Arylcyclohexylamine derivatives and their use in treatment of psychiatric disorders

Abstract

Provided herein are aryl cyclohexylamine derivatives and their use in the treatment of psychiatric disorders.

Description

[0001] This application is a divisional application of the patent application with the original application date of December 28, 2020, application number 202080097657.8 (international application number PCT / US2020 / 067235), and invention name "Arylcyclohexylamine derivatives and their use in the treatment of mental disorders".

[0002] Related applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 093,830 filed on December 26, 2019, U.S. Provisional Application No. 63 / 037,044 filed on June 10, 2020, and U.S. Provisional Patent Application No. 63 / 093,830 filed on October 20, 2020, each of which is incorporated herein by reference in its entirety. Background Art

[0004] Approximately one-third of patients with major depressive disorder (MDD) fail to achieve remission of their symptoms even after multiple cycles of treatment with several known classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs) (Rush et al. 2006). The high prevalence of treatment-resistant depression (TRD) clearly indicates the need for new, more effective pharmacotherapy for depression that will target new mechanisms and / or patient populations. In recent years, ketamine, a drug long used as a dissociative anesthetic, has attracted considerable attention due to its secondary use as a fast-acting antidepressant with potent efficacy even in patients with TRD (Zarate et al. 2006; Berman et al. 2000). The antidepressant effects of this drug are also noteworthy because they persist for days or weeks after a single dose. Importantly, the S enantiomer of ketamine (S-ket) has recently been approved by the United States Food and Drug Administration for the treatment of depression.

[0005] Unfortunately, the potent dissociative anesthetic effects of ketamine and S-ket make these drugs attractive to recreational drug users and limit their widespread clinical application by restricting their use to situations under the direct supervision of a healthcare provider. Given that ketamine's primary molecular target is the N-methyl-D-aspartate receptor (NMDAR), whose inhibition accounts for the drug's anesthetic effects, many have proposed that inhibition of this target also accounts for ketamine's antidepressant effects. This mechanism suggests that ketamine's antidepressant and dissociative effects may be inseparable at the mechanistic level. However, a number of lines of evidence have challenged this hypothesis (Aleksandrova et al. 2017). First, the R enantiomer of ketamine (R-ket) has been found to be more potent and longer-lasting as an antidepressant than S-ket 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) has been shown to induce antidepressant effects in rodent models but only weakly binds to NMDAR and does not engage the receptor in vivo at dose levels that induce antidepressant effects (Zanos et al. 2016; Lumsden et al. 2019; Morris et al. 2017). Therefore, both R-ket and HNK can induce antidepressant effects while limiting the dissociative effects of ketamine.

[0006] However, other strategies proposed to attenuate the dissociative effects of ketamine (e.g., by targeting the NR2B subunit of the NMDAR or utilizing compounds with low capture properties) have yielded poor results. For example, many of these structurally distinct NMDAR antagonists (e.g., memantine, MK-0657, and lanisamine), despite reducing dissociation in some cases, have been found to be less effective and / or shorter-acting than ketamine in treating depression (Zanos et al. 2016; Qu et al. 2017; Cerecor 2019; Kadriu et al. 2019; Lepow et al. 2017). Similarly, agonists with higher affinity for NMDARs (e.g., MK-801) or targeting alternative binding sites on the channel (e.g., rapafenamide) have also failed (Yang et al. 2016; Al Idrus 2019). Thus, the precise molecular mechanisms underlying ketamine's antidepressant effects remain poorly understood, and this mechanism may involve other, as yet unidentified, targets. Furthermore, the magnitude of the antidepressant effects of NMDAR modulators and their accompanying dissociative effects is often highly unpredictable.At the same time, these findings have raised the exciting possibility that ketamine's antidepressant effects may actually be separable from its dissociative anesthetic effects.

[0007] 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). Therefore, for the treatment of MDD, ketamine is almost exclusively used via the intravenous (iv) route. The practical challenges of iv administration further necessitate the use of ketamine in a clinic or hospital setting under the supervision of a medical provider. Therefore, the inability to use ketamine via the oral route of administration is a major disadvantage that limits the widespread adoption of the drug and increases the medical costs associated with its use. Although other orally bioavailable NMDAR antagonists have been developed, these antagonists have not yet been marketed, nor have they demonstrated the robust clinical efficacy of ketamine as an antidepressant. Therefore, there remains a pressing need for new antidepressants in the ketamine class that have robust efficacy, reduced dissociative side effects, and increased oral bioavailability. Drugs that retain the antidepressant activity of ketamine while also reducing its dissociative effects and increasing oral bioavailability would provide a treatment option that is easier to administer and potentially feasible for home use due to their reduced dissociative effects and concomitant reduced potential for abuse. Summary of the Invention

[0008] The present disclosure provides, at least in part, arylcyclohexylamine compounds having significantly higher oral bioavailability, higher antidepressant potency, and / or a greater therapeutic index between antidepressant effect and side effects than ketamine, as well as compositions of single enantiomers or enantiomerically enriched mixtures of arylcyclohexylamines.

[0009] For example, the present disclosure provides compounds with increased oral bioavailability, for example, by having structural components that provide increased resistance to liver metabolism when compared to ketamine. For example, this can be seen from its higher stability in both rodent and human liver microsomal preparations. Importantly, despite this increase in oral bioavailability, the disclosed compounds retain a substantially short half-life, which is contrary to the more typical observation that increased liver stability may lead to slow clearance. Because the therapeutic efficacy of such compounds may not rely on sustained receptor occupancy, a short half-life may be desirable. On the contrary, the pulsatile engagement of NMDAR (or other) signaling may be sufficient to cause a therapeutic effect that lasts far longer than (days or weeks) drug elimination (hours), thereby limiting overall exposure and reducing the duration of any dissociation or other negative side effects. In addition, in some embodiments, the compounds provided herein have an increased antidepressant efficacy (particularly after oral administration) as a secondary effect of increased exposure, while retaining the high brain permeability of ketamine. Even in cases where the in vitro affinity of NMDAR is similar to or lower than that of ketamine, such compounds may be more potent as antidepressants. Furthermore, as demonstrated by displacement of radioligand from NMDAR-containing membranes isolated from rat cortex [3 H] MK-801 is determined, because the NMDAR binding affinity is ~ 1-5 μM, the compounds provided herein may show an increased antidepressant effect and a therapeutic index between the separation side effects. In certain embodiments, this affinity range may be useful in balancing the efficacy and side effects of antidepressants, which may be due to the rapid departure kinetics of such compounds. For example, compounds with too high NMDAR affinity (<1 μM) (such as racemic ketamine and S-ket) show a significant separation effect, which limits its use in a doctor-supervised environment and increases its abuse tendency. In addition, NMDAR high affinity may also reduce the therapeutic efficacy in depression (for example, MK-801 and S-ket both seem to show weaker and less persistent antidepressant effects than racemic ketamine and R-ket with lower affinity). In contrast, even when the dose is appropriately amplified for this lower affinity, compounds with too low NMDAR affinity (> 5 μM) may lose their antidepressant efficacy. Furthermore, even if effective, the very high doses required for such low-potency compounds may exacerbate toxicological challenges or lead to the introduction of undesirable off-targets (due to reduced selectivity for other weak binding partners).

[0010] In one aspect, provided herein are compounds having the general structure (I):

[0011]

[0012] wherein R1 is selected from phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of formula (II);

[0013] wherein when R1 is phenyl, then R2 and R3 are independently selected from H, C3, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; wherein D represents a deuterium-enriched H site; provided that one or more of R2 and R3 is not H; or

[0014] R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0015] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0016] Wherein when R1 is a part of the general formula (II):

[0017]

[0018] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; provided that one or more of R2 and R3 is not H; or

[0019] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0020] Among them, R6, R7, R8, R9 and R 10 Independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 11 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 12 R 13 、-SR 14 、-SO2R 15 、-CO2R 16 、-C(=O)NR 17 R 18 ; where R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 Each is 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;

[0021] The condition is R6-R 10 One or more of is not H; or

[0022] The condition is that when R6 is Cl and R7-R 10 is H, or when R7 is Cl and R6, R8-R 10 When R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0023] The condition is that when R7 is OH and R6, R8-R 10 When R2 or R3 is H, the other of R2 or R3 is a linear or branched C3-C10 alkyl group, a C2-C10 haloalkyl group or -R4-O-R5; or

[0024] Provided that when R6, R7 or R8 is OMe and R6-R 10 When the other R2 or R3 is H, the other R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5;

[0025] Wherein when R1 is selected from thiazole, thiophene, pyridine, each is optionally replaced by one or more OH, halogen (selected from F, Cl, Br, I), -OR 19 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 20 R 21 、-SR 22 、-SO2R 23 、-CO2R 24 、-C(=O)NR 25 R 26 Substitution; wherein R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 Each is 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;

[0026] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0027] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0028] In some embodiments, the compounds provided herein have the general structure (Ia):

[0029]

[0030] wherein R2 and R3 are independently selected from H, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; provided that one or more of R2 and R3 is not H; or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5;

[0031] wherein 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 being optionally substituted with one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0032] In some embodiments, the compounds provided herein have the general structure (Ib):

[0033]

[0034] wherein R3 is C1-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; and wherein R6, R7, R8, R9 and R 10 Independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 11 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 12 R 13 、-SR 14 、-SO2R 15 、-CO2R 16 、-C(=O)NR 17 R 18 ; where R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 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 R6-R 10 One or more of them is not H; or when R6 is Cl and R7-R 10 is H or when R7 is Cl and R6, R8-R 10When R7 is OH and R6, R8-R 10 When R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5.

[0035] In some embodiments, the compounds provided herein have the general structure (I), wherein R1 is selected from thiazole, thiophene, pyridine; each optionally replaced by one or more OH, halogen (selected from F, Cl, Br, I), -OR 19 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 20 R 21 、-SR 22 、-SO2R 23 、-CO2R 24 、-C(=O)NR 25 R 26 Substitution; wherein R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 R2 and R3 are 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; wherein 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 is optionally substituted with one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

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

[0037]

[0038] wherein R2 and R3 are independently selected from H, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein 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 not H.

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

[0040]

[0041] wherein R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

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

[0043]

[0044] wherein R2 and R3 together with the nitrogen ring to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

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

[0046]

[0047] wherein R2 is H and R3 is selected from branched or cyclic C3 alkyl, C4-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

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

[0049]

[0050] wherein R2 and R3 are independently selected from C2-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

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

[0052]

[0053] 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 with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

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

[0055]

[0056] Among them, R6, R7, R8, R9 and R 10 One or more of them is OH, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; provided that when R7 is OH and R6, R8-R 10 When it is H, then R3 is a C3-C10 alkyl group.

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

[0058]

[0059] Among them, R6, R7, R8, R9 and R 10 One or more of them is halogen (selected from F, Cl, Br, I), R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; provided that when R6 is Cl and R7-R 10 is H or when R7 is Cl and R6, R8-R 10 When it is H, then R3 is a C3-C10 alkyl group.

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

[0061]

[0062] Among them, R6, R7, R8, R9 and R 10 wherein one or more of them is OMe, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; provided that when R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is a C3-C10 alkyl group.

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

[0064]

[0065] Among them, R6, R7, R8, R9 and R 10 One or more of them is F, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

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

[0067]

[0068] Among them, R6, R7, R8, R9 and R 10 One or more of them is Me, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

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

[0070]

[0071] Among them, R6, R7, R8, R9 and R 10 One or more of them is OH, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; provided that when R7 is OH and R6, R8-R 10 When it is H, then R3 is a C3-C5 alkyl group.

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

[0073]

[0074] Among them, R6, R7, R8, R9 and R 10 wherein one or more of the components is OMe, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; provided that when R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is a C3-C5 alkyl group.

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

[0076]

[0077] Among them, R6, R7, R8, R9 and R 10 One or more of them is F, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0078] In some embodiments, the compounds provided herein have the general structure (Ib):

[0079]

[0080] Among them, R6, R7, R8, R9 and R 10 One or more of them is Me, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0081] In some embodiments, the compounds provided herein have the general structure (Ic):

[0082]

[0083] Among them, R6, R7, R8, R9 and R 10 wherein one or more is OH, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein 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; said ring being optionally substituted with one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0084] In some embodiments, the compounds provided herein have the general structure (Ic):

[0085]

[0086] Among them, R6, R7, R8, R9 and R 10 wherein one or more is OMe, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein 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; said ring being optionally substituted with one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0087] In some embodiments, the compounds provided herein have the general structure (Ic):

[0088]

[0089] Among them, R6, R7, R8, R9 and R 10 wherein one or more is F, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein 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; said ring being optionally substituted with one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0090] In some embodiments, the compounds provided herein have the general structure (Ic):

[0091]

[0092] Among them, R6, R7, R8, R9 and R 10 wherein one or more is Me, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein 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; said ring being optionally substituted with one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0093] In some embodiments, the compound provided herein is selected from:

[0094]

[0095]

[0096] or a pharmaceutically acceptable salt or ester thereof.

[0097] In some embodiments, the compound provided herein is selected from:

[0098]

[0099] In another aspect, provided herein are compositions comprising a carrier and a compound having the structure:

[0100]

[0101] where D represents a deuterium-rich H site.

[0102] In some embodiments, each D represents a deuterium-enriched H site and the deuterium level at each deuterium-enriched H site of the compound is 0.02% to 100%. In some embodiments, each D represents a deuterium-enriched H site and the deuterium level at each deuterium-enriched H site of the compound is 20%-100%, 50%-100%, 70%-100%, 90%-100%, 97%-100%, or 99%-100%.

[0103] In another aspect, provided herein are compounds having the general structure (III):

[0104]

[0105] where R 31 and R 32 Each is H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring is optionally substituted with one or more linear or branched C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and wherein R 27 、R 28 、R 29 、R 30 Each is independently selected from H, linear or branched C1-C10 alkyl, F, or R 27 and R 28 or R 29 and R 30 Together with the carbon atom to which they are attached, they form a cycloalkyl ring or together with the carbon atom to which they are attached and one or more heteroatoms, they form a cycloheteroalkyl ring; and wherein R 33 、R 34 、R 35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47 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 R 27 、R 28 、R 29 or R 30 At least one of them is not H; or if R 27 and R 28 One of them is Me and R 27 and R 28 When the other one is H, then R 32 is C2-C10 alkyl, C2-C10 haloalkyl or -R 38 -OR 39 .

[0106] In some embodiments, the compounds provided herein have the general structure (III):

[0107]

[0108] where R 31 and R 32 Each is H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring is optionally substituted with one or more linear or branched C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and wherein R 27 and R 28 is fluorine and R 29 and R 30 is H; and wherein R 33 、R 34 、R 35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47 Each is 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.

[0109] In some embodiments, the compounds provided herein have the general structure (III):

[0110]

[0111] where R 31 and R 32 Each is H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring is optionally substituted with one or more linear or branched C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and wherein R 27 and R 28 Together with the carbon and oxygen atoms to which they are attached, they form an oxetane ring; and wherein R 29 and R 30 is H; and wherein R 33 、R 34 、R 35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47 Each is 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.

[0112] In some embodiments, the compound provided herein is selected from:

[0113]

[0114]

[0115] In another aspect, provided herein are pharmaceutical compositions comprising one or more compounds. In some embodiments, the compositions described herein (eg, pharmaceutical compositions) are oral compositions.

[0116] In another aspect, provided herein is a method of treating depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, the method generally comprising administering to the subject a compound of structure (IV):

[0117]

[0118] where R 48 is selected from: phenyl, thiazole, thiophene, pyridine or a moiety of formula (V);

[0119]

[0120] where R 51 、R 52 、R 53 、R 54 and R 55 Each is independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1-C10 alkyl;

[0121] R 49 and R 50 are each independently selected from H and C1-C10 alkyl; or R 49 and R50 together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring optionally substituted with one or more C1-C10 alkyl groups,

[0122] The condition is that when R 51 is Cl and R 52 -R 55 is H, and R 49 or R 50 When H, R 49 or R 50 The other one is a C2-C10 alkyl group.

[0123] In some embodiments, the compound provided herein is selected from:

[0124]

[0125] In some embodiments, the compound provided herein is selected from:

[0126]

[0127] In another aspect, provided herein is a method of treating depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, the method generally comprising administering to the subject a compound:

[0128]

[0129] In another aspect, provided herein are compositions comprising a compound having the general structure (VI):

[0130]

[0131] wherein R1 is selected from phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of formula (VII);

[0132] Wherein when R1 is phenyl;

[0133] R2 and R3 are independently selected from H, C3, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; wherein D represents a deuterium-enriched H site; and wherein at least one of R2 and R3 is not H; or

[0134] R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0135] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0136] Wherein when R1 is a part of the general formula (VII):

[0137]

[0138] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; and wherein at least one of R2 and R3 is not H; or

[0139] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0140] R6, R7, R8, R9 and R 10 Independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 11 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 12 R 13 、-SR 14 、-SO2R 15 、-CO2R 16 、-C(=O)NR 17 R 18 ; where R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 Each is 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; wherein R6-R 10 At least one of is not H; and wherein R6 and R 10 None of them are halogens;

[0141] The condition is that when R7 is Cl and R6, R8-R 10is H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0142] The condition is that when R7 is OH and R6, R8-R 10 is H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0143] Provided that when R6, R7 or R8 is OMe and R6-R 10 When the other R2 or R3 is H, the other R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5;

[0144] Wherein when R1 is selected from thiazole, thiophene and pyridine, each is optionally replaced by one or more OH, halogen (selected from F, Cl, Br, I), -OR 19 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 20 R 21 、-SR 22 、-SO2R 23 、-CO2R 24 、-C(=O)NR 25 R 26 substituted; wherein R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 Each is 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;

[0145] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0146] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0147] or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in the compound over its opposite enantiomer.

[0148] In another aspect, is a composition comprising a carrier and a compound having the structure:

[0149]

[0150] wherein D represents a deuterium-enriched H site, and wherein the composition is enriched in the compound over its opposite enantiomer.

[0151] In another aspect, provided herein are compositions comprising a compound having the general structure (VIII):

[0152]

[0153] where R 31 and R 32 independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or

[0154] R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more linear or branched C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0155] where R 27 、R 28 、R 29 、R 30 Each is independently selected from H, linear or branched C1-C10 alkyl, F; wherein R 27 、R 28 、R 29 or R 30 At least one of is not H; or

[0156] R 27 and R 28 or R 29 and R 30 together with the carbon atom to which they are attached form a cycloalkyl ring or together with the carbon atom to which they are attached and one or more heteroatoms form a cycloheteroalkyl ring; and

[0157] where R 33 、R 34 、R 35 、R 36 and R37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47 Each is 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;

[0158] The condition is that when R 27 and R 28 One of them is Me, R 27 and R 28 The other one is H, R 29 -R 30 and R 33 -R 37 Each is H and R 31 or R 32 When H, R 31 or R 32 The other one is C2-C10 alkyl, C2-C10 haloalkyl or -R 38 -OR 39 ;

[0159] or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in the compound over its opposite enantiomer.

[0160] In another aspect, provided herein is a method of treating depression, anxious depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, the method generally comprising administering to the subject a compound of structure (IX):

[0161]

[0162] where R 48 Selected from: phenyl, thiazole, thiophene, pyridine or a moiety of formula (X):

[0163]

[0164] where R 51 and R 55 independently selected from H, OH, OMe, C1-C10 alkyl; and

[0165] where R 52 、R 53 and R 54 Each is independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1-C10 alkyl; and

[0166] where R 49 and R 50 are each independently selected from H and C1-C10 alkyl; or R 49 and R 50 Together with the nitrogen atom to which they are attached, they form a C3-C9 cycloheteroalkyl ring optionally substituted with one or more C1-C10 alkyl groups;

[0167] or a pharmaceutically acceptable salt or ester of a compound, wherein the compound is enriched over its opposite enantiomer.

[0168] In another aspect, provided herein is a method of treating depression, anxious depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, the method generally comprising administering to the subject a compound:

[0169]

[0170] In another aspect, provided herein are compositions comprising a compound having the general structure (XI):

[0171]

[0172] wherein R1 is selected from phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of formula (XII);

[0173] Wherein when R1 is phenyl;

[0174] R2 and R3 are independently selected from H, C3, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; wherein D represents a deuterium-enriched H site; and wherein at least one of R2 and R3 is not H; or

[0175] R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0176] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0177] Wherein when R1 is a moiety of the general formula (XII):

[0178]

[0179] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; and wherein at least one of R2 and R3 is not H; or

[0180] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0181] R6, R7, R8, R9 and R 10 Independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 11 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 12 R 13 、-SR 14 、-SO2R 15 、-CO2R 16 、-C(=O)NR 17 R 18 ; where R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 Each is 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; wherein R6-R 10 At least one of is not H; and wherein R6 and R 10 None of them are halogens;

[0182] The condition is that when R7 is Cl and R6, R8-R 10 is H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0183] The condition is that when R7 is OH and R6, R8-R 10 is H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0184] Provided that when R6, R7 or R8 is OMe and R6-R 10 When the other R2 or R3 is H, the other R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5;

[0185] Wherein when R1 is selected from thiazole, thiophene and pyridine, each is optionally replaced by one or more OH, halogen (selected from F, Cl, Br, I), -OR 19 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 20 R 21 、-SR 22 、-SO2R 23 、-CO2R 24 、-C(=O)NR 25 R 26 substituted; wherein R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 Each is 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;

[0186] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0187] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0188] or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in the compound over its opposite enantiomer.

[0189] In another aspect, provided herein are compositions comprising a carrier and a compound having the structure:

[0190]

[0191] wherein D represents a deuterium-enriched H site, and wherein the composition is enriched in the compound over its opposite enantiomer.

[0192] In another aspect, provided herein are compositions comprising a compound having the general structure (XIII):

[0193]

[0194] where R 31 and R 32 independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or

[0195] R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more linear or branched C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0196] where R 27 、R 28 、R 29 、R 30 Each is independently selected from H, linear or branched C1-C10 alkyl, F; wherein R 27 、R 28 、R 29 or R 30 At least one of is not H; or

[0197] R 27 and R 28 or R 29 and R 30 together with the carbon atom to which they are attached form a cycloalkyl ring or together with the carbon atom to which they are attached and one or more heteroatoms form a cycloheteroalkyl ring; and

[0198] where R 33 、R 34 、R35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47 Each is 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;

[0199] The condition is that when R 27 and R 28 One of them is Me, R 27 and R 28 The other one is H, R 29 -R 30 and R 33 -R 37 Each is H, and R 31 or R 32 When H, R 31 or R 32 The other one is C2-C10 alkyl, C2-C10 haloalkyl or -R 38 -OR 39 ;

[0200] or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in the compound over its opposite enantiomer. In another aspect, provided herein is a method of treating depression, anxious depression, mood disorders, anxiety disorders, or substance use disorders, and any symptoms or disorders associated therewith, in a subject in need thereof, the method generally comprising administering to the subject a compound of structure (XIV):

[0201]

[0202] where R 48is selected from: phenyl, thiazole, thiophene, pyridine or a moiety of formula (XV);

[0203]

[0204] where R 51 and R 55 independently selected from H, OH, OMe, C1-C10 alkyl; and

[0205] where R 52 、R 53 and R 54 Each is independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1-C10 alkyl; and

[0206] where R 49 and R 50 are each independently selected from H and C1-C10 alkyl; or R 49 and R 50 Together with the nitrogen atom to which they are attached, they form a C3-C9 cycloheteroalkyl ring optionally substituted with one or more C1-C10 alkyl groups;

[0207] or a pharmaceutically acceptable salt or ester of a compound, wherein the compound is enriched over its opposite enantiomer.

[0208] In another aspect, provided herein is a method of treating depression, anxious depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, the method generally comprising administering to the subject a compound:

[0209]

[0210] or a pharmaceutically acceptable salt or ester of a compound, wherein the compound is enriched over its opposite enantiomer.

[0211] In another aspect, provided herein are compounds having the general structure (XVI):

[0212]

[0213] where R 56 and R 57 together with the nitrogen atom to which they are attached, form a monocyclic or bicyclic C3-C8 cycloheteroalkyl ring, said ring being optionally substituted with one or more C1-C3 alkyl, F, OH, OMe or ═O, and optionally interrupted by one or more additional nitrogen or oxygen atoms; and

[0214] where R 58 、R 59 、R 60 、R61 and R 62 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 63 、-OC(=O)R 64 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 65 R 66 、-NH-C(=O)R 67 、-SR 68 、-SO2R 69 、-CO2R 70 、-C(=O)NR 71 R 72 ; where R 63 、R 64 、R 65 、R 66 、R 67 、R 68 、R 69 、R 70 、R 71 and R 72 Each is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl;

[0215] The condition is that when R 56 and R 57 When together with the nitrogen atom to which they are attached form an unsubstituted piperidine ring, R 58 、R 59 、R 60 、R 61 and R 62 At least one of them is not H;

[0216] or a pharmaceutically acceptable salt or ester thereof.

[0217] In another aspect, provided herein are compounds having the general structure (XVII):

[0218]

[0219] where R 73 and R 74 Together with the nitrogen atom to which they are attached, they form an azetidine ring, said ring being optionally substituted with one or more C1-C3 alkyl, F, OH or OMe; and

[0220] where R 75 、R 76 、R 77 、R 78 and R 79Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 80 、-OC(=O)R 81 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 82 R 83 、-NH-C(=O)R 84 、-SR 85 、-SO2R 86 、-CO2R 87 、-C(=O)NR 88 R 89 ; where R 80 、R 81 、R 82 、R 83 、R 84 、R 85 、R 86 、R 87 、R 88 and R 89 Each is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl;

[0221] or a pharmaceutically acceptable salt or ester thereof.

[0222] In another aspect, provided herein is a method of treating depression, anxious depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, the method generally comprising administering to the subject a compound disclosed herein.

[0223] In another aspect, provided herein is a method of treating depression or anxious depression in a subject in need thereof, the method generally comprising administering to the subject a compound disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0224] The subject matter considered to be the present invention is specifically pointed out and expressly claimed in the concluding portion of the specification. However, both the organization and method of operation, together with its objects, features and advantages, can be best understood by referring to the following detailed description when reading the accompanying drawings briefly described below. It should be understood that for simplicity and clarity of illustration, the elements shown in the figures are not necessarily drawn to scale. For example, for clarity, the dimensions of some elements may be exaggerated relative to other elements. In addition, where deemed appropriate, reference numerals may be repeated in the figures to indicate corresponding or similar elements.

[0225] Figure 1. X-ray crystal structure of 35R(1R)-(-)-camphorsulfonate crystals grown in toluene.

