Arylcyclohexylamine derivatives and their use in the treatment of psychiatric disorders - Patents.com

Abstract

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

Description

[Technical Field]

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

[0002] Approximately one-third of patients with major depressive disorder (MDD) fail to achieve symptomatic remission, even after multiple treatments with several known classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs) (Rush et al., 2006). This high prevalence of treatment-resistant depression (TRD) underscores the need for new, more effective depression pharmacotherapies that target novel mechanisms and / or patient populations. In recent years, ketamine, a drug long used as a dissociative anesthetic, has attracted significant attention for its second-line use as a rapid-acting antidepressant with robust efficacy in patients with TRD (Zarate et al., 2006; Berman et al., 2000). The drug's antidepressant effects are also notable in that they persist for days or weeks after a single administration. Importantly, the S-enantiomer of ketamine (S-ket) has recently been approved by the U.S. Food and Drug Administration for the treatment of depression.

[0003] Unfortunately, the potent dissociative anesthetic effects of ketamine and S-ket make these drugs attractive to recreational drug users and restrict their use to environments under direct medical supervision, limiting the broad clinical utility of these compounds. Considering that ketamine's primary molecular target is the N-methyl-D-aspartate receptor (NMDAR), whose inhibition is responsible for the drug's anesthetic effects, many have proposed that inhibition of this target is also responsible for ketamine's antidepressant effects. Such a mechanism suggests that ketamine's antidepressant and dissociative effects may be inseparable at the mechanistic level. However, a number of different 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 effective 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) induces antidepressant effects in rodent models but only weakly binds to NMDARs and has been shown not to associate with this receptor in vivo at dose levels that induce antidepressant effects (Zanos et al. 2016; Lumsden et al. 2019; Morris et al. 2017). Thus, both R-ket and HNK may induce antidepressant effects while limiting the dissociative effects of ketamine.

[0004] However, other approaches proposed to attenuate ketamine's dissociative effects, such as targeting the NR2B subunit of NMDAR or utilizing compounds with poor trapping properties, have met with unsatisfactory results. For example, many structurally distinct NMDAR antagonists (e.g., memantine, MK-0657, and lanicemine) have been shown to reduce dissociation in some cases but have been shown to be less effective and / or have a shorter duration of action 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 NMDAR (e.g., MK-801) or agonists targeting alternative binding sites on the channel (e.g., rapastinel) have also failed (Yang et al. 2016; Al Idrus 2019). Therefore, the precise molecular mechanisms underlying ketamine's antidepressant effects remain poorly understood, and other, as yet unidentified, targets may be involved. Furthermore, the magnitude of the antidepressant and associated dissociative effects of NMDAR modulators is generally highly unpredictable. Together, these findings raise the exciting possibility that ketamine's antidepressant effects may in fact be separable from its dissociative anesthetic effects.

[0005] In addition to its dissociative side effects, the use of ketamine for the treatment of depression is further limited by the drug's poor oral bioavailability (Clements et al. 1982). Therefore, for the treatment of MDD, ketamine is almost exclusively administered via the intravenous (iv) route. Practical challenges with iv administration further necessitate its use in a clinic or hospital setting under the supervision of a healthcare provider. Therefore, the inability to administer ketamine orally is a significant drawback that limits the drug's widespread application and increases the healthcare costs associated with its use. While other orally bioavailable NMDAR antagonists have been developed, none have been commercially available to date, nor have they demonstrated the robust clinical efficacy of ketamine as an antidepressant. Therefore, there remains a significant need for novel antidepressants in the ketamine class with robust efficacy, reduced dissociative side effects, and increased oral bioavailability. A drug that retains the antidepressant activity of ketamine while also reducing its dissociative effects and increasing its oral bioavailability would be easier to administer and offer a potentially viable treatment option for home use due to its reduced dissociative effects and concomitant reduced abuse potential. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Rush et al., 2006 [Non-patent document 2] Zarate et al., 2006 [Non-patent document 3] Berman et al., 2000 [Non-patent document 4] Aleksandrova et al., 2017 [Non-patent document 5] Zhang et al., 2014 [Non-patent document 6] Zanos et al. 2016 [Non-Patent Document 7] Lumsden et al. 2019 [Non-patent document 8] Morris et al. 2017 [Non-Patent Document 9] Qu et al. 2017 [Non-Patent Document 10] Cerecor 2019 [Non-Patent Document 11] Kadriu et al. 2019 [Non-Patent Document 12] Lepow et al. 2017 [Non-Patent Document 13] Yang et al. 2016 [Non-Patent Document 14] Al Idrus 2019 [Non-Patent Document 15] Clements et al. 1982 [Non-Patent Document 16] BERGE et al., 66 J. PHARM.SCI.1-19 (1977) Summary of the Invention [Means for solving the problem]

[0007] The present disclosure provides, at least in part, arylcyclohexylamine compounds, and compositions of single enantiomers or enantiomerically enriched mixtures of arylcyclohexylamines, that have significantly higher oral bioavailability, higher antidepressant potency, and / or a higher therapeutic index between antidepressant activity and side effects compared to ketamine.

[0008] For example, the present disclosure provides compounds with increased oral bioavailability, e.g., by possessing structural components that confer increased resistance to hepatic metabolism compared to ketamine. This can be confirmed, for example, by their increased stability in rodent and human liver microsome preparations. Importantly, despite such increased oral bioavailability, the disclosed compounds retain substantially short half-lives, in contrast to the more typical observation that increased hepatic stability can result in slower clearance. A short half-life may be desirable because the therapeutic efficacy of such compounds may not depend on sustained receptor occupancy. Instead, pulsatile engagement of NMDAR (or other) signaling may be sufficient to induce a therapeutic effect that lasts much longer (days or weeks) than drug elimination (hours), thereby limiting overall exposure and reducing the duration of dissociative or other negative side effects. Furthermore, in some embodiments, compounds are provided herein that retain the high brain permeability of ketamine, particularly after oral dosing, while also exhibiting increased antidepressant efficacy as a secondary effect of increased exposure. Such compounds may be more potent as antidepressants, even if their in vitro affinity for NMDARs is similar to or lower than that of ketamine. Furthermore, the compounds provided herein inhibit the radioligand [ 3As a result of the NMDAR binding affinity of approximately 1-5 μM, as determined by displacement of [H]MK-801, compounds may exhibit an increased therapeutic index between antidepressant activity and dissociative side effects. In certain embodiments, this affinity range, likely due to the rapid off-kinetics of such compounds, may be useful for balancing antidepressant efficacy and side effects. For example, compounds with very high affinity at the NMDAR (<1 μM), such as racemic ketamine and S-ket, exhibit significant dissociative effects that restrict their use to physician-monitored environments and increase their abuse liability. Furthermore, high affinity at the NMDAR may also reduce therapeutic efficacy in depression (e.g., both MK-801 and S-ket appear to exhibit weaker and shorter-lasting antidepressant activity than racemic ketamine and R-ket, which have lower affinities). In contrast, compounds with very low affinity at the NMDAR (>5 μM) may lose antidepressant efficacy even when doses are appropriately adjusted to account for such lower affinity. Furthermore, even if effective, the very high doses required for such low potency compounds may exacerbate toxicological challenges or result in the introduction of unwanted off-targets (due to reduced selectivity over other weakly binding partners).

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

[0010] [ka]

[0011] wherein R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of general formula (II), when R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cycloC3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, and D represents a deuterium-enriched H moiety, with the proviso that one or more of R2 and R3 are different from H; or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R1 is of general formula (II):

[0012] [ka]

[0013] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, with the proviso that one or more of R2 and R3 is different from H; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR12R13, —SR14, —S02R15, —C02R16, and —C(═O)NR17R18; and R11, R12, R13, R14, R15, R16, R17, and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, and C(═O)heteroaryl; provided that one or more of R6 to R10 is different from H, or provided that when R6 is Cl and R7 to R10 are H, or when R7 is Cl, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, or provided that when R7 is OH, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is linear or branched C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, provided that when R6, R7, or R8 is OMe, the others of R6 to R10 are each H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5; when R1 is selected from thiazole, thiophene, and pyridine, each is optionally substituted with one or more of OH, halogen (selected from F, Cl, Br, and I), —OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR20R21, —SR22, —S2R23, —C2R24, and —C(═O)NR25R26, wherein R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, and C(═O)heteroaryl; R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. Provided herein are compounds having the formula:

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

[0015] [ka]

[0016] wherein R2 and R3 are independently selected from H, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, with the proviso that one or more of R2 and R3 is different from H, or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; R4 is a 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 by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. It has.

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

[0018] [ka]

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

[0020] In some embodiments, compounds provided herein have the general structure (I), wherein R1 is selected from thiazole, thiophene, and pyridine, each optionally and optionally substituted with one or more of OH, halogen (selected from F, Cl, Br, and I), —OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR20R21, —SR22, —S2R23, —C2R24, and —C(═O)NR25R26, and R19, R20, R21, R22, R23, R24, R25, and R26 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, or hydroxyl. R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

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

[0022] [ka]

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

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

[0025] [ka]

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

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

[0028] [ka]

[0029] 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 by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. It has.

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

[0031] [ka]

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

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

[0034] [ka]

[0035] wherein R2 and R3 are independently selected from C2-C5 alkyl, C2-C5 fluoroalkyl, and -R4-O-R5, where R4 is C2-C5 alkylene, and R5 is selected from H and C1-C5 alkyl. It has.

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

[0037] [ka]

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

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

[0040] [ka]

[0041] wherein one or more of R6, R7, R8, R9, and R10 are OH; R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, and -R4-O-R5; R4 is C2-C10 alkylene; and R5 is selected from H and C1-C10 alkyl, with the proviso that when R7 is OH and R6, R8-R10 are H, then R3 is C3-C10 alkyl. It has.

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

[0043] [ka]

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

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

[0046] [ka]

[0047] wherein one or more of R6, R7, R8, R9, and R10 are OMe; R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, and -R4-O-R5; R4 is C2-C10 alkylene; and R5 is selected from H and C1-C10 alkyl, with the proviso that when R6, R7, or R8 is OMe and the other of R6-R10 is H, then R3 is C3-C10 alkyl. It has.

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

[0049] [ka]

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

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

[0052] [ka]

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

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

[0055] [ka]

[0056] (wherein one or more of R6, R7, R8, R9, and R10 are OH; R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, and —R4—O—R5; R4 is C2-C5 alkylene; and R5 is selected from H and C1-C5 alkyl, with the proviso that when R7 is OH and R6, R8 to R10 are H, then R3 is C3-C5 alkyl). It has.

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

[0058] [ka]

[0059] wherein one or more of R6, R7, R8, R9, and R10 are OMe; R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, and —R4—O—R5; R4 is C2-C5 alkylene; and R5 is selected from H and C1-C5 alkyl, with the proviso that when R6, R7, or R8 is OMe and the other of R6-R10 is H, then R3 is C3-C5 alkyl. It has.

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

[0061] [ka]

[0062] wherein one or more of R6, R7, R8, R9, and R10 are F; R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, and -R4-O-R5; R4 is C2-C5 alkylene; and R5 is selected from H and C1-C5 alkyl. It has.

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

[0064] [ka]

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

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

[0067] [ka]

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

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

[0070] [ka]

[0071] wherein one or more of R6, R7, R8, R9, and R10 is OMe; R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; R4 is C2-C5 alkylene; 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 by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. It has.

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

[0073] [ka]

[0074] wherein one or more of R6, R7, R8, R9, and R10 is F; R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; R4 is C2-C5 alkylene; 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 by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. It has.

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

[0076] [ka]

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

[0078] In some embodiments, the compounds provided herein comprise:

[0079] [ka]

[0080] [ka]

[0081] or a pharmaceutically acceptable salt or ester thereof.

[0082] In some embodiments, the compounds provided herein comprise:

[0083] [ka]

[0084] is selected from.

[0085] In another aspect, the carrier and structure:

[0086] [ka]

[0087] (wherein D represents a deuterium-enriched H site) Provided herein are compositions comprising a compound having the formula:

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

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

[0090] [ka]

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

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

[0093] [ka]

[0094] (In the formula, R31 and R32 are each H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 wherein R38 is a C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more linear or branched C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms, R27 and R28 are fluorine, R29 and R30 are H, and R33, R34, R35, R36 and R37 are each independently H, OH, halogen (F, Cl, Br, I), —OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR41R42, —SR43, —S02R44, —CO2R45, —C(═O)NR46R47, where R40, R41, R42, R43, R44, R45, R46, and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, and C(═O)heteroaryl. It has.

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

[0096] [ka]

[0097] (In the formula, R31 and R32 are each H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39wherein R38 is a C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more linear or branched C1-C2 alkyls or interrupted by one or more additional nitrogen or oxygen atoms, R27 and R28 together with the carbon and oxygen atoms to which they are attached form an oxetane ring, R29 and R30 are H, and R33, R34, R35, R36 and R37 are each independently and R40, R41, R42, R43, R44, R45, R46, and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, and C(=O)heteroaryl. It has.

[0098] In some embodiments, the compounds provided herein comprise:

[0099] [ka]

[0100] is selected from.

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

[0102] In another aspect, there is provided a method for treating depression, mood disorders, anxiety disorders, or substance use disorders and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject a compound having the general structure (IV):

[0103] [ka]

[0104] [Wherein R48 is phenyl, thiazole, thiophene, pyridine, or a group represented by the general formula (V);

[0105] [ka]

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

[0107] In some embodiments, the compounds provided herein comprise:

[0108] [ka]

[0109] is selected from.

[0110] In some embodiments, the compounds provided herein comprise:

[0111] [ka]

[0112] is selected from.

[0113] In another aspect, there is provided a method for treating depression, a mood disorder, an anxiety disorder, or a substance use disorder and any symptoms or disorders related thereto in a subject in need thereof, comprising generally:

[0114] [ka]

[0115] Provided herein are methods comprising administering to a subject a compound of formula (I)

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

[0117] [ka]

[0118] wherein R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of general formula (VII), When R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cycloC3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, D represents a deuterium-enriched H moiety, and at least one of R2 and R3 is other than H; or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R1 is represented by general formula (VII):

[0119] [ka]

[0120] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, and at least one of R2 and R3 is other than H; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR12R13, —SR14, —SO2R15, —CO2R16, and —C(═O)NR17R18; and R11, R12, and R13 , R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl, at least one of R6 to R10 is other than H, and neither R6 nor R10 is halogen; provided that when R7 is Cl, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, or provided that when R7 is OH, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, provided that when R6, R7, or R8 is OMe, the others of R6 to R10 are each H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5; when R1 is selected from thiazole, thiophene, and pyridine, each optionally and optionally substituted with one or more of OH, halogen (selected from F, Cl, Br, I), —OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR20R21, —SR22, —S2R23, —C2R24, —C(═O)NR25R26, wherein R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, C(═O)heteroaryl; R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. Provided herein are compositions comprising a compound having the formula:

[0121] In another aspect, the carrier and structure:

[0122] [ka]

[0123] (wherein D represents a deuterium-enriched H site) Provided herein are compositions comprising a compound having the formula:

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

[0125] [ka]

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

[0127] In another aspect, there is provided a method for treating depression, anxiety depression, mood disorders, anxiety disorders, or substance use disorders and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject a compound having the general structure (IX):

[0128] [ka]

[0129] [Wherein R48 is phenyl, thiazole, thiophene, pyridine, or a group represented by the general formula (X);

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

[0131] In another aspect, there is provided a method for treating depression, anxiety depression, mood disorders, anxiety disorders, or substance use disorders and any symptoms or disorders related thereto in a subject in need thereof, generally comprising administering to a subject a compound:

[0132] [ka]

[0133] Provided herein are methods comprising administering to a subject

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

[0135] [ka]

[0136] wherein R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of general formula (XII), When R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cycloC3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, D represents a deuterium-enriched H moiety, and at least one of R2 and R3 is other than H; or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R1 is represented by the general formula (XII):

[0137] [ka]

[0138] When it is a part of R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, and at least one of R2 and R3 is other than H; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR12R13, —SR14, —SO2R15, —CO2R16, and —C(═O)NR17R18; and R11, R12, and R13 , R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl, at least one of R6 to R10 is other than H, and neither R6 nor R10 is halogen; provided that when R7 is Cl, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, or provided that when R7 is OH, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, or provided that when R6, R7, or R8 is OMe, the others of R6 to R10 are each H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5; when R1 is selected from thiazole, thiophene, and pyridine, each optionally and optionally substituted with one or more of OH, halogen (selected from F, Cl, Br, I), —OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR20R21, —SR22, —S2R23, —C2R24, —C(═O)NR25R26, wherein R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, C(═O)heteroaryl; R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. or a pharmaceutically acceptable salt or ester of said compound, wherein the composition is enriched in said compound over its opposite enantiomer.

