WO2019152681A1

WO2019152681A1 - Spiro-lactam and bis-spiro-lactam nmda receptor modulators and uses thereof

Info

Publication number: WO2019152681A1
Application number: PCT/US2019/016103
Authority: WO
Inventors: M. Amin Khan
Original assignee: Aptinyx Inc.
Priority date: 2018-01-31
Filing date: 2019-01-31
Publication date: 2019-08-08

Abstract

Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders as well as other disorders.

Description

SPIRO-LACTAM AND BIS-SPIRO-LACTAM NMDA RECEPTOR MODULATORS

AND USES THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. Provisional Patent

Application No. 62/718,040, filed on August 13, 2018, and U.S. Provisional Patent Application No. 62/624,223, filed on January 31, 2018; the contents of each of which are hereby incorporated by reference herein in their 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 affect 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 Formula II:

or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof,

where R¹ and R² are independently selected from the group consisting of hydrogen, -Ci- Cgalkyl, -C(0)-Ci-C₆alkyl, -C(0)-0-Ci-C₆alkyl, and -0-CH₂-phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R³ is selected from the group consisting of hydrogen, -Ci-Cgalkyl, -C(0)-R³¹, -S(0)_w-R³¹, and - C(0)-0-R³², wherein -Cgalkyl is optionally substituted by one, two or three substituents each independently selected from R^s;

w is 0, 1, or 2;

n is 1, 2, or 3;

R³¹ is selected from the group consisting of hydrogen, -Ci-Cgalkyl; -C₃-Cgcycloalkyl, and phenyl, wherein Q-Cgalkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R³² is selected from the group consisting of -CpCgalkyl; -C Cgcycloalkyl, and phenyl, wherein Q-Cgalkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R⁴, R⁵, R⁶ and R⁷ are independently, for each occurrence, selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, Ci_C4alkyl, C2-C₄alkenyl, -NH-C(0)-Ci_ Cgalkyl, -NH-C(0)-Ci_C₆alkylene-phenyl, -NH-C(0)-0-Ci_C₆alkyl, and -NH-C(0)-0-Ci_ Cgalkylene-phenyl; wherein Ci_C4alkyl, Ci-Cgalkylene, C2-C4alkenyl, Ci_C4alkoxy, and phenyl are each optionally substituted by one, two, or three substituents each independently selected from R^p;

wherein for the compound of Formula I, an R⁶ and an R⁷ taken together with the adjacent carbons to which they are attached form a 3-membered carbocyclic ring which is optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -

R^a and R^b are independently, for each occurrence, selected from the group consisting of hydrogen, -C(0)-0-CH₂-phenyl, and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci-C₃alkyl is optionally substituted with one, two, or three halogens;

R^p is independently, for each occurrence, selected from the group consisting of -CO2H, hydroxyl, halogen, amino, phenyl, Ci-Cealkoxy, and Ci-Cealkyl, wherein each phenyl and Ci- C₆alkyl is optionally substituted by one, two, or threesubstituents each independently selected from the group consisting of halogen, hydroxyl and amino;

R^s is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, hydroxyl, -SH, phenyl, -0-CH₂-phenyl, and halogen, wherein phenyl is optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C₄alkoxy, -Ci-C₄alkyl, and -CF₃; and

R^T is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, -Ci-C₄alkoxy, -Ci-C₄alkyl, hydroxyl, and halogen, wherein Ci-C₄alkyl is optionally substituted with one, two, or three halogens.

Also provided herein is a compound having Formula III:

where R¹ and R² are independently selected from the group consisting of hydrogen and -CH₂- phenyl , where at least one of R¹ or R² is -CH₂-phenyl, and phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, C(0)NR^aR^b, -NR^aR^b, and -Ci-C₄alkoxy; R³ is selected from the group consisting of hydrogen, -Ci-C₆alkyl, -C(0)-R³¹, and -C(0)-0- R³², wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s;

R³¹ is hydrogen or -Ci-C₆alkyl;

R³² is -Ci-Cgalkyl;

R⁶ and R⁷ are each independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, C i ₄alkyl , C2-₄alkenyl, -NH-C(0)-Ci_ ₆alkyl, -NH-C(0)-Ci_₆alkylene-phenyl, -NH-C(0)-0-Ci_₆alkyl, and -NH-C(0)-0-Ci_₆alkylene- phenyl, wherein C_{| -4}alkyl, Ci_₆alkylene, C2-₄alkenyl, Ci_₄alkoxy, and phenyl are each optionally substituted by one, two, or threesubstituents each independently selected from R^p;

R^a and R^b are each independently, for each occurrence, selected from the group consisting of hydrogen, -C(0)-0-CH₂-phenyl, and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci-C₃alkyl is optionally substituted with one, two, or three halogens;

R^p is independently, for each occurrence, selected from the group consisting of -CO2H, hydroxyl, halogen, amino, phenyl, Ci_₆alkoxy, and Ci_₆alkyl, wherein each phenyl and Ci_

O, alkyl is optionally substituted by one, two, or threesubstituents each independently selected from the group consisting of halogen, hydroxyl and amino; and

R^s is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, hydroxyl, and halogen.

Also provided herein is a compound having Formula IV :

where R² is selected from the group consisting of hydrogen, -Ci-Cealkyl, -C(0)-Ci-C₆alkyl, and -C(0)-0-Ci-C₆alkyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s; R³ is selected from the group consisting of hydrogen, methyl, and -CFF-phenyl, wherein phenyl is optionally substituted by one, two or three substituents each independently selected from R^T; and

R⁹ is selected from the group consisting of hydrogen and -Ci-C₆alkyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s; R^a and R^b are each independently, for each occurrence, selected from the group consisting of hydrogen, phenyl, -Ci-C₃alkylene -phenyl and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -C_]-C₃alkyl, and halogen, and -Ci- C₃alkyl is optionally substituted with one, two, or three halogens;

R^T is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, -Ci-C₄alkoxy, -Ci-C₄alkyl, hydroxyl, and halogen.

In addition, provided herein is a compound represented by Formula V :

where R² is selected from the group consisting of hydrogen, -Ci-Cealkyl, -C(0)-Ci-C₆alkyl, and -C(0)-0-Ci-C₆alkyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s;

R³ is selected from the group consisting of hydrogen and -Ci-Cealkyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s; R^a and R^b are each independently, for each occurrence, selected from the group consisting of hydrogen, phenyl, -Ci-C₃alkylene -phenyl and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci- C₃alkyl is optionally substituted with one, two, or three halogens; and

R^s is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, hydroxyl, -SH, phenyl, -O-CFF-phenyl, and halogen, wherein phenyl is optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C₄alkoxy, -Ci-C₄alkyl, and -CF₃.

Further, provided herein is a compound represented by Formula VI or Formula VII:

R³ is selected from the group consisting of hydrogen, -Ci-C₆alkyl, -C(0)-R³¹, -S(0)_w-R³¹, and - C(0)-0-R³², wherein -Cgalkyl is optionally substituted by one, two or three substituents each independently selected from R^s;

w is 0, 1, or 2;

n is 1, 2, or 3;

R³¹ is selected from the group consisting of hydrogen, -Ci-C₆alkyl; -C₃-Cgcycloalkyl, and phenyl, wherein -Cgalkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R³² is selected from the group consisting of -Ci-C₆alkyl; -C₃-Cgcycloalkyl, and phenyl, wherein CpCgalkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T; R⁴, R⁵, R⁶ and R⁷ are independently, for each occurrence, selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, Ci-C₄alkyl, C2-C₄alkenyl, -NH-C(0)-Ci_ Cgalkyl, -NH-C(0)-Ci_C₆alkylene-phenyl, -NH-C(0)-0-Ci_C₆alkyl, and -NH-C(0)-0-Ci_ Cealkylene-phenyl; wherein Ci_C₄alkyl, Ci_Q,alkylene, C2-C₄alkenyl, Ci_C₄alkoxy, and phenyl are each optionally substituted by one, two, or threesubstituents each independently selected from R^p;

wherein for the compound of Formula I, an R⁶ and an R⁷ taken together with the adjacent carbons to which they are attached form a 3-membered carbocyclic ring which is optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C3alkyl, -Ci-C₃alkoxy, -C(0)NR^aR^b, and -NR^aR^b;

R^a and R^b are independently, for each occurrence, selected from the group consisting of hydrogen, -QOj-O-CFF-phenyl, and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci-C₃alkyl is optionally substituted with one, two, or three halogens;

R^p is independently, for each occurrence, selected from the group consisting of -CO2H, hydroxyl, halogen, amino, phenyl, Ci_C₆alkoxy, and Ci_Cr, alkyl, wherein each phenyl and Ci_

O, alkyl is optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl and amino;

R^s is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, hydroxyl, -SH, phenyl, -O-CFF-phenyl, and halogen, wherein phenyl is optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C₄alkoxy, -Ci-C₄alkyl, and -CF₃; and

R^T is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, -Ci-C₄alkoxy, -Ci-C₄alkyl, hydroxyl, and halogen, wherein Ci-C₄alkyl is optionally substituted with one, two, or three halogens. Further, provided herein is a compound represented by Formula VIII or Formula IX:

or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein:

R¹ and R² are independently selected from the group consisting of hydrogen, -Ci-C₆alkyl, - C(0)-Ci-C₆alkyl, -C( O )-0-C i -C₆alkyl , and -O-CFF-phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R³ is -S(0)_w-Ci-C₆alkyl;

w is 0, 1, or 2;

R^a and R^b are independently, for each occurrence, selected from the group consisting of hydrogen, -C(0)-0-CH₂-phenyl, and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -C_]-C₃alkyl, and halogen, and -C i -C_halky 1 is optionally substituted with one, two, or three halogens;

Further, provided herein is a compound represented by Formula X

R² is selected from the group consisting of hydrogen, -Ci-C₆alkyl, -C(0)-Ci-C₆alkyl, -C(0)-0- Ci-Cealkyl, and -0-CH₂-phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R³ is -S(0)_w-Ci-C₆alkyl;

w is 0, 1, or 2;

R⁹ is selected from the group consisting of hydrogen and -Ci-Cealkyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s; R¹⁰ is selected from the group consisting of hydrogen and -Ci-C₆alkyl;

R^a and R^b are each independently, for each occurrence, selected from the group consisting of hydrogen, phenyl, -Ci-C3alkylene -phenyl and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -Ci-Cealkyl, and halogen, and -Ci- C₃alkyl is optionally substituted with one, two, or three halogens;

R^T is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, -Ci-C₄alkoxy, -Ci-C₄alkyl, hydroxyl.

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 one 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 disorder or syndrome, a behavior disorder, an impulse control disorder, a substance abuse disorder, a sleep disorder, a cognitive impairment disorder such as a memory disorder or 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 may comprise administering to a patient a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, or a pharmaceutical composition including a disclosed compound, or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof.

In various embodiments, a method of this disclosure includes treating depression. In some embodiments, a method of this disclosure includes treating schizophrenia. In certain embodiments, a method of this disclosure includes treating Alzheimer’s disease. In various embodiments, a method of this disclosure includes treating attention deficit disorder. In some embodiments, a method of this disclosure includes treating anxiety. In certain embodiments, a method of this disclosure includes treating a migraine. In various embodiments, a method of this disclosure includes treating neuropathic pain. In some embodiments, a method of this disclosure includes treating traumatic brain injury. In certain embodiments, a method of this disclosure includes treating a neurodevelopment disorder related to a synaptic dysfunction. In various embodiments, a method of this disclosure includes treating a cognitive impairment disorder. Such methods may comprise administering to a patient a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, or a pharmaceutical composition including a disclosed compound, or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof.

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. In some embodiments, compounds described herein bind to NMDA receptors expressing certain NR2 subtypes. In some embodiments, the compounds described herein bind to one NR2 subtype and not another. It should be appreciated that the disclosed compounds may modulate other protein targets and/or specific NMDA receptor subtype.

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 -Ce alkyl, C₁-C₄ alkyl, and C₁-C₃ alkyl, respectively. For example,“Ci- C₆ alkyl” refers to a straight-chain or branched saturated hydrocarbon containing 1-6 carbon atoms. Examples of a C ₁ -C₆ alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, .vec-butyl, ieri-butyl, isopentyl, and neopentyl. In another example,“C₁-C₄ alkyl” refers to a straight-chain or branched saturated hydrocarbon containing 1-4 carbon atoms. Examples of a C₁-C₄ alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, .ver -butyl and ieri-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -propyl, 2- methyl-2-propyl, 2-methyl- l-butyl, 3 -methyl- 1 -butyl, 3-methyl-2-butyl, 2,2-dimethyl- l-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- l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl- l-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.

The term“alkylene” as used herein refers to the diradical of an alkyl group.

The term“alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein for example as C_2-C₆ alkenyl, and C_3-C₄ alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

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 Ci- C₆ alkoxy and C₂-C₆ alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy, isopropoxy, and tert-butoxy.

The term“carbonyl,” as used herein, refers to the radical -C(O)- or C=0.

The term“cyano,” as used herein, refers to the radical -CN. 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 (carbocyclic) system, for example, where each ring is either completely saturated or contains one or more units of unsaturation, but where no ring is aromatic. A cycloalkyl can have 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 terms“halo” and“halogen,” as used herein, refer to fluoro (F), chloro (Cl), bromo (Br), and/or iodo (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 term“heterocycloalkyl,”“heterocyclic ring,” or“heterocycle,” as used herein, is art-recognized and refer to saturated or partially unsaturated 3- to 8-membered ring systems, for example, 3- to 7- or 3- to 6-membered ring systems, whose ring system include one, two or three heteroatoms, such as nitrogen, oxygen, and/or sulfur. A heterocycloalkyl can be fused to one or more phenyl, partially unsaturated, or saturated rings. Examples of heterocycloalkyls include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.

The term“heteroaryl,” as used herein, refers to a monocyclic aromatic 5- to

8-membered ring system containing one or more heteroatoms, for example, one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, a heteroaryl can be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryls include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, and pyrimidine.

The terms“hydroxy” and“hydroxyl,” as used herein, refer to the radical -OH.

The term“oxo,” as used herein, refers to the radical =0 (double bonded oxygen). 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, 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, or an N-oxide thereof. It should be understood that a compound can refer to a pharmaceutically acceptable salt, or a hydrate, 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 Kvaemo, 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 heterocycloalkyl, 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 “£” 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 ²H (“D”), ¾, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, 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 ³H and ¹⁴C) can be useful in compound and/or substrate tissue distribution assays. Tritiated (/._<?., ³H) and carbon- 14 (/._<?., ¹⁴C) isotopes can be particularly preferred for their ease of preparation and

detectability. Further, substitution with heavier isotopes such as deuterium (/._<?., ²H) 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 Biologies 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. As used herein, the term“pharmaceutically acceptable salt” 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, “salts” 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,

glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy ethanesulfonate, 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 Ci_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., l,r-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.

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 from the context.

