SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of and priority to U.S. Provisional Patent Application No.63/374,919, filed on September 82022, which is incorporated by reference herein in its entirety. BACKGROUND An N-methyl-d-aspartate (“NMDA”) receptor is a postsynaptic, ionotropic receptor that is responsive to, inter alia, the excitatory amino acids glutamate and glycine and the synthetic compound NMDA. The NMDA receptor controls the flow of both divalent and monovalent ions into the postsynaptic neural cell through a receptor associated channel (Foster et al., Nature 1987, 329:395-396; Mayer et al., Trends in Pharmacol. Sci.1990, 11:254-260). The NMDA receptor has been implicated during development in specifying neuronal architecture and synaptic connectivity, and may be involved in experience-dependent synaptic modifications. In addition, NMDA receptors are also thought to be involved in long term potentiation and central nervous system disorders. The NMDA receptor plays a major role in the synaptic plasticity that underlies many higher cognitive functions, such as memory acquisition, retention and learning, as well as in certain cognitive pathways and in the perception of pain (Collingridge et al., The NMDA Receptor, Oxford University Press, 1994). In addition, certain properties of NMDA receptors suggest that they may be involved in the information-processing in the brain that underlies consciousness itself. The NMDA receptor has drawn particular interest since it appears to be involved in a broad spectrum of CNS disorders. For instance, during brain ischemia caused by stroke or traumatic injury, excessive amounts of the excitatory amino acid glutamate are released from damaged or oxygen deprived neurons. This excess glutamate binds to the NMDA receptors which opens their ligand-gated ion channels; in turn the calcium influx produces a high level of intracellular calcium which activates a biochemical cascade resulting in protein degradation and cell death. This phenomenon, known as excitotoxicity, is also thought to be responsible for the neurological damage associated with other disorders ranging from hypoglycemia and cardiac arrest to epilepsy. In addition, there are preliminary reports indicating similar involvement in the chronic neurodegeneration of Huntington's, Parkinson's and Parkinson’s related conditions such as dyskinesia and L-dopa induced dyskinesia and Alzheimer's diseases. Activation of the NMDA receptor has been shown to be responsible for post-stroke convulsions, and, in certain models of epilepsy, activation of the NMDA receptor has been shown to be necessary for the generation of seizures. Neuropsychiatric involvement of the NMDA receptor has also been recognized since blockage of the NMDA receptor Ca ⁺⁺ channel by the animal anesthetic PCP (phencyclidine) produces a psychotic state in humans similar to schizophrenia (reviewed in Johnson, K. and Jones, S., 1990). Further, NMDA receptors have also been implicated in certain types of spatial learning. The NMDA receptor is believed to consist of several protein chains embedded in the postsynaptic membrane. The first two types of subunits discovered so far form a large extracellular region, which probably contains most of the allosteric binding sites, several transmembrane regions looped and folded so as to form a pore or channel, which is permeable to Ca ⁺⁺ , and a carboxyl terminal region. The opening and closing of the channel is regulated by the binding of various ligands to domains (allosteric sites) of the protein residing on the extracellular surface. The binding of the ligands is thought to effect a conformational change in the overall structure of the protein which is ultimately reflected in the channel opening, partially opening, partially closing, or closing. A need continues to exist in the art for novel and more specific and/or potent compounds that are capable of modulating NMDA receptors, and provide pharmaceutical benefits. In addition, a need continues to exist in the medical arts for orally deliverable forms of such compounds. SUMMARY The present disclosure includes compounds that can be NMDA modulators. More specifically, the present disclosure provides a compound having Formula I: or a stereoisomer and/or a pharmaceutically acceptable salt thereof, where: X is selected from the group consisting of NR ¹ , N, O, and CR ² R ² ; Y is NR ¹ or CR ² R ² ; Z is NR ¹ or CR ² R ² ; wherein two of X, Y, and Z are CR ² R ² ; is a double bond when X is N and a single bond when X is NR ¹ , O or CR ² R ² ; p is 1, 2 or 3; R ¹ is selected from the group consisting of H, -C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, and -C(O)-O-C1-C6 alkyl; R ² is independently selected for each occurrence from the group consisting of H, -C ₁ -C ₆ alkyl, and halogen; R ⁵ is independently selected for each occurrence from the group consisting of H, -C ₁ -C ₆ alkyl, -S(O)w-C1-C4 alkyl, and halogen; or R ² and R ⁵ taken together with the adjacent carbons to which they are attached form a 3- membered carbocyclic ring which may be optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -C1- C ₄ alkyl, -C ₁ -C ₄ alkoxy, –C(O)NR ^a R ^b , and -NR ^a R ^b ; w is 0, 1, or 2; R ⁶ is independently selected for each occurrence from the group consisting of H, -C ₁ -C ₆ alkyl, and halogen; or R ⁵ and R ⁶ taken together with the adjacent carbons to which they are attached form a 3- membered carbocyclic ring which may be optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -C ₁ - C4 alkyl, -C1-C4 alkoxy, –C(O)NR ^a R ^b , and -NR ^a R ^b ; R ⁷ is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, -S-C _1- C ₄ alkyl, phenyl, and halogen; R ³ is selected from the group consisting of H, -C1-C6 alkyl, -C(O)-R ³¹ , and -C(O)-O-R ³² ; R ³¹ is selected from the group consisting of H, -C ₁ -C ₆ alkyl; -C ₁ -C ₆ haloalkyl, -C ₃ -C ₆ cycloalkyl, and phenyl; R ³² is selected from the group consisting of H, -C ₁ -C ₆ alkyl; -C ₁ -C ₆ haloalkyl, -C ₃ -C ₆ cycloalkyl, and phenyl; and R ^a and R ^b are each independently selected for each occurrence from the group consisting of H, -C(O)-O-CH2-phenyl, and -C1-C4 alkyl; or R ^a and R ^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein any aforementioned C1-C6 alkyl, independently for each occurrence, can be optionally substituted by one, two or three substituents each independently selected for each occurrence from –C(O)NR ^a R ^b , -NR ^a R ^b , -C(O)-O-R ³² , hydroxyl, -SH, phenyl, - S(O)w-C1-C4 alkyl, -O-CH2-phenyl, and halogen; and wherein any aforementioned phenyl, independently for each occurrence, can be optionally substituted by one, two or three substituents each independently selected for each occurrence from –C(O)NR ^a R ^b , - NR ^a R ^b , -C1-C4 alkoxy, hydroxyl, and halogen. The present disclosure also provides a compound having Formula VI: or a stereoisomer and/or a pharmaceutically acceptable salt thereof, where: R ⁹¹ is selected from the group consisting of H, C1-C6alkyl, phenyl, -C(O)-C1-C6alkyl, and -C(O)-O-C ₁ -C ₆ alkyl; R ⁹⁶ is independently for each occurrence selected from the group consisting of H, C ₁ -C ₆ alkyl, cyano, hydroxyl, phenyl, and halogen; R ⁹⁸ is methyl, ethyl or propyl, or R ⁸ and R ⁶ together with the carbons to which they are attached form a cyclopropyl, wherein cyclopropyl is optionally substituted with methyl; m is 1 or 2; R ⁹³ is selected from the group consisting of H, C1-C6 alkyl, phenyl, -C(O)R ³¹ and -C(O)OR ³² ; R ³¹ and R ³² are each independently selected from H, C1-C6alkyl, and phenyl; wherein each aforementioned C ₁ -C ₆ alkyl is independently for each occurrence optionally substituted by one, two or three substituents each independently selected from -C(O)NR ^a R ^b , -NR ^a R ^b , hydroxyl, S(O) _w -C ₁ -C ₄ alkyl, -SH, phenyl and halogen, and each aforementioned phenyl is independently for each occurrence optionally substituted by one, two or three substituents each independently selected from methyl, methoxy, CF ₃ , hydroxyl, and halogen; w is 0, 1, or 2; and R ^a and R ^b are each independently for each occurrence selected from the group consisting of H, phenyl, and C1-C4alkyl, or R ^a and R ^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring. The present disclosure also provides a compound having the Formula IV or Formula V: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, where: q is 1 or 2; R ¹¹ is selected from the group consisting of H, -C ₁ -C ₆ alkyl, and -S-C _1- C ₄ alkyl; R ²² is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; R ⁵⁵ is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; R ⁶⁶ is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; or R ⁵⁵ and R ⁶⁶ taken together with the adjacent carbons to which they are attached form a 3- membered carbocyclic ring which can be optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -C1- C4 alkyl, -C1-C4 alkoxy, –C(O)NR ^a R ^b , and -NR ^a R ^b ; R ⁷⁷ is independently selected for each occurrence from the group consisting of H, -C ₁ -C ₆ alkyl, -S-C1-C4 alkyl, phenyl, and halogen; R ³³ is selected from the group consisting of H, -C ₁ -C ₆ alkyl, -C(O)-R ³¹ , and -C(O)-O- R ³² ; R ³¹ is selected from the group consisting of H, -C ₁ -C ₆ alkyl; -C ₁ -C ₆ haloalkyl, -C ₃ -C ₆ cycloalkyl, and phenyl; R ³² is selected from the group consisting of H, -C ₁ -C ₆ alkyl; -C ₁ -C ₆ haloalkyl, -C ₃ -C ₆ cycloalkyl, and phenyl; and R ^a and R ^b are each independently selected for each occurrence from the group consisting of H, -C(O)-O-CH2-phenyl, and -C1-C4 alkyl; or R ^a and R ^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein any aforementioned C1-C6 alkyl, independently for each occurrence, can be optionally substituted by one, two or three substituents each independently selected for each occurrence from –C(O)NR ^a R ^b , -NR ^a R ^b , -C(O)-O-R ³² , hydroxyl, -SH, phenyl, - O-CH2-phenyl, and halogen; and any aforementioned phenyl, independently for each occurrence, can be optionally substituted by one, two or three substituents each independently selected for each occurrence from –C(O)NR ^a R ^b , -NR ^a R ^b , -C1-C4 alkoxy, hydroxyl, and halogen. Also provided herein are pharmaceutically acceptable compositions comprising a disclosed compound, and a pharmaceutically acceptable excipient. Such compositions can be suitable for administration to a patient orally, parenterally, topically, intravaginally, intrarectally, sublingually, ocularly, transdermally, or nasally, In some aspects, compounds described herein bind to NMDA receptors expressing certain NR2 subtypes. In some aspects, the compounds described herein bind to one NR2 subtype and not another. It is appreciated that disclosed compounds may modulate other protein targets and/or specific NMDA receptor subtype. In another aspect, a method of treating a condition selected from the group consisting of autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive-compulsive disorder, phobia, post-traumatic stress syndrome, a behavior disorder, an impulse control disorder, a substance abuse disorder, a sleep disorder, a memory disorder, a learning disorder, urinary incontinence, multiple system atrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down’s syndrome, fragile X syndrome, tuberous sclerosis, olivio-ponto-cerebellar atrophy, Rett syndrome, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer’s disease, Huntington’s chorea, spasticity, myoclonus, muscle spasm, Tourette's syndrome, epilepsy, cerebral ischemia, stroke, a brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, fibromyalgia, acute neuropathic pain, and chronic neuropathic pain, in a patient in need thereof, is provided. Such methods can include administering to the patient a pharmaceutically effective amount of a disclosed compound or pharmaceutically acceptable salts, stereoisomers, N-oxides, and hydrates thereof. In some embodiments, the method includes treating depression. For example, depression can include one or more of major depressive disorder, dysthymic disorder, psychotic depression, postpartum depression, seasonal affective disorder, bipolar disorder, mood disorder, and depression caused by a chronic medical condition. In certain embodiments, the method can treat schizophrenia. Such schizophrenia can be, for example, paranoid type schizophrenia, disorganized type schizophrenia, catatonic type schizophrenia, undifferentiated type schizophrenia, residual type schizophrenia, post-schizophrenic depression, or simple schizophrenia. DETAILED DESCRIPTION This disclosure is generally directed to compounds that are capable of modulating NMDA receptors, for example, NMDA receptor antagonists, agonists, or partial agonists, and compositions and/or methods of using the disclosed compounds. The term “alkyl,” as used herein, refers to a saturated straight-chain or branched hydrocarbon, such as a straight-chain or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C ₁ -C ₆ alkyl, C ₁ -C ₄ alkyl, and C ₁ -C ₃ alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2- methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl. The term “alkoxy,” as used herein, refers to an alkyl group attached to an oxygen atom (alkyl-O-). Alkoxy groups can have 1-6 or 2-6 carbon atoms and are referred to herein as C ₁ -C ₆ alkoxy and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropoxy. The term “haloalkyl” as used herein refers to an alkyl group, in which one or more hydrogen atoms of the alkyl group are replaced with one or more independently selected halogens. A haloalkyl group can have 1 to 10 carbon atoms (i.e., C _1- C ₁₀ haloalkyl group), for example, 1 to 6 carbon atoms (i.e., C1-C 6 haloalkyl group). Examples of haloalkyl groups include -CF ₃ , -C ₂ F ₅ , -CHF ₂ , -CH ₂ F, -CCl ₃ , -CHCl ₂ , -CH ₂ Cl, -CH ₂ CH ₂ Cl, -CHFCH ₂ Cl, and - C2Cl5. Perhaloalkyl groups, i.e., alkyl groups where all of the hydrogen atoms are replaced with halogen atoms (e.g., -CF ₃ and -C ₂ F ₅ ), are included within the definition of “haloalkyl.” The term “carbonyl,” as used herein, refers to the substituent -C(O)- or C=O. The phrase, “carbocyclic ring,” as used herein, refers to a hydrocarbon ring system in which all the ring atoms are carbon. Exemplary carbocyclic rings including cycloalkyls and phenyl. The term “cycloalkyl,” as used herein, refers to a monocyclic saturated or partially unsaturated hydrocarbon ring system, for example, having 3-6 or 4-6 carbon atoms in its ring system, referred to herein as C3-C6 cycloalkyl or C4-C6 cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, cyclobutyl, and cyclopropyl. The term “cyano,” as used herein, refers to the substituent -CN. The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, or I. The term “heteroatom,” as used herein, refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen (N), oxygen (O), silicon (Si), sulfur (S), phosphorus (P), and selenium (Se). The phrase “heterocyclic ring,” as used herein, is art-recognized and refers to saturated or partially unsaturated 4- to 7-membered ring structures, whose ring system include one, two or three heteroatoms, such as nitrogen, oxygen, and/or sulfur. A heterocyclic ring can be fused to one or more phenyl, partially unsaturated, or saturated rings. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. The terms “hydroxyl” and “hydroxyl,” as used herein, refer to the substituent -OH. The term “amino acid,” as used herein, includes any one of the following alpha amino acids: isoleucine, alanine, leucine, asparagine, lysine, aspartate, methionine, cysteine, phenylalanine, glutamate, threonine, glutamine, tryptophan, glycine, valine, proline, arginine, serine, histidine, and tyrosine. An amino acid also can include other art recognized amino acids such as beta amino acids. The term “compound,” as used herein, refers to the compound itself and its pharmaceutically acceptable salts, hydrates, esters and N-oxides including its various stereoisomers and its isotopically-labelled forms, unless otherwise understood from the context of the description or expressly limited to one particular form of the compound, i.e., the compound itself, a specific stereoisomer and/or isotopically-labelled compound, or a pharmaceutically acceptable salt, a hydrate, an ester, or an N-oxide thereof. It should be understood that a compound can refer to a pharmaceutically acceptable salt, or a hydrate, an ester or an N-oxide of a stereoisomer of the compound and/or an isotopically-labelled compound. The term “moiety,” as used herein, refers to a portion of a compound or molecule. The compounds of the disclosure can contain one or more chiral centers and/or double bonds and therefore, can exist as stereoisomers, such as geometric isomers, and enantiomers or diastereomers. The term “stereoisomers,” when used herein, consists of all geometric isomers, enantiomers and/or diastereomers of the compound. For example, when a compound is shown with specific chiral center(s), the compound depicted without such chirality at that and other chiral centers of the compound are within the scope of the present disclosure, i.e., the compound depicted in two-dimensions with “flat” or “straight” bonds rather than in three dimensions, for example, with solid or dashed wedge bonds. Stereospecific compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses all the various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers can be designated “(±)” in nomenclature, but a skilled artisan will recognize that a structure can denote a chiral center implicitly. It is understood that graphical depictions of chemical structures, e.g., generic chemical structures, encompass all stereoisomeric forms of the specified compounds, unless indicated otherwise. Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns, or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures also can be resolved into their component enantiomers by well-known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. Geometric isomers, resulting from the arrangement of substituents around a carbon- carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds of the present disclosure. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration, where the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans.” The term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.” The disclosure also embraces isotopically-labeled compounds which are identical to those compounds recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H (“D”), ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. For example, a compound described herein can have one or more H atoms replaced with deuterium. Certain isotopically-labeled compounds (e.g., those labeled with ³ H and ¹⁴ C) can be useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes can be particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ² H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence can be preferred in some circumstances. Isotopically-labeled compounds can generally be prepared by following procedures analogous to those disclosed herein, for example, in the Examples section, by substituting an isotopically- labeled reagent for a non-isotopically-labeled reagent. The phrases “pharmaceutically acceptable” and “pharmacologically acceptable,” as used herein, refer to compounds, molecular entities, compositions, materials, and/or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards. The phrases “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient,” as used herein, refer to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. Pharmaceutical acceptable carriers can include phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. The phrase “pharmaceutical composition,” as used herein, refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions can also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. The terms “individual,” “patient,” and “subject,” as used herein, are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and more preferably, humans. The compounds described in the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, for example, domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The mammal treated in the methods described in the disclosure is preferably a mammal in which treatment, for example, of pain or depression, is desired. The term “treating,” as used herein, includes any effect, for example, lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the condition, disease, disorder, and the like, including one or more symptoms thereof. Treating can be curing, improving, or at least partially ameliorating the disorder. The term “disorder” refers to and is used interchangeably with, the terms “disease,” “condition,” or “illness,” unless otherwise indicated. The term “modulation,” as used herein, refers to and includes antagonism (e.g., inhibition), agonism, partial antagonism, and/or partial agonism. The phrase “therapeutically effective amount,” as used herein, refers to the amount of a compound (e.g., a disclosed compound) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds described in the disclosure can be administered in therapeutically effective amounts to treat a disease. A therapeutically effective amount of a compound can be the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in lessening of a symptom of a disease such as depression. The phrase “pharmaceutically acceptable salt,” as used herein, refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure, which salt is compatible with pharmaceutical administration. As is known to those of skill in the art, a “salt” of the compounds of the present disclosure may be derived from inorganic or organic acids and bases. Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na ⁺ , NH4 ⁺ , and NW4 ⁺ (where W can be a C1-4 alkyl group), and the like. For therapeutic use, salts of the compounds of the present disclosure can be pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2- hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure can contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. The compounds disclosed herein can exist in a solvated form as well as an unsolvated form with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In some embodiments, the compound is amorphous. In certain embodiments, the compound is a single polymorph. In various embodiments, the compound is a mixture of polymorphs. In particular embodiments, the compound is in a crystalline form. The term “prodrug,” as used herein, refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation can occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and/or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit into the intestine, blood, or liver). Prodrugs are well known in the art (see e.g., see Rautio, Kumpulainen et al., Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound described herein or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can be an ester formed by the replacement of the hydrogen atom of the carboxylic acid group with a group such as (C ₁ -C ₈ )alkyl, (C ₂ -C ₁₂ )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as β- dimethylaminoethyl), carbamoyl-(C ₁ -C ₂ )alkyl, N,N-di(C ₁ -C ₂ )alkylcarbamoyl-(C ₁ -C ₂ )alkyl, piperidino-(C2-C3)alkyl, pyrrolidino-(C2-C3)alkyl or morpholino(C2-C3)alkyl. Similarly, if a compound described herein contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C ₁ -C ₆ )alkanoyloxy)ethyl (C ₁ -C ₆ )alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C ₁ -C ₆ )alkyl) ₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate). If a compound described herein incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-acyloxyalkyl derivative, an (oxodioxolenyl) methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. See, for example, Simplício, et al., Molecules 2008, 13, 519 and references therein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps. In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components. Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present disclosure and/or in methods of the present disclosure, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments can be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the disclosure(s) described and depicted herein. The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, “an element” means one element or more than one element. The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. It should be understood that the expression “at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context. The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context. Where the use of the term “about” is before a quantitative value, the present disclosure also include the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred. Where a percentage is provided with respect to an amount of a component or material in a composition, the percentage should be understood to be a percentage based on weight, unless otherwise stated or understood from the context. Where a molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an average molecule weight, unless otherwise stated or understood from the context. It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remain operable. Moreover, two or more steps or actions can be conducted simultaneously. At various places in the present specification, substituents are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₁ -C ₆ , C ₁ -C ₅ , C ₁ -C ₄ , C ₁ - C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl. By way of other examples, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Additional examples include that the phrase “optionally substituted with 1-5 substituents” is specifically intended to individually disclose a chemical group that can include 0, 1, 2, 3, 4, 5, 0-5, 0-4, 0-3, 0-2, 0-1, 1-5, 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, and 4-5 substituents. The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present disclosure and does not pose a limitation on the scope of the disclosure unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure. Further, if a variable is not accompanied by a definition, then the variable is defined as found elsewhere in the disclosure unless understood to be different from the context. In addition, the definition of each variable and/or substituent, for example, C ₁ -C ₆ alkyl, R ² , R ^b , w and the like, when it occurs more than once in any structure or compound, can be independent of its definition elsewhere in the same structure or compound. Definitions of the variables and/or substituents in formulae and/or compounds herein encompass multiple chemical groups. The present disclosure includes embodiments where, for example, i) the definition of a variable and/or substituent is a single chemical group selected from those chemical groups set forth herein, ii) the definition is a collection of two or more of the chemical groups selected from those set forth herein, and iii) the compound is defined by a combination of variables and/or substituents in which the variables and/or substituents are defined by (i) or (ii). Various aspects of the disclosure are set forth herein under headings and/or in sections for clarity; however, it is understood that all aspects, embodiments, or features of the disclosure described in one particular section are not to be limited to that particular section but rather can apply to any aspect, embodiment, or feature of the present disclosure. Compounds Disclosed compounds include a compound having the formula: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein: X is selected from the group consisting of NR ¹ , N, O, and CR ² R ² ; Y is NR ¹ or CR ² R ² ; Z is NR ¹ or CR ² R ² ; wherein two of X, Y, and Z is CR ² R ² ; is a double bond when X is N and a single bond when X is NR ¹ , O or CR ² R ² ; p is 1, 2 or 3; R ¹ is selected from the group consisting of H, -C1-C6 alkyl, -C(O)-C1-C6 alkyl, and - C(O)-O-C1-C6 alkyl; R ² is independently selected for each occurrence from the group consisting of H, -C ₁ -C ₆ alkyl, and halogen; R ⁵ is independently selected for each occurrence from the group consisting of H, -C ₁ -C ₆ alkyl, -S(O)w-C1-C4 alkyl, and halogen; or R ² and R ⁵ taken together with the adjacent carbons to which they are attached form a 3- membered carbocyclic ring which can be optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -C ₁ - C4 alkyl, -C1-C4 alkoxy, –C(O)NR ^a R ^b , and -NR ^a R ^b ; w is 0, 1, or 2; R ⁶ is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; or R ⁵ and R ⁶ taken together with the adjacent carbons to which they are attached form a 3- membered carbocyclic ring which can be optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -C1- C ₄ alkyl, -C ₁ -C ₄ alkoxy, –C(O)NR ^a R ^b , and -NR ^a R ^b ; R ⁷ is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, -S-C _1- C ₄ alkyl, phenyl, and halogen; R ³ is selected from the group consisting of H, -C1-C6 alkyl, -C(O)-R ³¹ , and -C(O)-O-R ³² ; R ³¹ is selected from the group consisting of H, -C1-C6 alkyl; -C1-C6 haloalkyl, -C3-C6 cycloalkyl, and phenyl; R ³² is selected from the group consisting of H, -C1-C6 alkyl; -C1-C6 haloalkyl, -C3-C6 cycloalkyl, and phenyl; and R ^a and R ^b are each independently selected for each occurrence from the group consisting of H, -C(O)-O-CH ₂ -phenyl, and -C ₁ -C ₄ alkyl; or R ^a and R ^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein any aforementioned C ₁ -C ₆ alkyl, independently for each occurrence, can be optionally substituted by one, two or three substituents each independently selected for each occurrence from –C(O)NR ^a R ^b , -NR ^a R ^b , -C(O)-O-R ³² , hydroxyl, -SH, phenyl, - S(O)w-C1-C4 alkyl, -O-CH2-phenyl, and halogen; and wherein any aforementioned phenyl, independently for each occurrence, can be optionally substituted by one, two or three substituents each independently selected for each occurrence from –C(O)NR ^a R ^b , - NR ^a R ^b , -C1-C4 alkoxy, hydroxyl, and halogen. In certain embodiments, X can be NR ¹ and Y and Z can be CR ² R ² . In some embodiments, Z can be NR ¹ and X and Y can be CR ² R ² . In particular embodiments, Y can be NR ¹ and X and Z can be CR ² R ² . In certain embodiments, p can be 1. In some embodiments, R ² , R ⁵ , and R ⁶ can be H. In certain embodiments, one or two of R ⁵ can be fluoro. For example, provided herein are compounds represented by: where R ¹ and R ³ are as described herein. In certain embodiments, R ¹ can be H. In various embodiments, R ¹ can be -C(O)-O-C1-C6 alkyl. For example, R ¹ can be -C(O)-O-tert-butyl. In certain embodiments, R ¹ can be -C(O)-C ₁ -C ₆ alkyl, where C ₁ -C ₆ alkyl, can be optionally substituted as described herein. For example, R ¹ can be selected from the group consisting of: where R ^a and R ^b are as described herein. In various embodiments, R ^a and R ^b can be H. In certain embodiments, R ¹ can be -C ₁ -C ₆ alkyl optionally substituted by one, two or three substituents independently selected from the group consisting of –C(O)NR ^a R ^b , hydroxyl, - SH, and halogen. For example, R ¹ can be selected from the group consisting of: where R ^a and R ^b are as defined herein. In various embodiments, R ^a and R ^b can be H. In certain embodiments, X is N, and Y and Z can be CR ² R ² . In some embodiments, R ² and R ⁶ can be H. In particular embodiments, R ⁵ can be -S-C1-C4 alkyl, for example, R ⁵ can be –S-CH3. For example, a compound disclosed herein can be represented by Formula II: where R ³ is as defined herein. In certain embodiments, X can be O, and Y and Z can be CR ² R ² . In some embodiments, R ² , R ⁵ , and R ⁶ can be H. For example, a compound disclosed herein can be represented by Formula III: where R ³ is as defined herein. In some embodiments, R ³ can be H. In various embodiments, R ³ can be -C ₁ -C ₆ alkyl, optionally substituted as described herein. For example, R ³ can be selected from the group consisting of: where R ⁶⁵ is -C ₁ -C ₄ alkoxy; and R ^a and R ^b are each independently selected for each occurrence from the group consisting of H and -C1-C6 alkyl. For example, R ⁶⁵ can be methoxy. In certain embodiments, R ¹ and/or R ³ and/or R ³³ and/or R ⁹¹ and/or R ⁹³ independently can be an amino acid or a derivative of an amino acid, for example, an alpha “amino amide” represented by H2N-CH(amino acid side chain)-C(O)NH2. In certain embodiments, the nitrogen atom of the amino group of the amino acid or the amino acid derivative is a ring nitrogen in a chemical formula described herein, for example, in Formula (I), (II), (III), (IV), (V) or (VI). In such embodiments, the carboxylic acid of the amino acid or the amide group of an amino amide (amino acid derivative) is not within the ring structure, i.e., not a ring atom. In certain embodiments, the carboxylic acid group of the amino acid or the amino acid derivative forms an amide bond with a ring nitrogen in a chemical formula disclosed herein, for example, in Formula (I), (II), (III), (IV), (V) or (VI), thereby providing an amino amide, where the amino group of the amino amide is not within the ring structure, i.e., not a ring atom. In certain embodiments, R ¹ and/or R ³ and/or R ³³ and/or R ⁹¹ and/or R ⁹³ independently can be an alpha amino acid, an alpha amino acid derivative, and/or another amino acid or amino acid derivative such as a beta amino acid or a beta amino acid derivative, for example, a beta amino amide. In various embodiments, a compound of the disclosure can be represented by: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, where R ¹ can be can be H, -C1-C4 alkoxy, or halogen; and R ^a and R ^b can be each independently for each occurrence selected from the group consisting of H and -C1-C6 alkyl. In some embodiments of compounds of the disclosure, R ¹ can be ; R ³ can be ; R ⁶⁵ can be H or -C ₁ -C ₄ alkoxy; and R ^a and R ^b each can be H. In certain embodiments of compounds of the disclosure, R ¹ can be ; and R ³ In particular embodiments, a compound of the disclosure can be represented by:

or a pharmaceutically acceptable salt thereof. The present disclosure also provides a compound having the Formula IV or Formula V: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, where: q is 1 or 2; R ¹¹ is selected from the group consisting of H, -C ₁ -C ₆ alkyl, and -S-C _1- C ₄ alkyl; R ²² is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; R ⁵⁵ is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; R ⁶⁶ is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; or R ⁵⁵ and R ⁶⁶ taken together with the adjacent carbons to which they are attached form a 3- membered carbocyclic ring which can be optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -C1- C4 alkyl, -C1-C4 alkoxy, –C(O)NR ^a R ^b , and -NR ^a R ^b ; R ⁷⁷ is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, -S-C1-C4 alkyl, phenyl, and halogen; R ³³ is selected from the group consisting of H, -C ₁ -C ₆ alkyl, -C(O)-R ³¹ , and -C(O)-O- R ³² ; R ³¹ is selected from the group consisting of H, -C ₁ -C ₆ alkyl; -C ₁ -C ₆ haloalkyl, -C ₃ -C ₆ cycloalkyl, and phenyl; R ³² is selected from the group consisting of H, -C1-C6 alkyl; -C1-C6 haloalkyl, -C3-C6 cycloalkyl, and phenyl; and R ^a and R ^b are each independently selected for each occurrence from the group consisting of H, -C(O)-O-CH ₂ -phenyl, and -C ₁ -C ₄ alkyl; or R ^a and R ^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein any aforementioned C ₁ -C ₆ alkyl, independently for each occurrence, can be optionally substituted by one, two or three substituents each independently selected for each occurrence from –C(O)NR ^a R ^b , -NR ^a R ^b , -C(O)-O-R ³² , hydroxyl, -SH, phenyl, - O-CH2-phenyl, and halogen; and any aforementioned phenyl, independently for each occurrence, can be optionally substituted by one, two or three substituents each independently selected for each occurrence from –C(O)NR ^a R ^b , -NR ^a R ^b , -C ₁ -C ₄ alkoxy, hydroxyl, and halogen. Disclosed compounds include a compound having the formula: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, where: R ⁹¹ is selected from the group consisting of H, C ₁ -C ₆ alkyl, phenyl, -C(O)-C ₁ -C ₆ alkyl, and -C(O)-O-C1-C6 alkyl; R ⁹⁶ is independently for each occurrence selected from the group consisting of H, C ₁ - C6alkyl, cyano, hydroxyl, phenyl, and halogen; R ⁹⁸ is methyl, ethyl or propyl, or R ⁸ and R ⁶ together with the carbons to which they are attached form a cyclopropyl, wherein cyclopropyl is optionally substituted with methyl; m is 1 or 2; R ⁹³ is selected from the group consisting of H, C1-C6 alkyl, phenyl, -C(O)R ³¹ and - C(O)OR ³² ; R ³¹ and R ³² are each independently selected from H, C ₁ -C ₆ alkyl, and phenyl; wherein each aforementioned C1-C6 alkyl is independently for each occurrence optionally substituted by one, two or three substituents each independently selected from -C(O)NR ^a R ^b , -NR ^a R ^b , hydroxyl, S(O)w-C1-C4alkyl, -SH, phenyl and halogen, and each aforementioned phenyl is independently for each occurrence optionally substituted by one, two or three substituents each independently selected from methyl, methoxy, CF3, hydroxyl and halogen; w is 0, 1, or 2; and R ^a and R ^b are each independently for each occurrence selected from the group consisting of H, phenyl, and C1-C4alkyl, or R ^a and R ^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring. In some embodiments, R ⁹⁸ can be methyl. In some embodiments, m can be 1. In some embodiments, R ⁹⁶ for each occurrence can be H. In some embodiments, R ⁹¹ can be -C(O)-O-C1-C6 alkyl. For example, R ⁹¹ can be tert- butyloxycarbonyl. In certain embodiments, R ⁹¹ can be -C(O)-C ₁ -C ₆ alkyl. For example, R ⁹¹ can be selected from the group consisting of: where R ^a and R ^b can be independently for each occurrence selected from the group consisting of H and -C1-C4alkyl. In some embodiments R ⁹¹ can be C ₁ -C ₆ alkyl. For example, R ⁹¹ can be methyl, ethyl, n-propyl, or isopropyl ( In some embodiments, R ⁹³ can be selected from the group consisting of: O where R ^a and R ^b can be independently for each occurrence selected from the group consisting of H and -C1-C4alkyl. In particular embodiments, R ⁹³ can be a benzyl group optionally substituted by one, two or three substituents each independently selected from methyl, methoxy, CF ₃ , hydroxyl and halogen. For example, R ⁹³ can be para-methoxybenzyl. In certain embodiments, a disclosed compound can be selected from the compounds in the Examples described herein and/or in Tables 1 and 2, and includes a stereoisomer and/or a pharmaceutically acceptable salt thereof. The compounds of the present disclosure and formulations thereof can have a plurality of chiral centers. Each chiral center can be independently R, S, or any mixture of R and S. For example, in some embodiments, a chiral center can have an R:S ratio of between about 100:0 and about 50:50, between about 100:0 and about 75:25, between about 100:0 and about 85:15, between about 100:0 and about 90:10, between about 100:0 and about 95:5, between about 100:0 and about 98:2, between about 100:0 and about 99:1, between about 0:100 and 50:50, between about 0:100 and about 25:75, between about 0:100 and about 15:85, between about 0:100 and about 10:90, between about 0:100 and about 5:95, between about 0:100 and about 2:98, between about 0:100 and about 1:99, between about 75:25 and 25:75, and about 50:50. Formulations of the disclosed compounds comprising a greater ratio of one or more isomers (i.e., R and/or S) may possess enhanced therapeutic characteristics relative to racemic formulations of a disclosed compound or mixture of compounds. In some instances, depicted chemical structures contain the descriptor “-(R)-” or “-(S)-” that is further attached to solid wedge or dashed wedge. This descriptor is intended to show a methine carbon (CH) that is attached to three other substituents and has either the indicated R or S configuration. In various embodiments, the disclosed compounds can provide for efficient cation channel opening at the NMDA receptor, for example, may bind or associate with the glutamate site or glycine site or other modulatory site of the NMDA receptor to assist in opening the cation channel. In some embodiments, the disclosed compounds can be used to regulate (turn on or turn off) the NMDA receptor through action as an agonist or antagonist. In some embodiments, the compounds described herein may bind to or associate with specific NMDA receptor subtypes. For example, a disclosed compound may bind to one NMDA receptor subtype and not another. In various embodiments, a disclosed compound can bind to one, or more than one NMDA receptor subtype, and/or can have substantially less (or substantial no) binding activity to certain other NMDA receptor subtypes. For example, in some embodiments, a disclosed compound (e.g., compound A) binds to NR2A with substantially no binding to NR2D. In some embodiments, a disclosed compound (e.g., compound B) binds to NR2B and NR2D with substantially lower binding to NR2A and NR2C. The compounds as described herein may bind to NMDA receptors. A disclosed compound may bind to the NMDA receptor resulting in agonist-like activity (facilitation) over a certain dosing range and/or may bind to the NMDA receptor resulting in antagonist-like activity (inhibition) over a certain dosing range. In some embodiments, a disclosed compound may possess a potency that is 10-fold or greater than the activity of existing NMDA receptor modulators. The disclosed compounds can exhibit a high therapeutic index. The therapeutic index, as used herein, refers to the ratio of the dose that produces a toxicity in 50% of the population (i.e., TD50) to the minimum effective dose for 50% of the population (i.e., ED50). Thus, the therapeutic index = (TD ₅₀ ):(ED ₅₀ ). In some embodiments, a disclosed compound can have a therapeutic index of at least about 10:1, at least about 50:1, at least about 100:1, at least about 200:1, at least about 500:1, or at least about 1000:1. Compositions In other aspects, a pharmaceutical formulation or a pharmaceutical composition including a disclosed compound and a pharmaceutically acceptable excipient is provided. In some embodiments, a pharmaceutical composition includes a racemic mixture of one or more of the disclosed compounds or a mixture of stereoisomers between a racemic mixture and a pure enantiomer (i.e., a varied composition of stereoisomeric compounds of one or more of the disclosed compounds). A formulation can be prepared in any of a variety of forms for use such as for administering an active agent to a patient, who may be in need thereof, as are known in the pharmaceutical arts. For example, the pharmaceutical compositions of the present disclosure can be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and/or systemic absorption), boluses, powders, granules, and pastes for application to the tongue; (2) parenteral administration by, for example, subcutaneous, intramuscular, intraperitoneal, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical administration, for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin; (4) intravaginal or intrarectal administration, for example, as a pessary, cream or foam; (5) sublingual administration; (6) ocular administration; (7) transdermal administration; or (8) nasal administration. For example, pharmaceutical compositions of the disclosure can be suitable for delivery to the eye, i.e., ocularly. Related methods can include administering a pharmaceutically effective amount of a disclosed compound or a pharmaceutical composition including a disclosed compound to a patient in need thereof, for example, to an eye of the patient, where administering can be topically, subconjunctivally, subtenonly, intravitreally, retrobulbarly, peribulbarly, intracomerally, and/or systemically. Amounts of a disclosed compound as described herein in a formulation can vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. “Dosage unit form,” as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the compound selected and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and/or gelatin. The compounds can be administered in a time release formulation, for example, in a composition which includes a slow release polymer. The compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are generally known to those skilled in the art. Sterile injectable solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the other required ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. In accordance with certain embodiments, a disclosed compound can be formulated with one or more additional compounds that enhance the solubility of the compound. Methods Methods of the disclosure for treating a condition in a patient in need thereof include administering a therapeutically effective amount of a compound described herein or a composition including such a compound. In some embodiments, the condition can be a mental condition. For example, a mental illness can be treated. In various embodiments, a nervous system condition can be treated. For example, a condition that affects the central nervous system, the peripheral nervous system, and/or the eye can be treated. In some embodiments, neurodegenerative diseases can be treated. In some embodiments, the methods include administering a compound to treat patients suffering from autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive-compulsive disorder (OCD), phobia, post-traumatic stress syndrome, a behavior disorder, an impulse control disorder, a substance abuse disorder (e.g., a withdrawal symptom, opiate addiction, nicotine addiction, and ethanol addition), a sleep disorder, a memory disorder (e.g., a deficit, loss, or reduced ability to make new memories), a learning disorder, urinary incontinence, multiple system atrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down’s syndrome, fragile X syndrome, tuberous sclerosis, olivio- ponto-cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer’s disease, Huntington’s chorea, spasticity, myoclonus, muscle spasm, infantile spasm, Tourette's syndrome, epilepsy, cerebral ischemia, stroke, a brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain, and chronic neuropathic pain. In some embodiments, methods of treating a memory disorder associated with aging, schizophrenia, special learning disorders, seizures, post-stroke convulsions, brain ischemia, hypoglycemia, cardiac arrest, epilepsy, Lewy body dementia, migraine, AIDS dementia, Huntington’s chorea, Parkinson’s disease, early stage Alzheimer’s disease, and Alzheimer’s disease are contemplated. In certain embodiments, methods for treating schizophrenia are provided. For example, paranoid type schizophrenia, disorganized type schizophrenia (i.e., hebephrenic schizophrenia), catatonic type schizophrenia, undifferentiated type schizophrenia, residual type schizophrenia, post-schizophrenic depression, and simple schizophrenia can be treated using the methods and compositions described herein. In particular embodiments, psychotic disorders such as schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, and psychotic disorders with delusions or hallucinations can also be treated using the compositions described herein. Paranoid schizophrenia can be characterized where delusions or auditory hallucinations are present, but thought disorder, disorganized behavior, or affective flattening are not. Delusions can be persecutory and/or grandiose, but in addition to these, other themes such as jealousy, religiosity, or somatization can also be present. Disorganized type schizophrenia can be characterized where thought disorder and flat affect are present together. Catatonic type schizophrenia can be characterized where the patient can be almost immobile or exhibit agitated, purposeless movement. Symptoms can include catatonic stupor and waxy flexibility. Undifferentiated type schizophrenia can be characterized where psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met. Residual type schizophrenia can be characterized where positive symptoms are present at a low intensity only. Post-schizophrenic depression can be characterized where a depressive episode arises in the aftermath of a schizophrenic illness where some low-level schizophrenic symptoms can still be present. Simple schizophrenia can be characterized by insidious and progressive development of prominent negative symptoms with no history of psychotic episodes. In some embodiments, methods are provided for treating psychotic symptoms that can be present in other mental disorders, including, but not limited to, bipolar disorder, borderline personality disorder, drug intoxication, and drug-induced psychosis. In various embodiments, methods for treating delusions (e.g., “non-bizarre”) that can be present in, for example, delusional disorder, are provided. In various embodiments, methods for treating social withdrawal in conditions including, but not limited to, social anxiety disorder, avoidant personality disorder, and schizotypal personality disorder are provided. In some embodiments, the disclosure provides methods for treating a neurodevelopmental disorder related to synaptic dysfunction in a patient in need thereof, where the methods generally include administering to the patient a therapeutically effective amount of a disclosed compound, or a pharmaceutical composition including a disclosed compound. In certain embodiments, the neurodevelopmental disorder related to synaptic dysfunction can be Rett syndrome also known as cerebroatrophic hyperammonemia, MECP2 duplication syndrome (e.g., a MECP2 disorder), CDKL5 syndrome, fragile X syndrome (e.g., a FMR1 disorder), tuberous sclerosis (e.g., a TSC1 disorder and/or a TSC2 disorder), neurofibromatosis (e.g., a NF1 disorder), Angelman syndrome (e.g., a UBE3A disorder), the PTEN hamartoma tumor syndrome, Phelan-McDermid syndrome (e.g., a SHANK3 disorder), or infantile spasms. In particular embodiments, the neurodevelopmental disorder can be caused by mutations in the neuroligin (e.g., a NLGN3 disorder and/or a NLGN2 disorder) and/or the neurexin (e.g., a NRXN1 disorder). In some embodiments, methods are provided for treating neuropathic pain. The neuropathic pain can be acute or chronic. In some cases, the neuropathic pain can be associated with a condition such as herpes, HIV, traumatic nerve injury, stroke, post-ischemia, chronic back pain, post-herpetic neuralgia, fibromyalgia, reflex sympathetic dystrophy, complex regional pain syndrome, spinal cord injury, sciatica, phantom limb pain, diabetic neuropathy such as diabetic peripheral neuropathy (“DPN”), and cancer chemotherapeutic-induced neuropathic pain. In certain embodiments, methods for enhancing pain relief and for providing analgesia to a patient are also provided. Further methods of the disclosure can include a method of treating autism in a patient need thereof, including administering a therapeutically effective amount of a disclosed compound to the patient. In some embodiments, a method for reducing the symptoms of autism in a patient in need thereof includes administering a therapeutically effective amount of a disclosed compound to the patient. For example, upon administration, the disclosed compound can decrease the incidence of one or more symptoms of autism such as eye contact avoidance, failure to socialize, attention deficit, poor mood, hyperactivity, abnormal sound sensitivity, inappropriate speech, disrupted sleep, and perseveration. Such decreased incidence can be measured relative to the incidence in the untreated individual or an untreated individual(s). Also provided herein is a method of modulating an autism target gene expression in a cell, where the method includes contacting a cell with an effective amount of a compound described herein. The autism gene expression can be, for example, selected from ABAT, APOE, CHRNA4, GABRA5,GFAP, GRIN2A, PDYN, and PENK. In various embodiments, a method of modulating synaptic plasticity in a patient suffering from a synaptic plasticity related disorder is provided, where the method includes administering to the patient an effective amount of a disclosed compound. In certain embodiments, a method of treating Alzheimer’s disease, or treatment of memory loss that accompanies early stage Alzheimer’s disease, in a patient in need thereof is provided, where the method includes administering a compound described herein. Also provided herein is a method of modulating an Alzheimer’s amyloid protein (e.g., beta amyloid peptide, e.g., the isoform Aβ1-42), in-vitro or in-vivo (e.g., in a cell). Such methods can include contacting the protein with an effective amount of a disclosed compound. For example, in some embodiments, a disclosed compound can block the ability of such amyloid protein to inhibit long-term potentiation in hippocampal slices as well as apoptotic neuronal cell death. In some embodiments, a disclosed compound can provide neuroprotective properties to a Alzheimer’s patient in need thereof, for example, can provide a therapeutic effect on later stage Alzheimer’s- associated neuronal cell death. In certain embodiments, the disclosed methods include treating a psychosis or a pseudobulbar affect (“PBA”) that is induced by another condition such as a stroke, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), multiple sclerosis, traumatic brain injury, Alzheimer’s disease, dementia, and/or Parkinson’s disease. Such methods, as with other methods of the disclosure, include administration of a pharmaceutically effective amount of a disclosed compound to a patient in need thereof. In various embodiments, a method of treating depression in a patient in need thereof includes administering a compound described herein. In some embodiments, the treatment can relieve depression or a symptom of depression without affecting behavior or motor coordination and without inducing or promoting seizure activity. Exemplary depression conditions that are expected to be treated according to these methods include, but are not limited to, major depressive disorder, dysthymic disorder, psychotic depression, postpartum depression, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder (SAD), bipolar disorder (or manic depressive disorder), mood disorder, and depressions caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, and post traumatic stress disorders. In addition, patients suffering from any form of depression often experience anxiety. Various symptoms associated with anxiety include fear, panic, heart palpitations, shortness of breath, fatigue, nausea, and headaches, among others. In various embodiments, anxiety or any of the symptoms thereof can be treated by administering a compound as described herein to a patient in need thereof. Also provided herein are methods of treating a condition in treatment-resistant patients, for example, patients suffering from a mental or central nervous system condition that does not, and/or has not, responded to adequate courses of at least one, or at least two, other compounds or therapeutics. For example, provided herein is a method of treating depression in a treatment resistant patient, where the method includes a) optionally identifying the patient as treatment resistant; and b) administering a therapeutically effective dose of a disclosed compound to the patient. In some embodiments, a compound described herein can be used for acute care of a patient. For example, a disclosed compound can be administered to a patient to treat a particular episode (e.g., a severe episode) of a condition described herein. Also contemplated herein are combination therapies including a disclosed compound in combination with one or more other active agents. For example, a disclosed compound can be combined with one or more antidepressants, such as tricyclic antidepressants, MAO-I’s, SSRI’s, double and triple uptake inhibitors, and/or anxiolytic drugs. Exemplary drugs that can be used in combination with a disclosed compound include Anafranil, Adapin, Aventyl, Elavil, Norpramin, Pamelor, Pertofrane, Sinequan, Surmontil, Tofranil, Vivactil, Parnate, Nardil, Marplan, Celexa, Lexapro, Luvox, Paxil, Prozac, Zoloft, Wellbutrin, Effexor, Remeron, Cymbalta, Desyrel (trazodone), and Ludiomill. In some embodiments, a disclosed compound can be combined with an antipsychotic medication. Non-limiting examples of antipsychotics include butyrophenones, phenothiazines, thioxanthenes, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, iloperidone, zotepine, sertindole, lurasidone, and aripiprazole. It should be understood that combinations of a disclosed compound and one or more of the above therapeutics can be used for treatment of any suitable condition and are not limited to use as antidepressants or antipsychotics. EXAMPLES The following examples are provided for illustrative purposes only, and are not intended to limit the scope of the disclosure. The following abbreviations may be used herein and have the indicated definitions: AIDS is acquired immune deficiency syndrome, Boc and BOC are tert-butoxycarbonyl, Boc2O is di-tert-butyl dicarbonate, Bn is benzyl, BOM-Cl is benzyloxymethyl chloride, CAN is ceric ammonium nitrate, Cbz is carboxybenzyl, DCM is dichloromethane, DIAD is diisopropyl azodicarboxylate, DIPEA is N,N-diisopropylethylamine, DMAP is 4-dimethylaminopyridine, DMF is N,N-dimethylformamide, DMSO is dimethyl sulfoxide, EDC and EDCI are 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride, ESI is electrospray ionization, EtOAc is ethyl acetate, Gly is glycine, h is hour, HATU is 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate, HIV is human immunodeficiency virus, HPLC is high performance liquid chromatography, LCMS is liquid chromatography/mass spectrometry, LiHMDS is lithium hexamethyldisilazane, MTBE is methyl tert-butyl ether, NMDAR is N- methyl-d-aspartate receptor, NMP is N-methyl-2-pyrrolidone, NMR is nuclear magnetic resonance, Pd/C is palladium on carbon, PMB is para-methoxybenzyl, RT is room temperature (e.g., from about 20 ºC to about 25 ºC), TBS and TBDMS are tert-butyldimethylsilyl, TEA is triethylamine, TLC is thin layer chromatography, TFA is trifluoroacetic acid, THF is tetrahydrofuran, TMS is trimethylsilyl, TMSCN is trimethylsilyl cyanide, and TPP is triphenylphosphine. A. SYNTHESIS OF COMPOUNDS Synthesis of Examples AA-1, AA-2, AB-1, AB-2, AC-1, and AC-2: Synthesis of methyl piperidine-4-carboxylate hydrochloride (1): To a stirring solution of piperidine-4-carboxylic acid (SM-1) (34 g, 263.5 mmol) in methanol (250 mL) was added thionyl chloride (47.2 mL, 880.1 mmol) dropwise at 0 °C. The reaction mixture was warmed to room temperature (“RT”) and stirred for 24 h. After consumption of the starting material (by TLC), the volatiles were concentrated under reduced pressure and the crude was triturated with n-hexane to afford compound 1 as its hydrochloride salt (32 g, 92%). ¹ H-NMR: (400 MHz, DMSO-d6): δ 9.24 (s, 1H), 9.08 (s, 1H), 3.62 (s, 3H), 3.20-3.16 (m, 2H), 2.93-2.85 (m, 2H), 2.72-2.65 (m, 1H), 1.99-1.94 (m, 2H), 1.82-1.72 (m, 2H). LCMS (m/z): 144.2 [M ⁺ +1]. Synthesis of 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (2): To a stirring solution of compound 1 (34 g, 189.9 mmol) in CH ₂ Cl ₂ (300 mL) was added Et3N (68.5 mL, 474.7 mmol) at 0 °C and the solution was stirred for 10 min. Then Boc- anhydride (62.1 mL, 284.9 mmol) was added at 0 °C; the reaction was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (100 mL) and extracted with CH ₂ Cl ₂ (2 x 100 mL). The combined organic layer was washed with saturated citric acid (1 x 100 mL) and brine (1 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 20% EtOAc/ hexanes to obtain compound 2 (35 g, 76%) as syrup. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 3.85-3.81 (m, 2H), 3.60 (s, 3H), 2.82 (br s, 2H), 2.53-2.49 (m, 1H), 1.81-1.77 (m, 2H), 1.44-1.40 (m, 2H), 1.38 (s, 9H). LCMS (ESI): m/z 144.1 [(M ⁺ +1)-Boc]. Synthesis of 1-(tert-butyl) 4-methyl 4-((benzyloxy)methyl)piperidine-1,4-dicarboxylate (3): To a stirring solution of compound 2 (25 g, 102.8 mmol) in THF (150 mL) was added LiHMDS (205.7 mL, 205.7 mmol) at -10 °C under nitrogen atmosphere and stirred for 1 h. To this mixture, BOM-chloride (19.2 mL, 123.3 mmol) was added drop wise and the reaction was stirred at -10 °C for 30 minutes, warmed to RT and stirred for 30 minutes. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH4Cl solution (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water (2 x 150 mL), followed by brine solution (2 x 100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain crude compound, which was purified by column chromatography by eluting with 10% EtOAc/ hexanes to afford compound 3 (30 g, 81%) as a colorless syrup. ¹ H-NMR: (400 MHz, DMSO-d6): δ 7.36-7.15 (m, 5H), 5.16-5.13 (m, 0.5H), 4.80-4.59 (m, 2H), 4.50-4.41 (m, 1.5H), 3.67 (s, 1H), 3.63 (s, 3H), 3.46-3.31 (m, 2H), 2.90 (br s, 1H), 1.98-1.85 (m, 2H), 1.43-1.38 (m, 2H), 1.37 (s, 9H). LCMS (ESI): m/z 264.2 [(M ⁺ +1)-Boc]. Synthesis of 4-((benzyloxy)methyl)-1-(tert-butoxycarbonyl)piperidine-4-ca rboxylic acid (4): To a stirring solution of compound 3 (30 g, 82.6 mmol) in MeOH and; THF (200 mL, 1:1) was added a NaOH solution (9.92 g in 100 mL of H2O) at RT. The reaction mixture was heated to 80 °C for 16 h. After consumption of the starting material (by TLC), the volatiles were evaporated under reduced pressure and the crude was diluted with water (100 mL), washed with diethyl ether (2 x 100 mL). The separated aqueous layer was acidified using 1 N HCl solution (pH~3) and extracted with EtOAc (2 x 250 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford crude compound, which was triturated with n-hexane to obtain compound 4 (18 g, 62%) as an off-white solid. ¹ H-NMR: (500 MHz, DMSO-d ₆ ): δ 7.36- 7.28 (m, 5H), 5.17-5.13 (m, 0.5H), 4.50-4.46 (m, 2H), 3.72-3.65 (m, 3H), 3.47-3.38 (m, 2H), 2.92 (br s, 1.5H), 1.92-1.81 (m, 4H), 1.38 (s, 9H). LCMS (ESI): m/z 349.4 [M ⁺ ]. Synthesis of 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carbox ylic acid (5): To a stirring solution of compound 4 (15 g, 42.9 mmol) in methanol (100 mL) was added 50% wet 10% Pd/C (4.5 g) at RT and stirred for 4 h under H ₂ atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite, and washed with EtOAc (50 mL). Obtained filtrate was concentrated under reduced pressure to afford compound 5 (10 g, 90%) as off white solid. ¹ H-NMR: (500 MHz, DMSO-d6): δ 12.33 (br s, 1H), 4.85 (br s, 1H), 3.72-3.69 (m, 2H), 3.45-3.38 (m, 2H), 2.86 (br s, 2H), 1.87-1.80 (m, 2H), 1.39 (s, 9H), 1.33-28 (m, 2H). LCMS (ESI): m/z 258.9 [M ⁺ ]. Synthesis of tert-butyl 4-(((2S,3R)-1,3-bis(benzyloxy)-1-oxobutan-2-yl)carbamoyl)-4- (hydroxymethyl)piperidine-1-carboxylate (6): To a stirring solution of compound 5 (5 g, 19.3 mmol) in DMF (50 mL) were added, Int- D (6.4 g, 19.3 mmol), HATU (8.8 g, 23.16 mmol) and DIPEA (10.6 mL, 57.9 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with ice- cold water (10 mL) and saturated brine solution (10 mL). The separated organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 50% EtOAc/ hexanes to obtain compound 6 ( 3.8 g, 77%) as a syrup. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.76 (d, J = 8.8, 1H), 7.31-7.21 (m, 10H), 5.33 (d, J = 4.8, 1H), 5.32 (s, 2H), 4.57-4.50 (m, 2H), 4.34-4.31 (m, 1H), 4.10-4.00 (m, 1H), 3.52-3.46 (m, 4H), 3.08-3.06 (m, 2H), 1.88-1.85 (m, 2H), 1.38 (s, 9H), 1.29- 1.27 (m, 2H), 1.19-1.13 (m, 3H). LCMS (m/z): 539.6 [M ⁺ -1]. Synthesis of tert-butyl 2-((2S,3R)-1,3-bis(benzyloxy)-1-oxobutan-2-yl)-1-oxo-2,7- diazaspiro[3.5] nonane-7-carboxylate (7): To a solution of TPP (5.8 g, 22.2 mmol) in THF (130 mL) was added DIAD (4.57 g, 22.2 mmol) at RT under nitrogen atmosphere and the reaction mixture was stirred for 15 minutes. The reaction mixture was cooled to 0 ^o C, compound 6 (6 g, 11.1 mmol) in THF (20 mL) was added, and the reaction was warmed to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with 1 N HCl (25 mL) and brine solution (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude compound which was purified by silica gel column chromatography eluting with 40% EtOAc/ hexanes to afford compound 7 (5 g, 86%) as a thick syrup. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.40-7.19 (m, 10H), 5.19-5.10 (m, 2H), 4.57-4.43 (m, 1H), 4.29-4.00 (m, 1H), 3.60-3.53 (m, 2H), 3.38-3.36 (m, 1H), 3.31-3.27 (m, 1H), 3.18-3.14 (m, 2H), 1.69-1.58 (m, 4H), 1.39 (s, 9H), 1.22-1.20 (m, 2H), 1.18-1.15 (m, 3H). LCMS (ESI): m/z 423.5 [(M ⁺ +1)- Boc]. Synthesis of (2S,3R)-2-(7-(tert-butoxycarbonyl)-1-oxo-2,7-diazaspiro[3.5] nonan-2-yl)-3- hydroxybutanoic acid (8): To a stirring solution of compound 7 (5 g, 9.57 mmol) in methanol (50 mL) was added 50% wet 10% Pd/C (2.5 g) at RT, and the reaction was stirred under H ₂ atmosphere (balloon pressure) for 24 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite, washed with EtOAc (50 mL). Obtained filtrate was concentrated under reduced pressure to afford compound 8 (3 g, 91%) as sticky syrup. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 12.86 (s, 1H), 5.04-5.03 (m, 0.5H), 4.19 (br s, 0.5H), 4.09-4.05 (m, 1H), 3.63-3.60 (m, 2H), 3.42-3.41 (m, 0.5H), 3.36-3.34 (m, 0.5H), 3.22-3.17 (m, 2H), 1.69-1.66 (m, 4H), 1.38 (s, 9H), 1.22-1.20 (m, 2H), 1.18-1.13 (m, 3H). LCMS (m/z): 341.1 [M ⁺ -1]. Synthesis of tert-butyl 2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,7- diazaspiro[3.5]nonane-7-carboxylate (AA-1 and AA-2): To a stirring solution of compound 8 (3 g, 8.77 mmol) in CH2Cl2 (50 mL) were added NH ₄ Cl (947 mg, 17.5 mmol), EDCI.HCl (2 g, 10.5 mmol), HOBt (1.42 g, 10.52 mmol) and DIPEA (4.8 mL, 26.3 mmol) at RT and the reaction was stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with CH ₂ Cl ₂ (2 x 50 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude compound which was purified by silica gel column chromatography eluting with 6% MeOH/ CH2Cl2 to afford a racemic mixture of AA-1 and AA-2 (1.5 g, 50%) as an off white solid. The racemic mixture was separated by chiral HPLC purification. AA-1: ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.49 (s, 1H), 7.09 (s, 1H), 4.92 (d, J = 5.2 Hz, 1H), 3.98-3.92 (m, 2H), 3.63-3.59 (m, 2H), 3.37-3.30 (m, 2H), 3.17-3.15 (m, 2H), 1.68-1.63 (m, 4H), 1.39 (s, 9H), 1.07 (d, J = 6.0 Hz, 3H). LCMS (ESI): m/z 340.0 [M ⁺ -1]. UPLC: 99.57%. AA-2: ¹ H-NMR: (400 MHz, DMSO-d6): δ 7.47 (s, 1H), 7.08 (s, 1H), 4.99 (d, J = 5.2 Hz, 1H), 3.95-3.90 (m, 2H), 3.62-3.59 (m, 2H), 3.22-3.20 (m, 1H), 3.17-3.15 (m, 3H), 1.65-1.61 (m, 4H), 1.39 (s, 9H), 1.07 (d, J = 5.6 Hz, 3H). LCMS (ESI): m/z 340.1 [M ⁺ -1]. UPLC: 98.63%. Synthesis of (2S,3R)-3-hydroxy-2-(1-oxo-2,7-diazaspiro[3.5]nonan-2-yl)but anamide (AB-1 and AB-2) To a stirred solution of a racemic mixture of AA-1 and AA-2 (350 mg, 1.02 mmol) in CH2Cl2 (5 mL) was added TFA (0.78 mL, 10.07 mmol) slowly at 0 °C; the reaction was then warmed to RT and stirred for 3 h. After completion of starting material (by TLC) the volatiles were evaporated under reduced pressure. Obtained crude was triturated with diethyl ether/ n- pentane to afford a racemic mixture of AB-1 and AB-2 (200 mg, 40%) as colorless hygroscopic material. The racemic mixture was separated by chiral HPLC purification. AB-1: ¹ H-NMR: (400 MHz, D2O):δ 4.30-4.25 (m, 2H), 3.59-3.57 (m, 2H), 3.12-3.09 (m, 2H), 2.89-2.79 (m, 2H), 1.95-1.88 (m, 4H), 1.29 (d, J = 6.0 Hz, 3H). LCMS (ESI): m/z 242.2 [M ⁺ +1]. AB-2: ¹ H-NMR: (400 MHz, D ₂ O):δ 4.27-4.18 (m, 2H), 3.53-3.50 (m, 2H), 3.18-3.15 (m, 2H), 2.92-2.87 (m, 2H), 1.96-1.93 (m, 4H), 1.30 (d, J = 6.0 Hz, 3H). LCMS (ESI): m/z 242.3 [M ⁺ +1]. Synthesis of benzyl ((2S,3R)-1-(2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1- oxo-2,7- diazaspiro[3.5]nonan-7-yl)-3-hydroxy-1-oxobutan-2-yl)carbama te (11): To a stirring solution of racemic mixture AB-1 and AB-2 (1 g, 2.81 mmol) in CH ₂ Cl ₂ (10 mL) were added, Int E (855 mg, 3.37 mmol), HATU (1.28 g, 3.37 mmol) and DIPEA (6.7 mL, 8.43 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was brought to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with 1 N HCl solution (10 mL) and extracted with 10% MeOH/ CH ₂ Cl ₂ (2 x 10 mL). The combined organic layer was washed with cold water (10 mL) and saturated brine solution (10 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 10% MeOH/ CH2Cl2 to obtain compound 11 as a racemic mixture (600 mg, 44%) as off white solid. LCMS (ESI): m/z 477.4 [M ⁺ +1]. Synthesis of (2S,3R)-2-(7-(L-threonyl)-1-oxo-2,7-diazaspiro[3.5]nonan-2-y l)-3-hydroxy butanamide (AC-1 and AC-2): To a stirring solution of compound 11 (600 mg, 1.26 mmol) in methanol (10 mL) was added 50% wet 10% Pd/C (200 mg) at RT under nitrogen atmosphere. The reaction mixture was stirred RT for 24 h under H ₂ atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with MeOH (5 mL). Obtained filtrate was concentrated under reduced pressure. Crude compound was triturated with diethyl ether and dried under vacuum to afford racemic AC-1 and AC-2 (400 mg, 93%) as an off-white solid. The racemic mixture was separated by chiral HPLC purification. AC-1: ¹ H-NMR: (400 MHz, D ₂ O):δ 4.31-4.28 (m, 2H), 4.12-4.06 (m, 1H), 4.00-3.94 (m, 3H), 3.64 (s, 2H), 3.59-3.52 (m, 1H), 3.41-3.34 (m, 1H), 2.02-1.93 (m, 4H), 1.30 (d, J = 5.6 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H). LCMS (ESI): m/z 343.4 [M ⁺ +1]. HPLC: 96.77%. AC-2: ¹ H-NMR: (400 MHz, D ₂ O):δ 4.30-4.20 (m, 2H), 4.12-4.07 (m, 1H), 3.99-3.89 (m, 3H), 3.58 (s, 2H), 3.56-3.53 (m, 1H), 3.40-3.34 (m, 1H), 2.00-1.94 (m, 4H), 1.33 (d, J = 6.0 Hz, 3H), 1.25 (d, J = 7.2 Hz, 3H). LCMS (ESI): m/z 343.4 [M ⁺ +1]. HPLC: 97.29%. Intermediates preparation Synthesis of (2S, 3R)-2-((tert-butoxycarbonyl) amino)-3-hydroxybutanoic acid (A) To a stirring solution of SM-2 (300 g, 2.52 mol) in water (2 L) was added NaHCO3 (801 g, 3.78 mol) portionwise at RT, and the reaction was stirred for 30 min. Then 1, 4-Dioxane (1 L) was added and the reaction was cooled to 0 °C. Boc-anhydride (867 mL, 3.78 mol) was added dropwise to the reaction mixture and the stirring was continued at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was concentrated under reduced pressure and obtained residue was diluted with water (200 mL) and acidified by using 4 N HCl (pH~2). The aqueous layer was extracted with EtOAc (2 x 300 mL). The combined organic layer was washed with brine (1 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford compound A (480 g, 86%) as thick syrup. ¹ H- NMR: (500 MHz, DMSO-d6): δ 12.5 (br s, 1H), 6.30 (d, J = 8.5 Hz, 1H), 4.50 (br s, 1H), 4.05- 4.02 (m, 1H), 3.88-3.86 (m, 1H), 1.39 (s, 9H), 1.08 (d, J = 6.0 Hz, 3H). LCMS (m/z): 218.1 [M ⁺ -1]. Synthesis of (2S, 3R)-3-(benzyloxy)-2-((tert-butoxycarbonyl) amino) butanoic acid (B) To a stirring solution of compound A (250 g, 1.44 mol) in DMF (1 L) was added 60% NaH (68 g, 2.85 mol) portionwise at -20 °C under N2 atmosphere and stirred for 2 h. To this was added benzyl bromide (167 mL, 1.36 mol) dropwise and the reaction mixture was stirred at RT for 3 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water and washed with diethyl ether (2 x 250 mL). The aqueous layer was acidified using citric acid solution (pH~2) and extracted with EtOAc (2 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford compound B (320 g, 90%) as thick syrup. ¹ H-NMR: (500 MHz, DMSO-d6): δ 12.64 (br s, 1H), 7.34-7.25 (m, 5H), 6.46 (d, J = 8.5 Hz, 1H), 4.53 (d, J = 11.5 Hz, 1H), 4.39 (d, J = 12.0 Hz, 1H), 4.00-3.98 (m, 2H), 1.39 (s, 9H), 1.15 (d, J = 6.0 Hz, 3H). Synthesis of (2S, 3R)-benzyl 3-(benzyloxy)-2-((tert-butoxycarbonyl) amino) butanoate (C): To a stirring solution of compound B (290 g, 0.93 mol) in DMF (1.4 L) was added K2CO3 (388 g, 2.81 mol) at 0 °C under N2 atmosphere and the reaction was stirred for 30 min. To this benzyl bromide (138 mL, 1.12 mol) was added dropwise at 0 °C; the reaction was warmed to RT and stirred for 16 h. The reaction mixture was quenched with ice cold water and extracted with diethyl ether (2 x 250 mL). The separated organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 20% EtOAc/ hexanes to afford compound C (319 g, 85%) as thick syrup. ¹ H-NMR: (500 MHz, DMSO-d ₆ ): δ 7.37-7.18 (m, 10H), 6.81 (d, J = 9.0 Hz, 1H), 5.08 (s, 2H), 4.49 (d, J = 12.0 Hz, 1H), 4.32 (d, J = 12.0 Hz, 1H), 4.25-4.22 (m, 1H), 4.01-3.98 (m, 1H), 1.38 (s, 9H), 1.15 (d, J = 6.0 Hz, 3H). Mass (ESI): m/z 399.4 [M ⁺ +1]. Synthesis of (2S, 3R)-benzyl 2-amino-3-(benzyloxy) butanoate (D): To a stirring solution of compound C (290 g, 0.74 mol) in diethyl ether (500 mL) was added 2 M HCl in diethyl ether (1 L) at 0 °C and the reaction was stirred at RT for 10 h. After consumption of the starting material (by TLC), the reaction mixture was concentrated under reduced pressure. The crude material was triturated with diethyl ether/ n-pentane (100 mL/100 mL) and dried under reduced pressure to afford compound D (187 g, 86%) as white solid (HCl salt). ¹ H-NMR: (400 MHz, DMSO-d6): δ 8.59 (s, 2H), 7.50-7.25 (m, 10H), 5.23 (d, J = 12.5 Hz, 1H), 5.16 (d, J = 12.5 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.36 (d, J = 12.0 Hz, 1H), 4.12-4.09 (m, 1H), 4.09-3.99 (m, 1H), 1.29 (d, J = 6.5 Hz, 3H). Mass (ESI): m/z 299.4 [M ⁺ +1]. Synthesis of Examples AD-1 and AD-2: Synthesis of methyl piperidine-2-carboxylate hydrochloride (1): To a stirred suspension of piperidine-2-carboxylic acid (SM1) (25 g, 193.7 mmol) in methanol (250 mL) was added thionyl chloride (17.8 mL, 387.4 mmol) dropwise at -10 °C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 24 h. After consumption of the starting material (by TLC), the volatiles were concentrated under vacuum and the crude was triturated with n-hexane to afford compound 1 as hydrochloride salt (32g, 92%). ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 9.85 (s, 1H), 9.38 (s, 1H), 4.05 (d, J = 9.6 Hz, 1H), 3.74 (s, 3H), 3.21-3.15 (m, 1H), 2.91-2.86 (m, 1H), 2.07-2.03 (m, 1H), 1.73-1.50 (m, 5H). LCMS (m/z): 144.2 [M ⁺ +1]. Synthesis of 1-(tert-butyl) 2-methyl piperidine-1,2-dicarboxylate (2): To a stirring solution of compound 1 (20 g, 111.7 mmol) in 1,4-dioxane (200 mL) were added Et ₃ N (48.3 mL, 335.1 mmol) at 0 °C and the reaction was stirred for 10 min. Then Boc- anhydride (38.4 mL, 167.5 mmol) was added at 0 °C; the reaction was warmed to RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (50 mL) and extracted with CH2Cl2 (2 x 50 mL). The combined organic layer was washed with citric acid (1 x 50 mL), brine (1 x50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 20% EtOAC/ hexanes to obtain compound 2 (25 g, 92%) as syrup. ¹ H-NMR: (400 MHz, DMSO-d6): δ 4.72-4.64 (d, 1H), 3.82 (s, 3H), 2.92-2.88 (m, 1H), 2.76-2.72 (m, 1H), 2.08-2.04 (m, 1H), 1.62-1.59 (m, 3H), 1.47-1.40 (m, 2H), 1.33 (s, 9H). LCMS (ESI): m/z 144.1 [(M ⁺ +1)-Boc]. Synthesis of tert-butyl 1-oxo-2,5-diazaspiro[3.5]nonane-5-carboxylate (AD-1 and AD-2): To a stirring solution of compound 2 (2 g, 8.2 mmol) in THF (20 mL) were added paraformaldehyde (296 mg, 9.8 mmol) and LiHMDS (1.0M in THF) (24.6 mL, 24.6 mmol) at - 78 °C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction was quenched with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with brine solution (2 x 10 mL), dried over Na ₂ SO ₄ and concentrated to obtain crude compound which was purified by column chromatography by eluting with 35% EtOAc/ hexanes to afford racemic AD- 1 and AD-2 (600 mg, 31%) as colorless liquid. The racemic mixture was separated by chiral HPLC purification. AD-1: ¹ H-NMR: (500 MHz, DMSO-d6):δ 7.80 (s, 1H), 3.72-3.67 (m, 1H), 3.21 (d, J = 4.0 Hz, 1H), 3.14 (d, J = 4.8 Hz, 1H), 2.98-2.94 (m, 1H), 1.77-1.71 (m, 3H), 1.54-1.41 (m, 3H), 1.38 (s, 9H). LCMS (ESI): m/z 238.8 [M ⁺ -1]. AD-2: ¹ H-NMR: (500 MHz, DMSO-d6):δ 7.80 (s, 1H), 3.72-3.67 (m, 1H), 3.21 (d, J = 4.0 Hz, 1H), 3.14 (d, J = 4.8 Hz, 1H), 2.98-2.94 (m, 1H), 1.77-1.71 (m, 3H), 1.54-1.41 (m, 3H), 1.38 (s, 9H). LCMS (ESI): m/z 238.8 [M ⁺ -1]. Synthesis of Examples AE-1, AE-2, AF-1, AF-2, AG-1, and AG-2: Synthesis of ethyl piperidine-3-carboxylate hydrochloride (1): To a stirred solution of piperidine-3-carboxylic acid (SM1) (10 g, 77.5 mmol) in ethanol (120 mL) was added thionyl chloride (11.26 mL, 155 mmol) dropwise at 0 °C. The reaction mixture was warmed to RT and then heated to reflux for 16 h. After consumption of the starting material (by TLC), the reaction was cooled to RT. The reaction was concentrated under vacuum, triturated with diethyl ether and dried to afford compound 1 as hydrochloride salt (14 g, 94 %) as off white solid. ¹ H-NMR: (500 MHz, DMSO-d6): δ 9.20 (s, 1H), 4.12-4.09 (m, 2H), 3.32-2.77 (m, 5H), 2.50-1.53 (m, 4H), 1.21-1.18 (t, 3H). LCMS (m/z): 158.1 [M ⁺ +1]. Synthesis of 1-(tert-butyl) 3-ethyl piperidine-1,3-dicarboxylate (2): To a stirred suspension of compound 1 (14 g, 72.54 mmol) in DCM (200 mL) were added Boc-anhydride (19 mL, 87 mmol) and Et ₃ N (30 mL, 217.6 mmol) at 0 °C, and the reaction was stirred for 10 min. The reaction mixture was brought to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (200 mL) and extracted with CH ₂ Cl ₂ (2 x 200 mL). The combined organic layer was washed with brine solution (1 x 200 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with Hexane to 20% EtOAc/ hexanes to obtain compound 2 (16 g, 86%) as light yellow liquid. ¹ H-NMR: (500 MHz, CDCl ₃ ): δ 4.15-3.90 (q, 4H), 2.83-2.77 (m, 2H), 2.44-2.40 (t, 1H), 2.05-2.02 (q, 1H), 1.72-1.68 (m, 3H), 1.38 (s, 9H), 1.33-1.24 (m, 3H). Synthesis of 1-(tert-butyl) 3-ethyl 3-((benzyloxy)methyl)piperidine-1,3-dicarboxylate (3): To a stirring solution of compound 2 (13 g, 50.5 mmol) in THF (100 mL) was added LiHMDS (101 mL, 101 mmol) at -78 °C under nitrogen atmosphere, and the reaction was allowed to stir at RT for 1h. Again the reaction mixture was cooled to -78 °C and BOM-chloride (8.4 mL, 60.6 mmol) was added dropwise and the reaction was stirred at RT for another 2 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH4Cl solution (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with water (2 x 150 mL) followed by brine solution (2 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated to obtain crude compound which was purified by column chromatography by eluting with 25% EtOAC/ hexanes to afford compound 3 (18 g, crude) as light yellow syrup. LCMS (ESI): m/z 278.6 [(M ⁺ +1)-Boc]. Synthesis of 3-((benzyloxy)methyl)-1-(tert-butoxycarbonyl)piperidine-3-ca rboxylic acid (4): To a stirring solution of compound 3 (18 g, 47.75 mmol) in MeOH: THF (40 mL, 1: 1) was added NaOH solution (9.5 g in 40 mL H2O) at RT. The reaction mixture was heated to reflux for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure and the crude was diluted with water (200 mL) and extracted with Et2O (2 x 100 mL). The separated aqueous layer was acidified using 6 N HCl solution (pH~2) and extracted with EtOAc (2 x 250 mL). The combined organic layer was dried over Na2SO4 and concentrated to afford crude which was then triturated with n-hexane to obtain compound 4 (11 g, crude as light yellow syrup. LCMS (ESI): m/z 348.4 [M+-1]. Synthesis of 1-(tert-butoxycarbonyl)-3-(hydroxymethyl)piperidine-3-carbox ylic acid (5): To a stirring solution of compound 4 (11 g, 31.48 mmol) in methanol (100 mL) was added 50% wet 10% Pd/C (3.3 g) at RT, and the reaction was stirred for 16 h under H ₂ atmosphere. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite, and washed with EtOAc (50 mL). Obtained filtrate was concentrated under reduced pressure to afford compound 5 (8 g, crude) as light yellow syrup. LCMS (ESI): m/z 257.9 [M+-1]. Synthesis of tert-butyl 3-(((2S,3R)-1,3-bis(benzyloxy)-1-oxobutan-2-yl)carbamoyl)-3- (hydroxymethyl)piperidine-1-carboxylate (6): To a stirring solution of compound 5 (4.8 g, 17.76 mmol) in DMF (40 mL) were added Int D (6.6 g, 19.54 mmol), HATU (8.1 g, 21.3 mmol) and DIPEA (9.5 mL, 53.28 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2x10 mL). The separated organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 50% EtOAc/ hexanes to obtain compound 6 ( 6.2 g, crude) as syrup. LCMS (m/z): 541.6 [M ⁺ +1]. Synthesis of tert-butyl 2-((2S,3R)-1,3-bis(benzyloxy)-1-oxobutan-2-yl)-1-oxo-2,6- diazaspiro[3.5]nonane-6-carboxylate (7): To a solution of TPP (3.6 g, 13.55 mmol) in THF (50 mL) was added DIAD (2.7 mL, 13.55 mmol) at RT under nitrogen atmosphere and the reaction mixture was stirred for 20 minutes. The reaction mixture was cooled to -10 ^o C, compound 6 (6.1 g, 11.3 mmol) in THF (10 mL) was added, and the reaction was allowed to stir at RT for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with 1N HCl and brine solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude which was purified by silica gel column chromatography eluting with 20% to 40% EtOAc/ hexanes to afford compound 7 (7 g, crude) as thick syrup. LCMS (ESI): m/z 467.5 [(M ⁺ +1)- ^t Bu. Synthesis of (2S,3R)-2-(6-(tert-butoxycarbonyl)-1-oxo-2,6-diazaspiro[3.5] nonan-2-yl)-3- hydroxybutanoic acid (8): To a stirring solution of compound 7 (7 g, 13.4 mmol) in methanol (60 mL) was added 50% wet 10% Pd/C (2.1 g) at RT, and the reaction was stirred for 16 h under H2 atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with EtOAc (50 mL). Obtained filtrate was concentrated under reduced pressure and co-distilled with CH ₂ Cl ₂ to afford compound 8 (4 g, 91%) as sticky syrup. LCMS (m/z): 341.3 [M+-1]. Synthesis of tert-butyl 2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,6- diazaspiro[3.5]nonane-6-carboxylate (AE-1 and AE-2): To a stirring solution of compound 8 (3 g, 8.76 mmol) in DMF (15 mL) were added HATU (4 g, 10.51 mmol), NH4Cl (562 mg, 10.51 mmol) and DIPEA (4.6 mL, 28.28 mmol) at 0 ^o C under nitrogen atmosphere. The reaction mixture was stirred at RT for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with 5% MeOH/ CH ₂ Cl ₂ (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Obtained crude material was purified by silica gel column chromatography eluting with 3% MeOH/ CH ₂ Cl ₂ to afford racemic AG-1 and G-2 (500 mg) as off white solid. The racemic mixture was separated by chiral HPLC purification. AE-1: ¹ H-NMR: (400 MHz, D ₂ O): δ 4.30-4.27 (t, 2H), 3.86 (brs, 1H), 3.61-3.55 (t, 3H), 3.50-3.48 (d, 1H), 3.29 (brs, 1H), 2.12-1.94 (m, 2H), 1.83-1.57 (m, 2H), 1.48 (s, 9H), 1.30-1.29 (d, 3H). LCMS (ESI): m/z 340.0 [M+-1]. UPLC: 99.21%. AE-2: ¹ H-NMR: (400 MHz, D ₂ O): δ 4.30-4.27 (t, 2H), 3.86 (brs, 1H), 3.61-3.55 (t, 3H), 3.50-3.48 (d, 1H), 3.29 (br s, 1H), 2.12-1.94 (m, 2H), 1.83-1.57 (m, 2H), 1.48 (s, 9H), 1.30-1.29 (d, 3H). LCMS (ESI): m/z 340.0 [M+-1]. UPLC: 99.45%. Synthesis of (2S,3R)-3-hydroxy-2-(1-oxo-2,6-diazaspiro[3.5]nonan-2-yl)but anamide (AF-1): To a stirred solution of AE-1 (150 mg, 0.43 mmol) in DCM (5 mL) TFA (0.34 mL, 4.39 mmol) was added slowly at 0 °C. The reaction mixture was brought to RT and stirred for 3 h. After completion of starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude material was triturated with Et2O/ pentane (1:1) to afford AF-1 (75 mg) as colorless hygroscopic material. ¹ H-NMR: (400 MHz, D ₂ O): δ 4.31-4.26 (m, 2H), 3.73-3.59 (m, 3H), 3.48-3.09 (m, 3H), 2.13-2.01 (m, 3H), 1.95-1.88 (m, 1H), 1.34-1.30 (m, 3H). LCMS (ESI): m/z 242.1[M ⁺ +1]. UPLC: 98.54%. Synthesis of (2S,3R)-3-hydroxy-2-(1-oxo-2,6-diazaspiro[3.5]nonan-2-yl)but anamide (AF-2): To a stirred solution of AE-2(120 mg, 0.35 mmol) in CH2Cl2 (5 mL) TFA (0.3 mL, 3.51 mmol) was added slowly at 0 °C. The reaction mixture was warmed to RT and stirred for 3 h. After completion of starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude material was triturated with Et ₂ O/ pentane to afford AF-2 (80 mg) as colorless hygroscopic material. ¹ H-NMR: (400 MHz, D2O): δ 4.32-4.28 (m, 2H), 3.76-3.31 (m, 3H), 3.22-3.08 (m, 3H), 2.13-2.07 (m, 3H), 1.95-1.86 (m, 1H), 1.33-1.29 (m, 3H). LCMS (ESI): m/z 242.1 [M++1]. UPLC: 97.92%. Synthesis of (2S,3R)-3-hydroxy-2-(1-oxo-2,6-diazaspiro[3.5]nonan-2-yl)but anamide (AF-1 and AF-2, racemic): To a stirred solution of AE-1 and AE-2 (800 mg, 2.34 mmol, racemic) in CH ₂ Cl ₂ (5 mL) TFA (1.9 mL, 23.4 mmol) was added slowly at 0 °C. The reaction mixture was warmed to RT and stirred for 3 h. After completion of starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude material was triturated with Et2O/ pentane to afford AF- 1 and AF-2 (1g, crude; racemic) as colorless hygroscopic material. Synthesis of benzyl ((2S,3R)-1-(2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1- oxo-2,6- diazaspiro[3.5]nonan-6-yl)-3-hydroxy-1-oxobutan-2-yl)carbama te (11): To a stirring solution of AF-1 and AF-2 (1 g, 2.81 mmol; racemic) in DMF (10 mL) were added Int B (855 mg, 3.38 mmol), HATU (1.28 g, 3.38 mmol) and DIPEA (1.55 mL, 8.44 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was brought to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (10 mL) and extracted with 10% MeOH-DCM solvent mixture (2x15 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 3% to 10% MeOH/ CH2Cl2 to obtain compound 11 ( 800 mg, racemic). LCMS (ESI): m/z 477.4 [M ⁺ +1]. Synthesis of (2S,3R)-2-(6-(L-threonyl)-1-oxo-2,6-diazaspiro[3.5]nonan-2-y l)-3- hydroxybutanamide (AG-1 and AG-2): To a stirring solution of compound 11 (800 mg, 1.68 mmol; racemic) in methanol (10 mL) was added 50% wet 10% Pd/C (200 mg) at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 4 h under H ₂ atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with MeOH (5 mL). Obtained filtrate was concentrated under reduced pressure. Crude material was triturated with Et2O and dried under vacuum to afford racemic AG-1 and AG-2 (550 mg) as off white solid. The racemic mixture was separated by chiral HPLC purification and obtained 100 mg each of AG-1 and AG-2. AG-1: ¹ H-NMR: (400 MHz, D2O): δ 4.32-4.27 (m, 2H), 4.15-4.01 (m, 3H), 3.92-3.72 (m, 2H), 3.63-3.47 (m, 3H), 2.19-1.72 (m, 4H), 1.42-1.24 (m, 6H). LCMS (ESI): m/z 343.4 [M++1]. HPLC: 94.19%. AG-2: ¹ H-NMR: (400 MHz, D2O): δ 4.34-4.27 (m, 2H), 4.08-3.91 (m, 3H), 3.79-3.73 (m, 2H), 3.62-3.49 (m, 3H), 2.14-1.65 (m, 4H), 1.33-1.22 (m, 6H),1.25 (d, J = 7.2 Hz, 3H). LCMS (ESI): m/z 343.4 [M++1]. HPLC: 95.11%.