[0226] Figure 2 In rat liver microsomes (RLM), deuteration of compounds 14R and 14S at the N-methyl group (as in compounds 88R and 88S, respectively) attenuated the formation of metabolites 11R and 11S, respectively. The effect of deuteration of the R isomer was more pronounced. Compounds 88R and 88S were incubated with RLM under high-activity conditions, and the concentrations of formed 11R and 11S, respectively, were determined by LC-MS / MS. All data points represent the mean ± SEM of two incubations.

[0227] Figures 3A-3G . Showed that in mice susceptible to a depressive-like phenotype after chronic social defeat stress (CSDS), 35rac had an antidepressant-like effect and was superior to 37rac ​​when compared with racemic ketamine. (3A) Scheme of CSDS model, drug treatment and behavioral testing. CSDS was performed from day 1 to day 10, and the social interaction test (SIT) was performed on day 11. On day 12, saline (10 mL / kg), racemic ketamine (10 mg / kg), 37rac ​​(10 mg / kg and 30 mg / kg) or 35rac (10 mg / kg) was administered ip to CSDS-sensitive mice. Locomotion (LMT) and tail suspension test (TST) were performed 1 h and 3 h after injection, respectively. Forced swim test (FST) was performed 1 day after injection. Sucrose preference test (SPT) was performed 2, 4 and 7 days after injection. (3B) LMT (one-way ANOVA, F 5,50 =0.691, P=0.633). (3C)TST(F 5,50 =15.481, P<0.001). (3D)FST(F 5,50 =10.343, P<0.001). (3E) SPT (Day 14) (F 5,50 =6.670, P<0.001). (3F) SPT (Day 16) (F 5,50 =14.962, P<0.001). (3G) SPT (Day 19) (F 5,50 =11.310, P<0.001). Data are shown as mean ± SEM (n=8-12). *p<0.05, **p<0.01, ***p<0.001. ns=not significant, p>0.05.

[0228] Figures 4A-4G.Show the antidepressant-like effects of 35R vs. 35S in mice susceptible to a depressive-like phenotype after chronic social defeat stress (CSDS). (4A) Scheme of CSDS model, drug treatment and behavioral testing. CSDS was performed from day 1 to day 10, and the social interaction test (SIT) was performed on day 11. On day 12, saline (10 mL / kg), 35R (14.4 mg / kg) or 35S (14.4 mg / kg) was administered ip to CSDS-sensitive mice. Locomotor movement (LMT) and tail suspension test (TST) were performed 1 h and 3 h after injection, respectively. Forced swimming test (FST) was performed 1 day after injection. Sucrose preference test (SPT) was performed 2, 4 and 7 days after injection. (4B) LMT (single-factor ANOVA: F 3,28 =0.296, p=0.828). (4C)TST(F 3,28 =12.550, p<0.001). (4D)FST(F 3,28 =10.551, p<0.001). (4E) SPT (Day 14) (F 3,28 =7.062, p<0.001). (4F) SPT (Day 16) (F 3,28 =5.864, p<0.001). (4G) SPT (Day 19) (F 3,28 =17.874, p < 0.001). Data are shown as mean ± SEM (n = 8). *p < 0.05, **p < 0.01, ***p < 0.001. ns = not significant, p > 0.05.

[0229] Figure 5 Results for 2rac and 14rac in the forced swim test model are shown. Mice were treated with the drugs at the specified doses, and 30 minutes later, they were placed in the FST tank, and the cumulative duration of immobility was quantified throughout the 6-minute test session. Compounds 2rac and 14rac reduced immobility time and had a stronger effect than the control antidepressant imipramine. The other tested compounds had no effect. Unpaired two-tailed t-test (not corrected for multiple comparisons): **p<0.01, *p<0.05, relative to vehicle. n=10 per treatment. All values ​​are expressed as mean ± SEM.

[0230] Figure 6The antidepressant-like effect of compound 14rac in the forced swim test (FST) is shown. Mice were treated with drugs at specified doses, and 2 hours later, they were placed in the FST tank, and the cumulative duration of immobility was quantified in the last 4 minutes of the test session. Compound 14rac reduced the immobility time and had a stronger and more effective effect than racemic ketamine (rac-ketamine). Unpaired two-tailed t-test (not corrected for multiple comparisons): **p<0.01, *p<0.05, relative to vehicle. Except for the vehicle group and the rac-ketamine group (which represent n=20 per treatment), n=10 was treated each time. All values ​​are expressed as mean ± SEM.

[0231] Figure 7 . Indicates the activity of the compound on duration or immobility in the forced swim test (FST) of rats 23.5 h after treatment. For clarity, the data have been divided into two graphs, but the two graphs represent the same experiment and the vehicle, desipramine and ketamine groups in the two graphs are the same. One-way ANOVA: F 25,254 =9.163, p<0.0001. ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05 vs. vehicle. Except for the vehicle group and the desipramine group (which represent n=20 per treatment), n=10 per treatment. All values ​​are expressed as mean ± SEM.

[0232] Figure 8 Shows certain disclosed compounds and their effects on swimming behavior in the forced swim test (FST) of rats 23.5 h after treatment. For clarity, the data have been separated into two graphs, but the two graphs represent the same experiment, and the vehicle, desipramine, and ketamine groups in the two graphs are the same. One-way ANOVA: F 25,254 =3.862, p<0.0001. ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05 vs. vehicle. Except for the vehicle group and the desipramine group (which represent n=20 per treatment), n=10 per treatment. All values ​​are expressed as mean ± SEM.

[0233] Figure 9 . Shows certain disclosed compounds and their effects on increasing climbing behavior in the forced swim test (FST) of rats 23.5 hours after treatment. For clarity, the data have been separated into two graphs, but the two graphs represent the same experiment, and the vehicle, desipramine, and ketamine groups in the two graphs are the same. One-way ANOVA: F 25,254=3.048, p<0.0001. ***p<0.001, **p<0.01, *p<0.05 vs. vehicle. Except for the vehicle group and the desipramine group (which represent n=20 per treatment), n=10 per treatment. All values ​​are expressed as mean ± SEM.

[0234] Figure 10 Compound 14S induces significant preference in the conditioned place preference test of mice. One-way ANOVA: F 4,45 =4.399, p=0.0044. **p<0.01, *p<0.05 vs. saline vehicle. n=10 per treatment. All values ​​are expressed as mean ± SEM.

[0235] Figure 11 Compound 14R did not induce either preference or aversion in the conditioned place preference test in mice. Single-factor ANOVA: A:F 4,43 =4.559, p=0.0037. **p<0.01 vs. saline vehicle. n=10 per treatment. All values ​​are expressed as mean ± SEM. DETAILED DESCRIPTION

[0236] In the following detailed description, numerous specific details are set forth 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 cases, well-known methods, procedures, and components have not been described in detail in order to avoid obscuring the present invention.

[0237] In one aspect, provided herein are compounds having the general structure (I):

[0238]

[0239] wherein R1 is selected from phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of formula (II);

[0240] wherein when R1 is phenyl, then R2 and R3 are independently selected from H, C3, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; wherein D represents a deuterium-enriched H site; provided that one or more of R2 and R3 is not H; or

[0241] R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0242] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0243] Wherein when R1 is a part of the general formula (II):

[0244]

[0245] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; provided that one or more of R2 and R3 is not H; or

[0246] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0247] Among them, R6, R7, R8, R9 and R 10 Independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 11 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 12 R 13 、-SR 14 、-SO2R 15 、-CO2R 16 、-C(=O)NR 17 R 18 ; where R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 Each is 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;

[0248] The condition is R6-R 10 One or more of is not H; or

[0249] The condition is that when R6 is Cl and R7-R 10 is H or when R7 is Cl and R6, R8-R 10is H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0250] The condition is that when R7 is OH and R6, R8-R 10 is H, and when R2 or R3 is H, the other of R2 or R3 is a linear or branched C3-C10 alkyl group, a C2-C10 haloalkyl group or -R4-O-R5; or

[0251] Provided that when R6, R7 or R8 is OMe and R6-R 10 When the other R2 or R3 is H, the other R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5;

[0252] Wherein when R1 is selected from thiazole, thiophene, pyridine, each is optionally replaced by one or more OH, halogen (selected from F, Cl, Br, I), -OR 19 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 20 R 21 、-SR 22 、-SO2R 23 、-CO2R 24 、-C(=O)NR 25 R 26 Substitution; wherein R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 Each is 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;

[0253] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0254] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0255] In some embodiments, the compounds provided herein have the general structure (Ia):

[0256]

[0257] wherein R2 and R3 are independently selected from H, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; with the proviso that one or more of R2 and R3 is not H; or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein 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; said ring being optionally substituted with one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0258] In some embodiments, the compounds provided herein have the general structure (Ib):

[0259]

[0260] wherein R3 is C1-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; and wherein R6, R7, R8, R9 and R 10 Independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 11 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 12 R 13 、-SR 14 、-SO2R 15 、-CO2R 16 、-C(=O)NR 17 R 18 ; where R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 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 R6-R 10 One or more of them is not H; or when R6 is Cl and R7-R10 When R7 is Cl and R6, R8-R 10 When R7 is OH and R6, R8-R 10 When R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5.

[0261] In some embodiments, the compounds provided herein have the general structure (I), wherein R1 is selected from thiazole, thiophene, pyridine; each optionally replaced by one or more OH, halogen (selected from F, Cl, Br, I), -OR 19 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 20 R 21 、-SR 22 、-SO2R 23 、-CO2R 24 、-C(=O)NR 25 R 26 substituted; wherein R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 R2 and R3 are 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; wherein 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 is optionally substituted with one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0262] In some embodiments, the compounds provided herein have the general structure (Ia):

[0263]

[0264] wherein R2 and R3 are independently selected from H, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein 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 not H.

[0265] In some embodiments, the compounds provided herein have the general structure (Ia):

[0266]

[0267] wherein R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

[0268] In some embodiments, the compounds provided herein have the general structure (Ia):

[0269]

[0270] wherein R2 and R3 together with the nitrogen ring to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0271] In some embodiments, the compounds provided herein have the general structure (Ia):

[0272]

[0273] wherein R2 is H and R3 is selected from branched or cyclic C3 alkyl, C4-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0274] In some embodiments, the compounds provided herein have the general structure (Ia):

[0275]

[0276] wherein R2 and R3 are independently selected from C2-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0277] In some embodiments, the compounds provided herein have the general structure (Ia):

[0278]

[0279] 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 with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0280] In some embodiments, the compounds provided herein have the general structure (Ib):

[0281]

[0282] Among them, R6, R7, R8, R9 and R 10 One or more of them is OH, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; provided that when R7 is OH and R6, R8-R 10 When it is H, then R3 is a C3-C10 alkyl group.

[0283] In some embodiments, the compounds provided herein have the general structure (Ib):

[0284]

[0285] Among them, R6, R7, R8, R9 and R 10 One or more of them is halogen (selected from F, Cl, Br, I), R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; provided that when R6 is Cl and R7-R 10 is H or when R7 is Cl and R6, R8-R 10 When it is H, then R3 is a C3-C10 alkyl group.

[0286] In some embodiments, the compounds provided herein have the general structure (Ib):

[0287]

[0288] Among them, R6, R7, R8, R9 and R 10 wherein one or more of them is OMe, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; provided that when R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is a C3-C10 alkyl group.

[0289] In some embodiments, the compounds provided herein have the general structure (Ib):

[0290]

[0291] Among them, R6, R7, R8, R9 and R 10 One or more of them is F, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

[0292] In some embodiments, the compounds provided herein have the general structure (Ib):

[0293]

[0294] Among them, R6, R7, R8, R9 and R 10 One or more of them is Me, R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

[0295] In some embodiments, the compounds provided herein have the general structure (Ib):

[0296]

[0297] Among them, R6, R7, R8, R9 and R 10 One or more of them is OH, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; provided that when R7 is OH and R6, R8-R 10 When it is H, then R3 is a C3-C5 alkyl group.

[0298] In some embodiments, the compounds provided herein have the general structure (Ib):

[0299]

[0300] Among them, R6, R7, R8, R9 and R 10 wherein one or more of the components is OMe, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; provided that when R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is a C3-C5 alkyl group.

[0301] In some embodiments, the compounds provided herein have the general structure (Ib):

[0302]

[0303] Among them, R6, R7, R8, R9 and R 10 One or more of them is F, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0304] In some embodiments, the compounds provided herein have the general structure (Ib):

[0305]

[0306] Among them, R6, R7, R8, R9 and R 10 One or more of them is Me, R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0307] In some embodiments, the compounds provided herein have the general structure (Ic):

[0308]

[0309] Among them, R6, R7, R8, R9 and R 10 wherein one or more is OH, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein 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; said ring being optionally substituted with one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0310] In some embodiments, the compounds provided herein have the general structure (Ic):

[0311]

[0312] Among them, R6, R7, R8, R9 and R 10 wherein one or more is OMe, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein 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; said ring being optionally substituted with one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0313] In some embodiments, the compounds provided herein have the general structure (Ic):

[0314]

[0315] Among them, R6, R7, R8, R9 and R 10 wherein one or more is F, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein 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; said ring being optionally substituted with one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0316] In some embodiments, the compounds provided herein have the general structure (Ic):

[0317]

[0318] Among them, R6, R7, R8, R9 and R 10 wherein one or more is Me, R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein 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; said ring being optionally substituted with one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

[0319] In some embodiments, the compound provided herein is selected from:

[0320]

[0321]

[0322] In some embodiments, the compound provided herein is selected from:

[0323] In another aspect, provided herein are compositions comprising a carrier and a compound having the structure:

[0324]

[0325] where D represents a deuterium-rich H site.

[0326] In some embodiments, each D represents a deuterium-enriched H site and the deuterium level at each deuterium-enriched H site of the compound is 0.02% to 100%. In some embodiments, each D represents a deuterium-enriched H site and the deuterium level at each deuterium-enriched H site of the compound is 20%-100%, 50%-100%, 70%-100%, 90%-100%, 97%-100%, or 99%-100%.

[0327] In another aspect, provided herein are compounds having the general structure (III):

[0328]

[0329] where R 31 and R 32 Each is H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring is optionally substituted with one or more linear or branched C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and wherein R 27 、R 28 、R 29 、R 30 Each is independently selected from H, linear or branched C1-C10 alkyl, F, or R 27 and R 28 or R 29 and R 30 Together with the carbon atom to which they are attached, they form a cycloalkyl ring or together with the carbon atom to which they are attached and one or more heteroatoms, they form a cycloheteroalkyl ring; and wherein R 33 、R 34 、R 35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47are 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 R 27 、R 28 、R 29 or R 30 At least one of them is not H; or if R 27 and R 28 One of them is Me and R 27 and R 28 When the other one is H, then R 32 is C2-C10 alkyl, C2-C10 haloalkyl or -R 38 -OR 39 .

[0330] In some embodiments, the compounds provided herein have the general structure (III):

[0331]

[0332] where R 31 and R 32 Each is H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring is optionally substituted with one or more linear or branched C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and wherein R 27 and R 28 is fluorine and R 29 and R 30 is H; and wherein R 33 、R 34 、R 35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47 Each is 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.

[0333] In some embodiments, the compounds provided herein have the general structure (III):

[0334]

[0335] where R 31 and R 32 Each is H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring is optionally substituted with one or more linear or branched C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and wherein R 27 and R 28 Together with the carbon and oxygen atoms to which they are attached, they form an oxetane ring; and wherein R 29 and R 30 is H; and wherein R 33 、R 34 、R 35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R43 、R 44 、R 45 、R 46 and R 47 Each is 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.

[0336] In some embodiments, the compound provided herein is selected from:

[0337]

[0338]

[0339] In another aspect, provided herein is a method of treating depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, the method generally comprising administering to the subject a compound of structure (IV):

[0340]

[0341] where R 48 is selected from: phenyl, thiazole, thiophene, pyridine or a moiety of formula (V);

[0342]

[0343] where R 51 、R 52 、R 53 、R 54 and R 55 Each is independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1-C10 alkyl;

[0344] R 49 and R 50 are each independently selected from H and C1-C10 alkyl; or R 49 and R 50 together with the nitrogen atom to which they are attached, form a C3-C9 cycloheteroalkyl ring optionally substituted with one or more C1-C10 alkyl groups,

[0345] The condition is that when R 51 is Cl and R 52 -R 55 is H, and R 49 or R 50 When H, R 49 or R 50 The other one is a C2-C10 alkyl group.

[0346] In some embodiments, the compound provided herein is selected from:

[0347]

[0348] In some embodiments, the compound provided herein is selected from:

[0349]

[0350] In another aspect, provided herein are methods of treating depression, mood disorders, anxiety disorders, or substance use disorders, and any symptoms or disorders associated therewith, in a subject in need thereof, the methods generally comprising administering to the subject a compound:

[0351]

[0352] In another aspect, provided herein are compositions comprising a compound having the general structure (VI):

[0353]

[0354] wherein R1 is selected from phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of formula (VII);

[0355] Wherein when R1 is phenyl;

[0356] R2 and R3 are independently selected from H, C3, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; wherein D represents a deuterium-enriched H site; and wherein at least one of R2 and R3 is not H; or

[0357] R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0358] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0359] Wherein when R1 is a part of the general formula (VII):

[0360]

[0361] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; and wherein at least one of R2 and R3 is not H; or

[0362] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0363] R6, R7, R8, R9 and R 10 Independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 11 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 12 R 13 、-SR 14 、-SO2R 15 、-CO2R 16 、-C(=O)NR 17 R 18 ; where R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 Each is 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; wherein R6-R 10 At least one of is not H; and wherein R6 and R 10 None of them are halogens;

[0364] The condition is that when R7 is Cl and R6, R8-R 10 is H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0365] The condition is that when R7 is OH and R6, R8-R 10 is H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0366] Provided that when R6, R7 or R8 is OMe and R6-R 10When the other R2 or R3 is H, the other R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5;

[0367] Wherein when R1 is selected from thiazole, thiophene and pyridine, each is optionally replaced by one or more OH, halogen (selected from F, Cl, Br, I), -OR 19 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 20 R 21 、-SR 22 、-SO2R 23 、-CO2R 24 、-C(=O)NR 25 R 26 Substitution; wherein R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 Each is 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;

[0368] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0369] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0370] or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in the compound over its opposite enantiomer.

[0371] In some embodiments, the compound has the general structure (VIa):

[0372]

[0373] wherein R2 and R3 are independently selected from H, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; and wherein at least one of R2 and R3 is not H; or

[0374] R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0375] R2 and R3 together with the nitrogen ring to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0376] In some embodiments, the compound has the general structure (VIb):

[0377]

[0378] wherein R3 is C1-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; and

[0379] Among them, R6, R7, R8, R9 and R 10 Independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 11 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 12 R 13 、-SR 14 、-SO2R 15 、-CO2R 16 、-C(=O)NR 17 R 18 ; where R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 Each is 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; wherein R6-R 10 At least one of is not H; and wherein R6 and R 10 None of them are halogens;

[0380] The condition is that when R7 is Cl and R6, R8-R 10 When is H, then R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0381] The condition is that when R7 is OH and R6, R8-R 10 When is H, then R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0382] Provided that when R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5.

[0383] In some embodiments, the compound has the general structure (VI):

[0384]

[0385] wherein R1 is selected from thiazole, thiophene and pyridine; each optionally substituted by one or more OH, halogen (selected from F, Cl, Br, I), -OR 19 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 20 R 21 、-SR 22 、-SO2R 23 、-CO2R 24 、-C(=O)NR 25 R 26 substituted; wherein R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 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

[0386] wherein R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0387] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0388] In some embodiments, the compound has the general structure (VIa):

[0389]

[0390] wherein R2 and R3 are independently selected from H, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; wherein at least one of R2 and R3 is not H.

[0391] In some embodiments, the compound has the general structure (VIa):

[0392]

[0393] wherein R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

[0394] In some embodiments, the compound has the general structure (VIa):

[0395]

[0396] wherein R2 and R3 together with the nitrogen ring to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0397] In some embodiments, the compound has the general structure (VIa):

[0398]

[0399] wherein R2 is H and R3 is selected from branched or cyclic C3 alkyl, C4-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0400] In some embodiments, the compound has the general structure (VIa):

[0401]

[0402] wherein R2 and R3 are independently selected from C2-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0403] In some embodiments, the compound has the general structure (VIa):

[0404]

[0405] 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 with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0406] In some embodiments, the compound has the general structure (VIb):

[0407]

[0408] Among them, R6, R7, R8, R9 and R 10 One or more of is OH; and

[0409] wherein R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl;

[0410] The condition is that when R7 is OH and R6, R8-R 10 When it is H, R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5.

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

[0412]

[0413] wherein one or more of R7, R8 and R9 is halogen (selected from F, Cl, Br, I); and

[0414] wherein R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl;

[0415] The condition is that when R7 is Cl and R6, R8-R 10 When it is H, R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5.

[0416] In some embodiments, the compound has the general structure (VIb):

[0417]

[0418] Among them, R6, R7, R8, R9 and R 10 One or more of is OMe; and

[0419] wherein R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl;

[0420] Provided that when R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5.

[0421] In some embodiments, the compound has the general structure (VIb):

[0422]

[0423] wherein one or more of R7, R8 and R9 is F; and

[0424] wherein R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

[0425] In some embodiments, the compound has the general structure (VIb):

[0426]

[0427] Among them, R6, R7, R8, R9 and R 10 One or more of is Me; and

[0428] wherein R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

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

[0430]

[0431] Among them, R6, R7, R8, R9 and R 10 One or more of is OH; and

[0432] wherein R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl;

[0433] The condition is that when R7 is OH and R6, R8-R 10 When it is H, R3 is C3-C5 alkyl, C2-C5 fluoroalkyl or -R4-O-R5.

[0434] In some embodiments, the compound has the general structure (VIb):

[0435]

[0436] Among them, R6, R7, R8, R9 and R 10 One or more of is OMe; and

[0437] wherein R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl;

[0438] Provided that when R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is C3-C5 alkyl, C2-C5 fluoroalkyl or -R4-O-R5.

[0439] In some embodiments, the compound has the general structure (VIb):

[0440]

[0441] wherein one or more of R7, R8 or R9 is F; and

[0442] wherein R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0443] In some embodiments, the compound has the general structure (VIb):

[0444]

[0445] Among them, R6, R7, R8, R9 and R 10 One or more of is Me; and

[0446] wherein R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

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

[0448]

[0449] Among them, R6, R7, R8, R9 and R 10 One or more of is OH; and

[0450] wherein R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; or

[0451] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0452] In some embodiments, the compound has the general structure (VIc):

[0453]

[0454] Among them, R6, R7, R8, R9 and R 10 One or more of is OMe; and

[0455] wherein R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; or

[0456] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0457] In some embodiments, the compound has the general structure (VIc):

[0458]

[0459] wherein one or more of R7, R8 and R9 is F; and

[0460] wherein R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; or

[0461] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0462] In some embodiments, the compound has the general structure (VIc):

[0463]

[0464] Among them, R6, R7, R8, R9 and R 10 One or more of is Me; and

[0465] wherein R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; or

[0466] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0467] In some embodiments, the compound is selected from:

[0468]

[0469]

[0470] In some embodiments, the compound is selected from:

[0471]

[0472] In another aspect, provided herein are compositions comprising a carrier and a compound having the structure:

[0473]

[0474] wherein D represents a deuterium-enriched H site, and wherein the composition is enriched in the compound over its opposite enantiomer.

[0475] In some embodiments, each D represents a deuterium-enriched H site and the deuterium level at each deuterium-enriched H site of the compound is from 0.02% to 100%.

[0476] In some embodiments, each D represents a deuterium-enriched H site and the deuterium level at each deuterium-enriched H site of the compound is 20%-100%, 50%-100%, 70%-100%, 90%-100%, 97%-100%, or 99%-100%.

[0477] In another aspect, provided herein are compositions comprising a compound having the general structure (VIII):

[0478]

[0479] where R 31 and R 32 independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38-OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or

[0480] R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more linear or branched C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0481] where R 27 、R 28 、R 29 、R 30 Each is independently selected from H, linear or branched C1-C10 alkyl, F; wherein R 27 、R 28 、R 29 or R 30 At least one of is not H; or

[0482] R 27 and R 28 or R 29 and R 30 together with the carbon atom to which they are attached form a cycloalkyl ring or together with the carbon atom to which they are attached and one or more heteroatoms form a cycloheteroalkyl ring; and

[0483] where R 33 、R 34 、R 35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47Each is 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;

[0484] The condition is that when R 27 and R 28 One of them is Me, R 27 and R 28 The other one is H, R 29 -R 30 and R 33 -R 37 Each is H and R 31 or R 32 When H, R 31 or R 32 The other one is C2-C10 alkyl, C2-C10 haloalkyl or -R 38 -OR 39 ;

[0485] or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in the compound over its opposite enantiomer.

[0486] In some embodiments, the compound has the general structure (VIII):

[0487]

[0488] where R 31 and R 32 independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or

[0489] R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more linear or branched C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0490] where R 27 and R 28 is fluorine and R 29 and R 30 is H; and

[0491] where R 33 、R 34 、R 35 、R 36 and R37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47 Each is 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.

[0492] In some embodiments, the compound has the general structure (VIII):

[0493]

[0494] where R 31 and R 32 independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or

[0495] R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more linear or branched C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0496] where R 27 and R 28 Together with the carbon and oxygen atoms to which they are attached, they form an oxetane ring; and

[0497] where R 29 and R 30 is H; and

[0498] where R 33 、R34 、R 35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47 Each is 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.

[0499] In some embodiments, the compound is selected from:

[0500]

[0501]

[0502] In some embodiments, the compound is selected from:

[0503]

[0504] In some embodiments, the optical purity of the compound is >5%, >25%, >50%, >75%, >90%, >95%, >97%, >98%, or >99%.

[0505] In another aspect, provided herein is a method of treating depression, anxious depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, comprising administering to the subject a composition comprising a compound of structure (IX):

[0506]

[0507] where R 48 is selected from: phenyl, thiazole, thiophene, pyridine or a moiety of formula (X);

[0508]

[0509] where R 51 and R 55 independently selected from H, OH, OMe, C1-C10 alkyl; and

[0510] where R 52 、R 53 and R 54 Each is independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1-C10 alkyl; and

[0511] where R 49 and R 50 are each independently selected from H and C1-C10 alkyl; or R 49 and R 50 Together with the nitrogen atom to which they are attached, they form a C3-C9 cycloheteroalkyl ring optionally substituted with one or more C1-C10 alkyl groups;

[0512] or a pharmaceutically acceptable salt or ester of a compound, wherein the compound is enriched over its opposite enantiomer.

