Prodrugs of ketamine, compositions and uses thereof

Abstract

To provide prodrugs of (S)- or (R)-ketamine, including isotopically labeled ketamine, and compositions and use of the prodrugs.SOLUTION: Compounds having a formula (Ia) or (Ib) as prodrugs of (S)- or (R)-ketamine, including isotopically labeled ketamine, are provided. Pharmaceutical compositions comprising the compounds provided herein are used for treating or preventing a CNS disease. More specifically, the related diseases include depression and pain.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Patent Application No. 62 / 615,948, filed in the U.S. Patent and Trademark Office on January 10, 2018, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of pharmaceutical technology, more particularly to prodrugs of (S)- or (R)-ketamine, including isotope-labeled ketamine, compositions and their uses. More specifically, the compounds disclosed herein can be used as NMDA (N-methyl-D-aspartate) receptor antagonists for treating, preventing or alleviating central nervous system neurological and psychiatric disorders or diseases associated with NMDA receptors. The pharmaceutical compositions disclosed herein also have the function of preventing, treating or alleviating diseases associated with NMDA receptors. More specifically, the associated diseases include depression and pain. [Background technology]

[0003] Antidepressants are central nervous system medications used to treat disorders such as major depressive disorder (MDD), dysthymic disorder, and seasonal affective disorder. MDD, also known as clinical depression, is a condition that lasts for more than two weeks and impairs a person's ability to carry out daily tasks and enjoy activities that previously brought them pleasure.

[0004] Glutamate is the brain's main excitatory neurotransmitter. Like classical neurotransmitters, glutamate is released from neurons, binds to receptors, and is removed by reuptake transporters. The glutamate receptor system is highly complex and can be separated into a variety of different receptor subtypes depending on their molecular and pharmacological properties. Most clinical studies targeting multiple CNS indications have focused on drugs that modulate glutamate function via the NMDA receptor. Glutamate and its receptor subtypes play fundamental roles in synaptic plasticity and influence basic human emotion, cognition, and reward processing. Further roles include neurodevelopmental and neurotrophic effects, as well as neurodegeneration.

[0005] Ketamine is classified as an NMDA receptor antagonist, but its pharmacological profile is complex and binds to multiple receptors. It was first approved by the US FDA as a general anesthetic 50 years ago. Chemically, ketamine is a racemic mixture of (R)- and (S)-ketamine. In 1998, (S)-ketamine was approved in the EU as a general anesthetic.

[0006] Repeated-dose ketamine may be an antidepressant continuation strategy for patients who show an initial response to ketamine infusions. In 10 TRD patients who had failed an average of eight antidepressants over their lifetime, repeated intravenous ketamine administration (six infusions) over a two-week period reduced MADRS (Mongomery-Asberg Depression Rating Scale) scores by an average of 85% after the sixth infusion.

[0007] Despite the efficacy of intravenous infusion of ketamine and its favorable status compared to other drugs in the treatment of treatment-resistant depression, this dosing regimen requires patients to receive treatment in a clinic. Ketamine has been studied in humans to evaluate its oral bioavailability. Ketamine was found to have only 17% oral bioavailability in humans as a result of extensive first-pass metabolism, which has hindered the development of oral regimens. Furthermore, ketamine's side effects may be related to its high Cmax after bolus administration.

[0008] To overcome the deficiencies of ketamine's pharmacokinetics, a prodrug approach is utilized to identify viable ketamine derivatives that can significantly improve the pharmacokinetic profile of ketamine upon oral administration. To avoid possible side effects, sustained release formulations may be desirable to eliminate peaks and troughs in drug plasma concentrations. Summary of the Invention

[0009] The following is merely a summary of some aspects of the present invention, but is not limited thereto. All references herein are incorporated by reference in their entirety. Where the disclosure of the present specification differs from the citation, the disclosure of the present specification shall prevail. The present invention provides compounds and pharmaceutical compositions that modulate NMDA receptor antagonism, their preparations, and corresponding pharmaceutical compositions. The compounds and / or pharmaceutical compositions of the present invention can potentially be used to manufacture medicaments for preventing, treating, or ameliorating certain disorders or diseases associated with NMDA receptors in patients, including depression and pain.

[0010] Specifically, in one aspect, the invention relates to compounds having the structure of Formula (Ia) or (Ib), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof: [ka] In the formula, R is -C(=O)R 1 , -C(=O)OR 2 , -C(=O)O(CHR 3 )OC(=O)R 4 or CD3, X is -CH3 or CD3, R 1 is an optionally substituted or unsubstituted aryl-OH, aryl-NH2, alkenyl-OH, alkenyl-NH2, alkyl-NH2, alkyl-OH, carbocyclyl, or heterocyclyl containing one or more N or O, and X is -CH3 or CD3; R 2is an optionally substituted or unsubstituted alkyl, aryl, carbocyclyl, or heterocyclyl containing one or more O; X is -CH3 or CD3; R 3 is H or substituted or unsubstituted alkyl, while R 4 is independently substituted or unsubstituted alkyl, aryl, azaaryl, carbocyclyl, or heterocyclyl containing one or more O or N, and X is -CH3 or CD3.

[0011] The object of the present invention is that the compounds having the structure of formula (Ia) or (Ib) are prodrugs of (S)- or (R)-ketamine, where the "NR" moiety can be cleaved in vivo via chemical hydrolysis or metabolic processes by endogenous enzymes. The compounds having formula (Ia) or (Ib) can have the following characteristics: i) significantly improved oral bioavailability compared to ketamine, and ii) compatible with sustained release formulations suitable for QD or BID to meet patient compliance and convenience.

[0012] In another aspect, provided herein are compounds having the structure of Formula (IIa) or (IIb), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof. [ka] In the formula, R 1 is an optionally substituted or unsubstituted aryl-OH, aryl-NH2, alkenyl-OH, alkenyl-NH2, alkyl-NH2, alkyl-OH, carbocyclyl, or heterocyclyl containing one or more N or O, and X is -CH3 or CD3.

[0013] In one embodiment, R 1 Amino C 1-6 Alkyl, -R 1a NHCOR 1b , -R 1a O.C.O.R. 1b , -R 1a COOR 1b , [ka] Or C 3-6 is heterocyclyl, In the formula, R 1 is C 1-6 optionally substituted with alkyl, -OH or oxo (=O); R 1a and R 1b are independently H, C 1-6 Alkyl or C 2-6 alkenyl, R 1c -OH, C 1-3 Hydroxyalkyl, -OCOR 1b or CH2OCOR 1b It is.

[0014] In one embodiment, the heterocyclyl containing one or more N or O is [ka] It is.

[0015] In another aspect, provided herein are compounds having the structure of Formula (IIIa) or (IIIb), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof. [ka] In the formula, R 2 is an optionally substituted or unsubstituted alkyl, aryl, carbocyclyl, or heterocyclyl containing one or more O, and X is -CH3 or CD3.

[0016] In one embodiment, R 2 is C 1-6 Alkyl, C 1-6 Hydroxyalkyl, Amino C 1-6 Alkyl, -R 2a S(O) n1 R 2b, -R 2a COOR 2b , C 3-6 Aryl or C 3-6 is heterocyclyl, R 2 is C 1-6 Alkyl [ka] If replaced by C 1-6 Alkyl, -OH, C 1-6 Hydroxyalkyl, [ka] or R 2a COOR 2b optionally replaced by R 2a is C 1-6 is alkyl, R 2a is optionally C 1-6 substituted with alkyl or NH2; R 2b is H or C 1-6 is alkyl, n1 is 0, 1, or 2.

[0017] In another aspect, provided herein are compounds having the structure of Formula (IVa) or (IVb), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof. [ka] In the formula, R 3 is H or substituted or unsubstituted alkyl, while R 4 is independently substituted or unsubstituted alkyl, aryl, azaaryl, carbocyclyl, or heterocyclyl containing one or more O or N, and X is -CH3 or CD3.

[0018] In one embodiment, R 3 is H or C 1-6It is an alkyl.

[0019] In one embodiment, R 4 is C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -R 4a NCOR 4b , -R 4a OCOR 4b , -R 4a S(O) n2 R 4b , C 1-6 Heterocyclyl, C 1-5 Azaaryl or [ka] and R 4 is C 1-6 Alkyl [ka] If replaced by C 1-6 Alkyl, -NH2, oxo(=O), C 1-6 Hydroxyalkyl, [ka] optionally replaced by R 4a is C 1-6 is alkyl, R 4b is C 1-6 Alkyl or C 1-6 is haloalkyl, R 4c is benzyl, and R 4d is H or R 4c and R 4d However, together with the carbon atom to which they are attached, 5-6 forming a heterocyclyl, n2 is 0, 1, or 2.

[0020] In one embodiment, C 1-6Heterocyclyl is [ka] It is.

[0021] In one embodiment, C 1-5 Azaaryl is [ka] is optionally substituted with one or more methyl or -NH2, or a combination thereof.

[0022] In one embodiment, [ka] It is.

[0023] In another aspect, provided herein is a compound having the structure of Formula (Va) or (Vb) or (Vc) or (Vd), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof. [ka]

[0024] In another aspect, provided herein are pharmaceutical compositions comprising compounds of the invention.

[0025] In one embodiment, the pharmaceutical composition further comprises at least one pharma- ceutically acceptable excipient carrier, adjuvant, vehicle, or a combination thereof.

[0026] In one embodiment, the pharmaceutical composition further comprises a pharma- ceutical effective amount of one or more adjunct therapeutic agents, which are used in the treatment of neurological and psychiatric disorders or diseases of the central nervous system.

[0027] In one embodiment, the neurological or psychiatric disorder or disease of the central nervous system is depression or pain.

[0028] In one embodiment, the adjunctive therapeutic agent is selected from the group consisting of at least one member of lithium, pharmaceutical or herbal antidepressants, anticonvulsants, mood stabilizers, antipsychotics, and benzodiazepines.

[0029] In another aspect, there is provided herein the use of a compound or pharmaceutical composition in the manufacture of a medicament for the prevention, management, treatment or amelioration of a neurological or psychiatric disorder or disease of the central nervous system in a patient.

[0030] In another aspect, provided herein is the use of a compound or pharmaceutical composition in the manufacture of a medicament for antagonizing an NMDA receptor.

[0031] In another aspect, there is provided herein a compound or pharmaceutical composition for use in the prevention, management, treatment or amelioration of neurological and psychiatric disorders or diseases of the central nervous system in a patient.

[0032] In another aspect, provided herein is a compound or pharmaceutical composition for use in antagonizing an NMDA receptor.

[0033] In another aspect, provided herein is a method for preventing, managing, treating or ameliorating the effects of a neurological or psychiatric disorder or disease in a patient, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition to a patient in need thereof.

[0034] In another aspect, provided herein is a method of antagonizing an NMDA receptor in a patient, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition to a patient in need thereof.

[0035] In another aspect, provided herein are methods for preparing, isolating, and purifying the compounds represented by Formulas (Ia)-(Vd).

[0036] Biological test results demonstrate that the compounds provided herein have good antagonism against NMDA receptors and exhibit superior pharmacokinetic properties and bioavailability.

[0037] In certain embodiments of the compounds, pharmaceutical compositions, and methods of the present invention, the compound of Formulas (Ia)-(Vd) is a compound selected from the species described or exemplified in the detailed description below, or a pharma- ceutically acceptable salt of such a compound.

[0038] In another preferred embodiment, the present invention relates to a method for preparing a pharmaceutical composition comprising an effective amount of at least one of the compounds of formulae (Ia)-(Vd) or a pharma- ceutically acceptable salt of the compound of formulae (Ia)-(Vd), respectively. The pharmaceutical composition according to the present invention may further comprise at least one pharma- ceutically acceptable excipient, carrier, adjuvant, solvent, support or a combination thereof.

[0039] When formulated as a fixed dose, such combination products employ the compounds of the invention within the dosage ranges described herein (or known to those skilled in the art), and other pharma- ceutical active or therapeutic agents within the dosage ranges. The compounds of the invention may also be administered sequentially with known antidepressants and analgesics when a combination formulation is inappropriate. In any combination therapy, the invention is not limited to the order of administration. The compounds of formulae (Ia)-(Vd) may be administered either before or after the administration of known antidepressants and analgesics. Such techniques are within the skill of those skilled in the art as well as the attending physician.

[0040] Yet another embodiment is a method of administering a compound of the invention to a subject (eg, a human) in need thereof by administering to the subject a pharmaceutical formulation of the invention.

[0041] Yet another embodiment is a process for preparing a pharmaceutical formulation of the invention by mixing at least one pharma- ceutically acceptable compound of the invention, and, optionally, one or more pharma- ceutically acceptable additives or excipients.

[0042] When preparing pharmaceutical compositions from the compounds described by this invention, inert, pharma- ceutically acceptable carriers can be either solid or liquid. Solid preparations include powders, tablets, dispersible granules, capsules, beads, cachets, and suppositories. Powders and tablets can contain about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharma- ceutically acceptable carriers and methods of manufacturing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0043] Liquid form preparations include solutions, suspensions and emulsions, for example water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

[0044] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharma- ceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.

[0045] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0046] The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and / or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

[0047] The compounds of the invention may also be deliverable subcutaneously.

[0048] Preferably, the compounds are administered orally or intravenously.

[0049] Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0050] The amount of active compound in a unit dose of the preparation may vary or be adjusted depending on the particular application within the range of about 1 mg to about 1000 mg, preferably about 1 mg to about 500 mg, more preferably about 1 mg to about 300 mg, and even more preferably about 1 mg to about 200 mg.

[0051] The actual dosage used may vary depending on the condition of the patient and the severity of the condition being treated. Determination of the appropriate dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions throughout the day as needed. The amount and frequency of administration of the compounds of the present invention and / or their pharma-ceutically acceptable salts will be adjusted according to the judgment of the attending clinician, taking into account factors such as the age, condition and size of the patient, and the severity of the condition being treated. A typical recommended daily dosage regimen for oral administration may range from about 1 mg / day to about 300 mg / day, preferably 10 mg / day to 200 mg / day, in one to two divided doses.

[0052] Any embodiment disclosed herein can be combined with other embodiments, even if those embodiments are described under different aspects of the present invention, as long as they are not inconsistent with each other. Furthermore, any technical feature in one embodiment can be applied to the corresponding technical feature in another embodiment, even if the embodiments are described under different aspects of the present invention, as long as they are not inconsistent with each other.

[0053] The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These and other aspects and embodiments are more fully described below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] For the sake of brevity, the disclosures of the publications cited in this specification, including patents and patent applications, are hereby incorporated by reference in their entireties.

[0055] Most chemical names herein have been generated using IUPAC nomenclature. Some chemical names have been generated using different nomenclature or alternative or trade names known in the art. In the event of a discrepancy between a name and a structure, the structure shall prevail.

[0056] Definitions and General Terms Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. The present invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differ or contradict this application, this application will control, including but not limited to defined terms, term usage, described techniques, etc.

[0057] It will be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination.

[0058] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0059] As used herein, the following definitions shall apply unless otherwise indicated: For purposes of this invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. 1994. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito, 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York, 2007, the entire contents of which are incorporated herein by reference.

[0060] Throughout this disclosure, the following terms used above shall be understood to have the following meanings unless otherwise indicated. In the absence of definitions, conventional definitions known to those skilled in the art shall prevail. In the event that the definitions provided herein conflict or differ from those provided in the cited publications, the definitions provided herein shall prevail.

[0061] As used herein, the terms "comprise", "contain" and "including" are used in their open, non-limiting sense.

[0062] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0063] In order to provide a more concise description, some quantitative expressions given herein are not modified with the term "about". Regardless of whether the term "about" is explicitly used, it is understood that all amounts given herein are meant to refer to the actual given value, and also to the approximation of such given value that is reasonably estimated based on the ordinary skill of a person skilled in the art. Such given values ​​include the same values ​​and approximations according to experimental and / or measurement conditions. Whenever a yield is given as a percentage, such a yield refers to the mass of the object, where the yield is given for the maximum amount of the same object obtained under specific stoichiometric conditions. Concentrations given as percentages refer to mass ratios, unless otherwise specified.

[0064] The term "optional" or "optionally" refers to the fact that a subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0065] The terms "optionally substituted" and "unsubstituted or substituted" may be used interchangeably herein and mean that a structure is unsubstituted or substituted with one or more of the substituents disclosed herein. Substitution may occur at any suitable site on the structures or groups provided herein, at any valence permitted.

[0066] In general, the term "substituted" refers to the replacement of one or more hydrogen radicals in a given structure or group with the radical of a specified substituent. Unless otherwise indicated, a substituent may have a substituent at each suitable substitutable position of the group. When multiple positions in a given structure can be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at each position. Substituents disclosed herein include, but are not limited to, D, F, Cl, Br, I, -N3, -CN, -NO2, -OH, -SH, -NH2, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

[0067] chemical definition As used herein, "alkyl" refers to a saturated straight or branched chain hydrocarbon group having from 1 to 12 carbon atoms. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like, as well as longer alkyl groups such as heptyl, octyl, and the like.

[0068] At various places in the present specification, substituents of the compounds disclosed herein are disclosed in groups or ranges. It is specifically intended that the invention include each and every subcombination of all members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0069] The term "D" refers to a single deuterium atom.

[0070] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon sp2 double bond, including radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Alkenyl groups can be optionally substituted with one or more substituents described herein.

[0071] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon sp triple bond, which alkynyl radical can be optionally substituted with one or more substituents described herein.

[0072] The terms "halogen" or "halo" are used interchangeably herein and refer to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0073] The term "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Unless otherwise specified, an alkoxy group contains 1-12 carbon atoms. In one embodiment, an alkoxy group contains 1-6 carbon atoms. In other embodiments, an alkoxy group contains 1-4 carbon atoms. In yet other embodiments, an alkoxy group contains 1-3 carbon atoms. An alkoxy group may be optionally substituted with one or more substituents disclosed herein. As used herein, "alkoxyalkyl" means -(alkylenyl)-O-(alkyl), where each "alkyl" is independently an alkyl group as defined above.

[0074] "Aryl" means a monocyclic, bicyclic, or tricyclic aromatic group, in which all rings are aromatic. In the case of a bicyclic or tricyclic system, the individual aromatic rings are fused together. Exemplary aryl groups include, but are not limited to, phenyl, naphthalene, and anthracene.