Synthesis of Examples AH-1, AH-2, AI-1, and AI-2: Synthesis of ethyl piperidine-3-carboxylate hydrochloride (1): To a stirring solution of piperidine-3-carboxylic acid (SM1) (10 g, 77.5 mmol) in ethanol (120 mL) was added thionyl chloride (11.26 mL, 155 mmol) dropwise at 0 °C. The reaction mixture was warmed to RT and then stirred under reflux for 16 h. After consumption of the starting material (by TLC), the reaction was brought to RT. The reaction was concentrated under vacuum, triturated with diethyl ether and dried to afford compound 1 as hydrochloride salt (14 g, 94 %) as off white solid. ¹ H-NMR: (500 MHz, DMSO-d6): δ 9.20 (s, 1H), 4.12-4.09 (m, 2H), 3.32-2.77 (m, 5H), 2.50-1.53 (m, 4H), 1.21-1.18 (t, 3H). LCMS (m/z): 158.1 [M+1]. Synthesis of 1-(tert-butyl) 3-ethyl piperidine-1,3-dicarboxylate (2): To a stirring solution of compound 1 (14 g, 72.54 mmol) in CH ₂ Cl ₂ (200 mL) were added Boc-anhydride (19 mL, 87 mmol) and Et3N (30 mL, 217.6 mmol) at 0 °C and the reaction was stirred for 10 min. The reaction mixture was brought to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (200 mL) and extracted with CH2Cl2 (2 x 200 mL). The combined organic layer was washed with brine solution (1 x 200 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with hexane to 20% EtOAc/ hexanes to obtain compound 2 (16 g, 86%) as light yellow liquid. ¹ H-NMR: (500 MHz, CDCl3): δ 4.15-3.90 (q, 4H), 2.83-2.77 (m, 2H), 2.44-2.40 (t, 1H), 2.05- 2.02 (q, 1H), 1.72-1.68 (m, 3H), 1.38 (s, 9H), 1.33-1.24 (m, 3H). Synthesis of tert-butyl 1-oxo-2,6-diazaspiro[3.5]nonane-6-carboxylate (AH-1 and AH-2): To a stirring suspension of compound 2 (1.4 g, 5.44 mmol) and paraformaldehyde (196 mg, 6.53 mmol) in THF (10 mL) was added LiHMDS (16.3 mL, 16.32 mmol) dropwise at -78 °C. The reaction mixture was warmed to RT and stirred for 2 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH ₄ Cl solution (50 mL) and extracted with EtOAc (2 x 50 mL). The separated organic layer was washed with water (20 mL) and brine solution (20 mL). The separated organic layer was dried over Na ₂ SO ₄ and concentrated to afford crude which was purified by column chromatography eluting with 30% EtOAc/ hexanes to EtOAc afforded racemic AH-1 and AH-2 (1 g, 76%) as off white solid. The racemic mixture was separated by chiral HPLC purification and obtained 350 mg of AH-1 and 360 mg of AH-2. AH-1: ¹ H-NMR: (500 MHz, DMSO-d ₆ ): δ 7.82 (s, 1H), 3.73-3.56 (m, 2H), 3.30-2.98 (m, 4H), 1.76-1.63 (m, 4H), 1.38 (s, 9H). LCMS (ESI): m/z 239.1 [M+-1]. UPLC: 99.27%. AH-2: ¹ H-NMR: (500 MHz, DMSO-d6): δ 7.82 (s, 1H), 3.73-3.56 (m, 2H), 3.30-2.98 (m, 4H), 1.76-1.63 (m, 4H), 1.38 (s, 9H). LCMS (ESI): m/z 239.0 [M+-1]. UPLC: 98.83%. Synthesis of 6-(2,2,2-trifluoroacetyl)-2,6l4-diazaspiro[3.5]nonan-1-one (4-F1): To a stirred solution of AH-1 (280 mg, 1.12 mmol) in CH2Cl2 (5 mL) was added TFA (1.1 mL, 13.99 mmol) slowly at RT and the reaction was stirred for 2 h. After completion of starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude was triturated with Et2O/ pentane to afford compound 4-F1 (280 mg, crude) as light yellow syrup. This product was taken to the next step without any further purification. LCMS (ESI): m/z 141.3 [M+1]. Synthesis of benzyl ((2S,3R)-3-hydroxy-1-oxo-1-(1-oxo-2,6-diazaspiro[3.5]nonan-6 - yl)butan-2-yl)carbamate (5-F1): To a stirring solution of compound 4-F1 (280 mg, 1.18 mmol) and Int A (329 mg, 1.29 mmol) in DMF (6 mL) were added HATU (538 mg, 1.42 mmol) and DIPEA (0.63 mL, 3.54 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was brought to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with EtOAc (10 mL). The organic layer was washed with cold water (10 mL) and saturated brine solution (10 mL). The separated organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 2% MeOH/ CH ₂ Cl ₂ to 5% MeOH/ CH ₂ Cl ₂ to obtain compound 5-F1 (260 mg, 83% by LCMS) as light yellow syrup. LCMS (ESI): m/z 376.4 [M ⁺ +1]. Synthesis of 6-(L-threonyl)-2,6-diazaspiro[3.5]nonan-1-one (AI-1): To a stirring solution of compound 5-F1 (260 mg, 0.69 mmol) in EtOAc: THF (9 mL. 2:1) was added 50% wet Pd/C (78 mg) under N2 atmosphere. The reaction mixture was stirred under H2 atmosphere (balloon pressure) at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with 20% MeOH/ CH2Cl2. Obtained filtrate was washed with Et2O and concentrated under reduced pressure to afford AI-1 (60 mg, 36%) as white semi solid. ¹ H-NMR: (400 MHz, D2O): δ 4.46-4.04 (m, 3H), 3.76-3.68 (m, 2H), 3.62-3.55 (m, 1 H), 3.31-3.22 (m, 2 H), 2.20-1.71 (m, 4H), 1.37-1.32 (m, 3H). LCMS (ESI): m/z 242.2 [M++1]. UPLC: 98.31%. Synthesis of 6-(2,2,2-trifluoroacetyl)-2,6l4-diazaspiro[3.5]nonan-1-one (4-F2): To a stirred solution of AH-2 (290 mg, 1.21 mmol) in CH ₂ Cl ₂ (6 mL) was added TFA (1.2 mL, 14.52 mmol) slowly at RT and the reaction was stirred for 2 h. After completion of starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude was triturated with Et2O/ n-pentane to afford compound 4-F2 (290 mg, crude) as light yellow syrup. This product was taken to the next step without any further purification. Synthesis of benzyl ((2S,3R)-3-hydroxy-1-oxo-1-(1-oxo-2,6-diazaspiro[3.5]nonan-6 - yl)butan-2-yl)carbamate (5-F2): To a stirring solution of compound 4-F2 (290 mg, 1.23 mmol) and Int A (342 mg, 1.35 mmol) in DMF (6 mL) were added HATU (561 mg, 1.47 mmol) and DIPEA (0.65 mL, 3.69 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with EtOAc (10 mL). The organic layer was washed with cold water (10 mL) and saturated brine solution (10 mL). The separated organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting 2%-5% MeOH/ CH ₂ Cl ₂ and preparative HPLC purification to obtain compound 5-F2 (260 mg, 83% by LCMS) as light yellow syrup. ¹ H-NMR: (400 MHz, DMSO- d ₆ ): δ 7.95-7.84 (t, 1 H), 7.35-7.31 (m, 5H), 7.10-7.01 (t, 1H), 5.02 (s, 2H), 4.72-3.80 (m, 6H), 2.95-2.68 (m, 3H), 1.79-1.02 (m, 7H). LCMS (ESI): m/z 376.4 [M++1]. Synthesis of 6-(L-threonyl)-2,6-diazaspiro[3.5]nonan-1-one (AI-2): To a stirring solution of compound 5-F2 (150 mg, 0.40 mmol) in EtOAc (10 mL) was added 50% wet Pd/C (45 mg) under N ₂ atmosphere. The reaction mixture was stirred under H ₂ atmosphere (balloon pressure) at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with 20% MeOH/CH2Cl2. Obtained filtrate was washed with Et2O and concentrated under reduced pressure to afford AI-2 (60 mg, 62.5%) as light yellow syrup. ¹ H-NMR: (400 MHz, D2O): δ 4.46-4.04 (m, 3H), 3.76-3.68 (m, 2H), 3.62-3.55 (m, 1 H), 3.31-3.22 (m, 2 H), 2.20-1.71 (m, 4H), 1.37-1.32 (m, 3H). LCMS (ESI): m/z 242.2 [M ⁺ +1]. Synthesis of ((benzyloxy)carbonyl)-L-threonine (A): To a stirring solution of NaHCO ₃ (529 g, 6.30 mol) in water (1 L) was added L-threonine (SM2) (250 g, 2.10 mol) at RT and the reaction was stirred for 30 min. The reaction mixture was cooled to 0 °C, Cbz-Cl (850 mL, 2.52 mol, 50% in PhCH ₃ ) was added dropwise and stirred for 1 h. The reaction mixture was warmed to RT and stirred for 28 h. To this MTBE (1 L) was added and stirred for 20 min. The separated aqueous layer in toluene was stirred for 20 min. The aqueous layer was acidified with 1N HCl (pH~1-2) and extracted with EtOAc (3x 1.5 L). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was stirred with dicyclohexylamine (819 mL, 4.20 mol) for 4 h to get white solid, and the white solid was filtered and dried. Obtained solid was refluxed with EtOAc (1.5 L) for 1h and then filtered. The solid material was dissolved in water (1 L) and acidified with dilute H2SO4 and again stirred for 30 min. The aqueous layer was extracted with EtOAc (3x 1 L). The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Obtained crude material was triturated with n-hexane to afford Int A (230 g, 43%) as white solid. ¹ H-NMR: (400 MHz, DMSO-d6): δ 12.55 (br m, 1H), 7.37-7.30 (m, 5H), 6.94 (d, J = 8.8 Hz, 1H), 5.05 (s, 2H), 4.08- 3.94 (m, 2H), 1.02 (d, J = 6.4 Hz, 3H). UPLC (ELSD purity): 84.66%. Synthesis of Examples AJ-1 and AJ-2: Synthesis of ethyl piperidine-3-carboxylate hydrochloride (1): To a stirred solution of piperidine-3-carboxylic acid (SM1) (10 g, 77.5 mmol) in ethanol (120 mL) was added thionyl chloride (11.26 mL, 155 mmol) dropwise at 0 °C. The reaction mixture was warmed to RT and then stirred under reflux for 16 h. After consumption of the starting material (by TLC), the reaction was brought to RT. The reaction was concentrated under vacuum, triturated with Et2O and dried to afford compound 1 as hydrochloride salt (14 g, 94 %) as off white solid. 1H-NMR: (500 MHz, DMSO-d6): δ 9.20 (s, 1H), 4.12-4.09 (m, 2H), 3.32- 2.77 (m, 5H), 2.50-1.53 (m, 4H), 1.21-1.18 (t, 3H). LCMS (m/z): 158.1 [M++1]. Synthesis of 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (2): To a stirred suspension of compound 1 (4.2 g, 21.76 mmol) in CH ₂ Cl ₂ (40 mL) were added Et3N (9.1 mL, 65.28 mmol) and Cbz-Cl (8.1 mL, 23.94 mmol) at 0 °C. The reaction mixture was brought to RT and stirred for 16 h. After completion of starting material (by TLC), the reaction mass was diluted with CH2Cl2 (20 ml) and washed with 1 N HCl solution (10 mL), water and saturated NaHCO ₃ solution (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain crude which was purified by column chromatography eluting with 30% EtOAc/ hexanes to afford compound 2 (5 g, 79%) as light yellow syrup. LCMS (ESI): m/z 292.2 [M++1]. Synthesis of benzyl 1-oxo-2,6-diazaspiro[3.5]nonane-6-carboxylate (3): To a stirring suspension of compound 2 (4 g, 13.74 mmol) and paraformaldehyde (454 mg, 15.12 mmol) in THF (30 mL) was added LiHMDS (41 mL, 41.22 mmol) dropwise at -78 °C. The reaction mixture was warmed to RT and stirred for 4 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH ₄ Cl solution (50 mL) and extracted with EtOAc (2 x 50 mL). The separated organic layer was washed with water (20 mL) and brine solution (20 mL). The separated organic layer was dried over Na ₂ SO ₄ and concentrated to afford crude which was purified by column chromatography eluting with 30% EtOAc / hexanes to EtOAc and preparative HPLC purification afforded racemic compound 3 (500 mg ) as off white solid. The racemic mixture was separated by chiral HPLC purification and obtained 160 mg of F-I and 160mg of F-II. 1H-NMR: (400 MHz, DMSO-d6):δ 7.82 (s, 1H), 7.39-7.29 (m, 5H), 5.10-5.02 (q, 2H), 3.76-2.97 (m, 6H), 1.98-1.40 (m, 4H). LCMS (ESI): m/z 275.3 [M+- 1]. Synthesis of 2,6-diazaspiro[3.5]nonan-1-one (AJ-1): To a stirring solution of compound-3-F-I (160 mg, 0.58 mmol) in EtOAc (5 mL) was added 50% wet Pd/C (70 mg) under N2 atmosphere. The reaction mixture was stirred under H2 atmosphere (balloon pressure) at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with 30% MeOH/ CH ₂ Cl ₂ . Obtained filtrate was washed with Et ₂ O and concentrated under reduced pressure to afford AJ-1 (70 mg, 86%) as light yellow syrup. 1H-NMR: (500 MHz, DMSO): δ 7.70 (brs, 1H), 3.32-2.41 (m, 7H), 1.70-1.23 (m, 4H). LCMS (ESI): m/z 141.1 [M ⁺ +1]. Synthesis of 2,6-diazaspiro[3.5]nonan-1-one (AJ-2): To a stirring solution of compound-3-F-II (160 mg, 0.58 mmol) in EtOAc (5 mL) was added 50% wet Pd/C (70 mg) under N2 atmosphere. The reaction mixture was stirred under H2 atmosphere (balloon pressure) at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with 20% MeOH/ CH2Cl2. Obtained filtrate was washed with Et2O and concentrated under reduced pressure to afford AJ-2 (74 mg, 91%) as light yellow sticky syrup. 1H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.67 (brs, 1H), 3.30-2.50 (m, 7H), 1.73-1.34 (m, 4H). LCMS (ESI): m/z 141.1 [M ⁺ +1]. Synthesis of Examples AK-1 and AK-2: Synthesis of Ethyl piperidine-3-carboxylate hydrochloride (1): To a stirred solution of Piperidine-3-carboxylic acid (SM) (10 g, 77.5 mmol) in ethanol (120 mL) was added thionyl chloride (11.3 mL, 155.0 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was concentrated under vacuum and the crude was triturated with diethyl ether to afford Compound 1 as hydrochloride salt (13.2 g, 93 %) as white solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 9.21 (s, 1H), 9.10 (s, 1H), 4.11 (q, J = 6.8 Hz, 2H), 3.32 (s, 1H), 3.17-3.14 (m, 1H), 2.93-2.81 (m, 3H), 1.99-1.95 (m, 1H), 1.78-1.70 (m, 2H), 1.61- 1.50 (m, 1H), 1.19 (t, J = 6.8 Hz, 3H). LCMS (m/z): 157.2 [M ⁺ +1]. Synthesis of 1-(Tert-butyl)- 3-ethyl piperidine-1,3-dicarboxylate (2): To a stirring solution of compound 1 (13.2 g, 68.3 mmol) in CH2Cl2 (130 mL) was added Et ₃ N (28.6 mL, 204.9 mmol) at 0 °C and the reaction was stirred for 10 min. Then Boc- anhydride (18.7 mL, 81.9 mmol) was added at 0 °C and the reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (100 mL) and extracted with CH2Cl2 (2 x 100 mL). The combined organic layer was washed with citric acid (1 x 50 mL), brine (1 x50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 20% EtOAC/ hexanes to obtain compound 2 (16.4 g, 94%) as light green syrup. ¹ H-NMR: (400 MHz, CDCl ₃ ): 4.13 (q, J = 7.2 Hz, 2H), 2.83-2.77 (m, 1H), 2.45-2.39 (m, 1H), 2.05-2.01 (m, 1H), 1.72-1.68 (m, 2H), 1.67-1.59 (m, 4H), 1.45 (s, 9H), 1.25 (t, J = 7.2 Hz, 3H). LCMS (m/z): 257.3 [(M ⁺ +1)-Boc]. Synthesis of tert-butyl- 1-oxo-2,6-diazaspiro[3.5]nonane-6-carboxylate (3): To a stirring solution of compound 2 (3 g, 11.6 mmol) in THF (30 mL) were added paraformaldehyde (420 mg, 13.9 mmol) and LiHMDS (1.0M in THF) (35 mL, 34.8 mmol) at - 78 °C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 4 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous ammonium chloride solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine solution (2 x 10 mL), dried over Na2SO4 and concentrated to obtain crude compound which was purified by column chromatography by eluting with 30% EtOAC/ hexanes to afford compound 3 (1.9 g, 68%) as an off-white solid. ¹ H-NMR: (400 MHz, CDCl3): 5.63 (s, 1H), 4.13-4.09 (m, 1H), 3.92 (br s, 1H), 3.29-3.17 (m, 2H), 3.12-3.10 (m, 1H), 2.88-2.82 (m, 1H), 1.93-1.89 (m, 2H), 1.78-1.73 (m, 2H), 1.45 (s, 9H). LCMS (m/z): 240.3 [M ⁺ +1]. Synthesis of 6-(2,2,2-trifluoroacetyl)-2,6-diazaspiro[3.5]nonan-1-one (4): To a stirred solution of compound 3 (500 mg, 2.1 mmol) in CH2Cl2 (5 mL) TFA (1.59 mL, 2.08 mmol) was added slowly at 0 °C. The reaction mixture was brought to RT and stirred for 2 h. After completion of starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude was triturated with diethyl ether to afford compound 4 (510 mg, 40%) as a white solid. ¹ H-NMR: (500 MHz, DMSO-d6): 5.75 (s, 1H), 4.48 (s, 1H), 3.40-3.36 (m, 2H), 3.13-3.05 (m, 2H), 2.92-2.88 (m, 2H), 1.83-1.77 (m, 2H), 1.68-1.65 (m, 2H). LCMS (ESI): m/z 237.3 [M ⁺ +1]. Synthesis of Benzyl ((2S)-3-hydroxy-1-oxo-1-(1-oxo-2,6-diazaspiro[3.5] nonan-6-yl)propan- 2-yl) carbamate (5-F1 &F2): To a stirred solution of compound 4 (1.5 g, 6.3 mmol) in DMF (15 mL) were added Int- B (1.76 g, 6.9 mmol), HATU (2.88 g, 7.5 mmol) and DIPEA (3.4 mL, 18.9 mmol) at RT under nitrogen atmosphere. After addition, the reaction mixture was stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (15 mL) and extracted with 10% MeOH/ CH2Cl2 solvent mixture (3x30 mL). The organic layer was washed with cold water (10 mL) and saturated brine solution (10 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 7% EtOAc/ MeOH to obtain compound 5 (400 mg, 18%) as a white solid. The racemic mixture was separated by Chiral HPLC to afford compound 5-F1 (165 mg) and compound 5-F2 (180 mg). Compound 5-F1: ¹ H-NMR: (500 MHz, DMSO-d ₆ ):δ 7.94-7.85 (d, 1H), 7.45-7.31 (m, 5H), 5.06-4.97 (m, 2H), 4.84-4.81 (m, 1H), 4.62-4.54 (m, 1H), 4.27-3.87 (m, 2H), 3.54-3.41 (m, 2H), 3.25-3.10 (m, 2H), 2.97-2.91 (m, 2H), 2.75-2.63 (m, 1H), 1.79-1.65 (m, 2H), 1.46-1.23 (m, 2H). LCMS (ESI): m/z 362.4 [M ⁺ +1]. Compound 5-F2: ¹ H-NMR: (500 MHz, DMSO-d6):δ 7.91-7.86 (d, 1H), 7.41-7.30 (m, 5H), 5.05-4.98 (m, 2H), 4.81-4.79 (m, 1H), 4.51-4.49 (m, 1H), 4.10-4.05 (m, 1H), 3.96-3.74 (m, 1H), 3.58-3.56 (m, 2H), 3.27-3.16 (m, 3H), 3.15-2.87 (m, 2H), 1.78-1.66 (m, 2H), 1.48-1.23 (m, 2H). LCMS (ESI): m/z 362.4 [M ⁺ +1]. Synthesis of 6-(L-seryl)-2,6-diazaspiro[3.5]nonan-1-one (AK-1): To a stirred solution of compound 5-F1 (165 mg, 0.4 mmol) in ethyl acetate (5 mL) was added 50% wet 10% Pd/C (70 mg) at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h under H2 atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with 20% MeOH/ CH ₂ Cl ₂ (10 mL). Obtained filtrate was concentrated under reduced pressure to afford AK-1 (80 mg, 77%) as syrup. ¹ H-NMR: (400 MHz, D2O): δ 4.20-3.96 (m, 2H), 3.78-3.69 (m, 4H), 3.56-3.50 (m, 1H), 3.34-3.27 (m, 2H), 2.10-1.85 (m, 3H), 1.75-1.62 (m, 1H). LCMS (ELSD): m/z 227.2 [M ⁺ +1]. HPLC: 98.71%. Synthesis of 6-(L-seryl)-2,6-diazaspiro[3.5]nonan-1-one (AK-2): To a stirred solution of compound 5-F2 (180 mg, 0.4 mmol) in ethyl acetate (5 mL) was added 50% wet 10% Pd/C (75 mg) at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h under H ₂ atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with 20% MeOH/CH2Cl2 (10 mL). Obtained filtrate was concentrated under reduced pressure to afford AK-2 (85 mg, 77%) as syrup. ¹ H-NMR: (400 MHz, D ₂ O):δ 4.15-3.99 (m, 2H), 3.84-3.60 (m, 4H), 3.54-3.40 (m, 1H), 3.34-3.23 (m, 2H), 2.11-1.85 (m, 3H), 1.73-1.71 (m, 1H). LCMS (ELSD): m/z 227.2 [M ⁺ +1]. HPLC: 98.26%. Intermediate-preparation: Synthesis of ((benzyloxy)carbonyl)-L-serine (B): To a stirring solution of SM2 (50 g, 475 mmol) in THF / water (130 mL/65 mL) was added NaHCO3 (119.3 g, 1420 mmol) at RT. Cbz-Cl (87.8 mL, 615 mmol) was then added at 0 °C dropwise and the reaction was stirred for 16 h at RT. After completion of starting material (by TLC), the reaction mass was diluted with EtOAc (300 ml). The separated aqueous layer in toluene was stirred for 20 minutes, then the aqueous layer was acidified with 2N HCl (pH~1-2) and extracted with EtOAc (3x 1.5 L). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to afford Int B (33 g, 30 %) as thick syrup. ¹ H-NMR: (500 MHz, DMSO-d6): δ 7.37-7.27 (m, 5H), 5.71 (brs,1H), 5.16 (s, 2H), 4.45 (m, 1H), 4.45 (brs, 1H), 4.14-4.11 (dd, J =11.0, 3.5 Hz, 1H), 3.93-3.91 (dd, J=11.0, 3.5 Hz, 1H). LCMS (ESI): m/z 240.2 [M ⁺ +1]