[0513] In some embodiments, the compound is selected from:

[0514]

[0515]

[0516] In some embodiments, the compound has the structure:

[0517]

[0518] In some embodiments, the disorder to be treated in the subject is depression or anxious depression.In some embodiments, the composition is administered orally.

[0519] In another aspect, provided herein is a method of treating depression, anxious depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, comprising administering to the subject a composition comprising:

[0520]

[0521] or a pharmaceutically acceptable salt or ester of a compound, wherein the compound is enriched over its opposite enantiomer.

[0522] In another aspect, provided herein are compositions comprising a compound having the general structure (XI):

[0523]

[0524] wherein R1 is selected from phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of formula (XII);

[0525] Wherein when R1 is phenyl;

[0526] R2 and R3 are independently selected from H, C3, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; wherein D represents a deuterium-enriched H site; and wherein at least one of R2 and R3 is not H; or

[0527] R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl-, R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0528] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0529] Wherein when R1 is a moiety of the general formula (XII):

[0530]

[0531] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; and wherein at least one of R2 and R3 is not H; or

[0532] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0533] R6, R7, R8, R9 and R 10 Independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 11 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 12 R 13 、-SR 14 、-SO2R 15 、-CO2R 16、-C(=O)NR 17 R 18 ; where R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 Each is 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; wherein R6-R 10 At least one of is not H; and wherein R6 and R 10 None of them are halogens;

[0534] The condition is that when R7 is Cl and R6, R8-R 10 When R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0535] The condition is that when R7 is OH and R6, R8-R 10 is H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0536] Provided that when R6, R7 or R8 is OMe and R6-R 10 When the other R2 or R3 is H, the other R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5;

[0537] Wherein when R1 is selected from thiazole, thiophene and pyridine, each is optionally replaced by one or more OH, halogen (selected from F, Cl, Br, I), -OR 19 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 20 R 21 、-SR 22 、-SO2R 23 、-CO2R 24 、-C(=O)NR 25 R 26 substituted; wherein R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R26 Each is 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;

[0538] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0539] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring is optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0540] or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in the compound over its opposite enantiomer.

[0541] In some embodiments, the compound has the general structure (XIa):

[0542]

[0543] wherein R2 and R3 are independently selected from H, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; and wherein at least one of R2 and R3 is not H; or

[0544] R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0545] R2 and R3 together with the nitrogen ring to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0546] In some embodiments, the compound has the general structure (XIb):

[0547]

[0548] wherein R3 is C1-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; and

[0549] Among them, R6, R7, R8, R9 and R10 Independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 11 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 12 R 13 、-SR 14 、-SO2R 15 、-CO2R 16 、-C(=O)NR 17 R 18 ; where R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 Each is 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; wherein R6-R 10 At least one of is not H; and wherein R6 and R 10 None of them are halogens;

[0550] The condition is that when R7 is Cl and R6, R8-R 10 When is H, then R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0551] The condition is that when R7 is OH and R6, R8-R 10 When is H, then R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5; or

[0552] Provided that when R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5.

[0553] In some embodiments, the compound has the general structure (XI):

[0554]

[0555] wherein R1 is selected from thiazole, thiophene and pyridine; each optionally substituted by one or more OH, halogen (selected from F, Cl, Br, I), -OR 19 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 20 R21 、-SR 22 、-SO2R 23 、-CO2R 24 、-C(=O)NR 25 R 26 substituted; wherein R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 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

[0556] wherein R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0557] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0558] In some embodiments, the compound has the general structure (XIa):

[0559]

[0560] wherein R2 and R3 are independently selected from H, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; wherein at least one of R2 and R3 is not H.

[0561] In some embodiments, the compound has the general structure (XIa):

[0562]

[0563] wherein R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

[0564] In some embodiments, the compound has the general structure (XIa):

[0565]

[0566] wherein R2 and R3 together with the nitrogen ring to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0567] In some embodiments, the compound has the general structure (XIa):

[0568]

[0569] wherein R2 is H and R3 is selected from branched or cyclic C3 alkyl, C4-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0570] In some embodiments, the compound has the general structure (XIa):

[0571]

[0572] wherein R2 and R3 are independently selected from C2-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0573] In some embodiments, the compound has the general structure (XIa):

[0574]

[0575] 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 with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0576] In some embodiments, the compound has the general structure (XIb):

[0577]

[0578] Among them, R6, R7, R8, R9 and R 10 One or more of is OH; and

[0579] wherein R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl;

[0580] The condition is that when R7 is OH and R6, R8-R 10When it is H, R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5.

[0581] In some embodiments, the compound has the general structure (XIb):

[0582]

[0583] wherein one or more of R7, R8 and R9 is halogen (selected from F, Cl, Br, I); and

[0584] wherein R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl;

[0585] The condition is that when R7 is Cl and R6, R8-R 10 When it is H, R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5.

[0586] In some embodiments, the compound has the general structure (XIb):

[0587]

[0588] Among them, R6, R7, R8, R9 and R 10 One or more of is OMe; and

[0589] wherein R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl;

[0590] Provided that when R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is C3-C10 alkyl, C2-C10 haloalkyl or -R4-O-R5.

[0591] In some embodiments, the compound has the general structure (XIb):

[0592]

[0593] wherein one or more of R7, R8 and R9 is F; and

[0594] wherein R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

[0595] In some embodiments, the compound has the general structure (XIb):

[0596]

[0597] Among them, R6, R7, R8, R9 and R 10 One or more of is Me; and

[0598] wherein R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl.

[0599] In some embodiments, the compound has the general structure (XIb):

[0600]

[0601] Among them, R6, R7, R8, R9 and R 10 One or more of is OH; and

[0602] wherein R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl;

[0603] The condition is that when R7 is OH and R6, R8-R 10 When it is H, R3 is C3-C5 alkyl, C2-C5 fluoroalkyl or -R4-O-R5.

[0604] In some embodiments, the compound has the general structure (XIb):

[0605]

[0606] Among them, R6, R7, R8, R9 and R 10 One or more of is OMe; and

[0607] wherein R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl;

[0608] Provided that when R6, R7 or R8 is OMe and R6-R 10 When the other is H, R3 is C3-C5 alkyl, C2-C5 fluoroalkyl or -R4-O-R5.

[0609] In some embodiments, the compound has the general structure (XIb):

[0610]

[0611] wherein one or more of R7, R8 or R9 is F; and

[0612] wherein R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0613] In some embodiments, the compound has the general structure (XIb):

[0614]

[0615] Among them, R6, R7, R8, R9 and R 10 One or more of is Me; and

[0616] wherein R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl.

[0617] In some embodiments, the compound has the general structure (XIc):

[0618]

[0619] Among them, R6, R7, R8, R9 and R 10 One or more of is OH; and

[0620] wherein R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; or

[0621] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0622] In some embodiments, the compound has the general structure (XIc):

[0623]

[0624] Among them, R6, R7, R8, R9 and R 10 One or more of is OMe; and

[0625] wherein R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; or

[0626] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0627] In some embodiments, the compound has the general structure (XIc):

[0628]

[0629] wherein one or more of R7, R8 and R9 is F; and

[0630] wherein R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; or

[0631] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0632] In some embodiments, the compound has the general structure (XIc):

[0633]

[0634] Among them, R6, R7, R8, R9 and R 10 One or more of is Me; and

[0635] wherein R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; wherein R4 is C2-C5 alkylene and R5 is selected from H and C1-C5 alkyl; or

[0636] R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[0637] In some embodiments, the compound is selected from:

[0638]

[0639]

[0640] In some embodiments, the compound is selected from:

[0641]

[0642] In another aspect, provided herein are compositions comprising a carrier and a compound having the structure:

[0643]

[0644] wherein D represents a deuterium-enriched H site, and wherein the composition is enriched in the compound over its opposite enantiomer.

[0645] In some embodiments, each D represents a deuterium-enriched H site and the deuterium level at each deuterium-enriched H site of the compound is from 0.02% to 100%.

[0646] In some embodiments, each D represents a deuterium-enriched H site and the deuterium level at each deuterium-enriched H site of the compound is 20%-100%, 50%-100%, 70%-100%, 90%-100%, 97%-100%, or 99%-100%.

[0647] In another aspect, provided herein are compositions comprising a compound having the general structure (XIII):

[0648]

[0649] where R 31 and R 32 independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or

[0650] R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more linear or branched C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0651] where R 27 、R 28 、R 29 、R 30 Each is independently selected from H, linear or branched C1-C10 alkyl, F; wherein R 27 、R 28 、R 29 or R 30 At least one of is not H; or

[0652] R 27 and R 28 or R 29 and R 30together with the carbon atom to which they are attached form a cycloalkyl ring or together with the carbon atom to which they are attached and one or more heteroatoms form a cycloheteroalkyl ring; and

[0653] where R 33 、R 34 、R 35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47 Each is 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;

[0654] The condition is that when R 27 and R 28 One of them is Me, R 27 and R 28 The other one is H, R 29 -R 30 and R 33 -R 37 Each is H and R 31 or R 32 When H, R 31 or R 32 The other one is C2-C10 alkyl, C2-C10 haloalkyl or -R 38 -OR 39 ;

[0655] or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in the compound over its opposite enantiomer.

[0656] In some embodiments, the compound has the general structure (XIII):

[0657]

[0658] where R 31 and R 32 independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or

[0659] R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more linear or branched C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0660] where R 27 and R 28 is fluorine and R 29 and R 30 is H; and

[0661] where R 33 、R 34 、R 35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47 Each is 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.

[0662] In some embodiments, the compound has the general structure (XIII):

[0663]

[0664] where R 31 and R 32 independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 ; where R 38 is a C2-C10 alkylene group and R 39 selected from H and C1-C10 alkyl; or

[0665] R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a C3-C6 cycloheteroalkyl ring; said ring being optionally substituted with one or more linear or branched C1-C2 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; and

[0666] where R 27 and R 28 Together with the carbon and oxygen atoms to which they are attached, they form an oxetane ring; and

[0667] where R 29 and R 30 is H; and

[0668] where R 33 、R 34 、R 35 、R 36 and R 37 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 40 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 41 R 42 、-SR 43 、-SO2R 44 、-CO2R 45 、-C(=O)NR 46 R 47 ; where R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 and R 47 Each is 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.

[0669] In some embodiments, the compound is selected from:

[0670]

[0671]

[0672]

[0673] In some embodiments, the compound is selected from:

[0674]

[0675] In some embodiments, the optical purity of the compound is >5%, >25%, >50%, >75%, >90%, >95%, >97%, >98%, or >99%.

[0676] In some embodiments, the compositions disclosed herein are pharmaceutical compositions.

[0677] In some embodiments, the disclosed compositions are oral compositions.

[0678] In another aspect, provided herein is a method of treating depression, anxious depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, comprising administering to the subject a composition comprising a compound of structure (XIV):

[0679]

[0680] where R 48 is selected from: phenyl, thiazole, thiophene, pyridine or a moiety of formula (XV);

[0681]

[0682] where R 51 and R 55 independently selected from H, OH, OMe, C1-C10 alkyl; and

[0683] where R 52 、R 53 and R 54 Each is independently selected from H, OH, halogen (selected from F, Cl, Br, I), OMe, C1-C10 alkyl; and

[0684] where R 49 and R 50 are each independently selected from H and C1-C10 alkyl; or R 49 and R 50 Together with the nitrogen atom to which they are attached, they form a C3-C9 cycloheteroalkyl ring optionally substituted with one or more C1-C10 alkyl groups;

[0685] or a pharmaceutically acceptable salt or ester of a compound, wherein the compound is enriched over its opposite enantiomer.

[0686] In some embodiments, the compound is selected from:

[0687]

[0688] In some embodiments, the compound has the structure:

[0689]

[0690] In some embodiments, the compound has the structure:

[0691]

[0692] In some embodiments, the disorder to be treated in the subject is depression or anxious depression.

[0693] In some embodiments, the composition is administered orally.

[0694] In another aspect, provided herein is a method of treating depression, anxious depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, comprising administering to the subject a composition comprising:

[0695]

[0696] or a pharmaceutically acceptable salt or ester of a compound, wherein the compound is enriched over its opposite enantiomer.

[0697] In another aspect, provided herein are compounds having the general structure (XVI):

[0698]

[0699] where R 56 and R 57 together with the nitrogen atom to which they are attached, form a monocyclic or bicyclic C3-C8 cycloheteroalkyl ring, said ring being optionally substituted with one or more C1-C3 alkyl, F, OH, OMe or ═O, and optionally interrupted by one or more additional nitrogen or oxygen atoms; and

[0700] where R 58 、R 59 、R 60 、R 61 and R 62 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 63 、-OC(=O)R64 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 65 R 66 、-NH-C(=O)R 67 、-SR 68 、-SO2R 69 、-CO2R 70 、-C(=O)NR 71 R 72 ; where R 63 、R 64 、R 65 、R 66 、R 67 、R 68 、R 69 、R 70 、R 71 and R 72 Each is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl;

[0701] The condition is that when R 56 and R 57 When together with the nitrogen atom to which they are attached form an unsubstituted piperidine ring, R 58 、R 59 、R 60 、R 61 and R 62 At least one of them is not H;

[0702] or a pharmaceutically acceptable salt or ester thereof.

[0703] In some embodiments, the compound wherein R 56 and R 57 Together with the nitrogen atom to which they are attached, they form a piperidine ring, said ring being optionally substituted with one or more C1-C3 alkyl, F, OH, OMe or ═O; and

[0704] where R 58 、R 59 、R 60 、R 61 and R 62 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 63 、-OC(=O)R 64 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 65 R 66 、-NH-C(=O)R 67 、-SR68 、-SO2R 69 、-CO2R 70 、-C(=O)NR 71 R 72 ; where R 63 、R 64 、R 65 、R 66 、R 67 、R 68 、R 69 、R 70 、R 71 and R 72 Each is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl;

[0705] The condition is that when R 56 and R 57 When together with the nitrogen atom to which they are attached form an unsubstituted piperidine ring, R 58 、R 59 、R 60 、R 61 and R 62 At least one of them is not H;

[0706] or a pharmaceutically acceptable salt or ester thereof.

[0707] In some embodiments, the compound wherein R 56 and R 57 Together with the nitrogen atom to which they are attached, they form a pyrrolidine ring, said ring being optionally substituted with one or more C1-C3 alkyl, F, OH, OMe or ═O; and

[0708] where R 58 、R 59 、R 60 、R 61 and R 62 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 63 、-OC(=O)R 64 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 65 R 66 、-NH-C(=O)R 67 、-SR 68 、-SO2R 69 、-CO2R 70 、-C(=O)NR 71 R 72 ; where R 63 、R 64 、R65 、R 66 、R 67 、R 68 、R 69 、R 70 、R 71 and R 72 Each is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl;

[0709] or a pharmaceutically acceptable salt or ester thereof.

[0710] In some embodiments, the compound wherein R 56 and R 57 Together with the nitrogen atom to which they are attached, they form an azetidine ring, which is optionally substituted with one or more C1-C3 alkyl, F, OH, OMe, or ═O; and

[0711] where R 58 、R 59 、R 60 、R 61 and R 62 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 63 、-OC(=O)R 64 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 65 R 66 、-NH-C(=O)R 67 、-SR 68 、-SO2R 69 、-CO2R 70 、-C(=O)NR 71 R 72 ; where R 63 、R 64 、R 65 、R 66 、R 67 、R 68 、R 69 、R 70 、R 71 and R 72 Each is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl;

[0712] or a pharmaceutically acceptable salt or ester thereof.

[0713] In some embodiments, the compound wherein R 56 and R 57Together with the nitrogen atom to which they are attached, they form an azetidine ring, which is optionally substituted with one or more C1-C3 alkyl groups or F; and

[0714] where R 58 、R 59 、R 60 、R 61 and R 62 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 63 、-OC(=O)R 64 、C1-C3 alkyl、C2-C3 alkenyl、C2-C3 alkynyl、CN、CF3、OCF3、NO2、-NR 65 R 66 、-NH-C(=O)R 67 、-SR 68 、-SO2R 69 、-CO2R 70 、-C(=O)NR 71 R 72 ; where R 63 、R 64 、R 65 、R 66 、R 67 、R 68 、R 69 、R 70 、R 71 and R 72 Each is independently selected from H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl;

[0715] or a pharmaceutically acceptable salt or ester thereof.

[0716] In some embodiments, the compound is selected from:

[0717]

[0718]

[0719] or a pharmaceutically acceptable salt or ester thereof, and / or a specific S- or R-isomer thereof.

[0720] In some embodiments, the compound has the structure:

[0721]

[0722] or a pharmaceutically acceptable salt thereof.

[0723] In another aspect, provided herein are compounds having the general structure (XVII):

[0724]

[0725] where R 73 and R 74 Together with the nitrogen atom to which they are attached, they form an azetidine ring, said ring being optionally substituted with one or more C1-C3 alkyl, F, OH or OMe; and

[0726] where R 75 、R 76 、R 77 、R 78 and R 79 Each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR 80 、-OC(=O)R 81 、C1-C10 alkyl、C2-C10 alkenyl、C2-C10 alkynyl、CN、CF3、OCF3、NO2、-NR 82 R 83 、-NH-C(=O)R 84 、-SR 85 、-SO2R 86 、-CO2R 87 、-C(=O)NR 88 R 89 ; where R 80 、R 81 、R 82 、R 83 、R 84 、R 85 、R 86 、R 87 、R 88 and R 89 Each is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl;

[0727] or a pharmaceutically acceptable salt or ester thereof.

[0728] In some embodiments, the compound is selected from:

[0729]

[0730] or a pharmaceutically acceptable salt or ester thereof, and / or a specific S- or R-isomer thereof.

[0731] In another aspect, provided herein is an isolated, substantially enantiomerically pure compound selected from:

[0732]

[0733]

[0734] or a pharmaceutically acceptable salt thereof.

[0735] In another aspect, provided herein is an enantiomeric compound represented by:

[0736]

[0737]

[0738] 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.

[0739] In another aspect, provided herein is a compound selected from the group consisting of:

[0740]

[0741] In some embodiments, the compound is selected from:

[0742]

[0743] or a pharmaceutically acceptable salt thereof.

[0744] In some embodiments, the compound is

[0745] In another aspect, provided herein is a composition comprising an enantiomeric mixture of a compound selected from:

[0746]

[0747] The enantiomeric mixture has a significantly greater amount of the enantiomer with lower binding affinity at the NMDA receptor MK-801 site.

[0748] In some embodiments, the compound is selected from:

[0749]

[0750] In another aspect, provided herein is a composition comprising an enantiomeric mixture of a compound selected from:

[0751]

[0752]

[0753] The enantiomeric mixture has a significantly greater amount of the enantiomer with higher binding affinity at the NMDA receptor MK-801 site.

[0754] In another aspect, provided herein is a method of treating depression, anxious depression, mood disorders, anxiety disorders, or substance use disorders, and any symptoms or disorders associated therewith, in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound disclosed herein.

[0755] In some embodiments, the compound is selected from:

[0756]

[0757] In another aspect, provided herein is a method of treating depression, anxious depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a composition comprising an isolated, substantially enantiomerically pure compound selected from:

[0758]

[0759]

[0760] or a pharmaceutically acceptable salt thereof.

[0761] In another aspect, provided herein is a method of treating depression, anxious depression, mood disorders, anxiety disorders, or substance use disorders, and any symptoms or disorders associated therewith, in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a composition comprising a compound selected from the group consisting of:

[0762]

[0763] In some embodiments, the compound is selected from:

[0764]

[0765] In another aspect, provided herein is an isolated, substantially enantiomerically pure compound represented by:

[0766]

[0767] or a pharmaceutically acceptable salt thereof.

[0768] In another aspect, provided herein is a method of treating depression, anxious depression, a mood disorder, an anxiety disorder, or a substance use disorder, and any symptoms or disorders associated therewith, in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a composition comprising an isolated, substantially enantiomerically pure compound represented by:

[0769]

[0770] or a pharmaceutically acceptable salt thereof.

[0771] In another aspect, provided herein is a method of treating depression or anxious depression in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of an isolated, substantially enantiomerically pure compound represented by:

[0772]

[0773] or a pharmaceutically acceptable salt thereof.

[0774] In another aspect, provided herein is a compound selected from the group consisting of:

[0775]

[0776] or a pharmaceutically acceptable salt thereof.

[0777] In another aspect, provided herein is a method of treating depression or anxious depression in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound disclosed herein.

[0778] In some embodiments, the compound is administered orally.

[0779] Provided herein are methods for treating a psychiatric disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition disclosed herein. Contemplated psychiatric disorders may include depressive disorders, such as major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, disruptive mood dysregulation disorder, substance / medication-induced depressive disorder, and depressive disorder caused by another medical condition.

[0780] Also provided herein are compounds, methods, and compositions that can be used to treat refractory depression (e.g., patients with a depressive disorder that has not responded and / or has not responded to an adequate course of treatment with at least one or at least two other antidepressant compounds or therapeutic agents). As used herein, "depressive disorder" includes refractory depression.

[0781] In some embodiments, the compounds, methods, and compositions are useful for treating psychiatric disorders, including bipolar and related disorders, such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar and related disorders, and bipolar and related disorders caused by another medical condition.

[0782] In some embodiments, compound, method and composition can be used to treat psychiatric disorder, including substance-related disorder, for example, preventing substance use desire, reducing substance use desire and / or promoting substance use to stop or quit.Substance use disorder relates to the abuse of psychoactive compounds such as alcohol, caffeine, marijuana, inhalants, opioids, sedatives, hypnotic, antianxiety agents, stimulants, nicotine and tobacco. As used herein, "substance (substance)" or "substance (substances)" is addictive psychoactive compounds such as alcohol, caffeine, marijuana, hallucinogens, inhalants, opioids, sedatives, hypnotic, antianxiety agents, stimulants, nicotine and tobacco. For example, method and composition can be used to promote smoking cessation or stop opioid use.

[0783] In some embodiments, the compounds, methods, and compositions are useful for treating psychiatric disorders, including anxiety disorders, such as separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorders, and anxiety disorders caused by another medical condition.

[0784] In some embodiments, the compounds, methods, and compositions are useful for treating psychiatric disorders, including obsessive-compulsive and related disorders, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), excoriation (skin picking) disorder, substance / medication-induced obsessive-compulsive and related disorder, and obsessive-compulsive and related disorder caused by another medical condition.

[0785] In some embodiments, the compounds, methods, and compositions are useful for treating psychiatric disorders, including trauma- and stress-related disorders, such as reactive attachment disorder, disinhibited social engagement disorder, post-traumatic stress disorder, acute stress disorder, and adjustment disorder.

[0786] In some embodiments, the compounds, methods, and compositions are useful for treating psychiatric disorders, including feeding and eating disorders such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, and avoidant / restrictive food intake disorder.

[0787] In some embodiments, the compounds, methods and compositions can be used to treat psychiatric disorders, including neurocognitive disorders, such as delirium, severe neurocognitive disorder, mild neurocognitive disorder, severe or mild neurocognitive disorder due to Alzheimer's disease, severe or mild frontotemporal neurocognitive disorder, severe or mild neurocognitive disorder with Lewy bodies, severe or mild vascular neurocognitive disorder, severe or mild neurocognitive disorder due to traumatic brain injury, substance / medication-induced severe or mild neurocognitive disorder, severe or mild neurocognitive disorder due to HIV infection, severe or mild neurocognitive disorder due to prion disease, severe or mild neurocognitive disorder due to Parkinson's disease, severe or mild neurocognitive disorder due to Huntington's disease, severe or mild neurocognitive disorder due to another medical condition, and severe or mild neurocognitive disorder due to multiple etiologies.

[0788] In some embodiments, the compounds, methods, and compositions are useful for treating psychiatric disorders, including neurodevelopmental disorders, such as autism spectrum disorder, attention-deficit / hyperactivity disorder, stereotypic movement disorder, tic disorder, Tourette's Disorder, persistent (chronic) motor or vocal tic disorder, and transient tic disorder.

[0789] In some embodiments, the compounds, methods, and compositions are useful for treating psychiatric disorders, including personality disorders, such as borderline personality disorder.

[0790] In some embodiments, the compounds, methods, and compositions are useful for treating psychiatric disorders, including sexual dysfunction, such as delayed ejaculation, erectile dysfunction, female orgasmic disorder, female sexual interest / arousal disorder, genito-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation, and substance / medication-induced sexual dysfunction.

[0791] In some embodiments, the compounds, methods, and compositions are useful for treating psychiatric disorders, including gender dysphoria, such as gender dysphoria.

[0792] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound, material, composition, drug or other material that is effective to achieve a specific pharmacological and / or physiological effect, including but not limited to reducing the frequency or severity of sadness or lethargy, depressed mood, anxiety or sadness, decreased interest in all or nearly all activities, a significant increase or decrease in appetite leading to weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness, helplessness, inability to concentrate, and recurring thoughts of death or suicide; or providing a desired pharmacological and / or physiological effect, such as reducing, inhibiting or reversing one or more underlying pathophysiological mechanisms causing neurological dysfunction, modulating dopamine levels or signaling, modulating serotonin levels or signaling, modulating norepinephrine levels or signaling, modulating glutamate or GABA levels or signaling, modulating synaptic connectivity or neurogenesis in certain brain regions, or a combination thereof.

[0793] The term "therapeutic index," as used in reference to any compound and its associated therapeutic effects and side effects, refers to the ratio of the dose of the compound required to elicit a particular negative side effect to the dose of the compound required to elicit the desired therapeutic effect. For example, in the case of racemic ketamine, the antidepressant therapeutic effect and dissociative side effects occur at similar doses, and thus the compound has a therapeutic index of ~1:1 in this context. In contrast, the compounds disclosed herein may have an improved therapeutic index, e.g., 3:1, where a dose three times higher than the dose required for the antidepressant therapeutic effect is required to elicit the dissociative side effect.

[0794] In some embodiments, the methods comprise treating a psychiatric 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 can be, for example, about 0.1 to 300 mg, 0.1 to 250 mg, 0.1 to 200 mg, 0.1 to 150 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5 mg, 0.1 to 1 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 150 mg, 10 to 100 mg, 10 to 50 mg, 10 to 25 mg, 10 to 15 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 150 mg, 20 to 100 mg, 20 to 50 mg, 50 to 300 mg, 50 to 2 Examples include dosages of about 0.25, 0.5, 0.75, 1 mg, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 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.

[0795] In some embodiments, the dosage may include an amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in the range of about, for example, 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, with specific examples of dosages being 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, 10 mg, 15 mg, 0.15 mg, 0.2 mg, 10 mg, 15 mg, 0.15 mg, 0.2 mg, 10 mg, Doses of 9mg, 1.5mg, 1.0mg, 1.75mg, 2mg, 2.5mg, 2.75mg, 3mg, 3.5mg, 3.75mg, 4mg, 4.5mg, 4.75mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 10mg, 11mg, 12mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg and 200mg.