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“Ci_-6 alkyl” is specifically intended to individually disclose Ci, C₂, C₃, C₄, C₅, C₆, Ci-C₆, C₁-C₅, C₁-C₄, Ci- C₃, Ci-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 -C₆ alkyl, R², 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 Formula I or Formula II:

where

R¹ and R² are independently selected from the group consisting of hydrogen, -Ci-Cealkyl, - C(0)-Ci-C₆alkyl, -C(0)-0-Ci-C₆alkyl, and -O-CFF-phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R³ is selected from the group consisting of hydrogen, -Ci-C₆alkyl, -C(0)-R³¹, -S(0)_w-R³¹, and - C(0)-0-R³², wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s;

w is 0, 1, or 2;

n is 1, 2, or 3;

R³¹ is selected from the group consisting of hydrogen, -Ci-C₆alkyl; -C3-C6cycloalkyl, and phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R³² is selected from the group consisting of -Ci-C₆alkyl; -C3-C6cycloalkyl, and phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R⁴, R⁵, R⁶ and R⁷ are independently, for each occurrence, selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, Ci-C₄alkyl, C2-C₄alkenyl, -NH-C(0)-Ci_ Cgalkyl, -NH-C(0)-Ci_C₆alkylene-phenyl, -NH-C(0)-0-Ci_C₆alkyl, and -NH-C(0)-0-Ci_ Cealkylene-phenyl; wherein Ci_C₄alkyl, Ci_Q,alkylene, C2-C₄alkenyl, Ci_C₄alkoxy, and phenyl are each optionally substituted by one, two, or three substituents each independently selected from R^p;

wherein for the compound of Formula I, an R⁶ and an R⁷ taken together with the adjacent carbons to which they are attached form a 3-membered carbocyclic ring which is optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C₃alkyl, -Ci-C₃alkoxy, -C(0)NR^aR^b, and -NR^aR^b;

R^p is independently, for each occurrence, selected from the group consisting of -CO2H, hydroxyl, halogen, amino, phenyl, Ci_C₆alkoxy, and Ci_Cr, alkyl, wherein each phenyl and Ci- O, alkyl is optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl and amino;

In certain embodiments, R¹ and R² can be -CFF-phenyl, wherein phenyl is optionally substituted by one, two or three substituents each independently selected from R^T. In certain embodiments, at least one of R¹ and R² can be -CH2-phenyl, wherein phenyl is optionally substituted by one, two or three substituents each independently selected from R^T.

In certain embodiments, R¹ and R² can independently be -Ci-C₆alkyl each

independently and optionally substituted by one, two or three substituents independently selected from the group consisting of -C(0)NR^aR^b, hydroxyl, -SH, and halogen. For example, R¹ and R²can be independently selected from the group consisting of:

where R^a and R^b are each independently selected for each occurrence from the group consisting of hydrogen and -Ci-C^alkyl.In certain embodiments, R¹ and R² can be

independently selected from the group consisting of hydrogen, benzyl, 4-fluorobenzyl, -O-

CFF-phenyl,

In certain embodiments, R³ can be hydrogen. In certain embodiments, R³ can be -Ci- C₆alkyl optionally substituted by one, two or three substituents each independently selected from R^s. For example, R³ can be methyl, ethyl, isobutyl, or -CFF-phenyl.

In certain embodiments, R³ can be -C(0)-Ci-C₆alkyl. For example, R³ can be -C(O)- isopropyl or -C(0)-CH3. In certain embodiments, R³ can be -C(0)-0-Ci-C₆alkyl. For example, R³ can be -C(0)-0-tert-butyl.

In certain embodiments, R³ can be -S(0)_w-R³¹· In certain embodiments, R³ can be - S02-Ci-C6alkyl. For example, R³ can be -SO₂-CH₃.

In certain embodiments, R³ can be selected from the group consisting of hydrogen, methyl, ethyl, -C(0)-isopropyl, -C(0)-CH3, -C(0)-0-tert-butyl, -SO2-CH3, and benzyl.

In certain embodiments, R⁴, R⁵, R⁶, and R⁷ can be hydrogen. In other embodiments, one, two, three or four of R⁶ and R⁷, independently, can be fluoro. In certain embodiments, n is 1.

Also provided are compounds having Formula III:

where R¹ and R² are independently selected from the group consisting of hydrogen and -CFF- phenyl, where at least one of R¹ or R² is -CFF-phenyl, and phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, -C(0)NR^aR^b, -NR^aR^b, and -Ci-C₄alkoxy;

R³ is selected from the group consisting of hydrogen, -Ci-C₆alkyl, -C(0)-R³¹, and -C(0)-0- R³², where Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s;

R³¹ is hydrogen or -Ci-C₆alkyl;

R³² is -Ci-Cgalkyl;

R⁶ and R⁷ are each independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, C 1 ₄alkyl , C2-₄alkenyl, -NH-C(0)-Ci_ ₆alkyl, -NH-C(0)-Ci_₆alkylene-phenyl, -NH-C(0)-0-Ci_₆alkyl, and -NH-C(0)-0-Ci_₆alkylene- phenyl, wherein C 1 ₄alkyl , Ci_₆alkylene, C2-₄alkenyl, Ci_₄alkoxy, and phenyl are each optionally substituted by one, two, or threesubstituents each independently selected from R^p;

R^p is independently, for each occurrence, selected from the group consisting of -CO2H, hydroxyl, halogen, amino, phenyl, Ci_₆alkoxy, and Ci_₆alkyl, wherein each phenyl and Ci_ C₆alkyl is optionally substituted by one, two, or threesubstituents each independently selected from the group consisting of halogen, hydroxyl and amino; and R^s is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, hydroxyl, and halogen.

In certain embodiments, each R⁶ and R⁷ can be hydrogen. In certain embodiments, one, two, three or four of R⁶ and R⁷ can be fluoro.

In certain embodiments, R¹ and R² can be -CH2-phenyl.

In certain embodiments, R³ can be hydrogen. In other embodiments, R³ can be -C(O)- Ci-Cealkyl. In other embodiments, R³ can be -C(0)-Ci-C₆alkyl. For example, R³ can be isobutyl, -C(0)-isopropyl or -C(0)-CFl₃. In certain embodiments, R³ can be hydrogen or isobutyl.

Also provided are compounds having Formula IV

R³ is selected from the group consisting of hydrogen, methyl, and -CFF-phenyl, wherein phenyl is optionally substituted by one, two or three substituents each independently selected from R^T; and

R⁹ is selected from the group consisting of hydrogen and -C_|-Q, alkyl, wherein C i -C_halky 1 is optionally substituted by one, two or three substituents each independently selected from R^s;

R^a and R^b are each independently, for each occurrence, selected from the group consisting of hydrogen, phenyl, -Ci-C₃alkylene -phenyl and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci- C₃alkyl is optionally substituted with one, two, or three halogens; R^s is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, hydroxyl, -SH, phenyl, -O-CFF-phenyl, and halogen, wherein phenyl is optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C₄alkoxy, -Ci-C₄alkyl, and -CF₃; and

In certain embodiments, R⁹ is selected from the group consisting of:

where R^a and R^b are each independently selected for each occurrence from the group consisting of hydrogen and methyl.

In certain embodiments, R⁹ is selected from the group consisting of:

In certain embodiments, R⁹ is selected from the group consisting of:

In certain embodiments, R² is hydrogen.

In certain embodiments, R³ is H, methyl, -CFF-phenyl, or -ChF-i -F-phenyl).

In addition, provided herein is a compound represented by Formula V :

where R² is selected from the group consisting of hydrogen, -CrO, alkyl, -C(0)-Ci-Cealkyl, and -C(0)-0-Ci-Cealkyl, wherein CrO, alkyl is optionally substituted by one, two or three substituents each independently selected from R^s;

R³ is selected from the group consisting of hydrogen and -CrQ, alkyl, wherein CrO, alkyl is optionally substituted by one, two or three substituents each independently selected from R^s; R^a and R^b are each independently, for each occurrence, selected from the group consisting of hydrogen, phenyl, -Ci-C₃alkylene -phenyl and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -C_]-C₃alkyl, and halogen, and -Ci- C₃alkyl is optionally substituted with one, two, or three halogens; and

R^s is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, hydroxyl, -SH, phenyl, -0-CH₂-phenyl, and halogen, wherein phenyl is optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C₄alkoxy, -Ci-C₄alkyl, and -CF₃.In various embodiments, R² is hydrogen.

In some embodiments, R³ is hydrogen or methyl.

In certain embodiments, at least one of R^a and R^b is hydrogen. In particular embodiments, each of R^a and R^b is hydrogen.

Also provided is a compound represented by Formula VI or Formula VII:

w is 0, 1, or 2;

n is 1, 2, or 3;

R⁴, R⁵, R⁶ and R⁷ are independently, for each occurrence, selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, Ci_C4alkyl, C2-C₄alkenyl, -NH-C(0)-Ci_ Cgalkyl, -NH-C(0)-Ci_C₆alkylene-phenyl, -NH-C(0)-0-Ci_C₆alkyl, and -NH-C(0)-0-Ci_ Cgalkylene-phenyl; wherein Ci_C4alkyl, Ci_Cgalkylene, C2-C4alkenyl, Ci_C4alkoxy, and phenyl are each optionally substituted by one, two, or threesubstituents each independently selected from R^p;

wherein for the compound of Formula I, an R⁶ and an R⁷ taken together with the adjacent carbons to which they are attached form a 3-membered carbocyclic ring which is optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C3alkyl, -Ci-C3alkoxy, -C(0)NR^aR^b, and -NR^aR^b;

R^a and R^b are independently, for each occurrence, selected from the group consisting of hydrogen, -CfOj-O-CFF-phenyl, and -Ci-C4alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C3alkoxy, -Ci-C3alkyl, and halogen, and -Ci-C3alkyl is optionally substituted with one, two, or three halogens; R^p is independently, for each occurrence, selected from the group consisting of -CO2H, hydroxyl, halogen, amino, phenyl, Ci-Cealkoxy, and Ci-Cealkyl, wherein each phenyl and Ci_ C₆alkyl is optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl and amino;

In certain embodiments, R¹ and R² can be hydrogen. In certain embodiments, R¹ and R² can be -CH₂-phenyl, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T. In certain embodiments, at least one of R¹ and R² can be - CH2-phenyl, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T.

In certain embodiments, R¹ and R² can be -Ci-C₆alkyl each independently and optionally substituted by one, two or three substituents independently selected from the group consisting of -C(0)NR^aR^b, hydroxyl, -SH, and halogen. For example, R¹ and R² can be independently selected from the group consisting of:

where R^a and R^b are each independently selected for each occurrence from the group consisting of hydrogen and -Ci-C3alkyl.

In certain embodiments, R³ can be hydrogen. In certain embodiments, R³ can be -Ci- C₆alkyl optionally substituted by one, two or three substituents each independently selected from R^s. For example, R³ can be methyl, isobutyl, or -CFF-phenyl. In certain embodiments, , R³ can be hydrogen, methyl, or isobutyl.

In certain embodiments, R³ can be -C(0)-Ci-C₆alkyl. For example, R³ can be -C(O)- isopropyl or -C(0)-CH₃. In certain embodiments, R³ can be -C(0)-0-Ci-C₆alkyl. For example, R³ can be -C(0)-0-tert-butyl.

In certain embodiments, R³ can be -S(0)_w-R³¹· In certain embodiments, R³ can be - S0₂-Ci-C₆alkyl. For example, R³ can be -SO₂-CH₃.

In certain embodiments, R⁴, R⁵, R⁶, and R⁷ can be hydrogen. In other embodiments, one, two, three or four of R⁶ and R⁷, independently, can be fluoro.

In certain embodiments, n is 1.

Further, provided herein is a compound represented by Formula VIII or Formula IX:

R³ is -S(0)_w-Ci-C₆alkyl;

w is 0, 1, or 2;

R^a and R^b are independently, for each occurrence, selected from the group consisting of hydrogen, -C(0)-0-CH₂-phenyl, and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C3alkoxy, -Ci-C3alkyl, and halogen, and -Ci-C3alkyl is optionally substituted with one, two, or three halogens; R^s is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, hydroxyl, -SH, phenyl, -0-CH₂-phenyl, and halogen, wherein phenyl is optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C₄alkoxy, -Ci-C₄alkyl, and -CF₃; and

R^T is independently for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, -Ci-C₄alkoxy, -Ci-C₄alkyl, hydroxyl, and halogen, wherein Ci-C₄alkyl is optionally substituted with one, two, or three halogens.

In certain embodiments, R¹ and R² can be hydrogen.

In certain embodiments, R³ can be -SC^Me.

Further, provided herein is a compound represented by Formula X

R² is selected from the group consisting of hydrogen, -Ci-C₆alkyl, -C(0)-Ci-C₆alkyl, -C(0)-0- Ci-Cealkyl, and -O-CFF-phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R³ is -S(0)_w-Ci-C₆alkyl;

w is 0, 1, or 2;

R⁹ is selected from the group consisting of hydrogen and -Ci-Cealkyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s; R¹⁰ is selected from the group consisting of hydrogen and -C_]-Q, alkyl;

R^a and R^b are each independently, for each occurrence, selected from the group consisting of hydrogen, phenyl, -Ci-C3alkylene -phenyl and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci- C₃alkyl is optionally substituted with one, two, or three halogens; R^s is independently, for each occurrence, selected from the group consisting of -C(0)NR^aR^b, - NR^aR^b, hydroxyl, -SH, phenyl, -0-CH₂-phenyl, and halogen, wherein phenyl is optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C₄alkoxy, -Ci-C₄alkyl, and -CF₃; and

In certain embodiments, R² can be hydrogen or -O-CFF-phenyl.

In certain embodiments, R⁹ can be selected from the group consisting of:

wherein R^a and R^b can be independently, for each occurrence, selected from the group consisting of hydrogen and -Cr alkyl.

In certain embodiments, R⁹ can be selected from the group consisting of:

In certain embodiments, R⁹ can be selected from the group consisting of:

In certain embodiments, R¹⁰ can be hydrogen or methyl.

In certain embodiments of the compounds of the present disclosure, R¹, R², and/or R³ 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(0)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. 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, 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, R¹, R², and/or R³ 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 particular embodiments, a disclosed compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof.

In certain embodiments, a disclosed compound is selected from the compounds delineated in the Examples including Tables 1, 2, and 3, and includes a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof.

The compounds of the present disclosure and formulations thereof may have a plurality of chiral centers. Each chiral center may be independently R, S, or any mixture of R and S. For example, in some embodiments, a chiral center may have an R:S ratio of between about 100:0 and about 50:50 (“racemate”), 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 characteristic relative to racemic formulations of a disclosed compounds or mixture of compounds. In some instances, chemical formulas contain the descriptor“-I-“ 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.

Disclosed compounds may provide for efficient cation channel opening at the NMDA receptor, e.g. 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. The disclosed compounds may be used to regulate (turn on or turn off) the NMDA receptor through action as an agonist or antagonist.

The compounds described herein, in some embodiments, may bind to a specific NMDA receptor subtypes. For example, a disclosed compound may bind to one NMDA subtype and not another. In certain embodiments, a disclosed compound may bind to one, or more than one NMDA subtype, and/or may have substantially less (or substantial no) binding activity to certain other NMDA 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 lO-fold or greater than the activity of existing NMDA receptor modulators.

The disclosed compounds may 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 = (TD5o):(ED5o). In some embodiments, a disclosed compound may 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 of the disclosure, a pharmaceutical formulation or a pharmaceutical composition including a disclosed compound and a pharmaceutically acceptable excipient are provided. In some embodiments, a pharmaceutical composition includes a racemic mixture or a varied stereoisomeric mixture 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 therapeutically 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 may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may 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 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, poly anhydrides, 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 required other 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 some embodiments, a 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 generally include administering a therapeutically effective amount of a compound described herein or a composition including such a compound. In some embodiments, the condition may be a mental condition. For example, a mental illness may be treated. In some embodiments, a nervous system condition may be treated. For example, a condition that affects the central nervous system, the peripheral nervous system, and/or the eye may be treated. In some embodiments, neurodegenerative diseases may 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, the present disclosure provides methods of treating a cognitive impairment disorder, for example, a dysfunction in learning and/or memory such as that seen in age-related cognitive decline, Lewy body dementia, AIDS dementia, HIV dementia, vascular dementia, mild cognitive impairment in Huntington’s disease, Huntington’s disease dementia, mild cognitive impairment in Parkinson’s disease, Parkinson’s disease dementia, mild cognitive impairment in Alzheimer’s disease, Alzheimer’s dementia, frontotemporal dementia, cognitive impairment associated with schizophrenia (CIAS), and cognitive impairment associated with seizures, stroke, cerebral ischemia, hypoglycemia, cardiac arrest, migraine, multiple sclerosis, traumatic brain injury, and/or Down’s syndrome.