[0075] The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, where alkyl is as defined herein. Some non-limiting examples of such groups include, but are not limited to, -CF3, -CF2CF3, -CH2CF2CHF2, and the like. In one embodiment, "haloalkyl" refers to a lower C 1-4 It refers to haloalkyl, and is called "C 1-4 Haloalkyl" is a fluorine-substituted C 1-4 Haloalkyl, chlorine-substituted C 1-4Haloalkyl, Bromine-Substituted C 1-4 Haloalkyl, iodine-substituted C 1-4 haloalkyl, etc. Specifically, fluorine-substituted C 1-4 Haloalkyl includes -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CHFCF3, -CHFCHF2, -CHFCH2F, -CH2CH2CF3, -CH2CF2CHF2, etc. Haloalkyl is optionally substituted with one or more substituents described herein.

[0076] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, where the alkyl group is as defined herein and the amino group is optionally substituted.

[0077] The term "hydroxy-substituted alkyl" or "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, where alkyl is as defined herein. Some non-limiting examples of such groups include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like.

[0078] As used herein, the term "deuterium" refers to a stable isotope of hydrogen having one proton and one neutron.

[0079] The terms "carbocyclyl" and "carbocycle", as used interchangeably herein, refer to a monovalent or polyvalent ring that is saturated or has one or more degrees of unsaturation and has 3 to 12 carbon atoms as a monocyclic, bicyclic or tricyclic ring system, although aromatic rings cannot be present in a carbocyclyl group.

[0080] The term "hydroxy" refers to an --OH group.

[0081] The terms "heterocyclyl" and "heterocycle", as used interchangeably herein, refer to a mono- or polyvalent, monocyclic, bicyclic, or tricyclic ring containing from 3 to 12 carbon atoms, where one or more of each atom in the ring is independently replaced with a heteroatom, where the heteroatom is as defined herein, and the ring may be saturated or have one or more degrees of unsaturation, but aromatic rings cannot be present in the ring.

[0082] The term "cycloalkyl" refers to a mono- or polyvalent saturated ring having 3 to 12 ring carbon atoms as a monocyclic, bicyclic, or tricyclic ring system.

[0083] One of ordinary skill in the art will recognize that the species of heteroaryl and cycloalkyl groups listed or illustrated above are not exhaustive and that additional species may be selected within the scope of these defined terms.

[0084] As described herein, the compounds disclosed herein may be optionally substituted with one or more substituents, or as exemplified by the particular classes, subclasses, and varieties of the invention.

[0085] As used herein, the term "substituted" means that the specified group or moiety has one or more suitable substituents. As used herein, the term "unsubstituted" means that the specified group has no substituents. As used herein, the term "optionally substituted" means that the specified group is unsubstituted or substituted with a specified number of substituents. When the term "substituted" is used to describe a structural system, it means that the substitution occurs at any valence-allowed position on the system.

[0086] As used herein, the phrase "one or more substituents" refers to from one to the maximum possible number of substituents that may occur at any valence-allowed position on the system. In certain embodiments, one or more substituents refers to one, two, three, four, or five substituents. In other embodiments, one or more substituents refers to one, two, or three substituents.

[0087] Any atom represented herein with unsatisfied valences is considered to have a sufficient number of hydrogen atoms to satisfy the atom's valences.

[0088] Any variable moiety (e.g., alkyl, alkylenyl, heteroaryl, R 1 , R 2 , or R a When a variable occurs in more than one place in a formula or description provided herein, its definition in each occurrence is independent of its definition at every other occurrence.

[0089] Numeric ranges used herein are intended to include consecutive integers. For example, a range expressed as "0 to 4" or "0-4" includes 0, 1, 2, 3, and 4, and a range expressed as "10-20%" includes 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%. Similarly, numerical ranges are intended to include consecutive decimals. For example, a range expressed as "1-2%" includes 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, and 2.0%.

[0090] Where multifunctional moieties are indicated, the point of attachment to the core is indicated with a line or hyphen, e.g., aryloxy refers to a moiety where the aryl is attached to an oxygen atom, while the oxygen atom is the point of attachment to the core molecule.

[0091] Additional definitions As used herein, the term "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian genus, i.e., humans, non-human primates such as chimpanzees, other apes and monkey species, livestock animals such as cows, horses, sheep, goats, pigs, farm animals such as rabbits, dogs, and cats, laboratory animals including rodents such as rats, mice, and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the present invention, the mammal is a human.

[0092] A "patient" includes both humans and animals.

[0093] The term "inhibitor" refers to a molecule, such as a compound, drug, enzyme activator, or hormone, that blocks or otherwise interferes with a particular biological activity.

[0094] The term "modulator" refers to a molecule, such as a compound of the present invention, that increases, decreases, or otherwise affects the activity of a given protein, receptor and / or ion channel.

[0095] The term "effective amount" or "therapeutically effective amount" refers to an amount of an agent sufficient to provide a desired biological result. The result may be the alleviation and / or alleviation of the signs, symptoms, or causes of a disease or medical condition, or other desired changes in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound or a composition containing a compound required to provide a clinically significant change in a disease state, symptom, or medical condition. The appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation. Thus, the expression "effective amount" generally refers to the amount of an active agent that has a therapeutically desired effect.

[0096] As used herein, the term "treat" or "treatment" encompasses both "prophylactic" and "curative" treatment. "Prophylactic" treatment is meant to refer to delaying the onset of a disease, disease symptom, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurring a disease or condition. "Curative" treatment includes reducing the severity or inhibiting the worsening of an existing disease, symptom, or condition. Thus, treatment includes improving or preventing the worsening of an existing disease symptom, preventing the development of further symptoms, improving or preventing the underlying metabolic cause of a symptom, inhibiting a disorder or disease, for example, arresting the onset of a disorder or disease, relieving a disorder or disease, inducing regression of a disorder or disease, alleviating a condition resulting from a disease or disorder, or preventing a symptom of a disease or disorder.

[0097] As used herein, the terms "administration of" a compound and "administering" a compound should be understood to mean providing a compound of the invention, a pharmaceutical composition containing a compound, or a prodrug of a compound of the invention to an individual in need thereof. It will be appreciated by those of skill in the art, without limitation, that an effective amount of a compound of the invention can treat a patient currently suffering from a neurological or psychiatric disorder or can prophylactically treat a patient suffering from a disorder.

[0098] The term "composition" as used herein is intended to include any product that contains a specified amount of a specified component, as well as any product that is obtained directly or indirectly from the combination of a specified amount of a specified component. Such terms related to pharmaceutical compositions are intended to include any product that contains an active ingredient and an inactive ingredient that constitute the carrier, as well as any product that is obtained directly or indirectly from the combination, complexation or aggregation of any two or more components, or from any other type of reaction or interaction that causes dissociation of one or more components. Thus, the pharmaceutical composition of the present invention includes any composition that is made by mixing a compound of the present invention with a pharmaceutically acceptable carrier.

[0099] Additional chemical explanation Any formula provided herein is intended to represent compounds having the structure shown by the structural formula, as well as specific variations or forms. For example, any formula provided herein may have asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomers of the compounds of the general formula, including optical isomers, enantiomers, and diastereomers, and mixtures thereof, are considered to be within the scope of the formula. Furthermore, a particular structure may exist as a geometric isomer (i.e., cis and trans isomers), tautomers, or atropisomers. All such isomers and mixtures thereof are contemplated herein as part of the invention. Thus, any formula provided herein is intended to represent a racemate, one or more enantiomers, one or more diastereomers, one or more tautomers or atropisomers, and mixtures thereof.

[0100] "Stereoisomers" refer to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, atropisomers, etc.

[0101] "Chiral" refers to molecules that have the property of not being superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0102] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0103] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, or biological activity. Mixtures of diastereomers can separate under high resolution analytical methods such as electrophoresis and chromatography, e.g., HPLC.

[0104] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0105] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the tendency of the compound to rotate plane polarized light, with (-) or l meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. A specific stereoisomer may be referred to as an enantiomer, and a mixture of such stereoisomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0106] Any asymmetric atom of the compounds disclosed herein (e.g., carbon, etc.) may be racemic or enantiomerically enriched, e.g., in the (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0107] Depending on the selection of starting materials and procedures, the compounds can exist in one of the possible stereoisomers or in mixtures thereof, for example, as racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or separated using conventional techniques. When the compounds contain double bonds, the substituents can be in the E or Z configuration. When the compounds contain disubstituted cycloalkyls, the cycloalkyl substituents can have a cis or trans configuration relative to another substituent of the same cycloalkyl skeleton.

[0108] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers based on the physicochemical differences of the components, for example, by chromatography and / or fractional crystallization. Any resulting racemic compounds, either final products or intermediates, can be separated into their optical antipodes by methods known to those skilled in the art, for example, by separation of their diastereomeric salts. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. Preferred enantiomers can also be prepared by asymmetric synthesis. For example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,SHTables of Resolving Agents and Optical Resolutions p.268(ELEliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972);Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA, Weinheim, Germany, 2007).

[0109] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride, or by forming a mixture of diastereomeric salts), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., by hydrolysis or desalting). Enantiomers can also be separated using chiral HPLC columns.

[0110] The compounds of the present invention can form pharmaceutically acceptable salts, which are also within the scope of the present invention. "Pharmaceutically acceptable salts" refers to free acid or base salts of the compounds of formula A that are non-toxic, physiologically acceptable, compatible with the pharmaceutical compositions in which they are incorporated, and otherwise suitable for formulation and / or administration to subjects. Reference to a compound in this specification is understood to include reference to a pharmaceutically acceptable salt of said compound, unless otherwise indicated.

[0111] Complex salts include acid salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. Furthermore, when a given compound contains both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, carboxylic acid, one of ordinary skill in the art will recognize that the compound may exist as a zwitterion ("internal salt"). Such salts are included in the term "salt" as used herein. Salts of the compounds of the present invention can be prepared, for example, by reacting the compound with, for example, an equivalent amount of a suitable acid or base in a medium, such as an aqueous medium or a medium in which the salt precipitates, followed by lyophilization.

[0112] Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate ("mesylate"), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthoate)) salts. Pharmaceutically acceptable salts may include the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. Counterion can be any organic or inorganic moiety that stabilizes the charge of parent compound.In addition, pharmaceutically acceptable salts can have multiple charged atoms in their structure.When multiple charged atoms are part of pharmaceutically acceptable salts, they can have multiple counterions.Therefore, pharmaceutically acceptable salts can have one or more charged atoms and / or one or more counterions.

[0113] Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like.

[0114] Exemplary base salts include alkali metal salts such as ammonium, sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamine, tert-butylamine, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl bromide, phenethyl bromide), and the like.

[0115] Additionally, acids and bases that are generally considered suitable for forming pharma- ceutically useful salts from pharmaceutical compounds are discussed, for example, in P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (available from the Food & Drug Administration, MD, FDA), the disclosures of which are incorporated herein by reference thereto.

[0116] Additionally, any compound described herein is intended to refer to the unsolvated form, or hydrate, solvate, or polymorph of such compound, and mixtures thereof, even if such forms are not explicitly listed. "Solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Suitable solvates include those formed with pharma- ceutically acceptable solvents, such as water, ethanol, and the like. In some embodiments, the solvent is water, and the solvate is a hydrate.

[0117] One or more compounds of the present invention may be optionally converted into a solvate. Methods for preparing solvates are generally known. Thus, for example, M.Caira et al., J.Pharmaceutical Sci., 93(3), 601-611(2004) describes the preparation of antifungal fluconazole solvates in ethyl acetate and from water. Similar preparations of solvates, hemisolvates, hydrates, etc. are described in ECvan Tonder et al., AAPS PharmSciTech., 5(1), article 12(2004) and ALBingham et al., Chem.Commun., 603-604(2001). A typical, non-limiting method includes dissolving the compound of the present invention in a suitable amount of solvent (organic solvent or water or mixture thereof) at a temperature higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals that are then separated by standard methods. Analytical techniques such as, for example infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

[0118] The present invention also relates to pharma- ceutically active metabolites of the compounds of formula (A) and the use of such metabolites in the methods of the present invention. "Pharmaceutically active metabolites" refer to metabolic products of the compounds of formula (A) or salts thereof that are pharmacologically active in the body. Active metabolites of a compound can be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

[0119] Any formula provided herein is also intended to represent unlabeled forms of compounds as well as isotopically labeled forms.Isotopically labeled compounds have the structure shown by the formula described herein, except that one or more atoms are replaced with an atom having a selected atomic mass or mass number.Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 Such isotopically labeled compounds are useful in metabolic studies (e.g.14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiotherapy of patients. 18 F or 11 C labeled compounds are particularly suitable for PET or SPECT studies. 2 Substitution with heavier isotopes such as H) may confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased half-life in vivo or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by practicing the procedures disclosed in the schemes or examples and preparations set forth below, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0120] Use of the terms "salts," "solvates," "polymorphs," and the like with respect to the compounds described herein are intended to apply equally to the salts, solvates, and polymorphic forms of the enantiomers, stereoisomers, rotamers, tautomers, atropisomers, and racemates of the compounds of the invention.

[0121] Description of the compounds of the present invention Provided herein are prodrugs of (S)- or (R)-ketamine, including isotopically labeled ketamine, compositions, and uses thereof. More specifically, the compounds having formulas (Ia)-(Vd) disclosed herein as prodrugs of (S)- or (R)-ketamine, including isotopically labeled ketamine, can be used as NMDA receptor antagonists for treating, preventing, or alleviating neurological and psychiatric disorders or diseases of the central nervous system associated with the NMDA receptor. The pharmaceutical compositions disclosed herein also have the function of preventing, treating, or alleviating diseases associated with the NMDA receptor.

[0122] In one embodiment of the present invention, there is provided a compound having the structure of Formula (Ia) or (Ib), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof. [ka] In the formula, R is -C(=O)R 1 , -C(=O)OR 2 , -C(=O)O(CHR 3 )OC(=O)R 4 or CD3, X is -CH3 or CD3, R 1 is an optionally substituted or unsubstituted aryl-OH, aryl-NH2, alkenyl-OH, alkenyl-NH2, alkyl-NH2, alkyl-OH, carbocyclyl, or heterocyclyl containing one or more N or O, and X is -CH3 or CD3; R 2 is an optionally substituted or unsubstituted alkyl, aryl, carbocyclyl, or heterocyclyl containing one or more O; X is -CH3 or CD3; R 3 is H or substituted or unsubstituted alkyl, while R 4 is independently substituted or unsubstituted alkyl, aryl, azaaryl, carbocyclyl, or heterocyclyl containing one or more O or N, and X is -CH3 or CD3.

[0123] In another aspect, provided herein are compounds having the structure of Formula (IIa) or (IIb), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof. [ka] In the formula, R 1is an optionally substituted or unsubstituted aryl-OH, aryl-NH2, alkenyl-OH, alkenyl-NH2, alkyl-NH2, alkyl-OH, carbocyclyl, or heterocyclyl containing one or more N or O, and X is -CH3 or CD3.

[0124] In one embodiment, R 1 Amino C 1-6 Alkyl, -R 1a NHCOR 1b , -R 1a OCOR 1b , -R 1a COOR 1b , [ka] Or C 3-6 is heterocyclyl, R 1 is C 1-6 optionally substituted with alkyl, -OH or oxo (=O); R 1a and R 1b are independently H, C 1-6 Alkyl or C 2-6 alkenyl, R 1c -OH, C 1-3 Hydroxyalkyl, -OCOR 1b or CH2OCOR 1b It is.

[0125] In one embodiment, the heterocyclyl containing one or more N or O is [ka] It is.

[0126] In another aspect, [ka] [ka] [ka] [ka] Provided herein is a compound selected from the group consisting of: In the formula, X is -CH3 or CD3.

[0127] In another aspect, provided herein are compounds having the structure of Formula (IIIa) or (IIIb), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof. [ka] In the formula, R 2 is an optionally substituted or unsubstituted alkyl, aryl, carbocyclyl, or heterocyclyl containing one or more O, and X is -CH3 or CD3.

[0128] In one embodiment, R 2 is C 1-6 Alkyl, C 1-6 Hydroxyalkyl, Amino C 1-6 Alkyl, -R 2a S(O) n1 R 2b , -R 2a COOR 2b , C 3-6 Aryl or C 3-6 is heterocyclyl, R 2 is C 1-6 Alkyl [ka] If replaced by C 1-6 Alkyl, -OH, C 1-6 Hydroxyalkyl, [ka] or R 2a COOR 2b optionally replaced by R 2a is C 1-6 is alkyl, R 2a is optionally C 1-6 substituted with alkyl or NH2; R 2b is H or C 1-6 is alkyl, n1 is 0, 1, or 2.

[0129] In another aspect, [ka] [ka] Provided herein is a compound selected from the group consisting of: In the formula, X is -CH3 or CD3.

[0130] In another aspect, provided herein are compounds having the structure of Formula (IVa) or (IVb), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof. [ka] In the formula, R 3 is H or substituted or unsubstituted alkyl, while R 4 is independently substituted or unsubstituted alkyl, aryl, azaaryl, carbocyclyl, or heterocyclyl containing one or more O or N, and X is -CH3 or CD3.

[0131] In one embodiment, R 3 is H or C 1-6 It is an alkyl.

[0132] In one embodiment, R4 is C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -R 4a NCOR 4b , -R 4a OCOR 4b , -R 4a S(O) n2 R 4b , C 1-6 Heterocyclyl, C 1-5 Azaaryl or [ka] and R 4 is C 1-6 Alkyl [ka] If replaced by C 1-6 Alkyl, -NH2, oxo(=O), C 1-6 Hydroxyalkyl, [ka] optionally replaced by R 4a is C 1-6 is alkyl, R 4b is C 1-6 Alkyl or C 1-6 is haloalkyl, R 4c is benzyl, and R 4d is H or R 4c and R 4d However, together with the carbon atom to which they are attached, 5-6 forming a heterocyclyl, n2 is 0, 1, or 2.

[0133] In one embodiment, C 1-6 Heterocyclyl is [ka] It is.

[0134] In one embodiment, C 1-5 Azaaryl is [ka] and [ka] is optionally substituted with one or more methyl or -NH2, or a combination thereof.

[0135] In one embodiment, [ka] It is.

[0136] In another aspect, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Provided herein is a compound selected from the group consisting of: In the formula, X is -CH3 or CD3.

[0137] In another aspect, provided herein is a compound having the structure of Formula (Va) or (Vb) or (Vc) or (Vd), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof. [ka]

[0138] Unless otherwise specified, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts, and pharma- ceutically acceptable prodrugs of the compounds disclosed herein are within the scope of the invention.