[0796] Typically, the dosage of a 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 two days, every three days, once a week, or once a month. In some embodiments, the dosage is, for example, about 1-400 mg / day, or 1-300 mg / day, or 1-250 mg / day, or 1-200 mg / day, such as 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.

[0797] In some embodiments, pharmaceutical compositions for parenteral or inhalation (e.g., sprays or mists of a compound of the present invention, or a pharmaceutically acceptable salt thereof) include a concentration of about 0.005 mg / mL to about 500 mg / mL. In some embodiments, the composition includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, at a concentration of, for example, about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 100 mg / mL, about 0.005 mg / mL to about 500 mg / mL, about 0.1 mg / mL to about 50 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 25 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, or about 0.05 mg / mL to about 1 mg / mL.

[0798] In some embodiments, the composition includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, at a concentration of, for example, about 0.05 mg / mL to about 15 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.25 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 7 mg / mL, about 1 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 5 mg / mL to about 15 mg / mL, about 5 mg / mL to 25 mg / mL, about 5 mg / mL to 50 mg / mL, or about 10 mg / mL to 100 mg / mL. In some embodiments, the pharmaceutical composition is formulated into a total volume of about, for example, 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

[0799] Typically, dosage can be administered to a subject once, twice, three times, or four times a day, every two days, every three days, twice a week, once a week, twice a month, or once a month. In some embodiments, a compound disclosed herein is administered to a subject once in the morning or once in the evening. In some embodiments, a compound disclosed herein is administered to a subject once in the morning and once in the evening. In some embodiments, a compound disclosed herein is administered to a subject three times a day (e.g., at breakfast, lunch, and dinner) at a dosage of, for example, 50 mg / administration (e.g., 150 mg / day).

[0800] 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.

[0801] 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, a total daily dose of 0.01 mg to 500 mg of a compound disclosed herein is administered to a subject once, twice, three times or four times a day. In some embodiments, the total amount administered to a subject over a 24-hour period 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, a subject can start with a low dose and gradually increase the dosage. In some embodiments, a subject can start with a high dose and reduce the dosage.

[0802] In some embodiments, a compound or composition disclosed herein is administered to a patient under the supervision of a healthcare provider.

[0803] In some embodiments, a compound or composition disclosed herein is administered to a patient under the supervision of a healthcare provider at a clinic specializing in providing psychoactive treatment.

[0804] In some embodiments, a compound or composition disclosed herein is administered to a patient under the supervision of a healthcare provider at a dose intended to induce a psychedelic experience in the subject.

[0805] In some embodiments, dosing to a patient occurs periodically under the supervision of a healthcare provider to maintain a therapeutic effect in the patient, e.g., every three days, twice a week, once a week, twice a month, once a month, three times a year, twice a year, or once a year.

[0806] In some embodiments, a compound or composition disclosed herein is self-administered by the patient at home or elsewhere away from the supervision of a healthcare provider.

[0807] In some embodiments, self-administration by the patient occurs periodically to maintain a therapeutic effect in the patient, e.g., daily, every two days, every three days, twice a week, once a week, twice a month, or once a month.

[0808] In some embodiments, the compounds or compositions disclosed herein can be administered at specific intervals. For example, during treatment, the compound or composition can be administered to the patient at intervals of, for example, every 1 year, 6 months, 90 days, 60 days, 30 days, 14 days, 7 days, 3 days, 24 hours, 12 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hour, 0.5 hour, or 0.25 hour.

[0809] In some embodiments, the compounds disclosed herein are in the form of pharmaceutically acceptable salts thereof.

[0810] In some embodiments, pharmaceutical compositions comprise one or more compounds disclosed herein.

[0811] In some embodiments, salts of the compounds disclosed herein are used in any method, use, or composition.

[0812] In some embodiments, pharmaceutically acceptable salts of the compounds disclosed herein are used in any method, use, or composition.

[0813] In some embodiments, esters of the compounds disclosed herein are used in any method, use, or composition.

[0814] Any compound disclosed herein can be used in any disclosed method, use, or composition.

[0815] Any compound used in the disclosed methods, uses, or compositions may be replaced with any other compound disclosed herein.

[0816] Any disclosed general compound can be used in any disclosed method, use, or composition.

[0817] As used herein, the terms "about" or "approximately" refer to 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, according to the practice in the art, "about" can mean within 3 or more standard deviations. Alternatively, "about" can mean a range of up to 20%, a range of up to 10%, a range of up to 5%, and / or a range of up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, such as within 5 times or within 2 times of a value. "About" and "approximately" are used interchangeably herein.

[0818] In the context of the present invention, the term "thiazole" is understood to mean a thiazole having the structure wherein its connection to the backbone of the compounds disclosed herein is through any carbon atom of the ring.

[0819] In the context of the present invention, the term "thiophene" is understood to mean a thiophene having the structure wherein its connection to the backbone of the compounds disclosed herein is through any carbon atom of the ring.

[0820] In the context of this disclosure, the term "pyridine" is understood to refer to a compound having the structure wherein its connection to the backbone of the compounds disclosed herein is through any carbon atom of the ring.

[0821] In the context of the present disclosure, the term "alkyl" is understood to mean a linear, branched or, where possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, wherein all bonds connecting the atoms are sigma bonds.

[0822] In the context of the present invention, the term "alkenyl" is understood to mean a linear, branched or, where possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, wherein at least one bond between two carbon atoms of the chain is a double (π) bond.

[0823] In the context of the present invention, the term "alkynyl" is understood to mean a linear, branched or, where possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, wherein at least one bond between two carbon atoms of the chain is a triple bond.

[0824] In the context of the present invention, the term "aryl" is understood to mean a C5 to C10 aromatic system having one or more rings.

[0825] In the context of the present disclosure, the term "heteroaryl" is understood to mean an aromatic ring system wherein at least one carbon atom is replaced by a heteroatom selected from O, N, S.

[0826] In the context of the present disclosure, the term "alkylene" is understood to mean a linear, branched or, if possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, in which all bonds connecting the atoms are sigma bonds, in which two hydrogen atoms are removed, thus enabling connection with two open sigma bonds (valences).

[0827] In the context of the present disclosure, the term "heteroalkyl" is understood to mean a linear, branched or, if possible, cyclic hydrocarbon chain containing the specified number of carbon atoms, wherein 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.

[0828] In the context of the present disclosure, the term "haloalkyl" is understood to mean a linear, branched or, if possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, in which all bonds connecting the atoms are sigma bonds and in which at least one of the hydrogen atoms of the chain is replaced by a halogen atom selected from F, Cl, Br, I.

[0829] Compounds disclosed herein may include at least one asymmetric center. Depending on the configuration of the substituents around the chiral atom, these centers are named by the symbol "R" or "S". Unless otherwise specified in the structural formula, it is understood that the present invention includes all stereochemical isomeric forms, including diastereoisomers, enantiomers and epimeric forms as well as d-isomers and 1-isomers and mixtures thereof. A single stereoisomer of a compound can be synthesized from commercially available starting materials containing a chiral center, or prepared by preparing a mixture of enantiomeric products followed by separation (such as conversion into a mixture of diastereoisomers followed by separation or recrystallization, chromatography techniques, direct separation of enantiomers on a chiral chromatographic column, or any other appropriate method known in the art). The starting compound of a specific stereochemistry is commercially available, or can be prepared and split by techniques known in the art. In addition, compounds disclosed herein can exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and suitable mixtures thereof. In addition, compounds may exist as tautomers; the present invention provides all tautomers. In addition, the compounds disclosed herein may exist in unsolvated forms as well as solvated forms containing pharmaceutically acceptable solvents (such as water, ethanol, etc.). In general, solvated forms are considered equivalent to unsolvated forms.

[0830] In some embodiments, compositions disclosed herein can be enriched in the specific enantiomer of any compound disclosed herein (relative to the corresponding relative enantiomer of the compound) so that the mixture is not racemic. In this case, the main mixture of isomers is understood to have enantiomeric excess and optical purity>0%. The enantiomeric excess or optical purity of an isomer mixture can be>0%,>5%,>25%,>50%,>75%,>90%,>95%,>97%,>98% or>99%. The enantiomeric excess or optical purity of an isomer mixture can be 5-100%, 25-100%, 50-100%, 75-100%, 90-100%, 95-100%, 97-100%, 98-100% or 99-100%. Thus, for example, contemplated herein are compositions comprising the S enantiomer of a compound that is substantially free of the R enantiomer, or the R enantiomer that is substantially free of the S enantiomer. Furthermore, if the compound in question comprises more than one chiral center, the scope of this disclosure also includes compositions comprising mixtures of varying ratios between diastereomers, as well as compositions comprising one or more diastereomers that are substantially free of one or more other diastereomers. "Substantially free" means that the composition comprises less than 50%, 25%, 15%, 10%, 8%, 5%, 3%, 2%, or 1% of the minor enantiomer or diastereomer.

[0831] For clarity, in the context of this disclosure, chemical structures of compounds depicted with a particular stereochemical orientation at any particular chiral center, as defined by wedges and dashes, are intended to represent either that particular stereoisomer of that compound in substantially pure form, or a mixture enriched in the stereoisomer having the particular stereochemical orientation at the defined chiral center over the stereoisomer having the opposite orientation at that chiral center.

[0832] The present disclosure may also include any salt of the compounds disclosed herein, including any pharmaceutically acceptable salt, wherein the compounds disclosed herein have a net charge (positive or negative) and at least one counterion (having a counterbalancing negative or positive charge) is added thereto to form the salt. As used herein, the phrase "pharmaceutically acceptable salt" refers to those salts of the compounds disclosed herein that are safe and effective for pharmaceutical use in mammals and have 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, gentisate, 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. For a review of pharmaceutically acceptable salts, see BERGE et al., 66 J. PHARM. SCI. 1-19 (1977), incorporated herein by reference.

[0833] The present invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13 C and 14 C.

[0834] It should be noted that any carbon designation in the structures throughout this application, when used without further designation, is intended to refer to all isotopes of carbon, such as 12 C. 13 C or 14 C. In addition, any 13 C or 14 The compound of C can specifically have the structure of any compound disclosed herein.

[0835] It should also be noted that any hydrogen designation in the structures throughout this application, when used without further designation, is intended to refer to all isotopes of hydrogen, such as 1 H. 2 H or 3 H. In addition, any 2 H or 3The compound of H can specifically have the structure of any compound disclosed herein.

[0836] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art by substituting an appropriate isotopically labeled reagent for the non-labeled reagent employed.

[0837] In some embodiments, each D in the chemical structure represents a deuterium-enriched H site and the deuterium level at each deuterium-enriched H site of the compound is from 0.02% to 100%.

[0838] In some embodiments, each D in the chemical structure represents a deuterium-enriched H site and the deuterium level 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%.

[0839] It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns on the compounds used in the methods of the present invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by techniques known in the art. If a substituent is itself substituted with more than one group, it will be appreciated that these multiple groups can be on the same carbon or on different carbons, as long as a stable structure results.

[0840] In selecting compounds for use in the methods of the present invention, one of ordinary skill in the art will recognize that the various substituents, ie, R1, R2, etc., will be selected according to well-known principles of chemical structure connectivity.

[0841] As used herein, the term "treat" means the management and care of a patient for the purpose of combating a disease, disorder, or condition. The term is intended to include slowing the progression of the disease, disorder, or condition, alleviating or relieving symptoms and complications, and / or curing or eliminating the disease, disorder, or condition. The patient to be treated is preferably a mammal, particularly a human.

[0842] The present disclosure therefore also relates to pharmaceutical compositions comprising a compound as defined herein above and below in admixture with a pharmaceutically acceptable adjuvant and optionally other therapeutic agents. The adjuvant must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0843] 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 by implant. The compositions may be prepared by any method well known in the pharmaceutical art.

[0844] Such methods include the step of combining the compound or combination thereof used in the present invention with any adjuvant. Adjuvants, also known as auxiliary ingredients, include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavorings, antioxidants, and wetting agents. Such adjuvants are appropriately selected with respect to the intended form and route of administration, and consistent with conventional pharmaceutical practice.

[0845] Pharmaceutical compositions suitable for oral administration can be present as discrete dosage units (such as pills, tablets, dragees or capsules) or as powders or granules or as solutions or suspensions. The active ingredient can also be present as a bolus or paste. The composition can be further processed into a suppository or enema for rectal administration.

[0846] Tablets may contain the active ingredient compound and suitable binders, lubricants, disintegrants, colorants, flavorings, flow-inducing agents, and melting agents. Gelatin capsules may contain the active ingredient compound and a powdered carrier such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents may be used to prepare compressed tablets. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from atmospheric influences, or enteric-coated to selectively disintegrate in the gastrointestinal tract. For example, for oral administration in the form of a dosage unit of a tablet or capsule, the active drug component may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, calcium hydrogen phosphate, calcium sulfate, mannitol, sorbitol, and the like. Suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, gum 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, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0847] For oral administration in liquid dosage form, oral drug components and any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water etc. are combined.The example of suitable liquid dosage form is included in the solution or suspension, emulsion, syrup or elixir, suspension in water, pharmaceutically acceptable fat and oil, alcohol or other organic solvents (comprising ester), by non-effervescent granule reconstructed solution and / or suspension and the effervescent preparation reconstructed by effervescent granule.This type of liquid dosage form can contain for example suitable solvent, preservative, emulsifying agent, suspending agent, diluent, sweetener, thickening agent and melting agent.Can contain coloring agent and flavoring agent to increase patient's acceptance for the liquid dosage form of oral administration.

[0848] For parenteral administration, suitable compositions include aqueous and non-aqueous sterile solutions. Generally, water, suitable oil, saline, dextrose (glucose) aqueous solution and relevant sugar solution and glycol (such as propylene glycol or polyethylene glycol) are suitable carriers for parenteral solutions. The solution for parenteral administration preferably contains water-soluble salts of active ingredients, suitable stabilizers and buffer substances (if necessary). Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid (alone or in combination) are suitable stabilizers. Citric acid and its salt and sodium EDTA are also used. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methylparaben or propylparaben and chlorobutanol. Compositions can be present in unit dose or multidose containers, such as sealed vials and ampoules, and can be stored under freeze drying (lyophilization) conditions, only needing to add sterile liquid carriers, such as water, before use. For transdermal administration, for example gels, patches or sprays can be considered. Compositions or formulations suitable for pulmonary administration, for example, by nasal inhalation, include fine dusts or mists that can be produced by means of metered dose pressurized nebulizers, atomizers, or insufflators. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the selected injection type or delivery system.

[0849] The compounds used in the methods of the present disclosure can also be administered in the form of liposome delivery systems (such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles). Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholine. The compounds can be administered as a component of an emulsion targeted to tissue.

[0850] The compound used in the method of the present disclosure can also be coupled with a soluble polymer as a targetable drug carrier or as a prodrug. Such polymers include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine-phenol or the polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, compound can be coupled with a class of biodegradable polymers for realizing the controlled release of medicine, such as crosslinked or amphiphilic block copolymers of polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylate (polycyanoacylate) and hydrogel.

[0851] The pharmaceutical compositions herein can have an immediate release, delayed release, extended release, or modified release profile. In some embodiments, pharmaceutical compositions having different drug release profiles can be combined to produce a two-stage or three-stage release profile. For example, a pharmaceutical composition can have an immediate release and an extended release profile. In some embodiments, a pharmaceutical composition can have an extended release and a delayed release profile. Such compositions can be provided as pulsatile formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc.

[0852] The pharmaceutical compositions herein can be provided with abuse-deterrent characteristics by techniques known in the art, such as by preparing tablets that are difficult to crush or dissolve in water.

[0853] The invention also includes a pharmaceutical composition as described above in combination with packaging material comprising instructions for using the composition for the use as described above.

[0854] The exact dosage and administration regimen of the composition will necessarily depend on the type and extent of the therapeutic or nutritional effect to be achieved, and may vary depending on factors such as the specific compound, formulation, route of administration, or the age and condition of the individual subject to whom the composition is to be administered.

[0855] In addition, in some embodiments, pharmaceutical compositions disclosed herein may include a single enantiomer, diastereomer or structural isomer of a compound disclosed herein. In other embodiments, pharmaceutical compositions disclosed herein may include 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).

[0856] The compound used in the method of the present disclosure can be administered in various forms, including those described in detail herein. The treatment carried out with the compound can be an integral part of a conjoint therapy or adjuvant therapy, i.e., in combination with one or more compounds of the present invention, a subject or patient in need of a drug is treated or given with another drug for the disease. This conjoint therapy can be a sequential therapy, wherein the patient is first treated with a drug, and then another or two drugs are given simultaneously. Depending on the dosage form used, these can be administered independently by the same route of administration or by two or more different routes of administration.

[0857] It is contemplated that each embodiment disclosed herein is applicable to each of the other disclosed embodiments.Therefore, all combinations of the various elements described herein are within the scope of this disclosure.

[0858] It is understood that stereochemical names (such as some provided below) may be used when determined by, for example, X-ray crystallography. The R- and S-configurations of the compounds may be different.

[0859] Example 1. Preparation and characterization of compounds 35 and 37

[0860] General Notes. Reagents and solvents were obtained from commercial sources and used without further purification (including anhydrous solvents) unless otherwise noted. Reactions were monitored by TLC using solvent mixtures appropriate for each reaction. All column chromatography was performed on silica gel (40-63 μM). Preparative TLC was performed on glass plates coated with a 1 mm layer of silica. NMR spectra were recorded on a Bruker 400 or 500 MHz instrument. Chemical shifts are reported as δ values ​​in ppm, referenced to CDCl3 ( 1 HNMR = 7.26 and 13 C NMR=77.16)、MeOD( 1 H NMR = 3.31 and 13 C NMR=49.00) or DMSO-d6( 1 H NMR = 2.50 and 13 C NMR = 39.52). Multiplicities are indicated as follows: s (singlet); d (doublet); t (triplet); p (quintet); dd (double of doublets); ddd (double of doublets); dddd (double of doublets of doublets); td (triplet of doublets); dt (double of triplets); m (multiplet); br (broad). All carbon peaks are rounded to one decimal place unless such rounding would result in two closely spaced peaks becoming identical; in these cases, two decimal places are retained.

[0861]

[0862] Scheme 1. Preparation of compounds 35rac, 35R, 35S, and 37rac.

[0863] Cyclopentyl(2-fluorophenyl)methanone (79). To anhydrous THF (90 mL) under argon was added cyclopentylmagnesium bromide (2M 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), and the mixture was stirred at room temperature for 16 h. Note: Upon addition of CuBr·SMe2, the mixture turned from yellow to black and gas evolution occurred. At this point, water (20 mL) and 15% m / m aqueous H2SO4 (100 mL) were added, and the mixture was stirred for 1 h. The reaction was then extracted with hexanes (3 x 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 yellow-brown oil with minor impurities (9.54 g, 99%). 1 H NMR (500MHz, CDCl3) δ7.79(td,J=7.6,1.9Hz,1H),7.48(dddd,J=9.0,7.1,5.0,1.9Hz,1H),7.21(td,J=7.6 ,1.1Hz,1H),7.11(ddd,J=11.2,8.3,1.0Hz,1H),3.69-3.58(m,1H),1.98-1.82(m,4H),1.75-1.55(m,4H); 13 C NMR(126MHz,CDCl3)δ202.0(d,J C-F =3.8Hz),161.5(d,J C-F =253.8Hz),134.0(d,J C-F =9.0Hz),130.9(d,J C-F =2.9Hz),126.5(d,J C-F =13.1Hz),124.5(d,J C-F =3.3Hz),116.7(d,J C-F =24.0Hz),51.2(d,J C-F =5.9Hz),29.4,26.2.

[0864] (1-Bromocyclopentyl)(2-fluorophenyl)methanone (80). To a solution of compound 79 (9.52 g, 49.52 mmol) in CCl4 (50 mL) was added portionwise over 20 min at 0°C with a solution of Br2 (2.66 mL, 8.31 g, 52.00 mmol) in CCl4 (50 mL). Upon completion of the addition, the mixture was allowed to warm to room temperature and stirred for 60 min. The reaction mixture was then diluted with CHCl2 (100 mL), washed with saturated aqueous Na2S2O3 (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford bromoketone 80 as an orange-yellow oil (12.94 g, 96%) containing a minor impurity. 1 H NMR(500MHz, CDCl3)δ7.76(td,J=7.4,1.8Hz,1H),7.49-7.42(m,1H),7.19(td,J=7.6,1.1Hz,1H ),7.12(ddd,J=10.3,8.3,1.0Hz,1H),2.46-2.33(m,4H),2.10-1.99(m,2H),1.89-1.79(m,2H); 13 CNMR(126MHz,CDCl3)δ196.9,159.4(d,J C-F =252.1Hz),132.8(d,J C-F =8.5Hz),130.3(d,J C-F =2.8Hz),126.8(d,J C-F =15.0Hz),123.9(d,J C-F =3.6Hz),116.5(d,J C-F =22.2Hz),73.9,40.5(d,J C-F =2.1Hz),23.4.

[0865] 1-((2-Fluorophenyl)(methylimino)methyl)cyclopentan-1-ol (81). Liquid methylamine was freshly prepared as follows. Solid methylamine HCl (150 g) was treated dropwise with 50% m / m aqueous NaOH (200 g), and the evolved gas was passed through a drying tube containing NaOH pellets and condensed into a flask cooled to -78°C and covered with a condenser containing dry ice / acetone. After all the NaOH solution had been added, the neutralization reaction was warmed to 80°C to continue the evolution of gas. Once the desired amount of liquid methylamine had been collected, the reaction was carried out as follows. At -78°C, compound 80 (12.89 g, 47.54 mmol) and liquid methylamine (50 mL) were combined under argon (CAUTION: bromoketone is too viscous to stir at this temperature, so warming is necessary) and the resulting mixture was warmed to the boiling point of methylamine (-6°C) and stirred with a spatula until all the bromoketone had dissolved. The solution was then cooled back to -78°C and stirred for 20 minutes, and then stirred at -6°C for an additional 40 minutes. All methylamine was then carefully evaporated with a heat gun, and the resulting residue was dried in vacuo to give a sticky orange solid. The material was triturated with Et2O (100 mL), filtered, and the filter cake was washed with Et2O (2 x 50 mL). The combined filtrates were concentrated in vacuo to give imine 81 as an oily orange solid (10.32 g, 98%) containing a small amount of impurities. 1 H NMR(500MHz, CDCl3) δ7.38(dddd,J=8.3,7.3,5.4,1.8Hz,1H),7.20(td,J=7.5,1.1H z,1H),7.13(ddd,J=9.3,8.3,1.0Hz,1H),7.03(ddd,J=7.4,6.7,1.8Hz,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 CNMR(126MHz,CDCl3)δ171.3,158.4(d,J C-F =246.3Hz),130.8(d,J C-F =7.8Hz),129.3(d,J C-F =4.4Hz),124.3(d,J C-F =3.5Hz),122.5(d,J C-F =19.5Hz),116.0(d,J C-F =21.9 Hz), 84.2, 39.8, 38.2 and 38.0 (conformer), 24.0 and 23.7 (conformer).

[0866] 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 h of reflux (dark brown / black solution, TLC indicated slow conversion), PdCl (245 mg, 1.38 mmol) was added and reflux continued for an additional 2.5 h. The reaction mixture was cooled to room temperature, diluted with EtO (150 mL), and extracted with 2% m / m aqueous HCl (150 mL) and water (2 x 100 mL). The combined aqueous acidic extracts were washed with hexane (100 mL) and EtO (100 mL), basified with 25% m / m aqueous NaOH, and extracted with EtO (3 x 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). The material was purified by column chromatography (8:2 hexanes:EtOAc+2% Et3N, 1 column volume → 7:3 hexanes:EtOAc+2% Et3N, 4 column volumes) to provide a dark brown oil (4.56 g) still containing impurities. The material was further purified by additional column chromatography (1:1 hexanes:EtOAc, 2 column volumes → 3:7 hexanes:EtOAc, 3 column volumes → EtOAc, 1 column volume) to give racemic 35 (35rac), a viscous light brown oil (3.40 g, 33%) that slowly crystallized into a waxy solid. The material was converted to the HCl salt as follows. The 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 (3x) and dried to give 35rac HCl as a powdery white solid (3.98 g, quantitatively recovered). Free base: 1 H NMR (400MHz, CDCl3) δ7.40(td,J=7.8,1.8Hz,1H),7.29(dddd,J=8.1,7.1,5.1,1.8Hz,1H),7.19(td,J=7.5,1.3Hz,1H),7.04(ddd ,J=11.5,8.1,1.3Hz,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 C NMR(101MHz,CDCl3)δ210.1,161.2(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: 1 1H 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。

[0867] Chiral separation of 35 enantiomers (35R and 35S). The enantiomers of compound 35 were separated by crystallization of the diastereomeric tartrate salts formed with L-(+)- and D-(-)-tartaric acid. The 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). The mixture was gently warmed until a clear brown solution was obtained and allowed to stand at room temperature. After 16 h and then several hours in an acetone chamber (for vapor diffusion), no crystals had formed. Therefore, acetone (5.5 mL) was added to the solution, and the entire mixture quickly crystallized into a dense mass. The obtained crystals were collected by filtration, washed with a minimum of ice-cold 2: 1 acetone: water (2x, some crystals dissolved) and ice-cold acetone (2x), and dried to obtain crystal 1 (white needles, 344 mg, L-tartrate, ~80:20R:S). Crystal 1 was dissolved in water (1.5 mL) and placed in an acetone chamber (for vapor diffusion). After 84 h, the total volume of the solution was ~10-12 mL (therefore estimating ~6:1 acetone: water) and densely packed fine needle crystals had been formed. These crystals were collected by filtration, washed with room temperature acetone (2x) and dried to obtain crystal 2 (thin white needles, 176 mg, L-tartrate, R enantiomer, >95% ee). After a few hours, additional crystals were formed in the filtrate from crystal 2. At room temperature 2h, gained crystal is collected by filtration, and is washed and dried to obtain crystal 4 (white needles, 690mg, L-tartrate, 48:52R:S) with room temperature acetone (4x). Concentrated filtrate (white foam, 796mg, L-tartrate, 39:61R:S) from crystal 4 is rich in S enantiomer and is converted back into free alkali (almost colorless waxy solid, 425mg, 1.92mmol). A certain amount of this free alkali (419mg, 1.89mmol) is merged with D-(-)-tartaric acid (284mg, 1.89mmol) and water (1.13mL), and the mixture is gently heated until a transparent brown solution is obtained. After cooling to room temperature, acetone (3.39mL) is added and the mixture is placed for 2h, and then placed in an acetone chamber (for vapor diffusion) for 24h. At this point, a rosette of blade-shaped crystals has been formed, which appears to be a different polymorph.These crystals were collected by filtration, washed with ice-cold 3:1 acetone:HO (1x) and room temperature acetone (2x), and dried to give crystals 5 (white crystals, 311 mg, D-bitartrate salt, 46.5:53.5 R:S), but the enrichment of the S enantiomer was unexpectedly reduced, likely due to crystallization into a different polymorph. However, fine needles quickly formed in the filtrate of crystals 5, which appeared to be the same polymorph as in the earlier crystallizations. These crystals were collected by filtration, washed with room temperature acetone (3x), and dried to give crystals 6 (fine white needles, 159 mg, D-bitartrate salt, S enantiomer, >95% ee). Additional fine needles quickly formed in the filtrate of crystals 6. The product of the present invention is characterized in that: (1) 2-dimethyl-1-thiazolinone (5-1-oxo ... R =12.7min, 35S t R =11.7 min) to determine the ee of all crystal crops. Bitartrate salt (same for both R and S enantiomers): 1 H NMR (500MHz, DMSO-d6) δ7.52(td,J=7.8,1.8Hz,1H),7.37(tdd,J=7.5,5.2,1.8Hz,1H),7.25(td,J=7.6,1.3Hz,1H),7.16(ddd,J=11.8,8.2,1.3Hz,1H) ,4.20(s,2H),2.54(td,J=9.2,4.7Hz,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); 1H 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).