[0139] In another aspect, the carrier and structure:

[0140] [ka]

[0141] (wherein D represents a deuterium-enriched H site) Provided herein are compositions comprising a compound having the formula:

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

[0143] [ka]

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

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

[0146] or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in said compound relative to its opposite enantiomer. In another aspect, a method for treating depression, anxiety depression, mood disorders, anxiety disorders, or substance use disorders and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject a compound having the general structure (XIV):

[0147] [ka]

[0148] [Wherein R48 is phenyl, thiazole, thiophene, pyridine, or a group represented by the general formula (XV);

[0149] [ka]

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

[0151] In another aspect, there is provided a method for treating depression, anxiety depression, mood disorders, anxiety disorders, or substance use disorders and any symptoms or disorders related thereto in a subject in need thereof, generally comprising administering to a subject a compound:

[0152] [ka]

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

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

[0155] [ka]

[0156] wherein R56 and R57 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic C3-C8 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C3 alkyl, F, OH, OMe or =0, and optionally interrupted by one or more additional nitrogen or oxygen atoms; R58, R59, R60, R61 and R62 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR63, -OC(=O)R64, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR65R66, -NH-C(=O)R67, -SR68, -SO2R69, -CO2R70, -C(=O)NR71R72; R63, R64, R65, R66, R67, R68, R69, R70, R71 and R72 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, and heteroaryl; provided that when R56 and R57 together with the nitrogen atom to which they are attached form an unsubstituted piperidine ring, at least one of R58, R59, R60, R61 and R62 is other than H. or a pharmaceutically acceptable salt or ester thereof.

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

[0158] [ka]

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

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

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

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

[0163] [Figure 1] FIG. 1 shows the X-ray crystal structure of 35R(1R)-(−)-camphorsulfonate crystals grown in toluene. [Figure 2] Deuteration of compounds 14R and 14S at the N-methyl group, as in compounds 88R and 88S, respectively, reduced the formation of metabolites 11R and 11S, respectively, in rat liver microsomes (RLM). The effect of deuteration was more pronounced for the R isomer. Compounds 88R and 88S were incubated with RLM under high activity conditions, and the concentrations of 11R and 11S formed, respectively, were determined by LC-MS / MS. All data points represent the mean ± SEM of duplicate incubations. [Figure 3]Figure 3A shows the antidepressant-like effects of 35rac compared with and superior to racemic ketamine and 37rac ​​in mice susceptible to a depression-like phenotype after chronic social defeat stress (CSDS). (3A) Schedule of the CSDS model, drug treatment, and behavioral testing. CSDS was performed on days 1 to 10, and a social interaction test (SIT) was performed on day 11. Saline (10 mL / kg), racemic ketamine (10 mg / kg), 37rac ​​(10 mg / kg and 30 mg / kg), or 35rac (10 mg / kg) was administered intravenously to CSDS-susceptible mice on day 12. Locomotor activity (LMT) and tail suspension test (TST) were performed 1 and 3 hours after injection, respectively. A forced swim test (FST) was performed 1 day after injection. A sucrose preference test (SPT) was performed 2, 4, and 7 days after injection. (3B) LMT (One-way ANOVA, F5,50 = 0.691, P = 0.633). (3C) TST (F5,50 = 15.481, P < 0.001). (3D) FST (F5,50 = 10.343, P < 0.001). (3E) SPT on day 14 (F5,50 = 6.670, P < 0.001). (3F) SPT on day 16 (F5,50 = 14.962, P < 0.001). (3G) SPT on day 19 (F5,50 = 11.310, P < 0.001). Data are shown as mean ± SEM (n = 8–12). *p < 0.05, **p < 0.01, ***p < 0.001). ns = no significant difference, p>0.05. [Figure 4]Figure 4 shows the antidepressant-like effects of 35R versus 35S in mice susceptible to a depression-like phenotype after chronic social defeat stress (CSDS). (4A) Schedule of the CSDS model, drug treatment, and behavioral testing. CSDS was performed on days 1 to 10, and the social interaction test (SIT) was performed on day 11. Saline (10 mL / kg), 35R (14.4 mg / kg), or 35S (14.4 mg / kg) was administered intravenously to CSDS-susceptible mice on day 12. Locomotor activity (LMT) and tail suspension test (TST) were performed 1 and 3 hours after injection, respectively. The forced swim test (FST) was performed 1 day after injection. The sucrose preference test (SPT) was performed 2, 4, and 7 days after injection. (4B) LMT (one-way ANOVA: F = 0.296, p = 0.828). (4C) TST (F3,28 = 12.550, p<0.001). (4D) FST (F3,28 = 10.551, p<0.001). (4E) SPT on day 14 (F3,28 = 7.062, p<0.001). (4F) SPT on day 16 (F3,28 = 5.864, p<0.001). (4G) SPT on day 19 (F3,28 = 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. [Figure 5] Figure 1 shows the results of 2rac and 14rac in the forced swimming test model. Mice were treated with the indicated doses of drugs, and after 30 minutes, they were placed in the FST tank, and the cumulative immobility time was quantified over the entire 6-minute test session. Compounds 2rac and 14rac reduced immobility time and had a stronger effect than the control antidepressant imipramine. Other tested compounds had no effect. Unpaired two-tailed t-test (not corrected for multiple comparisons): **p<0.01, *p<0.05 vs. vehicle. n=10 per treatment. All values ​​are expressed as mean±SEM. [Figure 6]Figure 1 shows the antidepressant-like effect of compound 14rac in the forced swimming test (FST). Mice were treated with the indicated dose of drug, and after 2 hours, they were placed in the FST tank. The cumulative immobility time was quantified over the last 4 minutes of the test session. Compound 14rac reduced immobility time and had a stronger and more potent effect than racemic ketamine (rac-ketamine). Unpaired two-tailed t-test (uncorrected for multiple comparisons): **p<0.01, *p<0.05 vs. vehicle. n=10 per treatment, except for the vehicle and rac-ketamine groups, which had n=20 per treatment. All values ​​are expressed as mean ± SEM. [Figure 7] Figure 1 shows the activity of compounds on immobility time in the forced swim test (FST) in rats 23.5 hours after treatment. For clarity, the data are divided into two panels, but these are from the same experiment; vehicle, desipramine, and ketamine groups are the same in the two panels. One-way ANOVA: F25,254=9.163, p<0.0001. ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05 vs. vehicle. n=10 per treatment, except for the vehicle and desipramine groups, where n=20 per treatment. All values ​​are expressed as mean ± SEM. [Figure 8]

[0023] Figure 1 shows certain disclosed compounds and their effects on swimming behavior in the forced swim test (FST) in rats 23.5 hours after treatment. For clarity, the data are divided into two panels, but these are the same experiment, and the vehicle, desipramine, and ketamine groups are the same in the two panels. One-way ANOVA: F25,254 = 3.862, p < 0.0001. ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05 vs. vehicle. n = 10 per treatment, except for the vehicle and desipramine groups, where n = 20 per treatment. All values ​​are expressed as mean ± SEM. [Figure 9]

[0023] Figure 1 shows certain disclosed compounds and their effects on increasing climbing behavior in the forced swim test (FST) in rats 23.5 hours after treatment. For clarity, the data are divided into two panels, but these are from the same experiment; vehicle, desipramine, and ketamine groups are the same in the two panels. One-way ANOVA: F25,254 = 3.048, p < 0.0001. ***p < 0.001, **p < 0.01, *p < 0.05 vs. vehicle. n = 10 per treatment, except for the vehicle and desipramine groups, where n = 20 per treatment. All values ​​are expressed as mean ± SEM. [Figure 10] Compound 14S induced significant preference in the conditioned place preference assay in mice. One-way ANOVA: F4,45=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. [Figure 11] Compound 14R did not induce preference or aversion in the conditioned place preference assay in mice. One-way ANOVA: F4,43=4.559, p=0.0037. **p<0.01 vs. saline vehicle. n=10 per treatment. All values ​​are expressed as mean±SEM. DETAILED DESCRIPTION OF THE INVENTION

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

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

[0166] [ka]

[0167] wherein R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of general formula (II), when R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cycloC3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, and D represents a deuterium-enriched H moiety, with the proviso that one or more of R2 and R3 are different from H; or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R1 is of general formula (II):

[0168] [ka]

[0169] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, with the proviso that one or more of R2 and R3 is different from H; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR12R13, —SR14, —S02R15, —C02R16, and —C(═O)NR17R18; and R11, R12, R13, R14, R15, R16, R17, and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, —C(═O)H, —C(═O)alkyl, —C(═O)aryl, and —C(═O)heteroaryl; provided that one or more of R6 to R10 is different from H, or provided that when R6 is Cl and R7 to R10 are H, or when R7 is Cl, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, or provided that when R7 is OH, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is linear or branched C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, provided that when R6, R7, or R8 is OMe, the others of R6 to R10 are each H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5; when R1 is selected from thiazole, thiophene, and pyridine, each is optionally substituted with one or more of OH, halogen (selected from F, Cl, Br, and I), —OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR20R21, —SR22, —S2R23, —C2R24, and —C(═O)NR25R26, wherein R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, and C(═O)heteroaryl; R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. Provided herein are compounds having the formula:

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

[0171] [ka]

[0172] wherein R2 and R3 are independently selected from H, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, with the proviso that one or more of R2 and R3 is different from H, or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; R4 is a 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 by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. It has.

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

[0174] [ka]

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

[0176] In some embodiments, compounds provided herein have the general structure (I), wherein R1 is selected from thiazole, thiophene, and pyridine, each optionally and optionally substituted with one or more of OH, halogen (selected from F, Cl, Br, and I), —OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR20R21, —SR22, —S2R23, —C2R24, and —C(═O)NR25R26, and R19, R20, R21, R22, R23, R24, R25, and R26 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, or hydroxyl. R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms.

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

[0178] [ka]

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

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

[0181] [ka]

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

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

[0184] [ka]

[0185] 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 by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. It has.

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

[0187] [ka]

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

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

[0190] [ka]

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

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

[0193] [ka]

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

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

[0196] [ka]

[0197] wherein one or more of R6, R7, R8, R9, and R10 are OH; R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, and -R4-O-R5; R4 is C2-C10 alkylene; and R5 is selected from H and C1-C10 alkyl, with the proviso that when R7 is OH and R6, R8-R10 are H, then R3 is C3-C10 alkyl. It has.

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

[0199] [ka]

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

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

[0202] [ka]

[0203] wherein one or more of R6, R7, R8, R9, and R10 are OMe; R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, and -R4-O-R5; R4 is C2-C10 alkylene; and R5 is selected from H and C1-C10 alkyl, with the proviso that when R6, R7, or R8 is OMe and the other of R6-R10 is H, then R3 is C3-C10 alkyl. It has.

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

[0205] [ka]

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

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

[0208] [ka]

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

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

[0211] [ka]

[0212] (wherein one or more of R6, R7, R8, R9, and R10 are OH; R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, and —R4—O—R5; R4 is C2-C5 alkylene; and R5 is selected from H and C1-C5 alkyl, with the proviso that when R7 is OH and R6, R8 to R10 are H, then R3 is C3-C5 alkyl). It has.

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

[0214] [ka]

[0215] wherein one or more of R6, R7, R8, R9, and R10 are OMe; R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, and —R4—O—R5; R4 is C2-C5 alkylene; and R5 is selected from H and C1-C5 alkyl, with the proviso that when R6, R7, or R8 is OMe and the other of R6-R10 is H, then R3 is C3-C5 alkyl. It has.

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

[0217] [ka]

[0218] wherein one or more of R6, R7, R8, R9, and R10 are F; R3 is selected from C1-C5 alkyl, C2-C5 fluoroalkyl, and -R4-O-R5; R4 is C2-C5 alkylene; and R5 is selected from H and C1-C5 alkyl. It has.

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

[0220] [ka]

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

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

[0223] [ka]

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

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

[0226] [ka]

[0227] wherein one or more of R6, R7, R8, R9, and R10 is OMe; R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; R4 is C2-C5 alkylene; 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 by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. It has.

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

[0229] [ka]

[0230] wherein one or more of R6, R7, R8, R9, and R10 is F; R2 and R3 are independently selected from C1-C5 alkyl, C2-C5 fluoroalkyl, -R4-O-R5; R4 is C2-C5 alkylene; 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 by one or more C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. It has.

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

[0232] [ka]

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

[0234] In some embodiments, the compounds provided herein comprise:

[0235] [ka]

[0236] [ka]

[0237] is selected from.

[0238] In some embodiments, the compounds provided herein comprise:

[0239] [ka]

[0240] is selected from.

[0241] In another aspect, the carrier and structure:

[0242] [ka]

[0243] (wherein D represents a deuterium-enriched H site) Provided herein are compositions comprising a compound having the formula:

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

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

[0246] [ka]

[0247] (In the formula, R31 and R32 are each H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39wherein R38 is a C2-C10 alkylene and R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more linear or branched C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms, R27, R28, R29, R30 are each independently selected from H, linear or branched C1-C10 alkyl, F, or R27 and R28 or R29 and R30 together with the carbon atoms to which they are attached form a cycloalkyl ring, or together with the carbon and one or more heteroatoms to which they are attached form a cycloheteroalkyl ring, and R33, R34, R35, R36, and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —SR41R42, —SR43, —S02R44, —CO2R45, and —C(═O)NR46R47, and R40, R41, R42, R43, R44, R45, R46, and R47 are each independently H, C1-C10 alkyl, C and R32 is selected from C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, provided that when at least one of R27, R28, R29, or R30 is different from H, or one of R27 and R28 is Me and the other of R27 and R28 is H, R32 is C2-C10 alkyl, C2-C10 haloalkyl, or -R 38 -OR 39 is) Provided herein are compounds having the formula:

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

[0249] [ka]

[0250] (In the formula, R31 and R32 are each H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 wherein R38 is a C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more linear or branched C1-C2 alkyl or interrupted by one or more additional nitrogen or oxygen atoms, R27 and R28 are fluorine, R29 and R30 are H, and R33, R34, R35, R36 and R37 are each independently H, OH, halogen (F, Cl, Br, I), —OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR41R42, —SR43, —S02R44, —CO2R45, —C(═O)NR46R47, where R40, R41, R42, R43, R44, R45, R46, and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, and C(═O)heteroaryl. It has.