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 may be treated using the methods and compositions disclosed herein. Psychotic disorders such as schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, and psychotic disorders with delusions or hallucinations may also be treated using the compositions disclosed herein.

Paranoid schizophrenia may be characterized where delusions or auditory hallucinations are present, but thought disorder, disorganized behavior, or affective flattening are not.

Delusions may be persecutory and/or grandiose, but in addition to these, other themes such as jealousy, religiosity, or somatization may also be present. Disorganized type schizophrenia may be characterized where thought disorder and flat affect are present together. Catatonic type schizophrenia may be characterized where the patient may be almost immobile or exhibit agitated, purposeless movement. Symptoms can include catatonic stupor and waxy flexibility. Undifferentiated type schizophrenia may be characterized where psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met.

Residual type schizophrenia may be characterized where positive symptoms are present at a low intensity only. Post-schizophrenic depression may be characterized where a depressive episode arises in the aftermath of a schizophrenic illness where some low-level schizophrenic symptoms may still be present. Simple schizophrenia may 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 may be present in other mental disorders, including, but not limited to, bipolar disorder, borderline personality disorder, drug intoxication, and drug-induced psychosis. In some embodiments, methods for treating delusions (e.g.,“non-bizarre”) that may 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.

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 include a method of treating autism and/or an autism spectrum disorder in a patient need thereof, comprising administering an effective amount of a compound to the patient. In some embodiments, a method for reducing the symptoms of autism in a patient in need thereof comprises administering an effective amount of a disclosed compound to the patient. For example, upon administration, the compound may 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 may 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 comprising contacting a cell with an effective amount of a compound described herein.

The autism gene expression may be for example, selected from ABAT, APOE, CHRNA4, GABRA5,GFAP, GRIN2A, PDYN, and PENK. In certain embodiments, a method of modulating synaptic plasticity in a patient suffering from a synaptic plasticity related disorder is provided, comprising administering to the patient an effective amount of a compound.

In some embodiments, a method of treating Alzheimer’s disease, or e.g., treatment of memory loss that e.g., accompanies early stage Alzheimer’s disease, in a patient in need thereof is provided, comprising administering a compound. Also provided herein is a method of modulating an Alzheimer’s amyloid protein (e.g., beta amyloid peptide, e.g. the isoform Abi_ ₄₂), in-vitro or in-vivo (e.g. in a cell) comprising contacting the protein with an effective amount of a compound is disclosed. For example, in some embodiments, a compound may 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 may provide neuroprotective properties to a Alzheimer’s patient in need thereof, for example, may 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 therapeutically effective amount of a disclosed compound to a patient in need thereof.

In certain embodiments, a method of treating depression includes administering a therapeutically effective amount of a compound described herein. In some embodiments, the treatment may 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 this aspect 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. Anxiety or any of the symptoms thereof may be treated by administering a compound as described herein.

Also provided herein are methods of treating a condition in treatment-resistant patients, e.g., 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, comprising a) optionally identifying the patient as treatment resistant and b) administering an effective dose of a compound to said patient.

In some embodiments, a compound described herein may be used for acute care of a patient. For example, a compound may be administered to a patient to treat a particular episode (e.g., a severe episode) of a condition disclosed herein.

Also provided herein are combination therapies comprising a compound of the disclosure in combination with one or more other active agents. For example, a compound may be combined with one or more antidepressants, such as tricyclic antidepressants, MAO-I’s, SSRI’s, and double and triple uptake inhibitors and/or anxiolytic drugs. Exemplary drugs that may be used in combination with a 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 another example, a compound may 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 compound and one or more of the above therapeutics may 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: Ac is acetyl (-C(0)CH₃), ACN is acetonitrile, AIDS is acquired immune deficiency syndrome, Boc and BOC are tert- butoxycarbonyl, Boc₂0 is di-ieri-butyl dicarbonate, Bn is benzyl, BOM-C1 is benzyloxymethyl chloride, CAN is ceric ammonium nitrate, Cbz is carboxybenzyl, DCM is dichloromethane, DEA is diethylamine, DIAD is diisopropyl azodicarboxylate, DTAD is di- tert-butyl azodicarboxylate, DIPEA is /V,/V-diisopropylethylamine, DMAP is 4- dimethylaminopyridine, DMF is V.V-di methyl formamide, DMSO is dimethyl sulfoxide, EDC and EDCI are l-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- 1 H- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate, HIV is human immunodeficiency virus, HPLC is high performance liquid chromatography, IBCF is isobutyl chloroformate, LAH is lithium aluminum hydride, LCMS is liquid chromatography/mass spectrometry, LiHMDS is lithium hexamethyldisilazane, Ms is methanesulfonyl, NMDAR is N-methyl-d-apartate receptor, NMR is nuclear magnetic resonance, Pd/C is palladium on carbon, PMB is para- methoxybenzyl, RT is room temperature (e.g., from about 20 °C to about 25 °C), TEA is triethylamine, TLC is thin layer chromatography, TFA is trifluoroacetic acid, THF is tetrahydrofuran, TPP is triphenylphosphine, LDA is lithium diisopropylamide, TBSC1 is tert-butyldimethylsilyl chloride, TBAF is tetra-n-butylammonium fluoride, TsCl is tosyl chloride or p-toluenesulfonyl chloride, IBCF is isobutyl chloroformate, NMM is N- methylmorpholine, and DMP is Dess-Martin periodinane.

A. SYNTHESIS OF COMPOUNDS

Synthesis of AE & AF :

Synthesis of dimethyl l-benzylpyrrolidine-2,5-dicarboxylate (1):

To a solution of dimethyl 2,5-dibromohexanedioate (SM-1) (100 g, 0.301 mol) in toluene and water (400 mL, 3:1) were added K₂CO₃ (49.88 g, 0.361 mol) and benzylamine (32.23 g, 0.301 mol). The reaction mixture was heated to 80 °C under nitrogen atmosphere and stirred for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature and added EtOAc (200 mL). After stirring for 10 minutes, the organic layer was separated and washed with brine. The organic layer was dried over anhydrous Na SCL and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 20% EtOAc/n-hexane to afford meso compound 1 (48 g, 57%) as a brown thick liquid along with 13 g of racemic compound.

7.19 (m, 5H), 3.83 (s, 2H), 3.48 (s, 6H), 3.42-3.36 (m, 2H), 2.09-1.98 (m, 2H), 1.94-1.83 (m, 2H).

LCMS (ESI): m/z 277.9 [M⁺+l]

Synthesis of l-(tert-butyl) 2,5-dimethyl pyrrolidine- 1, 2, 5-tricarboxylate (2):

To a stirred solution of dimethyl l-benzylpyrrolidine-2,5-dicarboxylate (1) (65 g, 0.234 mol) in methanol (650 mL) were added B0C₂O (80.7 mL, 0.351 mol) and 10% Pd/C (50% wet , 32 g) at room temperature under nitrogen atmosphere. The reaction mixture was stirred under ¾ atmosphere (balloon pressure) for 24 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. The crude was purified by column chromatography eluting with 40% EtOAc/ /7-hexane to afford compound 2 (59 g, 88%) as an off white solid.

MHz, DMSO-ifc) d 4.30 - 4.17 (m, 2H), 3.65 (s, 3H), 3.63 (s, 3H), 2.27 - 2.12 (m, 2H), 1.96 - 1.87 (m, 2H), 1.34 (s, 9H).

LCMS (ESI): m/z 288.2 [M⁺+l]

Synthesis of 5-(tert-butyl) 6-methyl 2-(benzyloxy)-l-oxo-2,5-diazaspiro[3.4]octane-5,6- dicarboxylate (3):

To a solution of compound 2 (90 g, 0.313 mol) in THF (800 mL) was added to

LiHMDS (1M solution in THF, 470 mL, 0.47 mol) drop wise at -78 °C under nitrogen atmosphere. After being stirred at -78 °C for 1 h, a solution of Int-A (50.8 g, 0.376 mol) in THF (100 mL) was added and reaction mixture was stirred at room temperature for 16 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH₄Cl (500 mL) and extracted with EtOAc (2 x 500 mL). The separated organic layer was washed with brine, dried over Na₂S04 and concentrated under reduced pressure. Obtained crude was purified by column chromatography eluting with 30% EtO Ac/hexane to afford compound 3 (84 g, 68%) as a brown thick liquid.

7.36 (m, 5H), 4.95-4.85 (m, 2H), 4.29 (br d, J = 6.4 Hz, 1H), 4.07-3.99 (m, 1H), 3.71 (s, 3H), 3.55 (d, J = 10.7 Hz, 1H), 2.36-2.16 (m, 2H), 2.13-2.02 (m, 1H), 1.98-1.91 (m, 1H), 1.35 (s, 9H).

LCMS (ESI): m/z 391.3 [M⁺+l]

Synthesis of methyl 2-(benzyloxy)-l-oxo-2,5-diazaspiro[3.4]octane-6-carboxylate (4):

To a stirring solution of compound 3 (37 g, 0.094 mol) in CH2CI2 (370 mL) was added TFA (77.3 mL, 0.948 mol) at 0 °C and stirred at room temperature for 4 h. After consumption of the starting material (by TLC), reaction mixture was concentrated under reduced pressure. The crude was diluted with CH2CI2 (500 mL) and adjusted pH to 10-11 with saturated aqueous NaHC0₃. The organic layer was extracted with CH2CI2 (2 x 500 mL), dried over Na₂S04 and concentrated under reduced pressure to afford compound 4 (27 g, 98%) as a thick liquid.

7.25 (m, 5H), 4.96-4.75 (m, 2H), 3.67 (s, 3H), 3.65- 3.50 (m, 3H), 3.36 (d, J = 9.6 Hz, 1H), 1.97-1.74 (m, 4H).

LCMS (ESI): m/z 290.9 [M⁺+l] Synthesis of 2-(benzyloxy)-l-oxo-2,5-diazaspiro[3.4]octane-6-carboxamide (5):

To a solution of compound 4 (27 g, 0.093 mol) in MeOH (270 mL) was added methanolic ammonia (7.0 N solution, 270 mL) at -20 °C in a sealed tube under nitrogen atmosphere. 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. Crude was triturated with Et₂0 and dried under vacuum to afford compound 5 (20 g, 79%) as a white solid.

7.35 (m, 5H), 7.23-7.11 (m, 2H), 4.96-4.76 (m, 2H), 3.73 (s, 1H), 3.56 (d, J = 7.0 Hz, 1H), 3.53-3.43 (m, 2H), 1.99-1.89 (m, 1H), 1.85-1.67 (m, 3H). LCMS (ESI): m/z 275.9 [M⁺+l]

Synthesis of 2-(benzyloxy)-5-methyl-l-oxo-2,5-diazaspiro[3.4]octane-6-carboxamide (6):

To a solution of compound 5 (3 g, 10.9 mmol) in MeOH (30 mL) were added paraformaldehyde (982 mg, 32.7 mmol) and AcOH (0.12 mL, 2.18 mmol) at room temperature under nitrogen atmosphere. After being stirred for 1 h, NaBH₃CN (2.05 g, 32.7 mmol) was added portion wise and allowed to stir at 55 °C for 20 h. After consumption of the starting material (by TLC), the reaction mixture was cooled, quenched with ice and volatiles were evaporated under reduced pressure. Crude material was dissolved in CH2CI2 and washed with saturated aqueous NaHC0₃ and brine. Organic layer was dried over Na₂S04 and concentrated under reduced pressure. Crude material was purified by silica gel column chromatography eluting with 5% EtOAc/ n-hexane to afford compound 6 (2 g, 64%) as a thick liquid.

7.34 (m, 5H), 7.24-7.16 (m, 2H), 4.97-4.86 (m, 2H), 3.76 (d, J = 6.9 Hz, 1H), 3.47-3.431 (m, 2H), 2.24 (s, 3H), 2.03-1.89 (m, 2H), 1.82-1.77 (m, 2H).

LCMS (ESI): m/z 289.9 [M⁺+l]

Synthesis of 5-methyl-l-oxo-2,5-diazaspiro[3.4]octane-6-carboxamide (AE & AF):

To a stirring solution of Raney Nickel (1.5 g) in MeOH (10 mL) was added compound 6 (2 g, 6.92 mmol) in MeOH (10 mL) at room temperature and the reaction mixture was stirred under H₂ atmosphere (balloon) 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 MeOH (10 mL). Obtained filtrate was concentrated under reduced pressure. The crude was triturated with 77-pentane and dried under vacuum to afford mixture of AE & AF (1.2 g, 94%) as a white solid. The mixture of AE & AF was separated by chiral preparative HPLC purification to afford AE (330 mg) as a white solid and AF (270 mg) as a white solid.

AE

NMR (500 MHz, DMSO-rfe): d 7.36 (s, 1H), 7.23, 7.12 (2s, 2H), 3.44 (d, J = 12.8 Hz, 1H), 3.21 (br d, J = 4.6 Hz, 1H), 3.14 (dd, J = 12.5, 2.6 Hz, 1H), 2.32 (s, 3H), 2.09-1.96 (m, 3H),

1.82-1.75 (m, 1H)

LCMS (ESI): m/z 183.9 [M⁺+l]

HPLC: 96.25%

Chiral HPLC: >99%

Column : CHIRALPAK IC (250*4.6 mm, 5mhi)

Mobile Phase : A: 0.1% DEA in n- Hexane

Mobile Phase : B: EtOH : MeOH (50 : 50)

A : B :: 85 : 15; Flow rate : 1.0 mL/min

Retention time : 25.93

AF

1H-NMR (500 MHz, DMSO-rfc) d 7.36 (s, 1H), 7.23, 7.12 (2s, 2H), 3.44 (d, J = 12.8 Hz, 1H), 3.21 (br d, J = 5.2 Hz, 1H), 3.14 (dd, J = 12.8, 2.9 Hz, 1H), 2.32 (s, 3H), 2.12-1.95 (m, 3H),

1.82-1.73 (m, 1H)

LCMS (ESI): m/z 183.9 [M⁺+l]

HPLC: 99.95%

Chiral HPLC: >99%

Column : CHIRALPAK IC (250*4.6 mm, 5mhi)

Mobile Phase : A: 0.1% DEA in n- Hexane

Mobile Phase : B: EtOH : MeOH (50 : 50)

A : B :: 85 : 15; Flow rate : 1.0 mL/min

Retention time : 26.91 Synthesis of AA. AB. & AC:

Synthesis of compound 2 has been captured under the synthesis of AE & AF (as compound 2). Synthesis of tert-butyl l,7-dioxo-2,5,8-triazadispiro[3.1.36.24]undecane-5-carboxylate (3):

To a stirring solution of compound 2 (20 g, 0.069 mol) in THF (100 mL) was added paraformaldehyde (4.17 g, 0.139 mol) at -78 °C under nitrogen atmosphere. LiHMDS (1M solution in THF, 417 mL, 0.417 mol) was added drop wise at -78 °C. The 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 crushed ice (20 g) and filtered. The filtrate was evaporated under reduced pressure. Obtained crude was purified by column chromatography eluting with 4% MeOH/ CH₂CI₂ to afford compound 3 (8 g, 42%) as an off white solid.

(500 MHz, DMSO-cfe) d 8.02 - 7.81 (m, 2H), 3.58 (d, J = 4.6 Hz, 1H), 3.36 (d, J = 4.6 Hz, 1H), 3.23 - 3.09 (m, 2H), 2.18 - 1.98 (m, 4H), 1.38 (d, J = 2.3 Hz, 9H).

LCMS (ESI): m/z 226.0 [(M⁺+l)-i-Bu]

Synthesis of tert-butyl 2,8-dibenzyl-l,7-dioxo-2,5,8-triazadispiro[3.1.36.24]undecane-5- carboxylate (4):

To a stirring solution of compound 3 (7 g, 0.024 mol) in DMF (70 mL) were added CS₂CO₃ (32.43 g, 0.099 mol) and benzyl bromide (8.86 mL, 0.074 mol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h.