[0868] (R)-2-(2-Fluorophenyl)-2-(methylamino)cyclohexan-1-one (35R).t R =12.7 min (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).

[0869] (S)-2-(2-Fluorophenyl)-2-(methylamino)cyclohexan-1-one(35S).t R =11.7 min (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).

[0870] Determination of the absolute configuration of the 35 enantiomers (35R and 35S). X-ray quality crystals were grown as follows. A quantity of crystals 2 (20.5 mg, 0.055 mmol) was dissolved in water (10 mL), basified with 5% m / m NaOH aqueous solution, and extracted with Et2O (3 x 10 mL). The combined organics were washed with water (2 x 5 mL) and brine (5 mL), dried over Na2SO4, and concentrated to give the corresponding free base (11.6 mg, 0.052 mmol). This material was divided into two vials (5.8 mg, 0.026 mmol each), 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 mixture was gently warmed and stirred to homogenize, and then concentrated in vacuo to obtain the diastereoisomer camphorsulfonate. These salts were dissolved in minimal toluene and the solution was slowly evaporated at room temperature in a 4 mL vial with the cap slightly half open. Under these conditions, the crystals produced by the (-)-CSA salt had an acceptable quality for structural determination by single crystal X-ray diffraction. The absolute configuration was determined by both anomalous dispersion and with reference to the known configuration of the (-)-CSA counterion, and showed that crystal 2 had the R configuration (R factor = 0.0387). The crystallographic parameters are shown in Table 1, and a graphical representation of the determined crystal structure is shown in Figure 1 In case the absolute configuration of crystal 2 is known, the configuration and ee of the other crystal crops can be determined by chiral HPLC as described above.

[0871] Table 1. Crystallographic parameters of 35R(1R)-(-)-camsylate crystals grown in toluene.

[0872]

[0873] (2-Aminophenyl)(cyclopentyl)methanone (89). To a solution of 2-aminobenzonitrile (4.73 g, 40.00 mmol) in anhydrous THF (15 mL) was added cyclopentylmagnesium bromide (2 M in Et2O; 60.00 mL, 120.00 mmol) at 0°C under argon. After approximately 1 / 3 of the Grignard reagent had been added 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 viscosity and improve stirring, but this was largely ineffective. Therefore, the remaining 2 / 3 of the Grignard reagent was added over 5 minutes, and the mixture was manually vortexed during the addition to mix as thoroughly as possible, and then allowed to warm to room temperature. Upon reaching room temperature, additional anhydrous THF (40 mL) was added, and the mixture was further vortexed, which caused the thick, light yellow slurry to thin out sufficiently to allow stirring. At room temperature stirring after 3h, reaction is poured in the mixture of ice (150g) and 10% HCl aqueous solution (100mL), and gained two-phase yellow solution is placed, and occasionally mixes until TLC shows that imine intermediate is completely hydrolyzed.With solid NaHCO it is 7-8 that the mixture of hydrolysis is alkalized to pH and uses Et o (3x100mL) to extract.By the organic matter saturated NaHCO the aqueous solution (50mL) and salt solution (50mL) washing, through Na sO dry and concentrate in a vacuum to obtain the yellow oil (7.37g) that slowly crystallizes into waxy yellow solid.By column chromatography (9: 1 hexane: EtOAc) purifying this material to obtain pure amino ketone 89, it is waxy lemon yellow solid (6.72g, 89%). 1 H NMR (500MHz, CDCl3) δ7.79 (d, J = 8.4Hz, 1H), 7.25 (t, J = 7.8Hz, 1H), 6.69-6.61 (m, 2H), 6.27 (br s,2H),3.72(p,J=8.0Hz,1H),1.97-1.86(m,4H),1.80-1.70(m,2H),1.70-1.60(m,2H); 13 C NMR (126MHz, CDCl3) δ205.6,150.8,134.0,131.5,118.0,117.5,115.8,46.8,30.5,26.5.

[0874] Cyclopentyl(2-iodophenyl)methanone (90). To a solution of aminoketone 89 (6.68 g, 35.30 mmol) in CH3CN (141 mL) under argon 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 portionwise over ~30 min (~1 mL / min) while maintaining the temperature at <5°C. During the addition, effervescence was observed and the mixture quickly turned dark orange-brown, then nearly black (difficult to stir at this stage), and then turned 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 time, TLC showed that the mixture was still primarily starting material and no further progress had occurred, so the reaction was quenched. The mixture is poured into water (200mL), saturated NaHCO the aqueous solution (50mL) and saturated Na s o the aqueous solution (50mL), and uses Et o (3x 100mL) extraction mixture.The organic matter water (50mL) merged, 5% HCl aqueous solution (50mL), water (2x 50mL), saturated NaHCO the aqueous solution (25mL) and salt solution (25mL) washing, through Na s o dry and concentrate in a vacuum to obtain orange-yellow oil (7.70g).This material passes through column chromatography (40: 1 hexane: Et o, 2 column volumes → 30: 1 hexane: Et o, 3 column volumes → 5: 1 hexane: Et o, 2 column volumes) purifying to obtain residual starting material 89 (3.96g, 59%) as waxy, yellow solid and as iodine ketone 90 (3.42g, 32%) as yellow oil. 1 H NMR(400MHz, CDCl3) δ7.90(d,J=7.9Hz,1H),7.39(td,J=7.5,1.1Hz,1H),7.32(dd,J=7.6,1.8Hz,1H),7.1 0(td,J=7.6,1.8Hz,1H),3.54(p,J=7.9Hz,1H),2.00-1.81(m,4H),1.81-1.68(m,2H),1.68-1.56(m,2H); 13 C NMR (101MHz, CDCl3) δ207.8,145.7,140.4,131.3,128.0,127.8,91.6,50.5,29.7,26.3.

[0875] (1-Bromocyclopentyl)(2-iodophenyl)methanone (91). To a solution of iodine ketone 90 (1.71 g, 5.70 mmol) in CCl4 (5.8 mL) was added portionwise over 20 minutes at 0°C with a solution of Br2 (0.307 mL, 957 mg, 5.99 mmol) in CCl4 (5.8 mL). Upon completion of the addition, the mixture was allowed to warm to room temperature and stirred for 40 minutes. The reaction mixture was then diluted with CHCl2 (20 mL), washed with saturated aqueous Na2S2O3 (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to afford compound 91 as a yellow oil (2.14 g, 99%). 1 HNMR (500MHz, CDCl3) δ7.89 (dd, J=7.9, 1.1Hz, 1H), 7.70 (dd, J=7.7, 1.7Hz, 1H), 7.38 (td, J=7.6, 1.1Hz,1H),7.12(td,J=7.7,1.6Hz,1H),2.46-2.30(m,4H),2.11-2.00(m,2H),1.93-1.83(m,2H); 13 C NMR (101MHz, CDCl3) δ201.1,144.7,140.0,131.1,127.8,127.7,92.3,73.5,41.0,23.4.

[0876] 2-(2-iodophenyl)-2-(methylamino)cyclohexan-1-one (37rac). Liquid methylamine was freshly prepared as follows. Solid methylamine HCl (30 g) was dropwise treated with a 50% m / m NaOH aqueous solution (40 g), and the released gas was passed through a drying tube containing NaOH particles and condensed into a flask covered with a condenser containing dry ice / acetone. Once the required amount of liquid methylamine was collected, the reaction was carried out as follows. Under argon, compound 91 (2.12 g, 5.59 mmol) and liquid methylamine (4.5 mL) were combined at -10 ° C and the resulting mixture was stirred for 1 h. All methylamines were then carefully evaporated, and the resulting residue was dried in vacuo to obtain a light yellow solid (2.40 g). The substance was ground together with Et2O (10 mL), filtered, and the filter cake was washed with Et2O (2 x 5 mL). The combined filtrate was concentrated in vacuo to give crude 1-((2-iodophenyl)(methylimino)methyl)cyclopentan-1-ol as a waxy yellow solid (1.78 g). A certain amount (1.76 g) of this substance was dissolved in decalin (9.5 mL) and the yellow solution was refluxed under argon for 2 h. The reaction mixture (now dark brown) was then cooled to room temperature, diluted with Et2O (20 mL), and extracted with 2% HCl aqueous solution (20 mL) and water (2 x 20 mL). The combined aqueous extracts were washed with hexane (20 mL) and Et2O (20 mL), basified to a pH of 9-10 with a NaOH aqueous solution, and extracted with Et2O (3 x 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). The material was purified by column chromatography (8: 2 hexanes: EtOAc, 4 column volumes → 7: 3 hexanes: EtOAc, 4 column volumes) to provide an almost colorless oil (0.31 g) that slowly crystallizes into an off-white solid still containing impurities. The material was further purified by additional column chromatography (20: 1 hexanes: EtOAc+2% Et3N, 2 column volumes → 9: 1 hexanes: EtOAc+2% Et3N, 2 column volumes → 5.67: 1 hexanes: EtOAc+2% Et3N, 2 column volumes) to obtain racemic 37 (37rac), which is an almost colorless oil (267 mg, 15%, 2 steps) that slowly crystallizes into a waxy white solid. The material was converted to the HCl salt as follows. The free base 37rac ​​(267 mg, 0.811 mmol) was dissolved in Et2O (5 mL) and a 2.0 M solution of HCl in Et2O (0.61 mL, 1.22 mmol) was added with stirring at room temperature. The mixture was concentrated in vacuo, the resulting solid was triturated with hexanes, and the mixture was concentrated again to give 37rac ​​HCl as a powdery off-white solid (281 mg, 95% recovery). Free base: 1H NMR (500MHz, CDCl3) δ7.90(d,J=7.8Hz,1H),7.52(dd,J=7.9,1.7Hz,1H),7.36(t,J=7.6Hz,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: 1 H 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 (estimated m, 1H; buried under 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=13.9Hz,1H),1.74-1.64(m,1H),1.55-1.42(m,1H).

[0877] Example 2: Preparation of Compounds 14S and 14R

[0878]

[0879] Step 1: Preparation of (S)-2-(methylamino)-2-phenylcyclohexan-1-one (14S) and (R)-2-(methylamino)-2-phenylcyclohexan-1-one (14R)

[0880] To a solution of 2-(methylamino)-2-phenylcyclohexan-1-one hydrochloride (1.4 g, 1.97 mmol) (14 rac) in anhydrous methanol (20 mL) stirred at RT was added NaOH (0.25 g, 6.26 mmol) and the reaction mixture was stirred for 30 min. The mixture was filtered and the filtrate was concentrated in vacuo. After evaporation, the residue was separated by chiral chromatography using a 250 x 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 separated and combined to give the product free base, which was acidified with HCl in dioxane and concentrated to provide the HCl salt. The resulting product was 0.475 g of ENT-1 2-(methylamino)-2-phenylcyclohexan-1-one hydrochloride, tR = 18.150 min (for the free base) (here identified as the S isomer, 14S); m / z [M+H] + 204.0; 1 H NMR (DMSO-d6, 400 MHz) (for 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) (here identified as the R isomer, 14R); m / z [M+H] + 204.1; 1 H NMR (DMSO-d6, 400 MHz) (for 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).

[0881] Example 3: Preparation of Compounds 29R and 29S

[0882]

[0883] Step 1: Preparation of 0.8 M cyclopentylmagnesium bromide solution in THF

[0884] 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 RT to give cyclopentylmagnesium bromide in THF, which was used directly in the next step.

[0885] Step 2: Preparation of cyclopentyl(phenyl)methanol

[0886] To the RT solution (0.8M, 700mL, 560mmol, 1.5eq.) of cyclopentylmagnesium bromide in THF, a solution of benzaldehyde (40.3g, 380mmol) in THF (200mL) was added dropwise. The reaction mixture was stirred overnight at rt. The mixture was cooled with an ice-water bath, and then treated dropwise with a solution of NH4Cl (50g) in water (500mL). The resulting mixture was extracted with ethyl acetate (3x 400mL). The combined organic layer was washed with water, dried over anhydrous Na2SO4 and evaporated under reduced pressure. Via silica gel column chromatography (500gSiO2 / 25g reaction mixture, hexane / MTBE 20 / 1→1 / 1) purification of residue, 27g cyclopentyl (phenyl) methanol (yield 40%) was provided. 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).

[0887] Step 3: Preparation of cyclopentyl (phenyl) ketone

[0888] A solution of cyclopentyl(phenyl)methanol (27 g, 153 mmol) in anhydrous dichloromethane (250 mL) was stirred, cooled with an ice-water bath, and treated with 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. The residue was purified by silica gel column chromatography (100 g SiO2 / 10 g reaction mixture, hexane / DCM 10 / 1) to provide 17 g of cyclopentyl(phenyl)methanone (59% yield). 1H NMR(400MHz,DMSO-d6)δ7.98(d,J=7.7Hz,2H),7.62(t,J=7.3Hz,1H),7.52(t ,J=7.6Hz,2H),1.94-1.82(m,2H),1.75(q,J=6.8Hz,2H),1.71-1.56(m,4H).

[0889] Step 4: Preparation of (1-bromocyclopentyl)(phenyl)methanone

[0890] To a solution of cyclopentyl(phenyl)methanone (17 g, 90 mmol) in a mixture of anhydrous ethyl acetate (75 mL) and anhydrous CHCl 3 (75 mL) was added copper(II) bromide (60 g, 270 mmol) and the reaction mixture was stirred under reflux overnight. The mixture was cooled to RT 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.

[0891] Step 5: Preparation of 1-(((2-methoxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride

[0892] To a solution of (1-bromocyclopentyl)(phenyl)methanone (22 g, 86.9 mmol) in anhydrous 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. This compound was stirred in dioxane (1 M) and treated with HCl / dioxane (1.05 eq.), and then evaporated under reduced pressure to give 1-(((2-methoxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride. 1 H NMR (500MHz, chloroform-d) δ7.98 (dd, J=7.6, 1.9Hz, 1H), 7.50-7.31 (m, 3H), 7.05 ( dt,J=5.8,1.7Hz,1H),3.57(td,J=6.0,2.6Hz,1H),3.35-3.22(m,3H),2.4 3-2.32(m,1H),2.09-1.97(m,1H),1.89(dddd,J=22.6,10.8,5.5,2.8Hz,4 H), 1.65 (ddt, J=11.1, 5.6, 2.7Hz, 1H), 1.52 (ddt, J=7.8, 5.3, 2.9Hz, 1H).

[0893] Step 6: Preparation of 2-((2-methoxyethyl)amino)-2-phenylcyclohexan-1-one (29rac)

[0894] To a stirred Dowtherm (90 mL, 294 mmol) heated to 200° C. in an oil bath was added 1-(((2-methoxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride in portions. The reaction mixture was heated at 180° C. for 15 min, cooled to RT and diluted with CHCl (250 mL) and water (150 mL). The separated aqueous layer was washed with CHCl (2× 200 mL) and evaporated under reduced pressure. The residue was recrystallized (5 mL 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 H NMR (DMSO-d6, 400MHz): δ (ppm) 9.39 (s, 2H), 7.46 (m, 3H), 7.39 (m, J = 7.0Hz, 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=12.4,12.3,12.3Hz,1H),1.51(q,J=12.4,12.4,12.3Hz,1H).

[0895] Step 7: (R)-2-((2-methoxyethyl)amino)-2-phenylcyclohexan-1-one (29R) and (S)-2-((2-methoxyethyl)amino)-2-phenylcyclohexan-1-one Preparation of (2-(2-phenylethyl)amino)-2-phenylcyclohexan-1-one (29S)

[0896] The HCl salt of 29rac was basified with aqueous NaHCO 3 solution, extracted with CH 2 Cl 2 , and the organic extracts were concentrated to provide the free base (850 mg). This material was separated into enantiomers by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: A: CO 2 , B: 0.1% NH 3 H 2 O in ETOH, B%: 17%; multiple injection method with 1.2 min interval between injections) to provide ENT-1, RT = 1.080 min (241 mg) (identified here as the S isomer, 29S) and ENT-2, RT = 1.236 min (184 mg) (identified here as the R isomer, 29R). The retention times were determined using the following chiral analysis method: Column: Chiralpak OD-3, 100 x 4.6 mm ID, 3 μM; Mobile phase: A: CO2, B: Ethanol (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.

[0897] Example 4: Preparation of Compounds 30R and 30S

[0898]

[0899] Step 1: Preparation of 1-(((2-hydroxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride

[0900] To a solution of (1-bromocyclopentyl) (phenyl) ketone (17g, 67.15mmol) in anhydrous methanol (170mL) was added 2-aminoethanol (12.3g, 201.45mmol) and the reaction mixture was stirred at RT for 48h. After completion, the mixture was evaporated under reduced pressure, diluted with water (300mL), and extracted with ethyl acetate (300mL). The separated organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain 8g of 1-(((3-hydroxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol. The substance was stirred in dioxane (1M), treated with HCl / dioxane (1.05eq.), and evaporated under reduced pressure to obtain 1-(((3-hydroxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride. 1H NMR(400MHz, DMSO-d6)δ7.58-7.50(m,2H),7.27(dd,J=8.3,6.3Hz,3H),4.37(s,1H),3.48(td,J=7.4,3.1Hz,2H),3.1 7(s,1H),2.40(d,J=9.2Hz,1H),1.71-1.62(m,2H),1.59(d,J=7.2Hz,2H),1.58-1.46(m,2H),1.25(d,J=10.5Hz,2H).

[0901] Step 2: Preparation of 2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one (30rac)

[0902] To a stirred Dow Heat Transfer (70 mL, 228.7 mmol) heated to 200° C. in an oil bath was added 1-(((3-hydroxyethyl)imino)(phenyl)methyl)cyclopentan-1-ol hydrochloride in portions. The reaction mixture was heated to 180° C. for 15 min, cooled to RT, and diluted with CHCl (200 mL) and water (120 mL). The aqueous layer was washed with CHCl (2×150 mL) and evaporated under reduced pressure. The residue was recrystallized (5 mL 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 (400MHz, chloroform-d) δ7.55 (d, J = 7.7Hz, 2H), 7.43-7.32 (m, 3H), 7.32-7.23 (m, 2H),5.41(t,J=3.7Hz,1H),3.91(dd,J=10.7,3.8Hz,1H),3.85-3.73(m,2H),2 .94-2.81(m,1H),2.64(dd,J=13.7,3.0Hz,1H),2.21-2.06(m,2H),1.94(dt, J=12.6,3.4Hz,2H),1.86-1.68(m,2H),1.53-1.47(m,1H),1.31-1.18(m,1H).

[0903] Step 3: (R)-2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one (30R) and (S)-2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one Preparation of 2-phenylcyclohexan-1-one (30S)

[0904] To a solution of 2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one hydrochloride (1.7 g, 2 mmol) in anhydrous methanol (20 mL) was added NaOH (0.3 g, 7 mmol) and the reaction mixture was stirred at RT for 30 min. The mixture was then filtered and the filtrate concentrated in vacuo. The evaporation residue was separated on a 250 x 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 obtain the product free base. These free bases were treated with 10% HCl in dioxane (5 mL) and evaporated to dryness to obtain ENT-1 2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one hydrochloride 0.268 g, tR = 9.953 min (for the free base) (here identified as the R isomer, 30R); m / z [M+H] + 216.2; 1 H NMR (DMSO-d6, 400MHz) (for HCl): δ (ppm) 10.27 (s, 1H), 9.95 (s, 1H), 7.58 (d, J = 7.6Hz, 2H), 7.44 (t, 2H), 7.38 (t, J = 5.8Hz, 1H), 5.67 (br s,1H),4.01(d,J=13.3Hz,1H),3.93(t,J=14.0,14.0Hz,1H),3.09(d,J=15.6Hz ,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) (here identified as the S isomer, 30S); m / z [M+H] + 216.2; 1 H NMR (DMSO-d6, 400MHz) (for HCl): δ (ppm) 10.24 (s, 1H), 9.97 (s, 1H), 7.58 (d, J = 7.3Hz, 2H), 7.46 (t, J = 7.5, 7.5Hz, 2H), 7.39 (t, J = 7.6, 7.6Hz, 1H), 5.67 (b rs,1H),4.02(d,J=15.3Hz,1H),3.93(t,J=12.6,12.6Hz,1H),3.09(d,J=16 .4Hz,1H),2.73(m,1H),2.39(m,1H),2.14(m,5H),1.55(m,1H),0.96(m,1H).

[0905] Example 5: Preparation of Compounds 38R and 38S

[0906]

[0907] Step 1: Preparation of cyclopentyl(o-tolyl)methanol

[0908] To the THF solution of cyclopentylmagnesium bromide (0.8M, 700mL, 560mmol, 1.5eq.), a solution of 2-methylbenzaldehyde (37g, 380mmol) in THF (200mL) was added dropwise. The reaction mixture was stirred overnight at RT. The mixture was cooled with an ice-water bath and treated dropwise with a solution of NH4Cl (50g) in water (500mL). The resulting mixture was extracted with ethyl acetate (3x400mL). The combined organic layer was washed with water, dried over anhydrous Na2SO4 and evaporated under reduced pressure. Via silica gel column chromatography (500gSiO2 / 25g reaction mixture, hexane / MTBE 20 / 1→1 / 1) purification of residue, 25g cyclopentyl (o-tolyl) methanol (yield 39.5%) was provided. 1 H NMR (500MHz, chloroform-d) δ7.46-7.40(m,1H),7.26-7.19(m,1H),7.16(ddt,J=10.4,5.6,2.7Hz,2H),4.72(dd,J=8.2,2.2Hz,1H),2.45(s,3H),2. 29(dt,J=8.0,6.0Hz,2H),1.89(dtt,J=10.9,8.4,5.6Hz,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).

[0909] Step 2: Preparation of cyclopentyl (o-tolyl) ketone

[0910] To a solution of cyclopentyl (o-tolyl) methanol (25 g, 150 mmol) in anhydrous dichloromethane (250 mL) cooled with 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. The residue was purified by silica gel column chromatography (100 g SiO2 / 10 g reaction mixture, hexane / DCM 10 / 1) to provide 16 g of cyclopentyl (o-tolyl) ketone (yield 60%).

[0911] Step 3: Preparation of (1-bromocyclopentyl)(o-tolyl)methanone

[0912] To a solution of cyclopentyl(o-tolyl)methanone (16 g, 90 mmol) in a mixture of anhydrous ethyl acetate (75 mL) and anhydrous CHCl3 (75 mL) was added copper(II) bromide (57 g, 257 mmol) and the reaction mixture was stirred under reflux overnight. The mixture was cooled, filtered, and the filtrate was concentrated in vacuo to give 20 g of (1-bromocyclopentyl)(o-tolyl)methanone (yield 96%), which was used in the next step without further purification. 1 H 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).

[0913] Step 4: Preparation of 1-((methylimino)(o-tolyl)methyl)cyclopentan-1-ol hydrochloride

[0914] The mixture of (1-bromocyclopentyl) (o-tolyl) ketone (15g, 56.14mmol) and methylamine solution in methyl alcohol (150mL) was stirred 48h under RT.After completing, the mixture was evaporated under reduced pressure and the residue was diluted with water (300mL) and ethyl acetate (300mL). The organic layer separated was through anhydrous Na SO Drying and reduced pressure evaporation to obtain 9.5g 1-((methylimino) (o-tolyl) methyl) cyclopentan-1-ol. This material (1M) in dioxanes was processed and evaporated under reduced pressure to obtain 11.1g 1-((methylimino) (o-tolyl) methyl) cyclopentan-1-ol hydrochloride with HCl / dioxanes (1.05eq.). 1 H 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).

[0915] Step 5: Preparation of 2-(methylamino)-2-(o-tolyl)cyclohexan-1-one (38rac)

[0916] 1-((methylimino)(o-tolyl)methyl)cyclopentan-1-ol hydrochloride was added portionwise to a stirred Dow hot carrier (70 mL, 228.7 mmol) heated to 200 ° C with an oil bath. The reaction mixture was heated to 180 ° C and kept for 15 min, cooled to RT, and diluted with CHCl (250 mL) and water (150 mL). The aqueous layer was washed with CHCl (2 x 200 mL) and evaporated under reduced pressure. The residue was recrystallized (5 ml EtOH and a few drops of ACN per 1 g of crude product) to obtain 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).

[0917] Step 6: (R)-2-(methylamino)-2-(o-tolyl)cyclohexan-1-one (38R) and (S)-2-(methylamino)- Preparation of 2-(o-tolyl)cyclohexan-1-one (38S)

[0918] To a solution of 2-(methylamino)-2-(o-tolyl)cyclohexan-1-one hydrochloride (1.4 g, 2 mmol) in anhydrous methanol (20 mL) was added NaOH (0.3 g, 7 mmol) and the reaction mixture was stirred at RT for 30 min. The mixture was then filtered and the filtrate was concentrated in vacuo to obtain the free base. The residue after evaporation was separated on a 250 x 20 mm, 5 μM Chiralcel OJ-H column and eluted with a flow rate of 15 mL / min using 95:2.5:2.5 hexane-IPA-MeOH. The samples were separated and merged to obtain the product free base. The resulting free base was dissolved in dioxane, treated with 10% HCl in dioxane (5 mL), and then evaporated to dryness to give ENT-1 2-(methylamino)-2-(o-tolyl)cyclohexan-1-one hydrochloride 0.494 g, tR = 11.012 min (for the free base) (here identified as the S isomer, 38S); m / z [M+H] + 218.2; 1H NMR (DMSO-d6, 400 MHz) (for 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) (here identified as the R isomer, 38R); m / z [M+H] + 218.2; 1 H NMR (DMSO-d6, 400MHz) (for 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=12.0,12.0Hz,1H),1.76(d,J=15.3Hz,1H),1.59(m,2H).

