in 4:1 v / v MeOH:water) using zirconium oxide beads (115 mg ± 5 mg) in a Bullet Blender® homogenizer at speed 8 for 30 seconds. After homogenization, the samples were centrifuged at 14,000 rpm for 4 minutes, and 0.5 μL of each supernatant was analyzed for the drug using an LC-MS / MS method suitable for the purpose, with reference samples of each analyte used for calibration and identification.

[0841] Data analysis. Drug concentrations in samples below the lower limit of quantification (LLOQ) were designated as zero. Pharmacokinetic data analysis was performed using a non-compartmental, bolus injection or extravascular input analysis model in WinNonlin 5.2 (PharSight). Data points below the LLOQ were represented as missing values to improve the validity of the calculations. 1 / 2

[0842]

Table 7

[0843] ​

Table 8

Example

[0844] Oral bioavailability in rats In rats, the compounds disclosed herein had improved absolute oral bioavailability (F), longer half-life (t 1 / 2 ), higher maximum concentration (C max ), and higher absolute exposure (quantified by area under the curve (AUC)) in plasma (Table 9) compared to ketamine. These studies also showed that deuteration of the N-methyl group, as in compound 88R, increased the oral bioavailability of this compound compared to its non-deuterated counterpart 14R. The formation of metabolite 11R from 88R was also reduced compared to the formation of the same metabolite from non-deuterated compound 14R after oral administration (Table 10). Method A:

[0845] Animals. Male Sprague Dawley rats were used in these studies. The animals were randomly assigned to treatment groups and fasted overnight before oral administration.

[0846] Drugs. The test compounds were dissolved in normal saline and administered intravenously (iv) or orally (po) at a dose of 10 mg / kg (calculated based on the free base) and a volume of 5 mL / kg body weight. The compounds were tested as racemates (indicated by the "rac" designation).

[0847] Sample collection and bioanalysis. Blood samples were collected via the external jugular vein (by cannulation) at the time points of 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration (a total of 8 time points / rat, 4 rats per administration route). At each time point, approximately 0.2 mL of blood was withdrawn and transferred to a pre-labeled 0.5 mL microcentrifuge tube containing 4 μL of 200 mM K2EDTA solution as an anticoagulant, and gently mixed by inverting the tube to facilitate the mixing of the anticoagulant and blood. The blood samples were kept on ice until centrifugation. The collected blood samples were centrifuged at 4000 rpm for 10 minutes at 4°C. After centrifugation, the plasma samples were separated, transferred to pre-labeled tubes, and stored at -70°C until bioanalysis. For bioanalysis, 50 μL aliquots of plasma study samples or calibration standards were added to pre-labeled Eppendorf tubes, and 10 μL of internal standard solution (diclofenac, 5 μg / mL in 50:50 v / v methanol:water) was added. The samples were quenched with 500 μL of precipitation solution (0.1% v / v formic acid in acetonitrile) and vortexed. All samples were centrifuged at 14,000 rpm for 10 minutes at 4°C. Following centrifugation, 5 μL of each clear supernatant was analyzed using an LC-MS / MS method suitable for the purpose, with reference samples of the analyte used for calibration and identification.

[0848] Data analysis. Pharmacokinetic parameters were estimated using the non-compartmental analysis tool of Phoenix® WinNonlin software (Ver8.1). Drug concentrations in samples below the lower limit of quantification (LLOQ) were designated as zero. Method B:

[0849] Animals. Male Sprague Dawley rats were used in these studies. The animals were randomly assigned to treatment groups and fasted overnight before oral administration.

[0850] Drugs. The test compounds were dissolved in a vehicle consisting of normal saline (compounds 14R, 88R, 29rac, and 27rac) or a mixture of 5% v / v N-methyl-2-pyrrolidone, 5% v / v Solutol HS-15, and 90% v / v normal saline (compounds 84R and 84S). Then, these were administered intravenously (iv) or orally (po) at a dose of 10 mg / kg (calculated based on the free base) and a volume of 5 mL / kg body weight. The compounds were tested as racemates (indicated by the "rac" name) or pure enantiomers (indicated by the "R" or "S" name).

[0851] Sample collection and bioanalysis. Blood samples (about 120 μL) were collected from the retro-orbital sinus under light isoflurane anesthesia (Surgivet®) at time points of 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (a total of 8 time points / rats, 4 rats per administration route per compound). Immediately after blood collection, plasma was recovered by centrifugation at 4000 rpm for 10 minutes at 4°C, and the samples were stored at -70 ± 10°C until bioanalysis. For bioanalysis, 25 μL aliquots of plasma study samples or spiked plasma calibration standards were added to individual pre-labeled microcentrifuge tubes, followed by 100 μL of an internal standard solution (glypidide, 500 ng / mL in acetonitrile), and with the exception of those not filled in, 100 μL of acetonitrile was added. The samples were vortexed for 5 minutes and then centrifuged at 4000 rpm for 10 minutes at 4°C. Following centrifugation, 100 μL of each clear supernatant was transferred to a 96-well plate and analyzed using an LC-MS / MS method suitable for the purpose, with reference samples of each analyte used for calibration and identification. For compounds 14R and 88R, their metabolite 11R was also quantified in plasma samples.

[0852] Data analysis. Pharmacokinetic parameters were estimated using the non-compartmental analysis tool of Phoenix® WinNonlin software (Ver8.0).