After consumption of the starting material (by TLC), ice cold water (400 mL) was added and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine, dried over Na₂S0₄ and concentrated under reduced pressure. The crude was purified by column chromatography by eluting 30% EtOAc/ CH2CI2 to afford compound 4 (racemic, 4.3 g) and compound 4 (meso, 0.4 g) and compound 4 (mixture, 3 g) as off white solids.

NMR (400 MHz, DMSO-ifc) d 7.45 - 7.16 (m, 10H), 4.66 (dd, J = 4.5, 15.3 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.37 - 4.25 (m, 1H), 4.06 (br dd, J = 2.0, 15.3 Hz, 1H), 3.61 (d, J = 4.9 Hz, 1H), 3.42 - 3.36 (m, 1H), 3.25 - 3.17 (m, 1H), 3.12 (d, J = 5.0 Hz, 1H), 2.28 - 2.03 (m, 4H), 1.38 (s, 9H).

LCMS (ESI): m/z 462.2 [M⁺+l]

Synthesis of 2,8-dibenzyl-2,5,8-triazadispiro[3.1.36.24]undecane-l,7-dione (AA, AB):

To a stirring solution of racemic compound 4 (3 g, 6.50 mmol) in CH2CI2 (30 mL) was added TFA (4.97 mL, 65.07 mmol) at 0 °C and stirred at room temperature for 16 h. After consumption of the starting material (by TLC), reaction mixture was concentrated under reduced pressure. The crude was diluted saturated aqueous NaHC0₃ (100 mL) and adjusted pH to 8. The aqueous layer was extracted with EtOAc (3 x 100 mL) and washed with brine. Organic layer was dried over Na₂S0₄ and concentrated under reduced pressure. Obtained crude was purified by column chromatography eluting with 2% MeOH/ CH2CI2 to afford racemic mixture of AA & AB (1.4 g, 59%) as a white solid. The mixture of AA & AB was separated by chiral preparative HPLC purification to afford AA (500 mg) as a white solid and AB (400 mg) as a white solid.

AA

NMR (400 MHz, DMSO-ifc) d 7.42 - 7.33 (m, 4H), 7.32 - 7.21 (m, 6H), 4.44 - 4.33 (m, 2H), 4.32 - 4.25 (m, 2H), 4.20 (s, 1H), 3.24 (d, J = 5.1 Hz, 2H), 3.16 (d, J = 5.3 Hz, 2H), 2.09 - 1.99 (m, 4H)

LCMS (ESI): m/z 362.2 [M⁺+l]

HPLC: 99.75%

Chiral HPLC: 99.55%

Column : CHIRALPAK IC-3 (150*4.6 mm*3qm)

Mobile Phase : A: 0.1% DEA in n- Hexane

Mobile Phase : B: DCM : MeOH (50 : 50)

A : B :: 75 : 25; Flow rate : 1.0 mL/min

Retention time : 6.614 min AB

MHz, DMSO-ifc) d 7.41 - 7.33 (m, 4H), 7.31 - 7.22 (m, 6H), 4.45 - 4.33 (m, 2H),

4.33 - 4.24 (m, 2H), 4.19 (s, 1H), 3.24 (d, J = 5.3 Hz, 2H), 3.16 (d, J = 5.3 Hz, 2H), 2.13 - 1.96 (m, 4H)

LCMS (ESI): m/z 362.4 [M⁺+l]

HPLC: 99.40%

Chiral HPLC: 98.00%

Column : CHIRALPAK IC-3 (150*4.6 hihi*3mhi)

Mobile Phase : A: 0.1% DEA in n- Hexane

Mobile Phase : B: DCM : MeOH (50 : 50)

A : B :: 75 : 25; Flow rate : 1.0 mL/min

Retention time : 7.392 min

Synthesis of 2,8-dibenzyl-2,5,8-triazadispiro[3.1.36.24]undecane-l,7-dione (AC):

To a stirring solution of meso compound 4 (740 mg, 1.61 mmol) in CH2CI2 (10 mL) was added TFA (1.22 mL, 16.05 mmol) at 0 °C and stirred at room temperature for 16 h. After consumption of the starting material (by TLC), reaction mixture was concentrated under reduced pressure. The crude was diluted cold water (100 mL), basified with saturated aqueous NaHCCT (50 mL) and adjusted pH to 8. The aqueous layer was extracted with EtOAc (2 x 100 mL) and washed with brine. Organic layer was dried over Na₂S0₄ and concentrated under reduced pressure. Obtained crude was purified by column chromatography eluting with 5% MeOH/ CH2CI2 to afford AC (310 mg), which was further precipitated with CH2CI2 / ether and dried under vacuum to afford AC (205 mg) as a white solid.

AC

MHz, DMSO-ifc) d 7.42 - 7.32 (m, 4H), 7.31 - 7.19 (m, 6H), 4.45 - 4.33 (m, 2H), 4.32 - 4.22 (m, 2H), 4.08 (s, 1H), 3.20 (d, J = 5.1 Hz, 2H), 3.13 (d, J = 5.0 Hz, 2H), 2.17 - 1.94 (m, 4H)

LCMS (ESI): m/z 362.2 [M⁺+l]

HPLC: 99.72%

Chiral HPLC: 99.26%

Column : CHIRALPAK IC (250x4.6 mmxSpm)

Mobile Phase : A: 0.1% DEA in n- Hexane Mobile Phase : B: DCM : MeOH (50 : 50)

A : B :: 75 : 25; Flow rate : 1.0 mL/min

Retention time : 17.237 min

Synthesis of AD:

The experimental procedure for the synthesis of compound 1 has been captured under the synthesis of AE and AF (as compound 1).

Synthesis of dimethyl pyrrolidine-2, 5-dicarboxylate (2):

To a stirring solution of compound 1 (15 g, 0.054 mol, mixture) in methanol (100 mL) was added Pd/ C (50% wet) (6 g) at RT and stirred for 16 h under hb 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 (200 mL). Obtained filtrate was concentrated under reduced pressure. Crude material was triturated with methanol and ether to afford compound 2 (8 g, 79%) as white solid.

8.86 (m, 1H), 4.32 (br s, 2H), 3.73 (s, 6H), 2.28-2.18 (m, 2H), 2.06-1.96 (m, 2H).

LCMS (m/z): 188.1 [M⁺+l]

Synthesis of dimethyl l-isobutylpyrrolidine-2, 5-dicarboxylate (3):

To a stirring solution of compound 2 (3.9 g, 0.021 mol) in methanol (25 mL) were added isobutyraldehyde (2.2 g, 0.031 mol) and sodium cyanoborohydride (2.6 g, 0.041 mol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at RT for 4 h. After consumption of the starting material (by TLC), reaction mixture was quenched with ice water (1 mL) and concentrated under reduced pressure. Crude material was diluted with water (100 mL) and extracted with EtOAc (2 x 25 mL). Separated organic layer was dried over anhydrous Na₂S04 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 15% EtOAc/n-hexane to obtain compound 3 ( 3.5 g, 72%) as liquid.

3.60 (s, 6H), 3.31 (s, 2H), 2.39 (d, J = 7.4 Hz, 2H), 2.08-1.99 (m, 2H), 1.95-1.85 (m, 2H), 1.51-1.39 (m, 1H), 0.81 (s, 3H), 0.79 (s, 3H).

LCMS (m/z): 244.3 [M⁺+l]

Synthesis of 5-isobutyl-2,5,8-triazadispiro[3.1.36.24]undecane-l,7-dione (4):

To a stirring solution of compound 3 (4.5 g, 0.018 mol) in THF (60 mL) were added paraformaldehyde (1.1 g, 0.037 mol) and LiHMDS (1.0M in THF) (111 mL, 0.111 mol) at -50 °C under nitrogen atmosphere and stirred for lh. Then, reaction mixture was brought to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was quenched with ice water (25 mL) at 0 °C and extracted with EtOAc (3 x 25 mL). The combined organic layer was dried over Na₂S0₄ and concentrated to obtain crude compound which was purified by column chromatography by eluting with 10% MeOH/ DCM to afford compound 4

7.83 (s, 2H), 3.26 (d, J = 5.9 Hz, 2H), 3.08 (d, J = 5.9 Hz, 2H), 2.47 (d, J = 6.7 Hz, 1H), 2.34 (dd, J = 8.5, 13.4 Hz, 1H), 2.08-2.01 (m, 4H), 1.72-1.61 (m, 1H), 0.84 (d, J = 1.8 Hz, 3H), 0.82 (d, 7 = 1.9 Hz, 3H).

LCMS (ESI): m/z 238.0 [M⁺+l]

Synthesis of 2,8-dibenzyl-5-isobutyl-2,5,8-triazadispiro[3.1.36.24]undecane-l,7-dione (5):

To a stirring solution of compound 4 (1 g, 4.21 mmol) in DMF (6 mL) were added CS₂CO₃ (6.3 g, 19.38 mmol) and benzyl bromide (1.09 mL, 9.27 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was heated to 50 °C and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was cooled and diluted with Et₂0 (25 mL) and water (20 mL). Separated organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 20% EtOAc/n-hexane to afford compound 5 (1.2 g, 68%) as a white solid.

NMR (400 MHz, CDCl₃) d 7.39 - 7.27 (m, 6H), 7.22 - 7.19 (m, 4H), 4.54 - 4.45 (m, 2H), 4.27 - 4.18 (m, 2H), 3.38 (d, J = 6.0 Hz, 1H), 3.12 (d, J = 5.5 Hz, 1H), 3.02 (d, J = 5.9 Hz, 1H), 2.99 - 2.94 (m, 1H), 2.52 - 2.38 (m, 1H), 2.33 - 2.18 (m, 2H), 2.13 - 2.02 (m, 1H), 1.77 (s, 2H), 1.64 - 1.40 (m, 1H), 0.81 - 0.74 (m, 6H). LCMS (m/z): 418.2 [M⁺+l]

Synthesis of 2,8-dibenzyl-5-isobutyl-2,5,8-triazadispiro[3.1.36.24]undecane (AD):

To a stirring solution of AICI₃ (460 mg, 3.45 mmol) in Et₂0 (30 mL) was added LAH (1M in THF, 5.76 mL, 5.76 mmol) at 0 °C under nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was cooled to -30 °C, compound 5 (480 mg, 1.15 mmol) in Et₂0 (10 mL) was added dropwise and stirred at same temperature for 2 h. After consumption of the starting material (by TLC), reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (2 x 50 mL) and 10% MeOH/ CH₂Cl₂ (2 x 50 mL). The combined organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to afford crude compound which was purified by MPLC by eluting 10% MeOH/ EtOAc to obtain AD as an off white solid.

MHZ,CD₃OD) d 7.49 - 7.34 (m, 10H), 4.05 (s, 4H), 3.78 (br d, J = 9.7 Hz, 4H), 3.54 (br d, 7 = 10.0 Hz, 4H), 2.51 (d, 7 = 7.7 Hz, 2H), 2.16 (s, 4H), 1.54 - 1.45 (m, 1H), 0.83 (d, 7 = 6.5 Hz, 6H).

LCMS (m/z): 390 [M⁺+l]

Synthesis of AG & AH:

The experimental procedure for the synthesis of compound 3 has been captured under the synthesis of AE and AF (as compound 3).

Synthesis of 2-(benzyloxy)-5-(tert-butoxycarbonyl)-l-oxo-2,5-diazaspiro[3.4]octane-6- carboxylic acid (4):

To a solution of compound 3 (32 g, 0.082 mol) in MeOH, THF and water (480 mL, 1:1: 1) was added NaOH (9.84 g, 0.246 mol) at 0 °C and then stirred at room temperature for 16 h. After consumption of the starting material (by TLC), reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and washed with EtOAc. The aqueous layer was acidified with aqueous 2N HC1 (pH ~ 2.0) and extracted with EtOAc (2 x 200 mL). The organic layer was washed with brine, dried over Na₂S0₄ and concentrated under reduced pressure to afford compound 4 (32 g, crude) as a pale yellow semi solid. The crude was forwarded to next step without further purification.

MHz, DMSO-ri₆) d 12.89 (br s, 1H), 7.46-7.28 (m, 5H), 4.92-4.84 (m, 2H), 4.26 (br d, J = 7.0 Hz, 1H), 4.05-3.96 (m, 1H), 3.45 (br d, J = 11.0 Hz, 1H), 2.31-2.15 (m, 2H), 2.06- 1.88 (m, 2H), 1.35 (s, 9H).

LCMS (ESI): m/z 375.1 [M⁺-l]

Synthesis of 2-(benzyloxy)-5-(tert-butoxycarbonyl)-l-oxo-2,5-diazaspiro[3.4]octane-6- carboxylic (isobutyl carbonic) anhydride (5):

To a solution of compound 4 (46 g, 0.122 mol) in THF (460 mL) was added A-methyl morpholine (40.3 mL, 0.367 mol) and isobutyl chloroformate (20.5 mL, 0.159 mol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with water (230 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to afford compound 5 (35 g, crude) as a colourless thick liquid. The crude was forwarded to next step without further purification.

7.33 (m, 5H), 4.94-4.84 (m, 2H), 4.27 (br d, J = 6.7 Hz, 1H), 4.12-3.96 (m, 1H), 3.86 (d, J = 6.7 Hz, 1H), 3.63 - 3.51 (m, 1H), 3.46 (d, J = 10.7 Hz,

1H), 2.39-2.36 (m, 1H), 2.28-2.16 (m, 2H), 2.07-1.82 (m, 2H), 1.36 (s, 9H), 0.88 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H). Synthesis of tert-butyl 2-(benzyloxy)-6-(hydroxymethyl)-l-oxo-2,5-diazaspiro[3.4]octane- 5-carboxylate (6):

To a solution of compound 5 (35 g, 0.073 mol) in MeOH (350 mL) was added sodium borohydride (2.79 g, 0.073 mol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 2 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with ice and volatiles were evaporated under reduced pressure. The crude was diluted with EtOAc (200 mL) and washed with water followed by brine. The organic layer was dried over anhydrous Na SCA and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30% EtO Ac/hexane to afford compound 6 (6.7 g, 25%) as a colourless thick liquid.

MHz, DMSO-i¾) d 7.47-7.35 (m, 5H), 4.96-4.82 (m, 3H), 4.25 (d, J = 7.3 Hz, 1H), 3.90 (dd, J = 5.6, 11.2 Hz, 1H), 3.77-3.66 (m, 2H), 3.34 (d, J = 10.4 Hz, 1H), 2.17-2.07 (m, 1H), 2.02-1.91 (m, 1H), 1.83-1.73 (m, 2H), 1.38 (s, 9H).

LCMS (ESI): m/z 363.1 [M⁺+l]

Synthesis of tert-butyl 2-(benzyloxy)-6-formyl-l-oxo-2,5-diazaspiro[3.4]octane-5- carboxylate (7):

To a solution of crude compound 6 (6.7 g, 0.018 mol) in CH2CI2 (67 mL) was added Dess-Martin periodinane (9.42 g, 0.022 mol) at 0 °C under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 2 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with saturated aqueous NaHC0₃. The organic layer was separated, washed with brine and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 40% EtOAc/n-hexane to afford compound 7 (5.8 g, 87%) as a colourless thick liquid.

MHz, DMSO-ifc) d 9.50 (s, 1H), 7.48-7.35 (m, 5H), 4.96 - 4.84 (m, 2H), 4.30 (br s, 1H), 3.85 (br d, J = 10.4 Hz, 1H), 3.59-3.47 (m, 1H), 2.26 (br s, 2H), 2.05-1.98 (m, 1H), 1.82 (br s, 1H), 1.36 (s, 9H).