Synthesis of Examples AL-1, AL-2, and AM-2: Synthesis of 1-(tert-butoxycarbonyl) piperidine-2-carboxylic acid (1): To a stirred solution of piperidine-2-carboxylic acid (SM1) (20 g, 155.1 mmol) in acetonitrile: water (240 mL, 1:2) was added K2CO3 (85.6 g, 620.2 mmol) at 0 °C and the reaction was stirred for 10 minutes. Then Boc-anhydride (49.8 mL, 217.1 mmol) was added dropwise to the reaction mixture at 0-5 °C and stirring was continued at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (200 mL) and EtOAc (200 mL) and the organic layer was separated. The aqueous layer was acidified with 1N HCl (pH~2) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford compound 1 (34 g, 96%) as white solid. ¹ H-NMR: (500 MHz, DMSO-d6): δ 13.12 (br s, 1H), 4.58-4.51 (dd, 1H), 3.79 (d, 1H), 2.97-2.76 (td, J = 12.5, 3.5 Hz, 1H), 2.07 (s, 1H), 1.60-1.46 (m, 3H), 1.39-1.35 (s, 9H), 1.31-1.25 (m, 1H), 1.24-1.11 (m, 1H). LCMS (m/z): 228 [M ⁺ -1]. Synthesis of 2-benzyl 1-(tert-butyl) piperidine-1,2-dicarboxylate (2): To a stirring solution of compound 1 (2 g, 8.73 mmol) in DMF (20 mL) was added K2CO3 (3.6 g, 26.19 mmol) at 0 °C under N2 atmosphere. Then benzyl bromide (1.2 mL, 10.47 mmol) was added dropwise, stirred at 0 °C for 30 minutes and then at RT for 4 h. The reaction mixture was quenched with water (100 mL) and extracted with diethyl ether (2 x 150 mL). The separated organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 10% EtOAc/ hexanes to afford compound 2 (2.7 g, 95%) as colorless liquid. ¹ H- NMR: (500 MHz, DMSO-d ₆ ): δ 7.39-7.32 (m, 5H), 5.18 (s, 2H), 4.76-4.67 (dd, 1H), 3.82-3.79 (d, 1H), 2.97-2.76 (td, J = 12.0, 3.4 Hz, 1H), 2.09-2.05 (m, 1H), 1.61-1.58 (m, 3H), 1.33-1.32 (s, 9H), 1.30-1.29 (m, 1H), 1.13-1.07 (m, 1H). LCMS (m/z): 220.2 [(M ⁺ +1)-Boc]. Synthesis of 2-benzyl 1-(tert-butyl) 2-((benzyloxy)methyl)piperidine-1,2-dicarboxylate (3): To a stirring solution of compound 2 (6 g, 18.81 mmol) in THF (60 mL) was added LiHMDS (37.6 mL, 37.62 mmol) at -10 °C and the reaction was stirred for 45 minutes. To this BOM-chloride (5.2 mL, 36.62 mmol) was added dropwise at -5 °C and stirred for 5 h. After consumption of the starting material (by TLC), the reaction was quenched with ice water (50 mL) and extracted with Et2O (2 x 100 mL). The combined organic layer was washed with brine solution, dried over Na2SO4 and concentrated to obtain crude compound which was purified by column chromatography by eluting with 10% EtOAC/ hexanes to afford compound 3 (6.6 g, 80%) as yellow liquid. ¹ H-NMR: (500 MHz, DMSO-d6): δ 7.35-7.26 (m, 10H), 5.18-5.10 (m, 2H), 4.59-4.50 (m, 2H), 4.02 (d, J = 9.0 Hz, 1H), 3.73 (d, J = 10.5 Hz, 2H), 2.97-2.76 (t, J = 10.5 Hz, 1H), 2.13-2.09 (m, 1H), 1.66-1.54 (m, 5H), 1.29 (s, 9H). LCMS (m/z): 340.4 [(M ⁺ +1)-Boc]. Synthesis of 1-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperidine-2-carbox ylic acid (4): To a stirring solution of compound 3 (6.6 g, 15.01 mmol) in methanol (70 mL) was added 50% wet 10% Pd/C (4 g) at RT and the reaction was stirred for 14 h under H2 atmosphere. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with methanol (2x20 mL). Obtained filtrate was concentrated under reduced pressure to obtain crude compound which was purified by column chromatography by eluting with 1% MeOH/ CH2Cl2 to afford compound 4 (2 g, 52%) as thick syrup which was turned to white solid over a period of time. ¹ H-NMR: (400 MHz, DMSO-d6): δ 12.32 (s, 1H), 4.60 (s, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.67-3.64 (m, 1H), 3.62 (d, J = 11.2 Hz, 1H), 3.16-3.12 (m, 1H), 2.08-2.05 (m, 1H), 1.57-1.54 (m, 5H), 1.35 (s, 9H). LCMS (m/z): 258.2 [M ⁺ -1]. Synthesis of tert-butyl 2-(((2S,3R)-1,3-bis(benzyloxy)-1-oxobutan-2-yl)carbamoyl)-2- (hydroxymethyl)piperidine-1-carboxylate (5): To a solution of compound 4 (450 mg, 1.73 mmol) in DMF (5 mL) was added HATU (792 mg, 2.08 mmol) at 0 °C under nitrogen atmosphere and the reaction was stirred for 10 minutes. Then Int D (699 mg, 2.08 mmol) followed by drop wise addition of DIPEA (0.9 mL, 5.21 mmol) was completed. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x50 mL). The separated organic layer was washed with water (50 mL) and brine solution (50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 40% EtOAc/ hexanes to obtain compound 5 ( 300 mg, 32%) as thick syrup. ¹ H-NMR: (500 MHz, DMSO-d6): δ 8.07 (d, J = 7.5 Hz, 1H), 7.30-7.19 (d, 10H), 5.72 (br s, 1H), 5.14-5.06 (m, 2H), 4.60-4.42 (m, 2H), 4.30-4.28 (m, 1H), 4.08-4.04 (m, 2H), 3.72 (br s, 1H), 3.57-3.49 (m, 1H), 3.32 (br s, 1H), 2.04-1.96 (m, 1H), 1.68-1.65 (m, 1H), 1.53- 1.51 (m, 4H), 1.32-1.27 (s, 9H), 1.14-1.12 (d, 3H). LCMS (m/z): 441.6 [(M ⁺ +1)-Boc]. Synthesis of tert-butyl 2-((2S,3R)-1,3-bis(benzyloxy)-1-oxobutan-2-yl)-1-oxo-2,5- diazaspiro[3.5]nonane-5-carboxylate (6): To a solution of TPP (291 mg, 1.11 mmol) in THF (4 mL) was added DIAD (256 mg, 1.11 mmol) dropwise at RT under nitrogen atmosphere and the reaction was stirred for 30 minutes. The reaction mixture turned from clear to hazy solution. To this, compound 5 (300 mg, 0.55 mmol) in THF (2 mL) was added dropwise at 0-5 °C and allowed to stir at RT for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude material was purified by silica gel column chromatography eluting with 20% EtOAc/ hexanes to afford compound 6 (100 mg, 35%) as thick syrup. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.33-7.18 (m, 10H), 5.21-5.08 (m, 2H), 4.58-4.53 (m, 2H), 4.29-4.26 (d, J = 12.0 Hz, 1H), 4.21-4.18 (dd, J = 6.4, 2.8 Hz, 0.5H), 4.13-4.10 (dd, J = 6.0, 4.0 Hz, 0.5H), 3.75- 3.71 (m, 2H), 3.46-3.40 (m, 1H), 3.07-3.05 (m, 0.5H), 2.91-2.86 (m, 0.5H), 1.78-1.70 (m, 3H), 1.63-1.41 (m, 3H), 1.36 (s, 9H), 1.26-1.17 (d, 3H). LCMS (m/z): 541.7 [M ⁺ +1+H2O]. Synthesis of (2S,3R)-2-(5-(tert-butoxycarbonyl)-1-oxo-2,5-diazaspiro[3.5] nonan-2-yl)-3- hydroxybutanoic acid (7): A solution of compound 6 (100 mg, 0.19 mmol) in methanol (5 mL) was degassed under N2 atmosphere. Then 50% wet 10% Pd/C (50 g) was added at RT and the reaction was stirred for 16 h under H ₂ atmosphere. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad and filtrate was concentrated under reduced pressure. Obtained crude solid was washed with Et ₂ O (5 mL) and pentane (5 mL). Resultant solid material was dried under vacuum to afford compound 7 (40 mg, 61%) as white solid. ¹ H-NMR: (400 MHz, DMSO-d6): δ 4.18-4.01 (m, 2H), 3.76-3.72 (m, 1H), 3.67-3.65 (m, 0.5H), 3.54-3.52 (m, 0.5H), 3.49-3.45 (m, 1H), 3.00-2.92 (m, 1H), 1.84-1.70 (m, 3H), 1.51-1.43 (m, 3H), 1.35 (s, 9H), 1.15-1.07 (m, 3H). LCMS (m/z): 341.4 [M ⁺ -1]. Synthesis of tert-butyl 2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5- diazaspiro[3.5]nonane-5-carboxylate (AL-1 and AL-2): To a solution of compound 7 (440 mg, 1.28 mmol) in CH2Cl2 (5 mL) was added HATU (587 mg, 1.54 mmol) at 0 °C under nitrogen atmosphere and the reaction was stirred for 10 minutes. Then NH4Cl (206 mg, 3.85 mmol) was added followed by DIPEA (0.7 mL, 3.85 mmol) at 0-5 °C under nitrogen atmosphere. The reaction mixture was brought to RT for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Crude mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 500 mL). Combined organic layer was washed with 1 N HCl solution and brine solution. Organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Obtained crude material was purified by silica gel column chromatography eluting with 2% MeOH/ CH ₂ Cl ₂ to afford racemic AL-1 and AL-2 (200 mg, 46%) as an off white solid, which was purified by preparative HPLC to obtain 60 mg each of both fractions. AL-1: ¹ H-NMR: (400 MHz, DMSO-d6): δ 7.44 (s, 1H), 7.11 (s, 1H), 4.81 (d, J = 4.4 Hz, 1H), 4.04-4.00 (m, 1H), 3.92 (d, J = 5.6 Hz, 1H), 3.75-3.71 (m, 1H), 3.53 (d, J = 6.0 Hz, 1H), 3.49 (d, J = 6.0 Hz, 1H), 3.01-2.98 (m, 1H), 1.86-1.78 (m, 2H), 1.71-1.66 (m, 1H), 1.54-1.43 (m, 3H), 1.38 (s, 9H), 1.11 (d, J = 6.0 Hz, 3H). LCMS (m/z): 241.1 [(M ⁺ +1)-Boc]. HPLC: 99.63%. Chiral HPLC: 100%. AL-2: ¹ H-NMR: (400 MHz, DMSO-d6): δ 7.50 (s, 1H), 7.20 (s, 1H), 4.87 (d, J = 4.8 Hz, 1H), 4.05-4.00 (m, 1H), 3.94 (d, J = 4.4 Hz, 1H), 3.73-3.71 (m, 1H), 3.51 (d, J = 6.0 Hz, 1H), 3.46 (d, J = 6.0 Hz, 1H), 2.93-2.91 (m, 1H), 1.83-1.70 (m, 3H), 1.59-1.57 (m, 1H), 1.48-1.41 (m, 2H), 1.37 (s, 9H), 1.06 (d, J = 5.6 Hz, 3H). LCMS (m/z): 241.2 [(M ⁺ +1)-Boc] HPLC: 99.91%. Chiral HPLC: 100%. Synthesis of (2S,3R)-3-hydroxy-2-(1-oxo-2,5-diazaspiro[3.5]nonan-2-yl)but anamide.TFA (AM-2): To a stirred solution of AL-2 (100 mg, 0.29 mmol) in CH2Cl2 (5 mL) was added TFA (119 mL, 1.46 mmol) at 0 °C. The reaction mixture was brought to RT and stirred for 3 h. After completion of starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude was triturated with Et2O/ pentane to afford AM-2 (100 mg, 96%) as white solid. ¹ H-NMR: (400 MHz, D2O): δ 4.18-4.11 (m, 1H), 3.81-3.78 (m, 1H), 3.69-3.57 (m, 1H), 3.49- 3.41 (m, 1H), 3.31-3.25 (m, 2H), 2.21-2.15 (m, 1H), 2.06-2.00 (m, 1H), 1.83-1.68 (m, 4H), 1.39 (d, J = 6.4 Hz, 3H). LCMS (ESI): m/z 258.1 [M-+18]. HPLC: 95.74%. Chiral HPLC: 100%.

Synthesis of Examples AN-1, AN-2, AO-1, and AO-2: Synthesis of methyl piperidine-2-carboxylate (1): To a stirred suspension of piperidine-2-carboxylic acid (SM1) (20 g, 155.1 mmol) in methanol (200 mL) was added thionyl chloride (22.8 mL, 310.1 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was concentrated under vacuum and the crude was triturated with n-pentane to afford compound 1 (25 g, 90 %) as white solid. ¹ H- NMR: (400 MHz, DMSO-d6): δ 9.85 (s, 1H), 9.38 (s, 1H), 4.05 (d, J = 9.6 Hz, 1H), 3.74 (s, 3H), 3.21-3.15 (m, 1H), 2.91-2.86 (m, 1H), 2.07-2.03 (m, 1H), 1.73-1.50 (m, 5H). LCMS (m/z): 144.2 [M ⁺ +1]. Synthesis of 1-benzyl 2-methyl piperidine-1,2-dicarboxylate (2): To a stirring solution of compound 1 (25 g, 174.8 mmol) in CH2Cl2 (250 mL) was added Et ₃ N (75 mL, 524.4 mmol) at 0 °C and the reaction was stirred for 10 min. Then added Cbz-Cl (90 mL, 262.2 mmol) at 0 °C and the reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (50 mL) and extracted with CH2Cl2 (2 x 50 mL). The combined organic layer was washed with citric acid (1 x 50 mL), brine (1 x50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 10% EtOAC/ hexanes to obtain compound 2 (25 g, 51%) as liquid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.37-7.29 (m, 5H), 5.16-5.02 (m, 2H), 4.79 (s, 1H), 3.94-3.90 (dd, J = 16.0, 2.0 Hz, 1H), 3.67 (s, 3H), 3.01-2.80 (dt, 1H), 2.10-2.07 (m, 1H), 1.68-1.61 (m, 3H), 1.40-1.29 (m, 1H), 1.23-1.09 (m, 1H). LCMS (ESI): m/z 144.1 [(M ⁺ +1)-Boc] Synthesis of benzyl 1-oxo-2,5-diazaspiro[3.5]nonane-5-carboxylate (3): To a stirring solution of compound 2 (20 g, 72.2 mmol) in dry THF (100 mL) were added LiHMDS (1.0M in THF) (216 mL, 216.6 mmol) and paraformaldehyde (2.6 g, 86.6 mmol) at -78 °C under nitrogen atmosphere. The reaction mixture was brought to RT and stirred for 6 h. After consumption of the starting material (by TLC), the reaction was quenched with ice water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine solution (2 x 10 mL), dried over Na2SO4 and concentrated to obtain crude compound which was purified by column chromatography by eluting with 40% EtOAC/ hexanes to afford racemic compound 3 (6.5 g, 33%) as an off white solid. The racemic mixture (500 mg) was separated by chiral HPLC purification to give 165 mg of F-1 and 160 mg of F2. Compound 3-F1: ¹ H-NMR: (500 MHz, DMSO-d ₆ ):δ 7.87 (s, 1H), 7.37-7.31 (m, 5H), 5.10-5.07 (m, 2H), 3.80-3.77 (m, 1H), 3.28 (d, J = 4.5 Hz, 1H), 3.17 (d, J = 4.5 Hz, 1H), 3.09- 3.06 (m, 1H), 1.80-1.74 (m, 3H), 1.55-1.46 (m, 3H). LCMS (ESI): m/z 275.32 [M ⁺ +1]. Compound 3-F2: ¹ H-NMR: (500 MHz, DMSO-d6):δ 7.87 (s, 1H), 7.37-7.31 (m, 5H), 5.10-5.05 (m, 2H), 3.81-3.76 (m, 1H), 3.30 (d, J = 5.5 Hz, 1H), 3.17 (d, J = 4.5 Hz, 1H), 3.11- 3.06 (m, 1H), 1.80-1.74 (m, 3H), 1.56-1.44 (m, 3H). LCMS (ESI): m/z 275.32 [M ⁺ +1]. Synthesis of 2,5-diazaspiro[3.5]nonan-1-one (AN-1): To a stirring solution of compound 3 F-1(165 mg, 0.61 mmol) in ethyl acetate (15 mL) was added dry Pd/C (42 mg) at RT under N2 atmosphere. Then the reaction mixture was stirred for 30 minutes under H ₂ atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. Obtained crude was triturated with pentane and dried under vacuum to afford AN-1 (80 mg, 95%) as thick syrup. ¹ H-NMR: (500 MHz, DMSO-d6):δ 7.70 (s, 1H), 3.01 (d, J = 5.5 Hz, 1H), 2.95-2.89 (m, 2H), 2.61-2.53 (m, 1H), 1.73-1.61 (m, 2H), 1.58-1.53 (m, 1H), 1.46-1.35 (m, 3H). LCMS (ESI): m/z 141.19 [M ⁺ +1]. Synthesis of 2,5-diazaspiro[3.5]nonan-1-one (AN-2): To a stirring solution of compound 3-F2 (160 mg, 0.58 mmol) in ethyl acetate (20 mL) was added dry Pd/C (40 mg) at RT under N2 atmosphere. Then the reaction mixture was stirred for 30 minutes under H ₂ atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. Obtained crude was triturated with pentane and dried under vacuum to afford AN-1 (80 mg, 97%) as thick syrup. ¹ H-NMR: (500 MHz, DMSO-d6):δ 7.70 (s, 1H), 3.01 (d, J = 5.5 Hz, 1H), 2.95-2.86 (m, 2H), 2.61-2.53 (m, 1H), 1.71-1.61 (m, 2H), 1.57-1.53 (m, 1H), 1.47-1.37 (m, 3H). LCMS (ESI): m/z 466.55 [M ⁺ +1]. Synthesis of benzyl ((2S,3R)-3-(benzyloxy)-1-oxo-1-(1-oxo-2,5-diazaspiro[3.5]non an- 5-yl)butan-2-yl)carbamate (4): To a stirring solution of AN-1 and AN-2 (1.2 g, 8.57 mmol, racemic) and Int-C (3.52 g, 10.2 mmol) in DMF (20 mL) were added HATU (3.9 g, 10.2 mmol) and DIPEA (4.4 mL, 25.7 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 5 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH/ CH ₂ Cl ₂ (2x100 mL). Combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford compound racemic 4 (600 mg, 15%) as white solid. ¹ H-NMR: (500 MHz, DMSO-d ₆ ):δ 8.40- 8.34 (m, 1H), 7.35-7.24 (m, 10H), 5.11-5.01 (m, 2H), 4.58-4.45 (m, 2H), 3.95-3.80 (m, 3H), 3.67-3.61 (m, 1H), 3.44-3.16 (m, 1H), 2.64-2.62 (m, 1H), 2.35-2.25 (m, 1H), 1.59-1.35 (m, 4H), 1.33-1.04 (m, 5H). LCMS (ESI): m/z 466.55 [M ⁺ +1]. Synthesis of 5-(L-threonyl)-2,5-diazaspiro[3.5]nonan-1-one (AO-1 and AO-2): To a stirring solution of compound racemic 4 (600 mg, 1.29 mmol, racemic) in methanol (40 mL) was added 50% wet 10% Pd/C (600 mg) at RT and the reaction was stirred for 48 h under H2 atmosphere. After consumption of the starting material (by LCMS), the reaction mixture was filtered through a pad of celite and concentrated under reduced pressure. Obtained crude material was washed with pentane to afford racemic AO-1 and AO-2 (250 mg, 80%) as white solid. The racemic mixture was separated by chiral HPLC purification and obtained 20 mg each of AO-1 and AO-2. AO-1: ¹ H-NMR: (400 MHz, D2O):δ 4.19-4.13 (m, 1H), 4.05 (d, J = 2.8 Hz, 1H), 3.96 (d, J = 11.6 Hz, 1H), 3.89 (dd, J = 13.6, 4.4 Hz, 1H), 3.74 (d, J = 11.6 Hz, 1H), 3.59-3.52 (td, J = 13.2, 3.2 Hz, 1H), 2.47 (d, J = 12.0 Hz, 1H), 1.87-1.75 (m, 3H), 1.64-1.55 (m, 1H), 1.49-1.42 (m, 1H), 1.32 (d, J = 6.4 Hz, 3H). LCMS (ESI): m/z 242.39 [(M ⁺ 1)]. HPLC: 97.14%. AO-2: ¹ H-NMR: (400 MHz, D ₂ O):δ 4.14-4.09 (m, 1H), 4.04 (d, J = 2.8 Hz, 1H), 3.96 (d, J = 11.6 Hz, 1H), 3.89 (dd, J = 13.6, 4.4 Hz, 1H), 3.74 (d, J = 11.6 Hz, 1H), 3.57-3.49 (td, J = 13.2, 3.2 Hz, 1H), 2.49 (d, J = 13.2 Hz, 1H), 1.89-1.73 (m, 3H), 1.63-1.55 (m, 1H), 1.49-1.40 (m, 1H), 1.33 (d, J = 6.4 Hz, 3H). LCMS (ESI): m/z 242.39 [(M ⁺ 1)]. HPLC: 97.14%. Synthesis of Examples AP-1 and AP-2: Synthesis of tert-butyl 3-(((S)-1,3-bis(benzyloxy)-1-oxopropan-2-yl)carbamoyl)-3- (hydroxymethyl)piperidine-1-carboxylate (6): To a stirring solution of compound 5 (1 g, 3.86 mmol) in DMF (18 mL) were added Int D (1.24 g, 3.86 mmol), HATU (1.76g, 4.63 mmol) and DIPEA (2 mL, 11.58 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was brought to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2x10 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 40% EtOAc/ hexanes to obtain compound 6 ( 1.4 g, crude) as syrup. LCMS (m/z): 525.4 [M++1]. Synthesis of tert-butyl 2-((2S)-1,3-bis(benzyloxy)-1-oxopropan-2-yl)-1-oxo-2,6- diazaspiro[3.5]nonane-6-carboxylate (7): To a solution of TPP (0.84 g, 3.19 mmol) in THF (15 mL) was added DIAD (0.63 mL, 3.19 mmol) at RT under nitrogen atmosphere and the reaction mixture was stirred for 20 minutes. The reaction mixture was cooled to -10 ^o C, compound 6 (1.4 g, 2.66 mmol) in THF (10 mL) was added, then the reaction was warmed to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with 1N HCl and brine solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Obtained crude material was purified by silica gel column chromatography eluting with 20-40% EtOAc/ hexanes to afford compound 7 (1 g, crude) as thick syrup. LCMS (ESI): m/z: 453.5 [(M ⁺ +1)-tBu]. Synthesis of (2S)-2-(6-(tert-butoxycarbonyl)-1-oxo-2,6-diazaspiro[3.5]non an-2-yl)-3- hydroxypropanoic acid (8): To a stirring solution of compound 7 (1 g, 1.97 mmol) in methanol (15 mL) was added 50% wet 10% Pd/C (0.3 g) at RT and the reaction was stirred for 16 h under H2 atmosphere. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with EtOAc (50 mL). Obtained filtrate was concentrated under reduced pressure and co-distilled with DCM to afford compound 8 (0.7 g, crude) as sticky syrup. LCMS (m/z): 327.1 [M ⁺ -1]. Synthesis of tert-butyl 2-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-1-oxo-2,6- diazaspiro[3.5]nonane-6-carboxylate (AP-1 and AP-2): To a stirring solution of compound 8 (0.7 g, 2.13 mmol) in DMF (10 mL) were added HATU (0.97 g, 2.56 mmol), NH4Cl (137 mg, 2.56 mmol) and DIPEA (1.2 mL, 6.39 mmol) at 0 ^o C under nitrogen atmosphere. The reaction mixture was stirred at RT for 4 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with 5% MeOH/ CH2Cl2 (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Obtained crude material was purified by silica gel column chromatography eluting with 2-6% MeOH/ CH ₂ Cl ₂ to afford racemic AP-1 and AP-2 (140 mg) as off white solid. The racemic mixture was separated by SFC (chiral HPLC) purification. AP-1: ¹ H-NMR: (400 MHz, DMSO):δ 7.48 (s, 1H), 7.13 (s, 1H), 4.99-4.96 (t, 1H), 4.17- 4.14 (q, 1H), 3.83-3.80 (d, 1H), 3.69-3.56 (m, 3H), 3.22-3.15 (m, 3H), 2.96 (brs, 1H), 1.78-1.61 (m, 3H), 1.38 (s, 10H). LCMS (ESI): m/z 326.1 [M+-1]. ELSD: >99%. CHIRAL HPLC : 93.71%. AP-2: 1H-NMR: (400 MHz, DMSO):δ 7.45 (s, 1H), 7.13 (s, 1H), 5.00 (brs, 1H), 4.17- 4.14 (q, 1H), 3.77-3.55 (m, 4H), 3.23-3.20 (m, 2H), 3.02-2.96 (m, 1H), 2.96 (t, 1H), 1.82-1.63 (m, 3H), 1.38 (s, 10H). LCMS (ESI): m/z 326.1 [M+-1]. ELSD: 99.66%. CHIRAL HPLC : 99.71%. Synthesis of Examples AQ-1, AQ-2, AR-1, and AR-2: Synthesis of 2-oxopiperidine-4-carboxylic acid (1): To a stirred solution of 2-oxo-1, 2-dihydropyridine-4-carboxylic acid (SM) (15 g, 107.9 mmol) in methanol (250 mL) was added palladium hydroxide (6 g) under N2 atmosphere. The reaction mixture was stirred under H2 atmosphere (balloon pressure) at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. Obtained reside was triturated with ether and pentane and dried under vacuum to afford compound 1 (13 g, 85 %) as white solid. ¹ H-NMR: (400 MHz, DMSO-d6): δ 12.40 (s, 1H), 7.46 (s, 1H), 3.14-3.11 (m, 2H), 2.78- 2.71 (m, 1H), 2.32-2.20 (m, 2H), 1.98-1.92 (m, 1H), 1.73-1.64 (m, 1H). LCMS (m/z): 144.2 [M ⁺ +1]. Synthesis of methyl 2-oxopiperidine-4-carboxylate (2): To a stirred solution of compound 1 (13 g, 91.5 mmol) in methanol (150 mL) was added diazomethane in ether (20 g) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1h. After consumption of the starting material (by TLC), the reaction was concentrated under reduced pressure and the crude was triturated with ether and EtOAc to afford compound 2 (11 g, 77 %) as white solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.50 (s, 1H), 3.62 (s, 3H), 3.14-3.09 (m, 2H), 2.91-2.84 (m, 1H), 2.35-2.22 (m, 2H), 2.00-1.93 (m, 1H), 1.75-1.66 (m, 1H). LCMS (m/z): 158.2 [M ⁺ +1]. Synthesis of methyl 2-thioxopiperidine-4-carboxylate (3): To a stirred suspension of compound 2 (10 g, 63.6 mmol) in toluene (100 mL) was added Lawesson's reagent (12.8 g, 31.8 mmol) under nitrogen atmosphere. The reaction mixture was brought to reflux and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was brought to RT and the reaction was concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 20% EtOAC/ hexanes to obtain compound 3 (8 g, 73 %) as yellow solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 10.17 (s, 1H), 3.63 (s, 3H), 3.25-3.21 (m, 2H), 2.94-2.86 (m, 1H), 2.85-2.74 (m, 2H), 2.05-1.98 (m, 1H), 1.79-1.70 (m, 1H). LCMS (m/z): 174.4 [M ⁺ +1]. Synthesis of methyl 6-(methylthio)-2,3,4,5-tetrahydropyridine-4-carboxylate (4): To a stirring solution of compound 3 (7.5 g, 43.3 mmol) in acetone (200 mL) was added MeI (9.2 g, 65.02 mmol) at room temperature. The reaction mixture was stirred at RT for 5 h. After consumption of the starting material (by TLC), volatiles were concentrated under reduced pressure. Obtained crude was dissolved in ether and stirred for 15 minutes. The reaction mixture was washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford compound 4 (7.5 g, 92%) as colorless liquid. ¹ H-NMR: (400 MHz, DMSO-d6): δ 3.70-3.63 (m, 1H), 3.62 (s, 3H), 3.55-3.48 (m, 1H), 2.83-2.76 (m, 1H), 2.44-2.40 (m, 2H), 2.19 (s, 3H), 1.92-1.86 (m, 1H), 1.64-1.54 (m, 1H). LCMS: m/z 188.2 [(M ⁺ +1)]. Synthesis of 2-(4-methoxybenzyl)-6-(methylthio)-2,7-diazaspiro[3.5]non-6- en-1-one (AQ-1 and AQ-2): To a stirred solution of compound 4 (1.4 g, 7.4 mmol) in dry THF (15 mL) was added LiHMDS (1.0M in THF) (11.3 mL, 11.26 mmol) at -78 °C under nitrogen atmosphere. The reaction temperature was raised to 0 °C and stirred for 1 h. Then Int-B (1.3 g, 7.4 mmol) in THF (5 mL) was added to the reaction mixture dropwise at 0 °C. The reaction mixture was brought to RT and stirred for 2 h. After consumption of the starting material (by TLC), the reaction was quenched with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na2SO4 and concentrated to obtain crude compound which was purified by column chromatography by eluting 30% EtOAC/n-hexane to afford racemic AQ-1 and AQ-2 (600 mg, 27%) as a liquid. The racemic mixture was separated by chiral HPLC purification. AQ-1: ¹ H-NMR: (500 MHz, CD ₃ OD-d ₆ ):δ 7.18 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 4.33 (d, J = 15.0 Hz, 1H), 4.26 (d, J = 15.0 Hz, 1H), 3.90-3.84 (m, 1H), 3.78 (s, 3H), 3.66-3.60 (m, 1H), 3.09 (d, J = 6.0 Hz, 1H), 3.02 (d, J = 6.0 Hz, 1H), 2.63 (d, J = 17.5 Hz, 1H), 2.49 (d, J = 17.5 Hz, 1H), 2.26 (s, 3H), 1.92-1.88 (m, 1H), 1.81-1.77 (m, 1H). LCMS : m/z 305.3 [M ⁺ +1]. AQ-2: ¹ H-NMR: (500 MHz, CD3OD-d6):δ 7.18 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 4.33 (d, J = 15.0 Hz, 1H), 4.26 (d, J = 15.0 Hz, 1H), 3.90-3.84 (m, 1H), 3.78 (s, 3H), 3.66- 3.60 (m, 1H), 3.09 (d, J = 6.0 Hz, 1H), 3.02 (d, J = 6.0 Hz, 1H), 2.63 (d, J = 17.5 Hz, 1H), 2.49 (d, J = 17.5 Hz, 1H), 2.26 (s, 3H), 1.94-1.88 (m, 1H), 1.82-1.77 (m, 1H). LCMS : m/z 305.3 [M ⁺ +1]. Synthesis of 6-(methylthio)-2,7-diazaspiro[3.5]non-6-en-1-one (AR-1 and AR-2): To a solution of racemic AQ-1 and AQ-2 (2 g, 6.58 mmol) in ACN (45 mL) was added CAN (10.8 g, 19.74 mmol) in water (15 mL) at 0 °C and stirred for 3 h. After consumption of the starting material (by TLC), the reaction was diluted with EtOAc (10 mL) and saturated NaHCO ₃ solution. The organic layer was extracted with EtOAc (3 x 100 mL) from the aqueous emulsion layer and further washed with brine solution. Combined organic layer was dried over Na2SO4 and concentrated to obtain crude compound which was purified by column chromatography by eluting 2% MeOH/DCM to afford racemic AR-1 and AR-2 (250 mg, 21%) as an off white solid. The racemic mixture was separated by chiral HPLC purification and obtained 50 mg of AR-1 and 55 mg of AR-2. AR-1: ¹ H-NMR: (400 MHz, DMSO-d ₆ ):δ 7.82 (s, 1H), 3.82-3.75 (m, 1H), 3.63-3.56 (m, 1H), 3.05 (d, J = 5.6 Hz, 1H), 2.99 (d, J = 5.6 Hz, 1H), 2.50-2.47 (m, 2H), 2.21 (s, 3H), 1.78- 1.74 (m, 2H). LCMS (ESI): m/z 185.1.2 [M ⁺ +1]. UPLC: 99.96%. AR-2: ¹ H-NMR: (400 MHz, DMSO-d ₆ ):δ 7.82 (s, 1H), 3.82-3.75 (m, 1H), 3.63-3.56 (m, 1H), 3.05 (d, J = 5.6 Hz, 1H), 2.99 (d, J = 5.6 Hz, 1H), 2.50-2.47 (m, 2H), 2.21 (s, 3H), 1.78- 1.74 (m, 2H). LCMS (ESI): m/z 185.1.2 [M ⁺ +1]. UPLC: 99.56%. Intermediate preparation: Synthesis of 2-((4-(methoxymethyl) benzyl) amino) acetonitrile (Int-A): To a solution of (4-(methoxymethyl) phenyl) methanamine (15 g, 99.2 mmol) in DMF (150 mL) was added K2CO3 (22.6 g, 161.8 mmol) and 2-bromoacetonitrile (11.8 g, 99.2 mmol) at 0 °C and the reaction was stirred for 5 h under nitrogen atmosphere. After consumption of the starting material (by TLC), the reaction was quenched with water (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na2SO4 and concentrated to obtain crude compound which was purified by column chromatography by eluting with 40% EtOAC/ hexanes to afford Int-A (15 mg, 77%) as a liquid. ¹ H-NMR: (500 MHz, DMSO-d6-D2O exc): δ 7.20 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 3.84 (s, 3H), 3.70 (s, 2H), 3.64 (s, 2H), 3.48 (s, 2H). LCMS (m/z): 191 [M ⁺ +1].

