Ketamine prodrugs, compositions and their uses

Abstract

The present invention provides (S)- or (R)-ketamine prodrugs and compositions thereof for the treatment or prevention of depression and pain. [Solution] A compound of formula (1) or a pharmaceutically acceptable salt thereof (wherein R1 is hydrogen or alkyl, and R2 is a group of formula (6)) is provided. JPEG2026123016000361.jpg3980 JPEG2026123016000362.jpg2379

Description

[Technical Field]

[0001] Related applications This application claims priority and interest in U.S. Patent Application No. 62 / 615,948, filed with the U.S. Patent and Trademark Office on 10 January 2018, the entirety of which is incorporated herein by reference.

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

[0003] Antidepressants are central nervous system medications used to treat conditions such as major depressive disorder (MDD), dysthymia, 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 perform everyday tasks and enjoy activities that previously brought them pleasure.

[0004] Glutamate is the brain's primary excitatory neurotransmitter. Like classical neurotransmitters, glutamate is released from nerve cells, binds to receptors, and is removed by reuptake transporters. The glutamate receptor system is highly complex and can be separated into various distinct receptor subtypes depending on their molecular and pharmacological properties. Most clinical studies targeting multiple CNS indications focus on drugs that modulate glutamate function via NMDA receptors. 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, binding to a wide range of 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 a strategy for continuing antidepressants in patients who show an initial response to ketamine infusions. In 10 TRD patients who had not responded to an average of eight antidepressants in their lifetime, repeated intravenous ketamine infusions over two weeks (six infusions) resulted in an average 85% reduction in MADRS (Mongomery-Asberg Depression Rating Scale) scores after the sixth infusion.

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

[0008] To overcome the pharmacokinetic shortcomings of ketamine, a prodrug approach is employed to identify feasible ketamine derivatives that can significantly improve the pharmacokinetic profile of ketamine when administered orally. To avoid potential side effects, sustained-release formulations may be desirable to eliminate peaks and troughs in drug plasma concentrations. [Overview of the project]

[0009] The following is a summary of some aspects of the present invention, but is not limited thereto. All references herein are incorporated herein by reference in their entirety. In the event of any discrepancy between the disclosure herein and a reference, the disclosure herein shall prevail. The present invention provides compounds and pharmaceutical compositions that modulate NMDA receptor antagonism, preparations thereof, and corresponding pharmaceutical compositions. The compounds and / or pharmaceutical compositions of the present invention can potentially be used in the manufacture of agents for preventing, treating, or improving certain disorders or diseases related to NMDA receptors in patients, including depression and pain.

[0010] Specifically, in one embodiment, the present invention relates to a compound having the structure of formula (Ia) or (Ib), or its stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs. [ka] In the formula, R is -C(=O)R 1 , -C(=O)OR 2 -C(=O)O(CHR 3 )OC(=O)R 4 Or it is CD3, and X is -CH3 or CD3, R 1 X is optionally substituted or unsubstituted aryl-OH, aryl-NH2, alkenyl-OH, alkenyl-NH2, alkyl-NH2, alkyl-OH, carbocyrill, or heterocyclyl containing one or more N or O atoms, where X is -CH3 or CD3. R 2is optionally substituted or unsubstituted alkyl, aryl, carbocyclic, or heterocyclic containing one or more O, X is -CH3 or CD3, R 3 is H or substituted or unsubstituted alkyl, but R 4 is independently substituted or unsubstituted alkyl, aryl, azaaryl, carbocyclic, or heterocyclic containing one or more O or N, and X is -CH3 or CD3.

[0011] An object of the present invention is that a compound having the structure of formula (Ia) or (Ib) is a prodrug of (S)- or (R)-ketamine, and the "N-R" moiety can be cleaved in vivo via chemical hydrolysis or metabolic processes by endogenous enzymes. Compounds having formula (Ia) or (Ib) can have the characteristics of i) significantly improving oral bioavailability compared to ketamine, and ii) being suitable for sustained-release formulations suitable for QD or BID, meeting the patient's compliance and convenience.

[0012] In another aspect, provided herein are compounds having the structure of formula (IIa) or (IIb), or stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. [Chemical formula] In the formula, R 1 is optionally substituted or unsubstituted aryl-OH, aryl-NH2, alkenyl-OH, alkenyl-NH2, alkyl-NH2, alkyl-OH, carbocyclic, or heterocyclic containing one or more N or O, and X is -CH3 or CD3.

[0013] <​​​​​​​​​​​​​​​​​ [ka] or C 3-6 It is a heterocycline, In the formula, R 1 C 1-6 It can be optionally substituted with alkyl, -OH, or oxo (=O), R 1a and R 1b H and C are independent of each other. 1-6 Alkyl or C 2-6 It is alkenyl, R 1c is -OH, C 1-3 Hydroxyalkyl, -OCOR 1b Or CH2OCOR 1b That is the case.

[0014] In one embodiment, a heterocycline containing one or more N or O is [ka] That is the case.

[0015] In another embodiment, compounds having the structure of formula (IIIa) or (IIIb), or stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof are provided herein. [ka] In the formula, R 2 X is an optionally substituted or unsubstituted alkyl, aryl, carbocyryl, or heterocyclyl containing one or more oxygen atoms, and X is -CH3 or CD3.

[0016] In one embodiment, R 2 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 It is a heterocycline, R 2 C 1-6 Alkyl [ka] If replaced with C 1-6 alkyl, -OH, C 1-6 Hydroxyalkyl, [ka] or R 2a COOR 2b It is arbitrarily replaced with, R 2a C 1-6 It is alkyl, R 2a C is optional 1-6 Substituted with alkyl or NH2, R 2b H or C 1-6 It is alkyl, n1 is 0, 1, or 2.

[0017] In another embodiment, compounds having the structure of formula (IVa) or (IVb), or stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof are provided herein. [ka] In the formula, R 3 R is H or a substituted or unsubstituted alkyl, but 4 X is independently a substituted or unsubstituted alkyl, aryl, azaaryl, carbocykrill, or heterocyclyl containing one or more O or N atoms, where X is -CH3 or CD3.

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

[0019] In one embodiment, R 4 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 Azalea or [ka] And, R 4 C 1-6 Alkyl [ka] If replaced with C 1-6 Alkyl, -NH2, oxo (=O), C 1-6 Hydroxyalkyl, [ka] It is arbitrarily replaced with, R 4a C 1-6 It is alkyl, R 4b C 1-6 Alkyl or C 1-6 It is a haloalkyl, R 4c It is benzyl, and R 4d Is H or R 4c and R 4d However, along with the carbon atoms to which they are bonded, C 5-6 Forming heterocyclines, n2 is 0, 1, or 2.

[0020] In one embodiment, C 1-6Heterocyclines are, [ka] That is the case.

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

[0022] In one embodiment, [ka] That is the case.

[0023] In another embodiment, compounds having the structure of formula (Va), (Vb), (Vc), or (Vd), or stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof are provided herein. [ka]

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

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

[0026] In one embodiment, the pharmaceutical composition further comprises one or more pharmaceutically effective amounts of auxiliary therapeutic agents used for the treatment of neurological and psychiatric disorders or diseases of the central nervous system.

[0027] In one embodiment, the neurological and psychiatric disorders or diseases of the central nervous system are depression or pain.

[0028] In one embodiment, the adjunct 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 embodiment, this specification provides the use of compounds or pharmaceutical compositions in the manufacture of agents for the prevention, management, treatment or alleviation of neurological and psychiatric disorders or diseases of the central nervous system in patients.

[0030] In another embodiment, the use of a compound or pharmaceutical composition in the manufacture of a drug for antagonizing NMDA receptors is provided herein.

[0031] In another embodiment, the Specified Inventions provide compounds or pharmaceutical compositions for use in the prevention, management, treatment, or alleviation of neurological and psychiatric disorders or diseases of the central nervous system in patients.

[0032] In another embodiment, compounds or pharmaceutical compositions for use in antagonizing NMDA receptors are provided herein.

[0033] In another embodiment, this specification provides a method for preventing, managing, treating or alleviating a patient's neurological and psychiatric disorders or diseases, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition to a patient in need thereof.

[0034] In another embodiment, the Specified Provision provides a method for antagonizing a patient's NMDA receptor, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition to a patient in need thereof.

[0035] In another embodiment, methods for preparing, separating, and purifying compounds represented by formulas (Ia) to (Vd) are provided herein.

[0036] Biological test results demonstrate that the compounds provided herein exhibit favorable antagonistic activity against NMDA receptors, resulting in superior pharmacokinetic properties and bioavailability.

[0037] In certain embodiments of the compounds, pharmaceutical compositions, and methods of the present invention, the compounds of formulas (Ia) to (Vd) are compounds selected from the species described or illustrated in the following detailed description, or pharmaceutically acceptable salts of such compounds.

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

[0039] When formulated as a fixed dose, such combination product uses the compound of the present invention within the dose range described herein (or known to those skilled in the art) and other pharmaceutically active or therapeutic agents within that dose range. The compound of the present invention may also be administered sequentially with known antidepressants and analgesics if the combination formulation is unsuitable. In any combination therapy, the present invention is not limited to the order of administration. The compounds of formulas (Ia) to (Vd) may be administered either before or after the administration of known antidepressants and analgesics. Such techniques are within the scope of the skills of those skilled in the art and the attending physician.

[0040] Another embodiment involves administering the pharmaceutical formulation of the present invention to a subject (e.g., a human) that requires it, thereby administering the compound of the present invention to the subject.

[0041] Another embodiment is a method for preparing a pharmaceutical formulation of the present invention by mixing at least one pharmaceutically acceptable compound of the present invention with one or more pharmaceutically acceptable additives or excipients.

[0042] When preparing pharmaceutical compositions from the compounds described in this invention, the inert and pharmaceutically acceptable carrier may be either solid or liquid. Solid formulations include powders, tablets, dispersible granules, capsules, beads, cachets, and suppositories. Powders and tablets may contain about 5 to about 95 percent of the active ingredient. Suitable solid carriers are known in the art and include, for example, 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 pharmaceutically acceptable carriers and methods for producing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0043] Preparations in liquid form include solutions, suspensions, and emulsions. Examples include water or water-propylene glycol solutions for parenteral injection, or the addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Preparations in liquid form may also include solutions for intranasal administration.

[0044] Aerosol preparations suitable for inhalation may include powdered solutions and solids, which may be combined with a pharmaceutically acceptable carrier such as an inert compressed gas, e.g., nitrogen.

[0045] The collection also includes solid preparations that are intended to be converted into liquid preparations for either oral or parenteral administration immediately before use. Such liquid preparations include solutions, suspensions, and emulsions.

[0046] The compounds of the present invention may also be deliverable transdermally. The transdermal composition may take the form of a cream, lotion, aerosol, and / or emulsion, and may be included in a matrix or reservoir-type transdermal patch, as is customary in the art for this purpose.

[0047] The compounds of the present invention can also be delivered subcutaneously.

[0048] Preferably, the compound is administered orally or intravenously.

[0049] Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses of an appropriate size, each containing an appropriate amount, for example, an effective amount of the active ingredient to achieve the desired objective.

[0050] The amount of the active compound in a unit dose of the preparation is changed or adjusted 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, depending on the specific application.

[0051] The actual dosage used may vary depending on the patient's condition and the severity of the condition being treated. Determining an appropriate dosage regimen for a particular situation is within the realm of those skilled in the art. For convenience, the total daily dose may be divided and administered in small amounts throughout the day as needed. The amount and frequency of administration of the compounds of the present invention and / or their pharmaceutically acceptable salts will be adjusted at the discretion of the attending clinician, taking into account factors such as the patient's age, condition and size, and the severity of the condition being treated. A daily dose regimen usually recommended 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 or two divided doses.

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

[0053] The above is merely a summary of the specific embodiments disclosed herein and is not intended to be an intrinsic limit. These embodiments and other embodiments and models are described more fully below. [Modes for carrying out the invention]

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

[0055] Most chemical names in this specification were generated using IUPAC nomenclature. Some chemical names were generated using different nomenclature or alternative or trade names known in the art. In the event of any inconsistency between a name and a structure, the structure shall prevail.

[0056] Definitions and General Terms Herein, specific embodiments of the present invention are given in detail, examples of which are shown in the accompanying structures and formulas. The present invention is intended to encompass all alternatives, modifications, and equivalents that may fall 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 not limited in any way to the methods and materials described herein. If one or more incorporated documents, patents, and similar materials differ from or conflict with this application, this application shall prevail, including, but not limited to, defined terms, usage of terms, and described techniques.

[0057] Furthermore, it is understood that certain features of the present invention described in the context of separate embodiments for clarity can be provided in combination in a single embodiment. Conversely, various features of the present invention described in the context of a single embodiment for brevity can also be provided separately or in any suitable sub-combination.

[0058] Unless otherwise defined, technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this invention pertains. All patents and publications referenced herein are incorporated in their entirety by reference.

[0059] As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of this invention, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th Ed. 1994. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry" by 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 full contents of which are incorporated herein by reference.

[0060] Throughout this disclosure, the following terms used above shall be understood to have the meanings set forth below unless otherwise indicated. Where a definition is missing, the prior art definition known to those skilled in the art shall prevail. If any definition provided herein conflicts with or differs from any definition provided in any cited publication, the definition provided herein shall prevail.

[0061] As used herein, the terms “contains,” “includes,” and “includes” are used in their open and non-restrictive sense.

[0062] The singular forms "a," "an," and "the" refer to multiple objects unless otherwise explicitly indicated by the context.

[0063] To provide a more concise explanation, some quantitative expressions given herein are not modified with the term “approximately.” Whether the term “approximately” is explicitly used or not, all quantities given herein are understood to mean actual given values, and also to mean approximations of such given values ​​that can be reasonably inferred on the basis of the ordinary skill of a person skilled in the art. Such given values ​​include equivalents and approximations under experimental and / or measurement conditions. Whenever a yield is given as a percentage, such a yield refers to the mass of the substance for which the yield is given for the maximum amount of the same substance obtained under particular stoichiometric conditions. Concentrations given as percentages refer to mass ratios unless otherwise specified.

[0064] The terms "optional" or "optional" mean that the events or circumstances described later may occur but are not required, and that the descriptions include cases where the events or circumstances occur and cases where they do not.

[0065] The terms “optionally substituted” and “unsubstituted or substituted” are interchangeable herein and mean that the structure is either unsubstituted or substituted by one or more substituents disclosed herein. Substitutions occur at any acceptable valence at appropriate sites of the structures or groups provided herein.

[0066] Generally, the term “substituted” refers to the substitution of one or more hydrogen radicals in a given structure or group with the radical of a particular substituent. Unless otherwise indicated, substituents may have substituents at each suitable and substitutable position of a group. If multiple positions in a given structure can be substituted with multiple substituents selected from a particular 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 linear or branched hydrocarbon group having 1 to 12 carbon atoms. Typical 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 longer alkyl groups such as heptyl and octyl.

[0068] In various parts of this specification, substituents of the compounds disclosed herein are disclosed as groups or ranges. The present invention is particularly intended to include subcombinations of each of all members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually.

[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, and includes radicals having "cis" and "trans" orientations, or "E" and "Z" orientations. The alkenyl group may be optionally substituted with one or more substituents as described herein.

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

[0072] The terms "halogen" or "halo" are used interchangeably in the present invention and refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

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

[0074] "Aryl" means a monocyclic, bicyclic, or tricyclic aromatic group, and all rings of this group are aromatic. In the case of a bicyclic or tricyclic system, the individual aromatic rings are fused to each other. 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, and the alkyl group is as defined herein. Some non-limiting examples of such groups include, but are not limited to, -CF3, -CF2CF3, -CH2CF2CHF2, etc. In one embodiment, "haloalkyl" refers to lower C 1-4 haloalkyl, and "C 1-4 haloalkyl" refers to fluorine-substituted C 1-4 haloalkyl, chlorine-substituted C 1-4Haloalkyl, bromine-substituted C 1-4 Haloalkyl, iodine-substituted C 1-4 This includes haloalkyls, etc. Specifically, fluorine-substituted C 1-4 Haloalkyls include -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CHFCF3, -CHFCHF2, -CHFCH2F, -CH2CH2CF3, -CH2CF2CHF2, and others. Haloalkyls are optionally substituted with one or more substituents as 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 terms “hydroxysubstituted alkyl” or “hydroxyalkyl” refer to an alkyl group substituted with one or more hydroxyl groups, where alkyl groups are as defined herein. Some non-exclusive examples of such groups include, but are not limited to, hydroxymethyl, hydroxyethyl, and 1,2-dihydroxyethyl.

[0078] As used herein, the term “deuterium” means a stable isotope of hydrogen having one proton and one neutron.

[0079] The terms "carbocyclyl" and "carbocyclic" as used interchangeably herein refer to monovalent or polyvalent rings having 3 to 12 carbon atoms as monocyclic, bicyclic, or tricyclic ring systems, which are either saturated or have a degree of unsaturation of 1 or more, but aromatic rings cannot be present in the carbocyclyl group.

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

[0081] The terms “heterocyclyl” and “heterocyclic” as used interchangeably herein refer to monocyclic, bicyclic, or tricyclic rings containing 3 to 12 carbon atoms, where one or more atoms in the ring are independently substituted by heteroatoms as defined herein, and the ring may be saturated or have one or more degrees of unsaturation, except that aromatic rings cannot exist.

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

[0083] Those skilled in the art will recognize that the heteroaryl and cycloalkyl species listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

[0084] As described herein, the compounds disclosed herein may be optionally substituted with one or more substituents, or as exemplified by the specific classifications, subcategories, and types of the present invention.

[0085] As used herein, the term “substituted” means that the specified group or part has one or more preferred 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 either unsubstituted or substituted by a specified number of substituents. When the term “substituted” is used to describe a structural system, substitution means that it occurs at any position in the system where any valence is permissible.

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

[0087] In this specification, any atom represented by an unfulfilled valence is considered to have a sufficient number of hydrogen atoms to satisfy the atom's valence.

[0088] Some variable part (e.g., alkyl, alkylenyl, heteroaryl, R) 1 , R 2 , or R a If ) appears in more than one place in any formula or description provided herein, the definition of its variable part in each representation is independent of its definition in all other representations.

[0089] Numerical 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 also 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] When a polyfunctional moiety is shown, the bond point to the core is indicated by a line or a hyphen. For example, aryloxy refers to the moiety where the aryl atom is bonded to an oxygen atom, but the oxygen atom is the bond point to the core molecule.

[0091] Additional definitions As used herein, the term “subject” encompasses both mammals and non-mammals. Examples of mammals include, but are not limited to, all members of the mammalian species, namely humans, non-human primates such as chimpanzees, other apes and monkey species, domesticated animals such as cattle, horses, sheep, goats and pigs, pet animals such as rabbits, dogs and cats, and experimental animals such as rodents such as rats, mice and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish. In one embodiment of the present invention, the mammal is a human.

[0092] The term "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 molecules, such as the compounds of the present invention, that increase, decrease, or otherwise affect the activity of a given protein, receptor, and / or ion channel.

[0095] The term “effective dose” or “therapeutic effective dose” refers to the amount of a drug sufficient to produce a desired biological effect. This effect may be the reduction and / or alleviation of signs, symptoms, or causes of a disease or medical condition, or other desirable changes in the biological system. For example, an “effective dose” for therapeutic use is the amount of a compound or composition containing a compound required to provide a clinically significant change in a disease state, symptom, or medical condition. The appropriate “effective” dose in any individual case can be determined by those skilled in the art using conventional experiments. Therefore, the expression “effective dose” generally refers to the amount of an active substance that has a therapeutically desirable effect.

[0096] As used herein, the terms “to treat” or “treatment” encompass both “preventive” and “curative” treatments. “Preventive” treatment means delaying the onset of a disease, symptoms of a disease, or medical condition, suppressing any symptoms that may appear, or reducing the risk of the onset or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of an existing disease, symptom, or condition or preventing its worsening. Thus, treatment includes improving or preventing the worsening of existing disease symptoms, preventing the onset of further symptoms, improving or preventing the underlying metabolic causes of symptoms, inhibiting a disorder or disease, for example, stopping the onset of a disorder or disease, alleviating a disorder or disease, inducing regression of a disorder or disease, alleviating a condition caused by a disease or disorder, or blocking the symptoms of a disease or disorder.

[0097] As used herein, the terms “administering” and “administering” the compound should be understood to mean providing the compound of the present invention, a pharmaceutical composition containing the compound, or a prodrug of the compound of the present invention to an individual in need. Those skilled in the art, without limitation, have confirmed that effective amounts of the compound of the present invention can treat patients currently suffering from neurological and psychiatric disorders, or preventively treat patients suffering from such disorders.

[0098] As used herein, the term “composition” is intended to encompass any product containing a specified amount of a specified component, as well as any product obtained directly or indirectly from a specified amount of a specified combination of specified components. In relation to pharmaceutical compositions, such terminology is intended to encompass any product containing an active and inactive component constituting a carrier, as well as any product obtained directly or indirectly from any combination, complexation, or aggregation of any two or more components, or from other types of reactions or interactions that result in the dissociation of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass any composition prepared by mixing the compounds of the present invention with a pharmaceutically acceptable carrier.

[0099] Additional chemical explanation Any formula provided herein is intended to represent a compound having the structure shown by its structural formula, as well as a particular variation or form. For example, a compound of any formula provided herein may have a chiral or asymmetric center and therefore may exist in different stereoisomeric forms. All stereoisomers of a compound of a 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), a tautomer, or atropisomer. All such isomers and mixtures thereof are contemplated herein as part of the present invention. Accordingly, any formula provided herein is intended to represent a racemic compound, one or more enantiomers, one or more diastereomers, one or more tautomers or atropisomers, and mixtures thereof.

[0100] Stereoisomers are compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and atropisomers.

[0101] The term "chiral" refers to molecules that cannot be superimposed on their mirror image partners, while the term "achiral" refers to molecules that can be superimposed on those mirror image partners.

[0102] "Enantiomers" refer to two stereoisomers of a compound that cannot be superimposed onto each other as mirror images.

[0103] A "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated under high-resolution analytical methods such as electrophoresis and chromatography, such as HPLC.

[0104] The stereochemical definitions and conventions used herein generally follow SP. 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 an optically active form, that is, they have the ability to rotate the plane of polarization. In the description of optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to the chiral center. The prefixes d and l, or (+) and (-), are used to indicate the rotation of plane polarization by the compound, with (-) or l meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. Certain stereoisomers may also be called enantiomers, and a mixture of such stereoisomers is called an enantiomer mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemic compound, and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

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

[0107] Depending on the selection of starting materials and procedures, the compound may exist in one form of a possible stereoisomer, or as a mixture thereof, for example, as a racemic compound and a diastereomer mixture depending on the number of chiral carbon atoms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or separated using conventional techniques. If the compound contains a double bond, the substituent may be in an E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration with respect to another substituent on the same cycloalkyl skeleton.

[0108] The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, or diastereomers based on the physicochemical differences of their components, for example, by chromatography and / or fractional crystallization. Any racemic compound obtained as a final product or intermediate can be separated into optical isomers by methods known to those skilled in the art, for example, by separation of its diastereomer salts. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. 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] Diastereomer mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting the individual diastereomers into their corresponding pure enantiomers (e.g., by hydrolysis or desalting) through reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or moscherate, or the formation of a mixture of diastereomer salts). Enantiomers can also be separated using a chiral HPLC column.

[0110] The compounds of the present invention can form pharmaceutically acceptable salts, which is also within the scope of the present invention. “pharmaceutically acceptable salt” means a salt of a free acid or base of the compound of formula A that is non-toxic, physiologically acceptable, compatible with the pharmaceutical composition in which it is formulated, and otherwise suitable for formulation and / or administration to a subject. References to compounds herein, unless otherwise indicated, are understood to include references to pharmaceutically acceptable salts of such compounds.

[0111] Complex salts include acidic salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. Furthermore, if a given compound contains both a basic moiety, such as pyridine or imidazole, and an acidic moiety, such as a carboxylic acid, for example, those skilled in the art will recognize that the compound may exist as a zwitterion ("intramolecular 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 a salt-precipitating medium or an aqueous medium, and then freeze-drying.

[0112] Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bicarbonate tartrates, ascorbicates, succinates, maleates, gentisinates, fumarates, glucons, glucurons, saccharates, formates, benzoates, glutamates, methanesulfons ("mesylates"), ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthoate)) salts. Pharmaceutically acceptable salts may include the inclusion of other molecules, such as acetate ions, succinate ions, or other counterions. A counterion can be any organic or inorganic part that stabilizes the charge of the parent compound. Furthermore, a pharmaceutically acceptable salt may have multiple charged atoms in its structure. If multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counterions. Therefore, a pharmaceutically acceptable salt may 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, and toluenesulfonate (also known as tosylate).

[0114] Exemplary basic salts include alkali metal salts such as ammonium salts, 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 and tert-butylamine; and salts with amino acids such as arginine and lysine. Basic nitrogen-containing groups can 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 sulfates), long-chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), and aralkyl halides (e.g., benzyl bromide, phenethyl bromide).

[0115] Furthermore, acids and bases generally considered suitable for forming pharmaceutically 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 Food & Drug Administration, MD, FDA). These disclosures are incorporated herein by reference.

[0116] Furthermore, any compound described herein is intended to also refer to non-solvated forms of such compounds, or hydrates, solvates, or polymorphs, and mixtures thereof, even if such forms are not explicitly enumerated. “Solvate” means a physical bond between the compound of the present invention and one or more solvent molecules. This physical bond includes ionic and covalent bonds of varying degrees, including hydrogen bonds. In certain examples, for example, if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be isolated. “Solvate” encompasses both the solution phase and the isolateable solvate. Preferred solvates include those formed with a pharmaceutically acceptable solvent such as water or ethanol. In some embodiments, the solvent is water and the solvate is a hydrate.

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

[0118] The present invention also relates to pharmaceutically active metabolites of the compounds of formula (A) and to the use of such metabolites in the methods of the present invention. "Pharmaceutically active metabolite" means a pharmacologically active metabolite in vivo of a compound of formula (A) or a salt thereof. The active metabolites of a compound can be determined using conventional techniques known or available in the art. For example, see 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 both the unlabeled form and the isotopically labeled form of a compound. An isotopically labeled compound has a structure represented by the formula described herein, except that one or more atoms are replaced by atoms 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, for example, 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 I. Such isotopically labeled compounds are useful in metabolic studies (e.g.,14 C) Research on reaction kinetics (for example) 2 H or 3 H) Detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission tomography (SPECT), including drug or substrate tissue distribution assays, or useful for radiotherapy of patients. In particular, 18 F or 11 14C-labeled compounds are particularly suitable for PET or SPECT studies. Furthermore, deuterium (i.e., 2 Substitution with heavier isotopes, such as H), may result in specific therapeutic benefits arising from higher metabolic stability, such as an extended half-life in vivo or a reduction in the required dose. The isotope-labeled compounds of the present invention can generally be prepared by performing the procedures disclosed in the schemes or examples and preparations described below, by replacing the non-isotope-labeled reagent with a readily available isotope-labeled reagent.

[0120] The use of terms such as “salt,” “solvate,” and “polymorph” in relation to the compounds described herein is intended to apply equally to the enantiomers, stereoisomers, rotational isomers, tautomers, atropisomers, and salts, solvates, and polymorphic forms of the compounds of the present invention.

[0121] Description of the compound of the present invention This specification provides prodrugs, compositions, and uses thereof of (S)- or (R)-ketamine, including isotope-labeled ketamine. More specifically, compounds having formulas (Ia) to (Vd) disclosed herein as prodrugs of (S)- or (R)-ketamine, including isotope-labeled ketamine, can be used as NMDA receptor antagonists for the treatment, prevention, or mitigation of neurological and psychiatric disorders or diseases of the central nervous system associated with NMDA receptors. The pharmaceutical compositions disclosed herein also have functions for the prevention, treatment, or mitigation of diseases associated with NMDA receptors.

[0122] One embodiment of the present invention provides a compound having the structure of formula (Ia) or (Ib), or a stereoisomer thereof, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug. [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, and X is -CH3 or CD3, R 1 is optionally substituted or unsubstituted aryl-OH, aryl-NH2, alkenyl-OH, alkenyl-NH2, alkyl-NH2, alkyl-OH, carbocyrill, or heterocyclyl containing one or more N or O, where X is -CH3 or CD3. R 2 is optionally substituted or unsubstituted alkyl, aryl, carbocyryl, or heterocyclyl containing one or more O atoms, where X is -CH3 or CD3. R 3 R is H or a substituted or unsubstituted alkyl, but 4 X is independently a substituted or unsubstituted alkyl, aryl, azaaryl, carbocykrill, or heterocyclyl containing one or more O or N atoms, where X is -CH3 or CD3.

[0123] In another embodiment, compounds having the structure of formula (IIa) or (IIb), or stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof are provided herein. [ka] In the formula, R 1X is optionally a substituted or unsubstituted aryl-OH, aryl-NH2, alkenyl-OH, alkenyl-NH2, alkyl-NH2, alkyl-OH, carbocyrill, or heterocyclyl containing one or more N or O atoms, where X is -CH3 or CD3.

[0124] In one embodiment, R 1 is amino C 1-6 Alkyl, -R 1a NHCOR 1b , -R 1a OCOR 1b , -R 1a COOR 1b , [ka] or C 3-6 It is a heterocycline, R 1 C 1-6 It can be optionally substituted with alkyl, -OH, or oxo (=O), R 1a and R 1b H and C are independent of each other. 1-6 Alkyl or C 2-6 It is alkenyl, R 1c is -OH, C 1-3 Hydroxyalkyl, -OCOR 1b Or CH2OCOR 1b That is the case.

[0125] In one embodiment, a heterocycline containing one or more N or O is [ka] That is the case.

[0126] In another embodiment, [ka] [ka] [ka] [ka] Compounds selected from the group consisting of the following are provided herein: In the formula, X is either -CH3 or CD3.

[0127] In another embodiment, compounds having the structure of formula (IIIa) or (IIIb), or stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof are provided herein. [ka] In the formula, R 2 X is optionally a substituted or unsubstituted alkyl, aryl, carbocyryl, or heterocyclyl containing one or more oxygen atoms, and X is -CH3 or CD3.

[0128] In one embodiment, R 2 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 It is a heterocycline, R 2 C 1-6 Alkyl [ka] If replaced with C 1-6 alkyl, -OH, C 1-6 Hydroxyalkyl, [ka] or R 2a COOR 2b It is arbitrarily replaced with, R 2a C 1-6 It is alkyl, R 2a C is optional 1-6 Substituted with alkyl or NH2, R 2b H or C 1-6 It is alkyl, n1 is 0, 1, or 2.

[0129] In another embodiment, [ka] [ka] Compounds selected from the group consisting of the following are provided herein: In the formula, X is either -CH3 or CD3.

[0130] In another embodiment, compounds having the structure of formula (IVa) or (IVb), or stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof are provided herein. [ka] In the formula, R 3 R is H or a substituted or unsubstituted alkyl, but 4 X is independently a substituted or unsubstituted alkyl, aryl, azaaryl, carbocykrill, or heterocyclyl containing one or more O or N atoms, where X is -CH3 or CD3.

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

[0132] In one embodiment, R4 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 Azalea or [ka] And, R 4 C 1-6 Alkyl [ka] If replaced with C 1-6 Alkyl, -NH2, oxo (=O), C 1-6 Hydroxyalkyl, [ka] It is arbitrarily replaced with, R 4a C 1-6 It is alkyl, R 4b C 1-6 Alkyl or C 1-6 It is a haloalkyl, R 4c It is benzyl, and R 4d Is H or R 4c and R 4d However, along with the carbon atoms to which they are bonded, C 5-6 Forming heterocyclines, n2 is 0, 1, or 2.

[0133] In one embodiment, C 1-6 Heterocyclines are, [ka] is

[0134] In one embodiment, C 1-5 The azaryl is

Chemical formula

Chemical formula

[0135] In one embodiment,

Chemical formula

[0136] In another aspect,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

[0137] In another aspect, compounds having the structure of formula (Va) or (Vb) or (Vc) or (Vd), or stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof are provided herein.

Chem.

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

[0139] The compounds represented by the above formulas (Ia)-(Vd) can exist in various tautomeric forms, and all of these tautomers are intended to be within the scope of the present invention.

[0140] The N-oxides of the compounds disclosed herein are also within the scope of the present invention. The N-oxides of the compounds disclosed herein can be prepared by oxidizing the corresponding nitrogen bases 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, chloroform, or DCM containing 3-chloroperoxybenzoic acid.

[0141] Furthermore, if the compounds disclosed herein form hydrates or solvates, they fall within the scope of the present invention. Similarly, pharmaceutically acceptable salts of the hydrates and solvates of the compounds disclosed herein also fall within the scope of the present invention.

[0142] The compounds of formulas (Ia) to (Vd) can exist in the form of salts. In some embodiments, the salts are pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, or bicarbonate of Na, Ca, Mg, or K) or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent, or a mixture thereof. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred where feasible. Further lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "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, pharmaceutically acceptable acid addition salts can generally be formed by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic and organic acids. Typical pharmaceutically acceptable acid addition salts include hydrochlorides, hydrobroms, nitrates, methylnitrates, sulfates, hydrosulfates, sulfamates, phosphates, acetates, glycolates, phenyl acetate, propionates, butyrates, isobutyrates, valers, maleates, hydroxymaleates, acrylates, fumarates, malates, tartrates, citrates, salicylates, para-aminosalicylates, glycolates, lactates, enanates, phthalates, oxalates, succinates, benzoates, acetoxybenzoates, and chlorophosphates. This includes benzoates, methyl benzoate, binitrobenzoates, hydroxybenzoates, methoxybenzoates, mandelates, tannates, formates, stearates, ascorbic acid, palmitates, oleates, pyruvates, pamoates, malons, laurates, glutarates, glutamates, estrates, mesylates, ethyl sulfate, 2-hydroxyesylates, benzenesulfonates, para-aminobenzenesulfonates, para-methylbenzenesulfonates, and naphthalene-2-sulfonates.

[0144] Any formula provided herein is also intended to represent both the isotopically unenriched and isotopically enriched forms of a compound. An isotopically enriched compound has the structure represented by the general formula of the present invention unless one or more atoms are substituted by atoms 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, for example, 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 125Includes I.

[0145] In another embodiment, the compound of the present invention is, for example, 3 H, 14 C and 18 Radioactive isotopes such as F are present, 2 H and 13 This includes isotope-enriched compounds as defined herein, which contain non-radioactive isotopes such as 13C. Such isotope-labeled compounds are used in metabolic studies. 14 (At C) Reaction kinetics research (for example) 2 H or 3 It is useful in detection or imaging techniques, including drug or substrate tissue distribution assays, such as positron emission tomography (PET) or single-photon emission tomography (SPECT), or in radiotherapy for patients. 18 Compounds enriched with F are particularly desirable in PET or SPECT studies. Isotope-enriched compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by using appropriate isotope-labeled reagents instead of previously used unlabeled reagents, in a manner similar to that described in the attached examples and preparations.

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

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

[0148] In one embodiment, the pharmaceutical composition further comprises one or more pharmaceutically effective amounts of auxiliary therapeutic agents used for the treatment of neurological and psychiatric disorders or diseases of the central nervous system.

[0149] In one embodiment, the neurological and psychiatric disorders or diseases of the central nervous system are depression or pain.

[0150] In one embodiment, the adjunct 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 embodiment, this specification provides the use of compounds or pharmaceutical compositions in the manufacture of agents for the prevention, management, treatment or alleviation of neurological and psychiatric disorders or diseases of the central nervous system in patients.

[0152] In another embodiment, the use of a compound or pharmaceutical composition in the manufacture of a drug for antagonizing NMDA receptors is provided herein.

[0153] In another embodiment, the Specified Inventions provide compounds or pharmaceutical compositions for use in the prevention, management, treatment, or alleviation of neurological and psychiatric disorders or diseases of the central nervous system in patients.

[0154] In another embodiment, compounds or pharmaceutical compositions for use in antagonizing NMDA receptors are provided herein.

[0155] In another embodiment, this specification provides a method for preventing, managing, treating or alleviating a patient's neurological and psychiatric disorders or diseases, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition to a patient in need thereof.

[0156] In another embodiment, the Specified Provision provides a method for antagonizing a patient's NMDA receptor, 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 a method for preparing compounds of formulas (Ia) to (Vd) and pharmaceutically acceptable salts thereof.

[0158] Pharmaceutical compositions of the compounds of the present invention, as well as their preparation and administration. In one embodiment, the foregoing provides a pharmaceutical composition comprising a compound of formula (Ia) to (Vd), or its stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs. Optionally, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant, or excipient, and optionally other therapeutic and / or prophylactic components.

[0159] Suitable carriers, adjuvants, and excipients are known to those skilled in the art and are described in detail in 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, among others.

[0160] As used herein, “pharmaceutically acceptable excipients” means pharmaceutically acceptable materials, compositions, or vehicles that contribute to giving form or consistency to a pharmaceutical composition. Each excipient, when mixed, must be compatible with the other components of the pharmaceutical composition so as to avoid interactions that would substantially reduce the potency of the compounds of the present invention when administered to a patient and result in a pharmaceutically unacceptable composition. Furthermore, each excipient must, of course, be of sufficient purity to be pharmaceutically acceptable.

[0161] Pharmacoherently acceptable and suitable excipients will vary depending on the specific dosage form selected. Furthermore, pharmaceutically acceptable and suitable excipients may be selected for the specific function they can perform in the composition. For example, some pharmaceutically acceptable excipients may be selected for their ability to facilitate the manufacture of a uniform dosage form. Some pharmaceutically acceptable excipients may be selected for their ability to facilitate the manufacture of a stable dosage form. Some pharmaceutically acceptable excipients may be selected for their ability to facilitate the transport or delivery of the compound of the present invention, once administered to a patient, from one organ or part of the body to another. Some pharmaceutically acceptable excipients may be selected for their ability to improve patient adherence.

[0162] Suitable pharmaceutically acceptable excipients include those of the following types: diluents, fillers, binders, disintegrants, lubricants, flow enhancers, granulators, coatings, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste enhancers, colorants, anticaking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. Those skilled in the art will understand that a pharmaceutically acceptable excipient may perform multiple functions or substitute functions depending on the amount of excipient present in the formulation and other components present in the formulation.

[0163] Those skilled in the art possess the knowledge and skills in the art to enable them to select appropriate amounts of pharmaceutically acceptable and suitable excipients for use in the present invention. Furthermore, there are many resources available to those skilled in the art that describe pharmaceutically acceptable excipients and may be useful in selecting pharmaceutically acceptable and suitable 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] Remington discloses various carriers used in the formulation of pharmaceutically acceptable compositions, and known techniques for their preparation, in The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988–1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference. Unless a conventional carrier medium is incompatible with the compounds of the present invention, such as by producing some undesirable biological effect or otherwise interacting adversely with other components of the pharmaceutically acceptable composition, the use of such a medium is intended to be within the scope of the present invention.

[0165] The compounds of the present invention will typically be formulated into dosage forms suitable for administration to patients via a desired route of administration. For example, dosage forms may include: (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, and dry powders; and (6) formulations adapted for topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0166] It will also be understood that certain compounds of the present invention may exist in a free form for therapeutic purposes, or, where appropriate, as pharmaceutically acceptable derivatives or prodrugs thereof. According to the present invention, pharmaceutically acceptable derivatives or prodrugs include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts or derivatives that can be provided directly or indirectly at the time of administration to a patient in need, the compounds described separately herein, or their metabolites or residues.

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

[0168] The pharmaceutical compositions provided herein may be provided as compressed tablets, powder tablets, chewable lozenges, rapidly dissolving tablets, multi-compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that withstands the action of stomach acid but dissolves or disintegrates in the intestines, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammonia-treated shellac, and cellulose phthalate acetate. Sugar-coated tablets are compressed tablets encased in a sugar coating, which can 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 phthalate acetate. Film coatings provide the same general properties as sugar coatings. Multiple compression tablets are compression tablets manufactured using multiple compression cycles, such as layered tablets and press-coated or dry-coated tablets.

[0169] Tablet dosage forms can be prepared from the active ingredient in powder, crystalline, or granular form, either alone or in combination with one or more carriers or excipients described herein, such as binders, disintegrants, release-controlled polymers, lubricants, diluents, and / or colorants. Flavorings and sweeteners 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 made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), consist of two parts, one of which is placed over the other to completely enclose the active ingredient. Flexible elastic capsules (SECs) are soft spherical shells, such as gelatin shells, that are plasticized by the addition of glycerin, sorbitol, or similar polyols. The flexible gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propylparaben, 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 oil, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patents 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 prolong the dissolution of the active ingredient.

[0171] The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed as small spheres throughout another liquid, and may be oil-in-water or water-in-oil. Emulsions may contain pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions may contain pharmaceutically acceptable suspending agents and preservatives. Alcoholic aqueous solutions may contain pharmaceutically acceptable acetals such as di(lower alkyl) acetals of lower alkylaldehydes, 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 aqueous-alcoholic solutions. Syrups are concentrated aqueous solutions of sugars such as sucrose, and may contain preservatives. In the case of a liquid dosage form, for example, the solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, and conveniently measured for administration.

[0172] This specification provides pharmaceutical compositions that can be prepared in dosage forms suitable for administration to patients by inhalation, for example, as dry powders, aerosols, suspensions, or solution compositions. In one embodiment, the present invention relates to a dosage form suitable for administration to patients by inhalation as a dry powder. In one embodiment, the present invention relates to a dosage form suitable for administration to patients by inhalation as a dry powder. Dry powder compositions for delivery to the lungs by inhalation typically comprise a compound disclosed herein or a pharmaceutically acceptable salt thereof as a fine powder, together with one or more pharmaceutically acceptable fine powder excipients. Pharmaceutically acceptable excipients particularly suitable for use in dry powder form are known to those skilled in the art and include lactose, starch, mannitol, and monosaccharides, disaccharides, and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. Generally, compounds with reduced size (e.g., micronized) are approximately 1 to 10 microns in size. 50 It can be defined by a value (for example, when measured using laser diffraction).

[0173] Pharmaceutical compositions suitable for transdermal administration may be provided as individual patches intended to remain in close contact with the patient's epidermis over an extended period. For example, the active ingredient may be delivered from the patch by iontophoresis, as commonly described in Pharmaceutical Research, 3(6), 318 (1986).

[0174] Pharmaceutical compositions suitable 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 using aqueous or oily bases, for example, by adding suitable thickeners and / or gelling agents and / or solvents. Such bases may contain, for example, water and / or oil, such as liquid paraffin or vegetable oil (such as peanut oil or castor oil), or solvents such as polyethylene glycol. Depending on the properties of the base, suitable thickeners and gelling agents include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxypolymethylene and cellulose derivatives, and / or glyceryl monostearate and / or nonionic emulsifiers.

[0175] The compounds disclosed herein may also be bonded to soluble polymers as targeted drug carriers. Such polymers may include palmitoyl radical-substituted polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamidophenol, polyhydroxyethyl aspartamidophenol, or polyethylene oxide polylysine. The compounds may further be bonded to a class of biodegradable polymers suitable for achieving controlled drug release, such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0176] The pharmaceutical compositions provided herein may be administered parenterally by injection, infusion, or implantation for topical or systemic administration. Parenteral administration as used herein includes intravenous, intra-arterial, intraperitoneal, subarachnoid, 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 solutions or suspensions in liquid before 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 above).

[0178] A pharmaceutical composition intended for parenteral administration includes one or more pharmaceutically acceptable carriers and excipients, for example, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial or antiseptic agents that prevent the growth of microorganisms, stabilizers, dissolution accelerators, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, metal ion sequestering or chelating agents, cryoprotectants, lioprotectants, thickeners, pH adjusters, and inert gases.

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

[0180] The pharmaceutical compositions provided herein may be formulated for single or multiple doses. Single-dose formulations may be filled into ampoules, vials, or syringes. Multiple-dose parenteral formulations must contain an antimicrobial agent at a bacteriostatic or fungal concentration. As is known and practiced in the art, all parenteral formulations must be sterile.

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

[0182] In one embodiment, the therapeutic method disclosed herein includes administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need of treatment. Each example disclosed herein includes treating the above-mentioned disorder or disease by administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need of treatment.

[0183] In one embodiment, the compound of the present invention or its pharmaceutical composition may be administered by any preferred route of administration, including both systemic and topical administration. Systemic administration includes oral, parenteral, transdermal, and rectal administration. Parenteral administration refers to routes 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 topical application to the skin, as well as intraocular, ear, vaginal, inhalation, and intranasal administration. In one embodiment, the compound of the present invention or its pharmaceutical composition may be administered orally. In one embodiment, the compound of the present invention or its pharmaceutical composition may be administered by inhalation. In a further embodiment, the compound of the present invention or its pharmaceutical composition may be administered intranasally.

[0184] In one embodiment, the compound of the present invention or its pharmaceutical composition may be administered in a single dose or according to a dosing regimen in which a large dose is administered at various time intervals over a given period. For example, the dose may be administered once, two, three, or four times per day. In one embodiment, the dose is administered once daily. In a further embodiment, the dose is administered twice daily. The dose may be administered until the desired therapeutic effect is achieved, or indefinitely to maintain the desired therapeutic effect. A suitable dosing regimen for the compound of the present invention or its pharmaceutical composition depends on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, and can be determined by a person skilled in the art. Furthermore, a suitable dosing regimen, including the duration for which the compound of the present invention or its pharmaceutical composition 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 patient's medical history, the nature of the combination therapy, the desired therapeutic effect, and similar factors within the knowledge and expertise of a person skilled in the art. Such a person skilled in the art will further understand that a suitable dosing regimen may need to be adjusted to take into account the individual patient's response to the dosing regimen or the changes in the individual patient's requirements over time.

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

[0186] The compounds provided herein can be used in combination with sedatives, hypnotics, anxiolytics, antipsychotics, anxiety relievers, cyclopyrrolidone, imidazopyridine, pyrazolopyrimidine, minor tranquilizers, melatonin agonists and antagonists, melatonin agonists, benzodiazepines, barbiturates, 5HT-2 antagonists, etc. Examples: Adinazolan, alobarbital, aronimide, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, tacitin, brotizolam, bupropion, buspirone, butabarbital, butarbital, capride, carbochloral, chloral betaine, chloral hydrate, chlorodyne, clomipramine, clonazepam, domperidone, methaminodiazepoxide, chloretate, clozapine, ciprazepam, deci Pramin, dexcramo, diazepam, chloral salicylamide, divalproic acid, diphenhydramine, doxepin, estazolam, etochlorbinol, etomidate, phenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutetimide, harazepam, hydroxyzine, imipramine, lithium, olazepam, lormetazepam, maprotiline, mecloquarone, melatonin, methylphenobarbital, Meprobamate, Metaquaron, Midaflur, Midazolam, Nefazodone, Nisovamate, Nitrazepam, Nortriptyline, Oxezepam, Paraaldehyde, Paroxetine, Pentobarbital, Perlapine, Perphenazine, Phenelzine, Phenobarbital, Prazepam, Promethazine, Isopropylphenol, Protriptyline, Quazepam, Leclazepam, Rolipram, Secobarbital, Sertraline, Suprocron, Temazepam, Chi Oridazine, tracazolate, tranylcypromine, trazodone, triazole benzodiazepines, trepipam, tricetamide, trichloroethyl phosphate, trifluoperazine, trimethodine, trimeprimine, urdazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, and compositions thereof, or physical methods such as phototherapy or electrical stimulation may be used during administration of the compounds disclosed herein.

[0187] Furthermore, 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, upon administration to a patient, ultimately releases the compound of the present invention in vivo. Administration of a compound of the present invention as a prodrug may enable one or more of the following actions to be performed by those skilled in the art: (a) altering the onset of the compound’s action in vivo; (b) altering the duration of the compound’s action in vivo; (c) altering the transport or distribution of the compound in vivo; (d) altering the solubility of the compound in vivo; and (e) overcoming side effects or other problems that may arise with the compound. Typical functional derivatives used in the preparation of prodrugs include modifications of compounds 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 skilled in the art.

[0188] Use of 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 NMDA receptors, and can be used in the preparation of agents that antagonize NMDA receptors.

[0189] All disorders related to NMDA receptors can be selected from any type of neurological and psychiatric disorder or illness.

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

[0191] It should be understood that the symptoms or diseases described above are exacerbated or accelerated under certain environmental conditions such as pressure or fear (pressure can arise from social causes such as social pressure, or from physical causes such as physical pressure, including pressure caused by fear), and that the compounds disclosed herein are particularly useful in treating symptoms and diseases aggravated by these environments.

[0192] In addition to their usefulness in the treatment of humans, the compounds and compositions of the present invention are also useful in the veterinary treatment of animals such as companion animals, exotic animals, and domestic mammals. In other embodiments, the animals disclosed herein include horses, dogs, and cats. When used herein, the compounds disclosed herein include their pharmaceutically acceptable derivatives.

[0193] Preferred Embodiment of the Invention General synthesis methods The following examples are provided to help the invention be better understood. However, it should be understood that these embodiments merely provide methods for carrying out the invention, and the invention is not limited to these embodiments.

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

[0195] Those skilled in the art will recognize that the chemical reactions described can be readily applied to prepare many other compounds disclosed herein, and that alternative methods for preparing the compounds disclosed herein will be considered to fall within the scope of disclosure. Those skilled in the art will recognize that, as demonstrated by the following examples, the compounds encompassed by the present invention can be produced by modifying the starting materials and using further steps. In some cases, protection of certain reactive functional groups may be necessary to achieve the above modifications to some extent. Generally, such a need for protecting groups, and the conditions required to add and remove such groups, will be obvious to those skilled in the art. For example, the synthesis of compounds according to the present invention not illustrated can be successfully carried out by modifications obvious to those skilled in the art, for example, by appropriately protecting interfering groups, by using other suitable reagents known in the art other than those described, and / or by conventionally changing the reaction conditions. Alternatively, known reaction conditions or the reactions disclosed herein will be recognized as having applicability for preparing other compounds disclosed herein.

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

[0197] Preparation of compounds The compounds of the present invention (including their salts, esters, hydrates, or solvates) can be prepared using any known organic synthesis technique and can be synthesized according to any of many possible synthetic routes.

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

[0199] The reaction can be monitored according to any preferred 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) The compounds can be monitored by spectroscopic methods such as infrared spectroscopy, spectrophotometric methods (e.g., UV-Vis), and mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). The compounds can be purified by various 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, as well as synthetic methods known in the field of organic synthesis, or variations thereof that will be understood by those 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) to (Vd) can be synthesized according to the steps outlined in the exemplary general synthesis schemes listed below, where abbreviations of reactants or chemical groups of reactants included in the synthesis schemes are defined in the examples.

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

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

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

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

[0205] Preparation and Characterization of Exemplary Compounds The compounds contained herein can be prepared through various schemes. Detailed preparation methods for 108 exemplary compounds using various schemes are described below, along with their characterization results.

[0206] Unless otherwise specified, all reagents were purchased from commercial suppliers without further purification. Solvent drying was performed using standard methods where necessary. The plates used for thin-layer chromatography (TLC) were E. Merck silica gel 60F254 (thickness 0.24 nm) pre-coated on aluminum plates, and visualization was performed under UV light (365 nm and 254 nm) or by staining with 5% dodecamolybd phosphate in ethanol followed by heating. Column chromatography was performed using silica gel (200-400 mesh) from commercial suppliers. 1 HNMR spectra were recorded at room temperature using a BRUKER AVANCE III HD 500 MHz NMR spectrometer and a BRUKER AVANCE III HD 600 MHz NMR spectrometer. Solvent signals were also recorded. 1The following were used as references for 1H NMR (CDCl3, 7.26 ppm, CD3OD, 3.31 ppm, DMSO-d6, 2.50 ppm, acetone-d6, 2.05 ppm, D2O, 4.79 ppm). The following abbreviations were used to describe multiplicity: s=singlet, d=doublet, t=triplet, q=quartet, br.s=broadsinglet, dd=doubledoublet, td=tripledoublet, dt=doubletriplet, dq=doublequartet, m=multiplet. Other abbreviations used in the experimental details are as follows: δ = chemical shift value in ppm from tetramethylsilane at low magnetic field, 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 = dimethyl sulfoxide, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphine , 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 It should be noted that the embodiments of the present invention detailed below are merely illustrative for the purpose of illustrating the invention and should not be construed as limiting the invention. Examples that do not include specific techniques or conditions can be carried out in accordance with the techniques or conditions of the technical documentation or the product instructions. Reagents or equipment not specified by the manufacturer are available through general purchase. Those skilled in the art will recognize that, as demonstrated by the following examples, the starting materials can be varied and further steps can be used to produce the compounds encompassed by the present invention. [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), 1-chloroethyl carbonochloride (172 mg, 1.2 mmol) was slowly added at 0°C. The reaction mixture was stirred at 25°C for 1.5 hours. 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 obtain an oil, which was purified by silica gel column elution with hexane / EA (1 / 1 to 5 / 1) to obtain 276 mg (79% yield) of compound 2 as a white solid.

number

[0209] Et3N (0.31 mL, 2.18 mmol) was added to an acetone solution (1.7 mL) 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). The reaction mixture was stirred at 25°C for 5 hours. The reaction mixture was concentrated, redissolved in EA (20 mL), and washed with H2O (8 mL), saturated NaHCO3 aqueous solution (2 mL), and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 4 / 6) to obtain 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] 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) were dissolved in acetone (1.2 mL), to which Et3N (0.20 mL, 1.46 mmol) was added. The reaction mixture was stirred at 25°C for 5 hours and then concentrated. The mixture was diluted with EA (20 mL) and filtered. The filtrate was concentrated and then purified by silica gel column elution with hexane / EA (100% hexane ~ 4 / 6) to obtain 50 mg (yield 39%) of the title compound (A-2) as a white foam.

number

[0211] Example 3: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethylacetylglycinate(A-3) [ka] Et3N (0.35 mL, 2.5 mmol) was added 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). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (10 mL), and washed with saturated NaHCO3 aqueous solution (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 2) to obtain 110 mg (35% yield) of the title compound (A-3) as a white foam.

number

[0212] Example 4: 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)ethyl 2-(3-methyloxetan-3-yl)acetate (A-4) [ka] 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) were dissolved in acetone (9 mL), to which Et3N (0.53 mL, 3.8 mmol) was added. The reaction mixture was heated at 70°C for 3 hours. The reaction mixture 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 obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 1) to obtain yellow oil. Ether (3 mL) was added, filtered, and the solid was washed with cold ether to obtain 102 mg (yield 31%) of the title compound (A-4) as a white solid.

number

[0213] The filtrate was concentrated to obtain an oil, which was stored at -20°C to obtain a viscous solid. The mixture was diluted with ether (2 mL), and the filtrate was collected. The filtrate was concentrated to obtain 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)ethylacetyl-L-alaninate (A-5) [ka] Et3N (0.35 mL, 2.5 mmol) was added 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). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 1) to obtain 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)ethylacetyl-L-valinate (A-6) [ka] 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) were dissolved in acetone (6 mL), to which Et3N (0.35 mL, 2.5 mmol) was added. The reaction mixture was heated at 70 °C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 1) to obtain 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] Et3N (0.35 mL, 2.5 mmol) was added 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). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (10 mL), and washed with saturated NaHCO3 aqueous solution (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 4 / 1) to obtain 175 mg (68% yield) of Compound 3 as a white foam.

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[0217] Pd(OH)2 / C (11 mg) was added to a solution of compound 3 (100 mg, 0.19 mmol) in EA (10 mL). The reaction mixture was stirred at 25°C for 50 minutes under an H2 atmosphere. The reaction mixture was filtered through a Celite pad and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane to 1 / 4) to obtain 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), triethylamine (0.35 mL, 2.5 mmol) was added. The reaction mixture was heated at 70°C for 2 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 2) to obtain 180 mg (74% yield) of Compound 4 as a yellow oil.

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[0219] A solution of compound 4 (140 mg, 0.29 mmol) in MeOH (1.4 mL) was added dropwise to a solution of NaIO4 (62 mg, 0.29 mmol) in H2O (0.7 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 hours, filtered, and the filtrate was collected. The filtrate was concentrated and purified using a silica gel column eluted with DCM / MeOH (100% DCM~98 / 2) to obtain 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] A solution of compound 4 (141 mg, 0.29 mmol) in MeOH (1.1 mL) was added dropwise to a solution of Oxon (356 mg, 0.58 mmol) in H2O (0.9 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with H2O (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 1) to obtain 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-hydroxypronoate(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), Et3N (0.35 mL, 2.5 mmol) was added. The reaction mixture was heated at 70°C for 3.5 hours. The reaction mixture 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 obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 2) to obtain 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] Et3N (0.35 mL, 2.5 mmol) was added 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). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 65 / 35) to obtain 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] Et3N (0.18 mL, 1.25 mmol) was added 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). The reaction mixture was heated at 70°C for 3 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 1) to obtain 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] Et3N (0.11 mL, 0.78 mmol) was added 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). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 4 / 1) to obtain 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)ethylbenzo[d][1,3]dioxol-5-carboxylate(A-14) [ka] Compound 2 (86 mg, 0.25 mmol), NaI (39 mg, 0.26 mmol), and benzo[d][1,3]dioxol-5-carboxylic acid (125 mg, 0.75 mmol) were dissolved in acetone (3 mL), to which Et3N (0.18 mL, 1.25 mmol) was added. The reaction mixture was heated at 70 °C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 7 / 3) to obtain 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] Et3N (0.18 mL, 1.25 mmol) was added to a DMSO (1 mL) 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). The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated and then purified by silica gel column elution with DCM / MeOH (100% hexane ~ 95 / 5) to obtain 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] Et3N (0.18 mL, 1.25 mmol) was added 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). The reaction mixture was heated at 70°C for 3 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 4 / 1) to obtain 50 mg (46% yield) of the title compound (A-16) as a white solid.

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[0228] Example 17: 1-(2-(isobutylamide)acetoyloxy)ethyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-17) [ka] Et3N (0.18 mL, 1.25 mmol) was added to a solution of Compound 2 (86 mg, 0.25 mmol), NaI (75 mg, 0.5 mmol), and 2-(isobutylamido)acetic acid (109 mg, 0.75 mmol) in acetone (3 mL). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 1) to obtain 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] Et3N (0.18 mL, 1.25 mmol) was added 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). The reaction mixture was heated at 70°C for 22 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 2) to obtain 20 mg (yield 18%) 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] Et3N (0.18 mL, 1.25 mmol) was added 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). The reaction mixture was heated at 70°C for 22 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 2) to obtain 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] Chloromethyl chloroformate (121 mg, 0.94 mmol) was slowly added at 0°C 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). The reaction mixture was stirred at 25°C for 24 hours. The reaction mixture 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 obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 9 / 1) to obtain 93 mg (yield 75%) of compound 5 as a white solid.

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[0232] 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) were dissolved in acetone (3 mL), to which K2CO3 (173 mg, 1.25 mmol) was added. The reaction mixture was heated at 70°C for 2 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 2) to obtain 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] Et3N (0.18 mL, 1.25 mmol) was added 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). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA(7 / 3) to obtain 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), 1-chloroethyl carbonochloride (94 mg, 0.6 mmol) was slowly added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture 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 obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 1) to obtain 133 mg (yield 74%) of compound 6 as a colorless oil.

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[0235] 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) were dissolved in acetone (1 mL), to which Et3N (0.18 mL, 1.25 mmol) was added. The reaction mixture was heated at 70 °C for 10 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 2) to obtain 32 mg (yield 28%) of the title compound (A-22) as 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] Et3N (0.18 mL, 1.25 mmol) was added 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). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, dissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA(7 / 3) to obtain 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-oxocyclohexylmethylcarbamate(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), 1-chloro-2-methylpropyl chloroformate (312 mg, 1.83 mmol) was slowly added at 0°C, and the mixture was then stirred at 25°C for 1 hour. The reaction mixture 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 obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 9 / 1) to obtain 230 mg (yield 85%) of compound 7 as a white solid.

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[0238] 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) were dissolved in acetone (3 mL), to which Et3N (0.18 mL, 1.25 mmol) was added. The reaction mixture was heated at 70 °C for 5 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA(7 / 3) to obtain 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)propylacetylglycinate (A-25) [ka] Et3N (0.18 mL, 1.25 mmol) was added 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). The reaction mixture was heated at 70°C for 10 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (1 / 0~1 / 2) to obtain 18 mg (16% yield) of the title compound (A-25) as a white solid.

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[0240] Example 26: 1-(2-acetamidoacetyloxy)-2-methylpropyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-26) [ka] Et3N (0.18 mL, 1.25 mmol) was added 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). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA(2 / 3) to obtain 29 mg (yield 28%) 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] Et3N (0.18 mL, 1.25 mmol) was added 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). The reaction mixture was heated at 70°C for 2 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA(3 / 2) to obtain 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)cyclohexane-1-one (A-28) [ka] S-ketamine hydrochloride 1 (68 mg, 0.25 mmol) was mixed with a solution of iodomethane-d3 (109 mg, 0.75 mmol) and Cs2CO3 (163 mg, 0.5 mmol) in DMF (5 mL). The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture 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 obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 1) to obtain 16 mg (yield 23%) of the title compound (A-28) as a yellow solid.

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[0243] Example 29: (2-Acetamidoacetyloxy)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), K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 3 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane to 1 / 4) to obtain 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] 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) were dissolved in acetone (2 mL), to which K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 3 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane to 1 / 4) to obtain 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] Compound 5 (50 mg, 0.15 mmol), NaI (46 mg, 0.3 mmol), and (S)-2-acetamidopropanoic acid (60 mg, 0.46 mmol) were dissolved in acetone (1.8 mL), to which K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 13 / 7) to obtain 52 mg (81% yield) of the title compound (A-31) as a white foam.

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[0246] Example 32: (2-(isobutylamide)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-(isobutylamido)acetic acid (66 mg, 0.46 mmol) in acetone (1.8 mL), K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 1) to obtain 47 mg (70% yield) of the title compound (A-32) as a white foam.

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[0247] Example 33: ((S)-2-(isobutylamide)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-(isobutylamide)propanoic acid (72 mg, 0.45 mmol) in acetone (2 mL), K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 4 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 2) to obtain 30 mg (44% yield) of the title compound (A-33) as a white foam.

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[0248] Example 34: ((S)-2-(isobutylamide)-3-methylbutanoyloxy)methyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-34) [ka] Compound 5 (50 mg, 0.15 mmol), NaI (46 mg, 0.3 mmol), and (S)-2-(isobutyramide)-3-methylbutanoic acid (102 mg, 0.46 mmol) were dissolved in acetone (1.8 mL), to which K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 7 / 3) to obtain 67 mg (yield 93%) 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] Compound 5 (150 mg, 0.46 mmol), NaI (137 mg, 0.9 mmol), and N-(tert-butoxycarbonyl)-L-valine (297 mg, 1.4 mmol) were dissolved in acetone (5.4 mL), to which K2CO3 (315 mg, 2.3 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 4 / 1) to obtain 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), TFA (0.19 mL, 2.5 mmol) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated to obtain 67 mg of the title compound (A-35) in the form of the TFA salt as a colorless gum.

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[0251] Example 36: (S)-(((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)carbamoyl)oxy)methylglycinate (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), K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 7 / 3) to obtain 54 mg (76% yield) of compound 9 as a white foam.

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[0252] TFA (0.07 mL, 0.96 mmol) was added to a solution of compound 9 (25 mg, 0.05 mmol) in DCM (1.9 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to obtain the title compound (A-36) in the form of a 25 mg TFA salt 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 minutes. Formaldehyde (37% in H2O, 0.02 mmol) was added at 0°C and the reaction mixture was stirred at 25°C for 2.5 hours. The reaction was rapidly cooled with saturated NaHCO3 aqueous solution (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 obtain a solid. After washing the solid with hexane, it was recrystallized from DCM and hexane at 4°C. After 16 hours, the mixture was filtered, the filtrate was collected and concentrated to obtain 20 mg (46% yield) of the title compound (A-37) as a white solid.

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[0254] Example 38: (2-(N-methylacetamide)acetyloxy)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), K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane to 1 / 4) to obtain 25 mg (39% yield) of the title compound (A-38) as a white foam.

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[0255] Example 39: 1-(2-(N-methylacetamide)acetoyloxy)ethyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-39) [ka] Et3N (0.10 mL, 0.73 mmol) was added 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). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane to 1 / 4) to obtain 36 mg (57% yield) of the title compound (A-39) as a white foam.

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

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[0257] Example 41: (2-(propionamide)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), K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 2 / 3) to obtain 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] 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) were dissolved in acetone (5 mL), to which K2CO3 (314 mg, 2.27 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (10 mL), and washed with saturated NaHCO3 aqueous solution (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 2) to obtain 200 mg (91% yield) of compound 10 as a white foam.

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

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[0260] Example 43: 1-(2-(propionamide)acetoyloxy)ethyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-43) [ka] Compound 2 (103 mg, 0.3 mmol), NaI (47 mg, 0.315 mmol), and 2-(2,2,2-trifluoroacetamide)-acetic acid (154 mg, 0.9 mmol) were dissolved in acetone (4 mL), to which Et3N (0.21 mL, 1.5 mmol) was added. The reaction mixture was heated at 70 °C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 1) to obtain 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-trifluoroacetamide)acetoyloxy)methyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-44) [ka] 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) were dissolved in acetone (4 mL), to which Et3N (0.1 mL, 0.76 mmol) was added. The reaction mixture was heated at 70 °C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 7 / 3) to obtain 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)ethyldimethyl-L-alaninate (A-45) [ka] Et3N (0.06 mL, 0.45 mmol) was added 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). The reaction mixture was heated at 70°C for 20 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane to 1 / 3) to obtain 14 mg (yield 37%) of the title compound (A-45) as a yellow gum.

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[0263] Example 46: ((S)-2-(2,2,2-trifluoroacetamide)-3-methylbutanoyloxy)methyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbanate (A-46) [ka] Compound 5 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol), and (S)-2-(2,2,2-trifluoroacetamide)-3-methylbutanoic acid (97 mg, 0.45 mmol) were dissolved in acetone (2 mL), to which Et3N (0.11 mL, 0.76 mmol) was added. The reaction mixture was heated at 70 °C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 4 / 1) to obtain 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-trifluoroacetamide)acetoyloxy)propyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-47) [ka] Compound 6 (50 mg, 0.14 mmol), NaI (22 mg, 0.15 mmol), and 2-(2,2,2-trifluoroacetamide)-acetic acid (72 mg, 0.42 mmol) were dissolved in acetone (1.8 mL), to which Et3N (0.1 mL, 0.7 mmol) was added. The reaction mixture was heated at 70 °C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 1) to obtain 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-trifluoroacetamide)propanoyloxy)methyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-48) [ka] Compound 5 (50 mg, 0.15 mmol), NaI (45 mg, 0.30 mmol), and (S)-2-(2,2,2-trifluoroacetamide)propanoic acid (84 mg, 0.45 mmol) were dissolved in acetone (2 mL), to which Et3N (0.11 mL, 0.76 mmol) was added. The reaction mixture was heated at 70 °C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 4 / 1) to obtain 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-trifluoroacetamide)acetoyloxy)-2-methylpropyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-49) [ka] Compound 7 (93 mg, 0.25 mmol), NaI (39 mg, 0.26 mmol), and 2-(2,2,2-trifluoroacetamido)acetic acid (128 mg, 0.75 mmol) were dissolved in acetone (3 mL), to which Et3N (0.17 mL, 1.25 mmol) was added. The reaction mixture was heated at 70 °C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 1) to obtain 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-trifluoroacetamide)-3-methylbutanoyloxy)ethyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-50) [ka] Compound 2 (103 mg, 0.3 mmol), NaI (47 mg, 0.315 mmol), and (S)-2-(2,2,2-trifluoroacetamide)-3-methylbutanoic acid (192 mg, 0.9 mmol) were dissolved in acetone (4 mL), to which Et3N (0.21 mL, 1.5 mmol) was added. The reaction mixture was heated at 70 °C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 17 / 3) to obtain 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-trifluoroacetamide)propanoyloxy)ethyl(S)-1-(2-chlorophenyl)-2-oxocyclohexylmethylcarbamate (A-51) [ka] Compound 2 (103 mg, 0.3 mmol), NaI (47 mg, 0.315 mmol), and (S)-2-(2,2,2-trifluoroacetamide)propanoic acid (167 mg, 0.9 mmol) were dissolved in acetone (4 mL), to which Et3N (0.21 mL, 1.5 mmol) was added. The reaction mixture was heated at 70 °C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 4 / 1) to obtain 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] Compound 5 (100 mg, 0.3 mmol), NaI (90 mg, 0.6 mmol), and 4-methylpyridine-3-carboxylic acid (123 mg, 0.9 mmol) were dissolved in acetone (4 mL), to which Et3N (0.21 mL, 1.5 mmol) was added. The reaction mixture was heated at 70 °C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 2) to obtain 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] Compound 5 (100 mg, 0.3 mmol), NaI (90 mg, 0.6 mmol), and 2-methylpyridine-3-carboxylic acid (123 mg, 0.9 mmol) were dissolved in acetone (4 mL), to which Et3N (0.21 mL, 1.5 mmol) was added. The reaction mixture was heated at 70 °C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 2) to obtain 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] Compound 5 (100 mg, 0.3 mmol), NaI (90 mg, 0.6 mmol), and 6-methylpyridine-3-carboxylic acid (123 mg, 0.9 mmol) were dissolved in acetone (4 mL), to which Et3N (0.21 mL, 1.5 mmol) was added. The reaction mixture was heated at 70 °C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (1 / 0~3 / 2) to obtain 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] 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) were dissolved in acetone (4 mL), to which Et3N (0.21 mL, 1.5 mmol) was added. The reaction mixture was heated at 70 °C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 11 / 9) to obtain 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] 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) were dissolved in acetone (4 mL), to which K2CO3 (207 mg, 1.5 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 2) to obtain 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] 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) were dissolved in acetone (4 mL), to which Et3N (0.163 mL, 1.17 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture 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 obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 2 / 3) to obtain 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), K2CO3 (209 mg, 1.51 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 2) to obtain 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), K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 2 / 3) to obtain 40 mg (yield 60%) of the title compound (A-59) as a pale yellow foam.

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[0277] Example 60: 1-(2-acetamidoacetyloxy)ethyl(R)-1-(2-chlorophenyl)-2-oxocyclohexyl-methylcarbamate (A-60) [ka] 1-chloroethyl carbonochloride (1.50 g, 10.5 mmol) was slowly added at 0°C 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). The reaction mixture was stirred at 25°C for 1.5 hours. The reaction mixture 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 obtain oil. The oil was diluted with ice MeOH and filtered to obtain 1.14 g (80% yield) of compound 12 as a white solid.

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[0278] Et3N (0.1 mL, 0.75 mmol) was added 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). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (10 mL), and washed with saturated NaHCO3 aqueous solution (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (1 / 0~1 / 2) to obtain 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] 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) were dissolved in acetone (5 mL), to which K2CO3 (242 mg, 1.75 mmol) was added. The reaction mixture was heated at 70°C for 4 hours. The reaction mixture 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 obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 1) to obtain yellow oil. Ether (3 mL) was added, filtered, and the solid was washed with cold ether to obtain 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] Et3N (0.1 mL, 0.75 mmol) was added 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). The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 1) to obtain 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] 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) were dissolved in acetone (1 mL), to which Et3N (0.1 mL, 0.75 mmol) was added. The reaction mixture was heated at 70 °C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 1) to obtain 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] 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) were dissolved in acetone (3 mL), to which K2CO3 (254 mg, 1.84 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 2) to obtain 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] Et3N (1.05 mL, 7.5 mmol) was added 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). The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA(3 / 2) to obtain 188 mg (30% yield) of the title compound (A-65) as a white solid.

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[0284] Example 66: (2-Acetamidoacetyloxy)methyl 1-(2-chlorophenyl)-2-oxocyclohexyl-methylcarbamate (A-66) [ka] K2CO3 (105 mg, 0.76 mmol) was added 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). The reaction mixture was heated at 70°C for 3 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 4 / 1) to obtain 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), K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 3 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane to 1 / 4) to obtain 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] K2CO3 (105 mg, 0.76 mmol) was added 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). The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 13 / 7) to obtain 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), K2CO3 (104 mg, 0.75 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 2) to obtain 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] 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) were dissolved in acetone (2 mL), to which K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 2) to obtain 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), K2CO3 (105 mg, 0.76 mmol) was added. The reaction mixture was heated at 70°C for 1 hour. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 2 / 3) to obtain 42 mg (yield 64%) 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 12 mL solution of diphosgene (237 mg, 1.2 mmol) in DCM, a 12 mL solution of ethyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-tyrosinate (863 mg, 2 mmol) in DCM was slowly added at 0°C. Then, a 24 mL solution of DIPEA (1.05 mL, 6 mmol) in THF was added dropwise at 0°C within 30 minutes. The reaction mixture was stirred at 0°C for 30 minutes, and then compound 1 (274 mg, 1 mmol) and a 15 mL solution of DIPEA (0.18 mL, 1 mmol) in DCM were added. The reaction mixture was warmed to 25°C and stirred for 16 hours. The reaction mixture was poured into H₂O (50 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was then purified using a silica gel column eluted with hexane / EA (100% hexane to 1 / 4) to obtain 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), piperidine (0.21 mL, 2.2 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was washed with H2O (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with DCM / MeOH (100% DCM~97 / 3) to obtain 75 mg (yield 74%) of the title compound (A-72) as 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 6 mL solution of diphosgene (119 mg, 0.6 mmol) in DCM, a 6 mL solution of 2-hydroxyethyl acetate (104 mg, 1 mmol) in DCM was slowly added at 0°C, followed by the dropwise addition of a 6 mL solution of DIPEA (0.52 mg, 3 mmol) in THF (6 mL) at 0°C within 30 minutes. The reaction mixture was stirred at 0°C for 1 hour, after which compound 1 (137 mg, 0.5 mmol) and a 6 mL solution of DIPEA (0.087 mL, 0.5 mmol) in DCM were added. The reaction mixture was warmed to 25°C and stirred for 16 hours. The reaction mixture was poured into 20 mL of H2O and extracted with 20 mL x 2 of DCM. The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was then purified using a silica gel column eluted with hexane / EA (100% hexane to 1 / 2) to obtain 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] Compound (A-73) (74 mg, 0.2 mmol) was dissolved in THF (3 mL) and LiOH aqueous solution (0.5 mL, 1 M) was added at 0°C. The reaction mixture was stirred at 25°C for 1.5 hours and then concentrated. The mixture was diluted with H2O (3 mL), pH adjusted to 3 with HCl aqueous solution (1 M), and then extracted with DCM (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain 50 mg (yield 74%) 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 6 mL solution of diphosgene (119 mg, 0.6 mmol) in DCM, a 6 mL solution of 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (130 mg, 1 mmol) in DCM was slowly added at 0°C, followed by the dropwise addition of a 6 mL solution of DIPEA (0.52 mg, 3 mmol) in THF (6 mL) at 0°C within 30 minutes. The reaction mixture was stirred at 0°C for 1 hour, after which compound 1 (137 mg, 0.5 mmol) and a 6 mL solution of DIPEA (0.087 mL, 0.5 mmol) in DCM were added. The reaction mixture was warmed to 25°C and stirred for 16 hours. The reaction mixture was poured into 20 mL of H2O and extracted with 20 mL x 2 of DCM. The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was then purified using a silica gel column eluted with hexane / EA (100% hexane to 1 / 3) to obtain 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 4.5 mL solution of diphosgene (89 mg, 0.45 mmol) in DCM, a 4.5 mL solution of ethyl (S)-2-hydroxypropanoate (89 mg, 0.75 mmol) in DCM was slowly added at 0°C, and then a 9 mL solution of DIPEA (0.4 mL, 2.25 mmol) in THF was added dropwise at 0°C within 30 minutes. The reaction mixture was stirred at 0°C for 2 hours, and then compound 1 (68 mg, 0.25 mmol) and a 3.75 mL solution of DIPEA (0.044 mL, 0.25 mmol) in DCM were added. The reaction mixture was warmed to 25°C and stirred for 24 hours. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was then purified using a silica gel column eluted with hexane / EA (100% hexane ~ 1 / 4) to obtain 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 3 mL solution of diphosgene (59 mg, 0.3 mmol) in DCM, a 3 mL solution of (3-methyloxetan-3-yl)methanol (51 mg, 0.5 mmol) in DCM was slowly added at 0°C. Then, a 6 mL solution of DIPEA (0.26 mL, 1.5 mmol) in THF was added dropwise at 0°C within 30 minutes. The reaction mixture was stirred at 0°C for 2 hours, and then compound 1 (46 mg, 0.17 mmol) and a 3 mL solution of DIPEA (0.029 mL, 0.17 mmol) in DCM were added. The reaction mixture was warmed to 25°C and stirred for 24 hours. The reaction mixture was poured into H₂O (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was then purified using a silica gel column eluted with hexane / EA (100% hexane to 1 / 3) to obtain 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 the dropwise addition of a solution of DIPEA (1.57 mL, 9 mmol) in THF (36 mL) at 0°C within 30 minutes. The reaction mixture was stirred at 0°C for 2 hours, after which compound 1 (273 mg, 1.0 mmol) and a solution of DIPEA (0.175 mL, 1.0 mmol) in DCM (15 mL) were added. The reaction mixture was warmed to 25°C and stirred for 24 hours. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was then purified using a silica gel column eluted with hexane / EA (100% hexane to 1 / 3) to obtain 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] A solution of compound (A-78) (33 mg, 0.08 mmol) in MeOH (0.3 mL) was added dropwise to a solution of Oxon (96 mg, 0.16 mmol) in H2O (0.3 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with H2O (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (1 / 2) to obtain 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] A solution of compound (A-78) (85 mg, 0.2 mmol) in MeOH (0.8 mL) was added dropwise to a solution of NaIO4 (43 mg, 0.2 mmol) in H2O (0.4 mL) at 0°C. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL), and washed with H2O (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with DCM / MeOH (100% DCM~97 / 3) to obtain 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), an aqueous solution of LiOH (0.3 mL, 1 M) was added at 0°C. The reaction mixture was stirred at 25°C for 4 hours 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 obtain 16 mg (yield 37%) 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 13.5 mL solution of diphosgene (267 mg, 1.35 mmol) in DCM, a 13.5 mL solution of (2,2,5-trimethyl-1,3-dioxan-5-yl)methanol (361 mg, 2.25 mmol) in DCM was slowly added at 0°C. Then, a 27 mL solution of DIPEA (1.18 mL, 6.75 mmol) in THF was added dropwise at 0°C within 30 minutes. The reaction mixture was stirred at 0°C for 2 hours, and then compound 1 (206 mg, 0.75 mmol) and a 11 mL solution of DIPEA (0.131 mL, 0.75 mmol) in DCM were added. The reaction mixture was warmed to 25°C and stirred for 16 hours. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified using a silica gel column eluted with hexane / EA(9 / 1) to obtain 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), an HCl solution (0.42 mL, 0.2 M in EA) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated and then purified by silica gel column elution with hexane / EA (1 / 1) to obtain 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 13.5 mL solution of diphosgene (267 mg, 1.35 mmol) in DCM, a 13.5 mL solution of 1,2,3,4-tetra-O-acetyl-β-D-glucopyranose (361 mg, 2.25 mmol) in DCM was slowly added at 0°C. Then, a 27 mL solution of DIPEA (1.18 mL, 6.75 mmol) in THF was added dropwise at 0°C within 30 minutes. The reaction mixture was stirred at 0°C for 2 hours, and then compound 1 (206 mg, 0.75 mmol) and a 11 mL solution of DIPEA (0.131 mL, 0.75 mmol) in DCM were added. The reaction mixture was warmed to 25°C and stirred for 16 hours. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried with MgSO4, filtered, and concentrated to obtain crude oil 16, which was immediately used in the following reaction.

[0304] To a solution of compound 16 in MeOH (40 mL), 3% NaOMe (0.9 mL in MeOH) at 25°C was added. The reaction mixture was stirred at 25°C for 2 hours, then the pH was adjusted to 3 using Dowex® 50W x 4 hydrogenation, filtered, and concentrated to obtain an oil. This oil was purified by silica gel column elution with DCM / MeOH (100% DCM~9 / 1) to obtain 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), CH3I (1.01 g, 71.1 mmol) and Ag2O (1.16 g, 5.0 mmol) were added. The suspension was stirred at 25°C for 16 hours. The mixture was filtered through Celite and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 95 / 5) to obtain 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), NaBH4 (3.0 g, 78.3 mmol) was added. The reaction mixture was stirred at 25°C for 4 hours, and then compound 18 (965 mg, 4.35 mmol) was added. The reaction mixture was heated under reflux and stirred for 16 hours. The reaction mixture was poured into ice water and extracted with DCM. The organic layer was dried over MgSO4, filtered, and evaporated to obtain 836 mg (99% yield) of compound 19 as a white solid.

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

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[0308] Pd(OH)2 / C (15 mg) was added to a solution of compound 20 (100 mg, 0.22 mmol) in EA (10 mL). The reaction mixture was stirred at 25°C for 30 minutes under an H2 atmosphere. The reaction mixture was filtered through a Celite pad and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane~EA) to obtain 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 4.5 mL solution of diphosgene (89 mg, 0.45 mmol) in DCM, a 4.5 mL solution of (9H-fluoren-9-yl)methyl 3-hydroxypropyl methyl carbamate (234 mg, 0.75 mmol) in DCM was slowly added at 0°C, followed by the dropwise addition of a 9.0 mL solution of DIPEA (0.392 mL, 2.25 mmol) in THF at 0°C within 30 minutes. The reaction mixture was stirred at 0°C for 1 hour, and then compound 1 (134 mg, 0.49 mmol) and a 4.0 mL solution of DIPEA (0.044 mL, 0.25 mmol) in DCM were added. The reaction mixture was warmed to 25°C and stirred for 16 hours. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was then purified using a silica gel column eluted with hexane / EA(8 / 2) to obtain 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), piperidine (1 mL) was added. The reaction mixture was stirred at 25°C for 1.5 hours. The reaction mixture was poured into an aqueous HCl solution (20 mL, 1 M) and extracted with DCM (20 mL x 2). The organic layer was extracted with a saturated aqueous NaHCO3 solution (20 mL), then dried over MgSO4, filtered, and concentrated to obtain an oil. This oil was purified by silica gel column elution with hexane / EA (100% hexane ~ 2 / 5) to obtain 28 mg (yield 57%) 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 9.0 mL solution of diphosgene (166 mg, 0.84 mmol) in DCM, a 9 mL solution of (9H-fluoren-9-yl)methyl 3-hydroxypropyl carbamate (414 mg, 1.39 mmol) in DCM was slowly added at 0°C. Then, a 18 mL solution of DIPEA (0.728 mL, 4.17 mmol) in THF was added dropwise at 0°C within 30 minutes. The reaction mixture was stirred at 0°C for 1 hour, and then a 7.5 mL solution of compound 1 (127 mg, 0.46 mmol) and DIPEA (0.081 mL, 0.46 mmol) in DCM was added. The reaction mixture was warmed to 25°C and stirred for 16 hours. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was then purified using a silica gel column eluted with hexane / EA(8 / 2) to obtain 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), piperidine (1 mL) was added. The reaction mixture was stirred at 25°C for 1.5 hours. The reaction mixture was poured into an aqueous HCl solution (20 mL, 1 M) and extracted with DCM (20 mL x 2). The organic layer was extracted with a saturated aqueous NaHCO3 solution (20 mL), then dried over MgSO4, filtered, and concentrated to obtain an oil. This oil was purified by silica gel column elution with hexane / EA (100% hexane ~ 2 / 5) to obtain 30 mg (yield 67%) 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), acetic acid (0.011 mL, 0.193 mmol) and NaBH3CN (6.0 mg, 0.096 mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 5 minutes, and then formaldehyde (0.004 mL, 0.118 mmol) was added. The reaction mixture was warmed to 25°C and stirred for 2 hours. The reaction mixture was poured into a saturated NaHCO3 aqueous solution (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain 14 mg (yield 79%) 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-oxopropane-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), (S)-1-(chlorocarbonyl)ethyl acetate (0.17 mL, 1.4 mmol) was added dropwise at 0°C. The mixture was warmed to 25°C and stirred for 3 hours. The reaction product was poured into a saturated aqueous solution of NaHCO3 (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (85 / 15) to obtain 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), methyl (chlorocarbonyl)acetate (0.09 mL, 0.8 mmol) was added dropwise at 0°C. The reaction mixture was heated to 25°C and stirred for 3 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA (85 / 15) to obtain 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] Nicotinoyl chloride hydrochloride (534 mg, 3 mmol) was added at 0°C to a solution of compound 1 (237 mg, 1 mmol) and Et3N (0.63 mL, 4.5 mmol) in DCM (6 mL). The reaction mixture was heated to 25°C and stirred for 3 hours. The reaction mixture was poured into saturated NaHCO3 aqueous solution (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 3 / 2) to obtain 274 mg (yield 80%) 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-methylpyridine-1-ium iodide (A-91) [ka] To a solution of compound (A-90) (103 mg, 0.3 mmol) in CH3CN (3 mL), CH3I (0.09 mL, 1.5 mmol) was added. The reaction mixture was heated at 80 °C for 16 hours, and the solvent was removed under vacuum. Ether (3 mL) was added, the mixture was filtered, and the solid was washed with cold ether to obtain 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) and DIPEA (0.29 mL, 1.65 mmol) in DCM (3.0 mL), methyl 3-(chlorocarbonyl)propanoate (0.1 mL, 0.825 mmol) was added dropwise at 0°C. The reaction mixture was warmed to 25°C and stirred for 2 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA(3 / 1) to obtain 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), an aqueous solution of LiOH (0.7 mL, 1 M) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours and then concentrated. The mixture was diluted with H2O (3 mL), the pH was adjusted to 3 with aqueous HCl (1 M), and then extracted with DCM (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain 83 mg (yield 83%) 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-oxoethane-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), DIPEA (0.13 mL, 0.75 mmol) was added. The reaction mixture was microwaved at 70 °C for 20 minutes. The reaction mixture 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 obtain oil, which was purified by silica gel column elution with hexane / EA (1 / 0 to 3 / 2) to obtain a white foam. The white foam was dissolved in EA (1.5 mL) and HCl (0.15 mL, 2 N, EA solution) was added. The reaction mixture was stirred at 25°C for 16 hours, filtered, and the solid was washed with cold EA to obtain 35 mg (38% yield) of the title compound (A-94) as a white solid.

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[0321] Example 95: (S)-2-acetamide-N-(1-(2-chlorophenyl)-2-oxocyclohexyl)-N-methylacetamide (A-95) [ka] To a solution of compound (A-94) (35 mg, 0.12 mmol) and Et3N (0.033 mL, 0.24 mmol) in DCM (2 mL), acetyl chloride (0.013 mL, 0.18 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture 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 obtain an oil, which was purified by silica gel column elution with hexane / EA (100% hexane ~ 1 / 2) to obtain 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 mg, 0.6 mmol) in DCM (4 mL), DIPEA (0.26 mL, 1.5 mmol) was added. The reaction mixture was microwaved at 70 °C for 30 minutes. The reaction mixture 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 obtain an oil, which was purified by silica gel column elution with DCM / EA (100% DCM~9 / 1) to obtain 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), DIPEA (0.13 mL, 0.75 mmol) was added. The reaction mixture was microwaved at 70°C for 30 minutes. The reaction mixture 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 obtain oil, which was purified by silica gel column elution with DCM / EA (100% DCM~9 / 1) to obtain 47 mg (yield 51%) 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), DIPEA (0.26 mL, 1.5 mmol) was added. The reaction mixture was microwaved at 70°C for 20 minutes. The reaction product 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 obtain oil, which was purified by silica gel column elution with hexane / EA (1 / 0~2 / 1) to obtain a white foam. The white foam was dissolved in ether (1.5 mL) and HCl (1.5 mL, 2N ether solution) was added. The reaction mixture was stirred at 25°C for 16 hours, filtered, and the solid was washed with cold ether to obtain 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] Compound 1 (68 mg, 0.25 mmol), 4-(dimethylamino)butanoate (84 mg, 0.5 mmol), and HATU (190 mg, 0.5 mmol) were mixed in DCM (2 mL) and DIPEA (0.22 mL, 1.25 mmol) was added. The reaction mixture was microwaved at 70°C for 30 minutes. The reaction mixture 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 obtain an oil, which was purified by silica gel column elution with DCM / EA (1 / 1) to obtain 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)benzylisobutyrate (A-100) [ka] To a solution of compound 22 (304 mg, 2.0 mmol) in 1,4-dioxane (5 mL), isobutyric anhydride (0.497 mL, 3.0 mmol) and 1-methylimidazole (0.24 mL, 3.0 mmol) were added. The reaction mixture was stirred at 25°C for 1 hour, 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 obtain an oil, which was purified by silica gel column elution with hexane / EA(8 / 2) to obtain 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), oxalyl chloride (0.043 mL, 0.498 mmol) was added. The reaction mixture was stirred at 25°C for 4 hours, 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 mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with DCM (10 mL) and washed with H2O (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA (85 / 15) to obtain 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] 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) were dissolved in DCM (2 mL), to which DIPEA (0.13 mL, 0.75 mmol) was added. The reaction mixture was irradiated with microwaves at 70°C for 1 hour. The reaction product 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 obtain oil, which was purified by silica gel column elution with hexane / EA(7 / 3) to obtain 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), HCl (3 mL, 1 M solution in EA) was added. The reaction mixture was stirred at 25°C for 16 hours and filtered to obtain a solid. This solid was poured into a saturated aqueous solution of NaHCO3 (20 mL) and extracted with DCM (20 mL x 2). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with DCM / EA (1 / 1) to obtain 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), anhydride acetate (0.28 mL, 3.0 mmol) and 1-methylimidazole (0.240 mL, 3.0 mmol) were added. The reaction mixture was stirred at 25°C for 1 hour, and the solvent was removed under vacuum. The reaction mixture was diluted with DCM (10 mL) and washed with H2O (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was purified by silica gel column elution with hexane / EA(8 / 2) to obtain 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), oxalyl chloride (0.064 mL, 0.75 mmol) was added. The reaction mixture was stirred at 25°C for 4 hours, 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 mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with DCM (10 mL) and washed with H2O (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA(7 / 3) to obtain 22 mg (yield 21%) 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)phenylisobutyrate (A-103) [ka] 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) were dissolved in DCM (5 mL), to which DIPEA (0.33 mL, 1.9 mmol) was added. The reaction mixture was heated at 40°C for 3 hours. The reaction mixture 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 obtain an oil, which was purified by silica gel column elution with hexane / EA(3 / 1) to obtain 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)phenylacetate (A-104) [ka] To a solution of compound 26 (51.5 mg, 0.25 mmol) in DCM (2 mL), oxalyl chloride (0.043 mL, 0.5 mmol) was added. The reaction mixture was stirred at 25°C for 4 hours, 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 mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with DCM (10 mL) and washed with H2O (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain oil, which was purified by silica gel column elution with hexane / EA(7 / 3) to obtain 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), an aqueous solution of LiOH (0.8 mL, 1 M) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours 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 obtain an oil, which was recrystallized from DCM and hexane to obtain 12 mg (yield 66%) 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), Et3N (0.21 mL, 1.5 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 22 hours. 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 obtain 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), oxalyl chloride (0.26 mL, 3 mmol) and a few drops of DMF were added. The mixture was stirred at 25°C for 1 hour 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 mixture was stirred at 25°C for 2 hours. 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 obtain oil, which was purified by silica gel column elution with hexane / EA(4 / 1) to obtain 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 25 mL solution of compound 27 (1.3 g, 9.08 mmol) in DCM, (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) solutions were added dropwise. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was diluted with DCM (100 mL) and washed with H2O (25 mL). The organic layer was separated and washed with 1 M aqueous HCl, then saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain an oil, which was then purified using a silica gel column eluted with hexane / EA(7 / 3) to obtain 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), TFA (5.0 mL) was added. The reaction mixture was stirred at 25°C for 16 hours and then concentrated. The reaction mixture was diluted with DCM (10 mL) and washed with H2O (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain a sticky oil (360 mg), which was dissolved in DCM (8 mL) and saturated NaHCO3 aqueous solution (12 mL) was added. Diphosgene (166 mg, 0.84 mmol) was slowly added to the solution at 0°C. The mixture was stirred at 25°C for 5 hours. The reaction mixture was diluted with DCM (10 mL) and washed with H2O (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain compound 29 (373 mg) as a sticky oil.