[0139] The compounds of formulas (Ia)-(Vd) above can exist in various tautomeric forms, and all of these tautomeric forms are contemplated as being within the scope of the present invention.

[0140] N-oxides of the compounds disclosed herein are also within the scope of the present invention. N-oxides of the compounds disclosed herein can be prepared by oxidizing the corresponding nitrogen base using a conventional oxidizing agent (such as hydrogen peroxide) at high temperature in the presence of an acid such as acetic acid, or by reaction with a peracid such as peracetic acid in a suitable solvent such as DCM, ethyl acetate, methyl acetate, or in chloroform, or in DCM with 3-chloroperoxybenzoic acid.

[0141] Additionally, when the compounds disclosed herein form hydrates or solvates, they are within the scope of the present invention.Similarly, pharma- ceutically acceptable salts of the hydrates and solvates of the compounds disclosed herein are also within the scope of the present invention.

[0142] The compounds of formula (Ia)-(Vd) can exist in the form of salts. In some embodiments, the salts are pharma-ceutically acceptable salts. The pharma-ceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates of Na, Ca, Mg, or K) or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of both. In general, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Further lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0143] The compounds of the present invention are basic, and therefore pharma- ceutically acceptable acid addition salts can generally be formed by treating with a suitable acid. Suitable acids include pharma-ceutically acceptable inorganic and organic acids. Representative pharma-ceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, hydrosulfate, sulfamate, phosphate, acetate, glycolate, phenyl acetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, paraaminosalicylate, glycolate, lactate, enanthate, phthalate, oxalate, succinate, benzoate, acetoxybenzoate, chloro, benzoic acid ... These include benzoate, methyl benzoate, binitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, mesylate, ethyl sulfate, 2-hydroxyesylate, benzenesulfonate, para-aminobenzenesulfonate, para-methylbenzenesulfonate, and naphthalene-2-sulfonate.

[0144] Any formula provided herein is intended to represent isotopically unenriched forms of the compound as well as isotopically enriched forms. Isotopically enriched compounds have the structure represented by the general formula of the present invention unless one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125Contains I.

[0145] In another embodiment, the compound of the invention is, for example, 3 H, 14 C and 18 Radioactive isotopes such as F are present, or 2 H and 13 This includes isotopically enriched compounds, as defined herein, in which a non-radioactive isotope, such as C, is present. Such isotopically labeled compounds may be used in metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques including drug or substrate tissue distribution assays, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or in radiotherapy of patients. 18 Compounds enriched in F are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparations, substituting appropriate isotopically labeled reagents in place of previously used non-labeled reagents.

[0146] In another aspect, provided herein are pharmaceutical compositions comprising compounds of the invention.

[0147] In one embodiment, the pharmaceutical composition further comprises at least one pharma- ceutically acceptable excipient carrier, adjuvant, vehicle, or a combination thereof.

[0148] In one embodiment, the pharmaceutical composition further comprises a pharma- ceutical effective amount of one or more adjunct therapeutic agents, which are used in the treatment of neurological and psychiatric disorders or diseases of the central nervous system.

[0149] In one embodiment, the neurological or psychiatric disorder or disease of the central nervous system is depression or pain.

[0150] In one embodiment, the adjunctive therapeutic agent is selected from the group consisting of at least one member of lithium, pharmaceutical or herbal antidepressants, anticonvulsants, mood stabilizers, antipsychotics, and benzodiazepines.

[0151] In another aspect, there is provided herein the use of a compound or pharmaceutical composition in the manufacture of a medicament for the prevention, management, treatment or amelioration of a neurological or psychiatric disorder or disease of the central nervous system in a patient.

[0152] In another aspect, provided herein is the use of a compound or pharmaceutical composition in the manufacture of a medicament for antagonizing an NMDA receptor.

[0153] In another aspect, there is provided herein a compound or pharmaceutical composition for use in the prevention, management, treatment or amelioration of neurological and psychiatric disorders or diseases of the central nervous system in a patient.

[0154] In another aspect, provided herein is a compound or pharmaceutical composition for use in antagonizing an NMDA receptor.

[0155] In another aspect, provided herein is a method for preventing, managing, treating or ameliorating the effects of a neurological or psychiatric disorder or disease in a patient, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition to a patient in need thereof.

[0156] In another aspect, provided herein is a method of antagonizing an NMDA receptor in a patient, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition to a patient in need thereof.

[0157] In yet another aspect, the present invention relates to methods of making the compounds of Formulas (Ia)-(Vd) and pharma- ceutically acceptable salts thereof.

[0158] Pharmaceutical Compositions and Preparation and Administration of Compounds of the Invention In one aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (Ia)-(Vd), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof. Optionally, the pharmaceutical composition further comprises at least one pharma- ceutically acceptable carrier, adjuvant, or excipient, and optionally other therapeutic and / or prophylactic ingredients.

[0159] Suitable carriers, adjuvants and excipients are known to those skilled in the art and are described in detail in, for example, Ansel HC et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro AR et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

[0160] As used herein, "pharmaceutical acceptable excipient" refers to a pharmaceutical acceptable material, composition, or vehicle involved in giving form or consistency to a pharmaceutical composition. Each excipient must be compatible with the other components of the pharmaceutical composition when mixed, so as to avoid interactions that would substantially reduce the efficacy of the compound of the present invention when administered to a patient, resulting in a pharmaceutical unacceptable composition. In addition, each excipient must, of course, be of sufficiently high purity to be pharmaceutical acceptable.

[0161] Suitable pharma- ceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, suitable pharma- ceutically acceptable excipients may be selected for the particular function they may perform in the composition. For example, certain pharma- ceutically acceptable excipients may be selected for their ability to facilitate the production of uniform dosage forms. Certain pharma- ceutically acceptable excipients may be selected for their ability to facilitate the production of stable dosage forms. Certain pharma- ceutically acceptable excipients may be selected for their ability to facilitate the transport or transfer of the compounds of the present invention from one organ or part of the body to another organ or part of the body once administered to a patient. Certain pharma- ceutically acceptable excipients may be selected for their ability to improve patient compliance.

[0162] Suitable pharma- ceutically acceptable excipients include diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavorings, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffer types of excipients. One skilled in the art will appreciate that a given pharma-ceutically acceptable excipient may serve multiple functions and may serve alternative functions, depending on the amount of the excipient present in the formulation and the other ingredients present in the formulation.

[0163] Those skilled in the art have the knowledge and skill in the art to enable them to select suitable pharma- ceutically acceptable excipients in appropriate amounts for use in the present invention. In addition, there are many resources available to those skilled in the art that describe pharma-ceutically acceptable excipients and may be useful in selecting suitable pharma-ceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (American Pharmaceutical Association and Pharmaceutical Press).

[0164] Various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington, The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier medium is incompatible with the compounds of the present invention, such as causing any undesirable biological effect or otherwise interacting adversely with other components of the pharmaceutically acceptable composition, its use is contemplated within the scope of the present invention.

[0165] The compounds of the present invention will typically be formulated into a dosage form adapted for administration to a patient by a desired route of administration. For example, dosage forms include those adapted for: (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, dry powders, and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, gels, and the like.

[0166] It will also be understood that certain compounds of the invention can exist for treatment in free form or, where appropriate, as a pharma- ceutically acceptable derivative or prodrug thereof. In accordance with the present invention, a pharma- ceutically acceptable derivative or prodrug includes, but is not limited to, a pharma- ceutically acceptable prodrug, salt, ester, salt of such an ester, or any other adduct or derivative that may be provided, directly or indirectly, upon administration to a patient in need thereof, a compound as otherwise described herein, or a metabolite or residue thereof.

[0167] In one embodiment, the compounds disclosed herein can be prepared in oral dosage forms. In one embodiment, the compounds disclosed herein can be prepared in inhalation dosage forms. In one embodiment, the compounds disclosed herein can be prepared in nasal dosage forms. In one embodiment, the compounds disclosed herein can be prepared in transdermal dosage forms. In one embodiment, the compounds disclosed herein can be prepared in topical dosage forms.

[0168] The pharmaceutical compositions provided herein may be provided as compressed tablets, powder tablets, chewable lozenges, fast dissolving tablets, multiple compressed tablets, or enteric coated tablets, sugar-coated tablets, or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may help mask unpleasant tastes and odors and protect the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalates. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made with multiple compression cycles, including layered tablets, and press-coated or dry-coated tablets.

[0169] Tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, such as binders, disintegrants, release-controlling polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0170] The pharmaceutical compositions provided herein may be provided as soft or hard capsules that can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two sections, one over the other, completely enclosing the active ingredient. Soft elastic capsules (SEC) are soft globular shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such a solution can be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. The capsules may be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient.

[0171] The pharmaceutical compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are biphasic systems in which one liquid is dispersed throughout another in the form of small globules, and may be oil-in-water or water-in-oil. Emulsions may contain a pharma-ceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharma-ceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions may contain pharma-ceutically acceptable acetals, such as di(lower alkyl)acetals of lower alkyl aldehydes, e.g., acetaldehyde diethyl acetal, and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may contain preservatives. For a liquid dosage form, the solution, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharma- ceutically acceptable liquid carrier, for example water, to be conveniently measured for administration.

[0172] Provided herein are pharmaceutical compositions that can be prepared in a dosage form adapted for administration to a patient by inhalation, for example, as a dry powder, aerosol, suspension, or solution composition. In one embodiment, the invention relates to a dosage form adapted for administration to a patient by inhalation as a dry powder. In one embodiment, the invention relates to a dosage form adapted for administration to a patient by inhalation as a dry powder. Dry powder compositions for delivery to the lungs by inhalation typically include a compound disclosed herein or a pharma- ceutically acceptable salt thereof as a fine powder, together with one or more pharma- ceutically acceptable excipients as a fine powder. Pharmaceutically acceptable excipients that are particularly suitable for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. Generally, a reduced-size (e.g., micronized) compound will have a D of about 1 to 10 microns. 50 The optical properties of the material can be defined by its optical properties (eg, as measured using laser diffraction).

[0173] Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the patient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[0174] Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. Ointments, creams and gels may be formulated, for example, with an aqueous or oily base with the addition of suitable thickening and / or gelling agents and / or solvents. Such bases may thus, for example, contain water and / or an oil, for example liquid paraffin or a vegetable oil, such as peanut oil or castor oil, or a solvent, such as polyethylene glycol. Thickening and gelling agents that can be used, depending on the nature of the base, include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, wool fat, beeswax, carboxypolymethylene and cellulose derivatives, and / or glyceryl monostearate and / or non-ionic emulsifiers.

[0175] The compounds disclosed herein can also be coupled to soluble polymers as targeted drug carriers. Such polymers can include polyvinylpyrrolidone substituted with palmitoyl radicals, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethylene oxide polylysine. The compounds can also be coupled to classes of biodegradable polymers suitable for achieving controlled release of drugs, such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0176] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0177] The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmacy (see Remington: The Science and Practice of Pharmacy, supra).

[0178] Pharmaceutical compositions intended for parenteral administration may contain one or more pharma- ceutically acceptable carriers and excipients, such as, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to prevent the growth of microorganisms, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, viscosity enhancing agents, pH adjusting agents, and inert gases and the like.

[0179] The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0180] The pharmaceutical compositions provided herein can be formulated for single or multiple doses. Single dose formulations are packaged in ampoules, vials, or syringes. Multi-dose parenteral formulations must contain antibacterial agents in bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

[0181] The pharmaceutical compositions provided herein can be formulated with other active ingredients that do not impair the desired therapeutic action, or with substances that supplement the desired action.

[0182] In one embodiment, the methods of treatment disclosed herein include administering to a patient in need of treatment a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention. Each of the examples disclosed herein includes treating the above disorders or diseases by administering to a patient in need of treatment a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

[0183] In one embodiment, the compound of the present invention or a pharmaceutical composition thereof can be administered by any suitable route of administration, including both systemic and local administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Parenteral administration refers to a route of administration other than enteral or transdermal, usually by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin, as well as intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, the compound of the present invention or a pharmaceutical composition thereof can be administered orally. In one embodiment, the compound of the present invention or a pharmaceutical composition thereof can be administered by inhalation. In a further embodiment, the compound of the present invention or a pharmaceutical composition thereof can be administered intranasally.

[0184] In one embodiment, the compound of the present invention or a pharmaceutical composition thereof may be administered once or according to a dosing regimen in which multiple doses are administered at various time intervals over a given period of time. For example, a dose may be administered 1, 2, 3, or 4 times per day. In one embodiment, a dose is administered once per day. In a further embodiment, a dose is administered twice per day. A dose may be administered until a desired therapeutic effect is achieved, or indefinitely to maintain a desired therapeutic effect. A suitable dosing regimen for a compound of the present invention or a pharmaceutical composition thereof depends on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, and can be determined by one of ordinary skill in the art. Furthermore, a suitable dosing regimen, including the period during which the compound of the present invention or a pharmaceutical composition thereof is administered, depends on the disorder being treated, the severity of the disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of any combination therapy, the desired therapeutic effect, and similar factors within the knowledge and expertise of the skilled artisan. Such a skilled artisan will further appreciate that a suitable dosing regimen may need to be adjusted to account for an individual patient's response to the dosing regimen, or the changing needs of an individual patient over time.

[0185] The compounds of the invention may be administered simultaneously with, before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately by the same or different route of administration, or together in the same pharmaceutical composition as another agent.

[0186] The compounds provided herein may be used in combination with sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, cyclopyrrolidones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, etc. Examples include adinazolan, allobarbital, alonimide, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, tacitin, brotizolam, bupropion, buspirone, butabarbital, butalbital, capride, carbochloral, chloral betaine, chloral hydrate, chlorodyne, clomipramine, clonazepam, domperidone, metaminodiazepoxide, chloretate, clozapine, ciprazepam, decistatin, cyclosporine ... pramine, dexcuramin, diazepam, chloralsalicylamide, divalproic acid, diphenhydramine, doxepin, estazolam, etochlorvynol, etomidate, phenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, orazepam, lormetazepam, maprotiline, mecloqualone, melatonin, methylphenobarbital, Meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, isopropylphenol, protriptyline, quazepam, leclazepam, rolipram, secobarbital, sertraline, suproclon, temazepam, thiamine Oridazine, tracazolate, tranylcypromine, trazodone, triazole benzodiazepines, trepipam, tricetamide, trichloroethyl phosphate, trifluoperazine, trimetozine, trimeprimine, urdazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and salts and compositions thereof, etc. Alternatively, physical methods such as phototherapy or electrical stimulation can be used during administration of the compounds disclosed herein.

[0187] Additionally, the compounds of the present invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the present invention is a functional derivative of the compound that ultimately liberates the compound of the present invention in vivo when administered to a patient. The administration of the compounds of the present invention as prodrugs may enable one of ordinary skill in the art to do one or more of the following: (a) modify the onset of action of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transport or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome side effects or other problems encountered with the compound. Exemplary functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, including the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those of ordinary skill in the art.

[0188] Uses of the Compounds and Pharmaceutical Compositions The compounds or pharmaceutical compositions disclosed herein are effective as NMDA receptor antagonists for treating or preventing neurological and psychiatric disorders associated with the NMDA receptor, and can be used to prepare a medicament that antagonizes the NMDA receptor.

[0189] All diseases related to the NMDA receptor can be selected from any kind of neurological and psychiatric disorder or disease.

[0190] In one embodiment, diseases associated with the NMDA receptor include depression, anxiety disorders, seasonal affective disorder, mania, bipolar disorder, obsessive-compulsive disorder, insomnia and fatigue due to jet lag, schizophrenia, seizures, panic attacks, melancholia, alcoholism, drug addiction, alcoholism, drug abuse, drug withdrawal, insomnia, psychotic disorders, epilepsy, sleep disorders, sleep disorders, sleep apnea, eating disorders, fibromyalgia, stress, obesity, Parkinson's disease, cognitive disorders, memory disorders, premenstrual syndrome, migraine, memory loss, asymptomatic Alzheimer's disease, or disorders associated with normal or pathological aging.

[0191] It is understood that the above-mentioned symptoms or diseases are precipitated or accelerated under certain environmental conditions, such as stress or fear (the stress may result from social sources, such as social pressure, or from physical sources, such as physical pressure, including pressure caused by fear), and that the compounds disclosed herein are particularly useful in treating these environmentally-modulated symptoms and diseases.

[0192] In addition to being useful for human treatment, the compounds of the present invention and compositions thereof are also useful for veterinary treatment of animals, such as companion animals, exotic animals, and domestic mammals. In other embodiments, animals disclosed herein include horses, dogs, and cats. As used herein, the compounds disclosed herein include pharmaceutically acceptable derivatives thereof.

[0193] Preferred embodiments of the invention General synthesis method The following examples are provided so that the invention might be more fully understood, however, it should be understood that these embodiments merely provide methods of practicing the invention and that the invention is not limited to these embodiments.

[0194] In general, the compounds disclosed herein can be prepared by the methods described herein, and the substituents are as defined above for formula (Ia) or formula (Ib) unless otherwise noted. The following non-limiting schemes and examples are presented to further illustrate the invention.

[0195] Those skilled in the art will recognize that the described chemical reactions can be easily applied to prepare many other compounds disclosed herein, and alternative methods for preparing the compounds disclosed herein are considered to be within the scope disclosed herein. Those skilled in the art will recognize that starting materials can be varied and additional steps can be used to produce compounds encompassed by the present invention, as demonstrated by the following examples. In some cases, protection of certain reactive functional groups may be required to achieve some of the above variations. In general, such need for protecting groups, as well as the conditions required to add and remove such groups, will be apparent to those skilled in the art of organic synthesis. For example, the synthesis of compounds according to the present invention that are not exemplified can be successfully carried out by modifications apparent to those skilled in the art, such as by appropriately protecting blocking groups, by utilizing other suitable reagents known in the art other than those described, and / or by routinely modifying reaction conditions. Alternatively, it will be recognized that known reaction conditions or reactions disclosed in the present invention have applicability for preparing other compounds disclosed herein.

[0196] In the examples described below, all temperatures are in degrees Celsius unless otherwise noted. Reagents were purchased from commercial suppliers, such as Aldrich Chemical Company, Arcos Chemical Company, Alfa Aesar Chemical Company, and J&K Chemical Company, and used without further purification unless otherwise indicated.

[0197] Preparation of compounds The compounds of the invention (including their salts, esters, hydrates or solvates) may be prepared using any of the known techniques of organic synthesis, or may be synthesised according to any of a number of possible synthetic routes.