Synthesis of tert-butyl 6-((((2S,3R)-l-amino-3-hydroxy-l-oxobutan-2-yl)amino)methyl)-2- (benzyloxy)-l-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate (8):

To a solution of compound 7 (5.8 g, 0.016 mol) in MeOH (87 mL) was added Int-B (2.28 g, 0.019 mol) under nitrogen atmosphere and stirred at room temperature for 30 minutes. NaBH₃CN (2.02 g, 0.032 mol) was added and stirred at room temperature for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was washed with brine, dried over Na SCL and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 2%

MeOH/ CH₂CI₂ to afford diastereomeric mixture 8 (3.4 g, 46%) as a white solid.

MHz, DMSO-ifc) d 7.45 - 7.36 (m, 5H), 7.26 - 7.19 (m, 1H), 7.07 - 7.03 (m,

1H), 4.93 - 4.78 (m, 3H), 4.23 - 4.17 (m, 1H), 3.71 - 3.62 (m, 2H), 3.43 - 3.37 (m, 1H), 3.12 - 2.94 (m, 1H), 2.86 - 2.84 (m, 1H), 2.73 - 2.67 (m, 2H), 2.38 - 2.24 (m, 1H), 1.96 - 1.91 (m, 1H), 1.81 - 1.76 (m, 2H), 1.39 (s, 9H), 1.07 - 1.04 (m, 3H).

LCMS (ESI): m/z 463.2 [M⁺+l]

Synthesis of tert-butyl 6-((((2S,3R)-l-amino-3-hydroxy-l-oxobutan-2-yl)(methyl) amino)methyl)-2-(benzyloxy)-l-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate (9):

To a solution of compound 8 (1.8 g, 3.89 mmol) in MeOH (36 mL) were added paraformaldehyde (701 mg, 23.3 mmol) and AcOH (0.11 mL, 1.94 mmol). The reaction mixture was stirred at room temperature for 30 minutes. NaCNB¾ (734 mg, 11.6 mmol) was added to reaction mixture and stirred at 60 °C for 16 h. After consumption of the starting material (by TLC), cooled to room temperature and volatiles were evaporated. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by column chromatography by eluting with 4% MeOH/EtOAc to afford diastereomeric mixture 9 (1.3 g, 70%) as a white solid.

MHz, DMSO-ifc) d 7.48 - 7.36 (m, 5H), 7.32 (s, 1H), 7.00 (s, 1H), 4.92 - 4.80 (m, 2H), 4.22 (d, J = 6.8 Hz, 1H), 4.02 (s, 1H), 3.79 (d, J = 10.2 Hz, 2H), 3.48 (d, J = 10.3 Hz, 1H), 3.30 - 3.13 (m, 2H), 2.79 (d, J = 9.3 Hz, 1H), 2.41 (br s, 1H), 2.35 (s, 3H), 2.04 - 1.72 (m, 3H), 1.38 (s, 9H), 1.00 (d, J = 6.1 Hz, 3H).

LCMS (ESI): m/z All.2 [M⁺+l]

Synthesis of (2S,3R)-2-(((2-(benzyloxy)-l-oxo-2,5-diazaspiro[3.4]octan-6-yl)methyl) (methyl) amino)-3-hydroxybutanamide (10):

To a stirring solution of 9 (700 mg, 1.47 mmol) in CH₂CI₂ (14 mL) were added molecular sieves (700 mg) and BF₃.OEL₂ (49%) (417 mg, 2.94 mmol) drop wise at RT under nitrogen atmosphere. The reaction mixture was stirred for 4 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. The crude material was purified by reverse phase preparative HPLC to remove boron trifluoride diethyl etherate salts and obtained diastereomeric mixture 10 (235 mg, 42%) as a white solid.

7.27 (m, 6H), 6.94 (s, 1H), 4.94-4.77 (m, 2H), 4.79- 4.70 (m, 1H), 3.80-3.71 (m, 1H), 3.50-3.42 (m, 2H), 3.20-3.03 (m, 2H), 2.72 (d, J = 9.4 Hz, 1H), 2.41 (d, J = 14.7 Hz, 1H), 2.35 (s, 3H), 1.94-1.65 (m, 3H), 1.49-1.43 (m, 1H), 1.00 (d, J = 6.0 Hz, 3H).

LCMS (ESI): m/z 377.1 [M⁺+l]

Synthesis of (2S,3R)-3-hydroxy-2-(methyl((l-oxo-2,5-diazaspiro[3.4]octan-6-yl)methyl) amino)butanamide (11):

To a stirring mixture of 10 (1.2 g, 3.19 mmol) in MeOH (24 mL) was added Raney Ni (1.2 g) at RT and 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 MeOH (100 mL). Obtained filtrate was concentrated under reduced pressure to afford diastereomeric mixture 11 (800 mg, 92%) as white solid.

7.40 (br s, 1H), 7.15 (s, 1H), 6.93 (s, 1H), 5.02 (s, 1H), 3.80- 3.68 (m, 1H), 3.28 (d, J = 6.0 Hz, 1H), 3.14-3.06 (m, 3H), 2.82 (dd, J = 11.1, 2.6 Hz, 1H), 2.72 (d, J = 9.4 Hz, 1H), 2.39 (s, 3H), 2.37-2.33 (m, 1H), 1.92-1.74 (m, 3H), 1.63-1.51 (m, 1H), 0.99 (d, J = 6.0 Hz, 3H).

LCMS (ESI): m/z 271.1 [M⁺+l]

Synthesis of (2S,3R)-2-(((5-(4-fluorobenzyl)-l-oxo-2,5-diazaspiro[3.4]octan-6- yl)methyl)(methyl)amino)-3-hydroxybutanamide (AG & AH):

To a stirring mixture of 11 (1 g, 3.70 mmol) in DML (5 mL) were added K₂CO₃ (1.53 g, 11.1 mmol) and 4-fluoro benzyl bromide (1.04 g, 5.55 mmol) at RT under nitrogen atmosphere and reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), water (10 mL) was added and extracted with EtOAc (2 x 50 mL) and 10% MeOH and CH₂CI₂ (2 x 20 mL). The combined organic layer was dried over Na₂S0₄ and concentrated under reduced pressure. The crude was purified by basic alumina column chromatography by eluting 2% MeOH/ CH₂CI₂ to afford mixture of AG & AH (1 g) as an off white solid, which was further purified by chiral preparative HPLC purification to obtain AG (250 mg) as a white solid and AH (215 mg) as a white solid. AG

NMR (DMSO-_<¾, 500 MHz): d 7.39-7.32 (m, 2H), 7.27 (dd, J = 8.4, 5.5 Hz, 2H), 7.12 (t, J = 9.0 Hz, 2H), 6.94 (br s, 1H), 4.07 (d, J = 2.9 Hz, 1H), 4.04-4.39 (m, 1H), 3.84-3.76 (m, 1H), 3.35-3.31 (m, 1H), 3.26-3.22 (m, 1H), 3.01-2.91 (m, 2H), 2.86-2.81 (m, 1H), 2.77-2.72 (m, 2H), 2.38 (s, 3H), 2.19- 2.11 (m, 1H), 1.89-1.78 (m, 2H), 1.72-1.63 (m, 1H), 0.98 (d, J = 5.8 Hz, 3H)

LCMS (ESI): m/z 379.1 [M⁺+l]

HPLC: 97.13%

Chiral HPLC: 100.00%

Column : CHIRALPAK IC (250*4.6 mm, 5mhi)

Mobile Phase : A: 0.1% DEA in n-hexane

Mobile Phase : B: DCM : MeOH (80 : 20)

A : B :: 60 : 40; Flow rate : 1.0 mL/min

Retention time : 16.615

AH

NMR (DMSO-_<¾, 500 MHz) d 7.38 (br s, 2H), 7.31 (dd, J = 8.5, 5.7 Hz, 2H), 7.13 (t, J = 8.8 Hz, 2H), 6.97 (br s, 1H), 4.09-4.02 (m, 2H), 3.85-3.76 (m, 1H), 3.35 (s, 1H), 3.28 (s, 1H), 3.02- 2.90 (m, 2H), 2.86-2.73 (m, 3H), 2.42 (s, 3H), 2.26-2.12 (m, 1H), 1.90-1.78 (m, 2H), 1.74-1.64 (m, 1H), 1.01 (d, J = 6.0 Hz, 3H)

LCMS (ESI): m/z 379.1 [M⁺+l]

HPLC: 96.68%

Chiral HPLC: 99.08%

Column : CHIRALPAK IC (250*4.6 mm, 5mhi)

Mobile Phase : A: 0.1% DEA in n-hexane

Mobile Phase : B: DCM : MeOH (80 : 20)

A : B :: 60 : 40; Flow rate : 1.0 mL/min

Retention time : 18.965 Synthesis of AL

The experimental procedure for the synthesis of compound 11 has been captured under the synthesis of AG & AH (as compound 11).

Synthesis of (2S,3R)-2-(((5-benzyl-l-oxo-2,5-diazaspiro[3.4]octan-6- yl)methyl)(methyl)amino)-3-hydroxybutanamide (AL) :

To a stirring diastereomeric mixture of 11 (600 mg, 2.22 mmol) in DMF (10 mL) were added K₂CO₃ (919 mg, 6.66 mmol) and benzyl bromide (0.3 mL, 2.44 mmol) at RT under nitrogen atmosphere and the reaction mixture was stirred at RT for 12 h. After consumption of the starting material (by TLC), water (10 mL) was added and extracted with EtOAc (2 x 50 mL) and 10% MeOH/ CH₂CI₂ (2 x 20 mL). Combined organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to afford mixture of AL and AL-2 (500 mg, 62%) as an off white solid. The mixture of AL and AL-2 which was purified by chiral preparative HPLC purification to obtain AL (111 mg) as a white solid and AL-2 (95 mg, impure) as a white solid. AL

NMR (DMSO-_<¾, 500 MHz) d 7.40-7.19 (m, 7H), 6.95 (br s, 1H), 4.08 (d, J = 2.9 Hz, 1H), 4.06 (d, J = 13.9 Hz, 1H), 3.85-3.77 (m, 1H), 3.33 (d, J = 13.9 Hz, 1H), 3.30-3.25 (m, 1H), 3.03- 2.94 (m, 2H), 2.88-2.81 (m, 1H), 2.80-2.72 (m, 2H), 2.39 (s, 3H), 2.22-2.13 (m, 1H), 1.88-1.79 (m, 2H), 1.72-1.63 (m, 1H), 0.99 (d, J = 5.8 Hz, 3H)

LCMS (ESI): m/z 361.1 [M⁺+l]

HPLC: 99.09%

Chiral HPLC: 100.00%

Column : CHIRALPAK IA (250*4.6 mm, 5mhi)

Mobile Phase : A: 0.1% DEA in n-hexane

Mobile Phase : B: DCM : MeOH (80 : 20)

A : B :: 75 : 25; Flow rate : 1.0 mL/min

Retention time : 13.640

Synthesis of AK:

The experimental procedure for the synthesis of compound 10 has been captured under AG & AH (as compound 10).

Synthesis of (2S,3R)-2-(((2-(benzyloxy)-5-methyl-l-oxo-2,5-diazaspiro[3.4]octan-6- yl)methyl)(methyl)amino)-3-hydroxybutanamide (11):

To a stirring solution of 10 (1.1 g, 2.92 mmol) in MeOH (15 mL) were added paraformaldehyde (526 mg, 17.5 mmol) and AcOH (0.08 mL, 1.46 mmol) at 0 °C. After being stirred at RT for 30 minutes, NaCNBH₃ (551 mg, 8.71 mmol) was added and the reaction mixture was stirred at 60 °C for 12 h. After consumption of the starting material (by TLC), cooled to RT and volatiles were evaporated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (3x100 mL). The organic layer was dried over Na₂S0₄ and concentrated and the crude was purified by column chromatography by eluting 5% MeOH/CH₂Cl2 to afford compound 11 (1 g, 87%) as a white solid.

NMR (400 MHz, DMSO-i¾) d 7.46 - 7.32 (m, 6H), 6.95 (br s, 1H), 4.96 - 4.84 (m, 2H), 4.20 (d, J = 3.1 Hz, 0.5H), 4.11 - 4.05 (m, 0.5H), 3.85 - 3.71 (m, 1H), 3.58 (d, J = 10.8 Hz, 0.5H), 3.51 (d, J = 10.8 Hz, 0.5H), 3.30 - 3.15 (m, 2H), 2.82 - 2.68 (m, 2H), 2.65 - 2.52 (m, 1H), 2.33 (d, J = 9.8 Hz, 3H), 2.23 (d, J = 7.0 Hz, 3H), 2.12 - 1.81 (m, 2H), 1.74 - 1.60 (m, 2H), 1.00 (d, J = 6.0 Hz, 3H).

LCMS (ESI): m/z 391.1 [M⁺+l]

Synthesis of (2S,3R)-3-hydroxy-2-(methyl((5-methyl-l-oxo-2,5-diazaspiro[3.4]octan-6- yl)methyl)amino)butanamide (AK):

To a stirring solution of compound 11 (1 g, 2.56 mmol) in MeOH (50 mL) was added Raney Ni (5 g) at RT and stirred under H₂ atmosphere (balloon pressure) 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 MeOH (100 mL). Obtained filtrate was concentrated under reduced pressure to afford mixture of AK & AK-2 (650 mg, 89%) as white solid, which was purified by chiral preparative HPLC purification to obtain AK (221 mg) as a white solid.

AK

NMR (DMSO-<¾, 500 MHz) d 7.36, 7.26 (2br s, 2H), 6.93 (br s, 1H), 4.35-4.30 (m, 1H), 3.80-3.72 (m, 1H), 3.16-3.07 (m, 2H), 2.88-2.83 (m, 1H), 2.80-2.75 (m, 1H), 2.71-2.69 (m, 1H), 2.34 (s, 3H), 2.26 (s, 3H), 2.16 - 2.05 (m, 1H), 1.92-1.82 (m, 1H), 1.78-1.63 (m, 2H), 0.99 (d, J = 6.4 Hz, 3H) LCMS (ESI): m/z 285.1 [M⁺+l]

HPLC: 99.27%

Chiral HPLC: 100.00%

Column : CHIRALPAK IA (250*4.6 mm, 5mhi)

Mobile Phase : A: 0.1% DEA in n-hexane

Mobile Phase : B: DCM : MeOH (80 : 20)

A : B :: 75 : 25; Flow rate : 1.0 mL/min

Retention time : 14.252

Synthesis of AI & A.T:

The experimental procedure for the synthesis of compound 7 has been captured under AG & AH (as compound 7).

Synthesis of tert-butyl 2-(benzyloxy)-6-((((2S,3R)-3-hydroxy-l-(methylamino)-l- oxobutan-2-yl)amino)methyl)-l-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate (8):

To a solution of compound 7 (6 g, 16.6 mmol) in MeOH (70 mL) were added Int-D (2.6 g, 19.9 mmol) and AcOH (0.47 mL) at room temperature under nitrogen atmosphere. After being stirred for 30 minutes, NaBH₃CN (3.1 g, 49.9 mmol) was added portion wise and allowed to stir at RT for l6h. After consumption of the starting material (by TLC), the reaction mixture was quenched aqueous NaHC0₃ solution and volatiles were evaporated under reduced pressure. Crude material was diluted with NaHC0₃ solution (500 mL). The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3x500 mL). The organic layer was washed with brine solution, dried over Na₃S0₄ and concentrated under reduced pressure.

Obtained crude material was purified by column chromatography eluting with 3%

MeOH/CH2Cl2 to afford diastereomeric mixture 8 (5 g, 63%) as a white solid.

MHz, DMSO-i¾) d 7.76 (d, J = 4.6 Hz, 1H), 7.45 - 7.33 (m, 5H), 4.91 - 4.82 (m, 2H), 4.55 (s, 1H), 4.23 (d, J = 7.5 Hz, 1H), 3.68 (d, J = 9.9 Hz, 2H), 3.40 (d, J = 10.4 Hz, 1H), 3.05 (dd, J = 6.4, 12.2 Hz, 1H), 2.85 (t, J = 10.4 Hz, 1H), 2.75 (dd, J = 5.5, 8.4 Hz, 1H), 2.61 (d, J = 4.6 Hz, 3H), 2.29 - 2.18 (m, 1H), 2.15 - 2.07 (m, 1H), 2.02 - 1.91 (m, 1H), 1.85 - 1.73 (m, 2H), 1.38 (s, 9H), 1.03 (d, J = 5.8 Hz, 3H).