Synthesis of Examples AS-1 and AS-2: Synthesis of ethyl piperidine-3-carboxylate hydrochloride (1): To a stirred solution of piperidine-3-carboxylic acid (SM1) (10 g, 77.5 mmol) in ethanol (120 mL) was added thionyl chloride (11.26 mL, 155 mmol) dropwise at 0 °C. The reaction mixture was brought to RT and then stirred under reflux for 16 h. After consumption of the starting material (by TLC), the reaction was brought to RT. The reaction was concentrated under vacuum, triturated with Et ₂ O and dried to afford compound 1 as hydrochloride salt (14 g, 94 %) as off white solid. 1H-NMR: (500 MHz, DMSO-d6): δ 9.20 (s, 1H), 4.12-4.09 (m, 2H), 3.32- 2.77 (m, 5H), 2.50-1.53 (m, 4H), 1.21-1.18 (t, 3H). LCMS (m/z): 158.1 [M++1]. Synthesis of 1-(tert-butyl) 3-ethyl piperidine-1,3-dicarboxylate (2): To a stirred suspension of compound 1 (14 g, 72.54 mmol) in CH2Cl2 (200 mL) were added Boc-anhydride (19 mL, 87 mmol) and Et ₃ N (30 mL, 217.6 mmol) at 0 °C and the reaction was stirred for 10 min. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (200 mL) and extracted with CH2Cl2 (2 x 200 mL). The combined organic layer was washed with brine solution (1 x 200 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with hexane to 20% EtOAc/ hexanes to obtain compound 2 (16 g, 86%) as light yellow liquid. 1H-NMR: (500 MHz, CDCl3): δ 4.15-3.90 (q, 4H), 2.83-2.77 (m, 2H), 2.44-2.40 (t, 1H), 2.05-2.02 (q, 1H), 1.72-1.68 (m, 3H), 1.38 (s, 9H), 1.33-1.24 (m, 3H). LCMS (m/z): 258.1 [M++1]. Synthesis of 1-(tert-butyl) 3-ethyl 3-((benzyloxy)methyl)piperidine-1,3-dicarboxylate (3): To a stirring solution of compound 2 (13 g, 50.5 mmol) in THF (100 mL) was added LiHMDS (101 mL, 101 mmol) at -78 °C under nitrogen atmosphere and the reaction was warmed to RT and stirred for 1 h. Again the reaction mixture was cooled to -78 °C and BOM- chloride (8.4 mL, 60.6 mmol) was added dropwise and the reaction was stirred at RT for another 2 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH4Cl solution (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with water (2 x 150 mL) followed by brine solution (2 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated to obtain crude compound which was purified by column chromatography by eluting with 25% EtOAC/ hexanes to afford compound 3 (18 g, crude) as light yellow syrup. LCMS (ESI): m/z 278.6 [(M+1)-Boc]. Synthesis of 3-((benzyloxy)methyl)-1-(tert-butoxycarbonyl)piperidine-3-ca rboxylic acid (4): To a stirring solution of compound 3 (18 g, 47.75 mmol) in MeOH: THF (40 mL, 1:1) was added NaOH solution (9.5 g in 40 mL H2O ) at RT. The reaction mixture was heated to reflux for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure and the crude was diluted with water (200 mL) and extracted with Et2O (2 x 100 mL). The separated aqueous layer was acidified using 6N HCl solution (pH~2) and extracted with EtOAc (2 x 250 mL). The combined organic layer was dried over Na2SO4 and concentrated to afford crude which was triturated with n-hexane to obtain compound 4 (11 g, crude as light yellow syrup. LCMS (ESI): m/z 348.4 [M+-1]. Synthesis of 1-(tert-butoxycarbonyl)-3-(hydroxymethyl)piperidine-3-carbox ylic acid (5): To a stirring solution of compound 4 (11 g, 31.48 mmol) in methanol (100 mL) was added 50% wet 10% Pd/C (3.3 g) at RT and the reaction was stirred for 16 h under H ₂ atmosphere. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with EtOAc (50 mL). Obtained filtrate was concentrated under reduced pressure to afford compound 5 (8 g, crude) as light yellow syrup. LCMS (ESI): m/z 257.9 [M+-1]. Synthesis of tert-butyl 3-(((2S,3R)-1,3-bis(benzyloxy)-1-oxobutan-2-yl)carbamoyl)-3- (hydroxymethyl)piperidine-1-carboxylate (6): To a stirring solution of compound 5 (4.8 g, 17.76 mmol) in DMF (40 mL) were added Int D (6.6 g, 19.54 mmol), HATU (8.1 g, 21.3 mmol) and DIPEA (9.5 mL, 53.28 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was brought to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2x10 mL). Separated organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 50% EtOAc/ hexanes to obtain compound 6 ( 6.2 g, crude) as syrup. LCMS (m/z): 541.6 [M ⁺ +1]. Synthesis of tert-butyl 2-((2S,3R)-1,3-bis(benzyloxy)-1-oxobutan-2-yl)-1-oxo-2,6- diazaspiro[3.5]nonane-6-carboxylate (7): To a solution of TPP (3.6 g, 13.55 mmol) in THF (50 mL) was added DIAD (2.7 mL, 13.55 mmol) at RT under nitrogen atmosphere and the reaction mixture was stirred for 20 minutes. The reaction mixture was cooled to -10 °C, compound 6 (6.1 g, 11.3 mmol) in THF (10 mL) was added, and the reaction was allowed to stir RT for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with 1N HCl and brine solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Obtained crude material was purified by silica gel column chromatography eluting with 20% to 40% EtOAc/hexane to afford compound 7 (7 g, crude) as thick syrup. LCMS (ESI): m/z 467.5 [(M ⁺ +1)-tBu]. Synthesis of benzyl (2S,3R)-3-(benzyloxy)-2-(1-oxo-2,6-diazaspiro[3.5]nonan-2- yl)butanoate (8): To a stirred solution of compound 7 (3.8 g, 7.27 mmol) in CH2Cl2 (40 mL) TFA (3.5 mL, 45.4 mmol) was added slowly at 0 °C. The reaction mixture was brought to RT and stirred for 2 h. After completion of starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude was washed with pentane to afford crude compound 8 TFA salt (3.8 g). This was taken to the next step without any further purification. LCMS (ESI): m/z 423.2 [M ⁺ +1]. Synthesis of benzyl (2S,3R)-3-(benzyloxy)-2-(6-isobutyryl-1-oxo-2,6-diazaspiro [3.5]nonan- 2-yl) butanoate (9): To a solution of crude compound 8 (3.8 g, 9.01 mmol) in DCM (35 mL) Et3N (3.8 mL, 27.1 mmol) was added at 0 °C and the reaction was stirred for 5 min. Then isobutyryl chloride (1.14 g, 10.8 mmol) was added at 0 °C. The reaction mixture was warmed to RT and stirred for 30 min. After completion of starting material (by TLC), the reaction mixture was quenched with water. Separated organic layer was washed with citric acid solution and brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Obtained crude material was purified by silica gel column chromatography eluting with 20-25% EtOAc/ hexanes to afford compound 9 (2 g, 45%) as a liquid. ¹ H-NMR: (400 MHz, D ₂ O):δ 7.40-7.18 (m, 10 H), 5.22-5.10 (m, 2H), 4.62-4.55 (m, 2H), 4.28-4.11 (m, 2H), 3.67-3.63 (m, 1H), 3.38-3.36 (m, 1H), 3.24-3.18 (m, 3H), 2.89-2.83 (m, 1H), 1.98-1.70 (m, 3H), 1.44-1.38 (m, 1H), 1.23-1.15 (m, 4H), 0.93 (d, J = 5.2 Hz, 6H). LCMS (ESI): m/z 493.2 [M ⁺ +1] Synthesis of (2S,3R)-3-hydroxy-2-(6-isobutyryl-1-oxo-2,6-diazaspiro[3.5]n onan-2- yl)butanoic acid (10): To a stirring solution of compound 9 (2 g, 4.07 mmol) in methanol (15 mL) was added 50% wet 10% Pd/C (1 g) at RT and the reaction was stirred for 16 h under H2 atmosphere (balloon pressure). After consumption of the starting material (by LCMS), the reaction mixture was filtered through a pad of celite and concentrated under reduced pressure. Obtained crude material was washed with pentane to afford compound 10 (1 g, 78%) as white solid. LCMS (ESI): m/z 313.26 [M+1]. Synthesis of (2S,3R)-3-hydroxy-2-(6-isobutyryl-1-oxo-2,6-diazaspiro[3.5]n onan-2- yl)butanamide (AS-1 and AS-2): To a stirring solution of compound 10 (1 g, 3.21 mmol) in CH2Cl2 (10 mL) were added ammonium chloride (260 mg, 4.81 mmol), HATU (1.4 g, 3.85 mmol) and DIPEA (1.8 mL, 6.42 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was brought to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with DCM (10 mL), water (10 mL) and extracted with EtOAc (2x10 mL). Aqueous layer was further washed with 10% MeOH/ CH2Cl2 (2x10 mL). Combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 5% MeOH/ CH2Cl2 to afford racemic AS-1 and AS-2 (250 mg, 25%) as white solid. The racemic mixture was separated by chiral HPLC purification and obtained 60 mg of AS-1 and 50 mg of AS-2. AS-1: ¹ H-NMR: (400 MHz, D2O):δ 4.31-4.25 (m, 2H), 4.14 (d, J = 13.2 Hz, 0.5H), 4.01 (d, J = 14.0 Hz, 0.5H), 3.87 (d, J = 14.0 Hz, 0.5H), 3.83-3.78 (m, 0.5H), 3.58 (d, J = 13.2 Hz, 0.5H), 3.54-3.45 (m, 2.5H), 3.15-3.03 (m, 2H), 2.15-1.66 (m, 4H), 1.32 (d, J = 6.0 Hz, 3H), 1.12 (d, J = 7.2 Hz, 6H). LCMS (ESI): m/z 312.38 [(M ⁺ 1)]. HPLC: 92.32%. AS-2: ¹ H-NMR: (400 MHz, D ₂ O):δ 4.31-4.26 (m, 2H), 4.09 (d, J = 13.6 Hz, 0.5H), 3.95 (d, J = 14.0 Hz, 0.5H), 3.90 (d, J = 14.0 Hz, 0.5H), 3.81-3.75 (m, 0.5H), 3.63-3.51 (m, 3H), 3.10-3.03 (m, 2H), 2.15-1.69 (m, 4H), 1.30 (d, J = 6.0 Hz, 3H), 1.12 (d, J = 7.2 Hz, 6H). LCMS (ESI): m/z 312.38 [(M ⁺ 1)]. HPLC: 95.53%.

Synthesis of Examples AT-1, AT-2, AT-3, and AT-4: Synthesis of ethyl piperidine-3-carboxylate hydrochloride (1): To a stirred solution of piperidine-3-carboxylic acid (SM1) (5 g, 38.7 mmol) in ethanol (50 mL) was added thionyl chloride (5.6 mL, 72.5 mmol) dropwise at 0 °C. Then temperature was raised to 80 °C and the reaction was stirred for 16 h. After consumption of the starting material (by TLC), the reaction was brought to RT and volatiles were concentrated under reduced pressure. Crude material was triturated twice with diethyl ether and dried under vacuum to afford crude compound 1.HCl salt (7.5 g) as white solid, which was taken to the next step without any further purification. ¹ H-NMR: (400 MHz, DMSO-d6): δ 9.40 (s, 1H), 9.25 (s, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.32.3.13 (m, 2H), 2.94-2.75 (m, 3H), 1.99-1.96 (m, 1H), 1.77-1.71 (m, 2H), 1.60-1.58 (1H), 1.16 (t, J = 7.2 Hz, 3H). LCMS (m/z): 158.0 [M ⁺ +1]. Synthesis of 1-(tert-butyl) 3-ethyl piperidine-1,3-dicarboxylate (2): To a stirring solution of crude compound 1.HCl salt (7.4 g, 38.3 mmol) in CH ₂ Cl ₂ (60 mL) was added Et3N (16.6 mL, 114.9 mmol) at 0 °C and the reaction was stirred for 10 min. Then Boc-anhydride (10.6 mL, 46.5 mmol) was added at 0 °C and the reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (50 mL) and extracted with CH ₂ Cl ₂ (3 x 30 mL). Combined organic layer was washed with brine solution (30 mL), dried over Na2SO4 and concentrated under reduced pressure to afford crude material which was purified by column chromatography by eluting with 20% EtOAc/ hexanes to obtain compound 2 (7.48 g, 74%) as syrup. ¹ H-NMR: (400 MHz, DMSO- d6): δ 4.06 (q, J = 7.2 Hz, 2H), 3.89.3.85 (m, 1H), 3.64.3.59 (m, 1H), 2.93-2.88 (m, 2H), 2.42.2.37 (m, 1H), 1.89-1.86 (m, 1H), 1.63-1.54 (m, 2H), 1.38 (s, 9H), 1.37-1.34 (m, 1H), 1.18 (t, J = 7.2 Hz, 3H). LCMS (ESI): m/z 202.0 [(M ⁺ +1)-Boc]. Synthesis of tert-butyl 2-(4-methoxybenzyl)-1-oxo-2,6-diazaspiro[3.5] nonane-6- carboxylate (3): To a stirring solution of compound 2 (9 g, 34.9 mmol) in THF (80 mL) was added LiHMDS (1.0 M in THF) (70 mL, 69.9 mmol) dropwise at -78 °C under nitrogen atmosphere and the reaction was stirred for 45 min. To this 2-((4-methoxybenzyl)amino)acetonitrile (Int-A) (7.4 g, 41.8 mmol) in THF (20 mL) was added dropwise at -78 °C. The reaction mixture was brought to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH4Cl solution (20 mL) and extracted with EtOAc (2 x 30 mL). The separated organic layer was washed with water (20 mL) and brine solution (20 mL). The separated organic layer was dried over Na2SO4 and concentrated to afford crude which was purified by column chromatography eluting with 10% EtOAc/ hexanes to afford compound 3 (6.5 g, 51%) as brown syrup. ¹ H-NMR: (500 MHz, DMSO-d6): δ 7.16 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 4.05-4.00 (m, 2H), 3.73 (s, 3H), 3.58-3.55 (m, 2H), 3.21 (br s, 1H), 2.95- 2.91 (m, 3H), 1.76-1.74 (m, 2H), 1.65-1.62 (m, 1H), 1.38 (s, 9H), 1.37-1.32 (m, 1H). LCMS (ESI): m/z 305.0 [(M ⁺ +1)-Boc]. Synthesis of 2-(4-methoxybenzyl)-2,6-diazaspiro[3.5]nonan-1-one (4): To a stirred solution of compound 3 (4 g, 11.1 mmol) in CH2Cl2 (30 mL) was added TFA (8.7 mL, 111.1 mmol) slowly at 0 °C and then the reaction was stirred RT for 3h. After completion of starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude material was triturated with Et2O/ pentane to afford crude compound 4 (4 g) as light yellow syrup, which was taken to the next step without any further purification. ¹ H-NMR: (400 MHz, DMSO-d6): δ 8.79 (s, 1H), 8.62 (s, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.31-4.23 (m, 2H), 3.74 (s, 3H), 3.40-3.35 (m, 1H), 3.23-3.21 (m, 1H), 3.18-3.10 (m, 2H), 3.01-2.98 (m, 1H), 2.96-2.88 (m, 1H), 1.85-1.74 (m, 3H), 1.68-1.58 (m, 1H). Synthesis of 3-(benzyloxy)-2-(2-(4-methoxybenzyl)-1-oxo-2,6-diazaspiro[3. 5]nonan-6- yl)propanenitrile (5): To a mixture of crude compound 4 (4.5 g, 12.03 mmol) and 2-(benzyloxy)acetaldehyde (Int-C) (1.8 g, 12.03 mmol) in methanol (50 mL) was added a catalytic amount of glacial AcOH (0.2 mL) and the reaction was stirred at RT for 45 minutes. The reaction mixture was cooled to 0 °C and TMSCN (1.9 mL, 13.2 mmol) was slowly added dropwise. The reaction mixture was again brought to RT and stirred for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude material was dissolved in water (20 mL) and extracted with EtOAc (2 x 30 mL). Combined organic layer was washed with aqueous NH ₄ Cl solution (20 mL), dried over Na ₂ SO ₄ and concentrated to afford crude material which was purified by column chromatography eluting with 40% EtOAc/ hexanes to afford compound 5 (3 g, 60%) as brown syrup. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.37-7.28 (m, 5H), 7.16 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.52 (s, 2H), 4.30-4.15 (m, 3H), 3.73 (s, 3H), 3.72-3.70 (m, 1H), 3.65-3.60 (m, 1H), 3.00-2.87 (m, 2H), 2.79-2.66 (m, 3H), 2.38-2.27 (m, 1H), 1.76-1.43 (m, 4H). LCMS (ESI): m/z 420.1 [M ⁺ +1]. Synthesis of 3-(benzyloxy)-2-(2-(4-methoxybenzyl)-1-oxo-2,6-diazaspiro[3. 5]nonan-6- yl)propanamide (6): To a solution of compound 5 (3 g, 7.15 mmol) in DMSO (20 mL) was added K2CO3 (2.96 g, 21.4 mmol) and the reaction was stirred at RT 10 minutes. Then H ₂ O ₂ (30 wt% in H ₂ O) (6.49 mL, 57.2 mmol) was added slowly and then the reaction was stirred at RT for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). Organic layer was washed with saturated brine solution (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 5% MeOH/ CH2Cl2 to obtain compound 6 ( 2.2 g, 70%) as thick syrup. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.41-7.25 (m, 6H), 7.11-7.16 (m, 3H), 6.92-6.90 (m,2H), 4.45 (s, 2H), 4.23 (s, 2H), 3.78-3.75 (m, 1H), 3.73 (s, 3H), 3.63-3.50 (m, 1H), 3.21-3.18 (m, 0.5H), 2.97-2.87 (m, 2H), 2.84-2.81 (m, 0.5H), 2.75-2.61 (m, 2H), 2.53-2.49 (m, 2H), 1.65-1.57 (m, 3H), 1.49-1.48 (m, 1H). LCMS (ESI): m/z 438.1 [M ⁺ +1]. Synthesis of 3-hydroxy-2-(2-(4-methoxybenzyl)-1-oxo-2,6-diazaspiro[3.5]no nan-6- yl)propanamide (AT-1, AT-2, AT-3, and AT-4): To solution of compound 5 (2 g, 4.57 mmol) in methanol (10 mL) was added 50% wet Pd/C (1 g). The reaction mixture was placed in a steel bomb under H2 atmosphere (200 psi) at RT for 24 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with methanol. Obtained filtrate was concentrated under reduced pressure to afford crude racemic AT-1, AT-2, AT-3, and AT-4 (1.1 g), which was purified by chiral preparative purification to separate four isomers. AT-1 and AT- 2: 60mg each as thick syrup and AT-3 and AT-4: 70 mg each as off white solid. AT-1: ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.32 (s, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.91 (d, J = 8.4 Hz, 2H), 4.44 (t, J = 5.2 Hz, 1H), 4.27-4.18 (m, 2H), 3.76-3.70 (m, 4H), 3.58-3.52 (m, 1H), 3.03 (t, J = 6.4 Hz, 1H), 2.98 (d, J = 6.0 Hz, 1H), 2.90 (d, J = 6.0 Hz, 1H), 2.73-2.66 (m, 3H), 2.42-2.37 (m, 1H), 1.66-1.63 (m, 1H), 1.60-1.57 (m, 2H), 1.47-1.45 (m, 1H). HPLC: 94.52%. Chiral HPLC: 97.11%. LCMS (ESI): m/z 348.4 [M ⁺ +1]. AT-2: ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.33 (s, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.92 (d, J = 8.4 Hz, 2H), 4.45 (t, J = 5.2 Hz, 1H), 4.27-4.18 (m, 2H), 3.76-3.71 (m, 4H), 3.58-3.53 (m, 1H), 3.03 (t, J = 6.4 Hz, 1H), 2.98 (d, J = 6.0 Hz, 1H), 2.90 (d, J = 6.0 Hz, 1H), 2.73-2.66 (m, 3H), 2.42-2.37 (m, 1H), 1.66-1.63 (m, 1H), 1.60-1.57 (m, 2H), 1.49-1.43 (m, 1H). HPLC: 98.34%. Chiral HPLC: 97.47%. LCMS (ESI): m/z 348.4 [M ⁺ +1]. AT-3: ¹ H-NMR: (400 MHz, DMSO-d6): δ 7.26 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.04 (s, 1H), 6.92 (d, J = 8.4 Hz, 2H), 4.44 (t, J = 5.6 Hz, 1H), 4.27-4.19 (m, 2H), 3.72 (s, 3H), 3.69-3.66 (m, 1H), 3.56-3.51 (m, 1H), 2.99-2.90 (m, 3H), 2.83-2.80 (m, 1H), 2.66-2.55 (m, 2H), 2.42-2.37 (m, 1H), 1.65-1.57 (m, 3H), 1.49-1.43 (m, 1H). HPLC: 98.05%. Chiral HPLC: 98.12%. LCMS (ESI): m/z 348.4 [M ⁺ +1]. AT-4: ¹ H-NMR: (400 MHz, DMSO-d6): δ 7.26 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.03 (s, 1H), 6.92 (d, J = 8.4 Hz, 2H), 4.44 (t, J = 5.6 Hz, 1H), 4.27-4.19 (m, 2H), 3.72 (s, 3H), 3.69-3.66 (m, 1H), 3.56-3.51 (m, 1H), 2.99-2.90 (m, 3H), 2.83-2.80 (m, 1H), 2.67-2.55 (m, 2H), 2.42-2.37 (m, 1H), 1.65-1.57 (m, 3H), 1.47-1.43 (m, 1H). HPLC: 98.06%. Chiral HPLC: 99.27%. LCMS (ESI): m/z 348.4 [M ⁺ +1]. Intermediate preparation: Synthesis of 2-((4-methoxybenzyl) amino) acetonitrile (A): To a stirring solution of (4-methoxyphenyl) methanamine (SM4) (35 g, 0.25 mol) in CH2Cl2 (350 mL) were added Et3N (52.3 mL, 0.38 mol) and bromoacetonitrile (21.2 mL, 0.30 mol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h. The reaction was diluted with CH2Cl2 (150 mL) and washed with brine. The separated organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by column chromatography using 30% EtOAc/Hexane as eluent to afford compound A (22 g, 49%). ¹ H-NMR: (500 MHz, CDCl3): δ 7.27 (d, 2H), 6.90 (d, 2H), 3.87 (s, 2H), 3.84 (s, 3H), 3.56 (s, 2H). Synthesis of ((2,2-diethoxyethoxy)methyl)benzene (B): To a stirring solution of phenylmethanol (SM2) (2 g, 18.49 mmol) in THF (30 mL) was added NaH (814 mg, 20.34 mmol) lot wise at 0 °C and the reaction was stirred for 1 h at RT. Then 2-bromo-1,1-diethoxyethane (SM3) (3 mL, 20.34 mmol) was added followed by tetrabutyl ammoniumiodide (6.83 g, 18.49 mmol) at RT and the reaction mixture was heated to 70 °C for 16 h. After completion of starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. Obtained crude material was purified by column chromatography eluting with 2% EtOAc/Hexane to afford compound B (2.5 g, 60%) as yellow liquid. ¹ H-NMR: (400 MHz, CDCl3): δ 7.34-7.26 (m, 5H), 4.66 (t, J = 5.2 Hz, 1H), 4.58 (s, 2H), 3.71-3.65 (m, 4H), 3.60-3.51 (m, 2H), 1.21 (t, J = 7.2 Hz, 6H). LCMS (ESI): m/z 225.3 [M ⁺ +1]. Synthesis of 2-(benzyloxy) acetaldehyde (C): To a stirring solution of compound B (1.9 g, 8.47 mmol) in THF (20 mL) was added 2 N H2SO4 (8 mL, 930 mmol) at RT and the reaction mixture was heated to 80 °C for 1 h. After consumption of the starting material (by TLC), THF was removed under vacuum. The obtained crude compound was diluted with water (100 mL) and extracted with CH2Cl2 (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford compound C (1.2 g, 94%) as yellow liquid. ¹ H-NMR: (500 MHz, CDCl3): δ 9.73 (s, 1H), 7.39-7.25 (m, 5H), 4.63 (s, 2H), 4.10 (s, 2H). LCMS (ESI): m/z 150.18 [M ⁺ +1]. Synthesis of Example AU: Synthesis of methyl piperidine-4-carboxylate hydrochloride (1): To a stirred suspension of piperidine-4-carboxylic acid (SM) (15 g, 116.2 mmol) in methanol (150 mL) was added thionyl chloride (27.4 mL, 383.7 mmol) dropwise at 0 °C; the reaction was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was concentrated under reduced pressure. Crude material was triturated twice with diethyl ether and dried under vacuum to afford crude compound 1.HCl salt (19.5 g, 95%) as off white solid. ¹ H-NMR: (500 MHz, DMSO-d ₆ ): δ 9.13 (s, 1H), 8.95 (s, 1H), 3.62 (s, 3H), 3.20.3.18 (m, 2H), 2.92-2.86 (m, 2H), 2.70-2.66 (m, 1H), 1.98-1.95 (m, 2H), 1.79-1.71 (m, 1H). LCMS (m/z): 158.0 [M ⁺ +1]. Synthesis of 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (2): To a stirring solution of compound 1.HCl salt (20 g, 111.7 mmol) in CH2Cl2 (200 mL) was added Et3N (38.8 mL, 279.3 mmol) at 0 °C and the reaction was stirred for 10 min. Then Boc-anhydride (38.4 mL, 167.5 mmol) was added at 0 °C and the reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (100 mL) and extracted with CH ₂ Cl ₂ (3 x 100 mL). Combined organic layer was washed 1N HCl solution and brine solution. Organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude material which was purified by column chromatography by eluting with 15% EtOAc/ hexanes to obtain compound 2 (24 g, 88%) as colorless syrup. ¹ H- NMR: (500 MHz, CDCl3): δ 4.01 (br s, 2H), 3.69 (s, 3H), 2.85.2.80 (m, 2H), 2.48-2.42 (m, 1H), 1.88-1.86 (m, 2H), 1.66-1.60 (m, 2H), 1.45 (s, 9H). LCMS (ESI): m/z 202.0 [(M ⁺ +1)-Boc]. Synthesis of 1-(tert-butyl) 4-methyl 4-((benzyloxy)methyl)piperidine-1,4-dicarboxylate (3): To a stirring solution of compound 2 (24 g, 98.7 mmol) in THF (250 mL) was added LiHMDS (38 mL, 197.3 mmol) at -10 °C under nitrogen atmosphere and the reaction was allowed to stir 30 minutes. Then BOM-chloride (16.4 mL, 118.5 mmol) was added dropwise at - 10 °C. The reaction mixture was brought to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH ₄ Cl solution (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with water and brine solution. Organic layer was dried over Na ₂ SO ₄ and concentrated to obtain crude compound which was purified by column chromatography by eluting with 20% EtOAC/ hexanes to afford compound 3 (25 g, 71%) as light yellow syrup. LCMS (ESI): m/z 348.4 [M ⁺ +1]. Synthesis of 4-((benzyloxy)methyl)-1-(tert-butoxycarbonyl)piperidine-4-ca rboxylic acid (4): To a stirring solution of compound 3 (25 g, 68.8 mmol) in MeOH: THF (160 mL, 1:1) was added NaOH solution (13.7 g in 80 mL H ₂ O ) at RT. The reaction mixture was heated to reflux for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure and the crude was diluted with water (200 mL) and extracted with Et ₂ O (2 x 100 mL). Separated aqueous layer was acidified using 3 N HCl solution (pH~2) and extracted with EtOAc (2 x 250 mL). The combined organic layer was dried over Na ₂ SO ₄ and concentrated to afford compound 4 (16 g, 66%) as off white solid. ¹ H-NMR: (500 MHz, DMSO-d ₆ ): δ 12.53 (s, 1H), 7.35-7.25 (m, 5H), 4.45 (s, 2H), 3.67-3.65 (m, 2H), 3.47-3.45 (m, 2H), 2.93 (br s, 2H), 1.92-1.89 (m, 2H), 1.38-1.35 (m, 11H). HPLC: 94.52%. Synthesis of 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carbox ylic acid (5): To a stirring solution of compound 4 (8 g, 22.9 mmol) in methanol (100 mL) was added 50% wet 10% Pd/C (2.6 g) at RT and the reaction was stirred for 16 h under H2 atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to afford compound 5 (4.5 g, 75%) as white solid. LCMS (ESI): m/z 427.5 [(M ⁺ +1)-Boc]. Synthesis of tert-butyl (S)-4-((1-amino-3-((tert-butyldimethylsilyl)oxy)-1-oxopropan -2- yl)carbamoyl)-4-(hydroxymethyl)piperidine-1-carboxylate (6): To a stirring solution of compound 5 (3 g, 11.5 mmol) in CH ₂ Cl ₂ (100 mL) were added DIPEA (6.4 mL, 34.7 mmol), HATU (6.6 g, 17.3 mmol) and Int D (2.52 g, 11.58 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was brought to RT and stirred for 12 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH/ CH ₂ Cl ₂ (2x100 mL). Separated organic layer was washed with citric acid, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 5% MeOH/ DCM to obtain compound 6 ( 3.5 g, 65%) as white solid. ¹ H-NMR: (400 MHz, D2O): δ 4.03- 3.97 (m, 3H), 3.93-3.86 (m, 1H), 3.80-3.60 (m, 2H), 3.49-3.33 (m, 2H), 3.27-3.15 (m, 1H), 3.01- 2.95 (m, 1H), 1.26-1.23 (m, 3H). LCMS (ESI): m/z 243.2 [M ⁺ +1]. HPLC: 95.62%. Synthesis of tert-butyl (S)-2-(1-amino-3-((tert-butyldimethylsilyl)oxy)-1-oxopropan- 2-yl)-1- oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate (7): To a stirring solution of triphenylphosphine (1.71 g, 6.53 mmol) in THF (6 mL) DIAD (1.32 g, 6.53 mmol) was added at 0 °C and the reaction was stirred for 15 minutes. Then, compound 6 (2 g, 4.35 mmol) in THF (4 mL) was added dropwise and the reaction mixture was stirred at RT for 3 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with 1N HCl solution (20 mL) and extracted with 10% MeOH/ CH ₂ Cl ₂ (2 x100 mL). Separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 5% MeOH/ CH2Cl2 to afford compound 7 (800 mg, 24%) as off white solid. ¹ H-NMR: (500 MHz, DMSO-d6): δ 9.24 (s, 1H), 5.93-4.75 (m, 2H), 4.16-3.91 (m, 2H), 3.78-3.70 (m, 2H), 3.91 (d, J = 7.0 Hz, 1H), 3.77 (d, J = 7.0 Hz, 2H), 3.44-3.34 (m, 4H), 2.01-1.91 (m, 2H), 1.85- 1.68 (m, 6H), 2.11-1.68 (m, 4H), 1.40 (s, 9H), 1.38-1.18 (m, 3H), 0.80 (s, 9H), -0.02 (s, 6H). Mass (ESI): m/z 467.6 [M ⁺ +1]. Synthesis of tert-butyl (S)-2-(1-amino-3-hydroxy-1-oxopropan-2-yl)-1-oxo-2,7- diazaspiro[3.5]nonane-7-carboxylate (AU): To a stirring solution of compound 7 (800 mg, 1.81 mmol) in THF (10 mL) was added TBAF (1M in THF) (0.6 mL, 2.17 mmol) at 0 °C and then the reaction was stirred at RT for 2 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with water (10 mL) and extracted with 10% MeOH/ CH2Cl2 (2 x 50 mL). Combined organic layer was dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 3% MeOH/ CH2Cl2 to obtain AU (300 mg, 51%) as white solid. ¹ H-NMR: (500 MHz, D2O): δ 4.48-4.46 (m, 1H), 4.03-3.95 (m, 2H), 3.87-3.85 (m, 2H), 3.55-3.52 (m, 2H), 3.25 (s, 2H), 1.91-1.88 (m, 4H), 1.49 (s, 9H). LCMS (ESI): m/z 353.3 [M ⁺ +1]. HPLC: 88.9%. Synthesis of Intermediates: Synthesis of ((benzyloxy)carbonyl)-L-serine (Int A): To a stirring solution of L-serine (50 g, 0.47 mol) in THF: H2O (750 mL, 1: 2) were added NaHCO ₃ (119 g, 1.42 mol) and Cbz-Cl (87 mL, 0.61 mol) at 0 °C. The reaction mixture was brought to RT and stirred for 20 h. After completion of starting material (by TLC), the reaction mixture was acidified with 2N HCl solution (pH to 2.0) and extracted with EtOAc (3 x 200 ml). Separated organic layer was washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material, which was triturated with diethylether to afford Int A (33 g, 30%) as white solid. ¹ H-NMR: (400 MHz, DMSO-d6): δ 7.37-7.30 (m, 5H), 7.20 (d, J = 8.4 Hz, 1H), 5.06 (s, 2H), 4.78 (d, J = 6.8 Hz, 1H), 4.09-4.05 (m, 2H), 3.64 (s, 3H), 1.09 (d, J = 6.0 Hz, 3H). LCMS m/z: 268.2 [M ⁺ +1]. Synthesis of N-((benzyloxy)carbonyl)-O-(tert-butyldimethylsilyl)-L-serine (Int B): To a stirring solution of Int A (10 g, 41.8 mmol) in CH2Cl2 (100 mL) were added Imidazole (8.5g, 125.5 mmol), DMAP (510 mg, 4.18 mmol) and TBDMS-Cl (15.4 mL, 83.6 mmol) at 0 °C. The reaction mixture was brought to RT for 18 h. After completion of starting material (by TLC), the reaction was diluted with water (100 ml) and extracted with CH2Cl2 (3 x 200 mL). Separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography eluting with 3% MeOH/ CH2Cl2 to afford Int B (12 g, 81%) as thick syrup. ¹ H-NMR: (500 MHz, DMSO-d6): δ 12.75 (s, 1H), 7.35-7.28 ( m, 5H), 5.06-5.01 (m, 2H), 4.14-4.10 (m, 1H), 3.82-3.79 (m, 2H), 0.83 (s, 9H), 0.01 (s, 6H). LCMS m/z: 382.2 [M ⁺ +1]. Synthesis of benzyl (S)-(1-amino-3-((tert-butyldimethylsilyl)oxy)-1-oxopropan-2- yl)carbamate (Int C): To a stirring solution of Int B (11 g, 31.1 mmol) in CH ₂ Cl ₂ (100 mL) were added DIPEA (17.2 mL, 93.4 mmol), HATU (14.2 g, 37.3 mmol) and NH4Cl (2 g, 37.3 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was brought to RT and stirred for 12 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (100 mL) and extracted with CH ₂ Cl ₂ (3 x 100 mL). Separated organic layer was washed with citric acid and brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 5% MeOH/ CH2Cl2 to obtain Int C (9 g, 82%) as thick syrup. ¹ H-NMR: (500 MHz, DMSO-d6): δ 7.38-7.29 ( m, 5H), 7.15-7.09 ( m, 2H), 5.05-4.96 (m, 2H), 4.08-4.04 (m, 1H), 3.77-3.66 (m, 2H), 0.83 (s, 9H), 0.01 (s, 6H). LCMS (ESI): m/z 243.2 [M ⁺ +1]. HPLC: 95.62% Synthesis of (S)-2-amino-3-((tert-butyldimethylsilyl)oxy)propanamide (Int D): To a stirring solution of Int C (9 g, 25.5 mmol) in methanol (50 mL) was added 50% wet 10% Pd/C (3 g) at RT and the reaction was stirred for 12 h under H ₂ atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to afford Int D (4.5 g, 80%) as thick syrup. ¹ H-NMR: (500 MHz, DMSO-d6): δ 7.27 (s, 1H), 7.00 (s, 1H), 3.61 (t, J = 2.0 Hz, 2H), 3.18-3.16 (m, 1H), 1.81 (br s, 2H), 0.85 (s, 9H), 0.03 (s, 6H). LCMS (ESI): m/z 427.5 [(M ⁺ +1)-Boc].