[0919] Example 6: Preparation of Compounds 26R and 26S

[0920]

[0921] Step 1: Preparation of 2-phenylcyclohexan-1-ol

[0922] 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 a solution of phenylmagnesium bromide in THF (1500 mL, 1200 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. 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 provide 120 g of 2-phenylcyclohexan-1-ol (yield 62.5%). 1H 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).

[0923] Step 2: Preparation of 2-phenylcyclohexan-1-one

[0924] To a stirred solution of 2-phenylcyclohexan-1-ol (120 g, 680 mmol) in anhydrous dichloromethane (1500 mL) cooled in an ice-water bath was added Dess-Martin periodinane (DMP, 303 g, 715 mmol) in portions. The reaction mixture was stirred overnight at room temperature, poured into a mixture of KCO / ice (250 g, 2000 mL), stirred for 30 min, and filtered. The filtrate was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous NaSO 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 H 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).

[0925] Step 3: Preparation of 2-nitro-2-phenylcyclohexan-1-one

[0926] To a solution of 2-phenylcyclohexan-1-one (90 g, 470 mmol) in 1,2-dichloroethane (1200 mL) was added cerium (IV) ammonium nitrate (524 g, 956 mmol) and copper (II) acetate (17.3 g, 95 mmol). The reaction mixture was stirred at 60°C overnight, 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 (yield 87%).

[0927] Step 4: Preparation of 2-amino-2-phenylcyclohexan-1-one hydrochloride

[0928] 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 (26.8 g each, 410 mmol) at 30-minute intervals. The reaction mixture was stirred overnight at room temperature, filtered, and the filtrate evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed four times with saturated aqueous NaCO, acidified with HCl in dioxane, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (MTBE:MeOH (50:1→1:4)) to give 16 g of 2-amino-2-phenylcyclohexan-1-one hydrochloride (71.1 mmol, 10.4% yield over two steps). 1 H NMR(400MHz, DMSO-d6)δ8.81(s,2H),7.50(dd,J=9.2,3.7Hz,2H),7.48-7.35(m,3H),2.48(s,1H),2.43-2.25(m, 2H), 2.15(td,J=13.9,13.5,4.2Hz,1H),1.99-1.91(m,1H),1.81(d,J=11.7Hz,1H),1.59(dt,J=24.5,8.6Hz,2H).

[0929] Step 5: Preparation of 2-phenyl-2-(piperidin-1-yl)cyclohexan-1-one (26rac)

[0930] To a solution of 2-amino-2-phenylcyclohexan-1-one hydrochloride (3.5 g, 15.5 mmol) in DMF was added K2CO3 (6.4 g, 46.5 mmol) and 1,5-dibromopentane (2.11 mL, 15.5 mmol). The reaction mixture was stirred at 80 ° C overnight, cooled to RT, and poured into water. The aqueous layer was extracted 4 times with ethyl acetate. The combined organic layer was 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 min and evaporated under reduced pressure. The residue was purified via silica gel column chromatography (MTBE: MeOH (50: 1 → 1: 4)) to provide 1.1 g of 2-phenyl-2-(piperidin-1-yl)cyclohexan-1-one hydrochloride (26rac) (yield 24.2%). 1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),7.57-7.51(m,3H),7.45(br s,2H),3.42(d,J=11.7Hz,1H),3.24(d,J=13.7Hz,1H),3.07(d,J=11.4Hz,1H),2.67(q ,J=11.1Hz,1H),2.43-2.16(m,4H),2.05-1.57(m,8H),1.42(m,1H),1.29-1.17(m,1H).

[0931] Step 6: (R)-2-phenyl-2-(piperidin-1-yl)cyclohexan-1-one (26R) and (S)-2-phenyl-2-(piperidin-1-yl)cyclohexan-1-one Preparation of 2-(2-amino)cyclohexan-1-one (26S)

[0932] To 2-phenyl-2-(piperidin-1-yl) cyclohexane-1-one hydrochloride (1.1g, 3.74mmol) in anhydrous methanol (20mL) add NaOH (0.15g, 3.74mmol) and reactant mixture is stirred 30min under RT.Then filter mixture and concentrate filtrate in vacuo to obtain free alkali.Residue is separated on 250x 20mm, 5μM Chiralcel OJ-H posts, eluted with hexane-IPA-MeOH 70-15-15 at a flow rate of 12mL / min.Sample separation and merge to obtain product free alkali. The resulting free base was dissolved in dioxane, treated with 10% HCl in dioxane (5 mL), and evaporated to dryness to give 0.328 g of ENT-1 2-phenyl-2-(piperidin-1-yl)cyclohexan-1-one hydrochloride, tR = 9.303 min (for the free base) (here identified as the S isomer, 26S); m / z [M+H] + 258.2; 1 H NMR (DMSO-d6, 500 MHz) (for 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 ENT-2 2-phenyl-2-(piperidin-1-yl)cyclohexan-1-one hydrochloride, tR = 12.153 min (for the free base) (here identified as the R isomer, 26R); m / z [M+H] + 258.2; 1H NMR (DMSO-d6, 500MHz): δ (ppm) 10.04 (s, 1H), 7.57 (m, 3H), 7.49 (m, 2H), 3.45 (d, J = 10.1Hz, 1H), 3.28 (d, J = 13.6Hz, 1H), 3.14 (d, J = 10.9Hz, 1H), 2.70(q,J=10.9,10.9,10.0Hz,1H),2.42(m,2H),2.30(m,2H),2.04(q,J =13.9,13.9,13.8Hz,1H),1.93-1.57(m,7H),1.43(m,1H),1.25(m,1H).

[0933] Example 7: Preparation of Compounds 27R and 27S

[0934]

[0935] Step 1: Preparation of 2-phenyl-2-(pyrrolidin-1-yl)cyclohexan-1-one (27rac)

[0936] To a solution of 2-amino-2-phenylcyclohexan-1-one (4g, 17.7mmol, hydrochloride) in DMF was added K2CO3 (7.3g, 53mmol) and 1,4-dibromobutane (2.33mL, 19.5mmol). The reaction mixture was stirred at 80°C overnight, cooled to RT, and poured into water. The aqueous layer was extracted 4 times with ethyl acetate. The combined organic layer was washed 5 times with water, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was dissolved in dichloromethane (100mL) and HCl in dioxane (50mL) was added dropwise. The resulting mixture was stirred for 15min and evaporated under reduced pressure. The residue was purified via silica gel column chromatography (MTBE:MeOH (50:1→1:4)) to provide 1.5g of 2-phenyl-2-(pyrrolidin-1-yl)cyclohexan-1-one hydrochloride (27rac) (yield 30.2%). m / z[M+H] + 244.2; 1 H NMR (DMSO-d6, 400MHz): 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, 12.8Hz, 1H).

[0937] Step 2: (R)-2-phenyl-2-(pyrrolidin-1-yl)cyclohexan-1-one (27R) and (S)-2-phenyl-2-(pyrrolidin-1-yl)cyclohexan-1-one Preparation of 1-hydroxy-1-cyclohexan-1-one (27S)

[0938] The HCl salt of 27rac was basified with aqueous NaHCO 3 solution, extracted with CH 2 Cl 2 , and the organic extract was concentrated to provide 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: CO 2 , B: 0.1% NH 3 H 2 O / MeOH, B%: 36%; multiple injection method with a 3 min interval between injections) to provide ENT-1, RT = 2.177 min (300 mg) (identified here as the S isomer, 27S) and ENT-2, RT = 2.438 min (316 mg) (identified here as the R isomer, 27R). The retention times were determined using the following chiral analysis method: Column: Lux Cellulose-2, 100 x 4.6 mm ID, 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.

[0939] Example 8: Preparation of Compounds 19R and 19S

[0940]

[0941] Step 1: Preparation of cyclopentyl(3-fluorophenyl)methanol

[0942] To a solution of cyclopentylmagnesium bromide in THF (0.8M, 700mL, 560mmol, 1.5eq.) was added dropwise a solution of 3-fluorobenzaldehyde (39g, 380mmol) in THF (200mL). The reaction mixture was stirred overnight at RT. A solution of NH4Cl (50g) in water (500mL) was added dropwise to the mixture cooled with an ice-water bath. The resulting mixture was extracted with ethyl acetate (3x400mL). The combined organic layer was washed with water, dried over anhydrous Na2SO4 and evaporated under reduced pressure. Residue was purified via silica gel column chromatography (100gSiO2 / 10g reaction mixture, hexane / DCM 10 / 1) to provide 23g cyclopentyl (3-fluorophenyl) methanol (yield 39.5%).

[0943] Step 2: Preparation of cyclopentyl (3-fluorophenyl) ketone

[0944] To a solution of cyclopentyl(3-fluorophenyl)methanol (23 g, 150 mmol) in anhydrous 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 NaSO and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (100 g SiO / 10 g reaction mixture, hexane / DCM 10 / 1) to provide 16.5 g of cyclopentyl(3-fluorophenyl)methanone (57.3% yield).

[0945] Step 3: Preparation of (1-bromocyclopentyl)(3-fluorophenyl)methanone

[0946] To a solution of cyclopentyl(3-fluorophenyl)methanone (16.5 g, 86 mmol) in a mixture of anhydrous ethyl acetate (90 mL) and anhydrous CHCl3 (90 mL) was added copper(II) bromide (58 g, 258 mmol) and the reaction mixture was stirred under reflux overnight. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to afford 21 g of (1-bromocyclopentyl)(3-fluorophenyl)methanone (yield 90%), which was used in the next step without further purification. 1 H NMR (400MHz, chloroform-d) δ7.94(d,J=7.7Hz,1H),7.82(d,J=9.8Hz,1H),7.41(td,J=7.9,5.4Hz,1H),7.23(dd, J=9.3,7.0Hz,1H),2.44(dh,J=21.7,7.6,6.9Hz,4H),2.05(q,J=6.3,5.5Hz,2H),1.80(q,J=7.4Hz,2H).

[0947] Step 4: Preparation of 1-((3-fluorophenyl)(methylimino)methyl)cyclopentan-1-ol hydrochloride A mixture of (1-bromocyclopentyl)(3-fluorophenyl)methanone (21 g, 77.5 mmol) and methylamine in methanol (200 mL) was 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. The material in dioxane was diluted with HCl / dioxane and evaporated under reduced pressure to give 16.3 g of the hydrochloride salt.

[0948] Step 5: Preparation of 2-(3-fluorophenyl)-2-(methylamino)cyclohexan-1-one (19rac)

[0949] To a Dow Heater (100 mL, 326.7 mmol) heated to 200° C. in an oil bath was added portionwise 16 g of 1-((3-fluorophenyl)(methylimino)methyl)cyclopentan-1-ol. The reaction mixture was heated to 180° C. for 15 min, cooled to RT, and diluted with CHCl (250 mL) and water (150 mL). The aqueous layer was washed with CHCl (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 obtain 3.9 g of 2-(3-fluorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride (19 rac). 1 H NMR (500MHz, DMSO-d6)9.49(s,2H),7.59(q,J=7.5Hz,1H),7.37(td,J=8.5,2. 4Hz,1H),7.32(d,J=10.0Hz,1H),7.21(d,J=7.8Hz,1H),3.14(dd,J=14.2,3.1H z,1H),2.39(d,J=13.5Hz,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, 3.1Hz, 1H), 1.87-1.81 (m, 1H), 1.67-1.50 (m, 2H).

[0950] Step 6: (R)-2-(3-Fluorophenyl)-2-(methylamino)cyclohexan-1-one (19R) and (S)-2-(3-fluorophenyl)- Preparation of 2-(methylamino)cyclohexan-1-one (19S)

[0951] To 2-(3-fluorophenyl)-2-(methylamino) cyclohexane-1-one hydrochloride (1.9g, 2.5mmol) in anhydrous methanol (20mL) add NaOH (0.35g, 7.5mmol) and reaction mixture is stirred 30 minutes under RT.Then filter the mixture and concentrate the filtrate in a vacuum to provide free alkali.The residue after evaporation is separated on ChiralPak IA 250x20mm, 5μM posts, eluted with hexane-IPA-MeOH 90-5-5 with a flow rate of 12mL / min.Sample separation and merge to obtain product free alkali. The resulting free base in dioxane was treated with 10% HCl in dioxane (5 mL) and evaporated to dryness to give ENT-1 2-(3-fluorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride 0.406 g, tR = 14.233 min (for the free base) (here identified as the S isomer, 19S); m / z [M+H] + 222.0; 1H NMR (DMSO-d6, 500 MHz) (for 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 ENT-2 2-(3-Fluorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride, tR = 18.439 (for the free base) (here identified as the R isomer, 19R); m / z [M+H] + 222.0; 1 H NMR (DMSO-d6, 500MHz) (for HCl): δ (ppm) 10.03 (s, 1H), 9.42 (s, 1H), 7.60 (q, J= 7.3,7.3,6.6Hz,1H),7.38(t,J=8.3,8.3Hz,1H),7.31(d,J=10.2Hz,1H),7.20 (d,J=7.7Hz,1H),3.14(d,J=13.7Hz,1H),2.40(d,J=13.8Hz,1H),2.31(m,1H) ,2.11(s,3H),2.11(m,1H),1.96(m,1H),1.85(d,J=10.7Hz,1H),1.59(m,2H).

[0952] Example 9: Preparation of Compounds 88R and 88S

[0953]

[0954] Step 1: Preparation of 2-((methyl-d3)amino)-2-phenylcyclohexan-1-one (88rac)

[0955] To a solution of 2-amino-2-phenylcyclohexan-1-one hydrochloride (10 g, 44.3 mmol) in DMF was added K2CO3 (18.37 g, 133 mmol) and CD3I (3.3 mL, 53 mmol). The reaction mixture was stirred at 80 ° C overnight, cooled to RT, and poured into water. The aqueous layer was extracted 4 times with ethyl acetate. The combined organic layer was 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 min and evaporated under reduced pressure. The residue was purified via silica gel column chromatography (MTBE: MeOH (50: 1 → 1: 4)) to provide 1.7 g of 2-((methyl-d3)amino)-2-phenylcyclohexan-1-one as a hydrochloride (yield 15.8%). 1 H NMR(500MHz,DMSO-d6)δ9.59(s,2H),7.56-7.48(m,3H),7.43-7.36(m,2H),3.14(dq,J=13.9,3.2Hz,1H),2.40-2.34(m,1H) ,2.32-2.25(m,1H),2.12(td,J=13.4,4.1Hz,1H),1.95(ddd,J=12.8,6.3,3.3Hz,1H),1.88-1.81(m,1H),1.66-1.52(m,2H).

[0956] Step 2: (S)-2-((methyl-d3)amino)-2-phenylcyclohexan-1-one (88S) and (R)-2-((methyl-d3)amino)-2-phenylcyclohexan-1-one Preparation of 2-phenylcyclohexan-1-one (88R)

[0957] To 2-((methyl-d3) amino)-2-phenylcyclohexan-1-one (1.7g, 7mmol, hydrochloride) in anhydrous methanol (20mL) solution, add NaOH (0.28g, 7mmol) and reactant mixture is stirred 30min under RT.Then filter mixture and concentrate filtrate in vacuo to provide free alkali.The residue after evaporation is separated on ChiralPak AD 250x 30mm, 10 μM posts, eluted with the flow rate of 40mL / min with hexane-IPA-MeOH 95-5-5.Sample separation and merged to obtain product free alkali. The resulting free base in dioxane was treated with 10% HCl in dioxane (5 mL) and evaporated to dryness to give 0.317 g of ENT-1 2-((methyl-d3)amino)-2-phenylcyclohexan-1-one hydrochloride, tR = 14.656 min (for the free base) (here identified as the R isomer, 88R); m / z [M+H] + 207.1; 1H NMR (DMSO-d6, 400 MHz) (for 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 ENT-2 2-((Methyl-d3)amino)-2-phenylcyclohexan-1-one hydrochloride, tR = 30.684 min (for the free base) (here identified as the S isomer, 88S); m / z [M+H] + 207.2; 1 HNMR (DMSO-d6, 400MHz): δ (ppm) 10.01 (s, 1H), 9.34 (s, 1H), 7.54 (m, 3H), 7.41 (d, J = 7.5Hz, 2H), 3.15 (d, J = 13.8Hz, 1H) ,2.39(d,J=13.6Hz,1H),2.29(m,1H),2.14(t,J=11.6,11.6Hz,1H),1.96(m,1H),1.85(d,J=11.8Hz,1H),1.61(m,2H).

[0958] Example 10: Preparation of Compounds 86S and 86R

[0959]

[0960] Step 1: Preparation of 2-((2-fluoroethyl)amino)-2-phenylcyclohexan-1-one (86rac)

[0961] To a solution of 2-amino-2-phenylcyclohexan-1-one (9g, 40mmol, hydrochloride) in DMF, KCO (16.5g, 119.6mmol) and 1-fluoro-2-iodoethane (4ml, 47.9mmol) were added. The reaction mixture was stirred at 80°C overnight, cooled to RT, and poured into water. The aqueous layer was extracted 4 times with ethyl acetate. The combined organic layer was washed 5 times with water, dried over anhydrous NaSO and evaporated under reduced pressure. The residue was dissolved in dichloromethane (100mL) and HCl in dioxane (50mL) was added dropwise. The resulting mixture was stirred for 15min and evaporated under reduced pressure. The residue was purified via silica gel column chromatography (MTBE: MeOH (50:1→1:4)) to provide 1.8g of 2-((2-fluoroethyl)amino)-2-phenylcyclohexan-1-one (86rac) (yield 16.5%) as hydrochloride. 1H NMR (500 MHz, DMSO-d6) (for the 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).

[0962] Step 2: (S)-2-((2-fluoroethyl)amino)-2-phenylcyclohexan-1-one (86S) and (R)-2-((2-fluoroethyl)amino)-2-phenylcyclohexan-1-one Preparation of 2-amino-2-phenylcyclohexan-1-one (86R)

[0963] To 2-((2-fluoroethyl) amino)-2-phenylcyclohexan-1-one (1.8g, 6.6mmol, hydrochloride) in anhydrous methanol (20mL) solution, add NaOH (0.265g, 6.6mmol) and reactant mixture is stirred 30min under RT.Then filter mixture and concentrate filtrate in vacuum to provide free alkali.The residue after evaporation is separated with the hexane-IPA-MeOH 98-1-1 of flow velocity 18mL / min on 250x 20mm, 5 μ M Chiralpak AD-H.Sample separation and merge to obtain product free alkali. The resulting free base in dioxane was treated with 10% HCl in dioxane (5 mL) and evaporated to dryness to give 0.324 g of ENT-1 2-((2-fluoroethyl)amino)-2-phenylcyclohexan-1-one hydrochloride, tR = 14.667 min (for the free base) (here identified as the R isomer, 86R); m / z [M+H] + 236.0; 1 H NMR (DMSO-d6, 500 MHz) (for 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 ENT-2 2-((2-Fluoroethyl)amino)-2-phenylcyclohexan-1-one hydrochloride, tR = 16.727 min (for the free base) (here identified as the S isomer, 86S); m / z [M+H] + 236.0; 1H NMR (DMSO-d6, 500 MHz) (for the 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).

[0964] Example 11: Preparation of Compounds 28R and 28S

[0965]

[0966] Step 1: Preparation of 2-(isopropylamino)-2-phenylcyclohexan-1-one (28rac)

[0967] A mixture of 2-amino-2-phenyl-cyclohexan-1-one (4 g, 21.14 mmol, 1 eq.), 2-bromopropane (13.00 g, 105.68 mmol, 5 eq.), KI (701.71 mg, 4.23 mmol, 0.2 eq.) and K2CO3 (5.84 g, 42.27 mmol, 2 eq.) 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 C18250*70 mm, 10 μM; mobile phase: A: water (10 mM NH4HCO3); B: ACN; B%: 25%-55%, 25 min) to provide 2-(isopropylamino)-2-phenylcyclohexan-1-one (1 g, 4.32 mmol, yield 20.45%) (28 rac) as a white solid.

[0968] Step 2: (R)-2-(isopropylamino)-2-phenylcyclohexan-1-one (28R) and (S)-2-(isopropylamino)-2-phenylcyclohexan-1-one Preparation of Phenylcyclohexan-1-one (28S)

[0969] The racemate was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: CO 2 , B: 0.1% NH 3 H 2 O / EtOH, B%: 10%; multiple injection method with 5 min interval between injections) to provide ENT-1 0.659 min (230 mg) as a white solid and ENT-2 1.111 min (250 mg) as a white solid. The retention time was determined using the following chiral analysis method: column: Chiralpak AD-3, 100×4.6 mm ID, 3 μm; mobile phase: A:CO2B: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.

[0970] ENT-1, RT = 0.659 min (identified here as R isomer, 28R); LCMS R T =1.630 min; 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 min (here identified as S isomer, 28S); LCMS R T =1.636 min; MS calculated value: 231.33, [M+H] + =232.1; 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 C 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.

[0971] Example 12: Preparation of Compounds 84R, 84S, 11R and 11S

[0972]

[0973] Step 1: Preparation of 2-nitro-2-phenyl-cyclohexan-1-one

[0974] A mixture of 2-phenylcyclohexan-1-one (15 g, 86.09 mmol, 1 eq.), CAN (94.39 g, 172.18 mmol, 85.81 mL, 2 eq.) and Cu(OAc) (3.13 g, 17.22 mmol, 0.2 eq.) in DCE (150 mL) was stirred at 85 ° C for 12 h. After completion, the mixture was filtered and concentrated. The residue was purified by silica gel (PE: EA = 30: 1) to provide 2-nitro-2-phenyl-cyclohexan-1-one (10 g, 45.61 mmol, 52.98% yield) as a yellow oil. 1 H 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).

[0975] Step 2: Preparation of 2-amino-2-phenyl-cyclohexan-1-one (11rac)

[0976] A mixture of 2-nitro-2-phenyl-cyclohexan-1-one (10 g, 45.61 mmol, 1 eq.) and Zn (23.86 g, 364.90 mmol, 8 eq.) in AcOH (100 mL) was stirred at 20 ° C for 12 hours. After completion, the mixture was filtered and concentrated. The residue was dissolved in DCM, washed with saturated NaHCO , H O and brine, dried over Na SO , filtered and concentrated to provide 2-amino-2-phenyl-cyclohexan-1-one (7.5 g, 39.63 mmol, 86.88% yield) (11rac) as a brown oil. 1 H 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).

[0977] Step 3: Preparation of 2-(azetidin-1-yl)-2-phenyl-cyclohexan-1-one (84rac)

[0978] A mixture of 2-amino-2-phenyl-cyclohexan-1-one (2 g, 10.57 mmol, 1 eq.), 1,3-dibromopropane (2.77 g, 13.74 mmol, 1.40 mL, 1.3 eq.), KI (526.28 mg, 3.17 mmol, 0.3 eq.), and KCO (4.38 g, 31.70 mmol, 3 eq.) 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 afford 2-(azetidin-1-yl)-2-phenyl-cyclohexan-1-one (1 g, 4.36 mmol, 41.26% yield) (84 rac) as a white solid.

[0979] Step 4: (R)-2-(azetidin-1-yl)-2-phenyl-cyclohexan-1-one (84R) and (S)-2-(azetidin-1-yl)-2-phenyl-cyclohexan-1-one Preparation of 2-(4-( ...dimethylamino)-1-nitropropane)-2-nitropropane)-1-ol)-2-phenyl-cyclohexan-1-one (84S)

[0980] The racemate (84rac) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: CO 2 , B: 0.1% NH 3 H 2 O in ETOH; B%: 15%; multiple injection method) to provide ENT-1 0.736 min (340 mg) as a white solid and ENT-2 0.831 min (370 mg) as a white solid. The retention time was determined using the following chiral analysis method: Column: Chiralpak AD-3, 50 x 4.6 mm ID, 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.

[0981] ENT-1, RT = 0.736 min (identified as R isomer, 84R); LCMS (R T =1.534 min, MS calculated value: 229.15, [M+H] + =230.1); 1 H NMR (400MHz, chloroform-d) δppm7.47-7.41(m,2H),7.38-7.32(m,1H),7.16(d,J=7.6Hz,2H),3.29(q,J=7.2 Hz,2H),3.09(q,J=6.8Hz,2H),2.64(qd,J=3.2,14.0Hz,1H),2.39-2.26(m,2H),1.95-1.55(m,7H); 13 C 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 (here identified as S isomer, 84S); LCMS (R T =1.529 min, MS calculated value: 229.15, [M+H] + =230.1); 1H NMR (400MHz, chloroform-d) δppm7.49-7.40(m,2H),7.39-7.32(m,1H),7.16(d,J=7.6Hz,2H),3.30(q,J=6.8 Hz,2H),3.10(q,J=6.8Hz,2H),2.65(qd,J=3.2,14.0Hz,1H),2.39-2.26(m,2H),1.94-1.52(m,7H); 13 C 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.

[0982] Step 5: (S)-2-amino-2-phenyl-cyclohexan-1-one (11S) and (R)-2-amino-2-phenyl-cyclohexan-1-one Preparation of (11R)

[0983] Racemic 2-amino-2-phenyl-cyclohexan-1-one (11rac) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: CO 2 , B: 0.1% NH 3 H 2 O in MeOH]; B%: 42%; multiple injection method with an interval of 3.8 min between injections) to provide ENT-1 1.691 min (370 mg, 1.96 mmol) as an off-white solid and ENT-2 2.135 min (340 mg, 1.80 mmol) as an off-white solid. The retention time was determined using the following chiral analysis method: column: Chiralpak AD-3, 100×4.6 mm ID, 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.

[0984] ENT-1, RT = 1.691 min (determined to be S isomer, 11S); LCMS (R T =1.360 min, MS calculated value: 189.12, [M+H] + =190.1); 1H 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 (here identified as R isomer, 11R); LCMS (R T =1.387 min, MS calculated value: 189.12, [M+H] + =190.1); 1 H 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 C 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.