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

[0252] [ka]

[0253] (In the formula, R31 and R32 are each H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39wherein R38 is a C2-C10 alkylene, R39 is selected from H and C1-C10 alkyl, or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more linear or branched C1-C2 alkyls or interrupted by one or more additional nitrogen or oxygen atoms, R27 and R28 together with the carbon and oxygen atoms to which they are attached form an oxetane ring, R29 and R30 are H, and R33, R34, R35, R36 and R37 are each independently and R40, R41, R42, R43, R44, R45, R46, and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, and C(=O)heteroaryl. It has.

[0254] In some embodiments, the compounds provided herein comprise:

[0255] [ka]

[0256] is selected from.

[0257] In another aspect, there is provided a method for treating depression, mood disorders, anxiety disorders, or substance use disorders and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject a compound having the general structure (IV):

[0258] [ka]

[0259] [Wherein R48 is phenyl, thiazole, thiophene, pyridine, or a group represented by the general formula (V);

[0260] [ka]

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

[0262] In some embodiments, the compounds provided herein comprise:

[0263] [ka]

[0264] is selected from.

[0265] In some embodiments, the compounds provided herein comprise:

[0266] [ka]

[0267] is selected from.

[0268] In another aspect, there is provided a method for treating depression, a mood disorder, an anxiety disorder, or a substance use disorder and any symptoms or disorders related thereto in a subject in need thereof, comprising generally:

[0269] [ka]

[0270] Provided herein are methods that include administering a compound to a subject.

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

[0272] [ka]

[0273] wherein R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of general formula (VII), When R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cycloC3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, D represents a deuterium-enriched H moiety, and at least one of R2 and R3 is other than H; or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R1 is represented by general formula (VII):

[0274] [ka]

[0275] R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, and at least one of R2 and R3 is other than H; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR12R13, —SR14, —SO2R15, —CO2R16, and —C(═O)NR17R18; and R11, R12, and R13 , R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl, at least one of R6 to R10 is other than H, and neither R6 nor R10 is halogen; provided that when R7 is Cl, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, or provided that when R7 is OH, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5; provided that when R6, R7, or R8 is OMe, the others of R6 to R10 are each H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5; when R1 is selected from thiazole, thiophene, and pyridine, each optionally and optionally substituted with one or more of OH, halogen (selected from F, Cl, Br, I), —OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR20R21, —SR22, —S2R23, —C2R24, —C(═O)NR25R26, wherein R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, C(═O)heteroaryl; R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. Provided herein are compositions comprising a compound having the formula:

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

[0277] [ka]

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

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

[0280] [ka]

[0281] wherein R3 is C1-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl; R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR12R13, —SR14, —SO2R15, —CO2R16, and —C(═O)NR17R18; and R11, R12, and R 13, R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, at least one of R6-R10 is other than H, and neither R6 nor R10 is halogen; provided that when R7 is Cl and R6, R8 to R10 are H, R3 is C3 to C10 alkyl, C2 to C10 haloalkyl or -R4-O-R5, or provided that when R7 is OH, and R6, R8 to R10 are H, R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, or provided that when R6, R7, or R8 is OMe, and the others of R6 to R10 are H, R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5. It has.

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

[0283] [ka]

[0284] wherein R1 is selected from thiazole, thiophene, and pyridine, each optionally and optionally substituted with one or more of OH, halogen (selected from F, Cl, Br, I), —OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR20R21, —SR22, —S2R23, —C2R24, —C(═O)NR25R26; and R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, C(═O)heteroaryl; R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. It has.

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

[0286] [ka]

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

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

[0289] [ka]

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

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

[0292] [ka]

[0293] 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 by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. It has.

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

[0295] [ka]

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

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

[0298] [ka]

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

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

[0301] [ka]

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

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

[0304] [ka]

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

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

[0307] [ka]

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

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

[0310] [ka]

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

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

[0313] [ka]

[0314] wherein one or more of R7, R8, and R9 is F; R3 is selected from C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl. It has.

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

[0316] [ka]

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

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

[0319] [ka]

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

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

[0322] [ka]

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

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

[0325] [ka]

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

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

[0328] [ka]

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

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

[0331] [ka]

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

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

[0334] [ka]

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

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

[0337] [ka]

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

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

[0340] [ka]

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

[0342] In some embodiments, the compound is:

[0343] [ka]

[0344] [ka]

[0345] is selected from.

[0346] In some embodiments, the compound is:

[0347] [ka]

[0348] is selected from.

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

[0350] [ka]

[0351] (wherein D represents a deuterium-enriched H site) Provided herein are compositions comprising a compound having the formula:

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

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

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

[0355] [ka]

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

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

[0358] [ka]

[0359] (Wherein, R31 and R32 are independently H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39wherein R38 is a C2-C10 alkylene and R39 is selected from H and C1-C10 alkyl; or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more linear or branched C1-C2 alkyls or interrupted by one or more additional nitrogen or oxygen atoms; R27 and R28 are fluorine, R29 and R30 are H; R33, R34, R35, R36, and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR41R42, —SR43, —S02R44, —CO2R45, and —C(═O)NR46R47; and R40, R41, R42, R43, R44, R45, R46, and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, and C(═O)heteroaryl. It has.

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

[0361] [ka]

[0362] (Wherein, R31 and R32 are independently H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 wherein R38 is a C2-C10 alkylene and R39 is selected from H and C1-C10 alkyl; or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more linear or branched C1-C2 alkyls or interrupted by one or more additional nitrogen or oxygen atoms; R27 and R28 together with the carbon and oxygen atoms to which they are attached form an oxetane ring; R29 and R30 are H; R33, R34, R35, R36, and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR41R42, —SR43, —S02R44, —CO2R45, and —C(═O)NR46R47; and R40, R41, R42, R43, R44, R45, R46, and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, and C(═O)heteroaryl. It has.

[0363] In some embodiments, the compound is

[0364] [ka]

[0365] [ka]

[0366] is selected from.

[0367] In some embodiments, the compound is

[0368] [ka]

[0369] is selected from.

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

[0371] In another aspect, there is provided a method of treating depression, anxiety depression, mood disorders, anxiety disorders, or substance use disorders and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject having a compound of structure (IX):

[0372] [ka]

[0373] [Wherein R48 is phenyl, thiazole, thiophene, pyridine, or a group represented by the general formula (X);

[0374] [ka] wherein R51 and R55 are independently selected from H, OH, OMe, and C1-C10 alkyl; R52, R53, and R54 are each independently selected from H, OH, halogen (selected from F, Cl, Br, and I), OMe, and C1-C10 alkyl; R49 and R50 are each independently selected from H and C1-C10 alkyl, or R49 and R50 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring optionally substituted with one or more C1-C10 alkyl. selected from the group consisting of or a pharmaceutically acceptable salt or ester of the compound, wherein said compound is enriched relative to its opposite enantiomer.

[0375] In some embodiments, the compound is

[0376] [ka]

[0377] is selected from.

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

[0379] [ka]

[0380] It has.

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

[0382] In another aspect, there is provided a method for treating depression, anxiety depression, mood disorders, anxiety disorders, or substance use disorders and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject a compound:

[0383] [ka]

[0384] or a composition comprising a pharmaceutically acceptable salt or ester of a compound to a subject, wherein said compound is enriched relative to its opposite enantiomer.

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

[0386] [ka]

[0387] wherein R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of general formula (XII), When R1 is phenyl, R2 and R3 are independently selected from H, CD3, branched or cycloC3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, D represents a deuterium-enriched H moiety, and at least one of R2 and R3 is other than H; or R2 and R3 are independently selected from C2-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R1 is represented by the general formula (XII):

[0388] [ka]

[0389] When it is a part of R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl, and at least one of R2 and R3 is other than H; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR12R13, —SR14, —SO2R15, —CO2R16, and —C(═O)NR17R18; and R11, R12, and R13 , R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl, at least one of R6 to R10 is other than H, and neither R6 nor R10 is halogen; provided that when R7 is Cl, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, or provided that when R7 is OH, R6, R8 to R10 are H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, or provided that when R6, R7, or R8 is OMe, the others of R6 to R10 are each H, and R2 or R3 is H, the other of R2 or R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5; when R1 is selected from thiazole, thiophene, and pyridine, each optionally and optionally substituted with one or more of OH, halogen (selected from F, Cl, Br, I), —OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR20R21, —SR22, —S2R23, —C2R24, —C(═O)NR25R26, wherein R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, C(═O)heteroaryl; R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in the compound relative to its opposite enantiomer.

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

[0391] [ka]

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

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

[0394] [ka]

[0395] wherein R3 is C1-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5, R4 is C2-C10 alkylene, and R5 is selected from H and C1-C10 alkyl; R6, R7, R8, R9, and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR12R13, —SR14, —SO2R15, —CO2R16, and —C(═O)NR17R18; and R11, R12, and R 13, R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl, at least one of R6-R10 is other than H, and neither R6 nor R10 is halogen; provided that when R7 is Cl and R6, R8 to R10 are H, R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5; provided that when R7 is OH, and R6, R8 to R10 are H, R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5, or provided that when R6, R7, or R8 is OMe, and the others of R6 to R10 are H, R3 is C3 to C10 alkyl, C2 to C10 haloalkyl, or -R4-O-R5. It has.

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

[0397] [ka]

[0398] wherein R1 is selected from thiazole, thiophene, and pyridine, each optionally and optionally substituted with one or more of OH, halogen (selected from F, Cl, Br, I), —OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR20R21, —SR22, —S2R23, —C2R24, —C(═O)NR25R26; and R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, C(═O)heteroaryl; R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5, where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms. It has.

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

[0400] [ka]

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

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

[0403] [ka]

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

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

[0406] [ka]

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

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

[0409] [ka]

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

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

[0412] [ka]

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

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

[0415] [ka]

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

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

[0418] [ka]

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

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

[0421] [ka]

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

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

[0424] [ka]

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

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

[0427] [ka]

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

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

[0430] [ka]

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

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

[0433] [ka]

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

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

[0436] [ka]

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

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

[0439] [ka]

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

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

[0442] [ka]

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

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

[0445] [ka]

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

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

[0448] [ka]

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

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

[0451] [ka]

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

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

[0454] [ka]

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

[0456] In some embodiments, the compound is

[0457] [ka]

[0458] [ka]

[0459] [ka]

[0460] is selected from.

[0461] In some embodiments, the compound is

[0462] [ka]

[0463] is selected from.

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

[0465] [ka]

[0466] (wherein D represents a deuterium-enriched H site) Provided herein are compositions comprising a compound having the formula:

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

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

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

[0470] [ka]

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

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

[0473] [ka]

[0474] (Wherein, R31 and R32 are independently H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39wherein R38 is a C2-C10 alkylene and R39 is selected from H and C1-C10 alkyl; or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more linear or branched C1-C2 alkyls or interrupted by one or more additional nitrogen or oxygen atoms; R27 and R28 are fluorine, R29 and R30 are H; R33, R34, R35, R36, and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR41R42, —SR43, —S02R44, —CO2R45, and —C(═O)NR46R47; and R40, R41, R42, R43, R44, R45, R46, and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, and C(═O)heteroaryl. It has.

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

[0476] [ka]

[0477] (Wherein, R31 and R32 are independently H, C1-C10 alkyl, C2-C10 haloalkyl, -R 38 -OR 39 wherein R38 is a C2-C10 alkylene and R39 is selected from H and C1-C10 alkyl; or R31 and R32 together with the nitrogen atom to which they are attached form a C3-C6 cycloheteroalkyl ring, said ring being optionally substituted by one or more linear or branched C1-C2 alkyls or interrupted by one or more additional nitrogen or oxygen atoms; R27 and R28 together with the carbon and oxygen atoms to which they are attached form an oxetane ring; R29 and R30 are H; R33, R34, R35, R36, and R37 are each independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR40, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR41R42, —SR43, —S02R44, —CO2R45, and —C(═O)NR46R47; and R40, R41, R42, R43, R44, R45, R46, and R47 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C(═O)H, C(═O)alkyl, C(═O)aryl, and C(═O)heteroaryl. It has.

[0478] In some embodiments, the compound is

[0479] [ka]

[0480] [ka]

[0481] is selected from.

[0482] In some embodiments, the compound is

[0483] [ka]

[0484] is selected from.

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

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

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

[0488] In another aspect, there is provided a method of treating depression, anxiety depression, mood disorders, anxiety disorders, or substance use disorders and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject having a compound of structure (XIV):

[0489] [ka]

[0490] [Wherein R48 is phenyl, thiazole, thiophene, pyridine, or a group represented by the general formula (XV);

[0491] [ka]

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

[0493] In some embodiments, the compound is

[0494] [ka]

[0495] is selected from.

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

[0497] [ka]

[0498] It has.

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

[0500] [ka]

[0501] It has.

[0502] In some embodiments, the disorder being treated in the subject is depression or anxiety depression.

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

[0504] In another aspect, there is provided a method for treating depression, anxiety depression, mood disorders, anxiety disorders, or substance use disorders and any symptoms or disorders related thereto in a subject in need thereof, comprising administering to a subject a compound:

[0505] [ka]

[0506] or a composition comprising a pharmaceutically acceptable salt or ester of a compound to a subject, wherein said compound is enriched relative to its opposite enantiomer.

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

[0508] [ka]

[0509] wherein R56 and R57 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic C3-C8 cycloheteroalkyl ring, said ring being optionally substituted by one or more C1-C3 alkyl, F, OH, OMe or =0, and optionally interrupted by one or more additional nitrogen or oxygen atoms; R58, R59, R60, R61 and R62 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR63, -OC(=O)R64, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR65R66, -NH-C(=O)R67, -SR68, -SO2R69, -CO2R70, -C(=O)NR71R72; R63, R64, R65, R66, R67, R68, R69, R70, R71 and R72 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, and heteroaryl; provided that when R56 and R57 together with the nitrogen atom to which they are attached form an unsubstituted piperidine ring, at least one of R58, R59, R60, R61 and R62 is other than H. or a pharmaceutically acceptable salt or ester thereof.

[0510] In some embodiments, R56 and R57 together with the nitrogen atom to which they are attached form a piperidine ring, said ring being optionally substituted with one or more C1-C3 alkyl, F, OH, OMe, or =0; R58, R59, R60, R61 and R62 are each independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR63, -OC(=O)R64, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR65R66, -NH-C(=O)R67, -SR68, -SO2R69, -CO2R70, -C(=O)NR71R72; R63, R64, R65, R66, R67, R68, R69, R70, R71 and R72 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, and heteroaryl; provided that when R56 and R57 together with the nitrogen atom to which they are attached form an unsubstituted piperidine ring, at least one of R58, R59, R60, R61 and R62 is other than H, or a pharmaceutically acceptable salt or ester thereof.

[0511] In some embodiments, R56 and R57 together with the nitrogen atom to which they are attached form a pyrrolidine ring, said ring being optionally substituted with one or more C1-C3 alkyl, F, OH, OMe, or =0; R58, R59, R60, R61, and R62 are each independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR63, —OC(═O)R64, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR65R66, —NH—C(═O)R67, —SR68, —S2R69, —C2R70, and —C(═O)NR71R72; and R63, R64, R65, R66, R67, R68, R69, R70, R71, and R72 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, and heteroaryl, or a pharmaceutically acceptable salt or ester thereof.

