Hydroxynorketamine analogs and uses thereof

Abstract

The present invention relates to novel hydroxynorketamine (HNK) analogs, and uses thereof in the treatment of pain, inflammation and neurodegenerative diseases.

Description

[0001] HYDROXYNORKETAMINE ANALOGS AND USES THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel hydroxynorketamine (HNK) analogs and uses thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] (R,S)-Ketamine (hereinafter collectively referred to as ‘ketamine’) is an arylcyclohexylamine derivative consisting of two optical enantiomers, (S)- and (R)- ketamine. It has pharmacological properties as an anesthetic, analgesic, sedative, neuromodulator, anti-inflammatory, antihyperalgesic, bronchodilator and antidepressant. However, ketamine use is associated with deleterious side effects including psychomimetic effects and dissociative effects, as well as the potential for abuse due to its addictive nature.

[0006] Ketamine is rapidly and extensively metabolized into a wide range of N-demethylated, hydroxylated and unsaturated compounds and their respective enantiomeric and diastereomeric isomers. The major metabolite of ketamine is norketamine, which is converted into dehydronorketamine and hydroxynorketamines. 6-hydroxynorketamine (HNK) is the main hydroxynorketamine metabolite. Both (2R,6R)-HNK and (2S,6S)-HNK are pharmacologically active. Although HNK does not appear to be active as an anesthetic and psychostimulant, HNK retains antagonist activity of the alpha-7 nicotinic receptor and activates the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMP A) receptor. HNK has been indicated as responsible for the antidepressant like effect of ketamine. HNK is not a controlled substance and does not produce dissociative or euphoric effects and therefore for some indications such as depression it may be a safer alternative to ketamine.

[0007] There is a need for safe and effective treatments of depression and for non-opioid therapies for neuropathic pain. It would be desirable to optimize the pharmacological activity, ADMET profile, i.e., Adsorption, Distribution, Metabolism, Excretion, and Toxicity, and the pharmaceutical chemistry of hydroxynorketamine to produce an improved drug for treatment of depression and pain, without the unwanted side effects of ketamine. The present invention provides novel compounds as alternative treatment options.

[0008] SUMMARY OF THE INVENTION

[0009] The present invention pertains to novel amino cyclohexane, cyclohexene, and cyclohexanone compounds and to their use in for example the treatment of depression, pain (e.g., neuropathic pain), and inflammation. Moreover, the present invention provides novel HNK analogs to optimize the pharmacological use and efficacy thereof in the treatment of depression, neuropathic conditions, viral and bacterial induced inflammatory responses and neuroinflammation and to minimize common side effects associated with ketamine administration The compounds will be used in the treatment of neuropathic pain syndromes such as complex regional pain syndrome and migraine headaches, in major depressive, bipolar and post-traumatic stress disorders, neuroinflammatory diseases such as Alzheimer’s and Parkinson’s disease, in systemic diseases such as chronic kidney failure, and to combat viral-induced (or any other cause) immune cell hyperactivation such as the “cytokine storm” syndrome.

[0010] BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The various features of the invention will best be appreciated by simultaneous reference to the description which follows and the accompanying drawings, which are not drawn to scale and in which:

[0012] FIG. 1 is a line graph of an in vivo test for determining analgesic effect using the spared nerve injury (SNI) model. DETAILED DESCRIPTION

[0013] Definitions

[0014] Compounds disclosed herein are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure pertains.

[0015] As used herein the term ‘prodrug’ refers to an agent that is metabolized in the body to produce the pharmacologically active agent.

[0016] As used herein the terms ‘a’ and ‘an’ do not denote a limitation of quantity but rather denote the presence of at least one of the referenced items.

[0017] As used herein the term ‘chiral’ refers to molecules having the property of non- superimposability of the mirror image partner.

[0018] As used herein the term ‘stereoisomers’ refers to compounds having an identical chemical formula and sequence of bonded atoms, but which differ with regards to the three- dimensional orientation of the atoms or groups in space.

[0019] As used herein the term ‘diastereomer’ refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers may have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high-resolution analytical procedures such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral UPLC column.

[0020] As used herein the term ‘enantiomers’ refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0021] As used herein the terms ‘racemic mixture’ or ‘racemate’ refer to an equimolar (or 50:50) mixture of two enantiomeric species, devoid of optical activity. A racemic mixture may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory.

[0022] Where a compound exists in various tautomeric forms, the disclosure is not limited to any one of the specific tautomers, but rather includes all tautomeric forms.

[0023] The disclosure includes compounds of Formula I and Formula II having all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium.

[0024] Certain compounds are described herein using a general formula that includes variables, e.g., Ri, and R2. Unless otherwise specified, each variable within Formula I and Formula II is defined independently of other variables. Thus, if a group is said to be substituted, e.g., with 0-2 R*, then said group may be substituted with up to two R* groups, and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0025] Formulas I and II include all sub formulae thereof. For example, Formula I includes compounds I-XXX and XXXIX-LII and the pharmaceutically acceptable salts, prodrugs, and other derivatives, hydrates, polymorphs thereof. For example, Formula II includes compounds XXXI-XXXVIII and the pharmaceutically acceptable salts, prodrugs, and other derivatives, hydrates, polymorphs thereof. Included within the scope of the compounds of the invention are all solvates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of Formula I and Formula II and salts thereof.

[0026] As used herein the term ‘substituted’ means that at least one hydrogen on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When the substituent is oxo (i.e., =0), then 2 hydrogens on the atom are replaced. When aromatic moieties are substituted by an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example, a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent.

[0027] As used herein the term ‘optionally substituted’ indicates that a group, such as heteroaryl, may be unsubstituted, or substituted with one or more substituents as defined herein.

[0028] As used herein the term ‘pharmaceutically acceptable’ refers to those compounds, materials, salts, compositions and dosage forms, which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation or other problem, commensurate with a reasonable benefit / risk ratio.

[0029] As used herein the term ‘pharmaceutically acceptable salts’ refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. They may be derivatives of the disclosed compounds, wherein the parent compound is modified by making non-toxic acid or base addition salts thereof, and further refers to pharmaceutically acceptable solvates, including hydrates, of such compounds and such salts.

[0030] As used herein the term ‘treating’ means reversing, alleviating, inhibiting the progress of or preventing the disorder or conditions to which such term applies or one or more symptoms of such disorder or condition. As used herein the term ‘treatment’ refers to the act of ‘treating’.

[0031] As used herein the terms ‘inhibiting or attenuating’ includes but is not limited to any one or more of the following: abrogating, ameliorating, blocking, suppressing, reducing, delaying, halting, alleviating or preventing a certain medical effect (e.g., inhibiting the proinflammatory agents’ secretion from cells).

[0032] As used herein, the term ‘an effective amount’ refers to an amount of a compound, substance, agent or composition that is of sufficient quantity to result in a decrease in severity of disease or condition symptoms, an increase in a frequency or duration of symptom free periods, a cure of the condition or disease or a prevention of the condition or disease. The amount of a compound may be a single dose, or a dose regimen including multiple doses and may be taken alone or in combination with other substances.

[0033] As used herein the term ‘therapeutically effective amount’ refers to an amount of the active pharmaceutical agent (herein a compound according to Formula I or Formula II) effective in the treatment of a disease or disorder in a mammal.

[0034] As used herein the term ‘inflammation’ refers to a biological response of body tissues to harmful stimuli, such as pathogens (e.g., viral infections), damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation may be to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair. The term ‘inflammation’ also encompasses inflammatory conditions considered as ‘hyper-inflammation’. An exemplary inflammatory condition suitable for the herein treatment with the claimed compounds includes Acute Respiratory Distress Syndrome (ARDS).

[0035] As used herein, the term ‘hyper-inflammation’ refers to syndromes, disorders or conditions caused by severe and uncontrolled immune cell activation and hypercytokinemia (a.k.a., cytokine storm). The clinical presentation of hyper-inflammation inter-alia may include unremitting fever, splenomegaly, coagulopathy, hepatitis, cytopenia, and, if unrestrained, multi-organ failure and death.

[0036] As used herein, the term ‘Cytokine Storm’ encompasses a multi-factorial hyperinflammation associated, inter-alia, with increased expression of one or more of interleukins (IL), chemokines, granulocyte colony-stimulating stimulating factors (G- CSF), and tumor necrosis factor-la (TNF).

[0037] The herein compounds are suitable for treatment of viral infections associated with or causing hyper inflammation / exaggerated immune response. For example, coronaviruses, influenza viruses and respiratory syncytial viruses (RSV) infections can lead, in some cases, to a severe hyper inflammation in infected subjects.

[0038] As used herein, the term ‘coronavirus’ refers to a family of various viruses, including, without limitation, severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS) coronavirus (MERS-CoV), and SARS-CoV-2 (that causes COVID-19).

[0039] As used herein the term ‘subject’ means any human or non-human animal in need of medical treatment. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. The term ‘subject’ is interchangeable with the term ‘patient’.

[0040] As used herein a wavey line ( ) indicates the point of attachment to an R group.

[0041] As used herein the term ‘about’ refers to ± 15 %, ± 10 % or ± 5 %.

[0042] The term ‘consisting essentially of means that the composition, or method may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, or method.

[0043] The term ‘consisting of means including and limited to. As used herein the terms ‘comprising’, ‘including’, ‘containing’, ‘featuring’, ‘having’ and any forms of the terms thereof are inclusive and open ended and do not exclude additional elements or method steps, which are not recited.

[0044] Compounds

[0045] Reference is now made to certain compounds and methods. The disclosed embodiments are not intended to be limiting of the claims. The claims are intended to cover all alternatives, modifications and equivalents.

[0046] Compounds provided by the present invention are amino cyclohexanes and aminocyclohexenes. The amino cyclohexanes may be hydroxynorketamine analogs. The hydroxyl group of hydroxynorketamine may be replaced with moieties possessing, similar, stronger or weaker hydrogen bonding properties such as stronger hydrogen bond donors or stronger hydrogen bond acceptors as well as multi-component moieties that utilize defined steric and stereochemical space.

[0047] The compounds provided by the present invention may have the structure of Formula I:

[0048] Formula (I) in which R1 is H, or =0;

[0049] R2 is selected from the group consisting of

[0050] R3 and R4 are each independently selected from the group consisting of H, OH, F, F2,

[0051] wherein the six membered ring to which R3 and R4 are bound contains a double bond when

[0052] R3 or R4 is NH2

[0053] The compounds provided by the present invention may have the structure of Formula I:

[0054] Formula (I) in which

[0055] R1 is H, or =0;

[0056] and R4 is H; wherein the six membered ring to which R3 and R4 are bound contains a double bond when

[0057] R3 is NH2.

[0058] The compounds provided by the present invention may have the structure of Formula I:

[0059] Formula (I) in which

[0060] R1 is H, or =0;

[0061]

[0062] wherein the six membered ring to which R3 and R4 are bound contains a double bond when R4 is NH2.

[0063] Amino cyclohexanes provided by the present invention may have the structure of Formula II:

[0064] Formula (II) in which R2 is selected from the group consisting of where X=S, O, or NH

[0065] R5 is selected from H, Me, iPr, CFFOMe, and NH2; and R4 is H.

[0066] In some embodiments a compound provided by the present invention may have the structure of Formula I: or a pharmaceutically acceptable salt, or a stereoisomer, or an enantiomer thereof, wherein within Formula (I), the variables R1 - R4 carry the definitions as set forth above with the proviso that when R1 = O, Formula I does not include the following combination of variables R2 - R4:

[0067] The compounds of the embodiments include all stereoisomers (e.g., cis and trans) and all optical isomers (e.g., S and R enantiomers) of compounds described herein. The compounds of the embodiments may include cis isomers. The compounds of the embodiments may include trans isomers. The compounds of Formula I or II can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers, such as for example, racemates, mixtures of diastereomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. Although all stereoisomers are encompassed within the scope of the claims, particular stereoisomers may be preferred.

[0068] A compound of Formula I or II can be the (S) isomer. For example, a compound of Formula I can have the structure of Formula la

[0069] A compound of Formula I or II can be the (R) isomer. For example, a compound of

[0070] Formula I can have the structure of Formula lb

[0071] For example, a compound of Formula I can be the (R) isomer and can have the structure of Formula Ic

[0072] For example, a compound of Formula I can be the (S) isomer and can have the structure of Formula Id

[0073] A compound of Formula I, a compound of Formula la, a compound of Formula lb, a compound of Formula Ic a compound of Formula Id and a compound of Formula II can be a pharmaceutically acceptable salt.

[0074] A compound of Formula I can be selected from:

[0075]

[0076] Compound (III)

[0077] Compound (IV)

[0078]

[0079] Compound (VII)

[0080] Compound (VIII)

[0081]

[0082] Compound (X)

[0083] Compound (XII)

[0084]

[0085] Compound (XIV)

[0086] Compound (XVI)

[0087]

[0088] Compound (XIX)

[0089] Compound (XX)

[0090]

[0091] Compound (XXIII)

[0092] Compound (XXIV)

[0093]

[0094] Compound (XXVII)

[0095] Compound (XXVIII)

[0096]

[0097] Compound (XXXIX)

[0098] Compound (XL)

[0099] C

[0100] Compound (XLII)

[0101] Compound (XLIV)

[0102]

[0103] Compound (XL VI)

[0104] Compound (XL VII)

[0105]

[0106] Compound (XLIX)

[0107] Compound (LI)

[0108]

[0109] Compound (LII).

[0110] A compound of Formula II can be selected from:

[0111] Compound (XXXII)

[0112]

[0113] Compound (XXXVI)

[0114]

[0115] Compound (XXXVIII)

[0116] The present invention further provides a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or (II) and a pharmaceutically acceptable carrier.

[0117] The present invention provides methods of treating a disease or condition selected from the group consisting of a mental disorder, neurodegenerative disorders, Alzheimer's dementia, amyotrophic lateral sclerosis, inflammation, and pain in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof. Each possibility presents a separate embodiment of the invention.

[0118] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof for use in treating a disease or condition selected from the group consisting of a mental disorder, Alzheimer's dementia, amyotrophic lateral sclerosis, inflammation, and pain in a subject. Each possibility presents a separate embodiment of the invention.