[0985] Example 13: Preparation of Compounds 114S and 114R

[0986]

[0987] Step 1: Preparation of 2-(o-tolyl)cyclohexan-1-ol

[0988] A solution of 1-bromo-2-methylbenzene (10 g, 58.47 mmol, 1 eq.) in THF (100 mL) was cooled to -70 ° C. Then n-BuLi (2.5 M, 27 mL, 1.15 eq.) was added. The mixture was stirred at -70 ° C for 0.5 hours, and then 7-oxabicyclo[4.1.0]heptane (6.31 g, 64.31 mmol, 1.1 eq.) and BF3·Et2O (9.13 g, 64.31 mmol, 1.1 eq.) were added. The mixture was stirred at -70 ° C for 1.5 hours. After completion, the mixture was poured into a saturated NH4Cl aqueous solution (100 ml) and extracted with EA (50 mL x 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 provide 2-(o-tolyl)cyclohexan-1-ol (4 g, 21.02 mmol, 35.95% yield) as a colorless oil. 1 H 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).

[0989] Step 2: Preparation of 2-(o-tolyl)cyclohexan-1-one

[0990] To a mixture of 2-(o-tolyl)cyclohexan-1-ol (3.5 g, 18.39 mmol, 1 eq.) in DCM (15 mL) was added Dess-Martin periodinane (DMP, 11.70 g, 27.59 mmol, 1.5 eq.) at 0 ° C under N2. The mixture was stirred at 25 ° C for 12 hours. The mixture was filtered and the filtrate was washed with saturated Na2SO3 aqueous solution, saturated Na2CO3 aqueous solution and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel (PE: EA = 50: 1-8: 1) to provide 2-(o-tolyl)cyclohexan-1-one (2.9 g, 15.40 mmol, 83.74% yield) as a colorless 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).

[0991] Step 3: Preparation of 2-nitro-2-(o-tolyl)cyclohexan-1-one

[0992] A mixture of 2-(o-tolyl)cyclohexanone (2.4 g, 12.75 mmol, 1 eq.), ceric ammonium nitrate (CAN, 13.98 g, 25.50 mmol, 2 eq.) and Cu(OAc) (463 mg, 2.55 mmol, 0.2 eq.) in DCE (25 mL) was stirred at 85 ° C for 12 hours. The mixture was cooled, filtered and concentrated. The residue was purified by column chromatography (SiO , petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to provide 2-nitro-2-(o-tolyl)cyclohexan-1-one (1.2 g, 5.14 mmol, 40.35% yield) as a yellow oil. 1 HNMR (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).

[0993] Step 4: Preparation of 2-amino-2-(o-tolyl)cyclohexan-1-one (114rac)

[0994] A mixture of 2-nitro-2-(o-tolyl)cyclohexan-1-one (2 g, 8.57 mmol, 1 eq.) and Zn (3.92 g, 60.02 mmol, 7 eq) in AcOH (25 mL) was stirred at 20 ° C for 12 hours. The mixture was filtered and concentrated. The residue was dissolved in DCM, washed with saturated NaHCO3 aqueous solution, H2O and brine, dried over Na2SO4, filtered and concentrated to provide 2-amino-2-(o-tolyl)cyclohexan-1-one (900 mg, 4.43 mmol, 51.64% yield) (114 rac) as a brown oil.

[0995] Step 5: (S)-2-amino-2-(o-tolyl)cyclohexan-1-one (114S) and (R)-2-amino-2-(o-tolyl) Preparation of cyclohexan-1-one (114R)

[0996] The racemate was separated by SFC (column: REGIS (s,s) WHELK-O1 (250 mm*30 mm, 5 μm); mobile phase: A: A: CO2, B: 0.1% NH3 H2O in IPA; B%: 15%, multiple injection method with 10 min interval between runs) to afford ENT-1 1.591 min (260 mg, 1.28 mmol) as a yellow oil and ENT-2 1.906 min (330 mg, 1.62 mmol) as a yellow oil. The retention time was determined using the following chiral analysis method: column: (S,S)-WHELK-O1, 100×4.6 mm ID, 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.

[0997] ENT-1, RT = 1.591 min (determined to be S isomer, 114S); LCMS (R T =1.448 min, MS calculated value: 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 (here identified as R isomer, 114R); LCMS (R T =1.482 min, MS calculated value: 203.13, [M+H] + =204.1); 1HNMR (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 CNMR (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.

[0998] Example 14: Preparation of Compounds 31S and 31R

[0999]

[1000] Step 1: Preparation of 2-morpholino-2-phenylcyclohexan-1-one (31rac)

[1001] A mixture of 2-amino-2-phenyl-cyclohexan-1-one (2 g, 10.57 mmol, 1 eq.), 1-bromo-2-(2-bromoethoxy)ethane (7.35 g, 31.70 mmol, 3.97 mL, 3 eq.), KCO (4.38 g, 31.70 mmol, 3 eq.) and KI (526 mg, 3.17 mmol, 0.3 eq.) 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% NH 3 H 2 O + 10 mM NH 4 HCO 3 ), B: ACN; B%: 20%-55%, 30 min) to afford 2-morpholino-2-phenylcyclohexan-1-one (1.1 g, 4.24 mmol, 40.14% yield) as a white solid.

[1002] Step 2: (S)-2-morpholino-2-phenylcyclohexan-1-one (31S) and (R)-2-morpholino-2-phenylcyclohexan-1-one Preparation of (31R)

[1003] The racemate was separated by SFC (column: REGIS (R, R) WHELK-O1 (250 mm*25 mm, 10 μm); mobile phase: A: CO 2 , B: 0.1% NH 3 H 2 O in IPA; B%: 38%, multiple injection method with 6 min interval between injections) to provide ENT-1 1.950 min (434 mg) as a white solid and ENT-2 2.276 min (474 ​​mg) as a white solid. The retention time was determined using the following chiral analysis method: column: (S,S)-WHELK-O1, 100×4.6 mm ID, 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.

[1004] ENT-1, RT = 1.950 min (determined to be S isomer, 31S); LCMS (R T =1.425min, MS calculated value: 259.34, [M+H] + =260.1); 1 H 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 C 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; (here identified as the R isomer, 31R); LCMS (R T =1.439 min, MS calculated value: 259.34, [M+H] + =260.1); 1H 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.

[1005] Example 15: Preparation of compounds 117rac and 18rac

[1006]

[1007] Step 1: Preparation of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one

[1008] A mixture of 2-(4-fluorophenyl)cyclohexan-1-one (5 g, 26.01 mmol, 1 eq.), ceric ammonium nitrate (CAN, 28.52 g, 52.02 mmol, 2 eq.) and Cu(OAc) (945 mg, 5.20 mmol, 0.2 eq.) in DCE (50 mL) was stirred at 85 ° C for 12 hours. The mixture was cooled, filtered and concentrated. The residue was purified by column chromatography (SiO , petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to provide 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).

[1009] Step 2: Preparation of 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (117rac)

[1010] A mixture of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (3g, 12.65mmol, 1eq.) and Zn (19.85g, 303.51mmol, 24eq.) in AcOH (25mL) was stirred at 20°C for 12 hours. 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 provide 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1.5g, 7.24mmol, 57.23% yield) (117rac) as a brown oil. LCMS (R T =1.336 min, MS calculated value: 207.11, [M+H] + =208.1) 1 H 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 C 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.

[1011] Step 3: Preparation of 2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one (18rac)

[1012] A mixture of 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1.3 g, 6.27 mmol, 1 eq.) and methyl trifluoromethanesulfonate (1.03 g, 6.27 mmol, 1 eq.) in hexafluoroisopropanol (HFIP, 130 mL) was stirred at 0-25 ° C under an N atmosphere for 12 hours. The mixture was filtered and concentrated. The residue was adjusted to pH = 7 with saturated Na CO (20 ml). The aqueous phase was extracted with EA (50 mL x 2). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na SO , 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% NH 3 H 2 O), B: ACN; B%: 18%-48%, 32 min) to provide 2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one (590 mg, 4.02 mmol, 42.45% yield) (18 rac) as a white solid. LCMS (R T =1.415 min, MS calculated value: 221.12, [M+H] + =222.1); 1 H NMR (400 MHz, chloroform-d) δ = 7.26-7.17 (m, 2H), 7.07 (brt, 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 C 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.

[1013] Example 16: Preparation of compounds 118rac and 23rac

[1014]

[1015] Step 1: Preparation of 2-(m-tolyl)cyclohexan-1-ol

[1016] A mixture of 1-bromo-3-methylbenzene (15 g, 87.70 mmol, 10.64 mL, 1 eq.) in THF (150 mL) was cooled to -70°C. n-BuLi (2.5 M, 38.59 mL, 1.1 eq.) was then added. The mixture was stirred at -70°C for 0.5 hours, and then 7-oxabicyclo[4.1.0]heptane (9.47 g, 96.47 mmol, 9.76 mL, 1.1 eq.) and BF3·Et2O (13.69 g, 96.47 mmol, 11.91 mL, 1.1 eq.) were added. The mixture was stirred at -70°C for 1.5 hours. The mixture was poured into a saturated aqueous NH4Cl solution (200 mL) and extracted with EA (100 mL x 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 provide 2-(m-tolyl)cyclohexan-1-ol (13 g, 68.32 mmol, 77.9% yield) as a colorless oil. 1 H NMR (400MHz, chloroform-d) δ = 7.33-7.28 (m, 1H), 7.16-7.09 (m, 3H), 3.72 (dt, J = 4. 0,10.0Hz,1H),2.50-2.44(m,1H),2.41(s,3H),2.22-2.14(m,1H),1.92(br d,J=10.8Hz,2H),1.83(br d,J=12.4Hz,1H),1.61-1.36(m,4H).

[1017] Step 2: Preparation of 2-(m-tolyl)cyclohexan-1-one

[1018] At 0 ° C, to a mixture of 2- (m-tolyl) cyclohexan-1-ol (13g, 68.32mmol, 1eq.) in DCM (50mL) was added Dess-Martin periodinane (43.47g, 102.48mmol, 31.73mL, 1.5eq.) in several portions (maintaining the temperature at 0 ° C during the addition). The mixture was then stirred at 20 ° C for 12 hours. The mixture was filtered and the filtrate was washed with saturated Na2SO3 aqueous solution, saturated Na2CO3 aqueous solution and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE: EA = 1: 0-5: 1) to provide 2- (m-tolyl) cyclohexan-1-one (13g, crude product) as a white solid. 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).

[1019] Step 3: Preparation of 2-(m-tolyl)-2-nitro-cyclohexan-1-one

[1020] By 2- (m-tolyl) cyclohexan-1-one (11g, 58.43mmol, 1eq.), ceric ammonium nitrate (CAN, 64.06g, 116.86mmol, 58.24mL, 2eq.) and Cu (OAc) 2 (2.12g, 11.69mmol, 0.2eq.) mixture in DCE (200mL) is stirred at 85 DEG C for 12 hours.The mixture is cooled and filtered and the filter cake is washed with EtOAc (80mL x 4).The filtrate is concentrated under vacuum to obtain a residue, and the residue is passed through silica gel chromatography (SiO 2, PE / EtOAc=10 / 1) to provide 2- (m-tolyl) -2- nitro - cyclohexan-1-one (3g, 12.86mmol, 22.01% yield), which is 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).

[1021] Step 4: Preparation of 2-amino-2-(m-tolyl)cyclohexan-1-one (118rac)

[1022] To a mixture of 2-(m-tolyl)-2-nitro-cyclohexan-1-one (2.5g, 10.72mmol, 1eq.) in AcOH (30mL) was added Zn (16.82g, 257.22mmol, 24eq.) over 1 hour, and the mixture was then stirred at 20°C for 12 hours. After completion, the mixture was filtered and the filtrate was concentrated. The residue was dissolved with DCM (10mL), adjusted to pH=8 with saturated Na2CO3 and extracted with DCM (10mL x 2). The organic phase was dried over Na2SO4, filtered and concentrated to provide 2-amino-2-(m-tolyl)cyclohexan-1-one (1.90g, 9.35mmol, 87.21% yield) (118rac), which was 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.

[1023] Step 5: Preparation of 2-(methylamino)-2-(m-tolyl)cyclohexan-1-one (23rac)

[1024] To a mixture of 2-amino-2-(m-tolyl)cyclohexan-1-one (1.34 g, 6.59 mmol, 1 eq.) in hexafluoroisopropanol (HFIP, 140 mL) was added methyl trifluoromethanesulfonate (1.08 g, 6.59 mmol, 721.15 uL, 1 eq.) at 0°C. The mixture was then stirred at 25°C under an N2 atmosphere for 12 hours. The mixture was filtered and concentrated. The residue was adjusted to pH = 7 with a Na2CO3 aqueous solution (30 ml). The aqueous phase was extracted with EA (100 mL x 2). The combined organic phases were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Agela DuraShell C18250*70 mm, 10 μm; mobile phase: A: water (0.05% NH 3 H 2 O + 10 mM NH 4 HCO 3 ), B: ACN; B%: 29%-59%, 20 min) to provide 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 H 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 CNMR (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.

[1025] Example 17: Preparation of compounds 120rac and 119rac

[1026]

[1027] Step 1: Preparation of 2-(p-tolyl)cyclohexan-1-ol

[1028] A solution of 1-bromo-4-methylbenzene (15 g, 87.70 mmol, 10.79 mL, 1 eq.) in THF (200 mL) was cooled to -70 ° C. Then n-BuLi (2.5 M, 38.59 mL, 1.1 eq.) was added. The mixture was stirred at -70 ° C for 0.5 hours, and then 7-oxabicyclo [4.1.0] heptane (9.47 g, 96.47 mmol, 9.76 mL, 1.1 eq.) and BF3·Et2O (13.69 g, 96.47 mmol, 11.91 mL, 1.1 eq.) were added. The mixture was stirred at -70 ° C for 1.5 hours. After completion, the reaction was slowly quenched with NH4Cl saturated aqueous solution (40 mL), and then extracted with EtOAc (50 mL x 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 provide 2-(p-tolyl)cyclohexan-1-ol (13 g, 68.32 mmol, 77.9% yield) as a white solid. 1 H 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).

[1029] Step 2: Preparation of 2-(p-tolyl)cyclohexan-1-one

[1030] To a mixture of 2-(p-tolyl)cyclohexan-1-ol (13 g, 68.32 mmol, 1 eq.) in CHCl (50 mL) was added Dess-Martin periodinane (43.47 g, 102.48 mmol, 31.73 mL, 1.5 eq.) in portions at 0°C (maintaining the temperature at 0°C during the addition). The mixture was then stirred at 20°C for 12 hours. The mixture was filtered. The filtrate was washed with saturated aqueous NaSO, saturated aqueous NaCO, and brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EA = 50:1-5:1) to provide 2-(p-tolyl)cyclohexan-1-one (12.01 g, 63.82 mmol, 93.41% yield) as a white solid. 1H 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).

[1031] Step 3: Preparation of 2-nitro-2-(p-tolyl)cyclohexan-1-one

[1032] By 2- (p-tolyl) cyclohexan-1-one (11g, 58.43mmol, 1eq.), ceric ammonium nitrate (CAN, 64.06g, 116.86mmol, 58.24mL, 2eq.) and Cu (OAc) 2 (2.12g, 11.69mmol, 0.2eq.) mixture in DCE (150mL) is stirred at 85 DEG C for 12 hours.The reaction mixture is cooled, filtered and the filtrate is concentrated.The residue is purified by column chromatography (SiO 2, PE / EA=1 / 0 to 0 / 1) to provide 2-nitro-2- (p-tolyl) cyclohexan-1-one (5.98g, 25.64mmol, 43.88% yield) as a yellow oil. 1 H 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).

[1033] Step 4: Preparation of 2-amino-2-(p-tolyl)cyclohexan-1-one (120rac)

[1034] To a solution of 2-nitro-2-(p-tolyl)cyclohexan-1-one (4.98g, 21.35mmol, 1eq.) in AcOH (40mL) was added Zn (33.50g, 512.38mmol, 24eq.) at 0°C. The mixture was stirred at 25°C for 12 hours. After completion, the mixture was filtered and concentrated. The residue was adjusted to pH=7 with Na2CO3 aqueous solution (150mL). The aqueous phase was extracted with DCM (200mLx 2) and the combined organic matter was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE / EA=1 / 0 to 0 / 1) to provide 2-amino-2-(p-tolyl)cyclohexan-1-one (1.3g, 6.40mmol, 29.95% yield) (120rac), which was a yellow oil. LCMS (RT =1.618 min, MS calculated value: 203.3, [M+H] + =204.1); 1 H 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 C 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.

[1035] Step 5: Preparation of 2-(methylamino)-2-(p-tolyl)cyclohexan-1-one (119rac)

[1036] To a mixture of 2-amino-2-(p-tolyl)cyclohexan-1-one (583 mg, 2.87 mmol, 1 eq.) in hexafluoroisopropanol (HFIP, 60 mL) was added methyl trifluoromethanesulfonate (470.65 mg, 2.87 mmol, 313.76 uL, 1 eq.) at 0°C. The mixture was then stirred at 25°C under an N2 atmosphere for 12 hours. The mixture was filtered and concentrated. The residue was adjusted to pH = 7 with a saturated Na2CO3 aqueous solution (100 mL). The aqueous phase was extracted with EA (100 mL x 2). The combined organic phases were washed with brine (100 mL x 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% NH 3 H 2 O), B: ACN; B%: 10%-45%, 35 min) to provide 2-(methylamino)-2-(p-tolyl)cyclohexan-1-one (398.86 mg, 1.84 mmol, yield 64.00%) (119 rac) 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); 13C 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.

[1037] Example 18: Preparation of Compounds 25R and 25S

[1038]

[1039] Step 1: Preparation of 2-(diethylamino)-2-phenylcyclohexan-1-one (25rac)

[1040] A mixture of 2-amino-2-phenyl-cyclohexan-1-one (5 g, 26.42 mmol, 1 eq.), iodoethane (20.60 g, 132.10 mmol, 10.57 mL, 5 eq.) and K2CO3 (10.95 g, 79.26 mmol, 3 eq.) in MeCN (50 mL) was stirred at 100°C for 12 hours. 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 provide 2-(diethylamino)-2-phenylcyclohexane-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).

[1041] Step 2: (R)-2-(diethylamino)-2-phenylcyclohexanone (25R) and (S)-2-(diethylamino)-2-phenyl Preparation of cyclohexanone (25S)

[1042] The racemate was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); mobile phase: A: CO 2 , B: 0.1% NH 3 H 2 O in IPA; B%: 11%, multiple injection method with 5 min interval between injections) to provide ENT-1 1.103 min (343 mg) as a yellow oil and ENT-2 1.300 min (373 mg) as a yellow oil. The retention time was determined using the following chiral analysis method: column: Chiralcel OJ-3, 100×4.6 mm ID, 3 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.

[1043] ENT-1, RT = 1.103 min (determined to be S isomer, 25S); LCMS (R T =1.456 min, MS calculated value: 245.18, [M+H] + =246.1); 1 H NMR (400MHz, 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 =7.2Hz,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 C 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 min (here identified as R isomer, 25R); LCMS (R T =1.514 min, MS calculated value: 245.18, [M+H] + =246.1); 1H NMR (400MHz, 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 =7.2Hz,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 C 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.

[1044] Example 19: Preparation of Compound 128mix

[1045]

[1046] Step 1: Preparation of 2-(2-methylazetidin-1-yl)-2-phenylcyclohexan-1-one (128 mix)

[1047] A mixture of 2-amino-2-phenyl-cyclohexan-1-one (200 mg, 1.06 mmol, 1 eq), 1,3-dibromobutane (296.63 mg, 1.37 mmol, 1.3 eq.), KI (52.63 mg, 317.04 umol, 0.3 eq.) and K2CO3 (438.16 mg, 3.17 mmol, 3 eq.) in MeCN (2 mL) was stirred at 100° C. for 12 hours. The mixture was cooled, filtered and concentrated. The residue was purified by preparative HPLC (mobile phase: A: water (0.05% NH3H2O ​​+ 10mM NH4HCO3), B: ACN; B%: 25%-55%, 8min) to provide 2-(2-methylazetidin-1-yl)-2-phenylcyclohexan-1-one (50mg, 205.47umol, yield 19.44%) (128mix) as a mixture of all 4 diastereomers as a yellow oil. LCMS (R T =1.542 min, MS calculated value: 243.16, [M+H] + =244.1); 1H NMR (400 MHz, CHLOROFORM-d) (partial integration due to the presence of a 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).

[1048] Example 20: Preparation of Compound 129rac

[1049]

[1050] Step 1: Preparation of 2-(3-methylazetidin-1-yl)-2-phenyl-cyclohexan-1-one (129rac)

[1051] A mixture of 2-amino-2-phenyl-cyclohexan-1-one (300 mg, 1.59 mmol, 1 eq.), 1,3-dibromo-2-methylpropane (444.94 mg, 2.06 mmol, 1.3 eq.), KI (78.94 mg, 475.55 umol, 0.3 eq.) and KCO (657.24 mg, 4.76 mmol, 3 eq.) in MeCN (5 mL) was stirred at 100° C. for 12 hours. 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 provide 2-(3-methylazetidin-1-yl)-2-phenyl-cyclohexan-1-one (16 mg, 65.09 umol, yield 4.11%, purity 99%) (129 rac) as a white solid. LCMS (R T =1.602 min, MS calculated value: 243.16, [M+H] + =244.1); 1 H 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).

[1052] Example 21. Metabolic stability in human liver microsomes

[1053] The stability of the disclosed compounds was tested in human liver microsomes (HLM), and the results are summarized in Table 2. For some compounds, stability was tested under two microsomal incubation conditions: one with normal enzyme activity (low activity) and one with a higher enzyme load, longer incubation time, and lower compound concentration (high activity) (intended to increase metabolic instability). Under both conditions, the disclosed compounds exhibited greater metabolic stability than ketamine in this model.

[1054] Drug. Compounds were tested as racemates (indicated by the designation "rac") or pure enantiomers (indicated by the designation "R" or "S").

[1055] HLM stability (low activity). Mixed HLM (XenoTech H0630) from adult male and female donors was used. Microsomes were incubated in 96-well plates in 5 equal portions of 40 μL each (one portion for each time point). The liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), 6-phosphate glucose (5.3 mM) and 6-phosphate glucose dehydrogenase (0.67 units / mL), with 0.42 mg of liver 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 the microsomes at 37°C and shaking at 100 rpm. Incubations were performed in duplicate. Five time points over 40 minutes were analyzed. The reaction was stopped by adding 12 volumes of 90% acetonitrile-water to the incubation aliquot, followed by protein precipitation by centrifugation at 5500 rpm for 3 minutes. The supernatant was analyzed for the remaining parent compound using a targeted liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, with authentic samples of each analyte used for identity confirmation.

[1056] HLM stability (low activity, alternative method). Mixed HLM (Corning 452117) from adult male and female donors was used. Microsome incubation was performed in a multiwell plate. The liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM) and NADPH (1 mM), with 0.50 mg of liver microsomal protein per mL. A control incubation was performed by replacing the NADPH cofactor system with PBS. The test compound (1 μM, final solvent concentration 1.0%) was incubated with the microsomes at 37°C with constant shaking. Six time points were analyzed over 60 minutes, with 60 μL aliquots of the reaction mixture withdrawn at each time point. The reaction aliquot was stopped by adding 180 μL of cold (4° C.) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL salicylate as an internal standard (IS), followed by shaking for 10 minutes and then protein precipitation by centrifugation at 4000 rpm for 20 minutes at 4° C. A sample of the supernatant (80 μL) was diluted with water (240 μL) and analyzed for residual parent compound using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[1057] HLM stability (high activity). Mixed HLM from adult male and female donors (XenoTech H0630) was used. Microsomes were incubated in 96-well plates in 5 equal portions of 40 μL each (one portion for each time point). The liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), 6-phosphate glucose (5.3 mM) and 6-phosphate glucose dehydrogenase (0.67 units / mL), with 1.0 mg of liver microsomal protein per mL. A control incubation was performed by replacing the NADPH-cofactor system with PBS. The test compound (1 μM, final solvent concentration 1.6%) was incubated with the microsomes at 37°C and shaking at 100 rpm. Incubations were performed in duplicate. Five time points over 60 minutes were analyzed. The reaction was stopped by adding 12 volumes of 90% acetonitrile-water to the incubation aliquot, followed by protein precipitation by centrifugation at 5500 rpm for 3 minutes. The supernatant was analyzed for the remaining parent compound using a targeted liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, with authentic samples of each analyte used for identity confirmation.

[1058] Data analysis. Elimination constants (k) were determined from ln(AUC) versus time curves using linear regression analysis. el ), half-life (t 1 / 2 ) and intrinsic clearance (Cl int ).

[1059] Table 2. Intrinsic clearance (Cl) of ketamine and its analogs in the presence of HLM under two incubation conditions. int ) and half-life (t 1 / 2 ). NT = Not tested.

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068] *Data collected using the “Low Activity, Alternative Method”.

[1069] Example 22. Metabolic stability in mouse liver microsomes

[1070] The stability of the disclosed compounds was tested in mouse liver microsomes (MLM), and the results are summarized in Table 3. Two microsomal incubation conditions were used, one with normal enzyme activity (low activity) and one with a higher enzyme load (high activity) (intended to increase metabolic instability). Under both conditions, the disclosed compounds exhibited greater metabolic stability than ketamine in this model.

[1071] Drug. Compounds were tested as racemates (indicated by the designation "rac") or pure enantiomers (indicated by the designation "R" or "S").

[1072] MLM stability (low activity). Mixed MLM (XenoTech M1000) from male CD-1 mice was used. Microsomes were incubated in multiwell plates. Liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM) and NADPH (1 mM), with 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 continuous shaking. Six time points over 60 minutes were analyzed, with 60 μL aliquots of the reaction mixture taken at each time point. The reaction aliquot was stopped by adding 180 μL of cold (4° C.) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL salicylate as an internal standard (IS), followed by shaking for 10 minutes and then protein precipitation by centrifugation at 4000 rpm for 20 minutes at 4° C. A sample of the supernatant (80 μL) was diluted with water (240 μL) and analyzed for residual parent compound using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[1073] MLM stability (high activity). Mixed MLM (XenoTech M3000) from male BALB / c mice was used. Microsomes were incubated in 96-well plates in 5 equal portions of 40 μL each (one portion at each time point). The liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), 6-phosphate glucose (5.3 mM) and 6-phosphate glucose dehydrogenase (0.67 units / mL), with 1.0 mg of liver microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. The test compound (1 μM, final solvent concentration 1.6%) was incubated with the microsomes at 37°C, 100 rpm shaking. Incubations were performed in duplicate. Five time points over 60 minutes were analyzed. The reaction was stopped by adding 9 volumes of 90% acetonitrile-water to the incubation aliquot, followed by protein precipitation by centrifugation at 5500 rpm for 3 minutes. The supernatant was analyzed for the remaining parent compound using a targeted liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, with authentic samples of each analyte used for identity confirmation.