Synthesis of Examples AV and AW: Synthesis of methyl piperidine-4-carboxylate hydrochloride (1): To a stirred solution of piperidine-4-carboxylic acid (SM) (15 g, 116.2 mmol) in methanol (150 mL) was added thionyl chloride (27.4 mL, 383.7 mmol) dropwise at 0 °C; the reaction was then warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Crude material was triturated twice with diethyl ether and dried under vacuum to afford crude compound 1.HCl salt (19.5 g, 95%) as off white solid. ¹ H-NMR: (500 MHz, DMSO-d ₆ ): δ 9.13 (s, 1H), 8.95 (s, 1H), 3.62 (s, 3H), 3.20.3.18 (m, 2H), 2.92-2.86 (m, 2H), 2.70-2.66 (m, 1H), 1.98-1.95 (m, 2H), 1.79-1.71 (m, 1H). LCMS (m/z): 158.0 [M ⁺ +1]. Synthesis of 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (2): To a stirring solution of compound 1.HCl salt (20 g, 111.7 mmol) in CH2Cl2 (200 mL) was added Et ₃ N (38.8 mL, 279.3 mmol) at 0 °C and the reaction was stirred for 10 min. Then added Boc-anhydride (38.4 mL, 167.5 mmol) at 0 °C and the reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (100 mL) and extracted with CH ₂ Cl ₂ (3 x 100 mL). Combined organic layer was washed with 1N HCl solution and brine solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude material which was purified by column chromatography by eluting with 15% EtOAc/ hexanes to obtain compound 2 (24 g, 88%) as colorless syrup. ¹ H-NMR: (500 MHz, CDCl3): δ 4.01 (br s, 2H), 3.69 (s, 3H), 2.85.2.80 (m, 2H), 2.48-2.42 (m, 1H), 1.88-1.86 (m, 2H), 1.66-1.60 (m, 2H), 1.45 (s, 9H). LCMS (ESI): m/z 202.0 [(M ⁺ +1)-Boc]. Synthesis of tert-butyl 1-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate (AV): To a stirring solution of compound 2 (3 g, 12.3 mmol) in THF (20 mL) LiHMDS (1.0 M in THF) (37.0 mL, 37.0 mmol) was added dropwise at -78 °C under nitrogen atmosphere. Then paraformaldehyde (444 mg, 14.8 mmol) was added at -78 °C. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH ₄ Cl solution (20 mL) and extracted with EtOAc (2 x 30 mL). The separated organic layer was washed with water (20 mL) and brine solution (20 mL). The separated organic layer was dried over Na2SO4 and concentrated to afford crude which was purified by column chromatography eluting with 80% EtOAc/ hexanes to afford AV (500 g, 17%) as semi solid. ¹ H NMR (400MHz, DMSO-d6): δ 7.77 (br s, 1H), 3.61 (td, J = 13.3, 5.2 Hz, 2H), 3.19-3.11 (m, 2H), 3.03 (s, 2H), 1.68-1.62 (m, 4H), 1.39 (s, 9H). HPLC: 94.52%. Chiral HPLC: 97.11%. LCMS (ESI): m/z 348.4 [M ⁺ +1]. Synthesis of 7-(2,2,2-trifluoroacetyl)-2,7l4-diazaspiro[3.5]nonan-1-one (3): To a stirring solution of AV (1 g, 4.16 mmol) in CH ₂ Cl ₂ (20 mL) was added TFA (3.8 mL, 49.9 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 2 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure to obtain crude compound 3 (1 g, crude), which was taken to next step without any further purification. Synthesis of benzyl (S)-(3-hydroxy-1-oxo-1-(1-oxo-2,7-diazaspiro[3.5]nonan-7-yl) propan-2- yl)carbamate (4): To a stirring solution of compound 3 (1 g, 4.21 mmol) in CH ₂ Cl ₂ (10 mL) were added Int A (1.1 g, 4.64 mmol) HATU (1.92 g, 5.06 mmol) and DIPEA (2.2 mL, 12.6 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was portioned between CH ₂ Cl ₂ (50 mL) and water (50 mL). Separated organic layer was washed with 1 N HCl solution and brine solution. Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 5% MeOH/ CH2Cl2to obtain racemic compound 4 ( 420 mg, 28%) as an off white solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 8.22-8.13 (dd, 1H), 7.31-7.20 (m, 10H), 5.86-5.83 (m, 0.5H), 5.62-5.59 (m, 0.5H), 5.10 (s, 2H), 4.52-4.44 (m, 2H), 4.32-4.29 (m, 1H), 4.12-4.00 (m, 2H), 3.47-3.39 (m, 2H), 3.35-3.29 (m, 1H), 2.02-1.89 (m, 2H), 1.68-1.63 (m, 2H), 1.35-1.27 (s, 9H), 1.17 (d, J = 6.8 Hz, 3H). LCMS (ESI): m/z 427.5 [(M ⁺ +1)-Boc]. Synthesis of 7-(L-seryl)-2,7-diazaspiro[3.5]nonan-1-one (AW): To a stirring solution of compound 4 (180 mg, 0.49 mmol) in ethyl acetate (5 mL) was added 50% wet 10% Pd/C (60 mg) at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h under H2 atmosphere. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with 5% MeOH/ CH2Cl2. Obtained filtrate was concentrated under reduced pressure to afford AW (75 mg, 66%) as syrup. ¹ H-NMR: (400 MHz, D2O):δ 4.19-4.10 (m, 2H), 3.98-3.93 (m, 1H), 3.78- 3.72 (m, 2H), 3.56-3.48 (m, 1H), 3.38-3.26 (m, 3H), 2.04-1.86 (m, 4H). LCMS (ESI): m/z 243.2 [M ⁺ +1]. HPLC: 95.62% Synthesis of Example AX: Synthesis of methyl piperidine-4-carboxylate hydrochloride (1): To a stirred suspension of piperidine-4-carboxylic acid (SM1) (5 g, 38.7 mmol) in methanol (50 mL) was added thionyl chloride (9.4 mL, 127.7 mmol) dropwise at 0 °C. Then temperature was raised to RT and the reaction was stirred for 24 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Crude material was triturated twice with diethyl ether and dried under vacuum to afford crude compound 1.HCl salt (6.8 g, 86%) as white solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 9.23 (s, 1H), 9.07 (s, 1H), 3.62 (s, 3H), 3.20-3.16 (m, 2H), 2.90-2.85 (m, 2H), 2.71-2.68 (m, 1H), 1.99-1.94 (m, 2H), 1.79- 1.72 (m, 2H). LCMS (m/z): 144.1 [M ⁺ +1]. Synthesis of 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (2): To a stirring solution of crude compound 1.HCl salt (6 g, 33.5 mmol) in CH2Cl2 (50 mL) was added Et ₃ N (12.1 mL, 83.7 mmol) at 0 °C and the reaction was stirred for 10 min. Then Boc-anhydride (11.5 mL, 50.2 mmol) was added at 0 °C and the reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (50 mL) and extracted with CH2Cl2 (3 x 30 mL). Combined organic layer was washed with brine solution (30 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford crude material which was purified by column chromatography by eluting with 20% EtOAc/ hexanes to obtain compound 2 (7 g, 86%) as colorless syrup. LCMS (ESI): m/z 188.3 [(M ⁺ +1)-Boc]. Synthesis of tert-butyl 1-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate (AX): To a stirring solution of compound 2 (6.5 g, 26.7 mmol) in THF (65 mL) was added paraformaldehyde (962 mg, 32.1 mmol) at -78 °C under nitrogen atmosphere. Then, LiHMDS (1.0 M in THF) (80.2 mL, 80.1 mmol) was added dropwise at -78 °C. The reaction mixture was brought to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH ₄ Cl solution (20 mL) and extracted with EtOAc (2 x 30 mL). The separated organic layer was washed with water (20 mL) and brine solution (20 mL). The separated organic layer was dried over Na ₂ SO ₄ and concentrated to afford crude which was purified by column chromatography eluting with 50% EtOAc/ hexanes to afford AX (2.4 g, 37%) as semi solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 7.77 (br s, 1H), 3.61 (td, J = 13.3, 5.2 Hz, 2H), 3.19-3.11 (m, 2H), 3.03 (s, 2H), 1.68-1.62 (m, 4H), 1.39 (s, 9H). HPLC: 90.20%. LCMS (ESI): m/z 263.3 [Na ⁺ +1]. Synthesis of Examples AY and AZ: Synthesis of methyl piperidine-4-carboxylate hydrochloride (1): To a stirred suspension of piperidine-4-carboxylic acid (SM1) (5 g, 38.7 mmol) in methanol (50 mL) was added thionyl chloride (9.43 mL, 127.7 mmol) dropwise at 0 °C. The reaction mixture was brought to RT and stirred for 22 h. After consumption of the starting material (by TLC), the volatiles were evaporated under vacuum to afford compound 1 as hydrochloride salt (6 g, 86 %). ¹ H-NMR: (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 9.07 (s, 1H), 3.62 (s, 3H), 3.20-3.16 (m, 2H), 2.90-2.85 (m, 2H), 2.71-2.68 (m, 1H), 1.99-1.94 (m, 2H), 1.79- 1.72 (m, 2H). LCMS (m/z): 144.1 [M ⁺ +1]. Synthesis of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (2) : To a stirred suspension of compound 1 (5.0 g, 27.9 mmol) in CH ₂ Cl ₂ (40 mL) were added TEA (12.1 mL, 83.7 mmol) and Cbz-Cl (9.5 g, 55.8 mmol) at 0 °C. The reaction mixture was brought to RT and stirred for 16 h. After completion of starting material (by TLC), the reaction mass was diluted with CH2Cl2 (20 ml) and washed with saturated NaHCO3 solution (3 x 30 mL). Organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain crude which was purified by column chromatography eluting with 10% EtOAc/ hexanes to afford compound 2 (8 g, 83%) as colorless syrup. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.37-7.30 (m, 5H), 5.06 (s, 2H), 3.93-3.88 (m, 2H), 3.60 (s, 3H), 2.92 (br s, 2H), 2.60-2.52 (m, 1H), 1.84-1.81 (m, 2H), 1.48-1.38 (m, 2H). LCMS (ESI): m/z 278.3 [M ⁺ +1]. Synthesis of benzyl 2-(4-methoxybenzyl)-1-oxo-2,7-diazaspiro[3.5]nonane-7-carbox ylate (3): To a stirring solution of compound 2 (1 g, 3.61 mmol) in THF (10 mL) was added LiHMDS (7.2 mL, 7.22 mmol) dropwise at -10 °C and the reaction was stirred for 30 min. To this 2-((4-methoxybenzyl)amino)acetonitrile (Int-A) (762 mg, 4.33 mmol) was added dropwise and the reaction was stirred for 45 min at 0 °C. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH ₄ Cl solution (50 mL) and extracted with EtOAc (2 x 50 mL). The separated organic layer was washed with water (20 mL) and brine solution (20 mL). The separated organic layer was then dried over Na2SO4 and concentrated to afford crude which was purified by column chromatography eluting with 10% EtOAc/ hexanes to afford compound 3 (750 mg, 50%) as syrup. ¹ H-NMR: (400 MHz, DMSO-d6): δ 7.38-7.30 (m, 5H), 7.16 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.07 (s, 2H), 4.24 (s, 2H), 3.73 (s, 3H), 3.70-3.66 (m, 2H), 3.24 (s, 2H), 2.98 (s, 2H), 1.73-1.61 (m, 4H). LCMS (ESI): m/z 395.4 [M ⁺ +1]. Synthesis of benzyl 1-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate (4): To a stirring solution of compound 3 (600 mg, 1.52 mmol) in ACN: H2O (9 mL, 2:1) was added a solution of CAN in H ₂ O (2.5 g, 4.56 mmol) dropwise at 0 °C and the reaction was stirred for 1 h. After consumption of the starting material (by TLC), the reaction was diluted with water (10 mL) and EtOAc (10 mL). The separated organic layer was washed with saturated NaHCO3 solution (10 mL) and brine solution (10 mL). Organic layer was dried over Na2SO4 and concentrated to afford crude which was purified by column chromatography eluting with 10% EtOAc/ hexanes to afford compound 4 (170 mg, 41%) as a syrup. ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ 7.78 (s, 1H), 7.39-7.29 (m, 5H), 5.07 (s, 2H), 3.71-3.66 (m, 2H), 3.27-3.24 (m, 2H), 3.04 (s, 2H), 1.70-1.67 (m, 4H). LCMS (ESI): m/z 275.3 [M ⁺ +1]. Synthesis of 2,7-diazaspiro[3.5]nonan-1-one (AY): To a stirring solution of compound 4 (300 mg, 1.09 mmol) in EtOAc (10 mL) was added 50% wet Pd/C (200 mg) under N2 atmosphere. The reaction mixture was stirred under H2 atmosphere (balloon pressure) at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with methanol. Obtained filtrate was concentrated under reduced pressure to afford AY (120 mg, 78%) as syrup. ¹ H-NMR: (400 MHz, D ₂ O): δ 3.34 (s, 2H), 3.22-3.16 (m, 2H), 2.94-2.87 (m, 2H), 2.00-1.91 (m, 4H). LCMS (ESI): m/z 141.1 [M ⁺ +1]. Synthesis of benzyl ((2S,3R)-3-hydroxy-1-oxo-1-(1-oxo-2,7-diazaspiro[3.5]nonan-7 - yl)butan-2-yl)carbamate (5): To a stirring solution of AY (800 mg, 5.71 mmol) in CH ₂ Cl ₂ (20 mL) were added Int B (1.73 g, 6.85 mmol), HATU (2.6 g, 6.85 mmol) and DIPEA (3.15 mL, 17.13 mmol) at 0 °C and the reaction was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and CH2Cl2 (20 mL). The organic layer was washed with saturated brine solution (50 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 6% MeOH/ CH2Cl2 to obtain compound 5 ( 80 mg, 60%) as a white solid. ¹ H-NMR: (400 MHz, DMSO-d6): δ 7.79 (s,1H), 7.38-7.29 (m, 5H), 7.10-7.02 (m, 1H),5.03 (s, 2H), 4.74-4.70 (m, 1H), 4.44-4.41 (m, 1H), 3.90- 3.61 (m, 3H), 3.43-3.38 (m, 1H), 3.16-3.05 (m, 3H), 1.70-1.65 (m, 4H), 1.04 (d, J = 6.0 Hz, 3H). LCMS (ESI): m/z 376.4.1 [M ⁺ +1]. Synthesis of 7-(L-threonyl)-2,7-diazaspiro[3.5]nonan-1-one (AZ): To a stirring solution of compound 5 (500 mg, 1.33 mmol) in EtOAc (10 mL) was added 50% wet Pd/C (200 mg) under N2 atmosphere. The reaction mixture was stirred under H2 atmosphere (balloon pressure) at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with methanol. Obtained filtrate was concentrated under reduced pressure and triturated with Et ₂ O to afford AZ (200 mg, 62%) as white solid. ¹ H-NMR: (400 MHz, D2O): δ 4.15-4.02 (m, 1H), 4.00- 3.94 (m, 3H), 3.55-3.48 (m, 1H), 3.38-3.35 (m, 2H), 3.40-3.22 (m, 1H), 1.99-1.91 (m, 4H), 1.24 (d, J = 6.8 Hz, 3H). LCMS (ESI): m/z 242.2 [M ⁺ +1]. Preparation of Intermediates: Synthesis of 2-((4-methoxybenzyl) amino) acetonitrile (A): To a stirring solution of (4-methoxyphenyl) methanamine (SM2) (35 g, 0.25 mol) in DMF (350 mL) were added K2CO3 (52.3 g, 0.38 mol) and bromoacetonitrile (21.2 mL, 0.30 mol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at RT for 4 h. The reaction was diluted with EtOAc (150 mL) and washed with brine. The separated organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by column chromatography using 30% EtOAc/Hexane as eluent to afford compound A (22 g, 49%). ¹ H-NMR: (500 MHz, CDCl3): δ 7.27 (d, 2H), 6.90 (d, 2H), 3.87 (s, 2H), 3.84 (s, 3H), 3.56 (s, 2H). Synthesis of ((benzyloxy)carbonyl)-L-threonine (B): To a stirring solution of NaHCO3 (529 g, 6.30 mol) in water (1 L) was added L-threonine SM3 (250 g, 2.10 mol) at RT and the reaction was stirred for 30 min. The reaction mixture was cooled to 0 °C, Cbz-Cl (850 mL, 2.52 mol, 50% on PhCH3) was added dropwise and stirred for 1 h. The reaction mixture was warmed to RT and again stirred for 28 h. To this MTBE (1L) was added and stirred for 20 min. Separated aqueous layer in toluene was stirred for 20 min. Aqueous layer was acidified with 1N HCl (pH~1-2) and extracted with EtOAc (3x 1.5 L). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was stirred with dicyclohexylamine (819 mL, 4.20 mol) for 4 h to get white solid, filtered and dried. Obtained solid was refluxed with EtOAc (1.5 L) for 1h and then filtered. The solid material was dissolved in water (1 L) and acidified with dilute H ₂ SO ₄ and again stirred for 30 min. The aqueous layer was extracted with EtOAc (3x 1 L). The separated organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Obtained crude material was triturated with n-hexane to afford Int B (230 g, 43%) as white solid. ¹ H-NMR: (400 MHz, DMSO-d6): δ 12.55 (br m, 1H), 7.37-7.30 (m, 5H), 6.94 (d, J = 8.8 Hz, 1H), 5.05 (s, 2H), 4.08-3.94 (m, 2H), 1.02 (d, J = 6.4 Hz, 3H). UPLC (ELSD purity): 84.66%. Synthesis of Examples BA and BB: Synthesis of ethyl piperidine-3-carboxylate hydrochloride (1): To a stirred solution of piperidine-3-carboxylic acid (SM1) (10 g, 77.5 mmol) in ethanol (120 mL) was added thionyl chloride (11.26 mL, 155 mmol) dropwise at 0 °C. The reaction mixture was brought to RT and then stirred under reflux for 16 h. After consumption of the starting material (by TLC), the reaction was cooled to RT. Volatiles were concentrated under vacuum, triturated with Et ₂ O and dried to afford compound 1 as hydrochloride salt (14 g, 94 %) as off white solid. 1H-NMR: (500 MHz, DMSO-d6): δ 9.20 (s, 1H), 4.12-4.09 (m, 2H), 3.32- 2.77 (m, 5H), 2.50-1.53 (m, 4H), 1.21-1.18 (t, 3H). LCMS (m/z): 158.1 [M++1]. Synthesis of 1-(tert-butyl) 3-ethyl piperidine-1,3-dicarboxylate (2): To a stirred suspension of compound 1 (14 g, 72.54 mmol) in CH2Cl2 (200 mL) were added Boc-anhydride (19 mL, 87 mmol) and Et ₃ N (30 mL, 217.6 mmol) at 0 °C and the reaction was stirred for 10 min. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (200 mL) and extracted with CH2Cl2 (2 x 200 mL). The combined organic layer was washed with brine solution (1 x 200 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with hexanes to 20% EtOAc/ hexanes to obtain compound 2 (16 g, 86%) as light yellow liquid. 1H-NMR: (500 MHz, CDCl3): δ 4.15-3.90 (q, 4H), 2.83-2.77 (m, 2H), 2.44-2.40 (t, 1H), 2.05-2.02 (q, 1H), 1.72-1.68 (m, 3H), 1.38 (s, 9H), 1.33-1.24 (m, 3H). Synthesis of 1-(tert-butyl) 3-ethyl 3-((benzyloxy)methyl)piperidine-1,3-dicarboxylate (3): To a stirring solution of compound 2 (13 g, 50.5 mmol) in THF (100 mL) was added LiHMDS (101 mL, 101 mmol) at -78 °C under nitrogen atmosphere and the reaction was allowed to stir at RT for 1 h. Again the reaction mixture was cooled to -78 °C and BOM-chloride (8.4 mL, 60.6 mmol) was added dropwise and the reaction was stirred at RT for another 2 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH4Cl solution (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with water (2 x 150 mL) followed by brine solution (2 x 100 mL). The organic layer was dried over Na2SO4 and concentrated to obtain crude compound which was purified by column chromatography by eluting with 25% EtOAC/ hexanes to afford compound 3 (18 g, crude) as light yellow syrup. LCMS (ESI): m/z 278.6 [(M++1)-Boc]. Synthesis of 3-((benzyloxy)methyl)-1-(tert-butoxycarbonyl)piperidine-3-ca rboxylic acid (4): To a stirring solution of compound 3 (18 g, 47.75 mmol) in MeOH: THF (40 mL, 1:1) was added NaOH solution (9.5 g in 40 mL H ₂ O) at RT. The reaction mixture was heated to reflux for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure and the crude was diluted with water (200 mL) and extracted with Et ₂ O (2 x 100 mL). The separated aqueous layer was acidified using 6 N HCl solution (pH~2) and extracted with EtOAc (2 x 250 mL). The combined organic layer was dried over Na2SO4 and concentrated to afford crude which was triturated with n-hexane to obtain compound 4 (11 g, crude as light yellow syrup. LCMS (ESI): m/z 348.4 [M+-1]. Synthesis of 1-(tert-butoxycarbonyl)-3-(hydroxymethyl)piperidine-3-carbox ylic acid (5): To a stirring solution of compound 4 (11 g, 31.48 mmol) in methanol (100 mL) was added 50% wet 10% Pd/C (3.3 g) at RT and the reaction was stirred for 16 h under H2 atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with EtOAc (50 mL). Obtained filtrate was concentrated under reduced pressure to afford compound 5 (8 g, crude) as light yellow syrup. LCMS (ESI): m/z 257.9 [M+-1]. Synthesis of dibenzyl (1-(tert-butoxycarbonyl)-3-(hydroxymethyl)piperidine-3-carbo nyl)- L-glutamate(6): To a stirring solution of compound 5 (17 g, 65 mmol) in DMF (150 mL) were added Int- C (28.5 g, 79 mmol), HATU (30 g, 79 mmol) and DIPEA (25.4 g, 195 mmol) at 0 ^o C. The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. Ethyl acetate layer was separated, dried over Na2SO4 and filtered and concentrated. Obtained crude was purified by eluting with 15 % to 30 % ethyl acetate in hexanes. Relevant fractions were concentrated to afford compound 6 (18 g, 60 % by LCMS). LCMS (ESI): m/z 569.7 [M ⁺ +1]. Synthesis of dibenzyl (2S)-2-(6-(tert-butoxycarbonyl)-1-oxo-2,6-diazaspiro[3.5]non -2- yl)pentanedioate(7): To a stirring solution of compound 6 (5 g, 8.79 mmol) in THF (60 mL) was added DIAD (2.7 g, 13.18 mmol) and triphenyl phosphine (3.45 g, 13.18 mmol) at 0 ^o C; then the reaction was warmed to RT and stirred for 3 h. The reaction mixture was concentrated and crude was purified by eluting with 10-25 % EtOAc/ hexanes. Relevant fractions were concentrated to afford compound 7 (5 g, crude). LCMS (ESI): m/z 549.5 [M ⁺ -1]. Synthesis of (2S)-2-(6-(tert-butoxycarbonyl)-1-oxo-2,6-diazaspiro[3.5]non a-2- yl)pentanedioic acid (8): To a stirring solution of compound 7 (13 g, 23.64 mmol) in EtOAc (130 mL) was added 50% wet 10% Pd/C (2.5 g) at RT and the reaction was stirred for 16 h under H2 atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with EtOAc (100 mL). Obtained filtrate was concentrated under reduced pressure to afford compound 8 (12 g, crude) as light yellow syrup. LCMS (ESI): m/z 369.2 [M ⁺ -1]. Synthesis of tert-butyl 2-((S)-1,5-diamino-1,5-dioxopentan-2-yl)-1-oxo-2,6- diazaspiro[3.5]none-6-carboxylate (9) : To a stirred suspension of compound 8 (12 g, 32.4 mmol) in THF (100 mL) were added Boc-anhydride (20 mL, 87.5 mmol) and Pyridine (3.2 mL, 39.53 mmol) and (NH4)2CO3 (7.8 g, 81 mmol) at RT for 16 h. The reaction mixture was concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with hexanes- 8 % MeOH/ CH ₂ Cl ₂ to obtain compound 9 (4 g) as light yellow syrup. LCMS (ESI): m/z 369.3 [M ⁺ +1]. Synthesis of (2S)-2-(1-oxo-2,6-diazaspiro[3.5]nona-2-yl)pentanediamide TFA salt (10): To a stirring solution of compound 9 (5 g, 13.57 mmol) in DCM (50 mL) was added TFA (10.4 mL, 135 mmol) at 0 °C under nitrogen atmosphere and the reaction was allowed to stir at RT for 4h. After consumption of the starting material (by TLC), the reaction was concentrated to obtain crude which was triturated with diethyl ether (100 mL) and dried to afford compound 10 (5 g, crude) as colorless semi solid. LCMS (ESI): m/z 269.2 [(M ⁺ +1), free amine]. Synthesis of benzyl (2-(2-((S)-1,5-diamino-1,5-dioxopentan-2-yl)-1-oxo-2,6- diazaspiro[3.5]nona-6-yl)-2-oxoethyl)carbamate (11): To a stirring solution of compound 10 (5 g, 13.1 mmol) in CH2Cl2 (30 mL) and DMF (5 mL) were added Cbz-Gly-OH (2.74 g, 13.1 mmol), HATU (7.46 g, 19.65 mmol) and DIPEA (5 g, 39.3 mmol) at 0 ^o C. The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was then concentrated. Obtained crude was purified by eluting with CH ₂ Cl ₂ -5% MeOH/ CH2Cl2. The relevant fractions were concentrated and triturated with diethyl ether to afford compound 11 (3.9 g) as off white solid. LCMS (ESI): m/z 460.5 [M ⁺ +1]. Synthesis of (2S)-2-(6-glycyl-1-oxo-2,6-diazaspiro[3.5]non-2-yl)pentanedi amide: BA and BB: To a stirring solution of compound 11 (1 g, 2.17 mmol) in methanol (10 mL) was added 50% wet 10% Pd/C (0.5 g) at RT and the reaction was stirred for 16 h under H2 atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with MeOH (50 mL). Obtained filtrate was concentrated under reduced pressure to afford compound 5 (800 mg, crude), which was separated via chiral prep.HPLC to afford BA (240 mg) and BB (230 mg) as Hygroscopic white solid. BA: LCMS (ESI): m/z 326.3 [M ⁺ +1]. HPLC: 95.15%. CHIRAL: 96.23 %. ¹ HNMR (400 MHz, D2O): δ 4.40-4.29 (m, 1H), 3.94-3.87 (m, 1H), 3.81-3.73 (m, 1H), 3.71-3.66 (m, 2H), 3.63-3.50 (m, 1H), 3.48-3.42 (m, 1H), 3.41-3.31 (m, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.14 (q, J = 7.3 Hz, 2H), 2.08-1.92 (m, 2H), 1.91-1.77 (m, 1H), 1.76-1.61 (m, 1H). BB: LCMS (ESI): m/z 326.3 [M ⁺ +1]. HPLC: 98.20 %. CHIRAL : >99 %. 1 4.38 (m, 1H), 3.94-3.88 (m, 1H), 3.76-3.65 (m, 3H), 3.64-3.45 (m, 2H), 3.45-3.31 (m, 2H), 2.46-2.32 (m, 2H), 2.14 (q, J = 7.4 Hz, 2H), 2.09-1.93 (m, 2H), 1.92-1.79 (m, 1H), 1.76-1.62 (m, 1H). Intermediate synthesis: Synthesis of (tert-butoxycarbonyl)-L-glutamic acid (Int-A): To a stirring solution of L-glutamic acid (SM2) (5 g, 34.0 mmol) in DMF:H ₂ O (25 mL, 1.5:1) were added TEA (14.3 mL, 102.0 mmol) and Boc-anhydride (8.57 mL, 37.4 mmol) at 0 °C. The reaction mixture was stirred at RT for 1 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude material was diluted with EtOAc (100 mL) and washed with 1N HCl solution. Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford Int-A (7 g, 83%) as yellow syrup. ¹ (400MHz, CDCl ₃ ): δ 5.34-5.29 (m, 1H), 4.43-4.17 (m, 1H), 2.51 (td, J = 2.4, 7.1 Hz, 2H), 2.28-2.18 (m, 1H), 2.07-2.01 (m, 1H), 1.45 (s, 9H). LCMS (m/z): 246.0 [M ⁺ -1]. Synthesis of dibenzyl (tert-butoxycarbonyl)-L-glutamate (Int-B): To a stirring solution of Int-A (7 g, 28.3 mmol) in DMF (30 mL) were added K2CO3 (11.7 g, 85.0 mmol) and benzyl bromide (8.1 mL, 70.8 mmol) at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). Organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 20% EtOAc/ Hexane to obtain to afford Int-B (6.8 g, 56%) as brown syrup. ¹ H NMR (500MHz, CDCl3): δ 7.38-7.30 (m, 10H), 5.16 (s, 2H), 5.10 (s, 2H), 4.70 (br d, J = 4.0 Hz, 1H), 4.38 (br d, J = 4.6 Hz, 1H), 2.49-2.35 (m, 2H), 2.21 (br dd, J = 6.2, 12.9 Hz, 1H), 2.02-1.93 (m, 1H), 1.42 (s, 9H). Synthesis of dibenzyl (l2-chloranyl)-L-glutamate (Int-C): To a stirring solution of Int-B (5 g, 11.7 mmol) in in 1,4-dioxane (50 mL) was added 4M HCl in dioxane (4.39 mL) was added at 0 °C. The reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude material was triturated with pentane, ether and hexane and dried under vacuum to afford Int-C (6.9 g, 81%) as white solid. ¹ H NMR (500MHz, DMSO-d ₆ ): δ 8.65 (br s, 2H), 7.45-7.29 (m, 10H), 5.27-5.16 (m, 2H), 5.13-5.03 (m, 2H), 4.15-4.07 (m, 1H), 2.67-2.56 (m, 2H), 2.17-1.99 (m, 2H). LCMS (m/z): 328.2 [M ⁺ +1].