LCMS (ESI): m/z 477.5 [M⁺+l]

Synthesis of tert-butyl 2-(benzyloxy)-6-((((2S,3R)-3-hydroxy-l-(methylamino)-l- oxobutan-2-yl)(methyl)amino)methyl)-l-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate (9):

To a stirred solution mixture of 8 (2.5 g, 5.25 mmol) in MeOH (50 mL) was added paraformaldehyde (945 mg, 31.5 mmol) and acetic acid (0.2 mL, 2.62 mmol) at room temperature. After stirred for 1 h, sodium cyanoborohydride (989 mg, 15.7 mmol) was added portion wise. The reaction mixture was stirred at 70 °C for 16 h. After consumption of the starting material (by TLC), the reaction mixture was quenched aqueous NaHC0₃ and extracted with EtOAc (2 xlOO mL). Separated organic layer was washed with brine, dried over Na₂S0₄ and concentrated under reduced pressure. Obtained crude material was purified by column chromatography eluting with 3% MeOH/ CH2CI2 to afford diastereomeric mixture 9 (2.3 g, 92%) as an off white solid.

NMR (500 MHz, DMSO-i¾) d 7.83 (d, J = 4.5 Hz, 1H), 7.45-7.33 (m, 5H), 4.90-4.84 (m, 2H), 4.22 (d, J = 7.0 Hz, 1H), 4.05 (d, J = 2.9 Hz, 1H), 3.83-3.82 (m, 1H), 3.78 (d, J = 10.3 Hz, 1H), 3.48 (d, J = 10.1 Hz, 1H), 3.29 (s, 1H), 3.14 (d, J = 14.3 Hz, 1H), 2.76 (d, J = 9.1 Hz, 1H), 2.59 (d, J = 4.3 Hz, 3H), 2.43-2.36 (m, 1H), 2.35 (s, 3H), 2.00-1.74 (m, 3H), 1.38 (s, 9H), 0.96 (d, 7 = 6.1 Hz, 3H).

LCMS (ESI): m/z 491.1 [M⁺+l] Synthesis of (2S,3R)-2-(((2-(benzyloxy)-l-oxo-2,5-diazaspiro[3.4]octan-6-yl)methyl) (methyl)amino)-3-hydroxy-N-methylbutanamide (10):

To a stirring solution of 9 (800 mg, 1.63 mmol) in CH2CI2 (20 mL) were added molecular sieves (800 mg) and BF3.OEL2 (49%) (463 mg, 3.26 mmol) drop wise at RT under nitrogen atmosphere. The reaction mixture was stirred for 4 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure to afford diastereomeric mixture 10 (410 mg) as a hygroscopic white solid

7.84 (d, J = 4.5 Hz, 1H), 7.44-7.35 (m, 5H), 4.94-4.81 (m, 2H), 4.26 (s, 1H), 3.83-3.74 (m, 1H), 3.65 (d, J = 9.7 Hz, 1H), 3.45 (d, J = 6.7 Hz, 1H), 3.23 (br s, 1H), 3.06 (d, J = 9.7 Hz, 1H), 2.74-2.61 (m, 4H), 2.57 (d, J = 4.5 Hz, 3H), 2.34 (s, 2H), 1.90- 1.73 (m, 2H), 1.51-1.47 (m, 2H), 0.94 (d, J = 5.9 Hz, 3H).

LCMS (ESI): m/z 391.3 [M⁺+l]

Synthesis of (2S,3R)-3-hydroxy-N-methyl-2-(methyl((l-oxo-2,5-diazaspiro[3.4]octan-6- yl)methyl)amino)butanamide (AI & AJ):

To a solution mixture of 10 (2 g, 5.12 mmol) in MeOH (30 mL) was added Raney nickel (2 g) at room temperature and stirred under ¾ atmosphere (balloon) 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 MeOH (50 mL). Obtained filtrate was concentrated under reduced pressure to afford a mixture of AI & AJ (1.3 g) as an off white solid. Mixture of AI & AJ (1.3 g) was separated by chiral preparative HPLC purification to obtain AI (290 mg) as a white solid and AJ (280 mg) as a white solid.

MHz, DMSO-ri₆) d 7.86 (br d, J = 4.6 Hz, 1H), 7.13 (s, 1H), 4.32 (br s, 1H), 3.87 - 3.74 (m, 1H), 3.36 - 3.26 (m, 3H), 2.83 - 2.72 (m, 2H), 2.70 - 2.60 (m, 2H), 2.58 (d, J = 4.5 Hz, 3H), 2.36 (s, 3H), 1.93 - 1.72 (m, 2H), 1.69 - 1.48 (m, 2H), 0.95 (d, 7 = 6.0 Hz, 3H)

LCMS (ESI): m/z 285.1 [M⁺+l]

HPLC: 98.26%

Chiral HPLC: 100.00%

Column : CHIRALPAK IC (250*4.6 mm* 5 pm)

Mobile Phase : A: 0.1% DEA in n-hexane

Mobile Phase : B: DCM : MeOH (50 : 50) A : B :: 70 : 30; Flow rate : 1.0 mL/min

Retention time : 11.840

M

(400 MHz, DMSO-cfe) d 7.90 (br d, J = 4.5 Hz, 1H), 7.15 (s, 1H), 5.28 - 4.88 (m, 1H), 3.81 - 3.69 (m, 1H), 3.29 (br d, J = 5.9 Hz, 1H), 3.20 - 3.05 (m, 3H), 2.82 (dd, J = 2.5, 11.0 Hz,

1H), 2.69 (d, J = 9.4 Hz, 1H), 2.57 (d, J = 4.5 Hz, 3H), 2.34 (s, 3H), 2.31 (s, 1H), 1.91 - 1.71 (m, 3H), 1.61 - 1.44 (m, 1H), 0.94 (d, J = 6.1 Hz, 3H)

LCMS (ESI): m/z 285.1 [M⁺+l]

HPLC: 97.80%

Chiral HPLC: 100.00%

Column : CHIRALPAK IC (250*4.6 itpti*5miti)

Mobile Phase : A: 0.1% DEA in n-hexane

Mobile Phase : B: DCM : MeOH (50 : 50)

A : B :: 70 : 30; Flow rate : 1.0 mL/min

Retention time : 13.233

Synthesis of AM, AN, AO & AP:

The experimental procedure for the synthesis of compound 2 is captured under the synthesis of AE and AF (as compound 2).

Synthesis of l-(tert-butyl) 2,5-dimethyl 2,5-bis((benzyloxy)methyl)pyrrolidine-l,2,5- tricarboxylate (3):

To a stirred solution of compound 2 (59 g, 0.205 mol) in THF (590 mL) was added LiHMDS (1M solution in THF, 822 mL, 0.822 mol) drop wise at -10 °C under nitrogen atmosphere. After stirring at -10 °C for 30 minutes, BOM-C1 (96 g, 0.616 mol) was added and the reaction mixture was stirred at 0 °C for 1 h. After consumption of the starting material (by TLC), the reaction was quenched with ice cold water (200 mL) and extracted with EtOAc (3 x 200 mL). The organic layer was dried over Na SCL and concentrated under reduced pressure. The crude was purified by column chromatography eluting with 15% EtOAc/n -hexane to afford compound 3 (110 g) as a yellow color thick liquid.

LCMS (ESI): m/z 528.3 [M⁺+l]

Synthesis of 2, 5-bis((benzyloxy)methyl)-l-(tert-butoxycarbonyl)-5-(methoxy carbonyl) pyrrolidine-2-carboxylic acid (4):

To a solution of compound 3 (80 g, 0.151 mol) in MeOH and fLO (1 L, 4:1) was added LiOH. fLO (7.6 g, 0.181 mol) at room temperature and the reaction mixture was stirred at 75 °C for 16 h. After consumption of the starting material (by TLC), reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and washed with hexane. The aqueous layer was acidified with aqueous citric acid (pH ~ 4.0) and extracted with EtOAc (3 x 200 mL). The organic layer was dried over Na₂S0₄ and concentrated under reduced pressure. The crude was purified by column chromatography eluting with 15%

EtOAc/n-hexane to afford compound 4 (50 g) as a yellow thick liquid.

NMR (400 MHz, DMSO-ifc) d 12.67 - 12.43 (br s, 1H), 7.39 - 7.30 (m, 10H), 4.65 - 4.50 (m, 4H), 3.98 - 3.89 (m, 2H), 3.88 - 3.76 (m, 2H), 3.56 (br d, J = 13.6 Hz, 3H), 2.36 - 2.09 (m, 4H), 1.28, 1.27 (2s, 9H).

LCMS (ESI): m/z 512.3 [M⁺-l]

Synthesis of l-(tert-butyl) 2-methyl 5-(benzylcarbamoyl)-2,5-bis((benzyloxy)methyl) pyrrolidine-1 ,2-dicarboxylate (5) :

To a stirred solution of 4 (52 g, 0.101 mol) in DMF (300 mL) were added HATU (57.7 g, 0.152 mol), benzyl amine (110 mL, 0.101 mol) and DIPEA (52.6 mL, 0.303 mol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h.

After consumption of the starting material (by TLC), reaction mixture was quenched with ice cold water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (30 mL), dried over Na₂S0₄ and concentrated under reduced pressure. The crude was purified by column chromatography eluting with 20% EtOAc/n-hexane to afford compound 5 (36 g, 59%) as a yellow thick liquid.

NMR (400 MHz, DMSO-cfe) d 8.06 (br t , J = 5.5 Hz, 1H), 7.37 - 7.17 (m, 15H), 4.63 - 4.42 (m, 4H), 4.40 - 4.09 (m, 3H), 3.97 - 3.64 (m, 3H), 3.53 (br s, 3H), 2.44 - 2.35 (m, 1H), 2.29 - 2.09 (m, 3H), 1.23 (s, 9H).

LCMS (ESI): m/z 603.3 [M⁺+l]

Synthesis of l-(tert-butyl) 2-methyl 5-(benzylcarbamoyl)-2-((benzyloxy)methyl)-5- (hydroxymethyl)pyrrolidine-l,2-dicarboxylate (6):

To a solution of compound 5 (8 g, 0.012 mol) in MeOH (100 mL) was added 10% Pd/C (50% wet, 2 g) at room temperature under nitrogen atmosphere. The reaction mixture was stirred under ¾ atmosphere (balloon pressure) for 20 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. The crude was purified by column chromatography eluting with 20% EtOAc/n-hexane to afford compound 6 (5.5 g, 80%) as a colorless viscous liquid.

NMR (400 MHz, DMSO-cfe) d 8.02 (br d, J = 4.6 Hz, 1H), 7.40 - 7.05 (m, 10H), 4.64 - 4.00 (m, 6H), 3.78 - 3.59 (m, 6H), 2.45 - 2.31 (m, 1H), 2.27 - 2.07 (m, 3H), 1.26, 1.24 (2s, 9H). LCMS (ESI): m/z 513.6 [M⁺+l]

Synthesis of 5-(tert-butyl) 6-methyl 2-benzyl-6-((benzyloxy)methyl)-l-oxo-2,5- diazaspiro[3.4]octane-5,6-dicarboxylate (7) :

A mixture of PPh₃ (41 g, 0.156 mol) and DTAD (36 g, 0.156 mol) in THF (200 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. A solution of compound 6 (16 g, 0.0312 mol) in THF (100 mL) was added to the reaction mixture at 0 °C and stirred at room temperature for 16 h. After consumption of the starting material (by TLC), reaction mixture was quenched with water and extracted with EtOAc (3 x 100 mL). The organic layer was dried over Na₂S0₄ and concentrated under reduced pressure. The crude was purified by column chromatography eluting with 20% EtOAc/n-hexane to afford compound 7 (11 g, 71%) as a thick liquid.

NMR (400 MHz, DMSO-ifc) d 7.47 - 7.24 (m, 10H), 4.70 - 4.48 (m, 2H), 4.40 (s, 1H), 4.16

- 3.95 (m, 2H), 3.92 - 3.81 (m, 1H), 3.66 - 3.50 (m, 4H), 3.29 - 3.16 (m, 1H), 2.46 - 2.38 (m, 1H), 2.37 - 2.18 (m, 1H), 2.13 - 1.99 (m, 2H), 1.35, 1.28 (2s, 9H).

LCMS (m/z): 494.4 [M⁺]

Synthesis of 5-(tert-butyl) 6-methyl 2-benzyl-6-(hydroxymethyl)-l-oxo-2,5- diazaspiro[3.4]octane-5,6-dicarboxylate (8) :

To a stirred solution of compound 7 (3.3 g, 6.68 mmol) in methanol (50 mL) was added 10% Pd/C (50% wet, 1.5 g) at room temperature under nitrogen atmosphere. The reaction mixture was stirred under ¾ atmosphere (balloon pressure) for 20 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. The crude was purified by column

chromatography eluting with 60% EtOAc/n-hexane to afford compound 8 (1.6 g, 59%) as a viscous liquid.

NMR (400 MHz, DMSO-ifc_, rotamers) d 7.43 - 7.20 (m, 5H), 5.01 - 4.81 (m, 1H), 4.63 (br d, J = 15.3 Hz, 0.5H), 4.38 (d, J = 1.9 Hz, 1H), 4.16 - 3.98 (m, 0.5H), 3.91 - 3.71 (m, 2H), 3.65

- 3.49 (m, 4H), 3.26 - 3.12 (m, 1H), 2.44 - 2.31 (m, 1H), 2.28 - 2.14 (m, 1H), 2.04 - 1.90 (m, 2H), 1.34 (s, 9H).

LCMS (m/z) 349.2 [(M⁺+l) - i-Bu]

Synthesis of 5-(tert-butyl) 6-methyl 2-benzyl-6-formyl-l-oxo-2,5-diazaspiro[3.4]octane- 5,6-dicarboxylate (9):

To a solution of compound 8 (1.6 g, 3.96 mmol) in CH2CI2 (30 mL) was added Dess- Martin periodinane (2.5 g, 5.94 mmol) at 0 °C under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 2 h. After consumption of the starting material (by TLC), reaction mixture was quenched with saturated aqueous NaHCCT and extracted with CH2CI2 (2 x 100 mL). The organic layer was separated, washed with brine and concentrated under reduced pressure to afford compound 9 (2 g, crude) as a pale yellow solid. Crude was taken to next step without any further purification.

LCMS (m/z) 347.5 [(M⁺+l)-½ri-Bu] Synthesis of 5-(tert-butyl) 6-methyl 2-benzyl-6-((benzylamino)methyl)-l-oxo-2,5- diazaspiro[3.4]octane-5,6-dicarboxylate (10):

To a stirred solution of compound 9 (2 g, 4.97 mmol) in MeOH (30 mL) were added benzylamine (0.64 mL, 5.97 mmol) and AcOH (0.05 mL, 0.99 mmol) at room temperature under nitrogen atmosphere. After stirring for 20 minutes, NaBH₃CN (0.92 g, 14.9 mmol) was added portion wise at 0 °C and stirred at room temperature for 16 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with ice and volatiles were evaporated under reduced pressure. The crude was dissolved in EtOAc (100 mL) and washed with saturated aqueous NaHCCL and brine. Organic layer was dried over Na₂S0₄ and concentrated under reduced pressure. The crude was purified by column chromatography eluting with 50% EtOAc/n-hexane to afford compound 10 (1.2 g, 50%) as a colorless thick liquid.