[0512] In some embodiments, R56 and R57 together with the nitrogen atom to which they are attached form an azetidine ring, which is optionally substituted with one or more C1-C3 alkyl, F, OH, OMe, or ═O; R58, R59, R60, R61, and R62 are each independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR63, —OC(═O)R64, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, —NR65R66, —NH—C(═O)R67, —SR68, —S2R69, —C2R70, and —C(═O)NR71R72; and R63, R64, R65, R66, R67, R68, R69, R70, R71, and R72 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, and heteroaryl, or a pharmaceutically acceptable salt or ester thereof.

[0513] In some embodiments, R56 and R57 together with the nitrogen atom to which they are attached form an azetidine ring, said ring being optionally substituted with one or more C1-C3 alkyl or F; R58, R59, R60, R61, and R62 are each independently selected from H, OH, halogen (selected from F, Cl, Br, and I), —OR63, —OC(═O)R64, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, CN, CF3, OCF3, NO2, —NR65R66, —NH—C(═O)R67, —SR68, —S02R69, —C02R70, and —C(═O)NR71R72; and R63, R64, R65, R66, R67, R68, R69, R70, R71, and R72 are each independently selected from H, C1-C3 alkyl, C2-C3 alkenyl, and C2-C3 alkynyl, or a pharmaceutically acceptable salt or ester thereof.

[0514] In some embodiments, the compound is

[0515] [ka]

[0516] or a pharmaceutically acceptable salt or ester thereof, and / or the particular S- or R-isomer thereof.

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

[0518] [ka]

[0519] or a pharmaceutically acceptable salt thereof.

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

[0521] [ka]

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

[0523] In some embodiments, the compound is

[0524] [ka]

[0525] or a pharmaceutically acceptable salt or ester thereof, and / or the particular S- or R-isomer thereof.

[0526] In another aspect,

[0527] [ka]

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

[0529] In another aspect, [ka]

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

[0531] In another aspect, [ka]

[0532] Provided herein is a compound selected from:

[0533] In some embodiments, the compound is

[0534] [ka]

[0535] or a pharmaceutically acceptable salt thereof.

[0536] In some embodiments, the compound is

[0537] [ka]

[0538] is.

[0539] In another aspect,

[0540] [ka]

[0541] Provided herein is a composition comprising an enantiomeric mixture of a compound selected from the group consisting of:

[0542] In some embodiments, the compound is

[0543] [ka]

[0544] is selected from the group consisting of:

[0545] In another aspect,

[0546] [ka]

[0547] Provided herein is a composition comprising an enantiomeric mixture of a compound selected from the group consisting of:

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

[0549] In some embodiments, the compound is

[0550] [ka]

[0551] is selected from the group consisting of:

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

[0553] [ka]

[0554] [ka]

[0555] Provided herein are methods comprising administering an effective amount of a composition comprising an isolated, substantially enantiomerically pure compound selected from the group consisting of:

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

[0557] [ka]

[0558] Provided herein are methods comprising administering an effective amount of a composition comprising a compound selected from the group consisting of:

[0559] In some embodiments, the compound is

[0560] [ka]

[0561] is selected from the group consisting of:

[0562] In another aspect,

[0563] [ka]

[0564] Provided herein is an isolated, substantially enantiomerically pure compound represented by:

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

[0566] [ka]

[0567] or a pharmaceutically acceptable salt thereof.

[0568] In another aspect, there is provided a method of treating depression or anxiety depression in a subject in need thereof, comprising administering to a subject in need thereof:

[0569] [ka]

[0570] or a pharmaceutically acceptable salt thereof.

[0571] In another aspect,

[0572] [ka]

[0573] or a pharmaceutically acceptable salt thereof.

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

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

[0576] 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, severe mood dysregulation disorder, substance / medication-induced depressive disorder, and depressive disorders due to another medical condition.

[0577] Also provided herein are compounds, methods, and compositions useful for treating patients suffering from treatment-refractory depression, e.g., a depressive disorder that is unresponsive and / or has not responded to an adequate course of at least one, or at least two, other antidepressant compounds or therapeutic agents. As used herein, "depressive disorder" includes treatment-refractory depression.

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

[0579] In some embodiments, the compounds, methods, and compositions can be used to treat psychiatric disorders, including substance-related disorders, for example, to prevent substance craving, reduce substance craving, and / or promote cessation or cessation of substance use. Substance use disorders include the abuse of psychoactive compounds such as alcohol, caffeine, cannabis, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, a "substance" or "substances" refers to a potentially addictive psychoactive compound, such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, the methods and compositions may be used to promote smoking cessation or cessation of opioid use.

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

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

[0582] In some embodiments, the compounds, methods and compositions may be used to treat psychiatric disorders, including trauma and stressor-related disorders, such as reactive attachment disorder, disinhibited social interaction disorder, post-traumatic stress disorder, acute stress disorder, and adjustment disorder.

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

[0584] In some embodiments, the compounds, methods and compositions may 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 due to 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.

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

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

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

[0588] In some embodiments, the compounds, methods and compositions may be used to treat psychiatric disorders involving gender dysphoria, for example, gender dysphoria.

[0589] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound, material, composition, medicament, or other material effective to achieve a particular pharmacological and / or physiological effect, including, but not limited to, a reduction in the frequency or severity of sadness or lethargy, depressed mood, feelings of anxiety or sadness, decreased interest in all or nearly all activities, a significant increase or decrease in appetite resulting in weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness, helplessness, lack of concentration, and recurring thoughts of death or suicide, or to bring about a desired pharmacological and / or physiological effect, such as a reduction, inhibition, or reversal of one or more underlying pathophysiological mechanisms underlying neurological dysfunction, modulation of dopamine levels or signaling, modulation of serotonin levels or signaling, modulation of norepinephrine levels or signaling, modulation of glutamate or GABA levels or signaling, modulation of synaptic connectivity or neurogenesis in a particular brain region, or a combination thereof.

[0590] The term "therapeutic index," as used in connection with any compound and its associated therapeutic effects and side effects, refers to the ratio of the dose of the compound required to induce a specific negative side effect to the dose of the compound required to induce 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 therefore the therapeutic index of this compound in this context is approximately 1:1. In contrast, the compounds disclosed herein may have an improved therapeutic index, for example, 3:1, requiring a dose three times higher to induce dissociative side effects than the dose required for the antidepressant therapeutic effect.

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

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

[0593] Typically, dosages of the compounds disclosed herein or pharmaceutically acceptable salts thereof are administered to a patient in need thereof once, twice, three or four times daily, every other day, every three days, weekly, or monthly. In some embodiments, dosages are, for example, about 1-400 mg / day, or 1-300 mg / day, or 1-250 mg / day, or 1-200 mg / day, e.g., 300 mg / day, 250 mg / day, 200 mg / day, 150 mg / day, 100 mg / day, 75 mg / day, 50 mg / day, 25 mg / day, 20 mg / day, 10 mg / day, 5 mg / day, or 1 mg / day.

[0594] In some embodiments, parenteral or inhaled pharmaceutical compositions, e.g., sprays or mists, of the compounds of the present invention or pharmaceutically acceptable salts thereof contain a concentration of about 0.005 mg / mL to about 500 mg / mL. In some embodiments, the compositions contain 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.

[0595] In some embodiments, the composition comprises 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 about 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 to a total volume of, for example, about 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

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

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

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

[0599] In some embodiments, a compound or composition disclosed herein is administered to a patient under the supervision of a healthcare provider.

[0600] In some embodiments, a compound or composition disclosed herein is administered to a patient under the supervision of a medical provider at a clinic that specializes in providing psychoactive treatments.

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

[0602] In some embodiments, administration to a patient under the supervision of a healthcare provider is done on a regular basis to maintain therapeutic benefit in the patient, for example, 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.

[0603] In some embodiments, a compound or composition disclosed herein is administered by a patient self-administered at home or otherwise away from the supervision of a healthcare provider.

[0604] In some embodiments, self-administration is done on a regular basis to maintain therapeutic effect in the patient, for example daily, every other day, every three days, twice weekly, once weekly, twice monthly, or once monthly.

[0605] In some embodiments, the compounds or compositions disclosed herein may be administered at specified intervals. For example, during treatment, a patient may be administered the compound or composition at intervals of, for example, 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 hours, 0.5 hours, or 0.25 hours.

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

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

[0608] In some embodiments, a salt of a compound disclosed herein is used in any of the methods, uses, or compositions.

[0609] In some embodiments, a pharmaceutically acceptable salt of a compound disclosed herein is used in any of the methods, uses, or compositions.

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

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

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

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

[0614] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on the limitations of the method by which the value is measured or determined, i.e., the measurement system. For example, "about" can mean within 3 standard deviations or more than 3 standard deviations, according to practice in the art. Alternatively, "about" can mean within a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude of a value, e.g., within 5-fold or within 2-fold. As used herein, "about" and "approximately" are used interchangeably.

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

[0616] [ka]

[0617] wherein the attachment to the backbone of the compounds disclosed herein is via any carbon atom of the ring.

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

[0619] [ka]

[0620] where its attachment to the backbone of the compounds disclosed herein is via any carbon atom of the ring.

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

[0622] [ka]

[0623] wherein the attachment to the backbone of the compounds disclosed herein is via any carbon atom of the ring.

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

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

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

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

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

[0629] In the context of the present disclosure, the term "alkylene" should be understood to refer to a linear, branched, or, where possible, cyclohydrocarbon chain containing the indicated number of carbon atoms, where all bonds connecting the atoms are sigma bonds, where two hydrogen atoms have been removed, thus allowing for two open sigma bonds (atomic valences) to be connected.

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

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

[0632] The compounds disclosed herein may contain at least one asymmetric center. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral atom. Unless otherwise indicated in a structural formula, it should be understood that the invention encompasses all stereochemically isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by separation, such as preparing a mixture of enantiomeric products and then converting them to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatography column, or any other suitable method known in the art. Starting compounds of particular stereochemistry are commercially available or can be made and resolved by techniques known in the art. Furthermore, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers, with all tautomeric isomers being provided by the present invention. Furthermore, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

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

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

[0635] The present disclosure may also include any salt of the compounds disclosed herein above and below, including any pharmaceutically acceptable salt, where the compounds disclosed herein have a net charge (either positive or negative) and at least one counterion (having a counter negative or positive charge) is added thereto to form the salt. As used herein, the phrase "pharmaceutically acceptable salt" refers to a salt of a compound disclosed herein that is safe and effective for pharmaceutical use in mammals and possesses 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, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. 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.

[0636] The present invention is also intended to include all isotopes of atoms present on the compounds disclosed herein. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13 C and 14 Contains C.

[0637] Any designation of carbon in a structure throughout this application, when used without further designation, is: 12 C. 13 C or 14 It is noted that all isotopes of carbon, such as C, are intended to represent. 13 C or 14 Any compound containing C may specifically have the structure of any of the compounds disclosed herein.

[0638] Also, any designation of hydrogen in structures throughout this application, when used without further designation, is 1 H, 2 H or 3 It is noted that all isotopes of hydrogen, such as H, are intended to represent. 2 H or 3 Any compound containing H may have the structure of any of the compounds specifically disclosed herein.

[0639] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, substituting an appropriate isotopically labeled reagent for the non-labeled reagent utilized.

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

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

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

[0643] In selecting compounds for use in the methods of the present invention, one of skill in the art will recognize that the various substituents, i.e., R1, R2, etc., should be selected in accordance with well-known principles of chemical structure connectivity.

[0644] As used herein, the term "treatment" refers to the management and care of a patient for the purpose of combating a disease, disorder, or condition. The term is intended to include delaying the progression of the disease, disorder, or condition, alleviating or reducing 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.

[0645] Accordingly, the present disclosure also relates to pharmaceutical compositions comprising the compounds as defined herein below and above, in admixture with pharmaceutically acceptable excipients, and optionally other therapeutic agents. The excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

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

[0647] Such methods include the step of bringing into association the compound or combination thereof used in the present invention with any auxiliary agent. The auxiliary agents, also referred to as accessory ingredients, include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and wetting agents. Such auxiliary agents are suitably selected with regard to the intended form and route of administration and in accordance with conventional pharmaceutical practice.

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

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

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

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

[0652] 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 a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds can be administered as a component of a tissue-targeting emulsion.

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

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

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

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

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

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

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

[0660] Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments, and accordingly, all combinations of the various elements described herein are within the scope of the present disclosure.

[0661] It is understood that stereochemical assignments (eg, the R- and S-configurations of particular compounds provided below) may differ as determined, for example, by X-ray crystallography. [Example]

[0662] Preparation and characterization of compounds 35 and 37 General Considerations. Reagents and solvents were obtained from commercial sources and used without further purification unless otherwise stated (including anhydrous solvents). 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. Nuclear magnetic resonance spectra were recorded on a Bruker 400 or 500 MHz instrument. Chemical shifts were recorded using CDCl3 ( 1 H NMR=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) as the reference and reported as δ values ​​in ppm. Multiplicities are indicated as follows: s (singlet); d (doublet); t (triplet); p (quintet); dd (doublet of doublets); ddd (doublet of doublet of doublet); dddd (doublet of doublet of doublet of doublet); td (triplet of doublets); dt (doublet of triplet); m (multiplet); br (broad). All carbon peaks are rounded to one decimal place except when such rounding makes two adjacent peaks identical; in these cases, two decimal places are retained.

[0663] [ka] Scheme 1. Preparation of compounds 35rac, 35R, 35S, and 37rac.

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

[0665] (1-Bromocyclopentyl)(2-fluorophenyl)methanone (80). To a solution of compound 79 (9.52 g, 49.52 mmol) in CCl4 (50 mL) at 0 °C was added a solution of Br2 (2.66 mL, 8.31 g, 52.00 mmol) in CCl4 (50 mL) in small portions over 20 min. 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 NaS2O3 (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give bromoketone 80 as a yellow-orange oil (12.94 g, 96%) containing minor impurities. 1 H NMR (500 MHz, CDCl3) δ 7.76 (td, J = 7.4, 1.8 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.19 (td, J = 7.6, 1.1 Hz, 1H), 7.12 (ddd, J = 10.3, 8.3, 1.0 Hz, 1H), 2.46 - 2.33 (m, 4H), 2.10 - 1.99 (m, 2H), 1.89 - 1.79 (m, 2H); 13 C NMR (126 MHz, CDCl3) δ 196.9, 159.4 (d, J C-F = 252.1 Hz), 132.8 (d, J C-F = 8.5 Hz), 130.3 (d, J C-F = 2.8 Hz), 126.8 (d, J C-F = 15.0 Hz), 123.9 (d, J C-F = 3.6 Hz), 116.5 (d, J C-F = 22.2 Hz), 73.9, 40.5 (d, J C-F = 2.1 Hz), 23.4.