[0853]

Table 9

[0854] [Table 10] [Examples]

[0855] NMDA receptor binding The binding affinity of the disclosed compounds at the MK-801 binding site of the N-methyl-D-aspartic acid receptor (NMDAR) was determined in radioligand binding experiments (Table 11). The values shown for racemic ketamine (rac-ketamine) and its enantiomers were cited from the literature (Ebert et al. 1997). In general, the R enantiomers of the compounds of the present invention showed weaker binding affinity for NMDAR, suggesting that these compounds have reduced dissociative side effects compared to their corresponding S enantiomers or racemates. In contrast, the S isomers may have higher potency as anesthetics in light of their higher potency at NMDAR. For example, Compound 14R showed weaker NMDAR binding than rac-ketamine, (R)-ketamine, (S)-ketamine, and 14S, suggesting that it may have less pronounced dissociative side effects than equimolar doses of these compounds. For example, many of the compounds of the present invention, including 14R, 11S, 88R, 27rac, 29rac, 19S, 114S, and 18rac, showed affinity within the ideal range of 1-5 μM. In certain cases, the R isomers were active within the target affinity range, in other cases the S isomers were more desirable, and in some cases both stereoisomers or racemates fell within the desired range. Indeed, the eudysmic ratio for each pair of enantiomers showed considerable variability, being <2 in some cases while ranging up to about 10 in other cases.

[0856] [Table 11A]

[0857]

Table 11B

[0858] Radioactive ligand binding - Method A. The affinity of the test compound for NMDAR was determined in a radioactive ligand binding experiment using [³H]MK - 801 by Eurofins Panlabs under the conditions described in Table 12, using a method adapted from the literature (Javitt et al. 1987; Reynolds et al. 1989). 3

[0859]

Table 12

[0860] Radioactive ligand binding - Method B. The affinity of the test compound for NMDAR was determined in a radioactive ligand binding experiment using [³H]MK - 801 by WuXi AppTec (Hong Kong) under the conditions described in Table 13. 3

[0861]

Table 13

Example

[0862] Activity in Monoamine Transporters ​​The ability of the compounds of the present invention to inhibit the uptake of monoamines by the serotonin transporter (SERT), norepinephrine transporter (NET), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) (collectively monoamine transporters, MAT) was measured using a fluorescent substrate uptake assay in transfected cells (Table 14). The binding affinity of selected compounds was also determined in radioligand displacement assays at SERT, NET, and / or DAT (Table 14). Activity was generally greatest for compounds containing a cyclic moiety on the amine. For example, Compounds 26, 27, and 84 all showed an IC 50 for monoamine uptake of < 10 μM in one or more of the MATs tested. The activity of Compound 27S is particularly notable, which showed an IC 50was shown. However, there are notable exceptions to the trend of greater MAT inhibitory activity for cyclic amines, and the enantiomers of compound 31 containing a morpholine ring showed little activity against MAT. Inhibitors of MAT are known to have antidepressant and anxiolytic effects and are included among the most commonly prescribed drugs for mood disorders (e.g., fluoxetine, sertraline, venlafaxine, imipramine, etc.). Considering th...

Claims

【Request 1】 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof. 【Request 2】 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof, wherein the enantiomeric compound is present in an enantiomeric mixture having at least 90%, at least 95%, or at least 99% of the enantiomeric compound. 【Request 3】 【Chemistry 3】 A compound selected from: 【Request 4】 【Chemical 4】 3. The compound of claim 1 or 2, which is selected from: 【Request 5】 【Chemistry 5】 4. The compound of claim 3,

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and a pharma- ceutically acceptable excipient.

7. A method for treating depression, anxiety depression, mood disorder, anxiety disorder, or substance use disorder and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound described in any one of claims 1 to 5.

8. A method for treating depression or anxiety depression in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound described in any one of claims 1 to 5.

9. 【Chemical 6】 1. A composition comprising an enantiomeric mixture of a compound selected from the group consisting of:

10. The compound is 【Chemistry 7】 The composition of claim 9 selected from the group consisting of:

11. 【Chemical 8】 1. A composition comprising an enantiomeric mixture of a compound selected from the group consisting of:

12. The compound is 【Chemistry 9】 The composition of claim 11 selected from the group consisting of:

13. A method for treating depression, anxiety depression, mood disorder, anxiety disorder, or substance use disorder and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a composition described in any one of claims 9 to 12.

14. 13. A method for treating depression or anxiety depression in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound described in any one of claims 9 to 12.

15. 1. A method for treating depression, anxiety depression, mood disorder, anxiety disorder, or substance use disorder and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject in need thereof 【Chemistry 10A】 【Chemistry 10B】 20. A method comprising administering an effective amount of a composition comprising an isolated, substantially enantiomerically pure compound selected from the group consisting of:

16. 1. A method for treating depression, anxiety depression, mood disorder, anxiety disorder, or substance use disorder and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject in need thereof 【Chemistry 11】 A method comprising the step of administering an effective amount of a composition comprising a compound selected from the group consisting of:

17. The compound is 【Chemistry 12】 16. The method of claim 15, selected from the group consisting of:

18. 【Chemical 13】 or a pharma- ceutically acceptable salt thereof.

19. 1. A method for treating depression, anxiety depression, mood disorder, anxiety disorder, or substance use disorder and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject in need thereof 【Chemistry 14】 or a pharma- ceutically acceptable salt thereof.

20. 1. A method for treating depression or anxiety depression in a subject in need thereof, comprising administering to a subject in need thereof 【Chemistry 15】 or a pharma- ceutically acceptable salt thereof.

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