NMR (500 MHz, DMSO-ifc_, rotamers) d 7.45 - 7.18 (m, 10H), 4.64 (br d, J = 15.3 Hz, 0.5H), 4.45 - 4.32 (m, 1H), 4.09 (br d, J = 15.4 Hz, 0.5H), 3.87 - 3.68 (m, 2H), 3.63 - 3.49 (m, 4H), 3.29 - 3.28 (m, 1H), 3.27 - 3.14 (m, 1H), 3.05 - 2.90 (m, 2H), 2.34 - 2.23 (m, 1H), 2.08 - 1.88 (m, 3H), 1.38 - 1.21 (m, 9H).

LCMS (m/z) 494.4 [M⁺+l]

Synthesis of tert-butyl 2-benzyl-6-((benzylamino)methyl)-6-(hydroxymethyl)-l-oxo-2,5- diazaspiro[3.4]octane-5-carboxylate (11):

To a stirred solution of compound 10 (1.2 g, 2.43 mmol) in THF (20 mL) was added LiBH₄ (2M solution in THF, 4.86 mL, 9.72 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 20 h. After consumption of the starting material (by TLC), reaction mixture was quenched with saturated aqueous NaHCCL (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na₂S0₄ and concentrated under reduced pressure. The crude was purified by column chromatography by eluting with 10% MeOH/CH₂Cl₂ to afford compound 11 (0.8 g, 70%) as an off white solid. LCMS (m/z) 466.3 [M⁺+l]

Synthesis of tert-butyl 2-benzyl-6-((benzylamino)methyl)-6- (((methylsulfonyl)oxy)methyl)-l-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate (12):

To a stirred solution of compound 11 (200 mg, 0.43 mmol) in CH₂Cl₂ (5 mL) were added Et₃N (0.3 mL, 2.15 mmol) and methane sulfonyl chloride (0.1 mL, 0.64 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at same temperature for 15 minutes. After consumption of the starting material (by TLC), quenched with ice cold water (10 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic layer was washed with aqueous NaHCCT, dried over Na₂S0₄ and concentrated under reduced pressure to afford compound 12 (250 mg, crude) as a thick liquid. The crude was taken to next step without any further purification.

Synthesis of tert-butyl 2,8-dibenzyl-l-oxo-2,5,8-triazadispiro[3.1.36.24]undecane-5- carboxylate (13):

To a stirred solution of compound 12 (250 mg, 0.46 mmol) in acetonitrile (10 mL) was added Et₃N (0.66 mL, 4.60 mmol) at room temperature under nitrogen atmosphere and the reaction mixture was stirred at 70 °C for 2 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. The crude was diluted with water (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine, dried over Na₃S0₄ and concentrated under reduced pressure. The crude was purified by column chromatography by eluting with 3% MeOH/ CH2CI2 followed by reverse phase HPLC purification to afford compound 13 (10 mg) as a thick liquid.

NMR (400 MHz, DMSO-ifc) d 7.41 - 7.16 (m, 10H), 4.68 - 4.62 (m, 1H), 4.09 - 3.96 (m, 2H), 3.66 - 3.54 (m, 3H), 3.39 - 3.32 (m, 1H), 3.17 - 3.04 (m, 3H), 2.34 - 2.25 (m, 1H), 2.09 - 1.89 (m, 3H), 1.37 (s, 9H).

LCMS (m/z) 448.3 [M⁺+l]

Synthesis of 2,8-dibenzyl-2,5,8-triazadispiro[3.1.36.24]undecan-l-one (AM & AN):

To a stirred solution of compound 12 (250 mg, 0.55 mmol) in CH2CI2 (10 mL) were added molecular sieves (500 mg) and BF₃.OEL₂ (0.17 mL, 1.23 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was brought to room temperature and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with aqueous NaHC0₃ (10 mL) and extracted with 5% MeOH/ CH2CI2 (2 x 100 mL). The combined organic layer was washed with brine, dried over Na2S0₄ and concentrated under reduced pressure. The residue was purified by column chromatography by eluting with 3% MeOH/ CH2CI2 to afford mixture of AM & AN (160 mg) as a thick liquid. Mixture of AM & AN (320 mg, 2 batches) was separated by chiral preparative HPLC purification to obtain AM (65 mg) as colorless thick liquid and AN (75 mg) as colorless thick liquid. AM

NMR (400 MHz, CD₃OD) d 7.39 - 7.23 (m, 10H), 4.44 - 4.32 (m, 2H), 3.66 (s, 2H), 3.46 - 3.36 (m, 2H), 3.28 (d, J = 5.5 Hz, 1H), 3.24 - 3.16 (m, 3H), 2.24 - 2.13 (m, 2H), 2.08 - 1.99 (m, 2H)

LCMS (ESI): m/z 348.4 [M⁺+l]

HPLC: 94.05%

Chiral HPLC: 95.62%

Column : CHIRALPAK IG (250*4.6 ihhi*5mhi)

Mobile Phase : A: 0.1% DEA in n-Hexane

Mobile Phase : B:EtOH : MeOH (50 : 50)

A : B :: 75 : 25; Flow rate : 1.0 mL/min

Retention time : 16.150 min

AN

NMR (400 MHz, CD₃OD) d 7.39 - 7.22 (m, 10H), 4.44 - 4.31 (m, 2H), 3.64 (s, 2H), 3.43 - 3.36 (m, 2H), 3.28 (d, J = 5.5 Hz, 1H), 3.22 - 3.14 (m, 3H), 2.24 - 2.13 (m, 2H), 2.08 - 2.00 (m, 2H)

LCMS (ESI): m/z 348.5 [M⁺+l]

HPLC: 99.39%

Chiral HPLC: >99.00%

Column : CHIRALPAK IG (250*4.6 ihhi*5mhi)

Mobile Phase : A: 0.1% DEA in n-Hexane

Mobile Phase : B:EtOH : MeOH (50 : 50)

A : B :: 75 : 25; Flow rate : 1.0 mL/min

Retention time : 23.304 min

Synthesis of 2,8-dibenzyl-5-isobutyryl-2,5,8-triazadispiro[3.1.36.24]undecan-l-one (AO & AP):

To a stirring solution mixture of AM & AN (400 mg, 1.15 mmol) in l,4-dioxane and water (16 mL, 1:1) were added K₂C0₃ (1.27 g, 9.22 mmol) and isobutyric anhydride (0.73 mL, 4.60 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was heated to 90 °C and stirred for 36 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na₃S0₄ and concentrated under reduced pressure to afford AO & AP (300 mg) as a thick liquid. Mixture of AO & AP (300 mg) was separated by normal phase HPLC purification followed by chiral preparative HPLC

purification to obtain AO (55 mg) as an off white solid and AP (55 mg) as an off white solid.

AO

NMR (400 MHz, CD₃OD) d 7.45 - 7.21 (m, 10H), 4.74 - 4.47 (m, 1H), 4.44 - 4.26 (m, 1H), 4.19 - 4.08 (m, 1H), 3.92 - 3.71 (m, 3H), 3.55 - 3.39 (m, 2H), 3.29 - 3.07 (m, 2H), 2.49 - 2.38 (m, 1H), 2.24 - 1.90 (m, 4H), 1.17 - 1.13 (m, 2H), 0.99 (d, J = 6.4 Hz, 2H), 0.78 (d, J = 6.4 Hz, 2H)

LCMS (ESI): m/z 418.4 [M⁺+l]

HPLC: 98.88%

Chiral HPLC: >99.00%

Column : CHIRALPAK IG (250x4.6x5. Omhi)

Mobile Phase : A: 0.1% DEA in n-Hexane

Mobile Phase : B:DCM : MeOH (80 : 20)

A : B :: 80 : 20; Plow rate : 1.0 mL/min

Retention time : 10.727 min

AP

NMR (400 MHz, CD₃OD) d 7.46 - 7.21 (m, 10H), 4.75 - 4.48 (m, 1H), 4.44 - 4.26 (m, 1H), 4.19 - 4.06 (m, 1H), 3.94 - 3.71 (m, 3H), 3.56 - 3.38 (m, 2H), 3.29 - 3.14 (m, 2H), 2.49 - 2.38 (m, 1H), 2.25 - 1.91 (m, 4H), 1.17 - 1.13 (m, 2H), 0.99 (d, J = 6.4 Hz, 2H), 0.78 (d, J = 6.5 Hz, 2H)

LCMS (ESI): m/z 418.4 [M⁺+l]

HPLC: 98.50%

Chiral HPLC: 98.27%

Column : CHIRALPAK IG (250x4.6x5. Omhi)

Mobile Phase : A: 0.1% DEA in n-Hexane

Mobile Phase : B:DCM : MeOH (80 : 20)

A : B :: 80 : 20; Plow rate : 1.0 mL/min

Retention time : 13.178 min Synthesis of BP:

The experimental procedure for the synthesis of compound 1 is captured under the synthesis of AE and AF (as compound 1).

Synthesis of l-(feri-butyl) 2, 5-dimethyl pyrrolidine-1, 2, 5-tricarboxylate (2):

To a stirred solution of dimethyl l-benzylpyrrolidine-2,5-dicarboxylate (1) (65 g, 0.234 mol) in methanol (650 mL) were added Boo₂0 (80.7 mL, 0.351 mol) and 10% Pd/C (50% wet , 32 g) at room temperature under nitrogen atmosphere. The reaction mixture was stirred under ¾ atmosphere (balloon pressure) for 24 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. The crude was purified by column chromatography eluting with 40% EtOAc/ /7-hexane to afford compound 2 (59 g, 88%) as an off white solid.

NMR (400 MHz, DMSO-ri₆) d 4.30 - 4.17 (m, 2H), 3.65 (s, 3H), 3.63 (s, 3H), 2.27 - 2.12 (m, 2H), 1.96 - 1.87 (m, 2H), 1.34 (s, 9H).

LCMS (ESI): m/z 288.2 [M⁺+l]

Synthesis of tert-\mty\ l,7-dioxo-2,5,8-triazadispiro[3.1.36.24]undecane-5-carboxylate (3):

To a stirring solution of compound 2 (20 g, 0.069 mol) in THF (100 mL) was added paraformaldehyde (4.17 g, 0.139 mol) at -78 °C under nitrogen atmosphere. LiHMDS (1M solution in THF, 417 mL, 0.417 mol) was added drop wise at -78 °C. The 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 crushed ice (20 g) and filtered. The filtrate was evaporated under reduced pressure. Obtained crude was purified by column chromatography eluting with 4% MeOH/ CH2CI2 to afford compound 3 (8 g, 42%) as an off white solid.

(500 MHz, DMSO-ri₆) d 8.02 - 7.81 (m, 2H), 3.58 (d, J = 4.6 Hz, 1H), 3.36 (d, J = 4.6 Hz, 1H), 3.23 - 3.09 (m, 2H), 2.18 - 1.98 (m, 4H), 1.38 (d, J = 2.3 Hz, 9H). LCMS (ESI): m/z 226.0 [(M⁺+l)-i-Bu]

Synthesis of tert- butyl 2,8-dibenzyl-l,7-dioxo-2,5,8-triazadispiro[3.1.36.24]undecane-5- carboxylate (4):

To a stirring solution of compound 3 (4 g, 0.0142 mol) in DMF (70 mL) were added CS2CO3 (19.43 g, 0.0597 mol) and benzyl bromide (3.7 mL, 0.0313 mol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h.

After consumption of the starting material (by TLC), ice cold water (100 mL) was added and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine, dried over Na₂S04 and concentrated under reduced pressure. The crude was purified by column chromatography by eluting 50% EtOAc/ hexane to afford compound 4 (4.1 g) as off white solids.

NMR (400 MHz, DMSO-ri₆) d 7.45 - 7.16 (m, 10H), 4.66 (dd, J = 4.5, 15.3 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.37 - 4.25 (m, 1H), 4.06 (br dd, J = 2.0, 15.3 Hz, 1H), 3.61 (d, J = 4.9 Hz, 1H), 3.42 - 3.36 (m, 1H), 3.25 - 3.17 (m, 1H), 3.12 (d, J = 5.0 Hz, 1H), 2.28 - 2.03 (m, 4H), 1.38 (s, 9H).

LCMS (ESI): m/z 462.2 [M⁺+l]

Synthesis of 2,8-dibenzyl-5-methyl-2,5,8-triazadispiro[3.1.36.24]undecane (BP):

To a stirring solvent of diethyl ether (50 mL) were added AICI₃ (432 mg, 3.25 mmol) and LAH (1M in THF, 5.42 mL, 5.42 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 min. Again cooled to -10 °C, compound 4 (500 mg, 1.08 mmol) in THF (5 mL) was added drop wise and continued stirring for 2 h. After consumption of the starting material (by TLC), reaction mixture was quenched with ice cold water (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na₂S04 and concentrated under reduced pressure. Crude material was purified by basic alumina chromatography eluting with 5% MeOH/ CH₂Cl₂ to afford BP (150 mg) as an off white sticky solid.

NMR (400 MHz, CD30D) d 7.43 - 7.26 (m, 10H), 3.78 (s, 4H), 3.55 (br d, J = 9.3 Hz, 4H), 3.22 (d, J = 9.5 Hz, 4H), 2.54 (s, 3H), 2.11 (s, 4H).

LCMS (ESI): m/z 348.2 [M⁺+l]

HPLC: 96.45%. Synthesis of BO:

The experimental procedure for the synthesis of compound 4 is captured under the synthesis of BP (as compound 4).

Synthesis of 2,8-dibenzyl-2,5,8-triazadispiro[3.1.36.24]undecane-l,7-dione (5):

To a stirring solution of compound 4 (1 g, 2.16 mmol) in CH2CI2 (10 mL) was added TFA (1.65 mL, 21.6 mmol) drop wise at 0 °C under nitrogen atmosphere. The reaction mixture was brought to room temperature and stirred for 16 h. After consumption of the starting material (by TLC), reaction mixture was diluted with CH2CI2 (100 mL) and washed with saturated aqueous NaHCCL solution. The organic layer was dried over anhydrous Na2S0₄ and concentrated under reduced pressure. Crude material was purified by column chromatography eluting with 5% MeOH/ EtOAc to afford compound 5 (500 mg, 63%) as a white solid.

NMR (400 MHz, DMSO-d₆) d 7.54 - 7.08 (m, 10H), 4.42 - 4.25 (m, 4H), 3.24 (d, J = 5.3 Hz, 2H), 3.16 (d, J = 5.1 Hz, 2H), 2.07 - 1.97 (m, 4H), 1.38 (s, 1H).

LCMS (ESI): m/z: 362.2 [M⁺+l]

Synthesis of 2,8-dibenzyl-2,5,8-triazadispiro[3.1.36.24]undecane (BO):

To a stirring solvent of diethyl ether (50 mL) were added AICI3 (552 mg, 4.15 mmol) and LAH (1M in THF, 7.0 mL, 6.92 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 min. Again cooled to -10 °C, compound 4 (500 mg, 1.38 mmol) in THF (5 mL) was added drop wise and continued stirring for 2 h. After consumption of the starting material (by TLC), reaction mixture was quenched with ice cold water (15 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over anhydrous Na2S0₄ and concentrated under reduced pressure. Crude material was purified by basic alumina chromatography eluting with 15% MeOH/ CH2CI2 and which was re purified by neutral alumina chromatography eluting with 1% MeOH/ CH2CI2 to afford BO (80 mg) as white solid. NMR (400 MHz, CD₃OD) d 7.39 - 7.20 (m, 10H), 3.62 (s, 4H), 3.32 - 3.30 (m, 4H), 3.16 - 3.07 (m, 4H), 2.05 (s, 4H).

LCMS (ESI): m/z 334.3 [M⁺+l]

HPLC: 92.90%.

Following the above procedures, the following compounds and stereoisomers thereof were prepared:

Table 1

Additional compounds provided herein are as follows, which compounds are prepared using the above procedures and the knowledge of a skilled artisan.

Table 2

Table 3

B. 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 or NMDAR2B expressing HEK cell membranes as measured by increases in [³H]MK-80l binding.

In the assay, 300 pg 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 pM) and varying concentrations of test compound (lxl0 ¹⁵M - lxlO ⁷M), or 1 mM glycine. Following the addition of 0.3 pCi of [³H]MK-80l (22.5 Ci/mmol), reactions were again incubated for 15 minutes at 25 ⁰ C (nonequilibrium conditions). Bound and free [³H]MK-80l were separated via rapid filtration using a Brandel apparatus.

In analyzing the data, the DPM (disintegrations per minute) of [³H]MK-80l 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 [³H]MK-80l 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 EC50 and % maximal activity were then obtained from the best fit curve of the % maximal [³H]MK-80l binding data modelled using the GraphPad program and the log(agonist) vs. response( three parameters) algorithm.

The table below summarize the results for the wild type NMDAR agonists NMDAR2A and NMDAR2B, and whether the compound is not an agonist (-), is an agonist (+), or is a strong agonist (++), where column A is based on the % maximal [³H]MK-80l binding relative to 1 mM glycine (- = 0; < 100% = +; and > 100% = ++); and column B is based on log EC50 values (0 = -; > lxlO^-9 M (e.g., -8) = +; and < lxlO^-9 M (e.g., -10) = ++).

C. MICROSOMAL STABILITY

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

D. PLASMA STABILITY

Plasma stability of disclosed compounds was investigated. The following table indicates the percent of compound remaining after 60 minutes.

E. PHARMACOKINETICS ASSAYS

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 (T_max, C_max and AUCi_ast) are plasma values. An“N/D” indicates that the measurement was not done.

EQUIVALENTS

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.

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.

Claims

CLAIMS What is claimed is:

1. A compound represented by Formula I or Formula II:

R¹ and R² are independently selected from the group consisting of hydrogen, -Ci-C₆alkyl, - C(0)-Ci-C₆alkyl, -C(0)-0-Ci-C₆alkyl, and -O-CFF-phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

w is 0, 1, or 2;

n is 1, 2, or 3;

R³¹ is selected from the group consisting of hydrogen, -Ci-C₆alkyl; -C3-Cecycloalkyl, and phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R³² is selected from the group consisting of -Ci-C₆alkyl; -C3-Cecycloalkyl, and phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R⁴, R⁵, R⁶ and R⁷ are independently, for each occurrence, selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, Ci_C4alkyl, C2-C₄alkenyl, -NH-C(0)-Ci_ Cgalkyl, -NH-C(0)-Ci_C₆alkylene-phenyl, -NH-C(0)-0-Ci_C₆alkyl, and -NH-C(0)-0-Ci_ Cealkylene-phenyl; wherein Ci_C4alkyl, Ci-Cealkylene, C2-C₄alkenyl, Ci_C₄alkoxy, and phenyl are each optionally substituted by one, two, or three substituents each independently selected from R^p;

R^a and R^b are independently, for each occurrence, selected from the group consisting of hydrogen, -CfOj-O-CFF-phenyl, and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci-C₃alkyl is optionally substituted with one, two, or three halogens;

2. The compound of claim 1, wherein R¹ and R² are hydrogen.

3. The compound of claim 1, wherein at least one of R¹ and R² is -CFF-phenyl, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T.

4. The compound of claim 1, wherein R¹ and R² are -CH2-phenyl, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T.

5. The compound of claim 1, wherein R¹ and R² are -Ci-C₆alkyl each independently and optionally substituted by one, two or three substituents independently selected from the group consisting of -C(0)NR^aR^b, hydroxyl, -SH, and halogen.

6. The compound of claim 5, wherein R¹ and R² are independently selected from the group consisting of:

wherein R^a and R^b are each independently selected for each occurrence from the group consisting of hydrogen and -Cr alkyl.

7. The compound of any one of claims 1-6, wherein R³ is hydrogen.

8. The compound of any one of claims 1-6 wherein R³ is -Ci-C₆alkyl optionally substituted by one, two or three substituents each independently selected from R^s.

9. The compound of claim 8, wherein R³ is methyl, isobutyl, or -CH2-phenyl.

10. The compound of any one of claims 1-6, wherein R³ is -C(0)-Ci-C₆alkyl.

11. The compound of claim 10, wherein R³ is -C(0)-isopropyl.

12. The compound of claim 10, wherein R³ is -C(0)-CH₃.

13. The compound of any one of claims 1-6, wherein R³ is -C(0)-0-Ci-C₆alkyl.

14. The compound of claim 13, wherein R³ is -C(0)-0-tert-butyl.

15. The compound of any one of claims 1-6, wherein R³ is -S(0)_w-R³¹·

16. The compound of claim 15, wherein R³ is -S0₂-Ci-C₆alkyl.

17. The compound of claim 15, wherein R³ is -SO₂-CH₃.

18. The compound of any one of claims 1-17, wherein R⁴, R⁵, R⁶, and R⁷ are hydrogen.

19. The compound of any one of claims 1-17, wherein one, two, three or four of R⁶ and R⁷, independently, are fluoro.

20. The compound of any one of claims 1-19, wherein n is 1.

21. A compound represented by Formula III:

or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein: R¹ and R² are independently selected from the group consisting of hydrogen and -CFF-phenyl, where at least one of R¹ or R² is -CFF-phenyl, and phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, -C(0)NR^aR^b, -NR^aR^b, and -Ci-C₄alkoxy;

R³ is selected from the group consisting of hydrogen, -Ci-C₆alkyl, -C(0)-R³¹, and -C(0)-0- R³², wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s;

R³¹ is hydrogen or -Ci-C₆alkyl;

R³² is -Ci-Cgalkyl;

R⁶ and R⁷ are each independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, C 1 ₄alkyl , C2-₄alkenyl, -NH-C(0)-Ci_

₆alkyl, -NH-C(0)-Ci_₆alkylene-phenyl, -NH-C(0)-0-Ci_₆alkyl, and -NH-C(0)-0-Ci_₆alkylene- phenyl, wherein C 1 ₄alkyl , Ci_₆alkylene, C2-₄alkenyl, Ci_₄alkoxy, and phenyl are each optionally substituted by one, two, or threesubstituents each independently selected from R^p; R^a and R^b are each independently, for each occurrence, selected from the group consisting of hydrogen, -C(0)-0-CH₂-phenyl, and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci-C₃alkyl is optionally substituted with one, two, or three halogens;

R^p is independently, for each occurrence, selected from the group consisting of -CO2H, hydroxyl, halogen, amino, phenyl, Ci_₆alkoxy, and Ci_₆alkyl, wherein each phenyl and Ci_ C₆alkyl is optionally substituted by one, two, or threesubstituents each independently selected from the group consisting of halogen, hydroxyl and amino; and

22. The compound of claim 21, wherein each R⁶ and R⁷ is hydrogen.

23. The compound of any one of claim 21 or 22, wherein one, two, three or four of R⁶ and R⁷ are fluoro.

24. The compound of any one of claims 21-23, wherein R¹ and R² are -CH2-phenyl.

25. The compound of any one of claims 21-24, wherein R³ is hydrogen.

26. The compound of any one of claims 21-24 wherein R³ is -C(0)-Ci-C₆alkyl.

27. A compound represented by Formula IV

R² is selected from the group consisting of hydrogen, -Ci-Cealkyl, -C(0)-Ci-C₆alkyl, and -C(0)-0-Ci-C₆alkyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s; R³ is selected from the group consisting of hydrogen, methyl, and -CH₂-phenyl, wherein phenyl is optionally substituted by one, two or three substituents each independently selected from R^T; and

R⁹ is selected from the group consisting of hydrogen and -Ci-C₆alkyl, wherein Ci- C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s;

R^a and R^b are each independently, for each occurrence, selected from the group consisting of hydrogen, phenyl, -Ci-C₃alkylene -phenyl and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci- C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci-C₃alkyl is optionally substituted with one, two, or three halogens;

R^s is independently, for each occurrence, selected from the group consisting of - C(0)NR^aR^b, -NR^aR^b, hydroxyl, -SH, phenyl, -0-CH₂-phenyl, and halogen, wherein phenyl is optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C₄alkoxy, -Ci-C₄alkyl, and -CF₃; and

R^T is independently, for each occurrence, selected from the group consisting of - C(0)NR^aR^b, -NR^aR^b, -Ci-C₄alkoxy, -Ci-C₄alkyl, hydroxyl, and halogen.

28. The compound of claim 27, wherein R⁹ is selected from the group consisting of:

wherein R^a and R^b are each independently selected for each occurrence from the group consisting of hydrogen and methyl.

29. The compound of claim 27, wherein R⁹ is selected from the group consisting of:

30. The compound of claim 27, wherein R⁹ is selected from the group consisting of:

31. The compound of any one of claims 27-30, wherein R² is hydrogen.

32. The compound of any one of claims 27-31, wherein R³ is H, methyl, -CFF-phenyl, or -

CH₂-(/?-F-phenyl).

33. A compound represented by Formula V

R² is selected from the group consisting of hydrogen, -Ci-C₆alkyl, -C(0)-Ci-C₆alkyl, and -C(0)-0-Ci-C₆alkyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s;

R³ is selected from the group consisting of hydrogen and -Ci-Cealkyl, wherein Ci- C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s ;

R^a and R^b are each independently, for each occurrence, selected from the group consisting of hydrogen, phenyl, -Ci-Csalkylene -phenyl and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci- C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci-C₃alkyl is optionally substituted with one, two, or three halogens; and

R^s is independently, for each occurrence, selected from the group consisting of - C(0)NR^aR^b, -NR^aR^b, hydroxyl, -SH, phenyl, -O-CFF-phenyl, and halogen, wherein phenyl is optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -Ci-C₄alkoxy, -Ci-C₄alkyl, and -CF₃.

34. The compound of claim 33, wherein R² is hydrogen.

35. The compound of claim 33 or 34, wherein R³ is hydrogen or methyl.

36. The compound of any one of claims 33-35, wherein at least one of R^a and R^b is hydrogen.

37. The compound of any one of claims 33-35, wherein each of R^a and R^b is hydrogen.

38. A compound represented by Formula VI or Formula VII:

w is 0, 1, or 2;

n is 1, 2, or 3; R³¹ is selected from the group consisting of hydrogen, -Ci-C₆alkyl; -C3-C6cycloalkyl, and phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T;

R^a and R^b are independently, for each occurrence, selected from the group consisting of hydrogen, -CfOj-O-CFF-phenyl, and -Ci-C4alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C3alkoxy, -Ci-C3alkyl, and halogen, and -Ci-C3alkyl is optionally substituted with one, two, or three halogens;

R^p is independently, for each occurrence, selected from the group consisting of -CO2H, hydroxyl, halogen, amino, phenyl, Ci_C₆alkoxy, and Ci_C₆alkyl, wherein each phenyl and Ci_ C₆alkyl is optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl and amino;

39. The compound of claim 38, wherein R¹ and R² are hydrogen.

40. The compound of claim 38, wherein at least one of R¹ and R² is -CFF-phenyl, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T.

41. The compound of claim 38, wherein R¹ and R² are -CFF-phenyl, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T.

42. The compound of claim 38, wherein R¹ and R² are -Ci-C₆alkyl each independently and optionally substituted by one, two or three substituents independently selected from the group consisting of -C(0)NR^aR^b, hydroxyl, -SH, and halogen.

43. The compound of claim 42, wherein R¹ and R² are independently selected from the group consisting of:

wherein R^a and R^b are each independently selected for each occurrence from the group consisting of hydrogen and -Ci-C3alkyl.

44. The compound of any one of claims 38-43, wherein R³ is hydrogen.

45. The compound of any one of claims 38-43 wherein R³ is -Ci-C₆alkyl optionally substituted by one, two or three substituents each independently selected from R^s.

46. The compound of claim 45, wherein R³ is methyl, isobutyl, or -CFF-phenyl.

47. The compound of any one of claims 38-43, wherein R³ is -C(0)-Ci-C₆alkyl.

48. The compound of claim 47, wherein R³ is -C(0)-isopropyl.

49. The compound of claim 47, wherein R³ is -C(0)-CH₃.

50. The compound of any one of claims 38-43, wherein R³ is -C(0)-0-Ci-C₆alkyl.

51. The compound of claim 50, wherein R³ is -C(0)-0-tert-butyl.

52. The compound of any one of claims 38-43, wherein R³ is -S(0)_w-R³¹·

53. The compound of claim 52, wherein R³ is -SCF-Ci-Cealkyl.

54. The compound of claim 52, wherein R³ is -SO₂-CH₃.

55. The compound of any one of claims 38-54, wherein R⁴, R⁵, R⁶, and R⁷ are hydrogen.

56. The compound of any one of claims 38-54, wherein one, two, three or four of R⁶ and R⁷, independently, are fluoro.

57. The compound of any one of claims 38-56, wherein n is 1.

58. A compound represented by Formula VIII or Formula IX:

R¹ and R² are independently selected from the group consisting of hydrogen, -Ci-Cealkyl, - C(0)-Ci-C₆alkyl, -C(0)-0-Ci-C₆alkyl, and -O-CFF-phenyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s, and phenyl is optionally substituted by one, two or three substituents each independently selected from R^T; R³ is -S(0)_w-Ci-C₆alkyl; w is 0, 1, or 2; R^a and R^b are independently, for each occurrence, selected from the group consisting of hydrogen, -C(0)-0-CH₂-phenyl, and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci-C₃alkyl is optionally substituted with one, two, or three halogens;

59. The compound of claim 58, wherein R¹ and R² are hydrogen.

60. The compound of claim 58 or 59, wherein R³ is -SCFMe.

61. A compound represented by Formula X

R³ is -S(0)_w-Ci-C₆alkyl;

w is 0, 1, or 2; R⁹ is selected from the group consisting of hydrogen and -Ci-C₆alkyl, wherein Ci-C₆alkyl is optionally substituted by one, two or three substituents each independently selected from R^s;

R¹⁰ is selected from the group consisting of hydrogen and -Ci-C₆alkyl;

R^a and R^b are each independently, for each occurrence, selected from the group consisting of hydrogen, phenyl, -Ci-C₃alkylene -phenyl and -Ci-C₄alkyl; or R^a and R^b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, -Ci-C₃alkoxy, -Ci-C₃alkyl, and halogen, and -Ci- C₃alkyl is optionally substituted with one, two, or three halogens;

62. The compound of claim 61, wherein R² is hydrogen or -O-CtF-phenyl.

63. The compound of claim 61 or 62, wherein R⁹ is selected from the group consisting of:

wherein R^a and R^b are independently, for each occurrence, selected from the group consisting of hydrogen and -C i -C₃alkyl .

64. The compound of any one of claims 61-63, wherein R⁹ is selected from the group consisting of:

65. The compound of any one of claims 61-64, wherein R¹⁰ is hydrogen or methyl.

66. A compound selected from the group consisting of any one of Compounds AA-EZ and AAA-AFF; or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof.

67. A compound selected from the group consisting of:

68. A pharmaceutical composition comprising the compound of any one of claims 1-67, and a pharmaceutically acceptable excipient.

69. The pharmaceutical composition of claim 68, suitable for oral administration, parenteral administration, topical administration, intravaginal administration, intrarectal administration, sublingual administration, ocular administration, transdermal administration, or nasal administration.

70. A method of treating depression, Alzheimer’s disease, attention deficit disorder, schizophrenia, or anxiety, in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-67, or the pharmaceutical composition of claim 68 or 69.

71. A method of treating a migraine in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-67, or the pharmaceutical composition of claim 68 or 69.

72. A method of treating neuropathic pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-67, or the pharmaceutical composition of claim 68 or 69.

73. A method of treating traumatic brain injury in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-67, or the pharmaceutical composition of claim 68 or 69.

74. A method of treating a neurodevelopmental disorder related to synaptic dysfunction in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-67, or the pharmaceutical composition of claim 68 or 69.

75. A method of treating a cognitive impairment disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-67, or the pharmaceutical composition of claim 68 or 69.