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

[0667] 2-(2-Fluorophenyl)-2-(methylamino)cyclohexan-1-one (35rac). Compound 81 (10.20 g, 46.10 mmol) was dissolved in decalin (80 mL), and the mixture was refluxed under argon. After 1 h at reflux (dark brown / black solution, slow conversion by TLC), PdCl (245 mg, 1.38 mmol) was added, and refluxing was 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 × 100 mL). The combined acidic aqueous extracts were washed with hexane (100 mL) and EtO (100 mL), basified with 25% m / m aqueous NaOH, and extracted with EtO (3 × 100 mL). The combined organics were washed with water (50 mL) and brine (50 mL), dried over NaSO, and concentrated in vacuo to give a very dark brown oil (6.69 g). This material was purified by column chromatography (8:2 hexanes:EtOAc + 2% EtN, 1 column volume → 7:3 hexanes:EtOAc + 2% EtN, 4 column volumes) to yield a dark brown oil (4.56 g) still containing impurities. This 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) as a viscous light brown oil that slowly crystallized to a waxy solid (3.40 g, 33%). This material was converted to the HCl salt as follows. The free base 35rac (3.40 g, 15.37 mmol) was dissolved in EtO (100 mL) and 2.0 M HCl in EtO (11.53 mL, 23.06 mmol) was added with stirring at room temperature. The resulting precipitate was collected by filtration, washed with EtO (3×), and dried to give 35rac HCl as a powdery white solid (3.98 g, quantitative recovery). Free base: 11H NMR (400 MHz, CDCl3) δ 7.40 (td, J = 7.8, 1.8 Hz, 1H), 7.29 (dddd, J = 8.1, 7.1, 5.1, 1.8 Hz, 1H), 7.19 (td, J = 7.5, 1.3 Hz, 1H), 7.04 (ddd, J = 11.5, 8.1, 1.3 Hz, 1H), 2.79 - 2.68 (m, 1H), 2.54 - 2.37 (m, 2H), 2.11 (s, 3H), 2.07 (s, 1H), 1.99 - 1.89 (m, 1H), 1.86 - 1.62 (m, 4H); 13 13C NMR (101 MHz, CDCl3) δ 210.1, 161.2 (d, J C-F = 246.9 Hz), 129.5 (d, J C-F = 8.8 Hz), 128.9 (d, J C-F = 5.0 Hz), 127.3 (d, J C-F = 13.0 Hz), 124.3 (d, J C-F = 3.2 Hz), 116.4 (d, J C-F = 22.9 Hz), 68.5 (d, J C-F = 2.2 Hz), 39.5, 38.4, 29.4, 28.6, 22.1; HCl salt: 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 C NMR (101 MHz, DMSO-d6) δ 205.5, 160.7 (d, J C-F = 247.6 Hz), 133.2 (d, J C-F = 9.0 Hz), 130.9 (d, J C-F = 2.9 Hz), 125.7 (d, J C-F = 3.0 Hz), 118.2 (d, J C-F = 11.8 Hz), 116.8 (d, J C-F = 22.7 Hz), 68.7, 38.6 (d, J C-F = 1.8 Hz), 34.5, 28.3, 27.2, 21.1.

[0668] Chiral Separation of 35 Enantiomers (35R and 35S). The enantiomers of compound 35 were separated by crystallization of the diastereomeric hydrogen tartrate salts formed with L-(+)- and D-(-)-tartaric acid. 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), and the mixture was gently warmed until a clear brown solution was obtained, which was then allowed to stand at room temperature. After 16 hours and then several hours in an acetone chamber (for vapor diffusion), no crystals had yet formed. Therefore, acetone (5.5 mL) was added to the solution, and the entire mixture immediately crystallized as a dense mass. The resulting crystals were collected by filtration, washed with a minimal amount of ice-cold 2:1 acetone:water (2x, some crystals dissolved) and ice-cold acetone (2x), and dried to give Crystal 1 (white needles, 344 mg, hydrogen L-tartrate, approximately 80:20 R:S). Crystal 1 was dissolved in water (1.5 mL) and placed in an acetone chamber (for vapor diffusion). After 84 h, the total volume of the solution was approximately 10–12 mL (estimated approximately 6:1 acetone:water), and densely packed, fine needles had formed. These were collected by filtration, washed with room-temperature acetone (2x), and dried to give Crystal 2 (fine white needles, 176 mg, hydrogen L-tartrate, R enantiomer, >95% ee). Over several hours, additional crystals formed in the filtrate from Crystal 2. These were allowed to stand overnight, then collected, washed with room temperature acetone (2x), and dried to give crystalline 3 (fine white needles, 37.6 mg, hydrogen L-tartrate, R enantiomer, >95% ee). The concentrated filtrate from crystalline 1 and 3 (sticky off-white foam, 1.48 g) was dissolved in water (1.5 mL), acetone (3.0 mL) was added, and the mixture was seeded with crystalline 3. After 2 h at room temperature, the resulting crystals were collected by filtration, washed with room temperature acetone (4x), and dried to give crystalline 4 (white needles, 690 mg, hydrogen L-tartrate, 48:52 R:S). The concentrated filtrate from crystalline 4 (white foam, 796 mg, hydrogen L-tartrate, 39:61 R:S) was enriched in the S enantiomer and converted back to the free base (nearly colorless waxy solid, 425 mg, 1.92 mmol).A quantity of this free base (419 mg, 1.89 mmol) was combined with D-(-)-tartaric acid (284 mg, 1.89 mmol) and water (1.13 mL), and the mixture was gently warmed until a clear brown solution was obtained. After cooling to room temperature, acetone (3.39 mL) was added, and the mixture was allowed to stand for 2 hours and then placed in an acetone chamber (for vapor diffusion) for 24 hours. At this point, rosettes of blade-like crystals formed, which appeared to represent a different polymorph. These were collected by filtration, washed with ice-cold 3:1 acetone:HO (1x) and room temperature acetone (2x), and dried to give crystalline 5 (white crystals, 311 mg, hydrogen D-tartrate, 46.5:53.5 R:S), although the enrichment in the S enantiomer was surprisingly reduced, which may be due to crystallization as a different polymorph. However, fine needles soon formed in the filtrate of crystalline 5, which appeared to be the same polymorph as in the previous crystallization. These were collected by filtration, washed with room-temperature acetone (3x), and dried to give crystalline 6 (fine white needles, 159 mg, hydrogen D-tartrate, S enantiomer, >95% ee). Additional fine needles soon formed in the filtrate of crystalline 6. These were collected by filtration, washed with room-temperature acetone (3x), and dried to give crystalline 7 (fine white needles, 54.8 mg, hydrogen D-tartrate, S enantiomer, >95% ee). Crystal 5 was dissolved in water (1.0 mL) and placed in an acetone chamber (for vapor diffusion) over the weekend. After this time, as crystals were still forming, the solution was seeded with crystal 6. Crystals began to form within 30 minutes, and after standing at room temperature for 2 hours, they were collected by filtration, washed with room temperature acetone (3x), and dried to give crystalline 8 (fine white needles, 150 mg, hydrogen D-tartrate, 33:77 R:S). The ee of all crystalline crops was converted back to the free base form and the sample was subjected to chiral HPLC (Daicel Chiralcel AD column, 4.6 mm ID, 97:3 hexane:iPrOH+0.30% EtNH, 1 mL / min, 4 mg / mL sample concentration, 20 μL injection volume; 35 R:S). R =12.7 minutes, 35S t R=11.7 min). Hydrogen tartrate (identical for both R and S enantiomers): 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (td, J = 7.8, 1. 8 Hz, 1H), 7.37 (tdd, J = 7.5, 5.2, 1.8 Hz, 1H), 7.25 (td, J = 7.6, 1.3 Hz, 1H), 7.16 (ddd, J = 11.8, 8.2, 1.3 Hz, 1H), 4.20 (s, 2H), 2.54 (td, J = 9.2, 4.7 Hz, 1H), 2.42 - 2.35 (m, 1H), 2.31 - 2.24 (m, 1H), 2.02 (s, 3H), 1.96 - 1.86 (m, 1H), 1.86 - 1.72 (m, 3H), 1.59 - 1.50 (m, 1H); 1 H NMR (500 MHz, methanol-d4) δ 7.76 (td, J = 7.9, 1.7 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.47 (td, J = 7.7, 1.2 Hz, 1H), 7.32 (ddd, J = 11.8, 8.3, 1.2 Hz, 1H), 4.40 (s, 2H), 3.27 - 3.20 (m, 1H), 2.55 - 2.49 (m, 2H), 2.36 (s, 3H), 2.15 - 2.07 (m, 1H), 1.96 - 1.85 (m, 2H), 1.83 - 1.65 (m, 2H).

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

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

[0671] Assignment of the absolute configuration of 35 enantiomers (35R and 35S). X-ray quality crystals were grown as follows. A quantity of crystalline 2 (20.5 mg, 0.055 mmol) was dissolved in water (10 mL), basified with 5% m / m aqueous NaOH, and extracted with EtO (3 × 10 mL). The combined organics were washed with water (2 × 5 mL) and brine (5 mL), dried over NaSO, 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, then concentrated in vacuo to give the diastereomeric camphorsulfonic acid salts. These salts were dissolved in a minimum amount of toluene, and the solution was allowed to slowly evaporate at room temperature in a 4 mL vial with the cap slightly ajar. Under these conditions, the (-)-CSA salt yielded crystals of acceptable quality for structure assignment by single-crystal X-ray diffraction. The absolute configuration was assigned by both anomalous dispersion and by reference to the known configuration of the (-)-CSA counterion, indicating that crystalline 2 has the R configuration (R factor = 0.0387). Crystallographic parameters are listed in Table 1, and a representation of the determined crystal structure is shown in Figure 1. Knowing the absolute configuration of crystalline 2, it was possible to determine the configuration and ee of other crops of crystals by chiral HPLC, as described above.

[0672] [Table 1]

[0673] (2-Aminophenyl)(cyclopentyl)methanone (89). To a solution of 2-aminobenzonitrile (4.73 g, 40.00 mmol) in anhydrous THF (15 mL) under argon at 0 °C was added cyclopentylmagnesium bromide (2 M in EtO; 60.00 mL, 120.00 mmol). After approximately one-third of the Grignard reagent was added over 5 min, a thick yellow precipitate formed and the mixture became difficult to stir. Additional anhydrous THF (45 mL) was added in an attempt to reduce the viscosity and improve stirring, but this had little effect. Therefore, the remaining two-thirds of the Grignard reagent was added over 5 min, swirling the mixture manually during the addition to ensure as complete a mixture as possible, and then allowing it to warm to room temperature. Once at room temperature, additional anhydrous THF (40 mL) was added, and the mixture was swirled further until the thick, pale yellow slurry had thinned sufficiently to become stirrable. After stirring at room temperature for 3 h, the reaction was poured into a mixture of ice (150 g) and 10% aqueous HCl (100 mL). The resulting biphasic yellow solution was allowed to stand with occasional mixing until TLC indicated complete hydrolysis of the imine intermediate. The hydrolyzed mixture was basified to pH 7–8 with solid NaHCO3 and extracted with Et2O (3 × 100 mL). The combined organics were washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give a yellow oil that slowly crystallized to a waxy yellow solid (7.37 g). This material was purified by column chromatography (9:1 hexanes:EtOAc) to give pure aminoketone 89 as a waxy lemon-yellow solid (6.72 g, 89%). 1 H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 6.69 - 6.61 (m, 2H), 6.27 (br s, 2H), 3.72 (p, J = 8.0 Hz, 1H), 1.97 - 1.86 (m, 4H), 1.80 - 1.70 (m, 2H), 1.70 - 1.60 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 205.6, 150.8, 134.0, 131.5, 118.0, 117.5, 115.8, 46.8, 30.5, 26.5.

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

[0675] (1-Bromocyclopentyl)(2-iodophenyl)methanone (91). To a solution of iodoketone 90 (1.71 g, 5.70 mmol) in CCl4 (5.8 mL) at 0 °C was added a solution of Br2 (0.307 mL, 957 mg, 5.99 mmol) in CCl4 (5.8 mL) in small portions over 20 min. Upon completion of the addition, the mixture was allowed to warm to room temperature and stirred for 40 min. The reaction mixture was then diluted with CHCl2 (20 mL), washed with saturated aqueous NaS2O3 (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give compound 91 as a yellow oil (2.14 g, 99%). 1 H NMR (500 MHz, CDCl3) δ 7.89 (dd, J = 7.9, 1.1 Hz, 1H), 7.70 (dd, J = 7.7, 1.7 Hz, 1H), 7.38 (td, J = 7.6, 1.1 Hz, 1H), 7.12 (td, J = 7.7, 1.6 Hz, 1H), 2.46 - 2.30 (m, 4H), 2.11 - 2.00 (m, 2H), 1.93 - 1.83 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 201.1, 144.7, 140.0, 131.1, 127.8, 127.7, 92.3, 73.5, 41.0, 23.4.

[0676] 2-(2-Iodophenyl)-2-(methylamino)cyclohexan-1-one (37rac). Liquid methylamine was freshly prepared as follows: Solid methylamine HCl (30 g) was treated dropwise with 50% m / m aqueous NaOH (40 g). The evolved gas was passed through a drying tube containing NaOH pellets and condensed into a flask topped with a condenser containing dry ice / acetone. Once the required amount of liquid methylamine was collected, the reaction was carried out as follows: Compound 91 (2.12 g, 5.59 mmol) and liquid methylamine (4.5 mL) were combined under argon at −10° C., and the resulting mixture was stirred for 1 h. All methylamine was then carefully boiled off, and the resulting residue was dried in vacuo to give a pale yellow solid (2.40 g). This material was triturated with EtO (10 mL), filtered, and the filter cake was washed with EtO (2 × 5 mL). The combined filtrates were concentrated in vacuo to give crude 1-((2-iodophenyl)(methylimino)methyl)cyclopentan-1-ol as a waxy yellow solid (1.78 g). A portion of this material (1.76 g) 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 EtO (20 mL), and extracted with 2% aqueous HCl (20 mL) and water (2 × 20 mL). The combined aqueous extracts were washed with hexane (20 mL) and EtO (20 mL), basified to pH 9–10 with aqueous NaOH, and extracted with EtO (3 × 20 mL). The combined organics were washed with water (10 mL) and brine (10 mL), dried over NaSO, and concentrated in vacuo to give a viscous yellow oil (690 mg). This material was purified by column chromatography (8:2 hexanes:EtOAc, 4 column volumes → 7:3 hexanes:EtOAc, 4 column volumes) to yield a nearly colorless oil that slowly crystallized to an off-white solid (0.31 g) that still contained impurities.This material was further purified by additional column chromatography (20:1 hexanes:EtOAc+2% EtN, 2 column volumes → 9:1 hexanes:EtOAc+2% EtN, 2 column volumes → 5.67:1 hexanes:EtOAc+2% EtN, 2 column volumes) to afford racemic 37 (37rac) as a nearly colorless oil that slowly crystallized to a waxy white solid (267 mg, 15% over two steps). This material was converted to the HCl salt as follows: The free base 37rac ​​(267 mg, 0.811 mmol) was dissolved in EtO (5 mL) and 2.0 M HCl in EtO (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 hexane, and the mixture was concentrated again to afford 37rac ​​HCl as a powdery off-white solid (281 mg, 95% recovery). Free base: 1 H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 7.8 Hz, 1H), 7.52 (dd, J = 7.9, 1.7 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 6.94 (td, J = 7.6, 1.7 Hz, 1H), 2.76 - 2.66 (m, 1H), 2.54 - 2.44 (m, 2H), 2.18 - 2.08 (m, 2H), 2.07 (s, 3H), 1.94 - 1.84 (m, 1H), 1.83 - 1.75 (m, 3H); 13 C NMR (126 MHz, CDCl3) δ 207.6, 142.5, 142.2, 129.8, 128.9, 127.9, 98.3, 72.2, 39.9, 38.9, 29.3, 26.9, 21.7; HCl salt: 1H 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; hidden by HO peak as shown by COSY), 2.65–2.53 (m, 2H), 2.25 (s, 3H), 2.09–1.99 (m, 1H), 1.88 (td, J = 13.7, 3.4 Hz, 1H), 1.77 (br d, J = 13.9 Hz, 1H), 1.74 - 1.64 (m, 1H), 1.55 - 1.42 (m, 1H). [Example]

[0677] Preparation of Compounds 14S and 14R

[0678] [ka]

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

[0680] Preparation of Compounds 29R and 29S

[0681] [ka]

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

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

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

[0685] Step 4: Preparation of (1-bromocyclopentyl)(phenyl)methanone To a solution of cyclopentyl(phenyl)methanone (17 g, 90 mmol) in a mixture of dry ethyl acetate (75 mL) and dry CHCl (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 room temperature and filtered. The filtrate was concentrated in vacuo to give 22 g of (1-bromocyclopentyl)(phenyl)methanone (96.6% yield), which was used in the next step without further purification.