[0198] The reactions for preparing the compounds of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range, for example, from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. A suitable solvent for a particular reaction step can be selected by those skilled in the art depending on the particular reaction step.

[0199] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography mass spectrometry (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica chromatography.

[0200] The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of organic synthetic chemistry, or variations thereon as would be understood by one skilled in the art. Preferred methods include, but are not limited to, those described below. Specifically, the compounds of the present invention of formulas (Ia)-(Vd) can be synthesized according to the steps outlined in the exemplary general synthetic schemes listed below, and the abbreviations of the reactants or chemical groups of the reactants included in the synthetic schemes are defined in the examples.

[0201] In general, the synthesis to compounds having formula (IIa) or (IIb) can be carried out according to the following synthetic methods, but is not limited to these described methods. Formula (IIa) is shown below. Scheme 1 [ka] R 1 teeth, [ka] It could be. Scheme 2 [ka] R 1 teeth, [ka] It could be. Scheme 3 [ka] R 1 teeth, [ka] It could be. Scheme 4 [ka] R 1 teeth, [ka] It could be. Scheme 5 [ka] R 1 teeth, [ka] It could be.

[0202] In general, the synthesis to compounds having formula (IIIa) or (IIIb) can be carried out according to the following synthetic methods, but is not limited to these described methods. Formula (IIIa) is shown below. Scheme 6 [ka] R 2 teeth, [ka] It could be. Scheme 7 [ka] R 2 teeth, [ka] It could be. Scheme 8 [ka] R 2 teeth, [ka] It could be.

[0203] In general, the synthesis to compounds having formula (IVa) or (IVb) can be carried out according to the following synthetic methods, but is not limited to these described methods. Formula (IVa) is shown below. Scheme 9 [ka] [ka] teeth, [ka] It could be. Scheme 10 [ka] [ka] It could be. Scheme 11 [ka] [ka] It could be.

[0204] In general, the synthesis of compounds having formula (Va)-(Vd) can be carried out according to the following synthesis methods, but is not limited to these described methods. Formula (Va) or formula (Vb) is shown below. Scheme 12 [ka]

[0205] Preparation and Characterization of Exemplary Compounds The compounds encompassed by this disclosure can be prepared via various schemes. Detailed preparation methods of 108 exemplary compounds via various schemes are described below, and the characterization results are also listed.

[0206] Unless otherwise stated, all reagents were purchased from commercial suppliers without further purification. Standard methods of solvent drying were used where necessary. Plates used for thin-layer chromatography (TLC) were E. Merck silica gel 60F254 (0.24 nm thick) precoated on aluminum plates and visualized under UV light (365 nm and 254 nm) or by staining with 5% dodecamolybdophosphoric acid in ethanol followed by heating. Column chromatography was performed using silica gel (200-400 mesh) from commercial suppliers. 1 H NMR spectra were recorded at room temperature on a BRUKER AVANCE III HD 500 MHz NMR spectrometer and a BRUKER AVANCE III HD 600 MHz. Solvent signals were 1The following abbreviations were used to describe the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, br.s = broad singlet, dd = double doublet, td = triple doublet, dt = double triplet, dq = double quartet, m = multiplet. Other abbreviations used in the experimental details are: δ = chemical shift in ppm downfield from tetramethylsilane, Ar = aryl, Ac = acyl, Boc = tert-butyloxycarbonyl, Bn = benzyl, DCM = dichloromethane, DCE = dichloroethane, DMF = N,N'-dimethylformamide, NMP = N-methyl-2-pyrrolidone, DIBAL-H = diisobutylaluminum hydride, DIPEA = diisopropylethylamine, DMAP = 4-(dimethylamino)pyridine, DMSO = dimethylsulfoxide, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBT = 1-hydroxybenzotriazole, EA = ethyl acetate, Et = ethyl, Me = methyl, Hz = hertz, HPLC = high performance liquid chromatography, J = coupling constant (in NMR), min = minute, NMR = nuclear magnetic resonance, NBS = N-bromosuccinimide, NCS = N-chlorosuccinimide, prep = preparative, PE = petroleum ether, s-Bu = sec-butyl, t-Bu = tert-butyl, iPr = isopropyl, TBAF = tetrabutylammonium fluoride, tert = tertiary, TFA = trifluoroacetic acid, THF = tetrahydrofuran, MTBE = methyl tert-butyl ether, TLC = thin layer chromatography

[0207] example Please note that the embodiments of the present invention detailed below are merely illustrative examples for the present invention and are not to be construed as limiting the present invention. Examples that do not include specific techniques or conditions can be carried out according to the techniques or conditions in technical documents or according to the product instructions. Reagents or equipment that do not list manufacturers can be obtained by general purchase. Those skilled in the art will recognize that starting materials can be changed and additional steps can be used to produce compounds encompassed by the present invention, as demonstrated by the following examples. [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7]

[0208] Example 1: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate (A-1) [ka] To a solution of S-ketamine hydrochloride 1 (274 mg, 1.0 mmol) and DIPEA (260 mg, 1.0 mmol) in DCM (10 mL) was added 1-chloroethyl carbonochloridate (172 mg, 1.2 mmol) slowly at 0 °C. The reaction was stirred at 25 °C for 1.5 h. The reaction mixture was diluted with DCM (10 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (1 / 1 to 5 / 1) to give 276 mg (79% yield) of compound 2 as a white solid.

number

[0209] To a solution of compound 2 (150 mg, 0.44 mmol), NaI (65 mg, 0.44 mmol) and 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (292 mg, 2.18 mmol) in acetone (1.7 mL) was added Et3N (0.31 mL, 2.18 mmol). The reaction was stirred at 25 °C for 5 h. The reaction mixture was concentrated, redissolved in EA (20 mL) and washed with H2O (8 mL), saturated aqueous NaHCO3 (2 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 4 / 6) to give 95 mg (49% yield) of the title compound (A-1) as a colorless oil.

number

[0210] Example 2: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl (2S)-5-oxopyrrolidine-2-carboxylate (A-2) [ka] To a solution of compound 2 (100 mg, 0.29 mmol), NaI (43 mg, 0.29 mmol) and (S)-5-oxopyrrolidine-2-carboxylic acid (188 mg, 1.46 mmol) in acetone (1.2 mL) was added Et3N (0.20 mL, 1.46 mmol). The reaction was stirred at 25 °C for 5 h and then concentrated. The mixture was diluted with EA (20 mL) and filtered. The filtrate was concentrated and then purified on a silica gel column eluted with hexane / EA (100% hexane to 4 / 6) to give 50 mg (39% yield) of the title compound (A-2) as a white foam.

number

[0211] Example 3: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl acetylglycinate (A-3) [ka] To a solution of compound 2 (172 mg, 0.5 mmol), NaI (75 mg, 0.5 mmol) and acetylglycine (176 mg, 1.5 mmol) in acetone (6 mL) was added Et3N (0.35 mL, 2.5 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (10 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 1 / 2) to give 110 mg (35% yield) of the title compound (A-3) as a white foam.

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[0212] Example 4: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl 2-(3-methyloxetan-3-yl)acetate target (A-4) [ka] To a solution of compound 2 (262 mg, 0.76 mmol), NaI (114 mg, 0.76 mmol) and 2-(3-methyloxetan-3-yl)acetic acid (296 mg, 2.28 mmol) in acetone (9 mL) was added Et3N (0.53 mL, 3.8 mmol). The reaction was heated to 70 °C for 3 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with H2O (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 3 / 1) to give a yellow oil. Ether (3 mL) was added, filtered and the solid was washed with cold ether to give 102 mg (31% yield) of the title compound (A-4) as a white solid.

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[0213] The filtrate was concentrated to give an oil which was stored at -20°C to give a sticky solid. The mixture was diluted with ether (2 mL) and the filtrate was collected. The filtrate was concentrated to give 40 mg (12% yield) of the A-4 isomer as a colorless oil.

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[0214] Example 5: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl acetyl-L-alaninate (A-5) [ka] To a solution of compound 2 (172 mg, 0.5 mmol), NaI (150 mg, 1.0 mmol) and (S)-2-acetamidopropanoic acid (328 mg, 2.5 mmol) in acetone (6 mL) was added Et3N (0.35 mL, 2.5 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 1 / 1) to give 149 mg (68% yield) of the title compound (A-5) as a white foam.

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[0215] Example 6: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl acetyl-L-valinate (A-6) [ka] To a solution of compound 2 (172 mg, 0.5 mmol), NaI (150 mg, 1.0 mmol) and (S)-2-acetamido-3-methylbutanoic acid (239 mg, 1.5 mmol) in acetone (6 mL) was added Et3N (0.35 mL, 2.5 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 1 / 1) to give 159 mg (68% yield) of the title compound (A-6) as a white foam.

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[0216] Example 7: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl 3-hydroxy-2-(hydroxymethyl)propanoate (A-7) [ka] To a solution of compound 2 (172 mg, 0.5 mmol), NaI (75 mg, 0.5 mmol) and 2-phenyl-1,3-dioxane-5-carboxylic acid (520 mg, 2.5 mmol) in acetone (6 mL) was added Et3N (0.35 mL, 2.5 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (10 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 4 / 1) to give 175 mg (68% yield) of compound 3 as a white foam.

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[0217] To a solution of compound 3 (100 mg, 0.19 mmol) in EA (10 mL) was added Pd(OH)2 / C (11 mg). The reaction was stirred under H2 atmosphere at 25 °C for 50 min. The reaction was filtered through a pad of Celite and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 1 / 4) to give 40 mg (49% yield) of the title compound (A-7) as a white foam.

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[0218] Example 8: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl 2-(((3-methyloxetan-3-yl)methyl)sulfinyl)acetate (A-8) [ka] To a solution of compound 2 (172 mg, 0.5 mmol), NaI (75 mg, 0.5 mmol) and 2-(((3-methyloxetan-3-yl)-methyl)thio)acetic acid (264 mg, 1.5 mmol) in acetone (6 mL) was added triethylamine (0.35 mL, 2.5 mmol). The reaction was heated to 70 °C for 2 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 2 / 1) to give 180 mg (74% yield) of compound 4 as a yellow oil.

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[0219] To a solution of compound 4 (140 mg, 0.29 mmol) in MeOH (1.4 mL) was added a solution of NaIO4 (62 mg, 0.29 mmol) in HO (0.7 mL) dropwise at 0 °C. The reaction was stirred at 25 °C for 16 h and filtered to collect the filtrate. The filtrate was concentrated and purified on a silica gel column eluted with DCM / MeOH (100% DCM to 98 / 2) to give 38 mg (26% yield) of the title compound (A-8) as a white foam.

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[0220] Example 9: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl 2-(((3-methyloxetan-3-yl)methyl)sulfonyl)acetate (A-9) [ka] To a solution of compound 4 (141 mg, 0.29 mmol) in MeOH (1.1 mL) was added a solution of oxone (356 mg, 0.58 mmol) in HO (0.9 mL) dropwise at 0 °C. The reaction was stirred at 25 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with HO (5 mL). The organic layer was dried over MgSO, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 1 / 1) to give 42 mg (29% yield) of the title compound (A-9) as a white foam.

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[0221] Example 10: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl (2R)-2-hydroxypropanoate (A-10) [ka] To a solution of compound 2 (172 mg, 0.5 mmol), NaI (75 mg, 0.5 mmol) and R-lactic acid (227 mg, 2.5 mmol) in acetone (6 mL) was added EtN (0.35 mL, 2.5 mmol). The reaction was heated to 70 °C for 3.5 h. The reaction was concentrated, redissolved in DCM (10 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 2 / 1) to give 100 mg (50% yield) of the title compound (A-10) as a white foam.

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[0222] Example 11: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl (2R)-2-acetoxypropanoate (A-11) [ka] To a solution of compound 2 (172 mg, 0.5 mmol), NaI (79 mg, 0.525 mmol) and (R)-2-acetoxypropanoic acid (172 mg, 0.5 mmol) in acetone (6 mL) was added Et3N (0.35 mL, 2.5 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 65 / 35) to give 204 mg (93% yield) of the title compound (A-11) as a white foam.

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[0223] Example 12: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl nicotinate (A-12) [ka] To a solution of compound 2 (86 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and nicotinic acid (92 mg, 0.75 mmol) in acetone (3 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 3 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 3 / 1) to give 47 mg (47% yield) of the title compound (A-12) as a white solid.

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[0224] Example 13: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl 3-benzylbenzoate (A-13) [ka] To a solution of compound 2 (54 mg, 0.16 mmol), NaI (25 mg, 0.17 mmol) and 3-benzylbenzoic acid (100 mg, 0.47 mmol) in acetone (2 mL) was added Et3N (0.11 mL, 0.78 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 4 / 1) to give 60 mg (74% yield) of the title compound (A-13) as a colorless solid.

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[0225] Example 14: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl benzo[d][1,3]dioxole-5-carboxylate (A-14) [ka] To a solution of compound 2 (86 mg, 0.25 mmol), NaI (39 mg, 0.26 mmol) and benzo[d][1,3]dioxole-5-carboxylic acid (125 mg, 0.75 mmol) in acetone (3 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 7 / 3) to give 110 mg (93% yield) of the title compound (A-14) as a white solid.

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[0226] Example 15: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl 1-methylpiperidine-4-carboxylate (A-15) [ka] To a solution of compound 2 (86 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and 1-methylpiperidine-4-carboxylic acid (117 mg, 0.82 mmol) in DMSO (1 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was stirred at 25° C. for 3 h. The reaction was concentrated and then purified on a silica gel column eluted with DCM / MeOH (100% hexane to 95 / 5) to give 23 mg (20% yield) of the title compound (A-15) as a yellow oil.

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[0227] Example 16: 1-(isonicotinoyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-16) [ka] To a solution of compound 2 (86 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and isonicotinic acid (92 mg, 0.75 mmol) in acetone (3 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 3 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 4 / 1) to give 50 mg (46% yield) of the title compound (A-16) as a white solid.

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[0228] Example 17: 1-(2-(isobutyramido)acetoyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-17) [ka] To a solution of compound 2 (86 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and 2-(isobutyramido)acetic acid (109 mg, 0.75 mmol) in acetone (3 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 1 / 1) to give 57 mg (50% yield) of the title compound (A-17) as a white solid.

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[0229] Example 18: 1-(3-acetamidopropanoyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-18) [ka] To a solution of compound 2 (86 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and 3-acetamidopropanoic acid (98 mg, 0.75 mmol) in acetone (3 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 22 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 1 / 2) to give 20 mg (18% yield) of the title compound (A-18) as a pale yellow oil.

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[0230] Example 19: 1-(4-acetamidobutanoyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-19) [ka] To a solution of compound 2 (86 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and 4-acetamidobutanoic acid (109 mg, 0.75 mmol) in acetone (3 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 22 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 1 / 2) to give 72 mg (64% yield) of the title compound (A-19) as a white foam.

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[0231] Example 20: (2-(3-methyloxetan-3-yl)acetoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-20) [ka] To a solution of S-ketamine hydrochloride 1 (102 mg, 0.375 mmol) and DIPEA (97 mg, 0.75 mmol) in DCM (3.75 mL) was added chloromethyl chloroformate (121 mg, 0.94 mmol) slowly at 0° C. The reaction was stirred at 25° C. for 24 h. The reaction was diluted with DCM (5 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 9 / 1) to give 93 mg (75% yield) of compound 5 as a white solid.

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[0232] To a solution of compound 5 (82 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and 2-(3-methyloxetan-3-yl)acetic acid (98 mg, 0.75 mmol) in acetone (3 mL) was added K2CO3 (173 mg, 1.25 mmol). The reaction was heated to 70 °C for 2 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 1 / 2) to give 84 mg (80% yield) of the title compound (A-20) as a white solid.

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[0233] Example 21: 1-(oxetane-3-carboxyloyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-21) [ka] To a solution of compound 2 (86 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and oxetane-3-carboxylic acid (77 mg, 0.75 mmol) in acetone (3 mL) was added EtN (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO (5 mL) and brine (5 mL). The organic layer was dried over MgSO, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (7 / 3) to give 40 mg (49% yield) of the title compound (A-21) as a pale yellow oil.

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[0234] Example 22: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)propyl 2-(3-methyloxetan-3-yl)acetate (A-22) [ka] To a solution of S-ketamine hydrochloride 1 (137 mg, 0.5 mmol) and DIPEA (130 mg, 1.0 mmol) in DCM (5 mL) was added 1-chloroethyl carbonochloridate (94 mg, 0.6 mmol) slowly at 0 °C. The reaction was stirred at 25 °C for 16 h. The reaction was diluted with DCM (5 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 10 / 1) to give 133 mg (74% yield) of compound 6 as a colorless oil.

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[0235] To a solution of compound 6 (90 mg, 0.25 mmol), NaI (37 mg, 0.25 mmol), and 2-(3-methyloxetan-3-yl)acetic acid (98 mg, 0.75 mmol) in acetone (1 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 10 h. The reaction was concentrated, redissolved in DCM (5 mL), and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give an oil that was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 2 / 1) to give 32 mg (28% yield) of the title compound (A-22) as a yellow oil.

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[0236] Example 23: 1-(Tetrahydro-2H-pyran-4-carboxyloyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-23) [ka] To a solution of compound 2 (86 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and tetrahydro-2H-pyran-4-carboxylic acid (98 mg, 0.75 mmol) in acetone (3 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70° C. for 16 h. The reaction was concentrated, dissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (7 / 3) to give 72 mg (66% yield) of the title compound (A-23) as a white foam.

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[0237] Example 24: 1-(2-(3-methyloxetan-3-yl)acetoyloxy)-2-methylpropyl (S)-1-(2-chlorophenyl)-2-oxocyclohexyl methylcarbamate (A-24) [ka] To a solution of S-ketamine hydrochloride 1 (200 mg, 0.73 mmol) and DIPEA (0.25 mL, 1.46 mmol) in DCM (8 mL) was added 1-chloro-2-methylpropyl chloroformate (312 mg, 1.83 mmol) slowly at 0° C. and then stirred at 25° C. for 1 h. The reaction was diluted with DCM (5 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 9 / 1) to give 230 mg (85% yield) of compound 7 as a white solid.

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[0238] To a solution of compound 7 (93 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and 2-(3-methyloxetan-3-yl)acetic acid (98 mg, 0.75 mmol) in acetone (3 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 5 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (7 / 3) to give 15 mg (13% yield) of the title compound (A-24) as a white foam.

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[0239] Example 25: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)propyl acetylglycinate (A-25) [ka] To a solution of compound 6 (90 mg, 0.25 mmol), NaI (37 mg, 0.25 mmol), and acetylglycine (88 mg, 0.75 mmol) in acetone (1 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 10 h. The reaction was concentrated, redissolved in DCM (5 mL), and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (1 / 0 to 1 / 2) to give 18 mg (16% yield) of the title compound (A-25) as a white solid.

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[0240] Example 26: 1-(2-acetamidoacetoyloxy)-2-methylpropyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-26) [ka] To a solution of compound 7 (93 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and acetylglycine (88 mg, 0.75 mmol) in acetone (3 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (2 / 3) to give 29 mg (28% yield) of the title compound (A-26) as a colorless oil.

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[0241] Example 27: (Nicotinoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-27) [ka] To a solution of compound 5 (82 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol) and nicotinic acid (92 mg, 0.75 mmol) in acetone (3 mL) was added Et3N (0.18 mL, 1.25 mmol). The reaction was heated to 70 °C for 2 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (3 / 2) to give 32 mg (31% yield) of the title compound (A-27) as a white solid.

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[0242] Example 28: 2-(2-chlorophenyl)-2-(methyl(methyl-d3)amino)cyclohexan-1-one (A-28) [ka] To S-ketamine hydrochloride 1 (68 mg, 0.25 mmol) was added a solution of iodomethane-d3 (109 mg, 0.75 mmol) and Cs2CO3 (163 mg, 0.5 mmol) in DMF (5 mL). The reaction was stirred at 25 °C for 4 h. The reaction was diluted with DCM (5 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 3 / 1) to give 16 mg (23% yield) of the title compound (A-28) as a yellow solid.

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[0243] Example 29: (2-acetamidoacetoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-29) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol) and 2-acetamidoacetic acid (53 mg, 0.45 mmol) in acetone (2 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 3 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 1 / 4) to give 25 mg (40% yield) of the title compound (A-29) as a colorless gum.

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[0244] Example 30: ((S)-2-acetamido-3-methylbutanoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-30) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol) and (S)-2-acetamido-3-methylbutanoic acid (72 mg, 0.45 mmol) in acetone (2 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 3 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 1 / 4) to give 65 mg (95% yield) of the title compound (A-30) as a white foam.

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[0245] Example 31: ((S)-2-acetamidopropanoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-31) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (46 mg, 0.3 mmol) and (S)-2-acetamidopropanoic acid (60 mg, 0.46 mmol) in acetone (1.8 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 13 / 7) to give 52 mg (81% yield) of the title compound (A-31) as a white foam.

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[0246] Example 32: (2-(isobutyramido)acetoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-32) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (46 mg, 0.3 mmol) and 2-(isobutyramido)acetic acid (66 mg, 0.46 mmol) in acetone (1.8 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 1 / 1) to give 47 mg (70% yield) of the title compound (A-32) as a white foam.

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[0247] Example 33: ((S)-2-(isobutyramido)propanoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-33) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol) and (S)-2-(isobutyramido)propanoic acid (72 mg, 0.45 mmol) in acetone (2 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 4 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 3 / 2) to give 30 mg (44% yield) of the title compound (A-33) as a white foam.

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[0248] Example 34: ((S)-2-(isobutyramido)-3-methylbutanoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-34) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (46 mg, 0.3 mmol) and (S)-2-(isobutyramido)-3-methylbutanoic acid (102 mg, 0.46 mmol) in acetone (1.8 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 7 / 3) to give 67 mg (93% yield) of the title compound (A-34) as a yellow foam.

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[0249] Example 35: ((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)methyl L-valinate (A-35) [ka] To a solution of compound 5 (150 mg, 0.46 mmol), NaI (137 mg, 0.9 mmol) and N-(tert-butoxycarbonyl)-L-valine (297 mg, 1.4 mmol) in acetone (5.4 mL) was added K2CO3 (315 mg, 2.3 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 4 / 1) to give 191 mg (82% yield) of compound 8 as a white foam.

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[0250] To a solution of compound 8 (71 mg, 0.14 mmol) in DCM (5 mL) was added TFA (0.19 mL, 2.5 mmol). The reaction was stirred at 25° C. for 16 h. The reaction was concentrated to give 67 mg of the TFA salt form of the title compound (A-35) as a colorless gum.

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[0251] Example 36: (S)-(((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)methyl glycinate (A-36) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (46 mg, 0.3 mmol) and N-(tert-butoxycarbonyl)-L-glycine (102 mg, 0.46 mmol) in acetone (1.8 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 7 / 3) to give 54 mg (76% yield) of compound 9 as a white foam.

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[0252] To a solution of compound 9 (25 mg, 0.05 mmol) in DCM (1.9 mL) was added TFA (0.07 mL, 0.96 mmol). The reaction was stirred at 25° C. for 16 h. The reaction was concentrated to give 25 mg of the TFA salt form of the title compound (A-36) as a colorless gum.

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[0253] Example 37: ((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)methyldimethyl-L-valinate (A-37) [ka] Compound (A-35) TFA salt (52 mg, 0.1 mmol) was dissolved in MeOH (5.8 mL) and cooled to 0° C. in an ice bath. Acetic acid (0.02 mL, 0.4 mmol) and NaBH3CN (13 mg, 0.2 mmol) were added to the above solution and stirred at 0° C. for 5 min. Formaldehyde (37% in H2O, 0.02 mmol) was added at 0° C. and the reaction mixture was stirred at 25° C. for 2.5 h. The reaction was quenched with saturated aqueous NaHCO3 (5 mL) and diluted with water (5 mL). The aqueous layer was extracted with DCM (5 mL) and the organic layer was washed with brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give a solid. The solid was washed with hexane and then recrystallized from DCM and hexane at 4° C. After 16 h, the mixture was filtered and the filtrate was collected and concentrated to give 20 mg (46% yield) of the title compound (A-37) as a white solid.

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[0254] Example 38: (2-(N-methylacetamido)acetoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-38) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol) and 2-(N-methylacetamido)acetic acid (99 mg, 0.76 mmol) in acetone (2 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 1 / 4) to give 25 mg (39% yield) of the title compound (A-38) as a white foam.

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[0255] Example 39: 1-(2-(N-methylacetamido)acetoyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-39) [ka] To a solution of compound 2 (50 mg, 0.15 mmol), NaI (43 mg, 0.29 mmol) and 2-(N-methylacetamido)acetic acid (95 mg, 0.73 mmol) in acetone (2 mL) was added Et3N (0.10 mL, 0.73 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 1 / 4) to give 36 mg (57% yield) of the title compound (A-39) as a white foam.

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[0256] Example 40: 1-(2-(propionamido)acetoyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-40) [ka] To a solution of compound 2 (50 mg, 0.145 mmol), NaI (23 mg, 0.15 mmol) and 2-(propionamido)acetic acid (57 mg, 0.435 mmol) in acetone (1.8 mL) was added Et3N (0.1 mL, 0.725 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 1 / 1) to give 41 mg (65% yield) of the title compound (A-40) as a white foam.

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[0257] Example 41: (2-(propionamido)acetoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-41) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (23 mg, 0.3 mmol) and 2-(propionamido)acetic acid (60 mg, 0.46 mmol) in acetone (1.8 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 2 / 3) to give 45 mg (69% yield) of the title compound (A-41) as a white foam.

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[0258] Example 42: ((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)methyl L-alaninate (A-42) [ka] To a solution of compound 5 (150 mg, 0.45 mmol), NaI (136 mg, 0.91 mmol) and N-(tert-butoxycarbonyl)-N-methyl-L-alanine (258 mg, 1.36 mmol) in acetone (5 mL) was added K2CO3 (314 mg, 2.27 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (10 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 3 / 2) to give 200 mg (91% yield) of compound 10 as a white foam.

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[0259] To a solution of compound 10 (200 mg, 0.41 mmol) in DCM (15 mL) was added TFA (0.57 mL, 7.5 mmol). The reaction was stirred at 25° C. for 16 h. The reaction was concentrated to give 250 mg of the title compound (A-42) as a colorless gum.

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[0260] Example 43: 1-(2-(propionamido)acetoyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-43) [ka] To a solution of compound 2 (103 mg, 0.3 mmol), NaI (47 mg, 0.315 mmol) and 2-(2,2,2-trifluoroacetamido)-acetic acid (154 mg, 0.9 mmol) in acetone (4 mL) was added Et3N (0.21 mL, 1.5 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 3 / 1) to give 113 mg (79% yield) of the title compound (A-43) as a white solid.

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[0261] Example 44: (2-(2,2,2-trifluoroacetamido)acetoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-44) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (46 mg, 0.3 mmol) and 2-(2,2,2-trifluoroacetamido)-acetic acid (78 mg, 0.46 mmol) in acetone (4 mL) was added Et3N (0.1 mL, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 7 / 3) to give 14 mg (20% yield) of the title compound (A-44) as a white solid.

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[0262] Example 45: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl dimethyl-L-alaninate (A-45) [ka] To a solution of compound 2 (31 mg, 0.09 mmol), NaI (27 mg, 0.18 mmol) and (S)-2-(dimethylamino)-propanoic acid (32 mg, 0.27 mmol) in acetone (1 mL) was added Et3N (0.06 mL, 0.45 mmol). The reaction was heated to 70 °C for 20 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 1 / 3) to give 14 mg (37% yield) of the title compound (A-45) as a yellow gum.

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[0263] Example 46: ((S)-2-(2,2,2-trifluoroacetamido)-3-methylbutanoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbanate (A-46) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol) and (S)-2-(2,2,2-trifluoroacetamido)-3-methylbutanoic acid (97 mg, 0.45 mmol) in acetone (2 mL) was added Et3N (0.11 mL, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 4 / 1) to give 34 mg (44% yield) of the title compound (A-46) as a white gum.

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[0264] Example 47: 1-(2-(2,2,2-trifluoroacetamido)acetoyloxy)propyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-47) [ka] To a solution of compound 6 (50 mg, 0.14 mmol), NaI (22 mg, 0.15 mmol) and 2-(2,2,2-trifluoroacetamido)-acetic acid (72 mg, 0.42 mmol) in acetone (1.8 mL) was added Et3N (0.1 mL, 0.7 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 3 / 1) to give 28 mg (41% yield) of the title compound (A-47) as a white foam.

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[0265] Example 48: ((S)-2-(2,2,2-trifluoroacetamido)propanoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-48) [ka] To a solution of compound 5 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol) and (S)-2-(2,2,2-trifluoroacetamido)propanoic acid (84 mg, 0.45 mmol) in acetone (2 mL) was added Et3N (0.11 mL, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 4 / 1) to give 13 mg (18% yield) of the title compound (A-48) as a white solid.

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[0266] Example 49: 1-(2-(2,2,2-trifluoroacetamido)acetoyloxy)-2-methylpropyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-49) [ka] To a solution of compound 7 (93 mg, 0.25 mmol), NaI (39 mg, 0.26 mmol) and 2-(2,2,2-trifluoro-acetamido)acetic acid (128 mg, 0.75 mmol) in acetone (3 mL) was added Et3N (0.17 mL, 1.25 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 3 / 1) to give 51 mg (40% yield) of the title compound (A-49) as a white foam.

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[0267] Example 50: 1-((S)-2-(2,2,2-trifluoroacetamido)-3-methylbutanoyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-50) [ka] To a solution of compound 2 (103 mg, 0.3 mmol), NaI (47 mg, 0.315 mmol) and (S)-2-(2,2,2-trifluoro-acetamido)-3-methylbutanoic acid (192 mg, 0.9 mmol) in acetone (4 mL) was added Et3N (0.21 mL, 1.5 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 17 / 3) to give 128 mg (82% yield) of the title compound (A-50) as a white foam.

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[0268] Example 51: 1-((S)-2-(2,2,2-trifluoroacetamido)propanoyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-51) [ka] To a solution of compound 2 (103 mg, 0.3 mmol), NaI (47 mg, 0.315 mmol) and (S)-2-(2,2,2-trifluoro-acetamido)propanoic acid (167 mg, 0.9 mmol) in acetone (4 mL) was added Et3N (0.21 mL, 1.5 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 4 / 1) to give 81 mg (55% yield) of the title compound (A-51) as a white foam.

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[0269] Example 52: (4-Methylpyridine-3-carboxyloyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-52) [ka] To a solution of compound 5 (100 mg, 0.3 mmol), NaI (90 mg, 0.6 mmol) and 4-methylpyridine-3-carboxylic acid (123 mg, 0.9 mmol) in acetone (4 mL) was added Et3N (0.21 mL, 1.5 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 3 / 2) to give 45 mg (35% yield) of the title compound (A-52) as a white solid.

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[0270] Example 53: (2-Methylpyridine-3-carboxyloyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-53) [ka] To a solution of compound 5 (100 mg, 0.3 mmol), NaI (90 mg, 0.6 mmol) and 2-methylpyridine-3-carboxylic acid (123 mg, 0.9 mmol) in acetone (4 mL) was added Et3N (0.21 mL, 1.5 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 3 / 2) to give 56 mg (43% yield) of the title compound (A-53) as a white foam.

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[0271] Example 54: (6-Methylpyridine-3-carboxyloyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-54) [ka] To a solution of compound 5 (100 mg, 0.3 mmol), NaI (90 mg, 0.6 mmol) and 6-methylpyridine-3-carboxylic acid (123 mg, 0.9 mmol) in acetone (4 mL) was added Et3N (0.21 mL, 1.5 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (1 / 0 to 3 / 2) to give 44 mg (34% yield) of the title compound (A-54) as a white foam.

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[0272] Example 55: 1-((S)-2-acetamido-4-methylpentanoyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-55) [ka] To a solution of compound 2 (103 mg, 0.3 mmol), NaI (47 mg, 0.315 mmol) and (S)-2-acetamido-4-methylpentanoic acid (156 mg, 0.9 mmol) in acetone (4 mL) was added Et3N (0.21 mL, 1.5 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 11 / 9) to give 102 mg (71% yield) of the title compound (A-55) as a white foam.

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[0273] Example 56: ((S)-2-acetamido-4-methylpentanoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-56) [ka] To a solution of compound 5 (100 mg, 0.3 mmol), NaI (90 mg, 0.6 mmol) and (S)-2-acetamido-4-methylpentanoic acid (156 mg, 0.9 mmol) in acetone (4 mL) was added K2CO3 (207 mg, 1.5 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 3 / 2) to give 120 mg (86% yield) of the title compound (A-56) as a white foam.

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[0274] Example 57: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl 2-(3-methyloxetan-3-yl)acetate (A-57) [ka] To a solution of compound 2 (100 mg, 0.29 mmol), NaI (87 mg, 0.58 mmol) and (2S,3R)-2-acetamido-3-methylpentanoic acid (151 mg, 0.87 mmol) in acetone (4 mL) was added EtN (0.163 mL, 1.17 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with H2O (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 2 / 3) to give 88 mg (63% yield) of the title compound (A-57) as a white solid.

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[0275] Example 58: ((2S,3R)-2-acetamido-3-methylpentanoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-58) [ka] To a solution of compound 5 (100 mg, 0.30 mmol), NaI (91 mg, 0.60 mmol) and (2S,3R)-2-acetamido-3-methylpentanoic acid (157 mg, 0.91 mmol) in acetone (4 mL) was added K2CO3 (209 mg, 1.51 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 3 / 2) to give 130 mg (92% yield) of the title compound (A-58) as a white solid.

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[0276] Example 59: (S)-(((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)methyl 2-aminonicotinate (A-59) [ka] To a solution of compound 5 (100 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol) and 2-aminopyridine-3-carboxylic acid (63 mg, 0.45 mmol) in acetone (2 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 2 / 3) to give 40 mg (60% yield) of the title compound (A-59) as a pale yellow foam.

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[0277] Example 60: 1-(2-acetamidoacetoyloxy)ethyl (R)-1-(2-chlorophenyl)-2-oxocyclohexyl-methylcarbamate (A-60) [ka] To a solution of R-ketamine 11 (1.0 g, 4.2 mmol) and DIPEA (1.36 g, 10.5 mmol) in DCM (42 mL) was added 1-chloroethyl carbonochloridate (1.50 g, 10.5 mmol) slowly at 0° C. The reaction was stirred at 25° C. for 1.5 h. The reaction was diluted with DCM (10 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil. The oil was diluted with ice-MeOH and filtered to give 1.14 g (80% yield) of compound 12 as a white solid.

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[0278] To a solution of compound 12 (52 mg, 0.15 mmol), NaI (24 mg, 0.16 mmol) and acetylglycine (53 mg, 0.45 mmol) in acetone (1 mL) was added Et3N (0.1 mL, 0.75 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (10 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (1 / 0 to 1 / 2) to give 39 mg (61% yield) of the title compound (A-60) as a white foam.

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[0279] Example 61: 1-(2-(3-methyloxetan-3-yl)acetoyloxy)ethyl (R)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-61) [ka] To a solution of compound 12 (121 mg, 0.35 mmol), NaI (105 mg, 0.7 mmol) and 2-(3-methyloxetan-3-yl)acetic acid (137 mg, 1.05 mmol) in acetone (5 mL) was added K2CO3 (242 mg, 1.75 mmol). The reaction was heated to 70 °C for 4 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with H2O (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 3 / 1) to give a yellow oil. Ether (3 mL) was added, filtered and the solid was washed with cold ether to give 15 mg (10% yield) of the title compound (A-61) as a white solid.

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[0280] Example 62: 1-((S)-2-acetamidopropanoyloxy)ethyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-62) [ka] To a solution of compound 12 (52 mg, 0.15 mmol), NaI (24 mg, 0.16 mmol) and (S)-2-acetamidopropanoic acid (59 mg, 0.45 mmol) in acetone (1 mL) was added Et3N (0.1 mL, 0.75 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 1 / 1) to give 47 mg (72% yield) of the title compound (A-62) as a white foam.

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[0281] Example 63: 1-((S)-2-acetamido-3-methylbutanoyloxy)ethyl (R)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-63) [ka] To a solution of compound 12 (52 mg, 0.15 mmol), NaI (24 mg, 0.16 mmol) and (S)-2-acetamido-3-methylbutanoic acid (72 mg, 0.45 mmol) in acetone (1 mL) was added Et3N (0.1 mL, 0.75 mmol). The reaction was heated to 70 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 1 / 1) to give 49 mg (70% yield) of the title compound (A-63) as a white foam.

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[0282] Example 64: (2-(3-methyloxetan-3-yl)acetoyloxy)methyl (R)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-64) [ka] To a solution of compound 13 (152 mg, 0.46 mmol), NaI (138 mg, 0.92 mmol) and 2-(3-methyloxetan-3-yl)acetic acid (120 mg, 0.92 mmol) in acetone (3 mL) was added K2CO3 (254 mg, 1.84 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 1 / 2) to give 74 mg (38% yield) of the title compound (A-64) as a colorless oil.

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[0283] Example 65: (Nicotinoyloxy)methyl (R)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-65) [ka] To a solution of 13 (495 mg, 1.5 mmol), NaI (450 mg, 3.0 mmol) and nicotinic acid (554 mg, 4.5 mmol) in acetone (18 mL) was added Et3N (1.05 mL, 7.5 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (3 / 2) to give 188 mg (30% yield) of the title compound (A-65) as a white solid.

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[0284] Example 66: (2-acetamidoacetoyloxy)methyl 1-(2-chlorophenyl)-2-oxocyclohexyl-methylcarbamate (A-66) [ka] To a solution of 13 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol) and 2-acetamidoacetic acid (53.2 mg, 0.45 mmol) in acetone (2 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 3 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 4 / 1) to give 17 mg (27% yield) of the title compound (A-66) as a white foam.

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[0285] Example 67: ((S)-2-acetamido-3-methylbutanoyloxy)methyl 1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-67) [ka] To a solution of compound 13 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol) and (S)-2-acetamido-3-methylbutanoic acid (72 mg, 0.45 mmol) in acetone (2 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 3 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 1 / 4) to give 56 mg (82% yield) of the title compound (A-67) as a white foam.

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[0286] Example 68: ((S)-2-acetamidopropanoyloxy)methyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-68) [ka] To a solution of 13 (50 mg, 0.15 mmol), NaI (46 mg, 0.30 mmol) and (S)-2-acetamidopropanoic acid (60 mg, 0.45 mmol) in acetone (2 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 13 / 7) to give 54 mg (84% yield) of the title compound (A-68) as a white foam.

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[0287] Example 69: ((S)-2-acetamido-4-methylpentanoyloxy)methyl (R)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamemate (A-69) [ka] To a solution of compound 13 (50 mg, 0.15 mmol), NaI (45 mg, 0.3 mmol) and (S)-2-acetamido-4-methylpentanoic acid (78 mg, 0.45 mmol) in acetone (2 mL) was added K2CO3 (104 mg, 0.75 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 3 / 2) to give 55 mg (79% yield) of the title compound (A-69) as a white foam.

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[0288] Example 70: ((2S,3R)-2-acetamido-3-methylpentanoyloxy)methyl 1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-70) [ka] To a solution of compound 13 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol) and (2S,3R)-2-acetamido-3-methylpentanoic acid (79 mg, 0.45 mmol) in acetone (2 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (100% hexane to 3 / 2) to give 60 mg (85% yield) of the title compound (A-70) as a white foam.

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[0289] Example 71: (R)-(((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)methyl 2-aminonicotinate (A-71) [ka] To a solution of compound 13 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol) and 2-aminopyridine-3-carboxylic acid (63 mg, 0.45 mmol) in acetone (2 mL) was added K2CO3 (105 mg, 0.76 mmol). The reaction was heated to 70 °C for 1 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexanes / EA (100% hexanes to 2 / 3) to give 42 mg (64% yield) of the title compound (A-71) as a pale yellow foam.

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[0290] Example 72: Ethyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)phenyl)propanoate (A-72) [ka] To a solution of diphosgene (237 mg, 1.2 mmol) in DCM (12 mL) was slowly added a solution of ethyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-tyrosinate (863 mg, 2 mmol) in DCM (12 mL) at 0° C., followed by a solution of DIPEA (1.05 mL, 6 mmol) in THF (24 mL) dropwise at 0° C. within 30 min. The reaction was stirred at 0° C. for 30 min, then a solution of compound 1 (274 mg, 1 mmol) and DIPEA (0.18 mL, 1 mmol) in DCM (15 mL) was added. The reaction was warmed to 25° C. and stirred for 16 h. The reaction was poured into H2O (50 mL) and extracted with DCM (50 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 4 / 1) to give 590 mg (85% yield) of compound 14 as a white foam.

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[0291] To a solution of compound 14 (150 mg, 0.22 mmol) in DCM (4.5 mL) was added piperidine (0.21 mL, 2.2 mmol). The reaction was stirred at 25 °C for 3 h. The reaction was washed with H2O (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with DCM / MeOH (100% DCM to 97 / 3) to give 75 mg (74% yield) of the title compound (A-72) as a yellow gum.

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[0292] Example 73: Ethyl (S)-2-(((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)acetate (A-73) [ka] To a solution of diphosgene (119 mg, 0.6 mmol) in DCM (6 mL), a solution of 2-hydroxyethyl acetate (104 mg, 1 mmol) in DCM (6 mL) was added slowly at 0° C., followed by dropwise addition of a solution of DIPEA (0.52 mg, 3 mmol) in THF (6 mL) at 0° C. within 30 min. The reaction was stirred at 0° C. for 1 h, then a solution of compound 1 (137 mg, 0.5 mmol) and DIPEA (0.087 mL, 0.5 mmol) in DCM (6 mL) was added. The reaction was warmed to 25° C. and stirred for 16 h. The reaction was poured into H2O (20 mL) and extracted with DCM (20 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 2 / 1) to afford 70 mg (38% yield) of the title compound (A-73) as a white solid.

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[0293] Example 74: (S)-2-(((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)acetic acid (A-74) [ka] To a solution of compound (A-73) (74 mg, 0.2 mmol) in THF (3 mL) was added aqueous LiOH (0.5 mL, 1 M) at 0° C. The reaction was stirred at 25° C. for 1.5 h and then concentrated. The mixture was diluted with HO (3 mL), adjusted to pH=3 with aqueous HCl (1 M), and then extracted with DCM (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give 50 mg (74% yield) of the title compound (A-74) as a white foam.

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[0294] Example 75: (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)-(methyl)carbamate (A-75) [ka] To a solution of diphosgene (119 mg, 0.6 mmol) in DCM (6 mL), a solution of 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (130 mg, 1 mmol) in DCM (6 mL) was slowly added at 0° C., followed by dropwise addition of a solution of DIPEA (0.52 mg, 3 mmol) in THF (6 mL) at 0° C. within 30 min. The reaction was stirred at 0° C. for 1 h, then a solution of compound 1 (137 mg, 0.5 mmol) and DIPEA (0.087 mL, 0.5 mmol) in DCM (6 mL) was added. The reaction was warmed to 25° C. and stirred for 16 h. The reaction was poured into H2O (20 mL) and extracted with DCM (20 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 3 / 1) to give 45 mg (23% yield) of the title compound (A-75) as a colorless oil.

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[0295] Example 76: Ethyl (S)-2-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)-propanoate (A-76) [ka] To a solution of diphosgene (89 mg, 0.45 mmol) in DCM (4.5 mL) was slowly added a solution of (S)-ethyl 2-hydroxypropanoate (89 mg, 0.75 mmol) in DCM (4.5 mL) at 0° C., followed by dropwise addition of a solution of DIPEA (0.4 mL, 2.25 mmol) in THF (9 mL) at 0° C. within 30 min. The reaction was stirred at 0° C. for 2 h, then a solution of compound 1 (68 mg, 0.25 mmol) and DIPEA (0.044 mL, 0.25 mmol) in DCM (3.75 mL) was added. The reaction was warmed to 25° C. and stirred for 24 h. The reaction was poured into H2O (10 mL) and extracted with DCM (10 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 4 / 1) to afford 18 mg (18% yield) of the title compound (A-76) as a pale yellow oil.

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[0296] Example 77: (3-Methyloxetan-3-yl)methyl (S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)-carbamate (A-77) [ka] To a solution of diphosgene (59 mg, 0.3 mmol) in DCM (3 mL) was slowly added a solution of (3-methyloxetan-3-yl)methanol (51 mg, 0.5 mmol) in DCM (3 mL) at 0° C., followed by a solution of DIPEA (0.26 mL, 1.5 mmol) in THF (6 mL) dropwise at 0° C. within 30 min. The reaction was stirred at 0° C. for 2 h, then a solution of compound 1 (46 mg, 0.17 mmol) and DIPEA (0.029 mL, 0.17 mmol) in DCM (3 mL) was added. The reaction was warmed to 25° C. and stirred for 24 h. The reaction was poured into H2O (20 mL) and extracted with DCM (20 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 3 / 1) to afford 46 mg (76% yield) of the title compound (A-77) as a pale yellow oil.

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[0297] Example 78: 2-(((3-methyloxetan-3-yl)methyl)thio)ethyl (S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamate (A-78) [ka] To a solution of diphosgene (356 mg, 1.8 mmol) in DCM (18 mL), a solution of 2-((3-methyloxetan-3-yl)methylthio)ethanol (486 mg, 3 mmol) in DCM (18 mL) was slowly added at 0° C., followed by dropwise addition of a solution of DIPEA (1.57 mL, 9 mmol) in THF (36 mL) at 0° C. within 30 min. The reaction was stirred at 0° C. for 2 h, then a solution of compound 1 (273 mg, 1.0 mmol) and DIPEA (0.175 mL, 1.0 mmol) in DCM (15 mL) was added. The reaction was warmed to 25° C. and stirred for 24 h. The reaction was poured into H2O (20 mL) and extracted with DCM (20 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 3 / 1) to afford 238 mg (56% yield) of the title compound (A-78) as a yellow oil.

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[0298] Example 79: 2-(((3-methyloxetan-3-yl)methyl)sulfonyl)ethyl (S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamate (A-79) [ka] To a solution of compound (A-78) (33 mg, 0.08 mmol) in MeOH (0.3 mL) was added a solution of oxone (96 mg, 0.16 mmol) in HO (0.3 mL) dropwise at 0 °C. The reaction was stirred at 25 °C for 16 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with HO (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (1 / 2) to give 17 mg (47% yield) of the title compound (A-79) as a white foam.

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[0299] Example 80: 2-(((3-methyloxetan-3-yl)methyl)sulfinyl)ethyl ((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamate (A-80) [ka] To a solution of compound (A-78) (85 mg, 0.2 mmol) in MeOH (0.8 mL) was added a solution of NaIO4 (43 mg, 0.2 mmol) in HO (0.4 mL) dropwise at 0 °C. The reaction was stirred at 25 °C for 3 h. The reaction was concentrated, redissolved in DCM (5 mL) and washed with HO (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with DCM / MeOH (100% DCM to 97 / 3) to give 79 mg (89% yield) of compound (A-80) as a white foam.

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[0300] Example 81: (S)-2-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)propanoic acid (A-81) [ka] To a solution of compound (A-76) (46 mg, 0.12 mmol) in THF (1.8 mL) was added aqueous LiOH (0.3 mL, 1 M) at 0° C. The reaction was stirred at 25° C. for 4 h and then concentrated. The mixture was diluted with H2O (3 mL), adjusted to pH=3 with aqueous HCl (1 M), and extracted with DCM (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give 16 mg (37% yield) of the title compound (A-81) as a white solid.

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[0301] Example 82: 3-Hydroxy-2-(hydroxymethyl)-2-methylpropyl (S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamate (A-82) [ka] To a solution of diphosgene (267 mg, 1.35 mmol) in DCM (13.5 mL) was slowly added a solution of (2,2,5-trimethyl-1,3-dioxan-5-yl)methanol (361 mg, 2.25 mmol) in DCM (13.5 mL) at 0° C., followed by dropwise addition of a solution of DIPEA (1.18 mL, 6.75 mmol) in THF (27 mL) at 0° C. within 30 min. The reaction was stirred at 0° C. for 2 h, then a solution of compound 1 (206 mg, 0.75 mmol) and DIPEA (0.131 mL, 0.75 mmol) in DCM (11 mL) was added. The reaction was warmed to 25° C. and stirred for 16 h. The reaction was poured into H2O (20 mL) and extracted with DCM (20 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil, which was purified on a silica gel column eluted with hexane / EA (9 / 1) to give 141 mg (44% yield) of compound 15 as a white foam.

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[0302] To a solution of compound 15 (140 mg, 0.33 mmol) in MeOH (28 mL) was added HCl solution (0.42 mL, 0.2 M in EA). The reaction was stirred at 25° C. for 2 h. The reaction was concentrated and then purified on a silica gel column eluted with hexane / EA (1 / 1) to give 116 mg (92% yield) of the title compound (A-82) as a white foam.

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[0303] Example 83: ((2R,3S,4S,5R,6R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamate (A-83) [ka] To a solution of diphosgene (267 mg, 1.35 mmol) in DCM (13.5 mL) was slowly added a solution of 1,2,3,4-tetra-O-acetyl-β-D-glucopyranose (361 mg, 2.25 mmol) in DCM (13.5 mL) at 0° C., followed by dropwise addition of a solution of DIPEA (1.18 mL, 6.75 mmol) in THF (27 mL) at 0° C. within 30 min. The reaction was stirred at 0° C. for 2 h, then a solution of compound 1 (206 mg, 0.75 mmol) and DIPEA (0.131 mL, 0.75 mmol) in DCM (11 mL) was added. The reaction was warmed to 25° C. and stirred for 16 h. The reaction was poured into HO (20 mL) and extracted with DCM (20 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give a crude oil 16 which was used immediately in the next reaction.

[0304] To a solution of compound 16 in MeOH (40 mL) was added 3% NaOMe (in MeOH, 0.9 mL) at 25° C. The reaction was stirred at 25° C. for 2 h, then adjusted to pH=3 with Dowex® 50WX4 hydrogen form, filtered and concentrated to give an oil, which was purified on a silica gel column eluted with DCM / MeOH (100% DCM to 9 / 1) to give 40 mg (12% yield) of the title compound (A-83) as a white solid.

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[0305] Example 84: 3-Hydroxy-2-(hydroxymethyl)propyl (S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamate (A-84) [ka] To a solution of compound 17 (1.0 g, 4.8 mmol) in acetone (25.5 mL) was added CHI (1.01 g, 71.1 mmol) and AgO (1.16 g, 5.0 mmol). The suspension was stirred at 25 °C for 16 h. The mixture was filtered through Celite and concentrated to give an oil, which was purified on a silica gel column eluted with hexane / EA (100% hexane to 95 / 5) to give 965 mg (90% yield) of compound 18 as a white solid.

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[0306] To a solution of CaCl2 (4.3 g, 39.2 mmol) in THF (110 mL) was added NaBH4 (3.0 g, 78.3 mmol). The reaction was stirred at 25 °C for 4 h, then compound 18 (965 mg, 4.35 mmol) was added. The reaction was warmed to reflux and stirred for 16 h. The reaction was poured into ice water and extracted with DCM. The organic layer was dried over MgSO4, filtered, and evaporated to give 836 mg (99% yield) of compound 19 as a white solid.

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[0307] To a solution of diphosgene (267 mg, 1.35 mmol) in DCM (13.5 mL) was slowly added a solution of 19 (437 mg, 2.25 mmol) in DCM (13.5 mL) at 0° C., followed by dropwise addition of a solution of DIPEA (1.18 mL, 6.75 mmol) in THF (27 mL) at 0° C. within 30 min. The reaction was stirred at 0° C. for 2 h, then a solution of compound 1 (206 mg, 0.75 mmol) and DIPEA (0.131 mL, 0.75 mmol) in DCM (11 mL) was added. The reaction was warmed to 25° C. and stirred for 16 h. The reaction was poured into H2O (20 mL) and extracted with DCM (20 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil, which was purified on a silica gel column eluted with DCM / EA (100% DCM to 10 / 1) to give 243 mg (71% yield) of compound 20 as a white foam.

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[0308] To a solution of compound 20 (100 mg, 0.22 mmol) in EA (10 mL) was added Pd(OH)2 / C (15 mg). The reaction was stirred under H2 atmosphere at 25 °C for 30 min. The reaction was filtered through a pad of Celite and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to EA) to give 70 mg (86% yield) of the title compound (A-84) as a yellow oil.

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[0309] Example 85: 3-(Methylamino)propyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-85) [ka] To a solution of diphosgene (89 mg, 0.45 mmol) in DCM (4.5 mL) was slowly added a solution of (9H-fluoren-9-yl)methyl 3-hydroxypropylmethylcarbamate (234 mg, 0.75 mmol) in DCM (4.5 mL) at 0° C., followed by a solution of DIPEA (0.392 mL, 2.25 mmol) in THF (9.0 mL) dropwise at 0° C. within 30 min. The reaction was stirred at 0° C. for 1 h, then a solution of compound 1 (134 mg, 0.49 mmol) and DIPEA (0.044 mL, 0.25 mmol) in DCM (4.0 mL) was added. The reaction was warmed to 25° C. and stirred for 16 h. The reaction was poured into H2O (20 mL) and extracted with DCM (20 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (8 / 2) to give 80 mg (28% yield) of compound 21 as a white solid.

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[0310] To a solution of compound 21 (80 mg, 0.139 mmol) in DCM (5 mL) was added piperidine (1 mL). The reaction was stirred at 25° C. for 1.5 h. The reaction was poured into aqueous HCl (20 mL, 1 M) and extracted with DCM (20 mL×2). The organic layer was extracted with saturated aqueous NaHCO3 (20 mL), then the organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 2 / 5) to give 28 mg (57% yield) of the title compound (A-85) as a pale yellow solid.

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[0311] Example 86: 3-Aminopropyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-86) [ka] To a solution of diphosgene (166 mg, 0.84 mmol) in DCM (9.0 mL) was slowly added a solution of (9H-fluoren-9-yl)methyl 3-hydroxypropylcarbamate (414 mg, 1.39 mmol) in DCM (9 mL) at 0° C., followed by a solution of DIPEA (0.728 mL, 4.17 mmol) in THF (18 mL) dropwise within 30 min at 0° C. The reaction was stirred at 0° C. for 1 h, then a solution of compound 1 (127 mg, 0.46 mmol) and DIPEA (0.081 mL, 0.46 mmol) in DCM (7.5 mL) was added. The reaction was warmed to 25° C. and stirred for 16 h. The reaction was poured into H2O (20 mL) and extracted with DCM (20 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (8 / 2) to give 74 mg (29% yield) of compound 22 as a white solid.

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[0312] To a solution of compound 22 (74 mg, 0.13 mmol) in DCM (3.0 mL) was added piperidine (1 mL). The reaction was stirred at 25° C. for 1.5 h. The reaction was poured into aqueous HCl (20 mL, 1 M) and extracted with DCM (20 mL×2). The organic layer was extracted with saturated aqueous NaHCO3 (20 mL), then the organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 2 / 5) to give 30 mg (67% yield) of the title compound (A-86) as a sticky solid.

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[0313] Example 87: 3-(Methylamino)propyl (S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-87) [ka] To a solution of compound (A-85) (17 mg, 0.048 mmol) in MeOH (2.0 mL) was added acetic acid (0.011 mL, 0.193 mmol) and NaBH3CN (6.0 mg, 0.096 mmol) at 0 °C. The reaction was stirred at 0 °C for 5 min, then formaldehyde (0.004 mL, 0.118 mmol) was added. The reaction was warmed to 25 °C and stirred for 2 h. The reaction was poured into saturated aqueous NaHCO3 (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to give 14 mg (79% yield) of the title compound (A-87) as a white solid.

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[0314] Example 88: (S)-1-(((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate (A-88) [ka] To a solution of compound 1 (150 mg, 0.55 mmol) and DIPEA (0.36 mL, 2.2 mmol) in DCM (3.0 mL) was added (S)-1-(chlorocarbonyl)ethyl acetate (0.17 mL, 1.4 mmol) dropwise at 0 °C. The mixture was warmed to 25 °C and stirred for 3 h. The reaction was poured into saturated aqueous NaHCO3 (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (85 / 15) to give 138 mg (72% yield) of the title compound (A-88) as a pale yellow foam.

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[0315] Example 89: (S)-2-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-2-oxoethyl acetate (A-89) [ka] To a solution of compound 1 (150 mg, 0.55 mmol) and DIPEA (0.27 mL, 1.6 mmol) in DCM (3.0 mL) was added methyl (chlorocarbonyl)acetate (0.09 mL, 0.8 mmol) dropwise at 0 °C. The reaction was warmed to 25 °C and stirred for 3 h. The reaction was poured into saturated aqueous NaHCO3 (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (85 / 15) to give 94 mg (51% yield) of the title compound (A-89) as a white solid.

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[0316] Example 90: (S)-N-(1-(2-chlorophenyl)-2-oxocyclohexyl)-N-methylnicotinamide (A-90) [ka] To a solution of compound 1 (237 mg, 1 mmol) and Et3N (0.63 mL, 4.5 mmol) in DCM (6 mL) was added nicotinoyl chloride hydrochloride (534 mg, 3 mmol) at 0° C. The reaction was warmed to 25° C. and stirred for 3 h. The reaction was poured into saturated aqueous NaHCO3 (20 mL) and extracted with DCM (20 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 3 / 2) to give 274 mg (80% yield) of the title compound (A-90) as a pale yellow solid.

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[0317] Example 91: (S)-3-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)-1-methylpyridin-1-ium iodide (A-91) [ka] To a solution of compound (A-90) (103 mg, 0.3 mmol) in CH3CN (3 mL) was added CH3I (0.09 mL, 1.5 mmol). The reaction was heated to 80° C. for 16 h and the solvent was removed under vacuum. Ether (3 mL) was added, filtered, and the solid was washed with cold ether to give 111 mg (76% yield) of the title compound (A-91) as a white solid.

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[0318] Example 92: Methyl (S)-4-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-4-oxobutanoate (A-92) [ka] To a solution of compound 1 (150 mg, 0.55 mmol), DIPEA (0.29 mL, 1.65 mmol) in DCM (3.0 mL) was added methyl 3-(chlorocarbonyl)propanoate (0.1 mL, 0.825 mmol) dropwise at 0 °C. The reaction was warmed to 25 °C and stirred for 2 h. The reaction was poured into saturated aqueous NaHCO3 (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (3 / 1) to give 150 mg (78% yield) of the title compound (A-92) as a white solid.

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[0319] Example 93: (S)-4-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-4-oxobutanoic acid (A-93) [ka] To a solution of compound (A-92) (100 mg, 0.285 mmol) in THF (4.3 mL) was added aqueous LiOH (0.7 mL, 1 M) at 0° C. The reaction was stirred at 25° C. for 2 h and then concentrated. The mixture was diluted with H2O (3 mL), adjusted to pH=3 with aqueous HCl (1 M), and then extracted with DCM (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give 83 mg (83% yield) of the title compound (A-93) as a white solid.

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[0320] Example 94: (S)-2-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-2-oxoethan-1-aminium chloride (A-94) [ka] To a solution of compound 1 (68 mg, 0.25 mmol), (tert-butoxycarbonyl)glycine (111 mg, 0.375 mmol) and HATU (114 mg, 0.3 mmol) in DCM (2 mL) was added DIPEA (0.13 mL, 0.75 mmol). The reaction mixture was microwaved at 70° C. for 20 min. The reaction was diluted with DCM (5 mL) and washed with H2O (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (1 / 0 to 3 / 2) to give a white foam. The white foam was dissolved in EA (1.5 mL) and HCl (0.15 mL, 2N in EA) was added. The reaction was stirred at 25° C. for 16 h, filtered, and the solid was washed with cold EA to give 35 mg (38% yield) of the title compound (A-94) as a white solid.

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[0321] Example 95: (S)-2-acetamido-N-(1-(2-chlorophenyl)-2-oxocyclohexyl)-N-methylacetamide (A-95) [ka] To a solution of compound (A-94) (35 mg, 0.12 mmol) and EtN (0.033 mL, 0.24 mmol) in DCM (2 mL) was added acetyl chloride (0.013 mL, 0.18 mmol). The reaction was stirred at 25 °C for 16 h. The reaction was diluted with DCM (3 mL) and washed with H2O (3 mL) and brine (3 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (100% hexane to 2 / 1) to give 20 mg (50% yield) of the title compound (A-95) as a white solid.

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[0322] Example 96: Isopropyl (S)-4-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-4-oxobutanoate (A-96) [ka] To a solution of compound 1 (136 mg, 0.5 mmol), 3-(isopropoxycarbonyl)propanoic acid (121 mg, 0.75 mmol) and HATU (228, 0.6 mmol) in DCM (4 mL) was added DIPEA (0.26 mL, 1.5 mmol). The reaction mixture was microwaved at 70 °C for 30 min. The reaction was diluted with DCM (10 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with DCM / EA (100% DCM to 9 / 1) to give 77 mg (40% yield) of the title compound (A-96) as a colorless oil.

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[0323] Example 97: Ethyl (S)-4-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-4-oxobutanoate (A-97) [ka] To a solution of compound 1 (68 mg, 0.25 mmol), 3-(isopropoxycarbonyl)propanoic acid (55.1 mg, 0.375 mmol) and HATU (114 mg, 0.3 mmol) in DCM (2 mL) was added DIPEA (0.13 mL, 0.75 mmol). The reaction mixture was microwaved at 70 °C for 30 min. The reaction was diluted with DCM (10 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with DCM / EA (100% DCM to 9 / 1) to give 47 mg (51% yield) of the title compound (A-97) as a pale yellow foam.

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[0324] Example 98: (S)-4-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-4-oxobutan-1-aminium chloride (A-98) [ka] To a solution of compound 1 (137 mg, 0.5 mmol), (4-((tert-butoxycarbonyl)amino)butanoic acid (152 mg, 0.75 mmol) and HATU (228 mg, 0.6 mmol) in DCM (4 mL) was added DIPEA (0.26 mL, 1.5 mmol). The reaction mixture was microwaved at 70 °C for 20 min. The reaction was diluted with DCM (10 mL) and washed with HO (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (1 / 0 to 2 / 1) to give a white foam. The white foam was dissolved in ether (1.5 mL) and HCl (1.5 mL, 2N in ether) was added. The reaction was stirred at 25 °C for 16 h, filtered and the solid was washed with cold ether to give 69 mg (39% yield) of the title compound (A-98) as a white solid.

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[0325] Example 99: (S)-N-(1-(2-chlorophenyl)-2-oxocyclohexyl)-4-(dimethylamino)-N-methylbutanamide (A-99) [ka] To a solution of compound 1 (68 mg, 0.25 mmol), 4-(dimethylamino)butanoic acid hydrochloride (84 mg, 0.5 mmol) and HATU (190 mg, 0.5 mmol) in DCM (2 mL) was added DIPEA (0.22 mL, 1.25 mmol). The reaction mixture was microwaved at 70 °C for 30 min. The reaction was diluted with DCM (5 mL) and washed with H2O (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with DCM / EA (1 / 1) to give 13 mg (15% yield) of the title compound (A-99) as a white solid.

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[0326] Example 100: (S)-2-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)benzyl isobutyrate (A-100) [ka] To a solution of compound 22 (304 mg, 2.0 mmol) in 1,4-dioxane (5 mL) was added isobutyric anhydride (0.497 mL, 3.0 mmol) and 1-methylimidazole (0.24 mL, 3.0 mmol). The reaction was stirred at 25° C. for 1 h and the solvent was removed under vacuum. The residue was diluted with DCM (10 mL) and washed with H2O (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (8 / 2) to give 340 mg (77% yield) of compound 23 as a white solid.

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[0327] To a solution of compound 23 (83 mg, 0.374 mmol) in DCM (2 mL) was added oxalyl chloride (0.043 mL, 0.498 mmol). The reaction was stirred at 25° C. for 4 h and the solvent was removed under vacuum. The residue was dissolved in DCM (2 mL) and a solution of compound 1 (68 mg, 0.25 mmol) and DIPEA (0.065 mL, 0.375 mmol) in DCM (1 mL) was added. The reaction was stirred at 25° C. for 16 h. The reaction was diluted with DCM (10 mL) and washed with H2O (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluting with hexane / EA (85 / 15) to give 30 mg (27% yield) of the title compound (A-100) as a white solid.

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[0328] Example 101: (S)-N-(1-(2-chlorophenyl)-2-oxocyclohexyl)-N-methyl-4-(methylamino)butanamide (A-101) [ka] To a solution of compound 1 (68 mg, 0.25 mmol), 4-((tert-butoxycarbonyl)(methyl)amino)butanoic acid (81.4 mg, 0.375 mmol) and HATU (114 mg, 0.3 mmol) in DCM (2 mL) was added DIPEA (0.13 mL, 0.75 mmol). The reaction mixture was irradiated in a microwave at 70 °C for 1 h. The reaction was diluted with DCM (10 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (7 / 3) to give 45 mg (41% yield) of compound 24 as a white solid.

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[0329] To a solution of compound 24 (45 mg, 0.1 mmol) in EA (3 mL) was added HCl (3 mL, 1 M solution in EA). The reaction was stirred at 25° C. for 16 h and filtered to give a solid. The solid was poured into saturated aqueous NaHCO3 (20 mL) and extracted with DCM (20 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with DCM / EA (1 / 1) to give 14 mg (42% yield) of the title compound (A-101) as a white solid.

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[0330] Example 102: (S)-2-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)benzyl acetate (A-102) [ka] To a solution of compound 22 (304 mg, 2.0 mmol) in 1,4-dioxane (5 mL) was added acetic anhydride (0.28 mL, 3.0 mmol) and 1-methylimidazole (0.240 mL, 3.0 mmol). The reaction was stirred at 25° C. for 1 h and the solvent was removed under vacuum. The reaction was diluted with DCM (10 mL) and washed with H2O (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (8 / 2) to give 100 mg (26% yield) of compound 25 as a white solid.

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[0331] To a solution of compound 25 (73 mg, 0.375 mmol) in DCM (2 mL) was added oxalyl chloride (0.064 mL, 0.75 mmol). The reaction was stirred at 25° C. for 4 h and the solvent was removed under vacuum. The residue was dissolved in DCM (2 mL) and a solution of compound 1 (68 mg, 0.25 mmol) and DIPEA (0.065 mL, 0.375 mmol) in DCM (1 mL) was added. The reaction was stirred at 25° C. for 16 h. The reaction was diluted with DCM (10 mL) and washed with H2O (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (7 / 3) to give 22 mg (21% yield) of the title compound (A-102) as a sticky oil.

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[0332] Example 103: (S,E)-2-(3-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-3-oxoprop-1-en-1-yl)phenyl isobutyrate (A-103) [ka] To a solution of compound 1 (170 mg, 0.62 mmol), (E)-3-(2-(isobutyryloxy)phenyl)acrylic acid (219 mg, 0.9 mmol) and HATU (285 mg, 0.75 mmol) in DCM (5 mL) was added DIPEA (0.33 mL, 1.9 mmol). The reaction was heated to 40° C. for 3 h. The reaction was diluted with DCM (5 mL) and washed with H2O (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (3 / 1) to give 28 mg (10% yield) of the title compound (A-103) as a white solid.

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[0333] Example 104: (S,E)-2-(3-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-3-oxoprop-1-en-1-yl)phenyl acetate (A-104) [ka] To a solution of compound 26 (51.5 mg, 0.25 mmol) in DCM (2 mL) was added oxalyl chloride (0.043 mL, 0.5 mmol). The reaction was stirred at 25° C. for 4 h and the solvent was removed under vacuum. The residue was dissolved in DCM (2 mL) and a solution of compound 1 (68 mg, 0.25 mmol) and DIPEA (0.065 mL, 0.375 mmol) in DCM (1 mL) was added. The reaction was stirred at 25° C. for 16 h. The reaction was diluted with DCM (10 mL) and washed with H2O (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (7 / 3) to give 38 mg (36% yield) of the title compound (A-104) as a white solid.

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[0334] Example 105: (E)-N-((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)-3-(2-hydroxyphenyl)-N-methylacrylamide (A-105) [ka] To a solution of compound (A-104) (20 mg, 0.047 mmol) in THF (1 mL) was added aqueous LiOH (0.8 mL, 1 M) at 0° C. The reaction was stirred at 25° C. for 2 h and then concentrated. The mixture was diluted with H2O (3 mL), adjusted to pH=3 with aqueous HCl (1 M), and then extracted with DCM (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give an oil that was recrystallized from DCM and hexane to give 12 mg (66% yield) of the title compound (A-105) as a white solid.

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[0335] Example 106: (S,Z)-4-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-4-oxobut-2-enoic acid (A-106) [ka] To a solution of compound 1 (137 mg, 0.5 mmol) and furan-2,5-dione (392 mg, 4 mmol) in DCM (5 mL) was added Et3N (0.21 mL, 1.5 mmol) at 0° C. The reaction was stirred at 25° C. for 22 h. The mixture was diluted with DCM (5 mL) and washed with aqueous NaOH (20 mL, 1 M). The aqueous layer was adjusted to pH=3 with aqueous HCl (1 M) and then extracted with DCM (20 mL). The organic layer was dried over MgSO4, filtered and concentrated to give 76 mg (45% yield) of the title compound (A-106) as a pale yellow solid.

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[0336] Example 107: (S,Z)-4-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)-4-oxobut-2-enoic acid (A-107) [ka] To a solution of (E)-4-ethoxy-4-oxobut-2-enoic acid (216 mg, 1.5 mmol) in DCM (5 mL) was added oxalyl chloride (0.26 mL, 3 mmol) and a few drops of DMF. The mixture was stirred at 25° C. for 1 h and then dried under vacuum. The residue was dissolved in DCM (3 mL) and a solution of compound 1 (137 mg, 0.5 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DCM (3 mL) was added at 0° C. The reaction was stirred at 25° C. for 2 h. The mixture was diluted with DCM (5 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (4 / 1) to give 76 mg (40% yield) of the title compound (A-107) as a pale yellow foam.

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[0337] Example 108: (((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)-L-alanyl-L-proline (A-108) [ka] To a solution of compound 27 (1.3 g, 9.08 mmol) in DCM (25 mL) was added dropwise a solution of (tert-butoxycarbonyl)-L-alanine (2.06 g, 10.9 mmol), HOBT (2.21 g, 16.3 mmol), EDCI (3.13 g, 16.3 mmol) and DIPEA (5.69 mL, 32.7 mmol) in DCM (25 mL). The reaction was stirred at 25 °C for 4 h. The reaction was diluted with DCM (100 mL) and washed with H2O (25 mL). The organic layer was separated and washed with aqueous HCl (1 M), followed by saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (7 / 3) to give 1.71 g (60% yield) of compound 28 as a sticky oil.

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[0338] To a solution of compound 28 (527 mg, 1.67 mmol) in DCM (10 mL) was added TFA (5.0 mL). The reaction was stirred at 25 °C for 16 h and then concentrated. The reaction was diluted with DCM (10 mL) and washed with H2O (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give a sticky oil (360 mg), which was dissolved in DCM (8 mL) and saturated aqueous NaHCO3 (12 mL) was added. Diphosgene (166 mg, 0.84 mmol) was added slowly to the solution at 0 °C. The mixture was stirred at 25 °C for 5 h. The reaction was diluted with DCM (10 mL) and washed with H2O (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give compound 29 (373 mg) as a sticky oil.

[0339] To a solution of compound 29 (373 mg, 1.55 mmol) in DCM (10 mL) was added compound 1 (118 mg, 0.43 mmol) and Et3N (0.301 mL, 2.16 mmol). The reaction was heated to 70° C. overnight. The reaction was diluted with DCM (10 mL) and washed with H2O (5 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (6 / 4) to give 192 mg (94% yield) of compound 30 as a white solid.

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[0340] To a solution of compound 30 (187 mg, 0.39 mmol) in THF (4 mL) was added aqueous LiOH (2 mL, 1 M). The reaction was stirred at 25° C. for 1 h and then concentrated. The reaction was diluted with DCM (10 mL) and washed with pH 3 HCl solution (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to give an oil which was purified on a silica gel column eluted with hexane / EA (1 / 1) to give 110 mg (63% yield) of the title compound (A-108) as a white solid.

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[0341] Example 109: Metabolic Stability Assay for Test Compounds Metabolic stability assay of mouse, rat, dog, monkey and human liver S9 fraction Using mouse, rat, dog, monkey, or human liver S9 fraction metabolic stability assay protocols, the half-lives (T 1 / 2 ), and the release efficiency of their prodrugs converted to S-ketamine are measured in vitro.