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

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[0340] Compound 30 (187 mg, 0.39 mmol) was dissolved in THF (4 mL) and then LiOH aqueous solution (2 mL, 1 M) was added. The reaction mixture was stirred at 25°C for 1 hour and then concentrated. The reaction mixture 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 obtain an oil, which was purified by silica gel column elution with hexane / EA (1 / 1) to obtain 110 mg (63% yield) of the title compound (A-108) as a white solid.

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[0341] Example 109: Metabolic stability assay of a test compound Metabolic stability assay of the liver S9 fraction in mice, rats, dogs, monkeys, and humans. Using protocols for metabolic stability assays of the liver S9 fraction in mice, rats, dogs, monkeys, or humans, the half-life (T) of the compounds disclosed herein was determined. 1 / 2 ), and the release efficiency of their conversion to S-ketamine are measured in vitro.

[0342] The following is a summary of the S9 assay study. 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 were stored at -80°C before use. 2) Potassium phosphate buffer (100mM, pH 7.4) containing 3mM MgCl2 was pre-incubated in triplicate with the test substance (3μM, final acetonitrile concentration 0.1%) in a 37°C incubator for 10 minutes. 3) The reaction was initiated by adding the S9 fraction (1.0 mg / mL) preheated in the presence of 2mM NADPH. The final incubation mixture volume was 200 μL. 4) All reactions were completed at the predetermined time points (0-60 minutes) using 5 times the volume of extraction solvent. 5) Aliquots of the completed incubation mixture were centrifuged at 20,000 xg for 5 minutes. 6) The supernatant was analyzed by LC-MS / MS to determine the amount of remaining test substance 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 the liver S9 fractions of mice, rats, dogs, monkeys, and humans suggested that prodrug compounds could be converted to S-ketamine with varying release efficiencies, and that after administration to mice, rats, dogs, monkeys, and humans, they were converted to S-ketamine in the systemic circulation.

[0344] Mouse, rat, dog, monkey, and human whole blood metabolic stability assays The release efficiency of the conversion of the compounds disclosed from prodrugs to S-ketamine is determined in vitro using protocols for whole blood metabolic stability assays in mice, rats, dogs, monkeys, and humans.

[0345] The following is a summary of the whole blood assay study: 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 the Center of Toxicology and Preclinical Sciences (CTPS, QPS Taiwan), cynomolgus monkey heparinized whole blood pool (N=3) was purchased from the Laboratory Animal Center (LAC) of the 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) The test substance was incubated in preheated rat whole blood at 37°C at 3 μM (final acetonitrile concentration 1%) for up to 60 minutes at 37°C. 3) A 100 μL aliquot of the added sample solution was taken at a predetermined time (0-60 minutes) after incubation, immediately extracted by adding 5 times the volume of extraction solvent, and then centrifuged at 20,000xg for 5 minutes. 4) The supernatant fraction was analyzed by LC-MS / MS to determine the amount of remaining test substance and ketamine formation. Next, the conversion efficiency of the test compound to S-ketamine in whole blood was calculated using the measurement results. 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 suggested that prodrug compounds could be converted to S-ketamine with varying release efficiencies, and that after administration to mice, rats, dogs, monkeys, and humans, they were converted to S-ketamine in the systemic circulation.

[0347] Example 110: Pharmacokinetic studies The pharmacokinetic profiles of the test substances in mice / rats were 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 tubing before administration and at 3, 10, 30, 1, 2, 3, 4, 6, and 8 hours after intravenous administration (IV), and before administration and at 10, 30, 1, 2, 3, 4, 5, 6, and 8 hours after oral administration (PO). In the mouse PK study, 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, collected blood samples were immediately mixed with acetonitrile (containing 0.1% formic acid) in a 1:3 (v / v) ratio. Deproteinized samples were temporarily held on ice and then stored at -70°C before bioanalysis. Sample concentrations in blood 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 circulatory system, 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 alone at adjusted doses. The data are shown in Tables 3 and 4 below.

[0348] [Table 3]

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

[0350] In the pharmacokinetic study in dogs, male beagle dogs were housed individually. Dogs in the oral administration group were fasted overnight before administration, but were allowed free access to water. Dogs in the IV group were allowed free access to food and water. For S-ketamine HCl, a single dose of 3.75 μmol / kg was administered to each dog intravenously (IV). The vehicle used for S-ketamine HCl was physiological saline. For the other test compounds, a single dose of each test compound was administered to each dog by forced oral administration (n=3 / group). The doses of each test compound are listed in Table 5. After administration to individual dogs in the IV and PO groups, blood samples were collected at specified time points (before administration, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, and 8 hours after administration). To prevent the degradation of the compounds, the collected blood samples were immediately mixed with acetonitrile (containing 0.1% formic acid) in a 1:3 (v / v) ratio. Deproteinized samples were temporarily held on ice and then stored at -70°C before bioanalysis. Sample concentrations in blood 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 circulatory system, the bioavailability of S-ketamine after PO administration was calculated. The data are shown in Table 5 below.

[0351] [Table 5]

[0352] In the pharmacokinetic study in monkeys, three cynomolgus macaques (two males and one female) from a colony at the Laboratory Animal Center (LAC) of the National Defense Medical College (NDMC) were investigated. The average age of the subjects was 6 years, and the average weight was 6.6 kg (6–7 kg). A washout period of at least 7 days was performed between each treatment. On the day of the in vivo experiment, the monkeys were sedated by 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 dosage of each test compound is listed in Table 6, and it was administered by forced oral administration. The monkeys in the intravenous administration group were allowed to freely consume laboratory animal feed, while the monkeys in the oral treatment group were fasted overnight before treatment and fed 2–3 hours after administration of the test substance. During the study period, drinking water was freely provided. 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 at 10 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours after administration. For the PO group, blood samples were collected before administration and at 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, and 8 hours after administration. To prevent compound degradation, 100 μL of blood sample collected from the monkeys 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 held on ice and then stored at -70°C before bioanalysis. Sample concentrations in the blood were measured by LC-MS / MS.

[0353] [Table 6]

[0354] Finally, it should be noted that there are other ways of carrying out the present invention. Therefore, although embodiments of the present invention are described as examples, the present invention is not limited to those described, and further modifications may be made within the scope of the present invention or equivalents added to the claims.

[0355] All publications or patents referenced herein are incorporated by reference into the present invention.

[0356] Throughout this specification, any reference to “embodiments,” “several embodiments,” “one embodiment,” “another example,” “example,” “a specific example,” or “several examples” means that any particular feature, structure, material, or property described in relation to an embodiment or example is included in at least one embodiment or example of this disclosure. Therefore, phrases such as “in some embodiments,” “in one embodiment,” “in an embodiment,” “in another example,” “in an example,” “a specific example,” or “several examples” in various parts of this specification do not necessarily refer to the same embodiment or example of this disclosure. Furthermore, any particular feature, structure, material, or property can be combined in any preferred manner in one or more embodiments or examples.

[0357] Although explanatory embodiments have been provided, those skilled in the art will understand that the above embodiments should not be construed as limiting the disclosure, and that modifications, substitutions, and alterations may be made to the embodiments without departing from the spirit, principles, and scope of the disclosure.

Claims

1. Compounds having the structure of formula (Ia) or (Ib), or their stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs: 【Chemistry 1】 R is -C(=O)R １ , -C (=O) OR ２ , -C(=O)O(CHR ３ )OC(=O)R ４ or CD ３ Therefore, X is -CH ３ or CD ３ That is the case.

2. Compounds having the structure of formula (IIa) or (IIb), or their stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs: 【Chemistry 2】 R １ is optionally substituted or unsubstituted aryl-OH, aryl-NH ２ , alkenyl-OH, alkenyl-NH ２ , alkyl-NH ２ , alkyl-OH, carbocyclic or heterocyclic containing one or more N or O, and X is -CH ３ or CD ３ and is.

3. R １ However, Amino C １－６ Alkyl, -R １ａ NHCOR １ｂ , -R １ａ OCOR １ｂ , -R １ａ COOR １ｂ , 【Transformation 3】 or C ３－６ It is a heterocycline, R １ However, C １－６ It can be optionally substituted with alkyl, -OH, or oxo (=O), R １ａ and R １ｂ However, H and C were established independently. １－６ Alkyl or C ２－６ It is alkenyl, R １ｃ However, -OH, C １－３ Hydroxyalkyl, -OCOR １ｂ or CH ２ OCOR １ｂ The compound according to claim 2.

4. A heterocycline containing one or more N or O 【Chemistry 4】 The compound according to claim 2. 【Request Item 5】 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 Selected from the group consisting of, X is -CH ３ or CD ３ It is a compound.

6. Having the structure of formula (IIIa) or (IIIb), 【Transformation 6】 R ２ However, X is optionally a substituted or unsubstituted alkyl, aryl, carbocyryl, or heterocyclyl containing one or more oxygen atoms, where X is -CH ３ or CD ３ A compound, or its stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug.

7. R ２ However, 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 It is a heterocycline, R ２ However, C １－６ Alkyl 【Transformation 7】 If replaced with C １－６ Alkyl, -OH, C １－６ Hydroxyalkyl, 【Transformation 8】 or R ２ａ COOR ２ｂ It is arbitrarily replaced with, R ２ａ However, C １－６ It is alkyl, R ２ａ However, C is optional. １－６ Alkyl or NH ２ Replaced by, R ２ｂ However, H or C １－６ It is alkyl, n １ The compound according to claim 6, wherein the coefficient is 0, 1, or 2. 【Request Item 8】 【Chemistry 9-1】 【Chemistry 9-2】 Selected from the group consisting of, X is -CH ３ or CD ３ A compound that is

9. Compounds having the structure of formula (IVa) or (IVb), or their stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs: 【Chemistry 10】 R ３ While R is H or a substituted or unsubstituted alkyl group, ４ However, X is independently a substituted or unsubstituted alkyl, aryl, azaaryl, carbocykryl, or a heterocyclyl containing one or more O or N atoms, where X is -CH ３ or CD ３ That is the case.

10. R ３ However, H or C １－６ The compound according to claim 9, wherein it is alkyl.

11. R ４ However, 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 Azalea or 【Chemistry 11】 And, R ４ However, C １－６ Alkyl 【Chemistry 12】 If replaced with C １－６ Alkyl, -NH ２ , oxo (=O), C １－６ Hydroxyalkyl, 【Chemistry 13】 It is arbitrarily replaced with, R ４ａ is C １－６ alkyl, and R ４ｂ is C １－６ alkyl or C １－６ haloalkyl, R ４ｃ is benzyl, R ４ｄ is H, or R ４ｃ and R ４ｄ together with the carbon atom to which they are attached form a C ５－６ heterocyclyl, n ２ The compound according to claim 9, wherein the coefficient is 0, 1, or 2.

12. C １－６ Heterocyclines, 【Chemistry 14】 The compound according to claim 11.

13. C １－５ Azaaryl 【Chemistry 15】 And, 【Chemistry 16】 However, one or more methyl or NH ２ The compound according to claim 11, which is optionally substituted with a combination thereof. 【Request Item 14】 【Chemistry 17】 but, [Chemistry 18] The compound according to claim 11. 【Request Item 15】 【Chemistry 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 【Chemistry 19-4】 【Chemistry 19-5】 【Chemistry 19-6】 【Chemistry 19-7】 【Chemistry 19-8】 【Chemistry 19-9】 【Chemistry 19-10】 Selected from the group consisting of, X is -CH ３ or CD ３ It is a compound.

16. Compounds having the structure of formula (Va), (Vb), (Vc), or (Vd), or their stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs: 【Chemistry 20】 。

17. A pharmaceutical composition comprising the compound described in any one of claims 1 to 16.

18. The pharmaceutical composition according to claim 17, further comprising at least one pharmaceutically acceptable excipient carrier, adjuvant, vehicle, or combination thereof.

19. The pharmaceutical composition according to claim 18, further comprising one or more pharmaceutically effective amounts of auxiliary therapeutic agents, wherein the auxiliary therapeutic agents are used for the treatment of neurological and psychiatric disorders or diseases of the central nervous system.

20. The pharmaceutical composition according to claim 19, wherein the neurological and psychiatric disorder or disease of the central nervous system is depression or pain.

21. The pharmaceutical composition according to claim 19, wherein the auxiliary therapeutic agent is selected from the group consisting of lithium, pharmaceutical or herbal antidepressants, anticonvulsants, mood stabilizers, antipsychotics, and benzodiazepines, at least one of these members.

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 drug for preventing, managing, treating or alleviating neurological and psychiatric disorders or diseases of the central nervous system of a patient.

23. 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 drug for antagonizing NMDA receptors.

24. 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, management, treatment or alleviation of neurological and psychiatric disorders or diseases of the central nervous system in patients.

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 NMDA receptors.

26. A method for preventing, managing, treating or alleviating a patient's neurological or psychiatric disorder or disease, comprising administering a therapeutically effective amount of the compound described in any of claims 1 to 16 or the pharmaceutical composition described in any of claims 17 to 21 to a patient in need thereof.

27. A method for antagonizing a patient's NMDA receptor, comprising administering a therapeutically effective amount 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 to a patient in need thereof.

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