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

[0687] Step 6: Preparation of 2-((2-methoxyethyl)amino)-2-phenylcyclohexan-1-one (29rac) To 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 small portions. The reaction mixture was heated at 180 °C for 15 min, cooled to room temperature, 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 g 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, 400 MHz): δ (ppm) 9.39 (s, 2H), 7.46 (m, 3H), 7.39 (m, J=7.0 Hz, 2H), 3.44 (m, 2H), 3.34 (m, 1H), 3.19 (s, 3H), 3.01 (m, 1H), 2.41 (m, 2H), 2.31 (m, 1H), 2.12 (m, 1H), 1.90 (m, 1H), 1.82 (m, 1H), 1.64 (q, J=12.4, 12.3, 12.3 Hz, 1H), 1.51 (q, J=12.4, 12.4, 12.3 Hz, 1H).

[0688] Step 7: Preparation of (R)-2-((2-methoxyethyl)amino)-2-phenylcyclohexan-1-one (29R) and (S)-2-((2-methoxyethyl)amino)-2-phenylcyclohexan-1-one (29S) The HCl salt of 29rac was basified with aqueous NaHCO3, extracted with CHCl2, and the organic extract was concentrated to yield 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: CO2, B: 0.1% NH3HO in ETOH, B%: 17%; multiple injection process with 1.2 min interval between injections) to give ENT-1, RT = 1.080 min (241 mg) (herein assigned as the S isomer, 29S) and ENT-2, RT = 1.236 min (184 mg) (herein assigned as the R isomer, 29R). Retention times were determined using the following chiral analytical method: Column: Chiralpak OD-3, 100 × 4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: EtOH (0.1% IPAm, v / v); Gradient: (time (min) / A% / B%), (0.0 / 95 / 5, 0.5 / 95 / 5, 2.0 / 60 / 40, 3.0 / 60 / 40, 3.6 / 95 / 5, 4.0 / 95 / 5); Flow rate: 3.4 mL / min; Column temperature: 35 °C; ABPR: 1800 psi. [Example]

[0689] Preparation of Compounds 30R and 30S

[0690] [ka]

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

[0692] Step 2: 2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one (30rac) Preparation of To stirred Dowtherm (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 small portions. The reaction mixture was heated to 180 °C for 15 min, cooled to room temperature, 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 of EtOH + a few drops of ACN per g of crude product) to give 2.7 g of 2-((2-hydroxyethyl)amino)-2-phenylcyclohexan-1-one hydrochloride (30 rac). 1 H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 7.7 Hz, 2H), 7.43 - 7.32 (m, 3H), 7.32 - 7.23 (m, 2H), 5.41 (t, J=3.7 Hz, 1H), 3.91 (dd, J = 10.7, 3.8 Hz, 1H), 3.85 - 3.73 (m, 2H), 2.94 - 2.81 (m, 1H), 2.64 (dd, J = 13.7, 3.0 Hz, 1H), 2.21 - 2.06 (m, 2H), 1.94 (dt, J = 12.6, 3.4 Hz, 2H), 1.86 - 1.68 (m, 2H), 1.53 - 1.47 (m, 1H), 1.31 - 1.18 (m, 1H).

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

[0694] Preparation of Compounds 38R and 38S

[0695] [ka]

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

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

[0698] Step 3: Preparation of (1-bromocyclopentyl)(o-tolyl)methanone To a solution of cyclopentyl(o-tolyl)methanone (16 g, 90 mmol) in a mixture of dry ethyl acetate (75 mL) and dry CHCl (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 (96% yield), which was used in the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.74 (d, J = 7.7 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.27 - 7.14 (m, 2H), 2.36 (m, 7H), 2.05 (tt, J = 9.6, 5.3 Hz, 2H), 1.81 (q, J = 7.6 Hz, 2H).

[0699] Step 4: Preparation of 1-((methylimino)(o-tolyl)methyl)cyclopentan-1-ol hydrochloride A mixture of (1-bromocyclopentyl)(o-tolyl)methanone (15 g, 56.14 mmol) and a solution of methylamine in methanol (150 mL) was stirred at room temperature for 48 hours. Upon completion, 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 NaSO and evaporated under reduced pressure to give 9.5 g of 1-((methylimino)(o-tolyl)methyl)cyclopentan-1-ol. This material in dioxane (1 M) was treated with HCl / dioxane (1.05 equivalents) and evaporated under reduced pressure to give 11.1 g of 1-((methylimino)(o-tolyl)methyl)cyclopentan-1-ol hydrochloride. 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).

[0700] Step 5: Preparation of 2-(methylamino)-2-(o-tolyl)cyclohexan-1-one (38rac) To stirred Dowtherm (70 mL, 228.7 mmol) heated to 200 °C in an oil bath was added 1-((methylimino)(o-tolyl)methyl)cyclopentan-1-ol hydrochloride in small portions. The reaction mixture was heated to 180 °C for 15 min, cooled to room temperature, 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 ACN per g of crude product) to give 2.7 g of 2-(methylamino)-2-(o-tolyl)cyclohexan-1-one hydrochloride (38rac). 1 H NMR (400 MHz, chloroform-d) δ 7.45 (dd, J = 7.5, 1.7 Hz, 1H), 7.21 (dtd, J = 14.5, 7.2, 2.3 Hz, 2H), 7.14 (dd, J = 7.3, 1.8 Hz, 1H), 3.05 (dd, J = 15.2, 4.1 Hz, 1H), 2.37 (dd, J = 7.9, 3.1 Hz, 1H), 2.13 (s, 3H), 2.04 (s, 3H), 2.01 - 1.96 (m, 1H), 1.83 - 1.70 (m, 3H), 1.54 (dq, J = 14.2, 4.7 Hz, 1H).

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

[0702] Preparation of Compounds 26R and 26S

[0703] [ka]

[0704] Step 1: Preparation of 2-phenylcyclohexan-1-ol To a stirred solution of 7-oxabicyclo[4.1.0]heptane (107 g, 1090 mmol) in THF (1000 mL) was added CuI (20.76 g, 109 mmol). To the resulting mixture, cooled to 0 °C, was added dropwise a solution of phenylmagnesium bromide in THF (1500 mL, 1200 mmol). The reaction mixture was stirred 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 give 120 g of 2-phenylcyclohexan-1-ol (62.5% yield). 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).

[0705] Step 2: Preparation of 2-phenylcyclohexan-1-one To a stirred solution of 2-phenylcyclohexan-1-ol (120 g, 680 mmol) in dry dichloromethane (1500 mL) cooled in an ice-water bath, Dess-Martin periodinane (DMP, 303 g, 715 mmol) was added in small portions. The reaction mixture was stirred overnight at room temperature, poured into a K2CO3 / ice mixture (250 g, 2000 mL), stirred for 30 minutes, and filtered. The filtrate was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was diluted with hexane, refluxed, and filtered. The filtrate was evaporated under reduced pressure to give 90 g of 2-phenylcyclohexan-1-one (69% yield). 1 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).

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

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

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

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

[0710] Preparation of Compounds 27R and 27S

[0711] [ka]

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

[0713] Step 2: Preparation of (R)-2-phenyl-2-(pyrrolidin-1-yl)cyclohexan-1-one (27R) and (S)-2-phenyl-2-(pyrrolidin-1-yl)cyclohexan-1-one (27S) The HCl salt of 27rac was basified with aqueous NaHCO3, extracted with CHCl2, and the organic extract was concentrated to yield the free base (850 mg). This material was separated into enantiomers by SFC (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3HO in MeOH, B%: 36%; multiple injection process with 3 min interval between injections) to give ENT-1, RT = 2.177 min (300 mg) (herein assigned as the S isomer, 27S) and ENT-2, RT = 2.438 min (316 mg) (herein assigned as the R isomer, 27R). Retention times were determined using the following chiral analytical 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. [Example]

[0714] Preparation of Compounds 19R and 19S

[0715] [ka]

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

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

[0718] Step 3: Preparation of (1-bromocyclopentyl)(3-fluorophenyl)methanone To a solution of cyclopentyl(3-fluorophenyl)methanone (16.5 g, 86 mmol) in a mixture of dry ethyl acetate (90 mL) and dry CHCl (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 (90% yield), which was used in the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.94 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 9.8 Hz, 1H), 7.41 (td, J = 7.9, 5.4 Hz, 1H), 7.23 (dd, J = 9.3, 7.0 Hz, 1H), 2.44 (dh, J = 21.7, 7.6, 6.9 Hz, 4H), 2.05 (q, J = 6.3, 5.5 Hz, 2H), 1.80 (q, J = 7.4 Hz, 2H).

[0719] Step 4: Preparation of 1-((3-fluorophenyl)(methylimino)methyl)cyclopentan-1-ol hydrochloride A mixture of (1-bromocyclopentyl)(3-fluorophenyl)methanone (21 g, 77.5 mmol) and a solution of methylamine in methanol (200 mL) was stirred at room temperature for 48 hours. 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 NaSO and evaporated under reduced pressure to give 14 g of 1-((3-fluorophenyl)(methylimino)methyl)cyclopentan-1-ol. This material in dioxane was diluted with HCl / dioxane and evaporated under reduced pressure to give 16.3 g of the hydrochloride salt.

[0720] Step 5: Preparation of 2-(3-fluorophenyl)-2-(methylamino)cyclohexan-1-one (19rac) To Dowtherm (100 mL, 326.7 mmol) heated to 200 °C in an oil bath was added 16 g of 1-((3-fluorophenyl)(methylimino)methyl)cyclopentan-1-ol in small portions. The reaction mixture was heated to 180 °C for 15 min, cooled to room temperature, 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 give 3.9 g of 2-(3-fluorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride (19rac). 1H NMR (500 MHz, DMSO-d6) 9.49 (s, 2H), 7.59 (q, J = 7.5 Hz, 1H), 7.37 (td, J = 8.5, 2.4 Hz, 1H), 7.32 (d, J = 10.0 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 3.14 (dd, J = 14.2, 3.1 Hz, 1H), 2.39 (d, J = 13.5 Hz, 1H), 2.36 - 2.26 (m, 1H), 2.21 - 2.12 (m, 1H), 2.11 (s, 3H), 1.95 (ddd, J = 12.6, 6.2, 3.1 Hz, 1H), 1.87 - 1.81 (m, 1H), 1.67 - 1.50 (m, 2H).

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

[0722] Preparation of Compounds 88R and 88S

[0723] [ka]

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

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

[0726] Preparation of Compounds 86S and 86R

[0727] [ka]

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

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

[0730] Preparation of Compounds 28R and 28S

[0731] [ka]

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

[0733] Step 2: Preparation of (R)-2-(isopropylamino)-2-phenylcyclohexan-1-one (28R) and (S)-2-(isopropylamino)-2-phenylcyclohexan-1-one (28S) The racemate was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: CO, B: 0.1% NHH0 in EtOH, B%: 10%; multiple injection process with 5 min interval between injections) to give ENT-1 0.659 min (230 mg) as a white solid and ENT-2 1.111 min (250 mg) as a white solid. Retention times were determined using the following chiral analytical 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.

[0734] ENT-1, RT=0.659 min (here assigned as the R isomer, 28R); LCMS R T = 1.630 min; MS calculated: 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 assigned as S isomer, 28S); LCMS R T = 1.636 min; MS calculated: 231.33, [M+H]+ = 232.1; 1 H 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. [Example]

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

[0736] [ka]

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

[0738] Step 2: Preparation of 2-amino-2-phenyl-cyclohexan-1-one (11rac) A mixture of 2-nitro-2-phenyl-cyclohexan-1-one (10 g, 45.61 mmol, 1 equiv) and Zn (23.86 g, 364.90 mmol, 8 equiv) in AcOH (100 mL) was stirred at 20 °C for 12 h. Upon completion, the mixture was filtered and concentrated. The residue was dissolved in DCM, washed with saturated NaHCO, HO, and brine, dried over NaSO, filtered, and concentrated to give 2-amino-2-phenyl-cyclohexan-1-one (7.5 g, 39.63 mmol, 86.88% yield) (11rac) as a brown oil. 1 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).

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

[0740] Step 4: Preparation of (R)-2-(azetidin-1-yl)-2-phenyl-cyclohexan-1-one (84R) and (S)-2-(azetidin-1-yl)-2-phenyl-cyclohexan-1-one (84S) The racemate (84rac) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: CO, B: 0.1% NHH0 in ETOH; B%: 15%; multiple injection process) to give ENT-1 0.736 min (340 mg) as a white solid and ENT-2 0.831 min (370 mg) as a white solid. Retention times were determined using the following chiral analytical method: Column: Chiralpak AD-3, 50 × 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, 0.2 / 95 / 5, 1.2 / 50 / 50, 2.2 / 50 / 50, 2.6 / 95 / 5, 3.0 / 95 / 5); Flow rate: 3.4 mL / min; Column temperature: 35 °C; ABPR: 1800 psi.

[0741] ENT-1, RT=0.736 min (here assigned as the R isomer, 84R); LCMS (R T = 1.534 min, MS calculated: 229.15, [M+H] + = 230.1); 1H NMR (400 MHz, chloroform-d) δ ppm 7.47 - 7.41 (m, 2H), 7.38 - 7.32 (m, 1H), 7.16 (d, J = 7.6 Hz, 2H), 3.29 (q, J = 7.2 Hz, 2H), 3.09 (q, J = 6.8 Hz, 2H), 2.64 (qd, J = 3.2, 14.0 Hz, 1H), 2.39 - 2.26 (m, 2H), 1.95 - 1.55 (m, 7H); 13 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 assigned as S isomer, 84S); LCMS (R T = 1.529 minutes, MS cal.: 229.15, [M+H] + = 230.1); 1 H NMR (400 MHz, chloroform-d) δ ppm 7.49 - 7.40 (m, 2H), 7.39 - 7.32 (m, 1H), 7.16 (d, J = 7.6 Hz, 2H), 3.30 (q, J = 6.8 Hz, 2H), 3.10 (q, J = 6.8 Hz, 2H), 2.65 (qd, J = 3.2, 14.0 Hz, 1H), 2.39 - 2.26 (m, 2H), 1.94 - 1.52 (m, 7H); 13 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.

[0742] Step 5: Preparation of (S)-2-amino-2-phenyl-cyclohexan-1-one (11S) and (R)-2-amino-2-phenyl-cyclohexan-1-one (11R) Racemic 2-Amino-2-phenyl-cyclohexan-1-one (11rac)Separation by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: CO, B: 0.1% NH₃H₂O in MeOH; B%: 42%; multiple injection process with 3.8 min interval between injections) gave 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. Retention times were determined using the following chiral analytical 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.

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

[0744] Preparation of Compounds 114S and 114R

[0745] [ka]

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

[0747] Step 2: Preparation of 2-(o-tolyl)cyclohexan-1-one To a mixture of 2-(o-tolyl)cyclohexan-1-ol (3.5 g, 18.39 mmol, 1 equiv.) in DCM (15 mL) was added Dess-Martin periodinane (DMP, 11.70 g, 27.59 mmol, 1.5 equiv.) in one portion at 0 °C under N . The mixture was stirred at 25 °C for 12 h. The mixture was filtered, and the filtrate was washed with saturated aqueous Na SO , saturated aqueous Na CO , and brine, then dried over Na SO , filtered, and concentrated. The residue was purified by silica gel (PE:EA = 50:1 to 8:1) to give 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).

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

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

[0750] Step 5: Preparation of (S)-2-amino-2-(o-tolyl)cyclohexan-1-one (114S) and (R)-2-amino-2-(o-tolyl)cyclohexan-1-one (114R) The racemate was separated by SFC (Column: REGIS (s,s) WHELK-O1 (250 mm × 30 mm, 5 μm); Mobile phase: A: CO, B: 0.1% NH₃H₂O in IPA; B%: 15%, multiple injection process with 10 min interval between runs) to give 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. Retention times were determined using the following chiral analytical 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.

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

[0752] Preparation of Compounds 31S and 31R

[0753] [ka]

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

[0755] Step 2: Preparation of (S)-2-morpholino-2-phenylcyclohexan-1-one (31S) and (R)-2-morpholino-2-phenylcyclohexan-1-one (31R) The racemate was separated by SFC (Column: REGIS® WHELK-O1 (250 mm × 25 mm, 10 μm); Mobile phase: A: CO, B: 0.1% NH₃H₂O in IPA; B%: 38%, multiple injection process with 6 min interval between injections) to give ENT-1 1.950 min (434 mg) as a white solid and ENT-2 2.276 min (474 ​​mg) as a white solid. Retention times were determined using the following chiral analytical 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.

[0756] ENT-1, RT=1.950 min (here assigned as S isomer, 31S); LCMS (R T = 1.425 min, MS calculated: 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 assigned as R isomer, 31R); LCMS (R T = 1.439 min, MS calculated: 259.34, [M+H] + = 260.1); 1 H NMR (400 MHz, chloroform-d) δ = 7.42 - 7.36 (m, 2H), 7.34 - 7.29 (m, 1H), 7.28 - 7.23 (m, 2H), 3.73 - 3.63 (m, 4H), 2.52 (br s, 1H), 2.59 - 2.42 (m, 1H), 2.40 - 2.30 (m, 3H), 2.28 - 2.18 (m, 1H), 1.97 - 1.85 (m, 2H), 1.82 - 1.66 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ = 211.12, 135.77, 128.59, 128.23, 127.67, 74.54, 67.55, 47.47, 40.85, 31.98, 28.24, 22.17. [Example]

[0757] Preparation of compounds 117rac and 18rac

[0758] [ka]

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

[0760] Step 2: Preparation of 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (117rac) A mixture of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (3 g, 12.65 mmol, 1 equiv.) and Zn (19.85 g, 303.51 mmol, 24 equiv.) in AcOH (25 mL) was stirred at 20 °C for 12 h. The mixture was cooled, filtered, and concentrated. The residue was dissolved in DCM, washed with saturated NaHCO 3 , HO, and brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel (PE:EA=50:1 to 8:1) to give 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1.5 g, 7.24 mmol, 57.23% yield) (117 rac) as a brown oil. LCMS (R T = 1.336 min, MS calculated: 207.11, [M+H] + = 208.1) 1H NMR (400MHz, 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

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

[0762] Preparation of compounds 118rac and 23rac

[0763] [ka]

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

[0765] Step 2: Preparation of 2-(m-tolyl)cyclohexan-1-one To a mixture of 2-(m-tolyl)cyclohexan-1-ol (13 g, 68.32 mmol, 1 equiv.) in DCM (50 mL) was added Dess-Martin periodinane (43.47 g, 102.48 mmol, 31.73 mL, 1.5 equiv.) in portions at 0 °C (maintaining the temperature at 0 °C during the addition). The mixture was then stirred at 20 °C for 12 h. The mixture was filtered, and 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 = 1:0 to 5:1) to give 2-(m-tolyl)cyclohexan-1-one (13 g, crude) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.26–7.21 (m, 1H), 7.10–7.06 (m, 1H), 6.98–6.93 (m, 2H), 3.62–3.55 (m, 1H), 2.58–2.44 (m, 2H), 2.35 (s, 3H), 2.31–2.23 (m, 1H), 2.21–2.13 (m, 1H), 2.08–1.97 (m, 2H), 1.90–1.83 (m, 2H).

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

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

[0768] Step 5: Preparation of 2-(methylamino)-2-(m-tolyl)cyclohexan-1-one (23rac) To a mixture of 2-amino-2-(m-tolyl)cyclohexan-1-one (1.34 g, 6.59 mmol, 1 equiv.) in hexafluoroisopropanol (HFIP, 140 mL) was added methyl trifluoromethanesulfonate (1.08 g, 6.59 mmol, 721.15 uL, 1 equiv.) at 0 °C. The mixture was then stirred at 25 °C under a N atmosphere for 12 h. The mixture was filtered and concentrated. The residue was adjusted to pH = 7 with aqueous NaCO (30 mL). The aqueous phase was extracted with EA (100 mL × 2). The combined organic phase was washed with brine (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Agela DuraShell C18 250 x 70 mm, 10 μm; mobile phase: A: water (0.05% NH3H2O ​​+ 10 mM NH4HCO3), B: ACN; B%: 29% to 59%, 20 min) to give 2-(methylamino)-2-(m-tolyl)cyclohexan-1-one (742 mg, 3.41 mmol, 51.8% yield) (23 rac) as a brown oil. LCMS (R T = 1.551 min, MS calculated: 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 C NMR (101 MHz, chloroform-d) δ = 211.63, 138.66, 138.55, 128.63, 128.30, 127.73, 124.18, 69.86, 39.88, 35.28, 28.94, 27.81, 22.34, 21.62. [Example]

[0769] Preparation of Compounds 120rac and 119rac

[0770] [ka]

[0771] Step 1: Preparation of 2-(p-tolyl)cyclohexan-1-ol A solution of 1-bromo-4-methyl-benzene (15 g, 87.70 mmol, 10.79 mL, 1 equiv) in THF (200 mL) was cooled to −70 °C. n-BuLi (2.5 M, 38.59 mL, 1.1 equiv) was then added. The mixture was stirred at −70 °C for 0.5 h, and then 7-oxabicyclo[4.1.0]heptane (9.47 g, 96.47 mmol, 9.76 mL, 1.1 equiv) and BF EtO (13.69 g, 96.47 mmol, 11.91 mL, 1.1 equiv) were added. The mixture was stirred at −70 °C for 1.5 h. Upon completion, the reaction was slowly quenched with saturated aqueous NH Cl (40 mL) and then extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1, 5 / 1) to give 2-(p-tolyl)cyclohexan-1-ol (13 g, 68.32 mmol, 77.9% yield) as a white solid. 1 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).

[0772] Step 2: Preparation of 2-(p-tolyl)cyclohexan-1-one To a mixture of 2-(p-tolyl)cyclohexan-1-ol (13 g, 68.32 mmol, 1 equiv.) in CHCl (50 mL), Dess-Martin periodinane (43.47 g, 102.48 mmol, 31.73 mL, 1.5 equiv.) was added portionwise at 0 °C (maintaining the temperature at 0 °C during the addition). The mixture was then stirred at 20 °C for 12 h. 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 to 5:1) to give 2-(p-tolyl)cyclohexan-1-one (12.01 g, 63.82 mmol, 93.41% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.20–7.13 (m, 2H), 7.08–7.02 (m, 2H), 3.63–3.55 (m, 1H), 2.58–2.42 (m, 2H), 2.35 (s, 3H), 2.32–2.23 (m, 1H), 2.20–2.12 (m, 1H), 2.08–1.98 (m, 2H), 1.90–1.81 (m, 2H).

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

[0774] Step 4: Preparation of 2-amino-2-(p-tolyl)cyclohexan-1-one (120rac) To a solution of 2-nitro-2-(p-tolyl)cyclohexan-1-one (4.98 g, 21.35 mmol, 1 equiv.) in AcOH (40 mL) was added Zn (33.50 g, 512.38 mmol, 24 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. Upon completion, the mixture was filtered and concentrated. The residue was adjusted to pH = 7 with aqueous NaCO (150 mL). The aqueous phase was extracted with DCM (200 mL × 2), and the combined organics were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, PE / EA = 1 / 0 to 0 / 1) to give 2-amino-2-(p-tolyl)cyclohexan-1-one (1.3 g, 6.40 mmol, 29.95% yield) (120 rac) as a yellow oil. LCMS (R T = 1.618 min, MS calculated: 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.

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

[0776] Preparation of Compounds 25R and 25S

[0777] [ka]

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

[0779] Step 2: Preparation of (R)-2-(diethylamino)-2-phenylcyclohexanone (25R) and (S)-2-(diethylamino)-2-phenylcyclohexanone (25S) The racemate was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); mobile phase: A: CO, B: 0.1% NHH O in IPA; B%: 11%, multiple injection process with 5 min interval between injections) to give ENT-1 1.103 min (343 mg) as a yellow oil and ENT-2 1.300 min (373 mg) as a yellow oil. Retention times were determined using the following chiral analytical method: Column: Chiralcel OJ-3, 100 x 4.6 mm ID, 3 μm; Mobile phase: A:CO₂B: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.

[0780] ENT-1, RT=1.103 min (here assigned as S isomer, 25S); LCMS (R T = 1.456 min, MS calculated: 245.18, [M+H] + = 246.1); 1 H NMR (400 MHz, chloroform-d) δ = 7.31 - 7.20 (m, 4H), 7.20 - 7.14 (m, 1H), 2.58 - 2.48 (m, 1H), 2.43 (q, J = 7.2 Hz, 4H), 2.37 - 2.14 (m, 3H), 1.91 - 1.63 (m, 3H), 1.60 - 1.48 (m, 1H), 0.93 - 0.79 (m, 6H); 13 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 assigned as the R isomer, 25R); LCMS (R T = 1.514 min, MS calculated: 245.18, [M+H] + = 246.1); 1H NMR (400 MHz, chloroform-d) δ = 7.34 - 7.21 (m, 4H), 7.20 - 7.14 (m, 1H), 2.59 - 2.48 (m, 1H), 2.43 (q, J = 7.2 Hz, 4H), 2.36 - 2.13 (m, 3H), 1.92 - 1.62 (m, 3H), 1.60 - 1.48 (m, 1H), 0.96 - 0.80 (m, 6H); 13 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. [Example]

[0781] Preparation of Compound 128mix

[0782] [ka]

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

[0784] Preparation of compound 129rac

[0785] [ka]

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

[0787] Metabolic stability in human liver microsomes The disclosed compounds were tested for stability in human liver microsomes (HLM), and the results are summarized in Table 2. Some of the compounds were tested for stability under two microsome incubation conditions: one with normal enzyme activity (low activity) and one with higher enzyme load, longer incubation time, and lower compound concentration (high activity), which were intended to increase metabolic instability. The disclosed compounds exhibited greater metabolic stability than ketamine under both conditions in this model.

[0788] Drugs. Compounds were tested as racemates (denoted by the "rac" designation) or as pure enantiomers (denoted by the "R" or "S" designation).

[0789] HLM Stability (Low Activity). Pooled HLM (XenoTech H0630) from adult male and female donors was used. Microsome incubations were performed in 96-well plates with five 40 μL aliquots (one for each time point). Liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), glucose-6-phosphate (5.3 mM), and glucose-6-phosphate dehydrogenase (0.67 units / mL), and 0.42 mg of liver microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. Test compounds (2 μM, final solvent concentration 1.6%) were incubated with microsomes at 37°C with shaking at 100 rpm. Incubations were performed in duplicate. Five time points were analyzed over 40 min. 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 min. The supernatant was analyzed for remaining parent compound using a fit-for-purpose liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, with authentic samples of each analyte used for identity confirmation.

[0790] HLM Stability (Low Activity, Alternative Method). Pooled HLM (Corning 452117) from adult male and female donors was used. Microsome incubations were performed 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 constant shaking. Six time points were analyzed over 60 min, with 60 μL aliquots of the reaction mixture withdrawn at each time point. Reaction aliquots were stopped by adding 180 μL of cold (4° C.) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), followed by shaking for 10 min and then protein precipitation by centrifugation at 4000 rpm for 20 min at 4° C. Supernatant samples (80 μL) were diluted with water (240 μL) and analyzed for remaining parent compound using a purpose-built liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0791] HLM Stability (High Activity). Pooled HLM (XenoTech H0630) from adult male and female donors was used. Microsome incubations were performed in 96-well plates with five 40 μL aliquots (one for each time point). Liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), glucose-6-phosphate (5.3 mM), and glucose-6-phosphate dehydrogenase (0.67 units / mL), with 1.0 mg of liver microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.6%) were incubated with microsomes at 37°C with shaking at 100 rpm. Incubations were performed in duplicate. Five time points were analyzed over 60 min. 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 min. The supernatant was analyzed for remaining parent compound using a fit-for-purpose liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, with authentic samples of each analyte used for identity confirmation.

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

[0793] [Table 2A]

[0794] [Table 2B]

[0795] [Table 2C]

[0796] [Table 2D]

[0797] [Table 2E]

[0798] [Table 2F]

[0799] [Table 2G] [Example]

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

[0801] Drugs. Compounds were tested as racemates (denoted by the "rac" designation) or as pure enantiomers (denoted by the "R" or "S" designation).

[0802] MLM stability (low activity). Pooled MLM (XenoTech M1000) from male CD-1 mice was used. Microsome incubations were performed 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 constant shaking. Six time points were analyzed over 60 min, with 60 μL aliquots of the reaction mixture withdrawn at each time point. Reaction aliquots were stopped by adding 180 μL of cold (4° C.) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), followed by shaking for 10 min and then protein precipitation by centrifugation at 4000 rpm for 20 min at 4° C. Supernatant samples (80 μL) were diluted with water (240 μL) and analyzed for remaining parent compound using a purpose-built liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0803] MLM Stability (High Activity). Pooled MLM (XenoTech M3000) from male BALB / c mice was used. Microsome incubations were performed in 96-well plates with five 40 μL aliquots (one for each time point). Liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), glucose-6-phosphate (5.3 mM), and glucose-6-phosphate dehydrogenase (0.67 units / mL), with 1.0 mg of liver microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.6%) were incubated with microsomes at 37°C with shaking at 100 rpm. Incubations were performed in duplicate. Five time points were analyzed over 60 min. 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 min. The supernatant was analyzed for remaining parent compound using a fit-for-purpose liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, with authentic samples of each analyte used for identity confirmation.

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

[0805] [Table 3A]

[0806] [Table 3B]

[0807] [Table 3C]

[0808] [Table 3D]

[0809] [Table 3E]

[0810] [Table 3F] [Example]

[0811] Metabolic stability in rat liver microsomes The disclosed compounds were tested for stability in rat liver microsomes (RLM), and the results are summarized in Table 4. Two microsome 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. The disclosed compounds exhibited greater metabolic stability than ketamine under both conditions in this model. Furthermore, 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 (Table 4 and Figure 2). These effects on metabolism are more pronounced for the R isomer.

[0812] Drugs. Compounds were tested as racemates (denoted by the "rac" designation) or as pure enantiomers (denoted by the "R" or "S" designation).

[0813] RLM stability (low activity). Pooled RLM (XenoTech R1000) from male Sprague-Dawley rats was used. Microsome incubations were performed 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 constant shaking. Six time points were analyzed over 60 min, with 60 μL aliquots of the reaction mixture withdrawn at each time point. Reaction aliquots were stopped by adding 180 μL of cold (4° C.) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), followed by shaking for 10 min and then protein precipitation by centrifugation at 4000 rpm for 20 min at 4° C. Supernatant samples (80 μL) were diluted with water (240 μL) and analyzed for remaining parent compound using a purpose-built liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0814] RLM stability (high activity). Pooled RLM (XenoTech R1000, lot no. 1910100) from male Sprague Dawley rats was used. Microsome incubations were performed in 96-well plates with five 40 μL aliquots (one for each time point). The liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPH (3 mM), glucose-6-phosphate (5.3 mM), and glucose-6-phosphate dehydrogenase (0.67 units / mL), with 1.0 mg of liver microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.6%) were incubated with microsomes at 37°C with shaking at 100 rpm. Incubations were performed in duplicate. Five time points were analyzed over 60 min. Reactions were stopped by adding 9 volumes of 90% acetonitrile-water to the incubation aliquots, followed by protein precipitation by centrifugation at 5500 rpm for 3 min. Supernatants were analyzed for remaining parent compound using a fit-for-purpose liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, using authentic samples of each analyte for identity confirmation.

[0815] 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 fit-for-purpose liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, using authentic samples of each analyte for calibration and identity confirmation.

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

[0817] [Table 4A]

[0818] [Table 4B]

[0819] [Table 4C]

[0820] [Table 4D]

[0821] [Table 4E] [Example]

[0822] Oral bioavailability in mice

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

[0824] Method A:

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

[0826] 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) and a volume of 5 mL / kg body weight. Compounds were tested as racemates (indicated by the "rac" designation) or pure enantiomers (indicated by the "R" or "S" designation).

[0827] Sampling and Bioanalysis. Blood samples were collected from the orbital sinus under 2,2,2-tribromoethanol anesthesia (150 mg / kg, i.p.) into microvessels containing K2EDTA at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h (four 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 processed immediately, flash-frozen, and stored at -70 °C until further analysis. Plasma samples were isolated by centrifugation of whole blood, and aliquots (50 μL) were mixed with 200 μL of an internal standard solution (400 ng / mL in 1:1 v / v CH3CN:MeOH). After mixing by pipetting and centrifuging at 6000 rpm for 4 minutes, 0.5 μL of each supernatant was analyzed for drug using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, using authentic reference samples of each analyte for calibration and identification. Brain samples (mass 100 mg ± 1 mg) were dispersed in 500 μL of internal standard solution (400 ng / mL in 4:1 v / v MeOH:water) using zirconium oxide beads (115 mg ± 5 mg) in a Bullet Blender® homogenizer at speed 8 for 30 seconds. After homogenization, the samples were centrifuged at 14,000 rpm for 4 minutes, and 0.5 μL of each supernatant was analyzed for drug using a suitable LC-MS / MS method, using authentic reference samples of each analyte for calibration and identification.

[0828] Data Analysis. Drug concentrations in samples below the lower limit of quantitation (LLOQ) were designated as zero. Pharmacokinetic data analysis was performed using a non-compartmental, bolus injection, or extravascular input analysis model in WinNonlin 5.2 (PharSight). Data points below the LLOQ were assigned a t1 / 2 They were represented as missing to improve the validity of the calculations.

[0829] Method B:

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

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

[0832] Sample Collection and Bioanalysis. Blood samples (approximately 60 μL) were collected from the retro-orbital sinus under light isoflurane anesthesia (Surgivet®) at 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (four animals per time point). Immediately after blood collection, plasma was collected by centrifugation at 4000 rpm for 10 minutes at 4°C, and samples were stored at -70±10°C until bioanalysis. Following blood collection, animals were immediately sacrificed, the abdominal vena cava was incised, and the whole body was perfused transcardially with 10 mL of normal saline. Brain samples were collected from all animals. After isolation, brain samples were rinsed three times in ice-cold normal saline (each rinse for 5-10 seconds using approximately 5-10 mL of normal saline in a disposable Petri dish) and dried with absorbent paper. Brain samples were homogenized using ice-cold phosphate-buffered saline (pH 7.4). The total homogenate volume was three times the tissue mass. All homogenates were stored at -70 ± 10°C until bioanalysis. For bioanalysis, 25 μL aliquots of plasma / brain research samples or spiked plasma / brain calibration standards were added to individual pre-labeled microcentrifuge tubes, followed by the addition of 100 μL of internal standard solution (glipizide, 500 ng / mL in acetonitrile) and, except for blanks, 100 μL of acetonitrile. Samples were vortexed for 5 minutes and then centrifuged at 4000 rpm for 10 minutes at 4°C. Following centrifugation, 100 μL of each clear supernatant was transferred to a 96-well plate and analyzed using a purpose-built LC-MS / MS method, using authentic samples of each analyte for calibration and identification.

[0833] Data Analysis: Pharmacokinetic parameters were estimated using the non-compartmental analysis tool in Phoenix® WinNonlin software (Version 8.0).

[0834] [Table 5A]

[0835] [Table 5B]

[0836] [Table 6A]

[0837] [Table 6B] [Example]

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

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

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

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

[0842] [Table 7]

[0843] [Table 8] [Example]

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

[0845] Animals. Male Sprague Dawley rats were used in these studies. Animals were randomly assigned to treatment groups and fasted overnight prior to oral dosing.

[0846] 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) and a volume of 5 mL / kg body weight. Compounds were tested as racemates (denoted by the "rac" designation).

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

[0848] Data Analysis. Pharmacokinetic parameters were estimated using the non-compartmental analysis tool in Phoenix® WinNonlin software (Version 8.1). Drug concentrations in samples below the lower limit of quantitation (LLOQ) were designated as zero. Method B:

[0849] Animals. Male Sprague Dawley rats were used in these studies. Animals were randomly assigned to treatment groups and fasted overnight prior to oral dosing.

[0850] Drugs. 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) and a volume of 5 mL / kg body weight. Compounds were tested as racemates (indicated by the "rac" name) or pure enantiomers (indicated by the "R" or "S" name).

[0851] Sample Collection and Bioanalysis. Blood samples (approximately 120 μL) were collected from the retro-orbital sinus under light isoflurane anesthesia (Surgivet®) at 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (a total of eight time points per rat, four rats per administration route per compound) under light isoflurane anesthesia (Surgivet®). Immediately after blood collection, plasma was collected by centrifugation at 4000 rpm for 10 minutes at 4°C, and samples were stored at -70±10°C until bioanalysis. For bioanalysis, 25 μL aliquots of plasma study samples or spiked plasma calibration standards were added to individual pre-labeled microcentrifuge tubes, followed by the addition of 100 μL of internal standard solution (glipizide, 500 ng / mL in acetonitrile). Except for blanks, 100 μL of acetonitrile was added. Samples were vortexed for 5 minutes and then centrifuged at 4000 rpm for 10 minutes at 4°C. Following centrifugation, 100 μL of each clear supernatant was transferred to a 96-well plate and analyzed using a purpose-built LC-MS / MS method, using authentic samples of each analyte for calibration and identification. In the case of compounds 14R and 88R, their metabolite 11R was also quantified in plasma samples.

[0852] Data Analysis: Pharmacokinetic parameters were estimated using the non-compartmental analysis tool in Phoenix® WinNonlin software (Version 8.0).

[0853] [Table 9]

[0854] [Table 10] [Example]

[0855] NMDA receptor binding The binding affinity of the disclosed compounds at the MK-801 binding site of N-methyl-D-aspartate receptors (NMDAR) was determined in radioligand binding experiments (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, suggesting that these compounds have reduced dissociative side effects compared to their corresponding S enantiomers or racemates. In contrast, S isomers may have higher efficacy as anesthetics, given their higher potency at NMDAR. For example, compound 14R exhibits weaker NMDAR binding than rac-ketamine, (R)-ketamine, (S)-ketamine, and 14S, suggesting that it may have less pronounced dissociative side effects than these compounds at equimolar doses. For example, many of the compounds of the present invention, including 14R, 11S, 88R, 27rac, 29rac, 19S, 114S, and 18rac, exhibited affinities within the ideal range of 1-5 μM. In certain cases, the R isomer demonstrated activity within the target affinity range; in other cases, the S isomer was more desirable; and in some cases, both stereoisomers or the racemate fell within the desired range. Indeed, the eudysmic ratio for each pair of enantiomers varied considerably, being <2 in some cases and ranging up to about 10 in others.

[0856] [Table 11A]

[0857] [Table 11B]

[0858] Radioligand Binding - Method A. The affinity of test compounds for NMDAR was determined using a method adapted from the literature (Javitt et al. 1987; Reynolds et al. 1989) under the conditions described in Table 12 by Eurofins Panlabs. 3 The binding activity was determined in radioligand binding experiments using [H]MK-801.

[0859] [Table 12]

[0860] Radioligand Binding - Method B. The affinity of test compounds for NMDAR was determined by radioligand binding assay using WuXi AppTec (Hong Kong) Ltd. under the conditions described in Table 13. 3 The binding activity was determined in radioligand binding experiments using [H]MK-801.

[0861] [Table 13] [Example]

[0862] Activity in monoamine transporters The ability of compounds of the present invention to inhibit monoamine uptake by the serotonin transporter (SERT), norepinephrine transporter (NET), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) (collectively monoamine transporters, MATs) was measured using a fluorescent substrate uptake assay in transfected cells (Table 14). The binding affinity of select compounds was also determined in radioligand displacement assays at SERT, NET, and / or DAT (Table 14). Activity was generally greatest for compounds containing a cyclic moiety on the amine. For example, compounds 26, 27, and 84 all had IC50 for monoamine uptake of <10 μM at one or more of the MATs tested. 50 The activity of compound 27S was particularly noteworthy, as it showed an IC of 0.041 μM at SERT. 50However, there was a notable exception to the trend of greater MAT inhibitory activity for cyclic amines; the enantiomer of compound 31, which contains a morpholine ring, showed little activity at MAT. Given that MAT inhibitors are well-known for their antidepressant and anxiolytic effects and are among the most commonly prescribed drugs for mood disorders (e.g., fluoxetine, sertraline, venlafaxine, imipramine, etc.), it is expected that MAT blockade by certain compounds of the present invention will synergize with their NMDAR inhibition to increase their therapeutic activity for treating depression and related disorders. Indeed, such synergy between these two mechanisms of action has been demonstrated in animal models (Ates-Alagoz and Adejare 2013). Furthermore, compounds with sufficient potency at both targets could be envisioned as alternatives to two separate drugs that target MAT and NMDAR separately. For example, compounds such as 27S have significant affinity for both SERT and NMDAR, and can replace the combination of a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine and an NMDAR antagonist such as ketamine with a single therapeutic agent. Furthermore, the ability to adjust the ratio between MAT and NMDAR, and between different MATs, is useful for obtaining an optimal therapeutic profile according to the intended clinical indication. For example, compounds with greater selectivity for NMDAR, such as 14R, 11S, 88R, 29rac, 19S, 114S, or 18rac, may be a preferred treatment for patients who cannot tolerate the side effects of MAT inhibitors. Alternatively, compounds with significant inhibitory activity at DAT, such as 26R or 28S, may be a useful treatment for psychostimulant abuse.

[0863] [Table 14A]

[0864] [Table 14B]

[0865] Uptake inhibition. The ability of test compounds to block monoamine uptake by SERT, NET, DAT, and VMAT2 was determined using the Neurotransmitter Transporter Uptake Assay Kit (Cat. No. R8173) from Molecular Devices. Briefly, stably transfected cells expressing the MAT of interest (HEK293 cells for SERT and NET; CHO cells for DAT) were grown and plated 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 16–20 hours. 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 plates were then centrifuged at 300 rpm for 15 seconds 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 fluorescence was quantified using 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 an endogenous substrate of MAT, thereby actively transporting it into 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. Thus, the overall fluorescence of the system increases as the fluorescent dye is transported into the cell. In the presence of an inhibitor of the MAT under study, dye uptake is reduced, and therefore fluorescence, allowing this inhibition to be quantified.

[0866] Radioligand binding. The affinity of test compounds for SERT, NET, and DAT was determined by radioligand binding assays performed by WuXi AppTec (Hong Kong) under the conditions described in Table 15. 3 H]imipramine, [ 3 H]nisoxetine, and [ 3 The binding activity of HO and HO was determined in radioligand binding experiments using HO and WIN35,428, respectively.

[0867] [Table 15] [Example]

[0868] Effects on behavioral tests following chronic social defeat stress in mice In mice, compound 35rac reversed the prodepressant effects induced by chronic social defeat stress (CSDS) in several behavioral tests (Figure 3). This antidepressant-like activity was observed at the same dose (10 mg / kg, i.p.) as that of racemic ketamine. Compound 37rac ​​was not effective at this dose level in the same model and was only partially effective at a three-fold higher dose (30 mg / kg, i.p.) (Figure 3). Furthermore, the enantiomers of compound 35, 35R and 35S, induced antidepressant-like effects in the same CSDS model (Figure 4). Notably, when the same doses of each drug were administered, the antidepressant-like effects of the 35R enantiomer were more robust and longer-lasting than those of the 35S enantiomer. At the same time, despite equipotent antidepressant activity, compound 35R exhibited weaker NMDAR binding than compounds 35S and 35rac, racemic ketamine, and R-ketamine (see Example 27 above), suggesting that it may have better separation between dissociative side effects (driven by potency of binding at NMDAR) and therapeutic efficacy in depression.

[0869] Animals. Eight-week-old male adult C57BL / 6 mice (weight 20–25 g, Japan SLC Co., Ltd., Hamamatsu, Japan) and 13–15-week-old male adult CD1 mice (weight >40 g, Japan SLC Co., Ltd., Hamamatsu, Japan) were used in the experiments. The animals were housed under controlled temperature and a 12-h light / dark cycle (lights on between 07:00 and 19:00) and provided with food and water ad libitum. The protocol was approved by the Chiba University Institutional Animal Care and Use Committee (approval numbers: 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.

[0870] Drugs and Drug Administration. Racemic ketamine hydrochloride for injection was obtained as a commercially available solution (Ketalar®, ketamine hydrochloride, Daiichi Sankyo Co., Ltd., Tokyo, Japan) and administered intraperitoneally (i.p.) at a dose of 10 mg / kg. Compounds 35rac and 37rac ​​were synthesized as ...

Claims

1. A compound of the following formula: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

2. 13. A pharmaceutical composition comprising a compound of claim 1 and a pharma- ceutically acceptable excipient.

3. A pharmaceutical composition for treating depression, anxiety depression, mood disorder, anxiety disorder, or substance use disorder and any symptoms or disorders related thereto, comprising an effective amount for said treatment of a compound according to claim 1.

4. A compound of the following formula: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the compound of claim 4 and a pharma- ceutically acceptable excipient.

6. A pharmaceutical composition for treating depression, anxiety depression, mood disorder, anxiety disorder, or substance use disorder and any symptoms or disorders related thereto, comprising an effective amount for said treatment of a compound described in claim 4.

7. The compound of the following formula: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound of claim 7 and a pharma- ceutically acceptable excipient.

9. A pharmaceutical composition for treating depression, anxiety depression, mood disorder, anxiety disorder, or substance use disorder and any symptoms or disorders related thereto, comprising an effective amount for said treatment of a compound described in claim 7.

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