[1074] Data analysis. Elimination constants (k) were determined from ln(AUC) versus time curves using linear regression analysis. el ), half-life (t 1 / 2 ) and intrinsic clearance (Cl int ).

[1075] Table 3. Intrinsic clearance (Cl) of ketamine and its analogs in the presence of MLM under two incubation conditions. int ) and half-life (t 1 / 2 ). NT = Not tested.

[1076]

[1077]

[1078]

[1079]

[1080]

[1081]

[1082]

[1083] Example 23. Metabolic stability in rat liver microsomes

[1084] The stability of the disclosed compounds was tested in rat liver microsomes (RLM), and the results are summarized in Table 4. Two microsomal incubation conditions were used differently, one with normal enzyme activity (low activity) and one with a higher enzyme load (high activity) (intended to increase metabolic instability). Under both conditions, the disclosed compounds exhibited greater metabolic stability than ketamine in this model. In addition, the deuterated compounds 88R and 88S exhibited increased metabolic stability and reduced formation of their respective metabolites 11R and 11S compared to their non-deuterated counterparts 14R and 14S (Tables 4 and 5). Figure 2 These effects on metabolism are more pronounced for the R isomer.

[1085] Drug. Compounds were tested as racemates (indicated by the designation "rac") or pure enantiomers (indicated by the designation "R" or "S").

[1086] RLM stability (low activity). Mixed RLM (XenoTech R1000) from male Sprague Dawley rats was used. Microsomes were incubated in a multi-well plate. Liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM) and NADPH (1 mM), with 0.50 mg of liver microsomal protein per mL. Control incubation was performed by replacing the NADPH-cofactor system with PBS. Test compound (1 μM, final solvent concentration 1.0%) was incubated with microsomes at 37°C with continuous shaking. Six time points over 60 minutes were analyzed, with 60 μL aliquots of the reaction mixture taken at each time point. The reaction aliquot was stopped by adding 180 μL of cold (4° C.) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL salicylate as an internal standard (IS), followed by shaking for 10 minutes and then protein precipitation by centrifugation at 4000 rpm for 20 minutes at 4° C. A sample of the supernatant (80 μL) was diluted with water (240 μL) and analyzed for residual parent compound using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[1087] RLM stability (high activity). Mixed RLM from male Sprague Dawley rats (XenoTech R1000, lot # 1910100) was used. Microsomes were incubated in 96-well plates in 5 equal portions of 40 μL each (one portion at each time point). The liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), 6-phosphate glucose (5.3 mM) and 6-phosphate glucose dehydrogenase (0.67 units / mL), with 1.0 mg of liver microsomal protein per mL. Control incubation was performed by replacing the NADPH-cofactor system with PBS. The test compound (1 μM, final solvent concentration 1.6%) was incubated with the microsomes at 37°C, 100 rpm shaking. The incubation was performed in duplicate. Five time points within 60 minutes were analyzed. The reaction was stopped by adding 9 volumes of 90% acetonitrile-water to the incubation aliquot, followed by protein precipitation by centrifugation at 5500 rpm for 3 minutes. The supernatant was analyzed for the remaining parent compound using a targeted liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, with authentic samples of each analyte used for identity confirmation.

[1088] These conditions were also used in experiments measuring the formation of metabolite 11R from compounds 14R and 88R, and metabolite 11S from compounds 14S and 88S. The concentrations of 11R and 11S formed during the incubation were quantified using a tailored liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, with authentic samples of each analyte used for calibration and identity confirmation.

[1089] Data analysis. Elimination constants (k) were determined from ln(AUC) versus time curves using linear regression analysis. el ), half-life (t 1 / 2 ) and intrinsic clearance (Cl int ).

[1090] Table 4. Intrinsic clearance (Cl) of ketamine and its analogs in the presence of RLM under two incubation conditions. int ) and half-life (t 1 / 2 ). NT = Not tested.

[1091]

[1092]

[1093]

[1094]

[1095]

[1096] Example 24. Oral bioavailability in mice

[1097] In mice, the disclosed compounds showed improved absolute oral bioavailability (F), longer half-life (t ) and longer survival (P ) in both plasma (Table 5) and brain (Table 6) compared to ketamine as quantified by area under the curve (AUC). l / 2 ), a higher maximum concentration (C max ) and higher absolute exposure.

[1098] Method A:

[1099] Animals. Male CD-1 mice were used in these studies. Animals were randomly assigned to treatment groups and fasted for 4 h before dosing.

[1100] Drugs. 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) in a volume of 5 mL / kg body weight. Compounds were tested as racemates (indicated by the designation "rac") or pure enantiomers (indicated by the designation "R" or "S").

[1101] Sample Collection and Bioanalysis. Blood samples were collected from the orbital sinus into microcontainers containing K2EDTA under 2,2,2-tribromoethanol anesthesia (150 mg / kg, ip) at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h (4 animals per time point). Immediately after blood collection, 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 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 centrifugation at 6000 rpm for 4 min, 0.5 μL of each supernatant was analyzed for drug using a targeted liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, with authentic samples of each analyte used for calibration and identification. Use zirconium oxide beads (115 mg ± 5 mg) in Bullet Brain samples (weight 100 mg ± 1 mg) were dispersed in 500 μL of internal standard solution (400 ng / mL in 4:1 v / v MeOH:water) in a homogenizer for 30 s at speed 8. After homogenization, the samples were centrifuged at 14,000 rpm for 4 min and 0.5 μL of each supernatant was analyzed for drug using the appropriate LC-MS / MS method, with authentic samples of each analyte used for calibration and identification.

[1102] Data Analysis. Sample drug concentrations below the lower limit of quantitation (LLOQ) were assigned a value of zero. Pharmacokinetic data were analyzed using the noncompartmental, bolus, or extravascular input analysis model in WinNonlin 5.2 (PharSight). Data points below the LLOQ were rendered as missing to improve t 1 / 2 Calculation effectiveness.

[1103] Method B:

[1104] Animals. Male CD-1 mice were used in these studies. Animals were randomly assigned to treatment groups and fasted for 4 h before oral administration.

[1105] Drug. 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) in a volume of 5 mL / kg body weight. Compounds were tested as racemates (indicated by the designation "rac") or as pure enantiomers (indicated by the designation "R" or "S").

[1106] Sample collection and bioanalysis. At 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 h (4 animals per time point), the animals were collected under light isoflurane anesthesia. Blood samples (about 60 μ L) were collected from the retroorbital plexus at 4 ℃, 4000 rpm. Immediately after collecting the blood, plasma was harvested by centrifugation for 10 min at 4 ℃, 4000 rpm and the sample was stored at -70 ± 10 ℃ until bioanalysis. After collecting the blood, the animal was immediately killed, the abdominal vena cava was cut, and 10 mL of normal saline was used to perfuse the whole body from the heart, and brain samples were collected from all animals. After separation, the brain sample was rinsed three times (5-10 seconds / rinsing, each rinse using the 5-10 mL normal saline in a disposable culture dish) in ice-cold normal saline and dried on absorbent paper. Ice-cold phosphate buffered saline (pH 7.4) was used to homogenize the brain sample. The total homogenate volume was three times the weight of the tissue. All homogenates were stored at -70 ± 10 ℃ until bioanalysis. For bioanalysis, 25 μL aliquots of plasma / brain study samples or spiked plasma / brain calibration standards were added to separate pre-labeled microcentrifuge tubes, followed by 100 μL of internal standard solution (glipizide, 500 ng / mL in acetonitrile), except for blanks, in which 100 μL of acetonitrile was added. The samples were vortexed for 5 minutes and then centrifuged at 4°C, 4000 rpm for 10 minutes. After centrifugation, 100 μL of each clarified supernatant was transferred to a 96-well plate and analyzed using the intended LC-MS / MS method, with authentic samples of each analyte used for calibration and identification.

[1107] Data analysis and usage Pharmacokinetic parameters were estimated using the non-compartmental analysis tool of WinNonlin software (version 8.0).

[1108] Table 5. Selected pharmacokinetic parameters of ketamine and analogs in plasma of CD-1 mice.

[1109]

[1110]

[1111]

[1112] *For parameters determined by Method B, AUC values ​​represent AUC 0-last And the calculated F is based on these values ​​rather than on the AUC 0-inf .

[1113] Table 6. Selected pharmacokinetic parameters of ketamine and analogs in the brain of CD-1 mice.

[1114]

[1115]

[1116] *For parameters determined by Method B, AUC values ​​represent AUC 0-last And the calculated F is based on these values ​​rather than on the AUC 0-inf .

[1117] **Calculated based on brain exposure.

[1118] Example 25. Exposure after intraperitoneal administration in mice

[1119] In mice, intraperitoneal (ip) administration of compounds 14R and 14S at 3.16 mg / kg produced maximum concentration values ​​(C0.05) in both plasma (Table 7) and brain (Table 8), as quantified by the area under the curve (AUC). max ) and absolute exposures were comparable to or higher than those achieved by ketamine after a higher dose of 10 mg / kg. Thus, when measured on a dose-equivalent basis, exposures of 14R and 14S were much higher than those of ketamine after IP administration. Furthermore, after the same dose, exposure (AUC) of 14R was approximately twice that of 14S, suggesting greater metabolic stability of the R isomer.

[1120] Animals. Male CD-1 mice were used in these studies. Animals were randomly assigned to treatment groups and fasted for 4 hours before dosing.

[1121] Drug. Test compounds (HCl salts) were dissolved in deionized water and administered intraperitoneally (ip) at the indicated doses (calculated based on the free base) in a volume of 5 mL / kg body weight. As indicated, compounds were tested as racemates (indicated by the designation "rac") or pure enantiomers (indicated by the designation "R" or "S").

[1122] Pharmacokinetics. Blood samples were collected from the orbital sinus into microcontainers containing K2EDTA under 2,2,2-tribromoethanol anesthesia (150 mg / kg, ip) at 0.083, 0.25, 0.5, 1, and 2 h (ketamine, 4 animals per time point) or 0.083, 0.25, 0.5, 1, 2, 4, and 8 h (14R and 14S, 4 animals per time point). Immediately after blood collection, mice were euthanized by cervical dislocation and brain samples were collected at the same time points. All samples were immediately processed, quickly frozen, and stored at -70°C until subsequent analysis. Plasma samples were separated by centrifugation of whole blood, and aliquots (50 μL) were mixed with 200 μL of internal standard solution (400 ng / mL in 1:1 v / v CH3CN:MeOH). After mixing by pipetting and centrifugation at 6000 rpm for 4 min, 0.5 μL of each supernatant was analyzed for drug using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, with authentic samples of each analyte used for calibration and identification. Zirconia beads (115 mg ± 5 mg) were used in a Bullet Brain samples (weight 200 mg ± 1 mg) were dispersed in 800 μL of internal standard solution (400 ng / mL in 4:1 v / v MeOH:water) in a homogenizer for 30 s at speed 8. After homogenization, the samples were centrifuged at 14,000 rpm for 4 min and 0.5 μL of each supernatant was analyzed for drug using the appropriate LC-MS / MS method, with authentic samples of each analyte used for calibration and identification.

[1123] Data Analysis. Sample drug concentrations below the lower limit of quantitation (LLOQ) were assigned a value of zero. Pharmacokinetic data were analyzed using the noncompartmental, bolus, or extravascular input analysis model in WinNonlin 5.2 (PharSight). Data points below the LLOQ were rendered as missing to improve t 1 / 2 Calculation effectiveness.

[1124] Table 7. Selected pharmacokinetic parameters of ketamine and analogs in plasma of CD-1 mice following ip administration.

[1125]

[1126] Table 8. Selected pharmacokinetic parameters of ketamine and analogs in the brain of CD-1 mice following ip administration.

[1127]

[1128] Example 26. Oral bioavailability in rats

[1129] In rats, the compounds disclosed herein exhibit improved absolute oral bioavailability (F), longer half-life (t l / 2 ), a higher maximum concentration (C max ) and higher absolute exposure (Table 9). These studies also showed that deuteration of the N-methyl group (as in compound 88R) increased the oral bioavailability of the compound compared to its non-deuterated counterpart 14R. The formation of the same metabolite from 88R was also reduced compared to the formation of the metabolite 11R from the non-deuterated compound 14R after oral administration (Table 10).

[1130] Method A:

[1131] Animals. Male Sprague Dawley rats were used in these studies. Animals were randomly assigned to treatment groups and fasted overnight before oral dosing.

[1132] Drugs. 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) in a volume of 5 mL / kg body weight. The compounds were tested as racemates (indicated by the designation "rac").

[1133] Sample Collection and Bioanalysis. Blood samples were collected from the external jugular vein (via cannula) at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after dosing (a total of 8 time points / rat, 4 rats per dosing route). At each time point, ~0.2 mL of blood was removed 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 promote mixing of the anticoagulant with the blood. The blood samples were kept on ice until centrifugation. The collected blood samples were centrifuged at 4°C, 4000 rpm for 10 min. After centrifugation, 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. 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. After centrifugation, 5 μL of each clear supernatant was analyzed using the appropriate LC-MS / MS method, with authentic samples of the analyte used for calibration and identification.

[1134] Data analysis and usage Pharmacokinetic parameters were estimated using the non-compartmental analysis tool of WinNonlin software (version 8.1). Drug concentrations of samples below the lower limit of quantitation (LLOQ) were assigned a value of zero.

[1135] Method B:

[1136] Animals. Male Sprague Dawley rats were used in these studies. Animals were randomly assigned to treatment groups and fasted overnight before oral dosing.

[1137] Drug. 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). They were then administered intravenously (iv) or orally (po) at a dose of 10 mg / kg (calculated based on the free base) in a volume of 5 mL / kg body weight. Compounds were tested as racemates (indicated by the designation "rac") or as pure enantiomers (indicated by the designation "R" or "S").

[1138] Sample collection and bioanalysis. At 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 h (a total of 8 time points / rat, 4 rats per compound per administration route), the rats were collected under light isoflurane anesthesia. Blood samples (about 120 μ L) were collected from the retroorbital plexus at 4 ° C, 4000 rpm. Immediately after collecting blood, plasma was harvested by centrifugation for 10 min at 4 ° C, 4000 rpm and the samples were stored at -70 ± 10 ° C until bioanalysis. For bioanalysis, 25 μ L aliquots of plasma research samples or spiked plasma calibration standards were added to separate pre-labeled microcentrifuge tubes, followed by the addition of 100 μ L internal standard solutions (glipizide, 500 ng / mL in acetonitrile), except for the blank, in which 100 μ L acetonitrile was added. The sample was vortexed for 5 minutes and then centrifuged for 10 minutes at 4 ° C, 4000 rpm. After centrifugation, 100 μ L of each clear supernatant was transferred to a 96-well plate and analyzed using the LC-MS / MS method for the purpose, wherein the true sample of each analyte was used for calibration and identification. In the case of compounds 14R and 88R, their metabolite 11R was also quantitatively analyzed in plasma samples.

[1139] Data analysis and usage Pharmacokinetic parameters were estimated using the non-compartmental analysis tool of WinNonlin software (version 8.0).

[1140] Table 9. Selected pharmacokinetic parameters of ketamine and analogs in plasma of Sprague Dawley rats.

[1141]

[1142]

[1143] Table 10. Exposure of metabolite 11R in plasma of Sprague Dawley rats following iv or po administration of compounds 14R and 88R at 10 mg / kg.

[1144]

[1145]

[1146] Example 27. NMDA Receptor Binding

[1147] The binding affinity of the disclosed compounds at the MK-801 binding site of the N-methyl-D-aspartate receptor (NMDAR) was determined in a radioligand binding experiment (Table 11). The values ​​shown for racemic ketamine (rac-ketamine) and its enantiomers are taken from the literature (Ebert et al. 1997). In general, the R enantiomers of the compounds of the present invention exhibit weaker binding affinity to NMDAR, which suggests that the isolated side effects of these compounds are reduced compared to their corresponding S enantiomers or racemates. In contrast, given that the S isomers have higher potency at NMDAR, they may have higher potency as anesthetics. For example, compound 14R showed weaker NMDAR binding than rac-ketamine, (R)-ketamine, (S)-ketamine, and 14S, which suggests that it may have less obvious isolated side effects than these compounds at equimolar doses. Many compounds of the invention exhibit affinities within the desired range of 1-5 μM, including, for example, 14R, 11S, 88R, 27rac, 29rac, 19S, 114S, and 18rac. In some cases, the R isomer exhibits activity within the target affinity range, in other cases the S isomer is more desirable, and in some cases, both stereoisomers or racemates fall within the desired range. In fact, the eudysmic ratio of each pair of enantiomers varies widely, in some cases <2, and in other cases, ranging up to ˜10.

[1148] Table 11. Binding affinity at the MK-801 site of NMDAR.

[1149]

[1150]

[1151]

[1152] *Ebert et al. 1997

[1153] **Mixture of all 4 diastereomers

[1154] Radioligand Binding—Method A. Radioligand binding was performed by Eurofins Panlabs, Inc. using a method adapted from the literature (Javitt et al. 1987; Reynolds et al. 1989) and under the conditions described in Table 12. 3 H]MK-801 was used to determine the affinity of test compounds for NMDAR in radioligand binding experiments.

[1155] Table 12. NMDAR radioligand binding experimental parameters for Method A.

[1156]

[1157]

[1158] *Historical value

[1159] Radioligand Binding - Method B. Radioligand binding was performed by WuXi AppTec (Hong Kong) Limited under the conditions described in Table 13 using [ 3 H]MK-801 was used to determine the affinity of test compounds for NMDAR in radioligand binding experiments.

[1160] Table 13. NMDAR radioligand binding experimental parameters for Method B.

[1161] Receptor source Male Sprague Dawley rat cortex Incubation time 1h Incubation temperature 25℃ Incubation buffer 50 mM Tris-HCl, pH 7.4 ligand <![CDATA[5.0nM[ 3 H]MK-801]]> Nonspecific ligands 10.0 μM (+)-MK-801

[1162] Example 28. Activity on monoamine transporters

[1163] The ability of the compounds of the invention to inhibit the uptake of monoamines by serotonin transporter (SERT), norepinephrine transporter (NET), dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) (collectively referred to as monoamine transporters, MATs) was measured in transfected cells using a fluorescent substrate uptake assay (Table 14). The binding affinity of the selected compounds to SERT, NET and / or DAT was also determined in a radioligand displacement assay (Table 14). The activity of compounds containing a cyclic moiety on the amine was generally the greatest. For example, compounds 26, 27 and 84 all exhibited a monoamine uptake IC<10 μM in one or more of the MATs tested. 50 The activity of compound 27S is particularly noteworthy as it exhibited an IC of 0.041 μM in SERT. 50. However, there is a clear exception to the trend of greater MAT inhibitory activity for cyclic amines, as the enantiomer of compound 31 containing a morpholine ring shows almost no activity against MAT. Considering that inhibitors of MAT are well known to have antidepressant and antianxiety effects and are the most commonly prescribed drugs for mood disorders (e.g., fluoxetine, sertraline, venlafaxine, imipramine, etc.), it is expected that the blockade of MAT by certain compounds of the present invention will synergize with their NMDAR inhibition to increase the therapeutic activity for treating depression and related conditions. In fact, this synergy between these two mechanisms of action has been demonstrated in animal models (Ates-Alagoz and Adejare 2013). In addition, it is conceivable that compounds with sufficient efficacy for both targets can be used as alternatives to two separate drugs that target MAT and NMDAR, respectively. For example, compounds with significant affinity for both SERT and NMDAR (such as 27S) can replace the combination of selective serotonin reuptake inhibitors (SSRIs) (such as fluoxetine) and NMDAR antagonists (such as ketamine) with a single therapeutic agent. In addition, the ability to adjust the ratio between MAT and NMDAR and between different MATs themselves can be used to obtain the best treatment plan according to the expected clinical indication. For example, compounds with higher selectivity for NMDAR (such as 14R, 11S, 88R, 29rac, 19S, 114S or 18rac) may be the preferred treatment for patients who are intolerant to the side effects of MAT inhibitors. Alternatively, compounds with significant inhibitory activity on DAT (such as 26R or 28S) may be useful treatments for psychostimulant abuse.

[1164] Table 14. Uptake inhibitory activity and binding affinity to monoamine transporters.

[1165]

[1166]

[1167] Uptake inhibition. The ability of the test compound to block the uptake of monoamines by SERT, NET, DAT, and VMAT2 was determined using the Neurotransmitter Transporter Uptake Assay Kit (Cat# R8173) manufactured by Molecular Devices. Briefly, stable transfected cells expressing the MAT of interest (HEK293 cells were used for SERT and NET; CHO cells were used for DAT) were grown and seeded into 384-well plates at a concentration of 20,000 cells per well. The plates were then incubated at 37°C and 5% CO2 for 16-20h. The medium was then aspirated and replaced with 25 μL of assay buffer (20 mM HEPES in HBSS containing 0.1% BSA) containing the test compound at the appropriate concentration. The plate was then centrifuged at 300 rpm for 15s and then incubated at 37°C for 30 minutes. At this point, 25 μL of a proprietary fluorescent dye solution was added, the plate was incubated at 37°C for 60 minutes, and then the fluorescence was quantified on a plate reader (excitation wavelength = 440 nm, emission wavelength = 520 nm). The proprietary dye solution contains a mixture of: 1) a fluorescent dye that mimics the endogenous substrate of MAT and is therefore actively transported to the intracellular compartment in the absence of an inhibitor; and 2) a masking dye that inhibits the fluorescence of dye 1 in the extracellular compartment. Therefore, as the fluorescent dye is transported into the cell, the overall fluorescence of the system increases. In the presence of an inhibitor of MAT under study, the uptake of the dye is reduced, and therefore the fluorescence is also reduced, enabling this inhibition to be quantified.

[1168] Radioligand binding. Under the conditions described in Table 15, the radioligands were prepared by WuXi AppTec (Hong Kong) Limited using [ 3 H] imipramine, [ 3 H] nisoxetine and [ 3 H]WIN35,428 was used to determine the affinity of test compounds for SERT, NET, and DAT in radioligand binding experiments.

[1169] Table 15. SERT, NET and DAT radioligand binding experimental parameters.

[1170]

[1171] Example 29. Effects of chronic social defeat stress on behavioral tests in mice

[1172] In mice, compound 35rac reversed the prodepressive effect (Figure 3) caused by chronic social defeat stress (CSDS) in several behavioral tests. This antidepressant-like activity was observed at a dose (10 mg / kg, ip) identical to the effective dose of racemic ketamine. In the same model, compound 37rac ​​was ineffective at this dose level and was only partially effective even at 3 times the dose (30 mg / kg, ip) (Figure 3). In addition, the enantiomers 35R and 35S of compound 35 caused antidepressant-like effects (Figure 4) in the same CSDS model. It is worth noting that when each drug was given at the same dose, the antidepressant-like effect of the 35R enantiomer was more robust and lasted longer than the 35S enantiomer. At the same time, despite having equivalent antidepressant activity, compound 35R showed weaker NMDAR binding than compounds 35S and 35rac, racemic ketamine, and R-ketamine (see Example 27 above), suggesting that it may have excellent separation between side effects (driven by binding potency to NMDAR) and therapeutic effects on depression.

[1173] Animals. Male adult C57BL / 6 mice aged 8 weeks (weighing 20-25 g, Japan SLC, Inc., Hamamatsu, Japan) and male adult CD1 mice aged 13-15 weeks (weighing >40 g, Japan SLC, Inc., Hamamatsu, Japan) were used in the experiments. Animals were housed under a controlled temperature and 12-h light / dark cycle (lights on between 07:00 and 19:00) with food and water ad libitum. This protocol was approved by the Chiba University Institutional Animal Care and Use Committee (Permit Nos. 29-397 and 30-397). This study was conducted in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Every effort was made to minimize suffering.

[1174] Drugs and drug administration. Racemic ketamine hydrochloride for injection as a commercial solution ( Ketamine hydrochloride (Ketamine hydrochloride, Daiichi Sankyo Pharmaceutical Ltd., Tokyo, Japan) was obtained and administered intraperitoneally (ip) at a dose of 10 mg / kg. Compounds 35rac and 37rac ​​were synthesized as described above (Example 1) and administered ip as HCl salts at doses of 10 mg / kg (35rac and 37rac) and 30 mg / kg (37rac ​​alone). Enantiomers 35R and 35S of compound 35 were synthesized as described above (Example 1) and administered ip as bitartrate salts 35R-L-tartrate and 35S-D-tartrate at a dose...

Claims

1. A substantially enantiomerically pure compound selected from: or a pharmaceutically acceptable salt thereof.

2. An enantiomeric compound represented by: or a pharmaceutically acceptable salt thereof, wherein the enantiomeric compound is present in an enantiomeric mixture having at least 90% of the enantiomeric compound.

3. A compound selected from:

4. The compound according to claim 1 or 2, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 3, wherein the compound is 6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient.

7. A composition comprising a mixture of enantiomers of a compound selected from: wherein the enantiomeric mixture has a significantly greater amount of the enantiomer having a lower binding affinity at the NMDA receptor MK-801 site.

8. The composition according to claim 7, wherein the compound is selected from:

9. A composition comprising a mixture of enantiomers of a compound selected from: The enantiomeric mixture has a significantly greater amount of the enantiomer having a higher binding affinity at the NMDA receptor MK-801 site.

10. The composition according to claim 9, wherein the compound is selected from:

11. Use of a compound according to any one of claims 1 to 5 in the preparation of a medicament for treating depression, mood disorders or substance use disorders and any symptoms or disorders associated therewith in a subject in need thereof.

12. The use according to claim 11, wherein the depression is anxious depression, and the mood disorder is an anxiety disorder.

13. Use of the composition according to any one of claims 7 to 10 in the preparation of a medicament for treating depression, mood disorders or substance use disorders and any symptoms or disorders associated therewith in a subject in need thereof.

14. The use according to claim 13, wherein the depression is anxious depression, and the mood disorder is an anxiety disorder.

15. Use of a composition for the preparation of a medicament for treating depression, mood disorders or substance use disorders and any symptoms or disorders associated therewith in a subject in need thereof, wherein the composition comprises a substantially enantiomerically pure compound selected from: or a pharmaceutically acceptable salt thereof.

16. Use of a composition for the preparation of a medicament for treating depression, mood disorders or substance use disorders and any symptoms or disorders associated therewith in a subject in need thereof, wherein the composition comprises an effective amount of a compound selected from the group consisting of:

17. A substantially enantiomerically pure compound represented by: or a pharmaceutically acceptable salt thereof.

18. Use of a compound according to claim 17 in the preparation of a medicament for treating depression, mood disorders or substance use disorders and any symptoms or disorders associated therewith in a subject in need thereof.

Images