[0342] The following is a study outline of the S9 assay. 1) For the S-ketamine release efficiency assay, pooled liver S9 fractions (mouse, rat, dog, monkey, or human) were obtained from commercial vendors (e.g., CD-1 male mouse liver S9, SD female rat liver S9, male beagle dog liver S9, and pooled male and female human liver S9 were purchased from Corning (Woburn, MA, USA), and male cynomolgus monkey liver S9 was purchased from Gibco (Thermo Fisher Scientific Inc. USA)) and stored at -80°C before use. 2) Potassium phosphate buffer (100 mM, pH 7.4) containing 3 mM MgCl2 was preincubated with the test substance (3 μM, final acetonitrile concentration 0.1%) in a 37°C incubator for 10 min in triplicate. 3) The reaction was initiated by adding pre-warmed S9 fractions (1.0 mg / mL) in the presence of 2 mM NADPH. The volume of the final incubation mixture was 200 μL. 4) All reactions were terminated at predefined time points (0-60 min) using 5 volumes of extraction solvent. 5) Aliquots of the mixtures after incubation were centrifuged at 20,000 x g for 5 min. 6) The supernatants were analyzed by LC-MS / MS to determine the amount of test article remaining and S-ketamine formation. The data are shown in Table 1 below. [Table 1-1] [Table 1-2]

[0343] In vitro S-ketamine release efficiency assays using mouse, rat, dog, monkey, and human liver S9 fractions indicated that the prodrug compounds could be converted to S-ketamine with varying release efficiencies, suggesting that they were converted to S-ketamine in the systemic circulation after administration to mice, rats, dogs, monkeys, and humans.

[0344] Mouse, rat, dog, monkey, and human whole blood metabolic stability assays Mouse, rat, dog, monkey and human whole blood metabolic stability assay protocols are used to determine the release efficiency of the conversion of the prodrug of the compounds of the present disclosure to S-ketamine in vitro.

[0345] The following is a study outline of the whole blood assay. 1) For the S-ketamine release efficiency assay, male and female rat whole blood was obtained from commercial vendors (e.g., CD-1 mouse heparinized whole blood pool (N>5) and SD rat whole blood pool (N>5) were purchased from BioLASCO (Yi-Lan, Taiwan), beagle dog heparinized whole blood pool (N=3) was purchased from Center of Toxicology and Preclinical Sciences (CTPS, QPS Taiwan), cynomolgus monkey heparinized whole blood pool (N=3) was purchased from Laboratory Animal Center (LAC) of National Defense Medical College (NDMC), and fresh human heparinized whole blood was obtained from healthy donors (N>6)) and stored at 4°C before use. 2) Test substances were incubated in 37°C pre-warmed rat whole blood at 3μM (final acetonitrile concentration 1%) for up to 60 minutes at 37°C. 3) 100 μL aliquots of the spiked sample solution were removed at predefined time points (0-60 min) after incubation and immediately extracted by addition of 5 volumes of extraction solvent, followed by centrifugation at 20,000xg for 5 min. 4) The supernatant fraction was analyzed by LC-MS / MS to determine the amount of test substance remaining and ketamine formation. The results were then used to calculate the conversion efficiency of the test compound to S-ketamine in whole blood. The data are shown in Table 2 below. [Table 2-1] [Table 2-2] [Table 2-3]

[0346] In vitro S-ketamine release efficiency assays using whole blood from mice, rats, dogs, monkeys, and humans demonstrated that the prodrug compounds could be converted to S-ketamine with varying release efficiencies, suggesting that they were converted to S-ketamine in the systemic circulation after administration to mice, rats, dogs, monkeys, and humans.

[0347] Example 110: Pharmacokinetic studies The mouse / rat pharmacokinetic profile of the test article was evaluated after administration of S-ketamine or oral (S-ketamine or prodrug) to CD-1 mice and SD rats. Blood samples were collected from the facial vein using heparinized tubes at pre-dose and 3 min, 10 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, and 8 h after intravenous administration (IV) and at pre-dose and 10 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, and 8 h after oral administration (PO). For mouse PK studies, mice were subgrouped for a sparse sampling strategy. Each mouse provided two blood samples at different collection times. Blood samples were collected alternately from groups of three mice at each time point. To prevent compound degradation, blood samples once collected were immediately mixed with acetonitrile (containing 0.1% formic acid) in a 1:3 (v / v) ratio. Deproteinized samples were temporarily kept on ice and then stored at -70°C prior to bioanalysis. Blood analyte concentrations were measured by LC-MS / MS. Various pharmacokinetic parameters were calculated using Phoenix™ WinNonlin® software. To quantify the bioconversion efficiency of the test compound in the circulation, the relative bioavailability of S-ketamine after oral administration was calculated. The relative bioavailability value was expressed as the ratio of the AUC of S-ketamine converted from the test compound to the AUC of S-ketamine HCl salt administered intravenously at a dose adjusted alone. The data are shown in Tables 3 and 4 below.

[0348] [Table 3]

[0349] [Table 4-1] [Table 4-2]

[0350] For the dog pharmacokinetic study, male beagle dogs were housed individually. Dogs in the oral dosing group were fasted overnight prior to use, but had free access to water. Dogs in the IV group had free access to food and water. For S-ketamine HCl, a single dose of 3.75 μmol / kg was administered to each dog via intravenous (IV) administration. The vehicle used for S-ketamine HCl was saline. For the other test compounds, a single dose of each test compound was administered to each dog via oral gavage (n=3 / group). The dose of each test compound is listed in Table 5. After administration to individual dogs in the IV and PO groups, blood samples were collected at the indicated time points (pre-dose, 10 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h after dosing). To prevent compound degradation, blood samples were immediately mixed with acetonitrile (containing 0.1% formic acid) in a ratio of 1:3 (v / v) once collected. Deproteinized samples were kept temporarily on ice and then stored at -70°C prior to bioanalysis. Analyte concentrations in blood were measured by LC-MS / MS. Various pharmacokinetic parameters were calculated using Phoenix™ WinNonlin® software. To quantify the biotransformation efficiency of the test compounds in the circulation, the bioavailability of S-ketamine after PO administration was calculated. The data are shown in Table 5 below.

[0351] [Table 5]

[0352] For the monkey pharmacokinetic study, three cynomolgus monkeys (two males, one female, cynomolgus monkey) from the colony of the Laboratory Animal Center (LAC) of the National Defense Medical College (NDMC) were investigated. The subjects' average age was 6 years and their average body weight was 6.6 kg (range 6-7 kg). At least 7 days of washout were performed between each treatment. On the day of the in vivo experiment, the monkeys were sedated with an intramuscular injection of Alfaxan (5 mg / kg) and dexmedetomidine (10 mcg / kg). For intravenous administration, S-ketamine HCl solution was administered slowly as a bolus injection via the cephalic vein at a dose of 3.2 μmol / kg. For oral administration, the doses of each test compound are listed in Table 6 and were administered by oral gavage. The monkeys in the intravenous treatment group were allowed to consume laboratory chow ad libitum, while the monkeys in the oral treatment group were fasted overnight before treatment and fed 2-3 hours after administration of the test substance. Drinking water was provided ad libitum during the study period. Blood samples (0.35 mL / each) were collected from the saphenous vein of the monkeys. The collected blood samples were placed in tubes containing heparin as an anticoagulant. Blood samples from the intravenous (IV) group were collected before administration and 10 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, and 8 h after administration. For the PO group, blood samples were collected before administration and 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, and 8 h after administration. To prevent compound degradation, 100 μL of blood sample once collected from the monkey was immediately mixed with 300 μL of acetonitrile (containing 0.1% formic acid) in a 1:3 (v / v) ratio. The deproteinized samples were temporarily kept on ice and then stored at -70 °C before bioanalysis. Analyte concentrations in blood were measured by LC-MS / MS.

[0353] [Table 6]

[0354] Finally, it should be noted that there are other ways of implementing the invention. Thus, although the embodiments of the invention are described by way of example, the invention is not limited to what has been described, and further modifications may be made within the scope of the invention or equivalents appended to the claims.

[0355] All publications or patents cited herein are hereby incorporated by reference.

[0356] References throughout this specification to "embodiments," "some embodiments," "one embodiment," "another example," "an example," "particular example," or "some examples" mean that a particular feature, structure, material, or characteristic described in connection with an embodiment or example is included in at least one embodiment or example of the disclosure. Thus, appearances of phrases such as "in some embodiments," "in one embodiment," "in an embodiment," "in another example," "in an example," "particular example," or "in some examples" in various places throughout this specification are not necessarily all referring to the same embodiment or example of the disclosure. Furthermore, particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples.

[0357] While illustrative embodiments have been shown and described, those skilled in the art will appreciate that the above embodiments should not be construed as limiting the disclosure, and that changes, substitutions, and modifications may be made to the embodiments without departing from the spirit, principles, and scope of the disclosure.

[0358] [Claim 1] A compound having the structure of Formula (Ia) or (Ib), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof: [C1] TIFF2025028934000328.tif2880 R is -C(=O)R 1 , -C(=O)OR 2 , -C(=O)O(CHR 3 )OC(=O)R 4or CD3, and X is -CH3 or CD3. [Claim 2] A compound having the structure of Formula (IIa) or (IIb), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof: [Case 2] TIFF2025028934000329.tif2899 R 1 is optionally substituted or unsubstituted aryl-OH, aryl-NH2, alkenyl-OH, alkenyl-NH2, alkyl-NH2, alkyl-OH, carbocyclyl or heterocyclyl containing one or more N or O, and X is -CH3 or CD3. [Claim 3] R 1 But Amino C 1-6 Alkyl, -R 1a NHCOR 1b , -R 1a O.C.O.R. 1b , -R 1a COOR 1b , [C3] TIFF2025028934000330.tif2131 Or C 3-6 is heterocyclyl, R 1 But, C 1-6 optionally substituted with alkyl, -OH or oxo (=O); R 1a and R 1b However, independently, H, C 1-6 Alkyl or C 2-6 alkenyl, R 1c But -OH, C 1-3 Hydroxyalkyl, -OCOR 1b or CH2OCOR 1b 3. The compound of claim 2, [Claim 4] Heterocyclyl containing one or more N or O is [C4] TIFF2025028934000331.tif26101 3. The compound of claim 2, [Claim 5] [C5-1] TIFF2025028934000332.tif154141 [C5-2] TIFF2025028934000333.tif205164 [C5-3] TIFF2025028934000334.tif154141 [C5-4] TIFF2025028934000335.tif205160 is selected from the group consisting of The compound wherein X is -CH3 or CD3. [Claim 6] having the structure of formula (IIIa) or (IIIb): [6] TIFF2025028934000336.tif28118 R 2 is an optionally substituted or unsubstituted alkyl, aryl, carbocyclyl, or heterocyclyl containing one or more O, and X is -CH3 or CD3, or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof. [Claim 7] R 2 But, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, Amino C 1-6 Alkyl, -R 2a S(O) n1 R 2b , -R 2a COOR 2b , C 3-6 Aryl or C 3-6 is heterocyclyl, R 2 But, C 1-6 Alkyl [7] TIFF2025028934000337.tif33122 If replaced by C 1-6 Alkyl, -OH, C1-6 Hydroxyalkyl, [8] TIFF2025028934000338.tif33113 or R 2a COOR 2b optionally replaced by R 2a But, C 1-6 is alkyl, R 2a But, arbitrarily, C 1-6 substituted with alkyl or NH2; R 2b But H or C 1-6 is alkyl, The compound according to claim 6, wherein n1 is 0, 1 or 2. [Claim 8] [C9-1] TIFF2025028934000339.tif134153 [C9-2] TIFF2025028934000340.tif134153 is selected from the group consisting of Compounds in which X is -CH3 or CD3. [Claim 9] A compound having the structure of Formula (IVa) or (IVb) or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof: [C10] TIFF2025028934000341.tif28139 R 3 is H or substituted or unsubstituted alkyl, while R 4 is independently substituted or unsubstituted alkyl, aryl, azaaryl, carbocyclyl, or heterocyclyl containing one or more O or N; and X is -CH3 or CD3. [Claim 10] R 3 But H or C 1-6 10. The compound of claim 9, wherein said compound is alkyl. [Claim 11] R 4 But, C 1-6 Alkyl, Amino C1-6 Alkyl, C 1-6 Hydroxyalkyl, -R 4a NCOR 4b , -R 4a OCOR 4b , -R 4a S(O) n2 R 4b , C 1-6 Heterocyclyl, C 1-5 Azaaryl or [C11] TIFF2025028934000342.tif2432 and R 4 But, C 1-6 Alkyl [C12] TIFF2025028934000343.tif1849 If replaced by C 1-6 Alkyl, -NH2, oxo(=O), C 1-6 Hydroxyalkyl, [C13] TIFF2025028934000344.tif1852 optionally replaced by R 4a But, C 1-6 is alkyl, R 4b But, C 1-6 Alkyl or C 1-6 is haloalkyl, R 4c is benzyl and R 4d is H or R 4c and R 4d However, together with the carbon atom to which they are attached, 5-6 forming a heterocyclyl, 10. The compound of claim 9, wherein n2 is 0, 1, or 2. [Claim 12] C 1-6 Heterocyclyl is [C14] TIFF2025028934000345.tif26147 12. The compound of claim 11, wherein [Claim 13] C 1-5 Azaaryl is [C15] TIFF2025028934000346.tif2026 and [C16] TIFF2025028934000347.tif2026 is optionally substituted with one or more methyl or NH2, or a combination thereof. [Claim 14] [C17] TIFF2025028934000348.tif2232 but, [C18] TIFF2025028934000349.tif2394 12. The compound of claim 11, wherein [Claim 15] [C19-1] TIFF2025028934000350.tif205158 [C19-2] TIFF2025028934000351.tif233160 [C19-3] TIFF2025028934000352.tif76160 [C19-4] TIFF2025028934000353.tif210161 [C19-5] TIFF2025028934000354.tif134160 [C19-6] TIFF2025028934000355.tif205160 [C19-7] TIFF2025028934000356.tif230160 [C19-8] TIFF2025028934000357.tif76167 [C19-9] TIFF2025028934000358.tif210167 [C19-10] TIFF2025028934000359.tif134167 is selected from the group consisting of The compound wherein X is -CH3 or CD3. [Claim 16] A compound having the structure of Formula (Va) or (Vb) or (Vc) or (Vd), or a stereoisomer, N-oxide, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof:

[20] TIFF2025028934000360.tif27168. [Claim 17] A pharmaceutical composition comprising a compound according to any one of claims 1 to 16. [Claim 18] 18. The pharmaceutical composition of claim 17, further comprising at least one pharma- ceutically acceptable excipient carrier, adjuvant, vehicle, or a combination thereof. [Claim 19] 20. The pharmaceutical composition of claim 18, further comprising a pharma- ceutical effective amount of one or more adjunctive therapeutic agents, wherein the adjunctive therapeutic agent is used to treat neurological and psychiatric disorders or diseases of the central nervous system. [Claim 20] 20. The pharmaceutical composition of claim 19, wherein the neurological and psychiatric disorder or disease of the central nervous system is depression or pain. [Claim 21] 20. The pharmaceutical composition of claim 19, wherein the adjunctive therapeutic agent is selected from the group consisting of at least one member of lithium, pharmaceutical or herbal antidepressants, anticonvulsants, mood stabilizers, antipsychotics, and benzodiazepines. [Claim 22] 22. Use of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 21 in the manufacture of a medicament for the prevention, management, treatment or amelioration of a neurological and psychiatric disorder or disease of the central nervous system in a patient. [Claim 23] 22. Use of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 21 in the manufacture of a medicament for antagonizing an NMDA receptor. [Claim 24] 22. A compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 21 for use in the prevention, control, treatment or amelioration of a neurological or psychiatric disorder or disease of the central nervous system in a patient. [Claim 25] A compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 21 for use in antagonizing an NMDA receptor. [Claim 26] A method for preventing, managing, treating or ameliorating a neurological or psychiatric disorder or disease in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-16 or a pharmaceutical composition according to any one of claims 17-21. [Claim 27] 22. A method for antagonizing an NMDA receptor in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-16 or a pharmaceutical composition according to any one of claims 17-21.

Claims

1. A compound having the structure of formula (IIIa) or (IIIb) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, provided that X is -CH ３ and -CD ３ Selected from: R ２ is unsubstituted C １－６ Alkyl, C １－６ Hydroxyalkyl, amino-C １－６ Alkyl, -R ２ａ S (O) ｎ１ R ２ｂ , -R ２ａ COOR ２ｂ , C ３－６ Aryl, or C ３－６ is heterocyclyl; R ２ａ is C １－６ alkyl, R ２ａ is arbitrarily C １－６ Alkyl or NH ３ is replaced by; R ２ｂ is hydrogen or C １－６ is alkyl; and n １ is 0, 1, or 2.

2. R ２ C １－６ The compound of claim 1 which is alkyl.

3. R ２ C １－６ The compound of claim 1 which is a hydroxyalkyl.

4. R ２ Amino-C １－６ The compound of claim 1 which is alkyl.

5. R ２ Ga-R ２ａ S (O) ｎ１ R ２ｂ The compound according to claim 1,

6. R ２ Ga-R ２ａ COOR ２ｂ The compound according to claim 1,

7. R ２ C ３－６ The compound of claim 1 which is aryl.

8. R ２ C ３－６ The compound of claim 1 which is a heterocyclyl.

9. Any of the following compounds or pharma- ceutically acceptable salts thereof, provided that: X is -CH ３ and -CD ３ Selected from: 【Chemistry 2-1】 【Chemistry 2-2】

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof.

11. 11. The pharmaceutical composition of claim 10 in the form of an oral formulation.

12. 1. A pharmaceutical composition for treating pain, comprising: A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof; or 12. A pharmaceutical composition according to claim 10 or 11.

13. 1. A pharmaceutical composition for treating depression, comprising: A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof; or 12. A pharmaceutical composition according to claim 10 or 11.

14. 1. A medicament for treating a neurological disorder, a psychiatric disorder or a disease of the central nervous system associated with NMDA receptor inhibition, comprising: A compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof; or A pharmaceutical composition according to claim 10 or 11.

15. A medicament for treating: A compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof; or A medicament comprising the pharmaceutical composition according to claim 10 or 11: Anxiety disorders, seasonal affective disorder, mania, bipolar disorder, obsessive-compulsive disorder, insomnia and fatigue due to jet lag, schizophrenia, seizures, panic attacks, melancholia, alcoholism, drug addiction, alcoholism, drug abuse, drug withdrawal, insomnia, psychotic disorders, epilepsy, somnipathy, sleep disorder, sleep apnea, mandatory eating disorder, fibromyalgia, stress, obesity, Parkinson's disease, cognitive impairment, memory impairment, premenstrual syndrome, migraine, memory loss, asymptomatic Alzheimer's disease, or disorders associated with normal or pathological aging.

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