[0119] In one or more embodiments, the pain is selected from the group consisting of complex regional pain syndrome (CRPS), chronic pain, severe pain, migraine, fibromyalgia, rheumatic pain, menstrual pain, neuropathic pain, and musculoskeletal pain. Each possibility presents a separate embodiment of the invention.

[0120] In one or more embodiments, the inflammation is caused by a pathogen, a trauma, a hazardous substance, or an autoimmune disease.

[0121] In one or more embodiments, the mental disorder is selected from the group consisting of bipolar depression, major depressive disorder, persistent depressive disorder, psychotic depression, suicidality, premenstrual dysphoric disorder (PMDD), atypical depression, postpartum depression, obsessive compulsive disorder, and post-traumatic stress disorder. Each possibility presents a separate embodiment of the invention.

[0122] (2R,6R)-HNK is a pharmacologically active molecule that may exert a therapeutic effect via interaction with several possible receptors, including the a-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid (AMP A) receptor and the nicotinic acetylcholine receptor. It appears that (2R,6R)-HNK may interact with its target receptor(s) through hydrogen bonding and hydrophobic interactions.

[0123] Without being bound by any theory or mechanism of action, the herein compounds, according to Formula I or II, may exert a biochemical effect by a mechanism including one or more of: inhibiting / blocking the N-methyl-D-aspartate (NMDA) receptor, inhibiting serine racemase (SR) enzyme activity, activating mTOR signaling pathway, activating a- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and inhibiting / blocking nicotinic acetylcholine receptors (nAChR), such as a7 nAChR and (1304 nAChR. Optionally, administration of the herein disclosed compounds may result in a reduction in the intracellular and / or extracellular concentrations of D-serine, a co-agonist of NMDA receptor. The herein compounds may be weak or non mu opioid receptor (MOR) agonists, and / or weak or non-positive allosteric modulators (PAMs) for MOR. Optionally, an enhanced efficacy may be attributed to an enhanced hydrogen bond donating-accepting property of a substituent at the C2 and / or C5, and / or C6 position on the cyclohexane or cyclohexanone ring of the herein compounds according to Formula I or II. The ability of (2R,6R)-HNK to achieve hydrogen bonding interactions may be derived from the NH2 substituent at C2 and the OH substituent at C6 of the molecule. Both moieties can act as hydrogen bond donor s / acceptors. Also, the ability of (2R,6R)-HNK to interact with a hydrophobic cleft or site on the respective receptor(s) and / or enzyme(s) is thought to be based upon the presence of the 2-cholorbenzyl moiety at the C2 position of the molecule. The C2 and C6 carbons in the (2R,6R)-HNK cyclohexanone ring are asymmetric, and the R stereochemical configuration at both sites may contribute to the observed pharmacological activity of the compound. The present compounds are designed to optimize the pharmacological use and efficacy of (2R,6R)-HNK through properties such as, but not limited to enhanced hydrogen bond donor / acceptor strength, steric and three- dimensional configurations of the molecules.

[0124] Synthesis Of The Compounds

[0125] General methods for preparing compounds of the present invention are set forth below.

[0126] General synthesis of alpha-substituted nor-ketamines

[0127] A nor-ketamine with a reactive group at the alpha position was synthesized by reacting the HC1 salt of starting material A with pyridinium tribromide. The starting material was either 2-amino-2-(2-ch1orophenyl)cyclohexan-l-one or 2-amino-2-(naphthalen-l- yl)cyclohexan-l-one. The resulting bromo alpha-substituted nor-ketamine was then converted to the nor-ketamine derivative with the desired Y group at the alpha position by a nucleophilic substitution reaction. General Synthesis of cvclohex-2-en-l-one analogues

[0128] A bromo alpha-substituted nor-ketamine building block was converted to the cyclohex-2- ene-l-one by substitution of the reactive Br group followed by the oxidation of the cyclohexane ring.

[0129] General Synthesis of beta-substituted nor-ketamines

[0130] In a first step a bromo alpha- substituted nor-ketamine building block was converted to the cyclohex-2-ene-l-one intermediate. The intermediate was then converted to the betasubstituted nor-ketamine by addition reaction with cyanide anion.

[0131] General Synthesis of aryl analogues of ketamine

[0132] A Suzuki cross-coupling reaction converts the starting material 1 -Cyclohexenyl trifluoromethanesulfonate to the 1 -(cyclohex- l-en-l-yl)aryl intermediate. In a second step the oxabicyclo heptane epoxide is formed. The epoxide is then opened to form the azido aryl cyclohexanol. The azido-ketone is formed from the azido-alcohol by Dess-Martin reaction. The azido-ketone is then reduced to form the amino-ketone. General Synthesis of Aryl Analogues of Hydroxy-nor-ketamine

[0133] In a first step the amino group is protected. The protected intermediate is then converted to the silyl-enol ether. In a further step the ether is converted to the epoxide. The epoxide is opened to form the cyclohexanol. In a final step the protection group is removed to form the aryl analogue of hydroxy-nor-ketamine.

[0134] The aryl analogues may be synthesized using a method based on Org. Lett. 2017, 19, 5224-5227 to Corey et al.

[0135] Pharmaceutical Compositions

[0136] The compounds disclosed herein may be administered alone, or as a pharmaceutical composition. A pharmaceutical composition may include a therapeutically effective amount of a compound of Formula I or II. Pharmaceutical compositions provided by the present application may feature a compound of Formula I or II or a stereoisomer or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. A carrier may include a diluent, excipient or vehicle with the compound or salt of Formula I or II. The pharmaceutical composition may contain a compound or salt of any one of Formulas I, or II including Compounds I -LII as the only active agent. In some embodiments, the composition may contain at least one additional active agent.

[0137] Carriers may include excipients and diluents and may be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier may be inert, or it may possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the herein compound may be sufficient to provide a practical quantity of material for administration per unit dose of the compound.

[0138] Classes of carriers and excipients may include but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidants, fillers, solvents, flow aids, disintegrants, polymeric carriers, plasticizers, lubricants, emulsifying agents, preservatives, stabilizers, surfactants, suspending agents, coatings, tableting agents, antimicrobials, coloring agents and wetting agents. Some carriers may be listed in more than one class; for example, vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers may include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the active agents of the present invention.

[0139] Pharmaceutical compositions of the present invention can be formulated for different routes of administration, such as, but not limited to orally, intravenously, subcutaneously, transbuccaly, rectally, dermally, intramuscularly, intraocularly, gastro-retentively and transcutaneously. Non-limiting examples of oral preparations include a tablet, a solution, a suspension and a lozenge.

[0140] The pharmaceutical composition may be formulated in any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. The dosage form may provide immediate release, sustained release, or a combination thereof.

[0141] Pharmaceutically acceptable salts of the compounds of the present invention may include inorganic salts and organic salts. Organic salts may be prepared from organic acids such as acetic, trifluoroacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC — (CH2)n — COOH where n is 0-4, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, and the like; and amino acid salts such as arginate, asparginate, glutamate, and the like, and combinations comprising one or more of the foregoing salts. The pharmaceutically acceptable salts may be prepared on site during the final isolation and purification of the compound or by separately reacting the purified compounds in its free acid or free base form or a non-pharmaceutically acceptable salt, with a suitable base or acid respectively. Examples of suitable inorganic salts may include ionic salts such as but not limited to chlorides, carbonates, bicarbonates and phosphates, for example, sodium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, potassium chloride, sodium sulfate, calcium carbonate and calcium phosphate.

[0142] Methods of Treatment

[0143] Methods of treatment in accordance with the present disclosure include, but are not limited to methods of treating central nervous system (CNS) or mental or neurological disorders / conditions / diseases, such as bipolar depression, major depressive disorder, postpartum depression, Alzheimer's dementia, amyotrophic lateral sclerosis, and pain (e.g. complex regional pain syndrome (CRPS)), chronic pain, severe pain, migraines, menstrual pain, or neuropathic pain, and / or inflammation associated with traumatized cells, irritants (a hazardous substance), an inflammatory disease, or infection, by administering a pharmaceutical composition containing an effective amount of one or more of a compound of Formula I or II, including exemplary Compounds I - LII or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier to a patient in need of such treatment.

[0144] The compound or salt of Formula I or II may be the only active agent administered or may be administered together with an additional active agent. For example, the compound of Formula I or II may be administered together with another active agent.

[0145] Administration of the herein compounds according to Formula I or II may be before, at the onset of, or following the detection of symptoms (e.g., hyper-inflammation, depression, pain) in the subject.

[0146] Compounds disclosed herein may be administered orally, intravenously, intraperitoneally, topically, parenterally, by inhalation or spray, sublingually, transdermal, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. In an embodiment of the present invention, the herein compounds, according to Formula I or II, may be further effective in treating subjects afflicted with an infectious disease.

[0147] In an embodiment of the invention, the herein compounds, according to Formula I or II, may be further effective in treating inflammation.

[0148] Reference is made to the following examples, which together with the above descriptions illustrates the invention in a non-limiting fashion. These examples are not intended to limit the scope of the invention, but to provide guidance to one of skill in the art to prepare and use the compounds and compositions of the present invention. The following examples describe the synthesis of intermediates and compounds of Formula I or II and the characterization of the intermediates and compounds of Formula I or II. It will be apparent to those skilled in the art that many modifications both to the materials and methods may be practiced without departing from the scope of the invention. In one or more embodiments, the amounts in the examples should be read with the prefix ‘about’.

[0149] The following abbreviations are used herein below:

[0150] EtOAc = ethyl acetate

[0151] NMR = nuclear magnetic resonance

[0152] LCMS = liquid chromatography - mass spectrometry

[0153] HPLC =high performance liquid chromatography

[0154] DMSO = dimethylsulfoxide

[0155] THF = tetrahydrofuran

[0156] DCM = dichloromethane

[0157] TLC = thin layer chromatography

[0158] MW = molecular weight

[0159] UPLC = ultra performance liquid chromatography ET2O - diethyl ether rac - racemic

[0160] MeOH = methanol

[0161] TMS = tetramethylsilane

[0162] Boc = tert-butyloxy carbonyl

[0163] TFA = trifluoro acetic acid

[0164] EXAMPLES

[0165] Design of the herein compounds - novel compounds that are potentially safe and effective analgesics: Using the attenuation of D-Ser synthesis as the functional outcome, a pharmacophore model was created to produce the compounds. Comparative Molecular Field Analysis (CoMFA) of D-Ser modulation: Initial studies demonstrated that dehydronorketamine (DHNK) and HNK decrease intracellular and extracellular D-Ser concentrations in PC- 12 cells. This effect was associated with decreases in intracellular Ca2+, which in turn, reduces Ca2+ -activated SR activity and consequently D-Ser production. In order to develop a template for the development of new drugs, the relationship between molecular structure and stereochemistry on intracellular D-Ser production in PC- 12 cells was investigated. In this study, the IC50 values associated with decreased intracellular D-Ser were determined for Ket and Ket metabolites. The CoMFA model was generated using methodology implemented in Sybyl-X 2.1.1, the molecular models of structures were prepared in Hyper-Chem v. 6.03 using Model Build procedure to ensure the same conformation of the common scaffold. The models were extracted to Sybyl and the Gasteiger-Huckel atomic charges were calculated. The models were aligned using 2-chlorobenzyl moiety as a common substructure. Two types of molecular fields (steric and electrostatic) were sampled on the grid lattice surrounding each structure. In the procedure default settings were used. pIC50 values presenting effects on intracellular D- Ser levels were subjected to 3D-QSAR modeling. The resulting model identified several steric fields that reached statistical significance in the analysis and allowed the design of the molecules.

[0166] Example 1 - synthesis of 2-amino-6-bromo-2-(2-chlorophenyl)cvclohexan-l-one

[0167] (±)-Norketamine hydrochloride (5.0 g, 19.219 mmol, 1.0 eq) and pyridinium tribromide (6.15 g, 19.219 mmol, 1.0 eq) were dissolved in acetic acid (96.09 ml, 0.2 M). The reaction mixture was stirred for 1 hour at 125°C under microwave irradiation. Acetic acid was evaporated, and the resulting crude material was diluted with water and NaHCOi. Then it was extracted using ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated. Then the compound was purified using flash column chromatography (0-70% EtOAc in hexane) affording 2-amino-6-bromo-2-(2- chlorophenyl)cyclohexan-l-one (4.5 g, 11.897 mmol, yield=62%, purity=80%). [M+H]=303.70 ’H NMR (300 MHz, DMSO-d6) 5 7.91 - 7.69 (m, 1H), 7.60 - 7.24 (m, 3H), 4.76 (dd, J = 10.2, 5.6 Hz, 1H), 2.70 (ddd, J = 11.7, 6.2, 2.6 Hz, 1H), 2.48 - 2.31 (m, 1H), 2.13 - 2.01 (m, 1H), 1.92 - 1.78 (m, 1H), 1.79 - 1.53 (m, 2H).

[0168] Example 2- synthesis of 2-amino-6-bromo-2-(naphthalen-l-yl)cvclohexan-l-one

[0169] 2-amino-2-(naphthalen-l-yl)cyclohexan-l-one (2.393 g, 9.299 mmol, 1.0 eq) was dissolved in diethyl ether and treated with 2.0M HC1 solution in diethyl ether to convert the free base into the HC1 salt. The HC1 salt was placed in acetic acid (37.2 ml, 0.25 M) and Pyridinium tribromide (4.461 g, 13.949 mmol, 1.5 eq) was added. The reaction was sealed and heated to 125 °C for 2 hours via microwave irradiation while stirring. The solution was then cooled, and the acetic acid removed by rotary evaporation. The crude material was then washed with aqueous sodium bicarbonate and extracted into ethyl acetate, ensuring the pH remained at pH 10. The organic phase was taken, and the solvent removed by rotary evaporation to give crude material. This crude material was purified by flash column chromatography eluting with ethyl acetate / hexane (gradient- 45:55 to 55:45) affording the product 2-amino-6-bromo-2-(naphthalen-l-yl)cyclohexan-l-one (2.15 g, 6.689 mmol, 72%) as a light beige solid. [M+H]=319.75 ’H NMR (300 MHz, DMSO-d6): 5 7.99 - 7.93 (m, 2H), 7.85 - 7.80 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.53 - 7.44 (m, 2H), 4.37 (dd, J = 11.9, 5.9 Hz, 1H), 3.06 (d, J = 12.5 Hz, 1H), 2.42 (dt, J = 5.6, 2.7 Hz, 1H), 2.01 - 1.74 (m, 4H).

[0170] Example 3 - synthesis of 6-(4-acetylpiperazin-l-yl)-2-amino-2-(2- chlorophenyl)cvclohexan-l-one (Compound II - C18H24C1N3O2)

[0171] To a stirred solution of 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.3 g, 0.922 mmol, 1.0 eq) in acetonitrile (4.61 ml, 0.2 M) at room temperature under argon was added 1 -(piperazin- l-yl)ethan-l -one (0.142 g, 1.106 mmol, 1.2 eq) and triethylamine (0.129 ml, 0.922 mmol, 1.0 eq). After 15 hours of stirring under reflux, LCMS analysis indicated the formation of the desired product. The volatiles were removed, and the residue was purified using preparative HPLC under basic conditions to afford 6-(4-acetylpiperazin- l-yl)-2-amino-2-(2-chlorophenyl)cyclohexan-l-one (0.044 g, 0.126 mmol, yield=13%, purity =97.62%) as a white solid. [M+H] 350.25 ’H NMR (400 MHz, DMSO-d6): 5 7.73 (d, J = 7.8 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 8.2 Hz, 1H), 3.38 (d, J = 4.6 Hz, 4H), 3.06 (dd, J = 10.5, 5.0 Hz, 1H), 2.74 (d, J = 14.9 Hz, 1H), 2.65 - 2.56 (m, 4H), 2.05 (br, 1H), 1.97 (s, 3H), 1.80 - 1.67 (m, 3H), 1.57 - 1.51 (m, 1H). Example 4 - synthesis of 2-amino-2-(2-chlorophenyl)-6-(pyridin-3-yloxy)cvclohexan-l- one (Compound XVII- C17H17C1N2O2)

[0172] To a stirred solution of 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.3 g, 0.922 mmol, 1.0 eq) in acetonitrile (4.61 ml, 0.2 M) at room temperature under argon was added 3-Hydroxypyridine (0.105 g, 1.106 mmol, 1.2 eq) and potassium carbonate (0.255 g, 1.844 mmol, 2.0 eq). The reaction mixture stirred at 85 °C for 12 h. The volatiles were removed, and the residue was purified using preparative HPLC under basic conditions to afford the desired product which was converted into the hydrochloride salt. This afforded 42 mg (14% yield) of 2-amino-2-(2-chlorophenyl)-6-(pyridin-3-yloxy)cyclohexan-l-one (0.042 g, 0.132 mmol, yield=14%, purity=89.56%) as a white solid, [M+H] 317.18 NMR (400 MHz, DMSO-d6): 5 8.27 (d, J = 4.5 Hz, 1H), 7.98 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.61 - 7.53 (m, 2H), 7.52 - 7.45 (m, 3H), 7.41 (dd, J = 7.9, 1.4 Hz, 2H), 5.81 (dd, J = 6.6, 2.9 Hz, 1H), 3.24 - 3.16 (m, 1H), 3.00 - 2.96 (m, 1H), 2.36 - 2.30 (m, 2H), 2.23 - 2.14 (m, 3H).

[0173] Example 5 - synthesis of 2-amino-2-(2-chlorophenyl)-6-(lH-1.2.3-triazol-l- yl)cvclohexan-l-one (compound XLIX-C14H15C1N4O) and 2-amino-2-(2-chlorophenyl)-6-(2H-1.2.3-triazol-2-yl)cvclohexan-l-one

[0174] (compound La-C14H15C1N4O) and czs-2-amino-2-(2-chlorophenyl)-6-(2H- 1 ,2,3 -triazol-2-yl)cvclohexan- 1 -one

[0175] (compound Lb- C14H15C1N4O)

[0176] To a stirred solution of 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.5 g, 1.322 mmol, 1.0 eq) in acetonitrile (8.81 ml, 0.15 M) at room temperature under argon was added 1,2,3-lH-triazole (0.183 g, 2.644 mmol, 2.0 eq) and potassium carbonate (0.365 g, 2.644 mmol, 2.0 eq). The reaction mixture stirred at 70 °C for 12 hours. The volatiles were removed and the residue was purified using preparative HPLC under basic conditions to afford: 2-amino-2-(2-chlorophenyl)-6-(lH-l,2,3-triazol-l-yl)cyclohexan-l-one (0.025 g, 0.082 mmol, yield=6%, purity=95.62%) as a mixture of diastereoisomers (3:1 ratio of cis / trans isomers), [M+H] 291.24 (400 MHz, DMSO-d6): 5 8.15 (minor isomer) and 8.09 (major isomer) (d, J = 1.0 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 7.55-7.48 (minor isomer) and 7.39-7.35 (major isomer) (m, 1H), 7.43 (minor isomer) and 7.29 (major isomer) (td, J = 7.6, 1.5 Hz, 1H), 6.25 (dd, J = 13.5, 5.4 Hz, 1H - major isomer), 5.48 (dd, J = 12.0, 6.7 Hz, 1H - minor isomer), 2.97 (d, J = 14.3 Hz, 1H), 2.81 (s, 2H), 2.68 - 2.55 (m, 2H), 2.39 - 2.33 (m, 2H), 1.93 - 1.83 (m, 2H); trazzs-2-amino-2-(2- chlorophenyl)-6-(2H-l,2,3-triazol-2-yl)cyclohexan-l-one (0.039 g, 0.13 mmol, yield=10%, purity=97.12%), [M+H] 291.24 ’H NMR (400 MHz, DMSO-d6): 5 7.82 (d, J = 4.3 Hz, 3H), 7.53 - 7.46 (m, 2H), 7.42 (td, J = 7.6, 1.6 Hz, 1H), 5.39 (dd, J = 12.7, 5.9 Hz, 1H), 2.95 - 2.91 (m, 1H), 2.60 - 2.52 (m, 1H), 2.41 -2.36 (m, 1H), 1.87 (m, 2H), 1.75- 1.68 (m, 1H); czs-2-amino-2-(2-chlorophenyl)-6-(2H-l,2,3-triazol-2-yl)cyclohexan-l-one (0.018 g, 0.061 mmol, yield=5%, purity=98.41%, dr=4: l cis / trans), [M+H] 291.24 NMR (400 MHz, DMSO-d6) 5 7.83 (d, J = 6.7 Hz, 3H), 7.57 - 7.45 (minor isomer), 7.37 - 7.26 (major isomer) (m, 3H), 6.18 (dd, J = 13.3, 5.3 Hz, 1H - major isomer), 5.43 (dd, J = 12.8, 6.1 Hz, 1H - minor isomer), 2.99 (d, J = 11.7 Hz, 1H - minor isomer), 2.80 - 2.68 (m, 2H), 2.38 - 2.29 (m, 2H), 1.93-1.79(m, 2H).

[0177] Example 6 - synthesis of l3-(2-chlorophenyl)-4-methyl-8-thia-2.3.5.6- tetraazatricvclo[7.4.0.03.71trideca-1.4,6-trien-13-amine (Compound XXXVIII- C15H16C1N5S)

[0178] To a stirred solution of 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.4 g, 1.058 mmol, 1.0 eq) in acetonitrile (5.29 ml, 0.2 M) was added 4-amino-5-methyl-4H- l,2,4-triazole-3-thiol (0.165 g, 1.269 mmol, 1.2 eq) and triethylamine (0.177 ml, 1.269 mmol, 1.2 eq). The reaction mixture stirred was at 70 °C for 15 hours, n-butanol (5.29 ml, 0.2 M) and trifluoroacetic acid (0.181 g, 1.586 mmol, 1.5 eq) were added to the reaction mixture and it was stirred at 110 °C for an additional 12 hours. The volatiles were removed and the residue was purified using preparative HPLC under neutral conditions to afford 13- (2-chlorophenyl)-4-methyl-8-thia-2,3,5,6-tetraazatricyclo[7.4.0.03,7]trideca-l,4,6-trien- 13-amine (0.034 g, 0.097 mmol, yield=9%, purity=95.06%) as white solid, [M+H] 334.05 ’H NMR (400 MHz, DMSO-d6): 5 7.99 (dd, J = 7.8, 1.5 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.35 (dd, J = 7.8, 1.4 Hz, 1H), 7.29 (td, J = 7.5, 1.6 Hz, 1H), 4.56 (dd, J = 12.0, 6.2 Hz, 1H), 2.33 - 2.25 (m, 2H), 2.11 - 2.01 (m, 4H), 1.95 - 1.86 (m, 1H), 1.79 - 1.69 (m, 2H).

[0179] Example 7:synthesis of 13-(2-chlorophenyl)-8-thia-2.3.5.6- tetraazatricvclo[7.4.0.03.71trideca-1.4,6-trien-13-amine (Compound XXXVII-

[0180] C14H14C1N5S) To a stirred solution of 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.4 g, 1.058 mmol, 1.0 eq) in acetonitrile (5.29 ml, 0.2 M) was added 4-amino-4H-l,2,4-triazole- 3-thiol (0.147 g, 1.269 mmol, 1.2 eq) and triethylamine (0.177 ml, 1.269 mmol, 1.2 eq). The reaction mixture stirred was at 70°C for 15 hours. Then n-butanol (5.29 ml, 0.2 M) and trifluoroacetic acid (0.181 g, 1.586 mmol, 1.5 eq) were added to the reaction mixture and it was stirred at 110 °C for an additional 12 hours. The volatiles were removed and the residue was purified using preparative HPLC under neutral conditions to afford 13 -(2- chlorophenyl)-8-thia-2,3,5,6-tetraazatricyclo[7.4.0.03,7]trideca-l,4,6-trien-13-amine (0.033 g, 0.099 mmol, yield=9%, purity=95.54%) as white solid [M+H] 320.02 (400 MHz, DMSO-d6): 5 8.79 (s, 1H), 8.00 (dd, J = 7.8, 1.3 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.34 - 7.28 (m, 1H), 4.69 (dd, J = 11.9, 6.2 Hz, 1H), 2.36 - 2.26 (m, 2H), 2.12 - 1.97 (m, 1H), 1.94 - 1.87 (m, 1H), 1.83 - 1.69 (m, 2H).

[0181] Example 8 - synthesis of 3 -amino-3-(2-chlorophenyl)-2-oxocvclohexane-l -carbonitrile (Compound LII-C13H13C1N2O)

[0182] Sodium cyanide (0.039 g, 0.793 mmol, 1.5 eq) and 2-amino-6-bromo-2-(2- chlorophenyl)cyclohexan-l-one (0.2 g, 0.529 mmol, 1.0 eq) were dissolved in dimethylformamide (2.64 ml, 0.2 M). The reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with distilled water and extracted into ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified using preparative HPLC under neutral conditions to afford 3-amino-3-(2-chlorophenyl)-2-oxocyclohexane- 1 -carbonitrile (0.048 g, 0.192 mmol, yield=36%, purity=99.72%) [M+H]=249.17 'H NMR (300 MHz, DMSO-d6) 5 7.63 (dd, J = 7.9, 1.7 Hz, 1H), 7.52 - 7.29 (m, 3H), 3.88 (d, J = 4.8 Hz, 1H), 2.71 (s, 2H), 2.21 - 2.03 (m, 2H), 1.85 - 1.65 (m, 2H), 1.47 - 1.21 (m, 2H). Example 9 - synthesis of 2-amino-6-(4-chlorophenoxyl-2-(2-chlorophenyllcvclohexan-l- one (cis / trans)

[0183] 2-amino-6-(4-chlorophenoxy)-2-(2-chlorophenyl)cyclohexan-l-one (cis) (Compound

[0184] XVIIIa - Cl 8H17C12NO2) and 2-amino-6-(4-chlorophenoxy)-2-(2-chlorophenyl)cyclohexan-l -one (trans)

[0185] (Compound XVIIIb- Cl 8H17C12NO2)

[0186] Cesium carbonate (0.451 g, 1.383 mmol, 1.5 eq) and 4-chlorophenol (0.119 g, 0.922 mmol, 1.0 eq) were dissolved in acetonitrile (4.61 ml, 0.2 M). The reaction mixture was stirred for 15 minutes and 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.3 g, 0.922 mmol, 1.0 eq) was added. The reaction mixture was stirred at 50 °C for 3 hours. The reaction mixture was diluted with distilled water and extracted into EtOAc. Then the extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a crude product. The crude product was purified using preparative HPLC under basic conditions obtaining two isomers: 2-amino-6-(4-chlorophenoxy)-2-(2- chlorophenyl)cyclohexan-l-one (0.03 g, 0.082 mmol, yield=9%, purity=96.24%, cis or trans) [M+H]=351.26 ’H NMR (400 MHz, DMSO-d6) 5 7.78 (dd, J = 8.0, 1.7 Hz, 1H), 7.45 (dd, J = 8.0, 6.8 Hz, 2H), 7.37 (ddd, J = 8.5, 6.8, 1.6 Hz, 1H), 7.33 - 7.23 (m, 2H), 6.97 - 6.87 (m, 2H), 4.90 - 4.80 (m, 1H), 2.87 - 2.75 (m, 1H), 2.37 - 2.19 (m, 3H), 1.87 - 1.72 (m, 3H), 1.71 - 1.53 (m, 1H) and 2-amino-6-(4-chlorophenoxy)-2-(2- chlorophenyl)cyclohexan-l-one (0.042 g, 0.119 mmol, yield=13%, purity=99.20%, trans or cis) [M+H]=351.22 ’H NMR (400 MHz, DMSO-d6) 5 7.78 (dd, J = 7.7, 1.8 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.32 - 7.23 (m, 3H), 6.94 - 6.86 (m, 2H), 5.70 (dd, J = 12.4, 5.7 Hz, 1H), 2.80 (s, 2H), 2.39 - 2.20 (m, 2H), 2.03 (qd, J = 12.3, 3.1 Hz, 1H), 1.90 - 1.77 (m, 2H).

[0187] Example 10 - synthesis of 2-amino-2-(2-chlorophenyl)-6-(3-fluorophenoxy)cvclohexan-l- one (Compound XX-C18H17C1FNO2)

[0188] Cesium carbonate (0.451 g, 1.383 mmol, 1.5 eq) was added to 3 -fluorophenol (0.103 g, 0.922 mmol, 1.0 eq) and 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.3 g, 0.922 mmol, 1.0 eq) dissolved in dimethylformamide (4.61 ml, 0.2 M). The reaction mixture was stirred at 50 °C for 3 hours. The mixture was diluted with water and extracted using EtOAc. Then the extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a crude product which was purified by preparative HPLC under basic conditions affording trans-2-amino-2-(2-chlorophenyl)-6- (3-fluorophenoxy)cyclohexan-l-one (0.044 g, 0.131 mmol, yield=14%, purity=99.15%). [M+H]=334.17 ’H NMR (400 MHz, DMSO-d6) 5 7.79 (dd, J = 7.7, 1.8 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.33 - 7.20 (m, 2H), 6.78 - 6.67 (m, 3H), 5.74 (dd, J = 12.4, 5.7 Hz, 1H), 2.83 (s, 2H), 2.43 (dd, J = 13.9, 5.0 Hz, 1H), 2.39 - 2.17 (m, 2H), 2.13 - 1.96 (m, 1H), 1.84 (dt, J = 12.2, 2.9 Hz, 2H).

[0189] Example 11 - synthesis of 3 -amino-3 -(naphthal en-l-y l)-2-oxocy cl ohexane-1 -carbonitrile (Compound XLVIII-C17H16N2O)

[0190]

[0191] Sodium cyanide (0.114 g, 2.333 mmol, 1.5 eq), (60100721-RMA01-059-1) 2-amino-6- bromo-2-(naphthalen-l-yl)cyclohexan-l-one (0.5 g, 1.556 mmol, 1.0 eq) were dissolved in dimethylformamide (7.78 ml, 0.2 M). The reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with distilled water and extracted using ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by preparative HPLC under neutral condition to afford 3 -amino-3 -(naphthal en-1- yl)-2-oxocyclohexane-l -carbonitrile (0.046 g, 0.165 mmol, yield=l 1%, purity=94.87%) as single geometric isomer (cis or trans). [M+H]=265.21 NMR (400 MHz, DMSO-t / e) 5 8.84 (s, 1H), 7.99 - 7.88 (m, 1H), 7.85 (d, J= 8.1 Hz, 1H), 7.66 - 7.34 (m, 5H), 2.48 - 2.18 (m, 4H), 1.82 (t, J= 29.2 Hz, 3H), 1.35 (s, 1H).

[0192] Example 12 - synthesis of 2-amino-2-(2-chlorophenyl)-6-[(5-methyl-lH-pyrazol-3- vDoxylcyclohexan-l-one (Compound XXIa-C16H18ClN3O2) and tra77s-2-amino-2-(2-chlorophenyl)-6-[(5-methyl-lH-pyrazol-3-yl)oxy1cvclohexan-l- one (Compound XXIb-C16H18ClN3O2) 3-Methyl-lH-pyrazol-5(4H)-one (0.09 g, 0.922 mmol, 1.0 eq), 2-amino-6-bromo-2-(2- chlorophenyl)cyclohexan-l-one (0.3 g, 0.922 mmol, 1.0 eq) and cesium carbonate (0.451 g, 1.383 mmol, 1.5 eq) were dissolved in dimethylformamide (4.61 ml, 0.2 M). The reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was diluted with distilled water and extracted using EtOAc. Then the extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a crude product. The resulting crude was purified by preparative HPLC in basic condition to afford two geometric isomers: cA-2-amino-2-(2-chlorophenyl)-6-[(5-methyl-lH-pyrazol-3- yl)oxy]cyclohexan-l-one (0.03 g, 0.094 mmol, yield=10%, purity=99.86%) [M+H] =320.17XH NMR (400 MHz, DMS O-d6) 5 11.57 - 11.35 (m, 1 H), 7.76 (dd, J = 7.8, 1.8 Hz, 1H), 7.41 - 7.31 (m, 3H), 7.31 - 7.23 (m, 1H), 5.78 (dd, J = 12.6, 6.0 Hz, 1H), 5.42 (dd, J = 2.3, 0.9 Hz, 1H), 2.61 (s, 2H), 2.45 - 2.31 (m, 2H), 2.31 - 2.17 (m, 1H), 2.12 (s, 3H), 1.99 - 1.85 (m, 1H), 1.85 - 1.72 (m, 1H) and tra«s-2-amino-2-(2-chlorophenyl)-6- [(5-methyl-lH-pyrazol-3-yl)oxy]cyclohexan-l-one (0.015 g, 0.042 mmol, yield=5%, punty=89.68%). [M+H]=320.22 ’H NMR (400 MHz, DMSO-d6) 5 11.45 (s, 1H), 7.79 - 7.71 (m, 1H), 7.48 - 7.39 (m, 3H), 7.39 - 7.32 (m, 1H), 5.40 (d, J = 2.1 Hz, 1H), 5.00 (dd, J = 10.8, 6.2 Hz, 1H), 2.92 - 2.78 (m, 1H), 2.54 (s, 2H), 2.44 - 2.32 (m, 1H), 2.10 (s, 3H), 1.85 - 1.47 (m, 3H).

[0193] Example 13 - synthesis of 2-amino-2-(2-chlorophenvB-6-(5,6.7.8-tetrahvdro-L6- naphthyridin-6-yl)cyclohexan-l-one (Compound X-C20H22C1N3Q)

[0194] 5,6,7,8-Tetrahydro-l,6-naphthyridine dihydrochloride (0.715 g, 3.453 mmol, 5.0 eq) was converted into free base separately (extraction with ethyl acetate and water under basic conditions was made) and then added to 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan- 1-one (0.22 g, 0.691 mmol, 1.0 eq) dissolved in acetonitrile anhydrous (3.45 ml, 0.2 M). The reaction mixture was stirred for 24 hours at reflux. Acetonitrile was evaporated and the crude mixture was purified by preparative HPLC under basic conditions to afford 2- amino-2-(2-chlorophenyl)-6-(5,6,7,8-tetrahydro-l,6-naphthyridin-6-yl)cyclohexan-l-one (0.07 g, 0.184 mmol, yield=27%, purity =93.66%). [M+H]=356.24 ’H NMR (400 MHz, DMSO-t / e) 5 8.30 (dd, J= 4.8, 1.7 Hz, 1H), 7.75 (dd, J= 7.9, 1.7 Hz, 1H), 7.48 - 7.38 (m, 3H), 7.33 (td, J = 7.6, 1.6 Hz, 1H), 7.12 (dd, J = 7.7, 4.7 Hz, 1H), 3.92 (d, J = 15.2 Hz, 1H), 3.79 (d, J= 15.2 Hz, 1H), 3.29 (dd, J= 11.2, 5.2 Hz, 2H), 3.00 (dq, J = 26.2, 6.0 Hz, 2H), 2.89 - 2.69 (m, 3H), 2.14 (dd, J= 10.5, 5.4 Hz, 2H), 2.00 - 1.65 (m, 3H), 1.65 - 1.45 (m, 1H).

[0195] Example 14 - synthesis of 2-amino-2-(2-chlorophenyl)-6-(morpholin-4-yl)cvclohexan-l- one hydrochloride (Compound I - C16H21C1N2O2)

[0196] To 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.3 g, 0.922 mmol, 1.0 eq) dissolved in anhydrous acetonitrile (4.61 ml, 0.2 M), morpholine (0.095 ml, 1.106 mmol, 1.2 eq) was added. It was stirred at 80 °C for 28 hours. The volatiles were removed and the residue was purified using preparative HPLC under basic conditions to afford the product which was then converted into 2-amino-2-(2-chlorophenyl)-6-(morpholin-4- yl)cyclohexan-l-one hydrochloride (cis or trans, 0.04 g, 0.113 mmol, yield= 12%; punty=97.26%), [M+H] 309.24 ’H NMR (400 MHz, DMSO-d6) 5 11.39 (s, 1H), 9.07 (s, 3H), 7.96 - 7.88 (m, 1H), 7.68 - 7.57 (m, 3H), 4.44 (s, 1H), 3.93 (s, 4H), 3.29 (d, J = 14.0 Hz, 2H), 3.10 (s, 2H), 2.62 - 2.51 (m, 2H), 2.12 - 1.95 (m, 2H), 1.90 - 1.77 (m, 1H), 1.72 - 1.56 (m, 1H).

[0197] Example 15;synthesis of 2-amino-2-(2-chlorophenyl)-6- [ (2- methoxy ethvBsulfanyllcv cl ohexan-1 -one (Compound XXII-C15H20C1NQ2S) To a solution of 2-methoxy ethane- 1 -thiol (0.093 g, 1.014 mmol, 1.1 eq) in anhydrous tetrahydrofuran (4.61 ml, 0.2 M), a solid sodium hydride (60% dispersion in mineral oil, 0.041 g, 1.014 mmol, 1.1 eq) was added and the mixture was stirred at room temperature for 1 hour. Then, 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.3 g, 0.922 mmol, 1.0 eq) was added and the reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed and the residue was purified using preparative HPLC under basic conditions to afford the product which was then converted into 2-amino-2-(2- chlorophenyl)-6- [(2-methoxy ethyl)sulfanyl] cy cl ohexan-1 -one hydrochloride (0.077 g, 0.236 mmol, yield= 26%; punty=96.16%), [M+H] 314.15 ’H NMR (300 MHz, DMSO- d6) 5 8.76 (br, 3H), 7.95 - 7.86 (m, 1H), 7.66 - 7.53 (m, 3H), 3.89 - 3.76 (m, 1H), 3.49 - 3.36 (m, 4H), 3.26 - 3.06 (m, 3H), 2.66 (t, J = 6.3 Hz, 1H), 2.44 - 2.33 (m, 1H), 2.08 - 1.50 (m, 4H).

[0198] Example _ 16;_ synthesis of _ 2-amino-2-(2-chlorophenyl)-6- [ (2- hydroxyethyDsulfanyllcyclohexan-l -one (Compound XXVILC14H18C1NO2S)

[0199] To a solution of 2-mercaptoethanol (0.071 ml, 1.014 mmol, 1.1 eq) in anhydrous tetrahydrofuran (4.61 ml, 0.2 M) at 0°C, a solid sodium hydride (60% dispersion in mineral oil, 0.041 g, 1.014 mmol, 1.1 eq) was added and the mixture was stirred at room temperature for 1 hour. Then, 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.3 g, 0.922 mmol, 1.0 eq) was added and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were removed and the residue was purified using preparative HPLC under basic conditions to afford the product which was then converted into 2-amino- 2-(2-chlorophenyl)-6-[(2-hydroxyethyl)sulfanyl]cyclohexan-l-one hydrochloride (0.052 g, 0.172 mmol, yield= 19%; punty=99.11%), [M+H] 300.15 ’H NMR (400 MHz, DMSO- d6) 5 8.72 (s, 3H), 7.94 - 7.86 (m, 1H), 7.65 - 7.54 (m, 3H), 4.75 (s, 1H), 3.81 - 3.68 (m, 1H), 3.54 - 3.42 (m, 2H), 3.18 (dd, J = 13.9, 2.8 Hz, 1H), 2.65 - 2.55 (m, 2H), 2.43 - 2.35 (m, 1H), 1.99 - 1.87 (m, 1H), 1.85 - 1.77 (m, 1H), 1.73 - 1.53 (m, 2H). Example _ 17 _;_ synthesis _ of _ 2-amino-2-(2-chlorophenvD-6-

[0200] (cvclopropanesulfonyl)cvclohexan-l-one (Compound XXX-C15H18C1NO3S)

[0201] To 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.3 g, 0.942 mmol, 1.0 eq), sodium cyclopropanesulfinate (0.483 g, 3.767 mmol, 4.0 eq) and benzyltri ethylammonium chloride (0.021 g, 0.094 mmol, 0.1 eq), dimethyl sulfoxide (3.14 ml, 0.3 M) was added and the reaction mixture was stirred at 35°C overnight. The mixture was filtrated, and the filtrate was directly used in preparative HPLC purification employing neutral conditions to afford 2-amino-2-(2-chlorophenyl)-6-(cyclopropanesulfonyl)cyclohexan-l-one (0.171 g, 0.496 mmol, yield= 53%; punty=95.06%). [M+H] 328.18 ’H NMR (400 MHz, DMSO- d6) 5 7.86 - 7.78 (m, 1H), 7.47 - 7.28 (m, 3H), 5.00 - 4.87 (m, 1H), 2.96 - 2.82 (m, 1H), 2.78 - 2.65 (m, 2H), 2.46 - 2.30 (m, 2H), 2.20 - 2.04 (m, 2H), 2.01 - 1.82 (m, 1H), 1.81 - 1.64 (m, 1H), 1.19 - 0.93 (m, 4H).

[0202] Example 18 -synthesis of 2.6-diamino-6-(2-chlorophenvBcvclohex-2-en-l-one

[0203] (compound LI-C12H13C1N2O)

[0204] To a stirred solution of 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.3 g, 0.793 mmol, 1.0 eq) in dimethyl sulfoxide (4 ml, 0.2 M) at room temperature under argon was added sodium azide (0.103 g, 1.586 mmol, 2.0 eq) and the reaction mixture stirred for 2 hours. The reaction mixture was diluted with water and the crude product extracted into ethyl acetate. The combined organics were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC under basic conditions to afford 2,6-diamino-6-(2- chlorophenyl)cyclohex-2-en-l-one (0.015 g, 0.045 mmol, yield=6%, purity=70.55%). [M+H] 237.19. ’H NMR (300 MHz, DMSO-d6): 5 7.94 (d, J = 8.0 Hz, 1H), 7.40 - 7.25 (m, 4H), 5.67 (d, J = 7.9 Hz, 1H), 4.26 (s, 2H), 2.65 - 2.58 (m, 2H), 2.20 - 2.07 (m, 1H), 1.68 - 1.58 (m, 1H).13C NMR (75 MHz, DMSO-d6): 5 194.6, 144.2, 138.7, 131.7, 130.6, 129.1, 129.0, 127.2, 112.5, 62.3, 55.4 (DCM), 35.0, 20.6.

[0205] Example 19

[0206] Synthesis of 6-amino-6-(2-chlorophenyl)cvclohex-2-en-l-one l,8-Diazabicyclo[5.4.0]undec-7-ene (0.019 g, 0.124 mmol, 1.0 eq) was added to 2-amino- 6-bromo-2-(2-chlorophenyl)cyclohexan-l-one (0.05 g, 0.124 mmol, 1.0 eq) dissolved in acetonitrile (0.62 ml, 0.2 M). The reaction mixture was stirred at 120 °C under microwave irradiation for 30 minutes. The solvent was evaporated, and the residue was purified using flash column chromatography (0-70% EtOAc / n-hexane) to afford 6-amino-6-(2- chlorophenyl)cyclohex-2-en-l-one (0.883 g, 3.226 mmol, yield=87%, purity=81%). [M+H] 221.06.

[0207] Example 20 -synthesis of trans-4-amino-4-(2-chlorophenyl)-3-oxocvclohexane-l- carbonitrile (Compound XL Vila- C 13H 13C1N2O) and cA-4-amino-4-(2-chlorophenyl)-3-oxocvclohexane-l -carbonitrile (Compound

[0208] XLVIIb- C13H13C1N2O)

[0209] Triethylamine hydrochloride (0.06 g, 0.439 mmol, 1.2 eq) and sodium cyanate (0.026 g, 0.402 mmol, 1.1 eq) were dissolved in a mixture of methanol (2.0 ml, 20.0 vol) and water (1.0 ml, 10.0 vol). Then a solution of 6-amino-6-(2-chlorophenyl)cyclohex-2-en-l-one (0.1 g, 0.365 mmol, 1.0 eq) in methanol was added. The reaction was stirred at room temperature for 24 hours. The solvents were evaporated and the residue was purified by preparative HPLC under neutral conditions to obtain two isomers, which were isolated: tra«s-4-amino-4-(2-chlorophenyl)-3-oxocyclohexane-l-carbonitrile (0.011 g, 0.044 mmol, yield=12%, punty=99.69% ) [M+H] 249.13 ’H NMR (400 MHz, DMSO-t76) 5 7.85 (dd, J= 7.9, 1.7 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.34 - 7.27 (m, 1H), 3.61 (dt, J= 6.9, 3.5 Hz, 1H), 3.25 (dd, J = 16.5, 6.9 Hz, 1H), 2.73 - 2.61 (m, 1H), 2.56 (dd, J = 3.2, 1.6 Hz, 2H), 2.51 (s, 1H), 2.37 (tt, J = 12.6, 4.1 Hz, 1H), 1.90 (dddd, J = 13.9, 5.9, 4.0, 1.7 Hz, 1H), 1.73 (dtd, J = 14.3, 3.9, 1.5 Hz, 1H) and czs-4-amino-4-(2-chlorophenyl)-3- oxocyclohexane-1 -carbonitrile (0.04 g, 0.16 mmol, yield=44%, purity=99.60% ) [M+H]

[0210] 249.12 ’H NMR (400 MHz, DMSO-d6) 5 7.88 - 7.80 (m, 1H), 7.42 - 7.26 (m, 3H), 3.53 - 3.35 (m, 1H), 3.23 - 3.07 (m, 1H), 2.78 - 2.64 (m, 1H), 2.56 (s, 2H), 2.42 - 2.22 (m, 2H),

[0211] 2.12 - 1.99 (m, 1H), 1.78 - 1.66 (m, 1H).

[0212] Example 21 -synthesis of l-(cyclohex-l-en-l-yl)naphthalene

[0213] 1 -(cyclohex- l-en-l-yl)naphthalene was prepared using Suzuki cross-coupling. 1- Cyclohexenyl trifluoromethanesulfonate (8.0 g, 34.752 mmol, 1.0 eq) were added to a flask containing 1 -naphthaleneboronic acid (6.874 g, 39.965 mmol, 1.15 eq), copper(I) chloride (2.58 g, 26.064 mmol, 0.75 eq), sodium hydroxide (5.56 g, 139.01 mmol, 4.0 eq) and 1,1'- bis(diphenylphosphino)ferrocene di chloropalladium (II) (1.271 g, 1.738 mmol, 0.05 eq) dissolved in anhydrous 1,4-dioxane (139.01 ml, 0.25 M) under argon. The reaction mixture was left stirring under micro wave radiation at 100 °C for 1 hour. The workup consisted of filtering the reaction mixture through a Celite pad and washing the resulting solid with DCM. This filtrate was passed through a short pad of silica pad. The purification resulted in 1 -(cyclohex- l-en-l-yl)naphthalene isolated as a thick dark brown oil (8.94 g, 20.601 mmol, yield=59%, purity=48%) and used as crude material for the subsequent reaction [M+H] 209.00.

[0214] Example 22 - synthesis of 2-(cvclohex-l-en-l-yl)naphthalene

[0215] 2-(Cyclohex-l-en-l-yl)naphthalene was prepared according to the general protocol of Suzuki cross coupling utilized in the synthesis of 1 -(cyclohex- l-en-l-yl)naphthalene using 1 -cyclohexenyl trifluoromethanesulfonate (4.0 g, 17.376 mmol, 1.0 eq), 2- naphthaleneboronic acid (3.437 g, 19.983 mmol, 1.15 eq), copper(I) chloride (1.29 g, 13.032 mmol, 0.75 eq), sodium hydroxide (2.78 g, 69.505 mmol, 4.0 eq), 1,1’- bis(diphenylphosphino)ferrocene di chloropalladium (II) (0.636 g, 0.869 mmol, 0.05 eq) and anhydrous 1,4-dioxane (79 ml, 0.22 M). 2-(cyclohex-l-en-l-yl)naphthalene was isolated as a thick orange oil (2.923 g, 8.7 mmol, yield=50%, purity=62%) and used for the subsequent reaction. [M+H] 209.00.

[0216] Example 23 - Synthesis of l-(cyclohex-l-en-l-yl)-2-methylbenzene 1 -(Cyclohex- l-en-l-yl)-2-methylbenzene was prepared according to the general protocol of Suzuki cross coupling utilized in the synthesis of 1 -(cyclohex- l-en-l-yl)naphthalene using 1 -cyclohexenyl trifluoromethanesulfonate (4.45 g, 19.331 mmol, 1.0 eq), 2- methylbenzeneboronic acid (3.022 g, 22.231 mmol, 1.15 eq), sodium hydroxide (3.093 g, 77.324 mmol, 4.0 eq), copper(I) chloride (1.435 g, 14.498 mmol, 0.75 eq) and 1,1'- bis(diphenylphosphino)ferrocene di chloropalladium (II) (0.707 g, 0.967 mmol, 0.05 eq) and anhydrous 1,4-dioxane (64.44 ml, 0.3 M). The crude product was purified by filtration through a short pad of silica (0-10% EtOAc / n-hexane) to afford 1 -(cyclohex- l-en-l-yl)-2- methylbenzene (2.7 g, 12.852 mmol, yield=66%, purity=82%). 1H NMR (300 MHz, DMSO-d6) 57.19 - 7.06 (m, 3H), 7.06 - 6.97 (m, 1H), 5.49 (dq, J = 3.8, 1.8 Hz, 1H), 2.22 (s, 3H), 2.19 - 2.06 (m, 4H), 1.77 - 1.56 (m, 4H).

[0217] Example 24 - synthesis of 1 -(naphthal en-1 -yl)-7-oxabicvclo[4.1.Olheptane

[0218] The epoxide was synthesized from the corresponding 1 -arylcyclohexene. 1 -(Cyclohex- 1- en-l-yl)naphthalene (8.94 g, 20.601 mmol, 1.0 eq) was dissolved in dichloromethane (60 ml) and cooled to 0 °C. Subsequently, 3 -chloroperbenzoic acid (7.11 g, 41.201 mmol, 2.0 eq) was slowly added as a solution in dichloromethane (43 mL). The reaction mixture was allowed to attain ambient temperature and stirred until complete consumption of the substrate was observed by TLC. Saturated aqueous NaHCO3 was added and after the layers were separated, the aqueous phase was extracted with dichloromethane and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. This material was purified by column chromatography, eluting with ethyl acetate / hexane (gradient - 0:100 to 5:95) to afford 1- (naphthalen-l-yl)-7-oxabicyclo[4.1.0]heptane (4.3 g, 17.062 mmol, yield=83%, purity=89%) as a light-yellow oil. [M+H] 224.90 1H NMR (300 MHz - Chloroform-d): 5 8.04 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.59-7.44 (m, 4H), 3.29 (s, 1H), 2.22-2.18 (m, 4H), 1.75-1.64 (m, 4H).

[0219] Example 25 - synthesis of l-(naphthalen-2-yl)-7-oxabicyclo[4.1.01heptane

[0220] 1-(Naphthalen-2-yl)-7-oxabicyclo[4.1.0]heptane was prepared according to the general protocol utilized in the synthesis of l-(naphthalen-l-yl)-7-oxabicyclo[4.1.0]heptane using

[0221] 2-(cyclohex-l-en-l-yl)naphthalene (2.923 g, 8.7 mmol, 1.0 eq), dichloromethane (30 ml),

[0222] 3 -chloroperbenzoic acid (3.003 g, 17.4 mmol, 2.0 eq) in dichloromethane (28 mb). The crude product was purified by column chromatography, eluting with ethyl acetate / hexane (gradient - 0: 100 to 5:95) to afford l-(naphthalen-2-yl)-7-oxabicyclo[4.1.0]heptane (0.814 g, 2.286 mmol, yield=26%, purity=63%) as a colorless oil. [M+H] 224.90 1H NMR (300 MHz, Chloroform-d): 5 7.85 (dd, J = 10.3, 4.2 Hz, 4H), 7.52 - 7.47 (m, 3H), 3.19 (s, 1H), 2.43 (ddd, J = 14.0, 8.5, 5.4 Hz, 1H), 2.23 (dt, J = 14.9, 5.3 Hz, 1H), 2.10 - 2.04 (m, 2H), 1.72 - 1.60 (m, 3H), 1.47 - 1.36 (m, 1H).

[0223] Example 26 - synthesis of l-(2-methylphenyl)-7-oxabicyclo[4.1.01heptane l-(2-Methylphenyl)-7-oxabicyclo[4.1.0]heptane was prepared according to the general protocol utilized in the synthesis of l-(naphthalen-l-yl)-7-oxabicyclo[4.1.0]heptane using 3 -chloroperbenzoic acid (4.435 g, 25.704 mmol, 2.0 eq), 1 -(cyclohex- l-en-l-yl)-2- methylbenzene (2.7 g, 12.852 mmol, 1.0 eq) and di chloromethane (42.84 ml, 0.3 M). The crude product was purified using flash column chromatography (0-5% MeOH / DCM) to afford l-(2-methylphenyl)-7-oxabicyclo[4.1.0]heptane (1.2 g, 5.736 mmol, yield=45%, punty=90%). 1H NMR (300 MHz, DMSO-d6) 57.27 - 7.21 (m, 1H), 7.18 - 7.10 (m, 3H), 3.10 - 3.01 (s, 1H), 2.32 (s, 3H), 2.05 - 1.78 (m, 4H), 1.40 (dddt, J = 18.0, 12.8, 6.3, 3.1 Hz, 4H).

[0224] Example 27 - Synthesis of 2-azido-2-(naphthalen-l-yl)cvclohexan-l-ol

[0225] To a suspension of l-(naphthalen-l-yl)-7-oxabicyclo[4.1.0]heptane (4.300 g, 17.0617 mmol, 1.0 eq) in toluene (85.31 ml, 0.2 M) was added diazidobis(propan-2-yloxy)titanium (10.775 g, 42.6544 mmol, 2.5 eq) and the resulting mixture was heated at 700C for 2 hours. The mixture was cooled to room temperature, diluted with EtOAc and IM aqueous solution of HC1 was added. The mixture was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-azido-2- (naphthalen-l-yl)cyclohexan-l-ol (5.197 g, 16.719 mmol, yield=98%, purity=86%). [M- N2+H] 239.90 1H NMR (300 MHz, Chloroform-d): 5 8.80 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 9.5 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 7.4 Hz, 1H), 4.69 (dd, J = 10.1, 4.3 Hz, 1H), 2.65 (d, 1H), 2.00-1.83 (m, 3H), 1.68-1.39 (m, 5H).

[0226] Example 28 - synthesis of 2-azido-2-(naphthalen-2-yl)cvclohexan-l-ol

[0227] 2-Azido-2-(naphthalen-2-yl)cyclohexan-l-ol was prepared according to the general protocol utilized in the synthesis of 2-azido-2-(naphthalen-l-yl)cyclohexan-l-ol using 1- (naphthalen-2-yl)-7-oxabicyclo[4.1.0]heptane (0.81 g, 2.275 mmol, 1.0 eq), toluene (11.38 ml, 0.2 M) and diazidobis(propan-2-yloxy)titanium (1.437 g, 5.688 mmol, 2.5 eq). Aqueous workup afforded 2-azido-2-(naphthalen-2-yl)cyclohexan-l-ol (1.054 g, 2.09 mmol, yield=92%, purity=53%). [M-N2+H] 239.80. Example 29 - Synthesis of 2-azido-2-(2-methylphenyl)cvclohexan-l-ol

[0228] 2-Azido-2-(2-methylphenyl)cyclohexan-l-ol was prepared according to the general protocol utilized in the synthesis of 2-azido-2-(naphthalen-l-yl)cyclohexan-l-ol using 1- (2-methylphenyl)-7-oxabicyclo[4.1.0]heptane (1.0 g, 4.78 mmol, 1.0 eq), diazidobis(propan-2-yloxy)titanium (3.019 g, 11.951 mmol, 2.5 eq) and toluene (15.93 ml, 0.3 M). The reaction mixture was stirred for 4 hours at 70°C. IM HC1 aqueous solution was added, and the mixture was extracted using Et2O. Aqueous workup afforded 2-azido- 2-(2-methylphenyl)cyclohexan-l-ol (2.2 g, 6.658 mmol, yield=100%,purity=70%). Conversion was analyzed on TLC (retention time of desired product was different than starting material). MW of desired product was not visible on UPLC.

[0229] Example 30 Synthesis of 2-azido-2-(naphthalen- 1 -vDcyclohexan- 1 -one

[0230] To a solution of 2-azido-2-(naphthalen-l-yl)cyclohexan-l-ol (5.197 g, 16.719 mmol, 1.0 eq) in dichloromethane (83.59 ml, 0.2 M) was added NaHCO3 (6.039 g, 71.89 mmol, 4.3 eq) and Dess-Martin periodinane (9.928 g, 23.406 mmol, 1.4 eq). After the substrate was consumed as judged by TLC, the reaction mixture was diluted with water. The mixture was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This afforded the desired product 2-azido-2-(naphthalen-l- yl)cyclohexan-l-one (5.15 g, 14.946 mmol, yield=89%, purity=77%), obtained as a yellow thick oil. [M-N2+H] 237.90 1H NMR (300 MHz, Chloroform-d): 5 8.07 - 8.01 (m, 1H), 7.92 (dd, J = 9.0, 3.6 Hz, 2H), 7.71 (d, J = 7.4 Hz, 1H), 7.58 - 7.49 (m, 3H), 3.05 (d, J = 14.6 Hz, 1H), 2.67 - 2.54 (m, 1H), 2.33 (ddd, J = 22.7, 13.6, 7.1 Hz, 2H), 2.12 - 1.90 (m, 4H).

[0231] Example 31 - synthesis of 2-azido-2-(naphthalen-2-yl)cyclohexan-l -one

[0232] 2-Azido-2-(naphthalen-2-yl)cyclohexan-l-one was prepared according to the general protocol utilized in the synthesis of 2-azido-2-(naphthalen-l-yl)cyclohexan-l-one using 2- azido-2-(naphthalen-2-yl)cyclohexan-l-ol (1.054 g, 2.09 mmol, 1.0 eq), dichloromethane (10.45 ml, 0.2 M), NaHCO3 (0.755 g, 8.985 mmol, 4.3 eq) and Dess-Martin periodinane (1.241 g, 2.925 mmol, 1.4 eq). The aqueous workup afforded 2-azido-2-(naphthalen-2- yl)cyclohexan-l-one (0.712 g, 1.932 mmol, yield=92%, purity=72%). [M-N2+H+] 237.95.

[0233] Example 32 - synthesis of 2-azido-2-(2-methylphenyl)cyclohexan-l-one

[0234] 2-Azido-2-(2-methylphenyl)cyclohexan-l-one was prepared according to the general protocol utilized in the synthesis of 2-azido-2-(naphthalen-l-yl)cyclohexan-l-one using Dess-martin periodinane (5.083 g, 11.984 mmol, 1.8 eq), sodium bicarbonate (3.132 g, 37.285 mmol, 5.6 eq), 2-azido-2-(2-methylphenyl)cyclohexan-l-ol (2.2 g, 6.658 mmol, 1.0 eq) and dichloromethane (44.39 ml, 0.15 M). The crude product was purified using flash column chromatography (0-4% MeOH / DCM) to afford 2-azido-2-(2- methylphenyl)cyclohexan-l-one (1.46 g, 4.457 mmol, yield=67%, purity=70%). 1H NMR (300 MHz, DMSO-d6) 5 7.55 - 7.46 (m, 1H), 7.29 (dtd, J = 9.3, 5.6, 3.6 Hz, 3H), 2.76 (dddd, J = 14.2, 5.8, 3.5, 1.6 Hz, 1H), 2.61 - 2.50 (m, 1H), 2.42 - 2.23 (m, 1H), 2.14 (s, 3H), 2.09 - 1.96 (m, 1H), 1.96 - 1.63 (m, 4H). Example 33 - synthesis of 2-amino-2-(naphthalen-l-vBcvclohexan-l-one (Compound

[0235] XLI-C16H17NO)

[0236] To a solution of 2-azido-2-(naphthalen-l-yl)cyclohexan-l-one (0.297 g, 1.119 mmol, 1.0 eq) in 8 mL of THF / H2O (4: 1) was added triphenylphosphine (0.44 g, 1.679 mmol, 1.5 eq). The reaction mixture was heated to 50 °C for 20 hours. Then organic solvent was removed under reduced pressure and residue was diluted with di chloromethane and IM aqueous solution of HC1. After separation, the aqueous layer was basified with saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a thick yellow oil. This oil was dissolved in diethyl ether and treated with 2.0M HC1 solution in diethyl ether to convert the free base into hydrochloride salt, this resulted in formation of 2-amino-2-(naphthalen-l-yl)cyclohexan-l-one hydrochloride (0.128 g, 0.524 mmol, 47%) as a white solid. [M+H] 240.26 1H NMR (300 MHz, Deuterium oxide): 5 8.06 - 7.97 (m, 3H), 7.66 - 7.49 (m, 4H), 3.37 (dd, J = 13.8, 2.7 Hz, 1H), 2.33 (d, J = 11.7 Hz, 1H), 2.10 (ddt, J = 18.4, 12.4, 5.4 Hz, 2H), 1.96 - 1.73 (m, 4H).

[0237] Example 34 - synthesis of 2-amino-2-(naphthalen-2-yl)cvclohexan-l-one (Compound

[0238] XLII-C16H17NO)

[0239] 2-Amino-2-(naphthalen-2-yl)cyclohexan-l-one was prepared according to the general protocol utilized in the synthesis of 2-amino-2-(naphthalen-l-yl)cyclohexan-l-one using 2-azido-2-(naphthalen-2-yl)cyclohexan-l-one (0.712 g, 1.932 mmol, 1.0 eq), THF / H2O (13 mL, 4: 1) and triphenylphosphine (0.76 g, 2.898 mmol, 1.5 eq). The isolated product was converted into hydrochloride salt to afford 2-amino-2-(naphthalen-2-yl)cyclohexan-l- one hydrochloride (0.389 g, 1.479 mmol, 77%) as a white solid. [M+H] 240.26 1H NMR (300 MHz, DMSO-d6): 5 8.74 (s, 3H), 8.04 (ddd, J = 14.9, 12.0, 7.1 Hz, 4H), 7.66 - 7.64 (m, 2H), 7.47 (dd, J = 8.7, 1.8 Hz, 1H), 3.19 (d, J = 13.8 Hz, 1H), 2.45 (d, J = 3.9 Hz, 2H), 2.15 (t, J = 11.6 Hz, 1H), 2.02-1.87 (m, 2H), 1.69 (t, J = 9.1 Hz, 2H).

[0240] Example 35 -synthesis of 2-amino-2-(2-methylphenyl)cvclohexan-l-one hydrochloride (Compound XLIII-C13H17NO)

[0241] 2-amino-2-(2-methylphenyl)cyclohexan-l-one hydrochloride was prepared according to the general protocol utilized in the synthesis of 2-amino-2-(naphthalen-l-yl)cyclohexan-l- one using 2-azido-2-(2-methylphenyl)cyclohexan-l-one (1.46 g, 4.457 mmol, 1.0 eq), triphenylphosphine (1.754 g, 6.686 mmol, 1.5 eq), tetrahydrofuran (17.83 ml) and water (8.76 ml). The crude product was purified using preparative HPLC under acidic conditions to afford the desired product which was converted into its hydrochloride: 2-amino-2-(2- methylphenyl)cyclohexan-l-one hydrochloride (0.030 g, 4.46 mmol, yield=3%, punty=99.18 %). [M+H] 204.27 1H NMR (400 MHz, DMSO-d6) 5 7.62 (dd, J = 7.6, 1.6 Hz, 1H), 7.27 - 7.09 (m, 4H), 2.62 - 2.51 (m, 2H), 2.29 - 2.18 (m, 1H), 2.12 (s, 2H), 2.07 (s, 3H), 1.96 - 1.83 (m, 1H), 1.83 - 1.51 (m, 4H).

[0242] Example 36 -synthesis of tert-butyl N-[l-(naphthalen-l-yl)-2-oxocvclohexyl1carbamate

[0243] To a solution of 2-amino-2-(naphthalen-l-yl)cyclohexan-l-one (0.777 g, 3.019 mmol, 1.0 eq) in toluene (15.1 ml, 0.2 M), was added anhydrous potassium carbonate (1.252 g, 9.058 mmol, 3.0 eq) and di-tert-butyl dicarbonate (0.988 g, 4.529 mmol, 1.5 eq). The resulting mixture was stirred at 80 °C for 15 hours. After cooling, the mixture was washed with water and aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography eluting with ethyl acetate / n-hexane (gradient - 0: 100 to 5:95) afforded the product tert-butyl N-[l-(naphthalen-l-yl)-2- oxocyclohexyl] carbamate (1.114 g, 2.855 mmol, yield=95%, purity=87%) as a white solid. [M+H+ACN]=402.95.

[0244] Example 37 -synthesis of tert-butyl N-[l-(naphthalen-2-yl)-2-oxocvclohexyl1carbamate

[0245] Tert-butyl N-[l-(naphthalen-2-yl)-2-oxocyclohexyl]carbamate was prepared according to the general protocol utilized in the synthesis of tert-butyl N-[l-(naphthalen-l-yl)-2- oxocyclohexyl] carbamate using 2-amino-2-(naphthalen-2-yl)cyclohexan-l-one (0.375 g, 1.426 mmol, 1.0 eq), anhydrous potassium carbonate (0.591 g, 4.278 mmol, 3.0 eq), di- tert-butyl dicarbonate (0.467 g, 2.139 mmol, 1.5 eq), and toluene (7.13 ml, 0.2 M). Aqueous workup afforded tert-butyl N-[l -(naphthal en-2-yl)-2-oxocy cl ohexyl] carbamate (0.382 g, 1.092 mmol, yield=77%, purity=97%) as a white solid. LCMS: [M+ACN+H] 403.00 1H NMR (300 MHz, DMSO-d6): 5 7.91 - 7.84 (m, 4H), 7.70 (s, 1H), 7.51 (dq, J = 6.8, 3.5 Hz, 2H), 7.42 (d, J = 8.2 Hz, 1H), 2.74 (td, J = 11.9, 5.0 Hz, 1H), 2.29-2.20 (m, 2H), 2.02 (m, 2H), 1.85 - 1.57 (m, 2H), 1.45 (s, 9H), 1.27 - 1.09 (m, 2H).

[0246] Example 38 -synthesis of tert-butyl N-[l-(2-methylphenyl)-2-oxocvclohexyl1carbamate Tert-butyl N-[l-(2-methylphenyl)-2-oxocyclohexyl]carbamate was prepared according to the general protocol utilized in the synthesis of tert-butyl N-[l-(naphthalen-l-yl)-2- oxocyclohexyl] carbamate using 2-amino-2-(2-methylphenyl)cyclohexan-l -one hydrochloride (0.789 g, 3.291 mmol, 1.0 eq), anhydrous potassium carbonate (1.365 g, 9.873 mmol, 3.0 eq), di-tert-butyl dicarbonate (1.077 g, 4.937 mmol, 1.5 eq), triethylamine (0.229 ml, 1.646 mmol, 0.5 eq) and toluene (16.46 ml). The crude product was purified by column chromatography (0-30% ethyl acetate / n-hexane) and afforded tert-butyl N-[l-(2- methylphenyl)-2-oxocyclohexyl]carbamate (0.516 g, 1.514 mmol, yield=46%, punty=89%). [M+ACN+Na]=367.00.

[0247] Example 39 -synthesis of tert-butyl N-[l-(naphthalen-l-yl)-2- [(trimethylsilyl)oxy1cvclohex-2-en-l-yl1 carbamate

[0248] To a solution of tert-butyl N-[l-(naphthalen-l-yl)-2-oxocyclohexyl]carbamate (0.6 g, 1.538 mmol, 1.0 eq) in anhydrous tetrahydrofuran (6.15 ml, 0.25 M) was added lithium diisopropylamide solution 1.0 M in THF / hexanes (3.845 ml, 3.845 mmol, 2.5 eq) at -78 °C. The resulting mixture was stirred at -78 °C for 2 hours before chlorotrimethylsilane (0.586 ml, 4.614 mmol, 3.0 eq) was added. After stirring at -78 °C for 1 hour, the mixture was stirred at room temperature for 1 additional hour. The reaction mixture was poured into saturated aqueous NH4C1, and aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl N-[l-(naphthalen-l-yl)-2- [(trimethylsilyl)oxy]cyclohex-2-en-l-yl] carbamate (0.85 g, 1.26 mmol, yield=82%, purity=61%) as a yellow oil. This crude product was used without further purification in the next step. [M+ACN+Na]=475.05.

[0249] Example 40 -synthesis of tert-butyl N-[l-(naphthalen-2-yl)-2- [(trimethylsilvDoxylcvclohex-2-en-l-yll carbamate

[0250] Tert-butyl N-[l-(naphthalen-2-yl)-2-[(trimethylsilyl)oxy]cyclohex-2-en-l-yl]carbamate was prepared according to the general protocol utilized in the synthesis of tert-butyl N-[l- (naphthalen-l-yl)-2-[(trimethylsilyl)oxy]cy cl ohex-2-en-l-yl] carbamate using tert-butyl N- [l-(naphthalen-2-yl)-2-oxocyclohexyl] carbamate (0.382 g, 1.092 mmol, 1.0 eq), lithium diisopropylamide solution 1.0 M in THF / hexanes (2.729 ml, 2.729 mmol, 2.5 eq), chlorotrimethylsilane (0.485 ml, 3.821 mmol, 3.5 eq) and anhydrous tetrahydrofuran (4.37 ml). The aqueous workup afforded tert-butyl N-[l -(naphthal en-2-yl)-2- [(trimethylsilyl)oxy]cyclohex-2-en-l-yl] carbamate (0.538 g, 0.837 mmol, yield=77%, purity=64%) as a yellow oil. This crude product was used without further purification in the next step. [M+ACN+Na]=475.10.

[0251] Example 41 -synthesis of tert-butyl N-[l-(2-methylphenyl)-2- [(trimethylsilyl)oxy1cvclohex-2-en-l-yl1 carbamate

[0252] Tert-butyl N-[l-(2-methylphenyl)-2-[(trimethylsilyl)oxy]cyclohex-2-en-l-yl]carbamate was prepared according to the general protocol utilized in the synthesis of tert-butyl N-[l- (naphthalen-l-yl)-2-[(trimethylsilyl)oxy]cy cl ohex-2-en-l-yl] carbamate using tert-butyl N- [ 1 -(2-methy lphenyl)-2-oxocy cl ohexyl] carbamate (0.516 g, 1.514 mmol, 1.0 eq), 1.0M lithium diisopropylamide solution 1.0 M in THF / hexanes (3.784 ml, 3.784 mmol, 2.5 eq), chlorotrimethylsilane (0.576 ml, 4.541 mmol, 3.0 eq) and anhydrous tetrahydrofuran (6.05 ml). Aqueous workup afforded tert-butyl N-[l-(2-methylphenyl)-2- [(trimethylsilyl)oxy]cyclohex-2-en-l-yl] carbamate (0.71 g, 1.04 mmol, yield=99%, purity=55%) which was used in the next step without further purification. [M+ACN+Na- TMS]=367.20. Example 42 -synthesis of tert-butyl N-[2-(naphthalen-l-vD-l-[(trimethylsilvBoxy1-7- oxabicyclo[4.1.OIheptan-2-yllcarbamate

[0253] Tert-butyl N-[l-(naphthalen-l-yl)-2-[(trimethylsilyl)oxy]cyclohex-2-en-l-yl]carbamate (0.85 g, 1.26 mmol, 1.0 eq) was dissolved in dichloromethane (6.3 ml, 0.2 M) and cooled to 0 °C. Subsequently, 3 -Chloroperbenzoic acid (0.435 g, 2.519 mmol, 2.0 eq) was added slowly to the solution. The reaction mixture was allowed to attain ambient temperature and stirred until complete consumption of the substrate was observed. Then saturated aqueous solution of sodium bicarbonate was added and after the layers were separated, the aqueous phase was extracted with dichloromethane and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the desired product tert-butyl N-[2-(naphthalen-l-yl)-l-[(trimethylsilyl)oxy]-7- oxabicyclo[4.1.0]heptan-2-yl]carbamate (1.118 g, 1.15 mmol, yield=91%, purity=44%) as a colorless oil. [M+ACN+Na-TMS] 419.00.

[0254] Example 43 -synthesis of tert-butyl N-[2-(naphthalen-2-yl)-l-[(trimethylsilyl)oxy1-7- oxabicyclo[4.1.OIheptan-2-yllcarbamate

[0255] Tert-butyl N-[2-(naphthalen-2-yl)-l -[(trimethylsilyl)oxy]-7-oxabicyclo[4.1 ,0]heptan-2- yl] carbamate was prepared according to the general protocol utilized in the synthesis of tert-butyl N-[2-(naphthalen-l-yl)-l-[(trimethylsilyl)oxy]-7-oxabicyclo[4.1.0]heptan-2- yl]carbamate using tert-butyl N-[l-(naphthalen-2-yl)-2-[(trimethylsilyl)oxy]cyclohex-2- en-l-yl] carbamate (0.538 g, 0.837 mmol, 1.0 eq), 3 -chloroperbenzoic acid (0.289 g, 1.673 mmol, 2.0 eq) and dichloromethane (4.18 ml). Aqueous workup afforded tert-butyl N-[2- (naphthalen-2-yl)-l-[(trimethylsilyl)oxy]-7-oxabicyclo[4.1.0]heptan-2-yl]carbamate (0.52 g, 0.778 mmol, yield=93%, purity=64%) as a colorless oil. This crude product was used without further purification in the next step. [M+ACN+Na+-TMS]=419.00.

[0256] Example 44 -synthesis of tert-butyl N-[2-(2-methylphenyl)-l-[(trimethylsilyl)oxy1-7- oxabicvclo[4.1 ,01heptan-2-yl1carbamate

[0257] Tert-butyl N-[2-(2-methylphenyl)-l -[(trimethylsilyl)oxy]-7-oxabicyclo[4.1 ,0]heptan-2- yl] carbamate was prepared according to the general protocol utilized in the synthesis of tert-butyl N-[2-(naphthalen-l-yl)-l-[(trimethylsilyl)oxy]-7-oxabicyclo[4.1.0]heptan-2- yl]carbamate using tert-butyl N-[l-(2-methylphenyl)-2-[(trimethylsilyl)oxy]cyclohex-2- en-l-yl] carbamate (0.71 g, 1.04 mmol, 1.0 eq), 3 -chloroperbenzoic acid (0.359 g, 2.079 mmol, 2.0 eq) and dichloromethane (5.2 ml). Aqueous workup afforded tert-butyl N-[2-(2- methylphenyl)-l-[(trimethylsilyl)oxy]-7-oxabicyclo[4.1.0]heptan-2-yl]carbamate (0.654 g, 0.635 mmol, yield=61%, purity=38%) as a colorless oil. The crude product was used without further purification in the next step. [M+H+ACN-TMS]=305.15, [M+ACN+Na- TMS]=419.19.

[0258] Example 45 -synthesis of tert-butyl N-[3-hydroxy-l-(naphthalen-l-yl)-2- oxocyclohexy 11 carbamate To tert-butyl N-[2-(naphthalen-l-yl)-l-[(trimethylsilyl)oxy]-7-oxabicyclo[4.1.0]heptan-2- yl]carbamate (1.118 g, 1.15 mmol, 1.0 eq) dissolved in THF (5.75 ml, 0.2 M) was added a pre-mixed solution (1: 1) of tetrabutylammonium fluoride solution 1.0 M in THF (2.301 ml, 2.301 mmol, 2.0 eq) and acetic acid (0.132 ml, 2.301 mmol, 2.0 eq). The resulting mixture was stirred for 30 minutes before saturated aqueous NaHCO3 was added. The mixture was separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (SiO2, hexanes / ethyl acetate 100% to 80% gradient elution) afforded tert-butyl N-[3-hydroxy-l- (naphthalen-l-yl)-2-oxocyclohexyl] carbamate (0.147 g, 0.405 mmol, yield=35%, punty=98%) as a white solid. [M+ACN+Na]=419.15 1H NMR (300 MHz, DMSO-d6): 5 7.99 - 7.87 (m, 3H), 7.79 (d, J = 8.6 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.48 (td, J = 7.1, 6.6, 4.2 Hz, 2H), 6.84 (s, 1H), 5.25 (d, J = 6.2 Hz, 1H), 3.68 - 3.61 (m, 2H), 2.09 (br, 1H), 1.85 - 1.75 (m, 2H), 1.62 - 1.53 (m, 1H), 1.16 (s, 9H).

[0259] Example 46 -synthesis of tert-butyl N-[3-hydroxy-l-(naphthalen-2-yl)-2- oxocyclohexyll carbamate tert-butyl N-[3-hydroxy-l-(naphthalen-2-yl)-2-oxocyclohexyl]carbamate was prepared according to the general protocol utilized in the synthesis of tert-butyl N-[3-hydroxy-l- (naphthalen-l-yl)-2-oxocyclohexyl] carbamate using tert-butyl N-[2-(naphthalen-2-yl)-l- [(trimethylsilyl)oxy]-7-oxabicyclo[4.1.0]heptan-2-yl]carbamate (0.52 g, 0.778 mmol, 1.0 eq), IM tetrabutylammonium fluoride solution in THF (1.557 ml, 1.557 mmol, 2.0 eq), acetic acid (0.089 ml, 1.557 mmol, 2.0 eq) and tetrahydrofuran (3.89 ml). The crude product was purified by column chromatography (hexanes / ethyl acetate 100% to 80% gradient elution) to afford tert-butyl N-[3-hydroxy-l-(naphthalen-2-yl)-2- oxocyclohexyl] carbamate (0.22 g, 0.613 mmol, yield=79%, purity=99%) as a white solid. [M+ACN+Na]=418.95.

[0260] Example 47 -synthesis of tert-butyl N-[3-hydroxy-l-(2-methylphenyl)-2- oxocyclohexy 1] carbamate tert-butyl N-[3-hydroxy-l-(2-methylphenyl)-2-oxocyclohexyl]carbamate was prepared according to the general protocol utilized in the synthesis of tert-butyl N-[3-hydroxy-l- (naphthalen-l-yl)-2-oxocyclohexyl] carbamate using tert-butyl N-[2-(2-methylphenyl)-l- [(trimethylsilyl)oxy]-7-oxabicyclo[4.1.0]heptan-2-yl]carbamate (0.654 g, 0.635 mmol, 1.0 eq), acetic acid (0.073 ml, 1.269 mmol, 2.0 eq) and 1.0M tetrabutylammonium fluoride solution in THF (1.269 ml, 1.269 mmol, 2.0 eq), and tetrahydrofuran (3.17 ml). The crude product was purified using flash column chromatography (0-30% EtOAc / n-hexane) to afford tert-butyl N-[3-hydroxy-l-(2-methylphenyl)-2-oxocyclohexyl]carbamate (0.28 g, 0.833 mmol, yield=131%, punty=95%). [M+ACN+Na]=382.95, [M+ACN+H- Boc]=260.95

[0261] Example 48 -synthesis of 2-amino-6-hydroxy-2-(naphthalen-l-yl)cyclohexan-l-one hydrochloride (Compound XLVI-C16H17NO2)

[0262] To a solution of tert-butyl N-[3-hydroxy-l-(naphthalen-l-yl)-2-oxocyclohexyl]carbamate (0.147 g, 0.405 mmol, 1.0 eq) in dichloromethane (2.7 ml, 0.15 M) was added trifluoroacetic acid (0.462 g, 4.053 mmol, 10.0 eq). The resulting mixture was stirred at room temperature for 1 h before the solvent and TFA were removed under reduced pressure. The residue was dissolved in water and a 1 : 1 mixture of saturated aqueous sodium bicarbonate and saturated aqueous potassium carbonate solution was added. The mixture was extracted with ethyl acetate, the extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the free base of the desired product which was treated with HC1 to afford 2-amino-6-hydroxy-2-(naphthalen-l- yl)cyclohexan-l-one hydrochloride (0.09 g, 0.304 mmol, yield=75%, purity=98.43%) as a white solid. [M+H]=256.20. 1H NMR (400 MHz, Deuterium Oxide-d6): 5 8.07 (d, J = 8.3 Hz, 1H), 8.01 - 7.98 (m, 2H), 7.66 - 7.59 (m, 2H), 7.58 - 7.54 (m, 2H), 4.04 (dd, J = 11.9, 7.0 Hz, 1H), 3.37 (dd, J = 14.0, 2.8 Hz, 1H), 2.16 (ddq, J = 13.0, 6.4, 3.2 Hz, 1H), 2.11 - 2.03 (m, 1H), 1.95 - 1.87 (m, 2H), 1.68 - 1.56 (m, 1H).

[0263] Example 49 - Synthesis of 2-amino-6-hydroxy-2-(naphthalen-2-yl)cvclohexan-l-one hydrochloride (Compound XLV-C21H25NO4)

[0264] 2-amino-6-hydroxy-2-(naphthalen-2-yl)cyclohexan-l-one hydrochloride was prepared according to the general protocol utilized in the synthesis of -amino-6-hydroxy-2- (naphthalen-l-yl)cyclohexan-l-one hydrochloride using tert- butyl N-[3 -hydroxy- 1- (naphthalen-2-yl)-2-oxocyclohexyl]carbamate (0.22 g, 0.613 mmol, 1.0 eq), trifluoroacetic acid (0.699 g, 6.128 mmol, 10.0 eq) and dichloromethane (4.09 ml). The desired product was isolated as a hydrochloride salt: 2-amino-6-hydroxy-2-(naphthalen-2-yl)cyclohexan- 1-one hydrochloride (0.115 g, 0.38 mmol, yield=65%, purity=96.47%) as a white solid. [M+H]=256.33. 1H NMR (400 MHz, Deuterium Oxide-d6): 5 8.00 (d, J = 8.7 Hz, 1H), 7.94 - 7.89 (m, 3H), 7.61 - 7.53 (m, 2H), 7.35 (dd, J = 8.7, 2.1 Hz, 1H), 4.33 (dd, J = 12.1, 6.8 Hz, 1H), 3.23 (dd, J = 14.1, 2.7 Hz, 1H), 2.20 (ddt, J = 9.6, 6.9, 2.8 Hz, 1H), 2.11 (td, J = 13.6, 4.0 Hz, 1H), 1.95-1.90 (m, 1H), 1.82 - 1.61 (m, 2H). Example 50 -synthesis of 2-amino-6-hvdroxy-2-(2-methylphenyl)cvclohexan- l -one hydrochloride (Compound XLIV - C13H17NO2)

[0265] 2-amino-6-hydroxy-2-(2-methylphenyl)cyclohexan-l-one hydrochloride was prepared according to the general protocol utilized in the synthesis of -amino-6-hydroxy-2- (naphthalen-l-yl)cyclohexan-l-one hydrochloride using tert-butyl N-[3-hydroxy-l-(2- methylphenyl)-2-oxocyclohexyl]carbamate (0.28 g, 0.833 mmol, 1.0 eq), trifluoroacetic acid (0.95 g, 8.328 mmol, 10.0 eq) and dichloromethane (5.55 ml). The desired product was isolated as a hydrochloride salt: 2-amino-6-hydroxy-2-(2-methylphenyl)cyclohexan- 1-one hydrochloride (0.112 g, 0.504 mmol, yield=61%, purity=98.77%) as a white solid. [M+H]=220.20 1H NMR (400 MHz, DMSO-d6) 5 8.70 (s, 3H), 7.66 (dt, J = 7.5, 3.7 Hz, 1H), 7.39 (dd, J = 5.8, 3.4 Hz, 2H), 7.29 (dd, J = 5.6, 3.7 Hz, 1H), 5.64 (s, 1H), 4.02 (dd, J = 11.5, 6.6 Hz, 1H), 3.15 (dd, J = 14.1, 2.8 Hz, 1H), 2.18 (s, 3H), 2.14 (d, J = 9.0 Hz, OH), 1.90 - 1.71 (m, 2H), 1.65 - 1.40 (m, 2H).

[0266] Example 51- Determination of D-Serine concentrations

[0267] PC- 12 cell line (derived from rat adrenal medulla cells) are seeded on 100 x 20 mm tissue culture plates and maintained at 37 °C under humidified 5% CO2 in air until they reach >70% confluence. The cells are then incubated for 36 h with media containing the test compounds. The medium is removed, and the cells are assessed for intracellular and extracellular D-serine levels, and expression of serine racemase (SR). All analyses may be repeated in three independent cell cultures (n=3). Intracellular D-serine concentrations are measured using capillary electrophoresis-laser induced fluorescence (CE-LIF) method using a P / ACE MDQ system equipped with a laser-induced fluorescence detector (Singh et al., Anal Biochem 2012; 421 : 460-466). The extracellular D-serine levels are determined by employing liquid chromatography with mass spectrometric detection (Singh et al., Br J Pharmacol 2015; 172: 4546-59). The expression of m-SR and d-SR in PC-12 cells may be determined using western blotting (Singh et al., Anesthesiology 2014; 121 : 149-59). The primary antibody for d-SR may be obtained from Santa Cruz Biotechnology (Dallas, TX, USA), and the antibody that recognizes both m-SR and d-SR may be purchased from Abeam, Inc. (Cambridge, MA). The primary antibody for P-actin is from Abeam. Immune reactive bands may be detected using the ECL Plus Western. Blotting Detection System (GE Healthcare, Piscataway, NJ, USA) and quantification may be accomplished by volume densitometry using ImageJ software (National Institutes of Health, Bethesda, MD) and normalization to P-actin.

[0268] Example 52- Measurement of cytokines release from primary human monocytes

[0269] Human primary monocytes are isolated (enriched) from buffy coats of healthy human blood donors. Cells are seeded in 24-well-plates for ELISA experiments. The results are normalized to LPS, provided as 100%, and presented as percentage of change cytokine levels. The various respective statistical significances are calculated by T-Test. The toxicity of the compounds on the cells is also tested using Alamar Blue. Treatment with toxic amounts of sodium fluoride (NaF at 250 pg / ml) are used as control.

[0270] Example 53- Treatment of SARS-CoV-2 positive patients with the herein compounds

[0271] SARS-CoV-2 positive patients (typically, but not necessarily mild to severe patients) are evaluated for the presence of elevated plasma and / or saliva concentrations of pro- inflammatory agents (e.g., interleukins (IL), chemokines, granulocyte colony-stimulating stimulating factors (G-CSF), and / or tumor necrosis factor-a (TNF- a)), and optionally also other markers of systemic inflammation. The patient’s temperature, blood oxygen levels, respiration rate and other determinants of clinical status are determined. Patient anxiety and depression may be further assessed using the Hospital Anxiety and Depression Scale (HADS). A pharmaceutical composition comprising one or more compounds according to Formula I or II is administered to the patient (optionally in a daily administration), and the plasma or saliva concentrations of the inflammatory markers, general clinical status, and anxiety and depression are monitored. A positive response is defined as reduced plasma / saliva concentrations of the pro- inflammatory agents, improved clinical status, and reduced anxiety and depression as measured by the HADS score. The pharmaceutical composition comprising one or more compounds according to Formula I or II may be administered via i.v. infusion, i.p. (intraperitoneal) administration, by intranasal, sublingual, or by oral administration, at an optional dose, below the normal anesthetic dose (e.g., 0.15 mg / kg - 0.3 mg / kg, based on total body weight for maximum 20 mg every 6 hours).

[0272] Example 54- Determine the analgesic effects of the compounds in the spared nerve injury (SNI) and Complete Freund’s Adjuvant (CFA) models of chronic neuropathic and inflammatory pain.

[0273] The SNI model produces a consistent neuropathy inducing both mechanical allodynia and heat hyperalgesia. Experimenters conducting all tests are blind to experimental conditions and sex. An N=8 mice per group is used for pain experiments, and 10 mice per group are used for conditioned place preference (CPP) experiments. All data is analyzed by t-test or ANOVA. Mice are subjected to SNI or sham surgery and tested for mechanical allodynia and heat hyperalgesia, as described in the test, over 8 weeks. For the SNI the common peroneal and tibial nerves are ligated and axotomized, keeping the sural nerve intact. Mechanical allodynia is tested beginning 2 weeks after the SNI surgery. After acclimation for 30 min, mice are tested starting with the 0.15 g filament and pain quantified using the up / down method of Chap lan. Compounds are tested at 3 doses, such as 3, 10, and 30 mg / kg, based upon the effective doses of HNK, plus vehicle, plus gabapentin (100 mg / kg), as positive control. One week later, if there is anti-allodynic activity, determination is made on whether this activity is blocked by the AMPA receptor antagonist NBQX (10 mg / kg) or the opioid antagonist naloxone (1 mg / kg), administered i.p. 15 min prior to the compounds. To determine whether antinociceptive actions of the compounds are specific to neuropathic pain, or more generalized chronic pain, compounds are tested in the CFA model of chronic inflammatory pain. When injected into the paw, CFA causes long-lasting inflammation and sensitivity of the paw that can be measured with von Frey filaments.

[0274] Figure 1 illustrates a test conducted using compound XXVII. The top set of data represents the sham operated animals or controls, and the second set is from the SNI experimental animals. The measurements reflect the pressure one can apply to the animal's paw with the

[0275] 1 higher numbers reflecting increased tolerance or less pain. In the SNI animals, ip administration of the vehicle does not increase tolerance or reduce pain. Compound XXVII produces significant pain relief at 30 min (** P < 0.01), peaks at 60 min (* P < 0.05) and is reduced but still significant ( P < 0.05) at 240 min. HNK does not produce significant pain relief at 30 min, produces significant relief at 60 min (* P < 0.05) which continues to increase at 240 min (* P < 0.05).

[0276] Example 55- the effect of the herein compounds on activation of opioid receptors, as direct agonists as well as allosteric modulators that potentiate the effect of opioid peptides.

[0277] The biological activity of the compounds was tested with human mu opioid receptor (MOR) expressed in UO5S cells, using a P-arrestin recruitment assay. MOR is a known target of ketamine and HNK; these drugs function as weak direct agonists as well as potent positive allosteric modulators (PAMs).

[0278] Materials: Met-enkephalin (Met-enk) (cat. No. 024-35) was from Phoenix Pharmaceuticals, Inc (Burlingame, CA). RS-ketamine (cat. No.K-2753), 2R,6R- hydroxynorketamine (cat. No. SML1873), 2S,6S- hydroxynorketamine (cat. No. SML1875), and protease inhibitor cocktail (cat. No. P2714) were from Millipore Sigma (St. Louis, MO). The PathHunter Chemiluminescence detection kit (cat. No. 93-0001) was from DiscoverX (Eurofins Corporation, Fremont, CA). GF / B filters (cat. No. FP-100) were from Brandel, Inc. (Gaithersburg, MD).

[0279] P -arrestin recruitment: UO5S cells expressing human MOR tagged with a ProLink / p-gal donor fragment at the C-terminal region and P-arrestin tagged with a complementary P-gal activator fragment (MORPgal) were from DiscoverX (Fremont, CA; cat. No. 93-0213C3). These cells were grown in MEM Alpha media containing 10% (vol / vol) FBS, streptomycin-penicillin, 500 pg / mL of geneticin, and 250 pg / mL of hygromycin. Saturation binding assays with [3H]DAMGO show that the cells exhibit a Kd of 6±lnM and a Bmax of 690±50 fmol / mg protein.

[0280] Cells expressing MORPgal were plated in each well of either a 96-well white clear bottom plate (Corning, Kennebunk, ME; cat. No. 3903; 10,000 cells / well) or a 384-well white clear bottom plate (Thermo Scientific, Rochester, NY; cat. No. 142762; 2,500 cells / well) in 100 pL media. The next day, cells were rinsed with 50 mM Tris-Cl buffer, pH 7.4, containing 100 mM NaCl, 10 mM MgC12, 0.2 mM EGTA, and protease inhibitor cocktail and treated for 60 min at 37° C with ketamine, HNK, or the herein compounds, in the presence or absence of 100 nM Met-enk. At the end of the incubation period, the bottoms of the plates were sealed with white vinyl sealing tape, and P-arrestin recruitment measured using the PathHunter Chemiluminescence detection kit, as described in the manufacturer’s protocol (DiscoverX).

[0281] Data Analysis: Each experiment was carried out in triplicates. Data were analyzed using GraphPad Prism 10 software. Statistical analysis was carried out in GraphPad Prism 10 using One-Way ANOVA with Tukey’s multiple comparison test with p<0.05 considered to be significant.

[0282] Modulation of MOR-mediated 0-arrestin recruitment by the herein compounds

[0283] To examine the effect of the herein compounds on MOR activation, the PathHunter enzyme-fragment complementation technology developed by DiscoverX to measure P- arrestin recruitment was used. This assay uses a cell line expressing human MOR tagged at the C-terminus with a small P -galactosidase fragment and P -arrestin tagged with a larger but catalytically inactive piece of P -galactosidase. Agonist-mediated activation of the receptor recruits P -arrestin, allowing the two fragments of P -galactosidase to assemble and produce an active enzyme. This provides a rapid, sensitive, and selective read-out of MOR activation, which is not affected by off-target effects of drugs on other cellular receptors. One concentration of Met-enk (100 nM) and two widely different concentrations of the compounds: 1 nM and 10 pM were used.

[0284] When tested in this assay at 10 pM, racemic ketamine and 2S,6S-HNK produced a small but statistically significant increase of 13-14% above basal signaling (Table 1). Although 2R,6R-HNK also produced a 13% increase above basal, this was not significant due to the large standard deviation (Table 1). When tested at 1 nM, neither racemic ketamine nor the two HNK stereoisomers showed any effect on P-arrestin recruitment (Table 1). Of the tested compounds some showed activation above basal when tested at 1 nM and some showed a significant activation when tested at 10 pM (Table 1).

[0285] When 100 nM Met-enk was included in the P-arrestin recruitment assay, the basal response greatly increased to 393% (Table 2), using the same units as the data in Table 1. Addition of ketamine or either HNK stereoisomer nearly doubled the efficacy of 100 nM Met-enk, with values ranging from 570-655% of the basal response. Of the tested compounds some showed PAM activity, with some compounds producing efficacies comparable to those of HNK when tested at 1 nM (e.g., compounds 1-3; Table 2). While certain compounds showed PAM activity and others showed direct agonist activity, only some compounds were both agonists and PAMs.

[0286] Thus, in some embodiments, the herein compound activates MOR. In some embodiments, the herein compound is a PAM of MOR. In some embodiments, the herein compound is used for treatment of depression and the compound activates MOR. In some embodiments, the herein compound is used for treatment of depression and the compound is a PAM of MOR. In some embodiments, the herein compound does not activate MOR. In some embodiments, the herein compound is not a PAM of MOR. In some embodiments, the herein compound does not activate MOR and the compound is used for treating pain. In some embodiments, the herein compound is not a PAM of MOR and the compound is used for treating pain.

[0287] Table 1. Direct agonist activity at MOR

[0288] One skilled in the art can appreciate from the foregoing description that the aspects of the present invention can be implemented in a variety of forms. Therefore, while the aspects of this invention have been described in connection with particular examples thereof, the true scope of the aspects of the invention should not be so limited since other modifications will become apparent to the skilled practitioner upon a study of the specification, and following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I), a stereoisomer, or a pharmaceutically accepted salt thereof:Formula (I) in whichR1 is H, or =0;R2 is selected from the group consisting ofR3 and R4 are each independently selected from the group consisting of H, OH, F, F2,wherein the six membered ring to which R3 and R4 are bound contains a double bond when R3 or R4 is NH2.

2. A compound of formula (I), a stereoisomer, or a pharmaceutically accepted salt thereof:Formula (I) in whichR1 is H, or =0;R2 is selected from the group consisting ofand R4 is H; wherein the six membered ring to which R3 and R4 are bound contains a double bond when R3 is NH2.

3. A compound of formula (I), a stereoisomer, or a pharmaceutically accepted salt thereof:Formula (I) in whichR1 is H, or =0;R2 is selected from the group consisting ofR3 is H; andR4 is selected from the group consisting of OH, F, F2, NH2,wherein the six membered ring to which R3 and R4 are bound contains a double bond whenR4 is NH24. A compound of formula (I) as claimed in any one of claims 1-3, the compound selected from:Compound (II)Compound (IV)Compound (VII)Compound (VIII)Compound (X)Compound (XII)Compound (XV)Compound (XVII)Compound (XX)Compound (XXI)Compound (XXV)Compound (XXIX)Compound (XL)Compound (XLI)CCompound (XLIII)Compound (XLV)Compound (XL VII)Compound (XL VIII)Compound (L)Compound (LII).

5. A compound of formula (II), a stereoisomer, or a pharmaceutically accepted salt thereof:Formula (II) in whichR2 is selected from the group consisting ofwhere X=S, O, or NHR5= H, Me, iPr, CH2OMe, or NH2;andR4 is H.

6. A compound of formula (II) as claimed in claim 5, the compound selected from:Compound (XXXII)Compound (XXXIV)Compound (XXXVI)Compound (XXXVII)Compound (XXXVIII).

7. A pharmaceutical composition comprising an effective amount of a compound of Formula (I) or (II) as claimed in any one of claims 1-6 and a pharmaceutically acceptable carrier.

8. A method of treating a disease or condition selected from the group consisting of a mental disorder, Alzheimer's dementia, amyotrophic lateral sclerosis, inflammation, and pain in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or (II) as claimed in any one of claims 1 -6 or a pharmaceutically acceptable salt thereof.9 .The method of claim 8, wherein the pain is selected from the group consisting of complex regional pain syndrome (CRPS), chronic pain, severe pain, migraine, fibromyalgia, rheumatic pain, menstrual pain, neuropathic pain, and musculoskeletal pain.10 .The method of claim 8, wherein the inflammation is caused by a pathogen, a trauma, a hazardous substance, or an autoimmune disease.

11. The method of claim 8, wherein the mental disorder is selected from the group consisting of bipolar depression, major depressive disorder, persistent depressive disorder, psychotic depression, suicidality, premenstrual dysphoric disorder (PMDD), atypical depression, postpartum depression, obsessive compulsive disorder, and post-traumatic stress disorder.

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