Synthesis of Examples BC and BD: Synthesis of methyl piperidine-4-carboxylate hydrochloride (1): To a stirred solution of piperidine-4-carboxylic acid (SM) (20 g, 0.155 mol) in methanol (200 mL) was added thionyl chloride (37.3 mL, 0.511 mol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was brought to RT and then stirred under reflux for 16 h. After consumption of the starting material (by TLC), the reaction was brought to RT. The reaction was concentrated under vacuum, triturated with pentane and Et ₂ O, and dried to afford crude compound 1 as hydrochloride salt (27 g) as white solid. LCMS (m/z): 180.2 [M ⁺ +1]. Synthesis of 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (2): To a stirred suspension of crude compound 1 salt (27 g, 0.151 mol) in CH ₂ Cl ₂ (270 mL) were added Et3N (53 mL, 0.377 mol) and Boc-anhydride (41.4 mL, 0.181 mol) slowly at 0 °C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (200 mL) and extracted with CH ₂ Cl ₂ (3 x 200 mL). Combined organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure. Obtained crude material was purified by column chromatography by eluting with 10% EtOAc/ hexanes to obtain crude compound 2 (36 g) as syrup. ¹ H NMR (400MHz, CDCl3): δ 4.04-3.99 (m, 2H), 3.69 (s, 3H), 2.83 (br t, J = 11.7 Hz, 2H), 2.49-2.41 (m, 1H), 1.90-1.84 (m, 2H), 1.68-1.63 (m, 1H), 1.61-1.57 (m, 1H), 1.46 (s, 9H). LCMS (m/z): 158.1 [M ⁺ -58]. Synthesis of 1-(tert-butyl) 4-methyl 4-((benzyloxy)methyl)piperidine-1,4-dicarboxylate (3): To a stirring solution of crude compound 2 (36 g, 0.148 mol) in THF (300 mL) was added LiHMDS (1M in THF) (296 mL, 0.296 mol) at -78 °C under nitrogen atmosphere and the reaction was allowed to stir at -50 °C for 2 h. Again the reaction mixture was cooled to -78 °C and BOM-chloride (24.8 mL, 0.177 mol) was added dropwise and stirred at -50 °C another 2 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH4Cl solution (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with water (2 x 100 mL) followed by brine solution (2 x 100 mL). The organic layer was dried over Na2SO4 and concentrated to obtain crude compound which was purified by column chromatography by eluting with 10% EtOAC/ hexanes to afford crude compound 3 (68 g) as syrup. LCMS (ESI): m/z 264.0 [M ⁺ +1-Boc]. Synthesis of 4-((benzyloxy)methyl)-1-(tert-butoxycarbonyl)piperidine-4-ca rboxylic acid (4): To a stirring solution of crude compound 3 (10 g, 0.027 mol) in MeOH: THF (60 mL, 1:1) was added NaOH solution (5.5 g in 60 mL H ₂ O) at RT. The reaction mixture was stirred at 70 °C for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure and the crude was washed with hexane, acidified using 4 N HCl solution (pH~2) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na ₂ SO ₄ and concentrated to afford crude which was triturated with n-hexane to obtain crude compound 4 (7 g) as syrup. ¹ H NMR (500 MHz, DMSO-d6): δ 12.35 (br s, 1H), 7.37-7.17 (m, 5H), 5.14-5.12 (m, 1H), 4.49-4.43 (m, 2H), 3.92-3.78 (m, 1H), 3.67-3.62 (m, 2H), 2.93-2.89 (m, 2H), 1.94-1.85 (m, 2H), 1.77-1.50 (m, 2H), 1.37 (s, 9H). LCMS (ESI): m/z 348.2 [M+-1]. Synthesis of 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carbox ylic acid (5): To a stirring solution of crude compound 4 (31 g, 0.088 mol) in methanol (300 mL) was added 50% wet 10% Pd/C (15 g) at RT and the reaction was stirred for 16 h under H ₂ atmosphere. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite, and washed with EtOAc (50 mL). Obtained filtrate was concentrated under reduced pressure. Crude material was triturated with hexane and EtOAc and dried under vacuum to afford compound 5 (12 g, 52%) as white solid. ¹ H NMR (400MHz, DMSO-d6): δ 12.30 (br s, 1H), 4.84 (br s, 1H), 3.73-3.68 (m, 2H), 3.41 (br s, 2H), 2.88-2.84 (m, 2H), 1.87-1.82 (m, 2H), 1.38 (s, 9H), 1.35-1.25 (m, 2H). LCMS (ESI): m/z 283.0 [M ⁺ +Na]. Synthesis of dibenzyl (1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carbo nyl)- L-glutamate (6): To a solution of compound 5 (11 g, 0.042 mol) in CH2Cl2 (100 mL) was added HATU (24 g, 0.063mol) at 0 °C under nitrogen atmosphere and then the reaction was stirred at room temperature for 10 minutes. Again the mixture was cooled to 0 °C, and Int-C (20 g, 0.055 mol) and DIPEA (22 mL, 0.127 mol) were added. The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3 x 200 mL). The combined organic layer was dried over Na ₂ SO ₄ and concentrated to afford compound 6 (14 g, 58%) as brown syrup. ¹ H NMR (400 MHz, DMSO-d6): δ 7.88 (d, J = 7.5 Hz, 1H), 7.41- 7.26 (m, 10H), 5.12-5.06 (m, 4H), 4.82 (t, J = 5.4 Hz, 1H), 4.41-4.36 (m, 1H), 3.93-3.87 (m, 1H), 3.66-3.60 (m, 2H), 3.42-3.32 (m, 1H), 2.84-2.78 (m, 2H), 2.47-2.39 (m, 2H), 2.18-2.04 (m, 1H), 1.96-1.88 (m, 2H), 1.76-1.53 (m, 1H), 1.38 (s, 9H), 1.36-1.21 (m, 2H). LCMS (ESI): m/z 567.5 [M ⁺ -1]. Synthesis of dibenzyl (S)-2-(7-(tert-butoxycarbonyl)-1-oxo-2,7-diazaspiro[3.5]nona n-2- yl)pentanedioate (7): To a stirring solution of TPP (28.7 g, 0.109 mol) in THF (200 mL) was added DIAD (21.4 mL, 0.109 mol) at 0 ^o C under nitrogen atmosphere. After formation of white precipitate, compound 6 (25 g, 0.043 mol) in THF (50 mL) was added at 0 ^o C. The reaction mixture was allowed to stir at RT for 4 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Crude material was dissolved in 40% Ether/ hexane and removed white precipitate through filtration. Obtained filtrate was concentrated under reduced pressure to afford compound 7 (18 g, 76%) as brown syrup. LCMS (ESI): m/z 549.6 [M ⁺ -1]. Synthesis of (S)-2-(7-(tert-butoxycarbonyl)-1-oxo-2,7-diazaspiro[3.5]nona n-2- yl)pentanedioic acid (8): To a stirring solution of compound 7 (21 g, 0.038 mol) in EtOAc (200 mL) was added 50% wet 10% Pd/C (10 g) at RT and the reaction was stirred for 16 h under H2 atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with EtOAc (100 mL). Obtained filtrate was concentrated under reduced pressure to afford crude compound 8 (17 g) as white solid. LCMS (ESI): m/z 369.1 [M ⁺ -1]. Synthesis of tert-butyl (S)-2-(1,5-diamino-1,5-dioxopentan-2-yl)-1-oxo-2,7- diazaspiro[3.5]nonane-7-carboxylate (9): To a stirred solution of crude compound 8 (17 g, 0.046 mol) in THF (170 mL) were added Boc-anhydride (27.6 mL, 0.124 mol), pyridine (4.5 mL, 0.056 mol) and (NH ₄ ) ₂ CO ₃ (11 g, 0.114 mol) at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 6-10% MeOH/ CH2Cl2 to afford compound 9 (8 g, 44%) as light yellow syrup. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.48 (s, 1H), 7.31 (s, 1H), 7.09 (s, 1H), 6.77 (s, 1H), 4.13-4.04 (m, 2H), 3.66-3.57 (m, 2H), 3.25 (d, J = 5.5 Hz, 1H), 3.21-3.13 (m, 2H), 2.12-2.02 (m, 2H), 1.94-1.77 (m, 2H), 1.70-1.62 (m, 4H), 1.40 (s, 9H). LCMS (ESI): m/z 367.7 [M ⁺ -1]. Synthesis of (S)-2-(1-oxo-2,7-diazaspiro[3.5]nonan-2-yl)pentanediamide (10): To a stirring solution of compound 9 (3 g, 8.14 mmol) in CH2Cl2 (30 mL) was added TFA (6.27 mL, 81.42 mmol) at 0 °C under nitrogen atmosphere and then the reaction was allowed to stir at RT for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude material was washed with Et ₂ O and dried under vacuum to afford compound 10 as TFA salt (1.95 g, 63%) as white solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.67-8.47 (m, 2H), 7.56-7.25 (m, 2H), 7.17-6.73 (m, 2H), 4.09 (dd, J = 9.5, 5.4 Hz, 1H), 3.33-3.19 (m, 4H), 3.09-3.05 (m, 2H), 2.13-1.79 (m, 8H). LCMS (ESI): m/z 269.3 [(M ⁺ +1), free amine]. Synthesis of benzyl (S)-(2-(2-(1,5-diamino-1,5-dioxopentan-2-yl)-1-oxo-2,7- diazaspiro[3.5]nonan-7-yl)-2-oxoethyl)carbamate (11): To a stirring solution of compound 10 (1.94 g, 5.07 mmol) in DMF (20 mL) were added Int-D (1.27 g, 6.09 mmol), HATU (4.82 g, 12.6 mmol) and DIPEA (3.5 mL, 20.3 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), material was directly purified by column chromatography by eluting with 10% MeOH/ DCM to afford compound 11, which was further stirred with the Et ₂ O/ CH2Cl2 for 2 h and dried under vacuum to obtain compound 11 (1.6 g, 65%) as white solid. ¹ H NMR (400MHz, DMSO-d6): δ 7.49 (s, 1H), 7.39-7.22 (m, 7H), 7.10 (s, 1H), 6.77 (br s, 1H), 5.03 (s, 2H), 4.08 (dd, J = 9.4, 5.3 Hz, 1H), 3.91-3.79 (m, 3H), 3.65-3.60 (m, 1H), 3.28-3.18 (m, 4H), 2.14-2.02 (m, 2H), 1.96-1.79 (m, 2H), 1.78-1.61 (m, 4H). LCMS (ESI): m/z 460.8 [M ⁺ +1]. Synthesis of (S)-2-(7-glycyl-1-oxo-2,7-diazaspiro[3.5]nonan-2-yl)pentaned iamide (BC and BD): To a stirring solution of compound 11 (1.6 g, 3.48 mmol) in methanol (100 mL) was added 50% wet 10% Pd/ C (0.8 g) at RT and the reaction was stirred for 16 h under H ₂ atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the pad was washed with MeOH (50 mL). Obtained filtrate was concentrated under reduced pressure. Crude material was triturated with Et ₂ O/ Pentane and dried under vacuum to afford 1.1 g of final compound as white solid, which was separated by chiral HPLC purification to obtain BC (135 mg, 12%) and BD (137 mg, 12%) as white solid. BC: ¹ H NMR (400 MHz, D ₂ O): δ 4.41-4.34 (m, 1H), 4.09-4.02 (m, 1H), 3.82-3.70 (m, 1H), 3.61 (d, J = 3.1 Hz, 2H), 3.52-3.47 (m, 2H), 3.42-3.27 (m, 2H), 2.43-2.38 (m, 2H), 2.19- 2.11 (m, 2H), 1.98-1.87 (m, 4H). LCMS (ESI): m/z 326.3 [M ⁺ +1]. HPLC: 94.13 %. Chiral HPLC: 100.00 %. SOR: +15.62 (c 1.0% in MeOH). BD: ¹ H NMR (400 MHz, D2O): δ 4.41-4.34 (m, 1H), 4.09-4.02 (m, 1H), 3.79-3.71 (m, 1H), 3.61 (d, J = 3.0 Hz, 2H), 3.52-3.46 (m, 2H), 3.43-3.26 (m, 2H), 2.44-2.36 (m, 2H), 2.20- 2.11 (m, 2H), 1.98-1.86 (m, 4H). LCMS (ESI): m/z 326.3 [M ⁺ +1]. HPLC: 95.25 %. Chiral HPLC: 99.09 %. SOR: -12.22 (c 1.0% in MeOH). Following the above procedures, the following compounds and stereoisomers thereof were or are prepared. It will be appreciated by a person of skill in the art that for the structures shown, additional stereoisomers such as diastereomers and/or enantiomers are within the compounds of the present disclosure.

1

-127- Synthesis of Example MM: Synthesis of 2-(4-methoxybenzyl)-7-oxa-2-azaspiro[3.5]nonan-1-one (MM): To a solution of tetrahydro-2H-pyran-4-carboxylic acid (SM) (1 g, 7.69 mmol) in CH2Cl2 (5 mL) were added oxalyl chloride (1.3 mL, 15.3 mmol) and catalytic amount of DMF (0.1 mL) at 0 °C under nitrogen atmosphere. Then temperature was raised to RT and stirred for 2 h. After consumption of the starting material (by TLC), volatiles were concentrated under reduced pressure. Obtained crude material was dissolved in CH2Cl2 (5 mL) and Et3N (5.2 mL, 38.4 mmol) was added slowly at -40 °C and stirred for 30 min. In another flask, a solution of Int-A (1.37 g, 3.07 mmol) in CH2Cl2 (5 mL) was added BF3.OEt2 (0.97 mL, 7.69 mmol) drop wise at RT and stirred for 15 minutes. Then, this mixture was added to crude material-Et ₃ N mixture at RT and stirred for 4 h. After consumption of the starting material (by TLC), the reaction was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). Combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude material which was purified by column chromatography by eluting with 40% EtOAc/ hexanes to obtain MM (400 mg, 20%) as thick syrup. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.17 (d, J = 8.7 Hz, 2H), 6.94-6.89 (m, 2H), 4.24 (s, 2H), 3.80-3.75 (m, 2H), 3.74 (s, 3H), 3.46-3.42 (m, 2H), 3.01 (s, 2H), 1.79-1.72 (m, 2H), 1.65-1.58 (m, 2H). LCMS (ESI): m/z 262.32 [M ⁺ +1]. HPLC: 99.39%. Chiral HPLC: 100.00%

Synthesis of Example MN: Synthesis of methyl 4-((benzyloxy)methyl)tetrahydro-2H-pyran-4-carboxylate (1): To a stirring solution of DIPEA (15.1 mL, 104.1 mmol) in THF (50 mL) was added n- BuLi (65 mL, 104.1 mmol) at -78 °C under nitrogen atmosphere and allowed to stir for 45 minutes. Then, methyl tetrahydro-2H-pyran-4-carboxylate (SM-1) (10 g, 69.4 mmol) was added at -78 °C and allowed to stir 15 minutes. Then, BOM-chloride (15 mL, 104.1 mmol) was added drop wise at -45 °C and allowed to stir for 2 h. After consumption of the starting material (by TLC), the reaction was diluted with water (100 mL) and extracted with ether (3 x 100 mL). The combined organic layer was washed with brine solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain crude compound which was purified by column chromatography by eluting with 30% EtOAc/ hexanes to afford compound 1 (18 g, 98%) thick syrup. ¹ H-NMR: (500 MHz, DMSO-d6): δ 7.34-7.26 (m, 5H), 4.44 (s, 2H), 3.70-3.66 (m, 2H), 3.63 (s, 3H), 3.46 (s, 2H), 3.36-3.31 (m,2H), 1.98-1.89 (m, 2H), 1.53-1.48 (m, 2H). Synthesis of 4-((benzyloxy)methyl)tetrahydro-2H-pyran-4-carboxylic acid (2): To a stirring solution of compound 1 (20 g, 75.7 mmol) in THF: MeOH (60 mL, 5:1) was added NaOH solution (6.1 g in 10 mL H2O ) at RT. The reaction mixture was heated to 80 °C and stirred for 3 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure and the crude was diluted with water (100 mL) and extracted with Et ₂ O (3 x 100 mL). Separated aqueous layer was acidified using citric acid solution and extracted with CH2Cl2 (2 x 100 mL). Combined organic layer was washed with brine solution, dried over Na ₂ SO ₄ and concentrated to afford compound 2 (14 g, 74%) as off white solid. ¹ H- NMR: (500 MHz, DMSO-d6): δ 12.52 (s, 1H), 7.35-7.26 (m, 5H), 4.46 (s, 2H), 3.70-3.66 (m, 2H), 3.46 (s, 2H), 3.40-3.35 (m, 2H), 1.90-1.87 (m, 2H), 1.50-1.45 (m, 2H). HPLC: 90.20%. Synthesis of 4-(hydroxymethyl)tetrahydro-2H-pyran-4-carboxylic acid (3): To a stirring solution of compound 2 (15 g, 60.0 mmol) in methanol (50 mL) was added 50% wet 10% Pd/C (7 g) at RT and stirred for 8 h under H ₂ atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to afford compound 3 (8 g, 83%) as off white solid. ¹ H-NMR: (500 MHz, DMSO-d6): δ 12.51 (s, 1H), 3.71-3.68 (m, 2H), 3.41- 3.31 (m, 5H), 1.84-1.81 (m, 2H), 1.44-1.35 (m, 2H). LCMS (ESI): m/z 427.5 [(M ⁺ +1)-Boc]. Synthesis of N-((2S,3R)-1-amino-3-((tert-butyldimethylsilyl)oxy)-1-oxobut an-2-yl)-4- (hydroxymethyl)tetrahydro-2H-pyran-4-carboxamide (4): To a stirring solution of compound 3 (2.4 g, 15.5 mmol) in CH ₂ Cl ₂ (15 mL) were added HATU (5.3 g, 14.1 mmol), Int A (3 g, 12.9 mmol) followed by DIPEA (6.6 mL, 37.9 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was brought to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with CH ₂ Cl ₂ (2 x 100 mL). Separated organic layer was washed with brine solution and citric acid, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 2% MeOH/ CH2Cl2 to obtain compound 4 ( 3.5 g, 72%) as off white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.27-7.14 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H), 5.46 (t, J = 5.1 Hz, 1H), 4.38-4.34 (m, 1H), 4.13 (dd, J = 8.8, 1.7 Hz, 1H), 3.75-3.61 (m, 2H), 3.49-3.40 (m, 4H), 1.92-1.81 (m, 2H), 1.58-152 (m, 1H), 1.36-1.32 (m,1H), 1.09 (d, J = 6.3 Hz, 3H), 0.84 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H). LCMS (ESI): m/z 243.2 [M ⁺ +1] HPLC: 98.58%. Synthesis of (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(1-oxo-7-oxa-2-az aspiro[3.5]nonan- 2-yl)butanamide (5): To a stirring solution of triphenylphosphine (1.3 g, 5.21 mmol) in THF (15 mL) was added and DIAD (1 g, 5.21 mmol) at 0 °C and stirred for 20 minutes. Then, compound 4 (1.5 g, 4.01 mmol) was added and the reaction mixture was stirred at RT for 2 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Crude material was washed with hexane: ether solvent mixture (2 x 25 mL, 9:1 ratio) to obtain solid material which was purified by column chromatography by eluting 5% MeOH/ CH2Cl2to afford compound 5 (1.3 g, 92%) as off white solid. ¹ H NMR (400 MHz, CHCl3): δ 6.34 (br s, 1H), 5.53 (br s, 1H), 4.43-4.39 (m, 1H), 4.24 (d, J = 3.7 Hz, 1H), 4.01-3.92 (m, 2H), 3.68-3.59 (m, 2H), 3.55 (d, J = 5.9 Hz, 1H), 3.42 (d, J = 6.0 Hz, 1H), 2.08-1.99 (m, 2H), 1.85-1.74 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H), 0.89 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H). Mass (ESI): m/z 467.6 [M ⁺ +1]. Synthesis of (2S,3R)-3-hydroxy-2-(1-oxo-7-oxa-2-azaspiro[3.5]nonan-2-yl)b utanamide (MN): To a stirring solution of compound 5 (1 g, 2.81 mmol) in THF (5 mL) were added CsF (423mg, 2.81) and TBAF (1M in THF) (0.27 mL, 0.27 mmol) at 0 °C; warmed to RT and stirred for 1 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude material was purified by column chromatography by eluting 2% MeOH/ CH2Cl2 to obtain MN (125 mg, 18%) as white solid. ¹ H NMR (400 MHz, CD3OD): δ 4.19-4.04 (m, 2H), 3.95-3.87 (m, 2H), 3.64-3.58 (m, 2H), 3.49-3.45 (m, 2H), 1.96-1.89 (m, 2H), 1.85-1.75 (m, 2H), 1.23 (d, J = 6.3 Hz, 3H). LCMS (ESI): m/z 353.3 [M ⁺ +1]. HPLC: 95.89%. Synthesis of (2S,3R)-2-amino-3-((tert-butyldimethylsilyl)oxy)butanamide (Int-A): To a stirring solution of (2S,3R)-2-amino-3-hydroxybutanamide (7 g, 0.593 mmol) in NMP (70 mL) was added and Et3N (12 g, 0.118 mmol) and TBS-Cl (13.34 g,0.0889 ) at 0 °C and stirred for 16 h. After consumption of the starting material (by TLC), reaction mixture was diluted with water and extracted with EtOAc, the volatiles were evaporated on reduced pressure to obtain the crude which was purified by column chromatography by eluting with 30% EtOAc/ hexanes to afford compound Int-A (5.9 g, 42.8%) as off white solid. Mass (ESI): m/z 234.2 [M ⁺ +1]. Following the above procedures, the following compounds and stereoisomers thereof were or are prepared. It will be appreciated by a person of skill in the art that for the structures shown, additional stereoisomers such as diastereomers and/or enantiomers are within the compounds of the present disclosure. Table 2. Synthesis of ZCK, ZCL, ZCM, ZCN, ZCO, ZCP, ZCQ, ZCR Synthesis of methyl-2-(benzylideneamino)acetate (1): To a mixture of benzaldehyde (SM1) (28 g, 0.264 mol) and methyl glycinate hydrochloride (SM2) (33 g, 0.264 mol) in DCM (560 mL) were added Et ₃ N (60 mL, 0.396 mol) and MgSO4 (8 g, 0.066 mol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature and for 16 h. After consumption of the starting material (by TLC), volume of reaction mixture was reduced to half and added hexane (200 mL). Organic layer was washed with aqueous NaHCO ₃ and brine. Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 1 (40 g, 85%) as a light yellow syrup. 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.80 - 7.76 (m, 2H), 7.47 - 7.40 (m, 3H), 4.42 (d, J = 1.2 Hz, 2H), 3.78 (s, 3H). Synthesis of methyl 4-cyano-4-methyl-5-phenylpyrrolidine-2-carboxylate (2-exo & 2-endo): To a mixture of compound 1 (12 g, .067 mol) Int-A (6.81 g, 0.101 mol) in THF (180 mL) were added P(Cy)3 (2.06 g, 0.007 mol), Cu(ACN)4BF4 (1.05 g, 0.003 mol) and Et3N (5.6 mL, 0.04 mol) at room temperature under nitrogen atmosphere. Reaction mixture was de-gassed for 15 minutes and allowed to stir at room temperature for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude was purified by column chromatography eluting 20% EtOAc/ n-hexane to afford compound 2-exo (13 g) and compound 2-endo (2.2 g) as a white solid. 2-exo: ¹ H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.5 Hz, 2H), 7.43 - 7.32 (m, 3H), 4.60 (s, 1H), 4.11 (dd, J = 6.4, 9.9 Hz, 1H), 3.82 (s, 3H), 2.78 (dd, J = 9.9, 13.3 Hz, 1H), 2.26 (dd, J = 6.1, 13.6 Hz, 1H), 1.00 (s, 3H). LCMS (ESI): m/z 245.0 [M ⁺ +1]. 2-endo: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.54 (d, J = 7.0 Hz, 2H), 7.46 - 7.36 (m, 3H), 4.12 - 3.91 (m, 2H), 3.86 (s, 3H), 2.86 (br dd, J = 3.5, 13.3 Hz, 1H), 2.32 (dd, J = 9.6, 13.6 Hz, 1H), 1.45 (s, 3H). LCMS (ESI): m/z 245.0 [M ⁺ +1]. Synthesis of 1-(tert-butyl) 2-methyl 4-cyano-4-methyl-5-phenylpyrrolidine-1,2- dicarboxylate (3-exo): To a solution of 2-exo (13 g, 0.053 mol) in CH ₂ Cl ₂ (150 mL) were added Et ₃ N (14.8 mL, 0.106 mol) at 0 °C and stirred for 5 min. Boc2O (14.6 mL, 0.063 mol) was added drop wise to the reaction mixture and stirred at room temperature for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. The crude was purified by column chromatography eluting 20% EtOAc/n-hexane to afford 3-exo (15 g, 81%) as a colourless gummy liquid. ¹ H NMR (500 MHz, CDCl3) δ 7.57 (br d, J = 7.5 Hz, 2H), 7.41 - 7.29 (m, 3H), 5.27 - 5.07 (m, 1H), 4.66 - 4.57 (m, 1H), 3.85 (s, 3H), 2.58 (br s, 1H), 2.16 (br d, J = 11.0 Hz, 1H), 1.40 (br s, 4.5H), 1.18 (br s, 4.5H), 1.00 (s, 3H). LCMS (ESI): m/z 285.9 [(M ⁺ +1- Boc)+ACN]. Synthesis of tert-butyl 7-cyano-2-(4-methoxybenzyl)-7-methyl-1-oxo-6-phenyl-2,5- diazaspiro[3.4]octane-5-carboxylate (ZCK, ZCL, ZCM, ZCN): To a solution of compound 3-exo (6 g, 0.017 mol) in THF (60 mL) was added LiHMDS (1M solution in THF, 43.5 mL, 0.043 mol) at -78 °C under nitrogen atmosphere. Reaction mixture was warmed to -40 °C and stirred for 20 minutes. Again cooled to at -78 °C and Int-B (4.5 g, 0.026 mol) in THF (15 mL) was added drop wise. Reaction mixture was brought to room temperature and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 200 mL). Organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography by eluting 20% EtOAc/n-hexane to afford mixture of compounds ZCK & ZCL (3.5 g) as an off white solid and mixture of compounds ZCM & ZCN (2.7 g) as a yellow syrup. Mixture of ZCK & ZCL (900 mg) was purified by reverse phase HPLC followed by chiral preparative HPLC to separate isomers ZCK (210 mg) and ZCL (210 mg). Mixture of ZCM & ZCN (500 mg) was purified by chiral preparative HPLC to separate isomers ZCM (100 mg) and ZCN (100 mg). ZCK: ¹ H NMR (400 MHz, DMSO-d ⁶ ): δ 7.56 - 7.47 (m, 2H), 7.42 - 7.21 (m, 5H), 6.96 - 6.90 (m, 2H), 5.15 (d, J = 16.6 Hz, 1H), 4.65 (d, J = 14.9 Hz, 0.5H), 4.47 - 4.41 (m, 0.5H), 4.35 - 4.29 (m, 0.5H), 4.07 (d, J = 14.9 Hz, 0.5H), 3.75 (s, 3H), 3.73 - 3.65 (m, 1H), 3.46 (dd, J = 5.0, 15.4 Hz, 1H), 2.71 - 2.60 (m, 1H), 2.28 (br dd, J = 9.0, 13.6 Hz, 1H), 1.34 (s, 4.5H), 1.08 (s, 4.5H), 0.94 (d, J = 10.9 Hz, 3H). LCMS (ESI): m/z 484.3 [M ⁺ +Na]. HPLC: 99.73%. Chiral HPLC: 100.00%; Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-Hexane; Mobile Phase B: DCM:MeOH (80:20); A:B :: 90:10; Flow rate: 1.0 mL/min; Retention time: 7.775. ZCL: ¹ H NMR (400 MHz, DMSO-d6): δ 7.55 - 7.47 (m, 2H), 7.43 - 7.21 (m, 5H), 6.97 - 6.90 (m, 2H), 5.15 (d, J = 16.6 Hz, 1H), 4.65 (d, J = 14.9 Hz, 0.5H), 4.46-4.41 (m, 0.5H), 4.35 - 4.28 (m, 0.5H), 4.07 (d, J = 14.8 Hz, 0.5H), 3.75 (s, 3H), 3.73 - 3.65 (m, 1H), 3.46 (dd, J = 5.0, 15.4 Hz, 1H), 2.70 - 2.60 (m, 1H), 2.35 - 2.24 (m, 1H), 1.34 (s, 4.5H), 1.08 (s, 4.5H), 0.94 (d, J = 11.0 Hz, 3H). LCMS (ESI): m/z 484.2 [M ⁺ +Na]. HPLC: 99.85%. Chiral HPLC: 100.00%. Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-Hexane; Mobile Phase B: DCM:MeOH (80:20); A:B :: 90:10; Flow rate: 1.0 mL/min; Retention time: 10.314. ZCM: ¹ H NMR (400 MHz, DMSO-d6): δ 7.41 - 7.21 (m, 5H), 7.16 (br d, J = 6.8 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 5.27 - 5.14 (m, 1H), 4.62 (br s, 0.5H), 4.46 - 4.26 (m, 1H), 4.03 (br d, J = 14.2 Hz, 0.5H), 3.81 - 3.72 (m, 4H), 3.46 - 3.37 (m, 1H), 2.77 (br d, J = 13.6 Hz, 1H), 2.56-2.51 (m, 1H), 1.35 (br s, 4.5H), 1.07 (br s, 4.5H), 0.91 (br d, J = 10.0 Hz, 3H). LCMS (ESI): m/z 462.3 [M ⁺ +1]. HPLC: 97.76%. Chiral HPLC: 100.00%; Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-Hexane; Mobile Phase B: DCM:MeOH (90:10); A:B :: 90:10; Flow rate: 1.0 mL/min; Retention time: 16.080. ZCN: ¹ H NMR (400 MHz, DMSO-d6): δ 7.40 - 7.21 (m, 5H), 7.16 (br d, J = 6.8 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 5.27 - 5.14 (m, 1H), 4.62 (br s, 0.5H), 4.45 - 4.27 (m, 1H), 4.03 (br d, J = 14.1 Hz, 0.5H), 3.77-3.71 (m, 4H), 3.45 - 3.37 (m, 1H), 2.78 (br d, J = 13.7 Hz, 1H), 2.57- 2.52 (m, 1H), 1.35 (br s, 4.5H), 1.07 (br s, 4.5H), 0.91 (br d, J = 10.3 Hz, 3H). LCMS (ESI): m/z 462.3 [M ⁺ +1]. HPLC: 99.35%. Chiral HPLC: 100.00%. Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-Hexane; Mobile Phase B: DCM:MeOH (90:10); A:B :: 90:10; Flow rate: 1.0 mL/min; Retention time: 18.498. Synthesis of 1-(tert-butyl) 2-methyl 4-cyano-4-methyl-5-phenylpyrrolidine-1,2- dicarboxylate (3-endo): To a solution of 2-endo (3.5 g, 14.3 mmol) in DCM (50 mL) were added Et ₃ N (4 mL, 28.6 mmol) at room temperature and stirred for 5 min. Boc2O (4 mL, 17.1 mmol) was added drop wise to the reaction mixture and stirred at room temperature for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude was purified by silica gel column chromatography eluting 20% EtOAc/n-hexane to afford 3-endo (4.5 g, 91%) as a pale yellow syrup. ¹ H NMR (400 MHz, DMSO-d6) δ 7.62 (br d, J = 6.3 Hz, 2H), 7.43 - 7.28 (m, 3H), 4.81 - 4.50 (m, 2H), 3.76 (s, 3H), 2.55 (br s, 2H), 1.54 (s, 3H), 1.44 - 0.90 (m, 9H) LCMS (ESI): m/z 245.0 [(M ⁺ +1-Boc)]. Synthesis of tert-butyl 7-cyano-2-(4-methoxybenzyl)-7-methyl-1-oxo-6-phenyl-2,5- diazaspiro[3.4]octane-5-carboxylate (ZCO to ZCR): To a solution of 3-endo (4.2 g, 12.1 mmol) in THF (50 mL) was added LiHMDS (1M in THF) (30.5 mL, 30.5 mmol) at -78 °C under nitrogen atmosphere. Reaction mixture was warmed to -40 °C and stirred for 30 minutes. Again cooled to at -78 °C and Int-B (2.1 g, 12.2 mmol) in THF (10 mL) was added drop wise. Reaction mixture was brought to room temperature and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 200 mL). Organic layer was dried over Na2SO4 and concentrated to obtain crude was purified by column chromatography by eluting 20% EtOAc/n-hexane to afford mixture of ZCO & ZCP (3.5 g) and mixture of ZCQ & ZCR (300 mg) as a yellow syrup. Mixture of ZCO & ZCP (1 g) was purified by chiral preparative HPLC to afford ZCO (177 mg) as an off-white solid and ZCP (205 mg) as a white solid. Mixture of ZCQ & ZCR (1 g) was purified by chiral preparative HPLC to afford ZCQ (200 mg) as an off-white solid and ZCR (156 mg) as an off-white solid. ZCO: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.55 (s, 2H), 7.43 - 7.19 (m, 5H), 6.93 (dd, J = 3.5, 8.3 Hz, 2H), 4.91 - 4.79 (m, 1H), 4.65 (d, J = 14.9 Hz, 0.5H), 4.45 - 4.28 (m, 1H), 4.05 (d, J = 15.0 Hz, 0.5H), 3.75 (s, 3H), 3.67 (dd, J = 4.8, 12.9 Hz, 1H), 3.45 - 3.35 (m, 1H), 2.69 - 2.58 (m, 1H), 2.55 (br s, 1H), 1.58 (s, 3H), 1.33 (s, 4.5H), 1.06 (s, 4.5H). LCMS (ESI): m/z 406.1 [M ⁺ -56]. HPLC: 99.83%. Chiral HPLC: 99.28%; Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:MeOH (80:20); A:B :: 90:10; Flow rate: 1.0 mL/min. Retention time: 7.802. ZCP: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.55 (s, 2H), 7.44 - 7.19 (m, 5H), 6.93 (dd, J = 3.5, 8.2 Hz, 2H), 4.92 - 4.78 (m, 1H), 4.65 (d, J = 15.1 Hz, 0.5H), 4.46 - 4.28 (m, 1H), 4.05 (d, J = 15.0 Hz, 0.5H), 3.75 (s, 3H), 3.67 (dd, J = 4.9, 12.9 Hz, 1H), 3.45 - 3.34 (m, 1H), 2.69 - 2.58 (m, 1H), 2.55 (br s, 1H), 1.58 (s, 3H), 1.33 (s, 4.5H), 1.06 (s, 4.5H). LCMS (ESI): m/z 406.1 [M ⁺ -56]. HPLC: 99.89%. Chiral HPLC: 98.71%. Column : CHIRALPAK IA (250*4.6 mm, 5µm). Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:MeOH (80:20); A:B :: 90:10; Flow rate: 1.0 mL/min; Retention time: 8.902. ZCQ: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.42 - 7.18 (m, 7H), 6.94 (d, J = 8.7 Hz, 2H), 4.91 - 4.71 (m, 1H), 4.62 (d, J = 14.6 Hz, 0.5H), 4.47 - 4.24 (m, 1H), 4.06 (d, J = 14.2 Hz, 0.5H), 3.78 (br s, 1H), 3.76 (s, 3H), 3.49 (br s, 1H), 2.77 (d, J = 13.4 Hz, 1H), 2.56 (br s, 1H), 1.58 (d, J = 15.9 Hz, 3H), 1.33 (br s, 4.5H), 1.02 (br s, 4.5H). LCMS (ESI): m/z 484.2 [M ⁺ +Na]. HPLC: 99.87%. Chiral HPLC: 100.00%. Column: CHIRALPAK IB (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:MeOH (50:50); A:B :: 95:05; Flow rate: 1.0 mL/min; Retention time: 9.698. ZCR: ¹ H NMR (400 MHz, DMSO-d6) δ 7.40 - 7.18 (m, 7H), 6.92 (d, J = 8.5 Hz, 2H), 4.88 - 4.71 (m, 1H), 4.61 (d, J = 14.1 Hz, 0.5H), 4.44 - 4.26 (m, 1H), 4.04 (d, J = 15.7 Hz, 0.5H), 3.76 (br s, 1H), 3.74 (s, 3H), 3.47 (br s, 1H), 2.75 (d, J = 13.3 Hz, 1H), 2.55 (br s, 1H), 1.56 (d, J = 15.9 Hz, 3H), 1.32 (br s, 4.5H), 1.00 (br s, 4.5H). LCMS (ESI): m/z 484.2 [M ⁺ +Na]. HPLC: 98.53%. Chiral HPLC: 97.83%. Column: CHIRALPAK IB (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:MeOH (50:50); A:B :: 95:05; Flow rate: 1.0 mL/min; Retention time: 10.597. Intermediate synthesis Synthesis of methacrylonitrile (Int-A): A mixture of methacrylamide (20 g, 0.235 mol) and P2O5 (50 g, 0.352 mol) was heated to 130 °C under nitrogen atmosphere. After being stirred for 20 minutes, reaction mixture was distilled and collected into a dry ice cooled flask under line vacuum to afford Int-A (4 g, 25%) as a colourless liquid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 5.95 - 5.92 (m, 2H), 1.96 (s, 3H). Synthesis of 2-((4-methoxybenzyl) amino) acetonitrile (B): To a solution of (4-methoxyphenyl) methanamine (200 g, 1.45 mol) in THF (1.2 L) were added Et ₃ N (315 mL, 2.18 mol) and bromo acetonitrile (173 g, 1.45 mol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), reaction was quenched with ice water and extracted with EtOAc (3x500 mL). Organic layer was washed brine solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by column chromatography using 30% EtOAc/Hexane as eluent to afford Int-B (172 g, 67%) as colorless syrup. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.23 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 3.73 (s, 3H), 3.67 (d, J = 5.2 Hz, 2H), 3.54 (d, J = 6.4 Hz, 2H), 2.92 (br t, J = 5.8 Hz, 1H). Synthesis of ZCS, ZCT, ZDA, ZDB, ZDI, ZDJ, ZDQ, ZDR: Synthesis of 2-(4-methoxybenzyl)-7-methyl-1-oxo-6-phenyl-2,5-diazaspiro[3 .4]octane-7- carbonitrile (ZCS, ZCT): To a mixture of ZCK & ZCL (1.2 g, 2.6 mmol) in CH2Cl2 (4 mL) was added TFA (2 mL, 26 mmol) at room temperature and stirred for 6 h. After consumption of the starting material (by TLC), volatiles were evaporated and co-distilled with Et2O under reduced pressure. The crude was washed with Et ₂ O and dried to afford mixture of ZCS and ZCT (1.0 g, 96.5%) as a white solid. Mixture of ZCS and ZCT (1g) was purified by chiral preparative HPLC to afford ZCS (210 mg) and ZCT (260 mg) as a white solid. ZCS: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47 (d, J = 7.2 Hz, 2H), 7.41 - 7.28 (m, 3H), 7.20 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.61 (d, J = 4.8 Hz, 1H), 4.35 - 4.25 (m, 2H), 4.11 (d, J = 4.8 Hz, 1H), 3.75 (s, 3H), 3.40 - 3.33 (m, 2H), 2.69 (d, J = 13.3 Hz, 1H), 2.28 (d, J = 13.3 Hz, 1H), 0.98 (s, 3H). LCMS (ESI): m/z 362.1 [M ⁺ +1]. HPLC: 98.66%. Chiral HPLC: 99.47%. Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n- hexane; Mobile Phase B: DCM:MeOH (50:50); A:B :: 80:20; Flow rate: 1.0 mL/min; Retention time: 7.005. ZCT: ¹ H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.39 (m, 2H), 7.37 - 7.27 (m, 3H), 7.17 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.57 (s, 1H), 4.33 - 4.22 (m, 2H), 4.13 (s, 1H), 3.70 (s, 3H), 3.35 (q, J = 5.5 Hz, 2H), 2.64 (d, J = 13.4 Hz, 1H), 2.25 (d, J = 13.4 Hz, 1H), 0.94 (s, 3H). LCMS (ESI): m/z 362.1 [M ⁺ +1]. HPLC: 99.61%. Chiral HPLC: 99.07%. Column : CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:MeOH (50:50); A:B :: 80:20; Flow rate: 1.0 mL/min; Retention time: 12.387. Synthesis of 2-(4-methoxybenzyl)-5,7-dimethyl-1-oxo-6-phenyl-2,5-diazaspi ro[3.4] octane- 7-carbonitrile (ZDA & ZDB): To a solution of mixture of ZCS & ZCT (900 mg, 2.49 mmol) in MeOH (15 mL) was added paraformaldehyde (590 mg, 19.9 mmol) and TFA (0.18 mL, 2.49 mmol) at 0 ^O C under nitrogen atmosphere. After being stirred at room temperature for 20 minutes, NaCNBH3 (890 mg, 14.4 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. TFA (0.18 mL, 2.49 mmol) and NaCNBH3 (890 mg, 14.4 mmol) were added to the reaction mixture and continued stirring at room temperature for 16 h. After consumption of the starting material (by TLC), cooled to room temperature and volatiles were evaporated under reduced pressure. The crue was diluted with EtOAc (50 mL) and extracted with water (2x100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure and purified by chiral preparative HPLC purification to afford ZDA(215 mg) as a white solid and ZDB (230 mg) as a colorless gummy liquid. ZDA: ¹ H NMR (500 MHz, DMSO-d6) δ 7.44 - 7.38 (m, 2H), 7.37 - 7.32 (m, 3H), 7.22 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.3 Hz, 2H), 4.41 (d, J = 15.1 Hz, 1H), 4.31 - 4.23 (m, 1H), 4.14 (s, 1H), 3.74 (s, 3H), 3.63 (d, J = 5.9 Hz, 1H), 3.19 (d, J = 5.9 Hz, 1H), 2.70 (d, J = 13.2 Hz, 1H), 2.26 (d, J = 13.2 Hz, 1H), 2.19 (s, 3H), 0.91 (s, 3H). LCMS (ESI): m/z 376.1 [M ⁺ +1]. HPLC: 97.23%. Chiral HPLC: 100.00%; Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:MeOH (50:50); A:B :: 90:10; Flow rate: 1.0 mL/min; Retention time: 8.690. ZDB: ¹ H NMR (500 MHz, DMSO-d6) δ 7.44 - 7.39 (m, 2H), 7.38 - 7.33 (m, 3H), 7.21 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.3 Hz, 2H), 4.41 (d, J = 14.6 Hz, 1H), 4.27 (d, J = 15.1 Hz, 1H), 4.14 (s, 1H), 3.75 (s, 3H), 3.63 (d, J = 5.9 Hz, 1H), 3.19 (d, J = 5.9 Hz, 1H), 2.70 (d, J = 13.7 Hz, 1H), 2.26 (d, J = 13.2 Hz, 1H), 2.19 (s, 3H), 0.91 (s, 3H). LCMS (ESI): m/z 376.1 [M ⁺ +1]. HPLC: 97.59%. Chiral HPLC: 97.39%. Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:MeOH (50:50); A:B :: 90:10; Flow rate: 1.0 mL/min; Retention time: 9.860. Synthesis of 5-isobutyl-2-(4-methoxybenzyl)-7-methyl-1-oxo-6-phenyl-2,5-d iazaspiro [3.4]octane-7-carbonitrile (ZDI & ZDJ): To a mixture of ZCS & ZCT (2 g, 5.54 mmol) in MeOH (20 mL) was added isobutyraldehyde (5.04 mL, 55.4 mmol) and TFA (0.42 mL, 5.54 mmol) at 0 ^o C under nitrogen atmosphere. After being stirred at room temperature for 20 minutes, NaCNBH ₃ (2.72 g, 44.3 mmol) was added to the reaction mixture and heated to 40 ^o C for 12 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to room temperature and volatiles were evaporated. The crude was diluted with DCM (50 mL) and extracted with water (3 x 100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude (2 g) was purified by chiral preparative HPLC to afford ZDI (350 mg) and ZDJ (310 mg) as a white solids. ZDI: ¹ H NMR (400 MHz, DMSO-d6) δ 7.40 - 7.28 (m, 3H), 7.22 (d, J = 8.7 Hz, 2H), 6.97 - 6.91 (m, 2H), 4.47 - 4.39 (m, 2H), 4.20 (d, J = 14.7 Hz, 1H), 3.74 (s, 3H), 3.40 - 3.35 (m, 2H), 3.32 (s, 3H), 2.60 (d, J = 13.3 Hz, 1H), 2.44 (dd, J = 5.8, 13.1 Hz, 1H), 2.25 (d, J = 13.3 Hz, 1H), 2.17 (dd, J = 9.3, 13.1 Hz, 1H), 1.43 - 1.30 (m, 1H), 0.88 (s, 3H), 0.74 (d, J = 6.5 Hz, 3H), 0.61 (d, J = 6.5 Hz, 3H). LCMS (ESI): m/z 418.2 [M ⁺ +1]. HPLC: 99.86%. Chiral HPLC: 99.44%. Column: CHIRALPAK IC (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n- hexane; Mobile Phase B: IPA; A:B :: 90:10; Flow rate: 1.0 mL/min; Retention time: 13.224. ZDJ: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.41 - 7.28 (m, 3H), 7.22 (d, J = 8.7 Hz, 2H), 6.97 - 6.91 (m, 2H), 4.47 - 4.39 (m, 2H), 4.21 (d, J = 14.7 Hz, 1H), 3.74 (s, 3H), 3.40 - 3.35 (m, 2H), 3.32 (s, 3H), 2.60 (d, J = 13.4 Hz, 1H), 2.44 (dd, J = 5.8, 13.0 Hz, 1H), 2.25 (d, J = 13.4 Hz, 1H), 2.17 (dd, J = 9.3, 13.1 Hz, 1H), 1.42 - 1.31 (m, 1H), 0.88 (s, 3H), 0.74 (d, J = 6.5 Hz, 3H), 0.61 (d, J = 6.7 Hz, 3H). LCMS (ESI): m/z 418.2 [M ⁺ +1]. HPLC: 99.26%. Chiral HPLC: 99.30%. Column: CHIRALPAK IC (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n- hexane; Mobile Phase B: IPA; A:B :: 90:10; Flow rate: 1.0 mL/min; Retention time: 15.494. Synthesis of 5-ethyl-2-(4-methoxybenzyl)-7-methyl-1-oxo-6-phenyl-2,5- diazaspiro[3.4]octane-7-carbonitrile (ZDQ & ZDR): To a mixture of ZCS & ZCT (1.5 g, 4.15 mmol) in MeOH (20 mL) was added AcOH (0.23 mL, 4.15 mmol) and acetaldehyde (2.32 mL, 41.5 mmol) and at 0 ^o C under nitrogen atmosphere. After being stirred at room temperature for 20 minutes, NaCNBH3 (1.5 g, 24.9 mmol) was added slowly to the reaction mixture and stirred at room temperature for 20 h. After consumption of the starting material (by TLC), reaction mixture was diluted with EtOAc (50 mL) and washed with aqueous NaHCO3 (3 x 100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude (800 mg) was purified by chiral preparative HPLC to afford ZDQ (190 mg) as white solid and ZDR (170 mg) as a white solid. ZDQ: ¹ H NMR (400 MHz, DMSO-d6): δ 7.46 (s, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.34- 7.26 (m, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 4.41 (s, 1H), 4.40-4.26 (m, 2H), 3.74 (s, 3H), 3.54 (d, J = 5.8 Hz, 1H), 3.31 (d, J = 5.9 Hz, 1H), 2.70-2.58 (m, 3H), 2.28-2.24 (m, 1H), 0.89 (s, 3H), 0.81 (t, J = 7.2 Hz, 3H). LCMS (ESI): m/z 390.1 [M ⁺ +1]. HPLC: 97.31%. Chiral HPLC: 100.00%. Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: IPA; A:B :: 95:05; Flow rate: 1.0 mL/min; Retention time: 11.843. ZDR: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.47 (s, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.35- 7.28 (m, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 4.42 (s, 1H), 4.40-4.26 (m, 2H), 3.75 (s, 3H), 3.54 (d, J = 5.8 Hz, 1H), 3.31 (d, J = 5.9 Hz, 1H), 2.70-2.58 (m, 3H), 2.27-2.24 (m, 1H), 0.89 (s, 3H), 0.82 (t, J = 7.2 Hz, 3H). LCMS (ESI): m/z 390.1 [M ⁺ +1]. HPLC: 99.30%. Chiral HPLC: 97.18%. Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: IPA; A:B :: 95:05; Flow rate: 1.0 mL/min; Retention time: 14.187. Synthesis of ZCU, ZCV, ZDC, ZDD, ZDK, ZDL, ZDS, ZDT:

Synthesis of 2-(4-methoxybenzyl)-7-methyl-1-oxo-6-phenyl-2,5-diazaspiro[3 .4]octane-7- carbonitrile (ZCU, ZCV): To a solution of ZCM & ZCN (2 g, 4.33 mmol) in CH ₂ Cl ₂ (20 mL) was added 2,6- Lutidine (0.69 mL, 65.0 mmol) and TMSOTf (1.17 mL, 64.9 mmol) at 0 ^o C under nitrogen atmosphere. The reaction mixture was stirred at 0-10 ^o C for 6 h. After consumption of the starting material (by TLC), diluted with water and extracted with CH2Cl2 (2 x 200 mL). Organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude was washed with Et2O and dried to afford to obtain mixture of ZCU and ZCV (400 mg, 26%) as an off white solid. Another batch was performed and obtained 480 mg of product. Combined mixture (880 mg) was purified by chiral preparative HPLC to afford ZCU (320 mg) as white solid and ZCV (350 mg) as white solid. ZCU: ¹ H NMR (400 MHz, DMSO-d6): δ 7.49-7.30 (m, 5H), 7.21 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 4.66 (d, J = 5.4 Hz, 1H), 4.40-4.19 (m, 3H), 3.75 (s, 3H), 3.38 (d, J = 5.4 Hz, 1H), 3.22 (d, J = 5.4 Hz, 1H), 2.66-2.63 (m, 1H), 2.48-2.43 (m, 1H), 0.89 (s, 3H). LCMS (ESI): m/z 362.1 [M ⁺ +1]. HPLC: 98.76%. Chiral HPLC: 100.00%. Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:MeOH (50:50); A:B :: 85:15; Flow rate: 1.0 mL/min; Retention time: 9.134. ZCV: ¹ H NMR (400 MHz, DMSO-d6): δ 7.47-7.27 (m, 5H), 7.21 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 4.66 (d, J = 5.4 Hz, 1H), 4.37-4.20 (m, 3H), 3.75 (s, 3H), 3.38 (d, J = 5.4 Hz, 1H), 3.22 (d, J = 5.4 Hz, 1H), 2.66-2.63 (m, 1H), 2.48-2.43 (m, 1H), 0.89 (s, 3H). LCMS (ESI): m/z 362.1 [M ⁺ +1]. HPLC: 99.76%. Chiral HPLC: 100.00%. Column: CHIRALPAK IA (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:MeOH (50:50); A:B :: 80:20; Flow rate: 1.0 mL/min; Retention time: 11.945. Synthesis of 2-(4-methoxybenzyl)-5,7-dimethyl-1-oxo-6-phenyl-2,5-diazaspi ro[3.4] octane- 7-carbonitrile (ZDC & ZDD): To a solution of ZCU & ZCV (1 g, 2.77 mmol) in MeOH (10 mL) was added paraformaldehyde (660 mg, 22.1 mmol) and acetic acid (0.15 mL, 2.77 mmol) at 0 ºC under nitrogen atmosphere. After being stirred at room temperature for 20 minutes, NaCNBH ₃ (1.03 g, 16.6 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. The crude was diluted with EtOAc (50 mL) and washed with aqueous NaHCO ₃ . Organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography by eluting 50% EtOAc/ n-hexane to afford mixture of ZDC & ZDD (1g), which was purified by chiral preparative HPLC purification to afford ZDC (320 mg) as white solid and ZDD (330 mg) as white solid. ZDC: ¹ H NMR (500 MHz, DMSO-d6): δ 7.44-7.35 (m, 3H), 7.28 (d, J = 7.5 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 4.43-4.33 (m, 1H), 4.28-4.21 (m, 2H), 3.74 (s, 3H), 3.35 (d, J = 5.8 Hz, 1H), 3.25 (d, J = 5.8 Hz, 1H), 2.71 (d, J = 13.9 Hz, 1H), 2.46 (s, 1H), 2.19 (s, 3H), 0.93 (s, 3H). LCMS (ESI): m/z 376.1 [M ⁺ +1]. HPLC: 98.45%. Chiral HPLC: 99.34%. Column: CHIRALPAK IC (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n- hexane; Mobile Phase B: DCM:IPA (50:50); A:B :: 50:50; Flow rate: 1.0 mL/min; Retention time: 5.748. ZDD: ¹ H NMR (500 MHz, DMSO-d6): δ 7.46-7.36 (m, 3H), 7.28 (d, J = 7.5 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 4.39-4.33 (m, 1H), 4.28-4.22 (m, 2H), 3.75 (s, 3H), 3.35 (d, J = 6.4 Hz, 1H), 3.25 (d, J = 5.8 Hz, 1H), 2.71 (d, J = 13.9 Hz, 1H), 2.46 (s, 1H), 2.19 (s, 3H), 0.93 (s, 3H). LCMS (ESI): m/z 376.0 [M ⁺ +1]. HPLC: 99.68%. Chiral HPLC: 99.34%. Column: CHIRALPAK IC (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n- hexane Mobile Phase B: DCM:IPA (50:50); A:B :: 50:50; Flow rate: 1.0 mL/min; Retention time: 7.278. Synthesis of 5-isobutyl-2-(4-methoxybenzyl)-7-methyl-1-oxo-6-phenyl-2,5-d iazaspiro [3.4]octane-7-carbonitrile (ZDK & ZDL): To a solution of ZCU & ZCV(1 g, 2.77 mmol) in MeOH (15 mL) was added isobutyraldehyde (2.51 mL, 27.7 mmol) and acetic acid (0.15 mL, 2.77 mmol) at 0 ^o C under nitrogen atmosphere. After being stirred at room temperature for 20 minutes, NaCNBH3 (1.03 g, 16.6 mmol) was added to the reaction mixture and heated to 40 ^o C for 16 h. After consumption of the starting material (by TLC), cooled to room temperature and volatiles were evaporated. The crude was diluted with EtOAc (50 mL) and washed with water (2 x 100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford mixture of ZDK & ZDL (360 mg, 31%) as white solid. Combined crude from other batches (920 mg) was purified by chiral preparative HPLC to afford ZDK (260 mg) as white solid and ZDL (240 mg) as a white solid. ZDK: ¹ H NMR (500 MHz, DMSO-d6): δ 7.40-7.29 (m, 5H), 7.19 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 4.42 (d, J = 14.5 Hz, 1H), 4.29 (s, 1H), 4.15 (d, J = 15.1 Hz, 1H), 3.74 (s, 3H), 3.36 (d, J = 5.2 Hz, 1H), 3.19 (d, J = 5.2 Hz, 1H), 2.75-2.66 (m, 2H), 2.53-2.51 (m, 1H), 2.00-1.88 (m, 1H), 1.39-1.28 (m, 1H), 1.00 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H), 0.58 (d, J = 6.4 Hz, 3H). LCMS (ESI): m/z 418.2 [M ⁺ +1]. HPLC: 98.42%. Chiral HPLC: 100.00%. Column: CHIRALPAK IC (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:IPA (90:10); A:B :: 70:30; Flow rate: 1.0 mL/min; Retention time: 14.738. ZDL: ¹ H NMR (500 MHz, DMSO-d6): δ 7.40-7.26 (m, 5H), 7.19 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 4.42 (d, J = 14.5 Hz, 1H), 4.29 (s, 1H), 4.15 (d, J = 15.1 Hz, 1H), 3.74 (s, 3H), 3.36 (d, J = 5.2 Hz, 1H), 3.19 (d, J = 5.2 Hz, 1H), 2.76-2.65 (m, 2H), 2.53-2.51 (m, 1H), 2.02-1.83 (m, 1H), 1.36-1.30 (m, 1H), 1.00 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H), 0.58 (d, J = 6.4 Hz, 3H). LCMS (ESI): m/z 418.6 [M ⁺ +1]. HPLC: 98.37%. Chiral HPLC: 99.85%. Column: CHIRALPAK IC (250*4.6 mm, 5µm). Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:IPA (90:10); A:B :: 70:30; Flow rate: 1.0 mL/min; Retention time: 19.018. Synthesis of 5-ethyl-2-(4-methoxybenzyl)-7-methyl-1-oxo-6-phenyl-2,5- diazaspiro[3.4]octane-7-carbonitrile (ZDS & ZDT): To a solution of mixture ZC & ZCV (1 g, 2.77 mmol) in MeOH (15 mL) was added AcOH (0.15 mL, 2.77 mmol) and acetaldehyde (1.55 mL, 27.7 mmol) and at 0 ^o C under nitrogen atmosphere. After being stirred at room temperature for 20 minutes, NaCNBH ₃ (0.515 g, 8.31 mmol) was added slowly to the reaction mixture and stirred at room temperature for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Crude was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude was purified by column chromatography by eluting 20% EtOAc/ n-hexane to afford mixture of ZDS & ZDT (500 mg). Antother batch was product was combined and 1g of mixture was purified by chiral preparative HPLC purification to afford ZDS (300 mg) as white solid and ZDT (210 mg) as white solid. ZDS: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.43-7.29 (m, 5H), 7.20 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 4.41 (s, 1H), 4.39-4.35 (m, 1H), 4.30-4.22 (m, 1H), 3.75 (s, 3H), 3.40 (d, J = 5.5 Hz, 1H), 3.32 (s, 1H), 3.20 (d, J = 5.6 Hz, 1H), 2.84-2.75 (m, 1H), 2.70-2.68 (m, 1H), 2.52-2.42 (m, 1H), 0.94 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): m/z 390.2 [M ⁺ +1]. HPLC: 99.02%. Chiral HPLC: 100.00%. Column: CHIRALPAK IC (250*4.6 mm, 5µm). Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:IPA (90:10); A:B :: 70:30; Flow rate: 1.0 mL/min; Retention time: 14.703. ZDT: ¹ H NMR (400 MHz, DMSO-d6): δ 7.47-7.31 (m, 5H), 7.20 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 4.41 (s, 1H), 4.40-4.34 (m, 1H), 4.31-4.21 (m, 1H), 3.75 (s, 3H), 3.40 (d, J = 5.6 Hz, 1H), 3.32 (s, 1H), 3.20 (d, J = 5.6 Hz, 1H), 2.84-2.75 (m, 1H), 2.70-2.68 (m, 1H), 2.52-2.42 (m, 1H), 0.95 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): m/z 390.1 [M ⁺ +1]. HPLC: 99.11%. Chiral HPLC: 100.00%. Column: CHIRALPAK IC (250*4.6 mm, 5µm); Mobile Phase A: 0.1% DEA in n-hexane; Mobile Phase B: DCM:IPA (90:10); A:B :: 70:30; Flow rate: 1.0 mL/min; Retention time: 21.380. Following the above procedures, the following compounds of Formula VI were or are prepared. It will be appreciated by a person of skill in the art that for the structures shown, additional stereoisomers such as diastereomers and/or enantiomers are included in the compounds of the present disclosure. Table 3.

B. POSITIVE EMOTIONAL LEARNING (PEL) TEST This example demonstrates the positive emotional learning (PEL) test. Experiments were conducted as described in Burgdorf et al., “The effect of selective breeding for differential rates of 50-kHz ultrasonic vocalizations on emotional behavior in rats,” Devel. Psychobiol., 51:34-46 (2009). Rat 50-kHz ultrasonic vocalization (hedonic USVs) is a validated model for the study of positive affective state and is best elicited by rough-and-tumble play.50-kHz ultrasonic vocalizations have previously been shown to be positively correlated with reward and appetitive social behavior in rats, and to reflect a positive affective state. The PEL assay measures the acquisition of positive (hedonic) 50-kHz ultrasonic vocalizations (USVs) to a social stimulus, heterospecific rough and tumble play stimulation. Heterospecific rough-and-tumble play stimulation was administered by the experimenter's right hand. One hour after administration of test compound or vehicle negative control (0.5% sodium carboxymethyl cellulose in 0.9% sterile saline vehicle), animals received 3 min of heterospecific rough-and-tumble play that consisted of alternating 15 sec blocks of heterospecific play and 15 sec of no-stimulation. High frequency ultrasonic vocalizations (USVs) were recorded and analyzed by sonogram with Avasoft SASlab Pro (Germany) as previously described by Burgdorf et al., “Positive emotional learning is regulated in the medial prefrontal cortex by GluN2B- containing NMDA receptors,” Neuroscience, 192:515-523 (2011). Frequency modulated 50- kHz USVs that occurred during each of the no-stimulation periods were quantified to measure PEL. Animals were not habituated to play stimulation before testing. Positive emotional learning was measured during the conditioned stimulus (CS) trials preceding the tickle unconditioned stimulus (UCS) trials. Animals received 15 second trials consisting of 6 CS and 6 UCS trials each (3 min total). The table below summarizes the findings. As each experiment includes its own vehicle group, an example (typical) vehicle score is shown. Max effect (mean number of 50 kHz USVs per 15 seconds) is reported as ^: <6.0; *: 6.0-7.6; **: 7.7-10; ***:10.1-20. C. NMDAR AGONIST ASSAYS Assays were conducted as described by Moskal et al., “GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator,” Neuropharmacology, 49, 1077-87, 2005. These studies were designed to determine if the test compounds act to facilitate NMDAR activation in NMDAR2A, NMDAR2B, NMDAR2C or NMDAR2D expressing HEK cell membranes as measured by increases in [ ³ H]MK-801 binding. In the assay, 300 µg of NMDAR expressing HEK cell membrane extract protein was preincubated for 15 minutes at 25° C in the presence of saturating concentrations of glutamate (50 µM) and varying concentrations of test compound (1x10 ^-15 M – 1x10 ^-7 M), or 1 mM glycine. Following the addition of 0.3 µCi of [ ³ H]MK-801 (22.5 Ci/mmol), reactions were again incubated for 15 minutes at 25 ° C (nonequilibrium conditions). Bound and free [ ³ H]MK-801 were separated via rapid filtration using a Brandel apparatus. In analyzing the data, the DPM (disintegrations per minute) of [ ³ H]MK-801 remaining on the filter were measured for each concentration of test compound or for 1 mM glycine. The DPM values for each concentration of a ligand (N=2) were averaged. The baseline value was determined from the best fit curve of the DPM values modeled using the GraphPad program and the log(agonist) vs. response(three parameters) algorithm was then subtracted from all points in the dataset. The % maximal [ ³ H]MK-801 binding was then calculated relative to that of 1 mM glycine: all baseline subtracted DPM values were divided by the average value for 1 mM glycine. The EC ₅₀ and % maximal activity were then obtained from the best fit curve of the % maximal [ ³ H]MK-801 binding data modelled using the GraphPad program and the log(agonist) vs. response(three parameters) algorithm. The tables below summarize the results for the wild type NMDAR agonists NMDAR2A, NMDAR2B, NMDAR2C, and NMDAR2D, and whether the compound is not an agonist (-), is an agonist (+), or is a strong agonist (++), where column A is based on the % maximal [ ³ H]MK- 801 binding relative to 1 mM glycine (- = 0; < 100% = +; and > 100% = ++); and column B is based on log EC50 values (0 = -; ≥ 1x10 ^-9 M (e.g., -8) = +; and < 1x10 ^-9 M (e.g., -10) = ++). An “ND” indicates that the assay was not done.

D. MICROSOMAL STABILITY Microsomal stability of disclosed compounds was investigated. The following table indicates the percent of compound remaining after 60 minutes. 167

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E. PLASMA STABILITY Plasma stability of disclosed compounds was investigated. The following table indicates the percent of compound remaining after 60 minutes. F. PHARMACOKINETICS Sprague Dawley rats were dosed intravenously using a normal saline formulation containing 2 mg/kg of the compounds identified in the below table. The table below summarizes the results of the IV pharmacokinetics. In another experiment, Sprague Dawley rats were dosed per os (oral gavage) using a normal saline formulation containing 10 mg/kg of the compounds identified in the table below. Plasma, brain, and CSF samples were analyzed at various time points over a 24 hour period. The table below summarizes the results of the oral pharmacokinetics, where the first three values (Tmax, Cmax and AUClast) are plasma values. An “ND” indicates that the measurement was not done.

EQUIVALENTS The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. Such equivalents are intended to be encompassed by the following claims. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein. INCORPORATION BY REFERENCE The entire contents of all patents, published patent applications, websites, and other references cited herein are hereby expressly incorporated herein in their entireties by reference. What is claimed is: