Inhibitors of glycine transporter 2 for the treatment of neuropathic pain

Abstract

A class of competitive and reversible GlyT2 inhibitors is provided that demonstrate a differentiated pharmacological profile from earlier inhibitors, such as ORG25543. ORG25543 and genetic GlyT2 knockout paradigms can elicit neuromotor or excitatory adverse effects. To overcome these challenges, SAR- and SKR-driven hit-to-lead campaigns were used to design improved, competitive and reversible GlyT2 inhibitors with improved drug-like characteristics and demonstrates a differentiated pharmacological profile. These improved GlyT2 inhibitors include indole, indoline, or indazole cores substituted with a variety of groups to modify the reversible binding activity thereof. The compounds described herein are shown to possess properties useful for safe, efficacious, and orally bioavailable non-opioid analgesics for the treatment of neuropathic pain.

Description

INHIBITORS OF GLYCINE TRANSPORTER 2 FOR THE TREATMENT OF NEUROPATHIC PAINCROSS REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims the benefit of U. S. Provisional Application Nos. 63 / 713,114, filed October 29, 2024, which are incorporated by reference as if disclosed herein in their entireties.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with government support under DA048879 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Approximately 116 million individuals in the United States experience chronic pain, with neuropathic pain accounting for an estimated 30-40% of these cases. Neuropathic pain arises from lesions or diseases affecting the somatosensory nervous system and is characterized by a spectrum of sensory abnormalities. These include allodynia, defined as pain elicited by normally innocuous stimuli; hyperalgesia, denoting an increased sensitivity to noxious stimuli; paresthesia, involving abnormal sensations such as tingling, burning, stabbing, or numbness; dysesthesia, which refers to spontaneous or evoked painful sensations; and paroxysmal pain, characterized by sudden, intense episodes of spontaneous pain.

[0004] Neuropathic pain represents a particularly debilitating subtype of chronic pain, distinguished by its complex pathophysiology and frequent resistance to conventional pharmacological and non-pharmacological treatments. This refractory nature significantly compromises patient functionality and quality of life. Moreover, a substantial proportion of individuals with neuropathic pain present with comorbid psychiatric and physiological conditions, including major depressive disorder, generalized anxiety disorder, and various sleep disturbances such as insomnia and fragmented sleep. These comorbidities not only are highly prevalent but also synergistically exacerbate symptom severity, impede treatment adherence, and further diminish overall quality of life, thereby amplifying the disease burden.

[0005] First-line pharmacological treatments for neuropathic pain include gabapentinoids, tricyclic antidepressants (TCAs), and serotonin-norepinephrine reuptake inhibitors (SNRIs), with opioid analgesics typically reserved for second-line use. Despite their widespread use, these therapies often provide limited efficacy and are associated with dose-limiting adverse effects. Opioids, in particular, carry significant risks, including the development of tolerance, dependence, misuse, and overdose-related mortality. The inadequate effectiveness of current analgesics has contributed to an overreliance on opioids, thereby exacerbating the public health crisis of opioid use disorder (OUD), marked by rising rates of morbidity and mortality.

[0006] Advances in our understanding of the neurobiological mechanisms underlying chronic pain have catalyzed efforts to identify alternative therapeutic strategies that circumvent p-opioid receptor engagement. Among the diverse pathophysiological processes implicated in neuropathic pain, disinhibition of nociceptive signaling in the spinal dorsal horn has emerged as a key mechanism. Our group and others have demonstrated that impaired glycinergic neurotransmission in this region contributes to mechanical hyperalgesia and allodynia in preclinical models. Enhancing spinal glycinergic signaling is therefore hypothesized to normalize inhibitory tone and attenuate abnormal nociceptive transmission to supraspinal structures. In this context, pharmacological inhibition of the glycine transporter 2 (GlyT2), which regulates extracellular glycine concentrations in the central nervous system (CNS), has garnered increasing interest.

[0007] Primary afferent input from both nociceptive and non-noxious stimuli is anatomically and functionally segregated within the dorsal horn of the spinal cord. These inputs are relayed to supraspinal centers via a complex neural circuit comprising nociceptive-specific and wide dynamic range projection neurons, as well as local excitatory and inhibitory interneurons and descending modulatory pathways. Inhibitory interneurons, particularly GABAergic and glycinergic populations, along with descending inhibitory projections from supraspinal regions, play a role in shaping dorsal horn excitability and maintaining normal pain thresholds by modulating projection neuron output. Disruption of these inhibitory circuits leads to disinhibition of nociceptive transmission, a pathophysiological mechanism in the development and maintenance of chronic neuropathic pain.

[0008] Glycinergic interneurons are particularly enriched in lamina III of the dorsal horn and restrain excitatory transmission. An accumulating body of evidence supports the hypothesis that diminished glycinergic neurotransmission contributes to spinal disinhibition and mechanical hyperalgesia and allodynia in neuropathic pain states.

[0009] A reduction in glycinergic signaling has been demonstrated within the dorsal horn following peripheral nerve injury. Specifically, decreased glycinergic synaptic transmission was observed from lamina III onto radial excitatory interneurons in lamina TI of adult rats subjected to spinal nerve ligation. This loss of inhibition encompasses both spontaneous and evoked glycinergic transmission and is associated with a subunit switch in glycine receptors (GlyRs) on PKCg-expressing excitatory interneurons. In this context, the predominant GlyRal and a3 subunits are replaced by GlyRa2, an isoform with reduced sensitivity and efficacy in response to synaptically released glycine, resulting in impaired inhibitory control.

[0010] In addition to receptor subunit composition, alterations in intracellular chloride homeostasis, particularly in lamina I projection neurons, further weaken glycinergic inhibition by disrupting the chloride reversal potential, thereby diminishing GlyR-mediated hyperpolarization. These molecular and cellular changes contribute to the functional disinhibition of spinal nociceptive circuits observed in neuropathic pain.

[0011] One emerging approach involves inhibition of GlyT2, a presynaptic solute carrier 6 (SLC6) transporter that plays a role in regulating glycinergic inhibitory neurotransmission. GlyT2 is a member of the SLC6 family of sodium- and chloride-dependent neurotransmitter transporters and is a candidate as a therapeutic target for pain. It is co-localized with glycine receptors and is predominantly expressed on presynaptic terminals in the brainstem, cerebellum, and spinal cord, with the highest expression in lamina III of the dorsal horn. GlyT2 sustains inhibitory glycinergic neurotransmission in the spinal cord dorsal horn through two primary mechanisms: (1) it facilitates the high-affinity reuptake of synaptically released glycine into presynaptic terminals, thereby terminating postsynaptic GlyR signaling; and (2) it enables efficient vesicular glycine refilling via its coupling to the vesicular inhibitory amino acid transporter, supporting ongoing synaptic transmission. Pharmacological inhibition of GlyT2 increases synaptic glycine concentrations, enhancing postsynaptic GlyR activation and thereby strengthening inhibitory signaling. This mechanism can directly address the maladaptive neuronal hyperexcitability characteristic of neuropathic pain. Owing to its restricted CNS distribution and high expression in spinal regions implicated in nociceptive processing, GlyT2 represents a particularly attractive therapeutic target for restoring inhibitory tone in neuropathic pain states.

[0012] Studies involving murine GlyT2" ' KO and small interfering RNA (siRNA) GlyT2 knockdown models provide valuable insights into the physiological role of GlyT2 and inform thetherapeutic potential and design considerations of GlyT2 inhibitors. Homozygous GlyT2‘ ' KO mice exhibit severe neurological phenotypes, including tremors, convulsions, and spasticity, and typically die by the second postnatal week. These phenotypes are attributed to impaired presynaptic glycine reuptake, leading to diminished glycine availability for vesicular packaging and subsequent reductions in glycinergic neurotransmission. In contrast, heterozygous GlyT2 / _KO and mutant mice are viable and do not display overt motor abnormalities or behavioral deficits. Similarly, human heterozygous carriers of SLC6A5 mutations, which encode GlyT2, do not exhibit hyperekplexia, a startle disease associated with glycinergic dysfunction. Furthermore, individuals harboring mutations in GLRA1, the gene encoding the GlyRal subunit, demonstrate heightened pain sensitivity and impaired central pain modulation relative to healthy controls. These findings underscore the role of glycinergic neurotransmission in pain modulation and support GlyT2 as a viable target, as partial inhibition is well tolerated in rodents and humans without adverse effects linked to complete loss of function. Further support for the therapeutic potential of GlyT2 inhibition comes from studies utilizing partial knockdown approaches. In a partial sciatic nerveligation (PSNL) mouse model, administration of siRNA that resulted in a 75% reduction in GlyT2 expression relative to wild-type controls led to a significant attenuation of mechanical allodynia, with the time course of behavioral improvement closely mirroring reductions in GlyT2 immunoreactivity. Importantly, these animals did not exhibit any adverse motor effects, addressing concerns that therapeutically relevant inhibition of GlyT2 could lead to mechanism-based toxicity.

[0013] Several GlyT2 inhibitors have been shown to produce dose-dependent analgesia in preclinical models of acute, inflammatory, visceral, cancer, herpetic, and neuropathic pain under both acute and chronic dosing regimens. Referring specifically to FIG. 1, representative GlyT2 inhibitors that have been reported to exhibit analgesic effects in preclinical pain models. The highlighted inhibitors include ORG25543 (1), compound 2 from Mingnorance-Le Meur, opiranserin (3, Unafra), GT-0198 (4), oleoyl-D-Lysine (ODLys) (5), ALX1393 (6),and ALX3225 (7). These data support the hypothesis that diverse pain pathologies may converge on a common mechanism involving impaired glycinergic inhibitory control within the spinal cord. The non-competitive inhibitor ORG25543 is the most extensively characterized GlyT2 tool compound, demonstrating potent inhibition (reported hGlyT2 ICso = 16 nM (14C-glycine uptake scintillation proximity assay, HEK293 cells); hGlyT2 ICso = 16 nM (Xenopus laevis oocyte electrophysiological assay)). However, its therapeutic utility is limited by exceptionally slow dissociation kinetics, with a transporter recovery half-life (ti / 2) exceeding 60 min post-washout. This sustained targetengagement is thought to contribute to the pronounced neuromotor side effects observed at analgesic dose levels, closely mirroring the phenotype of GlyT2 ' ’ KO mice, which exhibit impaired presynaptic glycine reuptake and recycling. Furthermore, GlyT2 inhibitors have been hindered by significant pharmacological limitations, including suboptimal binding kinetics, limited oral bioavailability, insufficient CNS exposure, and, in some cases, unacceptable on-target toxicity leading to adverse excitatory effects. These shortcomings have curtailed their translational potential and highlight the need for next-generation inhibitors with more favorable pharmacological properties.

[0014] What is desired, therefore, are non-opioid therapeutics that effectively manage chronic pain while avoiding the pitfalls of current treatments.SUMMARY

[0015] Aspects of the present disclosure are directed to competitive and reversible glycine transporter 2 (GlyT2) inhibitor compounds. In some embodiments, the compounds including a structure according to Formula (I):

[0016] In some embodiments, Ri and R2 are each independently hydrogen or Ci-C6 alkyl, or Ri and R2 together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered heterocycle optionally substituted from 1 to 10 times with Rn. In some embodiments, R3 and R4 are each independently hydrogen, deuterium, or Ci-Cn alkyl optionally substituted from 1 to 10 times with Rn; In some embodiments, R3 and R4 together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered carbocycle or heterocycle optionally substituted from 1 to 10 times with Rn;

[0017] In some embodiments, Rs, Re, R7, Rs, and R9 include hydrogen; halogen; deuterium, Ci-Cnalkyl optionally substituted from 1 to 10 times with Rn; cycloalkyl optionally substituted from 1 to 10 times with Rn; Rs and R9 together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered carbocycle or heterocycle optionally substituted from 1 to 10 times with Rn; aryl and heteroaryl optionally substituted from 1 to 10 times with Rn; -OR12, -NR12R13, -NR C(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)Ri2, -C(O)NRi2Ri3, C(O)RI2, or -NRI2C(S)RI3; 4-, 5- or 6-membered heterocycle containing one to two heteroatoms including oxygen, nitrogen and sulfur, optionally substituted from 1 to ten times with Rn; or Rs and R9 are oxo or thio.

[0018] In some embodiments, Rio includes hydrogen; halogen; deuterium; Ci-Cnalkyl optionally substituted from 1 to 10 times with Rn; cycloalkyl optionally substituted from 1 to 10 times with Rn; C5-C12 fused or spirocarbocycle or heterocycle optionally substituted from 1 to 10 times with Rn; aryl and heteroaryl optionally substituted from 1 to 10 times with Rn; -OR12, -NR12R13, -NR C(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)RI2, -C(O)NRI2RI3, C(O)RI2, or -NRI2C(S)RI3; or 4-, 5- or 6- membered heterocycle containing one to two heteroatoms including oxygen, nitrogen and sulfur, optionally substituted from 1 to ten times with Rn.

[0019] In some embodiments, Rn includes hydrogen; halogen; deuterium; gem-dialkyl gem-dihalo; -OR12, -NR12R13, -NR C(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)RI2, -C(O)NRI2RI3, C(O)RI2, or NRi2C(S)Ri3; 4-, 5- or 6- membered heterocycle containing one to two heteroatoms including oxygen, nitrogen and sulfur, optionally substituted from 1 to ten times with R12; or oxo or thio.

[0020] In some embodiments, R12 includes hydrogen; halogen; Ci-Cnalkyl, Ci-Cn alkenyl, Ci-Cnalkynyl, C3-C7 cycloalkyl, or C4-C7 cycloalkylalkyl, wherein each of the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted from one to eleven times with R13; or aryl or heteroaryl which is independently and optionally substituted from 1 to 7 times with R13.

[0021] In some embodiments, RI3includes hydrogen; halogen; or G-Cnalkyl, Ci-Cnalkenyl, Ci-Cnalkynyl, C3-C7 cycloalkyl, or C4-C7 cycloalkylalkyl.

[0022] In some embodiments, “A” is a ring including 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl optionally substituted from 1 to 12 times with R12, or 4-, 5-, 6-, 7-, or 8-membered heterocycle containing 1 to 4 heteroatoms including oxygen, nitrogen, and sulfur, optionally substituted from 1 to 10 times with R12.

[0023] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3.

[0024] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl or a 4-, 5-, 6- or 7-membered heterocycle containing a heteroatom including oxygen, nitrogen, and sulfur, wherein the 3-, 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered heterocycle are each optionally substituted from one to ten times with substituents as defined in R12.

[0025] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:

[0026] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:R3 and R4 are each independently hydrogen, deuterium, or CH3.

[0027] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:R3 and R4 are each independently hydrogen.

[0028] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:R3 and R4 are each independently hydrogen; and Rs, Re, and R7 are each independently hydrogen or fluorine.

[0029] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:R3 and R4 are each independently hydrogen; R5, Re, and R7 are each independently hydrogen or fluorine; Rs and R9 are each independently hydrogen, deuterium, or oxo.

[0030] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:R3 and R4 are each independently hydrogen; R5 and Re are each independently hydrogen or fluorine; R7 is hydrogen; Rs and R9 are each independently hydrogen, deuterium, or oxo.

[0031] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:R3 and R4 are each independently hydrogen; R5 and Re are each independently hydrogen or fluorine; R7 is hydrogen; Rs and R9 are each independently hydrogen, deuterium, or oxo; and Rio is Ci-Cn alkyl optionally substituted from 1 to 10 times with Rn, cycloalkyl optionally substituted from 1 to 10 times with Rn, aryl and heteroaryl optionally substituted from 1 to 10 times with Rn,-OR12, -NR12R13, -NR C(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)RI2, -C(O)NRi2Ri3, C(O)RI2, or -NR12C(S)R13.

[0032] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:Rs and R4 are each independently hydrogen; R5 and Re are each independently hydrogen or fluorine; R7 is hydrogen; Rg and R9 are each independently hydrogen, deuterium, or oxo; and Rio is Ci-Cnalkyl optionally substituted from 1 to 10 times with Rn, cycloalkyl optionally substituted from 1 to 10 times with Rn, aryl and heteroaryl optionally substituted from 1 to 10 times with Rn.

[0033] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:R3 and R4 are each independently hydrogen; R5 and Re are each independently hydrogen or fluorine; R7 is hydrogen; Rg and R9 are each independently hydrogen, deuterium, or oxo; Rio is aryl and heteroaryl optionally substituted from 1 to 10 times with Rn.

[0034] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:R3 and R4 are each independently hydrogen; R5 and Re are each independently hydrogen or fluorine; R7 is hydrogen; Rg and R9 are each independently hydrogen, deuterium, or oxo; Rio is aryl optionally substituted from 1 to 10 times with Rn.

[0035] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:R3 and R4 are each independently hydrogen; R5 and Re are each independently hydrogen or fluorine; R7 is hydrogen; Rs and R9 are each independently hydrogen, deuterium, or oxo; Rio is aryl optionally substituted from 1 to 10 times with Rn.

[0036] In some embodiments of the compound of formula (I), Ri and R2 are each individually CH3 and A is:O Q UR3 and R4 are each independently hydrogen; R5 and Re, are each independently hydrogen or fluorine; R7 is hydrogen; Rs and R9 are oxo; and Rio is aryl optionally substituted from 1 to 10 times with Rn.

[0037] Aspects of the present disclosure are directed to pharmaceutically acceptable salts of the compounds consistent with formula I, as well as compositions including concentrations of GlyT2) inhibitor compounds effective to produce a predetermined peak plasma concentration of the compound in a target.BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The drawings show embodiments of the disclosed subject matter for the purpose of illustrating the invention. However, it should be understood that the present application is not limited to the precise arrangements and instrumentalities shown in the drawings, wherein:

[0039] FIG 1. portray prior art representative glycine transporter 2 (GlyT2) inhibitor compounds;

[0040] FIG. 2 is an image showing a Scheme 1 for synthesizing chemical compounds consistent with embodiments of the present disclosure;

[0041] FIG. 3 is an image showing a Scheme 2 for synthesizing chemical compounds consistent with embodiments of the present disclosure;

[0042] FIG. 4 is an image showing a Scheme 3 for synthesizing chemical compounds consistent with embodiments of the present disclosure;

[0043] FIG. 5, is an image showing a Scheme 4 for synthesizing chemical compounds consistent with embodiments of the present disclosure;

[0044] FIG. 6 is an image showing a Scheme 5 for synthesizing chemical compounds consistent with embodiments of the present disclosure;

[0045] FIG. 7 is an image showing a Scheme 6 for synthesizing chemical compounds consistent with embodiments of the present disclosure;

[0046] FIG. 8 is an image showing a Scheme 7 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0047] FIG. 9 is an image showing a Scheme 8 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0048] FIG. 10 is an image showing a Scheme 9 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0049] FIG. 11 is an image showing a Scheme 10 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0050] FIG. 12 is an image showing a Scheme 11 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0051] FIG. 13 is an image showing a Scheme 12 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0052] FIG. 14 is an image showing a Scheme 13 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0053] FIG. 15 is an image showing a Scheme 14 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0054] FIG. 16 is an image showing a Scheme 15 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0055] FIG. 17 is an image showing a Scheme 16 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0056] FIG. 18 is an image showing a Scheme 17 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0057] FIG. 19 is an image showing a Scheme 18 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0058] FIG. 20 is an image showing a Scheme 19 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0059] FIG. 21 is an image showing a Scheme 20 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0060] FIG. 22 is an image showing a Scheme 21 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0061] FIG. 23 is an image showing a Scheme 22 for synthesizing GlyT2 inhibitor compounds consistent with embodiments of the present disclosure;

[0062] FIG. 24 portrays Table 4 which includes Mouse In Vivo Exposure Data for compound 22a consistent with embodiments of the present disclosure;

[0063] FIG. 25 is a graph portraying behavioral effects on Chronic Constriction Injury (CCI) Mice are shown of compound 22a consistent with embodiments of the present disclosure; and

[0064] FIG. 26 is a graph portraying behavioral effects on CCI and Partial Nerve Ligation Mouse Models of Neuropathic Pain (PSNL) Mice of compound 47a (RPI-GLYT2-82) consistent with embodiments of the present disclosure.DETAILED DESCRIPTION

[0065] Except where otherwise specified, where the structure of a compound according to embodiments of the present disclosure includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, racemic mixtures and isolated single enantiomers. All such isomeric forms of these compounds are expressly included in the present disclosure.Except where otherwise specified, each stereogenic carbon can be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry, e.g., all enantiomers and diastereomers) are included within the scope of the embodiments of the present disclosure, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. For example, the resolution can be carried out by preparative chromatography on a chiral column. Except where otherwise specified, the embodiments of the present disclosure are intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0066] It will be noted that any notations of a carbon in structures throughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as12C,13C, or14C. Furthermore, any compounds containing13C or14C can specifically have the structure of any of the compounds disclosed herein.

[0067] It will also be noted that any notations of a hydrogen (H) in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as1H,2H (D), or3H (T) except where otherwise specified.

[0068] Furthermore, any compounds containing2H or3H can specifically have the structure of any of the compounds disclosed herein except where otherwise specified.

[0069] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically labeled reagents in place of the nonlabelled reagents employed. Deuterium (2H or D) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen atom in a compound naturally occurs as a mixture of isotopes 1H (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.0156%. Thus, in a composition comprising molecules of a naturally occurring compound, the level of deuterium at a particular hydrogen atom site in that compound is expected to be and / or not exceed 0.0156%.

[0070] The term "substitution", "substituted" and "substituent" refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to nonhydrogen or non-carbon atoms, provided that normal valencies are maintained and thatthe substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon (s) or hydrogen (s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described above, and halogens, i.e., F, Cl, Br, and I; alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and ptrifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propyl sulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. In the compounds consistent with embodiments of the present disclosure, the substituents can be substituted or unsubstituted, unless specifically defined otherwise.

[0071] In the compounds consistent with embodiments of the present disclosure, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocycle, heterocycloalkyl, alkylheteroalkyl, alkylaryl, monocycle, bicycle, heteromonocycle, and heterobicycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl. It is understood that substituents and substitution patterns on the compounds of the present disclosure can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results.

[0072] In choosing the compounds consistent with embodiments of the present disclosure, one of ordinary skill in the art will recognize that the various substituents, i.e., Ri, R2, etc. are to be chosen according to well-known principles of chemical structure connectivity.

[0073] As used herein, "alkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and can be unsubstituted or substituted. Thus, Ci-Cnas in "Ci-Cnalkyl" is defined to include groups having 1, 2,...., n-1 or n carbons in a linear or branched arrangement. For example, Ci-Ce, as in "Ci-Ce alkyl" is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl, and hexyl. Unless otherwise specified, alkyl groups contain one to ten carbons. Alkyl groups can be unsubstituted or substituted with one or more substituents, including but not limited to halogen, alkoxy, alkylthio, trifluoromethyl, difluoromethyl, methoxy, and hydroxyl. "Haloalkyl" includes any alkyl group containing at least one halogen atom.

[0074] The term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds can be present. Thus, Ci-Cnalkenyl is defined to include groups having 1, 2...., n.i or n carbons. For example, "C2-C6 alkenyl" means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a Ccalkenyl, respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group can contain double bonds and can be substituted if a substituted alkenyl group is indicated.

[0075] The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1 carbon-to-carbon triple bond, and up to the maximum possible number of non-aromatic carboncarbon triple bonds can be present. Thus, C2-Cnalkynyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group can contain triple bonds and can be substituted if a substituted alkynyl group is indicated.

[0076] As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic, or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and can be unsubstituted or substituted. Examples of such aryl elements include but are not limited to:phenyl, / 2-toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is nonaromatic, it is understood that attachment is via the aromatic ring. The term "heteroaryl", as used herein, represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms including O, N and S. Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridazine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5- membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotri azolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazol opyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1, 4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroimidazolyl, dihydroisothiazolyl, dihydropyrazinyl, dihydrofuranyl, dihydroisooxazolyl, dihydrooxazolyl, dihydropyridinyl, dihydroquinolinyl, dihydrothiazolyl, dihydroazetidinyl, dihydroindolyl, dihydrooxadiazolyl, dihydropyrazolyl, di hydropyrrolyl, dihydrothiadiazolyl, dihydrotriazolyl, tetrahydrofuranyl, dihydropyrimidinyl, dihydrotetrazolyl, dihydrothienyl, methylenedioxybenzoyl, tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotri azolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra-hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0077] As used herein, "cycloalkyl" includes cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range, i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "Cycloalkylalkyl" includes any alkyl group containing at least one cycloalkyl ring. As used herein, "heteroalkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups having at least 1 heteroatom within the chain or branch."Alkylheteroalkyl" includes any alkyl group containing at least one heteroalkyl group. The term "heterocycle", "heterocyclyl" or "heterocyclic" refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Some heteroatoms include N, O, and / or S, including N-oxides, sulfur oxides, and dioxides. In some embodiments, the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. The heterocycle can be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings can be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3 -dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathiolane, and the like.

[0078] As used herein, "heterocycloalkyl" is intended to mean a 5- to 10-membered nonaromatic ring containing from 1 to 4 heteroatoms including O, N and S, and includes bicyclic groups."Heterocyclyl" therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0079] The term "alkylaryl" refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an "alkylaryl" group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group. Examples of arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1 -phenylethyl, 2 -phenyl ethyl, 3 -phenylpropyl, 2-phenylpropyl and the like.

[0080] As used herein, "monocycle" includes any stable polycyclic carbon ring of up to 10 atoms and can be unsubstituted or substituted. Examples of such non-aromatic monocycle elementsinclude but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such aromatic monocycle elements include but are not limited to: phenyl. As used herein, "heteromonocycle" includes any monocycle containing at least one heteroatom.

[0081] As used herein, "bicycle" includes any stable polycyclic carbon ring of up to 10 atoms that is fused to a polycyclic carbon ring of up to 10 atoms with each ring being independently unsubstituted or substituted. Examples of such non-aromatic bicycle elements include but are not limited to: decahydronaphthalene. Examples of such aromatic bicycle elements include but are not limited to: naphthalene. As used herein, "heterobicycle" includes any bicycle containing at least one heteroatom. The compounds consistent with embodiments of the present disclosure can be prepared by techniques well known in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.

[0082] The compounds consistent with embodiments of the present disclosure can be prepared by techniques known to those of skill in the art. The various R groups attached to the aromatic rings of the compounds disclosed herein can added to the rings by standard procedures.

[0083] As used herein, the term "pharmaceutically active agent" means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject. Pharmaceutically active agents which have pendant carboxylic acid groups can be modified in accordance with the present disclosure using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan can design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification can subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent's biological activity or effect.

[0084] As used herein, a "salt" is a salt of the compounds according to embodiments of the present disclosure which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat a disease or medical disorder, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols;alkali or organic salts of acidic residues such as carboxylic acids. The salts can be made using an organic or inorganic acid. Such acid salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the sodium, potassium, or lithium salts, and the like. Carboxylate salts are the sodium, potassium, or lithium salts, and the like. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic, and organic acid or base addition salts of compounds consistent with embodiments of the present disclosure. These salts can be prepared in situ during the final isolation and purification of the compounds consistent with embodiments of the present disclosure, or by separately reacting a purified compound consistent with embodiments of the present disclosure in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.

[0085] As used herein, "treating" means preventing, slowing, halting, or reversing the progression of a disease. Treating can also mean improving one or more symptoms of a disease. The compounds consistent with embodiments of the present disclosure can be administered in various forms, including those detailed herein. The treatment with the compound can be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed. As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier can be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier, as are capsules, coatings, and various syringes.

[0086] Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are withinthe scope of the present disclosure. Any of the disclosed generic or specific compounds can be applicable to any of the disclosed compositions, processes, or methods.

[0087] In some embodiments, the present disclosure is direct to compounds for inhibiting glycine transporter 2 (GlyT2). These compounds are configured to provide analgesia in neuropathic pain in a target, e.g., a human patient, upon administration. In some embodiments, the GlyT2 inhibitor compounds reversibly inhibit GlyT2.

[0088] In some embodiments, the GlyT2 inhibitor compounds include an indole core, indoline core, indazole core, or combinations thereof. In some embodiments, the GlyT2 inhibitor compounds include a structure according to Formula (I):In some embodiments, “(n)” includes 1-3 carbons. In some embodiments, Ri and R2 are each independently hydrogen or Ci-Ce alkyl, or Ri and R2 together with a carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered heterocycle; and combinations thereof.

[0089] In some embodiments, R3 and R4 are each independently hydrogen, deuterium, Ci-Cnalkyl, or R3 and R4 together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered carbocycle or heterocycle; and combinations thereof.

[0090] In some embodiments, Cnincludes C5-C7. In some embodiments, Cnincludes CG.

[0091] In some embodiments, Rs, Re, and R7 include hydrogen; halogen; deuterium; Ci-Cnalkyl; cycloalkyl; aryl or heteroaryl; -OR12, -NR12R13, -NR C(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)Ri2, -C(O)NRI2R13, C(O)Ri2, or -NRi2C(S)Ri3; 4-, 5- or 6- membered heterocycle containing one to two heteroatoms including oxygen, nitrogen and sulfur; and combinations thereof.

[0092] In some embodiments, Rs and R9 include hydrogen; halogen; deuterium; Ci-Cnalkyl; cycloalkyl; Rs and R9 together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered carbocycle or heterocycle; aryl; heteroaryl; -OR12, -NR12R13, -NR C(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)Ri2, -C(O)NRI2R13, C(O)Ri2, or -NRI2C(S)RI3; 4-, 5- or 6- membered heterocycle containing one to two heteroatoms including oxygen, nitrogen and sulfur; oxo or thio; and combinations thereof.

[0093] In some embodiments, Rio includes hydrogen; halogen; deuterium; Ci-Cnalkyl; cycloalkyl; C5-C12 fused or spirocarbocycle or heterocycle; aryl; heteroaryl, -OR12, -NR12R13, -NR C(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)Ri2, -C(O)NR12RI3, C(O)RI2, or -NRI2C(S)RI3; 4-, 5-or 6- membered heterocycle containing one to two heteroatoms including oxygen, nitrogen and sulfur; and combinations thereof.

[0094] In some embodiments, Rn includes hydrogen; halogen; deuterium; gem-dialkyl gem-dihalo, -OR12, -NR12R13, -NRC(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)Ri2, -C(O)NRI2RI3, C(O)R12, or -NRi2C(S)Ri3; 4-, 5- or 6- membered heterocycle containing one to two heteroatoms including oxygen, nitrogen and sulfur; oxo or thio; and combinations thereof.

[0095] In some embodiments, R12 includes hydrogen; halogen; Ci-Cnalkyl, Ci-Cnalkenyl, Ci-Cnalkynyl, C3-C7 cycloalkyl, or C4-C7 cycloalkylalkyl; aryl; heteroaryl; or combinations thereof.

[0096] In some embodiments, R13 includes hydrogen; halogen; Ci-Cnalkyl, Ci-Cnalkenyl, Ci-Cnalkynyl, C3-C7 cycloalkyl, or C4-C7 cycloalkylalkyl; of combinations thereof.

[0097] In some embodiments, A is a ring structure. In some embodiments, A includes a 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl; a 4-, 5-, 6-, 7-, or 8-membered heterocycle containing 1 to 4 heteroatoms including oxygen, nitrogen, and sulfur; or combinations thereof.

[0098] In some embodiments, the Ri and R2 heterocycle is substituted from 1 to 10 times with Rn.

[0099] In some embodiments, the R3 and R4 Ci-Cnalkyl is substituted from 1 to 10 times with Rn.

[0100] In some embodiments, the R3 and R4 carbocycle or heterocycle is substituted from 1 to 10 times with Rn.

[0101] In some embodiments, the Rs and R9 carbocycle or heterocycle is substituted from 1 to 10 times with Rn.

[0102] In some embodiments, the R5, Re, and R7 Ci-Cnalkyl is substituted from 1 to 10 times with Rn.

[0103] In some embodiments, the R5, Re, and R7 cycloalkyl is substituted from 1 to 10 times with Rn.

[0104] In some embodiments, the R5, Re, and R7 aryl or heteroaryl is substituted from 1 to 10 times with Rn.

[0105] In some embodiments, the R5, Re, and R74-, 5- or 6- membered heterocycle is substituted from 1 to 10 times with Rn.

[0106] In some embodiments, the Rs and R9 Ci-Cnalkyl is substituted from 1 to 10 times with Rn.

[0107] In some embodiments, the Rs and R9 cycloalkyl is substituted from 1 to 10 times with Rn. In some embodiments, the Rs and R9 aryl or heteroaryl is substituted from 1 to 10 times with Rn. In some embodiments, the Rs and R94-, 5- or 6- membered heterocycle is substituted from 1 to 10 times with Rn.

[0108] In some embodiments, the Rio Ci-Cnalkyl is substituted from 1 to 10 times with Rn. the Rio cycloalkyl is substituted from 1 to 10 times with Rn. In some embodiments, the Rio C5-C12 fused or spirocarbocycle or heterocycle is substituted from 1 to 10 times with Rn. In some embodiments, the Rio aryl and heteroaryl is substituted from 1 to 10 times with Rn. In some embodiments, the Rio 4-, 5- or 6- membered heterocycle is substituted from 1 to 10 times with Rn.

[0109] In some embodiments, the Rn 4-, 5- or 6- membered heterocycle is substituted from 1 to 10 times with R12. In some embodiments, the R12 Ci-Cnalkyl, Ci-Cnalkenyl, Ci-Cnalkynyl, C3-C7 cycloalkyl, or C4-C7 cycloalkylalkyl is substituted from one to eleven times with R13.

[0110] In some embodiments, the R12 aryl or heteroaryl is independently substituted from 1 to 7 times with R13.

[0111] In some embodiments, the A 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl is substituted from 1 to 12 times with R12. In some embodiments, the A 4-, 5-, 6-, 7-, or 8-membered heterocycle is substituted from 1 to 10 times with R12.

[0112] In one exemplary embodiment, Ri and R2 are each individually CH3.

[0113] In one exemplary embodiment, Ri and R2 are each individually CH3 and A is a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl or a 4-, 5-, 6- or 7-membered heterocycle containing a heteroatom including oxygen, nitrogen, and sulfur. In some embodiments, the A 3-, 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered heterocycle are each substituted from one to ten times with R12.

[0114] In one exemplary embodiment, Ri and R2 are each individually CH3 and A includes one or more of:

[0115] In some embodiments, R3 and R4 are each independently hydrogen, deuterium, or CH3. In some embodiments, R3 and R4 are each independently hydrogen. In some embodiments, R5, Re, and R7 are each independently hydrogen or fluorine. In some embodiments, Rs and R9 are each independently hydrogen, deuterium, or oxo. In some embodiments, R5 and Re are each independently hydrogen or fluorine and R7 is hydrogen. In some embodiments, Rio is Ci-Cnalkyl, cycloalkyl, aryl,or heteroaryl. In some embodiments, Rio is aryl or heteroaryl. In some embodiments, Rio is aryl. In some embodiments, the Rio Ci-Cn alkyl is substituted from 1 to 10 times with Rn. In some embodiments, the Rio cycloalkyl is substituted from 1 to 10 times with Rn. In some embodiments, the Rio aryl is substituted from 1 to 10 times with Rn,-ORi2, -NR12R13, -NR C(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)Ri2, -C(O)NRI2R13, C(O)RI2, or -NRI2C(S)RI3. In some embodiments, the Rio heteroaryl is substituted from 1 to 10 times with Rn,-ORi2, -NR12R13, -NR C(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)Ri2, -C(O)NRI2R13, C(O)RI2, or -NRI2C(S)RI3; or combinations thereof.

[0116] In one exemplary embodiment, Ri and R2 are each individually CH3; A includes one or more of:R.3 and R4 are each independently hydrogen; R5, Re, are each independently hydrogen or fluorine; R7 is hydrogen; Rs and R9 are each independently hydrogen, deuterium, or oxo; and Rio is aryl. In some embodiments, Rs and R9 are oxo. In some embodiments, the Rio aryl is substituted from 1 to 10 times with Rn.

[0117] In some embodiments, the compound includes one or more of the following structures:

[0118] Some embodiments of the present disclosure directed to pharmaceutically acceptable salts of the GlyT2 inhibitor compounds consistent with Formula I above and / or the particular compounds identified above. Some embodiments of the present disclosure are directed to a pharmaceutical composition including concentrations of one or more of the GlyT2 inhibitor compounds consistent with Formula 1 above and / or the compounds identified above. Some embodiments of the present disclosure are directed to a therapeutic composition including concentrations of one or more pharmaceutically acceptable salts of the GlyT2 inhibitor compounds consistent with Formula I above and / or the compounds identified above.

[0119] In some embodiments, the composition includes an amount of GlyT2 inhibitor compound and / or pharmaceutically acceptable salts thereof effective to treat the target, e.g., provide analgesiain neuropathic pain. In some embodiments, the composition includes an amount effective to produce a predetermined peak plasma concentration of the compound in the target to provide the desired level of therapeutic effect, e.g., pain relief. In some embodiments, administration of the composition to the target results in a predetermined peak plasma concentration of GlyT2 inhibitor compound in the target to provide the desired level of therapeutic effect. In some embodiments, the amount of GlyT2 inhibitor in the compound administered to the target is between about 10 mg / kg and about 250 mg / kg, i.e., mg of GlyT2 inhibitor compound per kg weight of the target organism be treated. In some embodiments, the amount of GlyT2 inhibitor in the compound administered to the target is between about 30 m / kg and about 150 mg / kg. In some embodiments, the composition includes one or more additional components such as small molecule drugs, proteins, nucleic acids, additional pharmaceutically active agent, diluent, carrier molecule, adjuvant, excipient, etc., or combinations thereof.

[0120] In some embodiments, the dosage of the compounds administered in treatment varies depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect. In some embodiments, dosage unit of the compounds can include a single compound or mixtures thereof with additional agents.

[0121] In some embodiments, the compounds are administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. In some embodiments, the compounds are administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g., by injection, topical application, or other methods, into or onto a site of disease, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

[0122] As discussed above, in some embodiments, the compounds used are administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. In some embodiments, the unit is in a form suitable for oral, rectal, topical, intravenous, or direct injection or parenteral administration. The compounds can be administered alone or mixed with apharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be coadministered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin, and agar. Capsule or tablets can be formulated and made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets can contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms can contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms can contain flavoring and coloring agents. Parenteral and intravenous forms can also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

[0123] Techniques and compositions for making dosage forms useful in the delivery of the compounds according to embodiments of the present disclosure are generally known in the art. Tablets can contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders can include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms can include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators can include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0124] The compounds according to embodiments of the present disclosure can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines. The compounds can be administered as components of tissue-targeted emulsions. The compounds consistent with embodiments of the present disclosure can also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels. Gelatin capsules can contain active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

[0125] For oral administration in liquid dosage form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms can contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration can contain a water-soluble salt of active ingredients, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions cancontain preservatives, such as benzalkonium chloride, methyl- or propyl -paraben, and chlorobutanol. Suitable pharmaceutical carriers are generally known in the art.

[0126] The compounds consistent with embodiments of the present disclosure can also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can generally be made continuous rather than intermittent throughout the dosage regimen.

[0127] In some embodiments, parenteral and intravenous forms also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.EXAMPLES

[0128] Exemplary embodiments of the present disclosure are demonstrated by the examples provided below. However, those skilled in the art will readily appreciate that these examples are illustrative of embodiments consistent with the contents of the present disclosure the claims provided herein.

[0129] All reactions were performed under a dry atmosphere of nitrogen unless otherwise specified. Indicated reaction temperatures refer to the reaction bath, while room temperature (rt) is noted as 25°C. Commercial grade reagents and anhydrous solvents were used as received from vendors and no attempts were made to purify or dry these components further. Removal of solvents under reduced pressure was accomplished with a Buchi rotary evaporator at approximately 28 mm Hg using a Teflon-linked KNF vacuum pump. The measurement of pH for neutralizations or acidifications was measured with Hydrion pH paper (MicroEssential Lab). Thin layer chromatography was performed using 1” x 3” AnalTech No. 02521 silica gel plates with fluorescent indicator. Visualization of TLC plates was made by observation with either short wave UV light (254 nm lamp), 10% phosphomolybdic acid in ethanol or in iodine vapors. Flash column chromatography was carried out using a Biot age" Selekt System with Teledyne Isco RediSepRf and Biotage Sfar silica gel columns. Proton NMR (’H NMR) spectra were obtained on a 600 MHz Bruker AV III nuclear magnetic resonance spectrometer. Chemical shifts (d) are reported in parts per million (ppm) and coupling constant (J) values are given in Hz, with the following spectral pattern designations: s, singlet; d, doublet; t, triplet, q, quartet; quint, quintet; m, multiplet; dd, doublet of doublets; dt, doublet of triplets; dq; doublet of quartets; br, broad signal.Tetramethyl silane was used as an internal reference. Peak listing, multiplicity designations, and coupling constant calculations were conducted using Mnova v.14 software (Mestrelab Research). Carbon NMR (13C NMR) spectra were obtained on a 600 MHz Bruker AV III nuclear magnetic resonance spectrometer and tetramethylsilane was used as an internal reference. Mass spectroscopic analyses were performed using ESI ionization on a Shimadzu LCMS-2020 single quadrupole mass spectrometer with a Shimadzu Nexcol C18 5mM, 50 x 3.0 mm column and a binary solvent system A and B using a gradient elusion [A, H2O with 0.1% formic acid; B, CH3CN with 0.1% formic acid] and flow rate = 0.5 mL / min. High pressure liquid chromatography (HPLC) purity analysis was performed using a Shimadzu LC-2050C HPLC system with a binary solvent system A and B using a gradient elusion [A, H2O with 0.1% formic acid; B, CH3CN with 0.1% formic acid] and flow rate = 0.5 mL / min, with UV detection at 254 nm (system equipped with a photodiode array (PDA) detector). An X Bridge C18 5mm 4.6 x 150 mm column was used. High resolution mass spectrometry (HRMS) analysis was was performed using an Agilent 6530 Accurate-Mass Q-TOF. All final compounds tested for in vitro and in vivo biological testing were purified to >95% purity, and these purity levels were measured by both 'HNMR and HPLC.

[0130] Referring now to FIG. 2, compounds consistent with embodiments of the present disclosure are prepared according to Scheme 1. In the exemplary embodiments of Scheme 1, the reagents and reaction conditions were as follows: (a) (CHQiN HC1, KCN, H2O, 0°C to rt, 24 h; (b) LiAlHi, Et2O, 0°C to rt, 20 h.

[0131] 4-(Aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine (“3a”). Step A: To a solution of tetrahydro-4H-pyran-4-one (“la”, 10.0 g, 100 mmol) in H2O (500 mL) was added N, N-dimethylamine hydrochloride (8.15 g, 100 mmol) followed by KCN (6.50 g, 100 mmol). The reaction mixture was stirred at rt for 16 h with completion of the reaction determined by TLC. The reaction mixture was extracted with Et2O (3 x 500 mL), and the combined organic layers were washed sequentially with H2O (2 x 500 mL) and saturated brine solution (200 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to afford 4-(dimethylamino)tetrahydro-2H-pyran-4-carbonitrile (“2a”) as a colorless oil (10.0 g, 65% yield), which was used in the next step without further purification. ’H NMR (600MHz, CD3OD) d 3.9-4.0 (m, 2 H), 3.58-3.62 (m, 2 H), 2.35 (s, 6H), 2.11-2.15 (m, 2 H), 1.68-1.73 (m, 2 H).

[0132] Step B: To a 0°C cooled solution of 4-(dimethylamino)tetrahydro-2H-pyran-4-carbonitrile (2a, 5.0 g, 32.46 mmol) in anhydrous Et2O (250 mL) stirring under an N2 atmosphere was slowly added IJAIH4 (2.5 g, 64.93 mmol). The reaction mixture continued to stir for 16 h while gradually warming to rt. After confirming complete consumption of the starting material by TLC, the reaction mixture was diluted with additional Et2O (250 mL) and cooled to 0°C. Dropwise addition of H2O (2.5 mL) was conducted slowly so as to maintain the temperature at 0°C, followed by sequential dropwise addition of 15% aqueous NaOH solution (2.5 mL) and additional H2O (7.5 mL). The reaction mixture to warm to rt over 1 h followed by addition of MgSCU (10 g). The resulting mixture was allowed to stir at rt for an additional 30 min. The resulting precipitate was filtered, and the filtrate was concentrated under reduced pressure to yield 4-(aminomethyl)-A, A-dimethyltetrahydro-2H-pyran-4-amine (3a) as a colorless oil (4.0 g, 80% yield), which was used as is in the next step without further purification. ’H NMR (600 MHz, CD3OD) d 3.82-3.85 (m, 2 H), 3.55-3.59 (m, 2 H), 2.86 (s, 2 H), 2.32 (s, 6 H), 1.78-1.83 (m, 2 H), 1.53-1.56 (m, 2 H);13C NMR (600 MHz, DMSO- 4) d 63.4, 55.8, 42.5, 37.7, 30.1; ESIMS m / z 159 [M + H]+.

[0133] l-(Aminomethyl)-N, N-dimethylcyclobutan-l -amine (“3b”). Compound 3b was prepared from cyclobutanone (“lb”), A, A-dimethylamine hydrochloride, and KCN according to a similar procedure described for the synthesis of 3a: ’H NMR (600 MHz, DMSO-rfe): 8.

[0134] l-(Aminomethyl)-N, N-dimethylcy cl opentan- 1 -amine (“3c”). Compound 3c was prepared from cyclopentanone (“lc”), M-V-di methyl amine hydrochloride, and KCN according to a similar procedure described for the synthesis of 3a:1H NMR (600 MHz, DMSO-de): 8.

[0135] l-(Aminomethyl)-N, N-dimethylcyclohexan-l -amine (“3d”). Compound 3d was prepared from cyclohexanone (“Id”), A, A-dimethylamine hydrochloride, and KCN according to a similar procedure described for the synthesis of 3a:1H NMR (600 MHz, DMSO-de): 8.

[0136] (±)-3-(Aminomethyl)-N, N-dimethyltetrahydrofuran-3-amine (“(±)-3e”). Compound (±)-3e was prepared from 3 -tetrahydrofuranyl (“le”), A( / -dimethyl amine hydrochloride, and KCN according to a similar procedure described for the synthesis of 3a: H NMR (600 MHz, DMSO-de) 8.

[0137] 3 -(Aminomethyl)-N, N-dimethylox etan-3 -amine (“3f”). Compound 3f was prepared from ox etan-3 -one (“If’), A, A-dimethylamine hydrochloride, and KCN according to a similar procedure described for the synthesis of 3a: ’H NMR (600 MHz, DMSO-de): 8.

[0138] (±)-3-(Aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-3-amine (“(±)-3g”).Compound (±)-3g was prepared from dihydro-2H-pyran-3(4H)-one (“1g”), N, A-dimcthylaminc hydrochloride, and KCN according to a similar procedure described for the synthesis of 3a:1H NMR (600 MHz, DMSO-e76): d 3.82-3.81 (m, 1H), 3.67-3.66 (m, 1H), 3.46-3.44 (m, 1H), 3.40-3.35 (m, 1H), 3.01-2.98 (m, 1H), 2.75-2.73 (m, 1H), 2.30 (s, 6H), 1.68-1.58 (m, 4H);13C NMR (CDCh, 150 MHz) 870.1, 68.3, 56.3, 41.4, 37.8, 25.1, 22.5.

[0139] Referring now to FIG. 3, compounds consistent with embodiments of the present disclosure are prepared according to Scheme 2. In the exemplary embodiments of Scheme 2, the reagents and reaction conditions were as follows: (a) (CH iN HC1, KCN, H2O, 0°C to rt, 24 h; (b) LiAIF, Et2O, 0°C to rt, 20 h.

[0140] (±)-(4-(3-Fluoropyrrolidin-l-yl)tetrahydro-2H-pyran-4-yl)m ethanamine (“(±)-5a”). Step A: To a solution of tetrahydro-41 / -pyran-4-one (la, 10.0 g, 99.8 mmol) in H2O (100 mL) was added a solution of (±)-3-fluoropyrrolidine hydrochloride (12.5 g, 99.8 mmol) and KCN (6.50 g, 99.8 mmol) in H2O (100 mL) dropwise at 0°C, The resulting mixture was stirred at room temperature for 24 h.K2CO3 (16.5 g, 119 mmol) was then added and the mixture stirred for 1 h then diluted with Et20 (100 mL), washed with H2O (50 mL), saturated K2CO3 (50 mL), and brine (50 mL). The organic layer was dried over anhydrous MgSCL, filtered, and concentrated under reduced pressure to give 4-(3-fluoropyrrolidin-l-yl)tetrahydro-2 / / -pyran-4-carbonitrile (“(±)-4a”) as a yellow solid (13.2 g, 67%), which was used in the next step without further purification:JH NMR (600 MHz, CDCI3) 5 5.30-5.20 (m, 1H), 4.01-3.98 (m, 2H), 3.70-3.65 (m, 2H), 3.14-3.04 (m, 2H), 2.89-2.82 (m, 1H), 2.67-2.64 (m, 1H), 2.31-2.10 (m, 2H), 2.02-2.00 (m, 2H), 1.91-1.84 (m, 2H);13C NMR (600 MHz, CDCI3) d 118.1, 92.2, 63.8, 54.5, 45.8, 35.5, 31.6.

[0141] Step A: To a 0°C cooled suspension of LiAlHj (1.43 g, 37.8 mmol) in Et2O (100 mL) was added a solution of 4-(3-fluoropyrrolidin-l-yl)tetrahydro-2 / 7-pyran-4-carbonitrile ((±)-4a, 5.00 g, 25.2 mmol) in Et2O (200 mL) dropwise under N2 atmosphere. Upon completion of addition, the resulting mixture was stirred for 24 h while gradually warming to room temperature. The mixture was then carefully quenched at 0°C with 15% NaOH(1.50 mL) and H2O (4.50 mL). The mixture was filtered through a pad of celite, which was further washed with Et2O (200 mL). The filtrate was dried over anhydrous MgSCU. filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (90-100% 90:9:1 CH2CI2 / CH3OH / NH4OH in CH2Q2) to give (±)-(4-(3-fluoropyrrolidin-l-yl)tetrahydro-2H-pyran-4-yl)methanamine ((±)-5a) as a colorless liquid (2.27 g, 44%): 'HNMR (600 MHz, CDCI3) 85.20-5.10 (m, 1H), 3.83-3.80 (m, 2H), 3.60-3.56 (m, 2H), 3.05-2.89 (m, 3H), 2.84 (s, 2H), 2.73-2.72 (m, 1H), 2.10-1.94 (m, 2H),1.75-1.71 (m, 2H), 1.58-1.54 (m, 2H);13C NMR (600 MHz, CDCh) d 93.3, 63.9, 54.7, 51.5, 43.7, 42.6, 32.4, 30.1.

[0142] (4-(3-Fluoropyrrolidin-l-yl)tetrahydro-2H-pyran-4-yl)methanamine (“5b”). Compound 5b was prepared from tetrahydro-4 / / -pyran-4-one (la) and A-methyl-2-fluoroethyl amine according to a similar procedure described for the synthesis of 5a:1H NMR (600 MHz, DMSO ): 8.

[0143] (4-((lR,5S)-3-Azabicyclo[3.1.0]hexan-3-yl)tetrahydro-2H-pyran-4-yl)methanamine (“5c”). Compound 5c was prepared from tetrahydro-47 / -pyran-4-one (la) and (77?,55)-3-azabicyclo[3.1.0]hexane according to a similar procedure described for the synthesis of 5a:1H NMR (600 MHz, CDCI3,) 53.75-3.72 (m, 2H), 3.57-3.53 (m, 2H), 2.79-2.75 (m, 6H), 1.71-1.66 (m, 2H), 1.53-1.50 (m, 2H), 1.34-1.33 (m, 2H), 0.62-0.61 (m, 1H), 0.36-0.33 (m, 1H);13C NMR(600 MHz, CDCI3,) 563.8, 53.8, 45.4, 44.0, 30.2, 14.9, 6.5.

[0144] (4-Morpholinotetrahydro-2H-pyran-4-yl)methanamine (“5d”). Compound 5d was prepared from tetrahydro-4 / / -pyran-4-one (la) and morpholine to a similar procedure described for the synthesis of 5a:XH NMR (600 MHz, CDC13,) 53.85-3.82 (m, 2H), 3.69-3.68 (m, 4H), 3.60-3.55 (m, 2H), 2.82 (s, 2H), 2.65-2.64 (m, 4H), 1.79-1.75 (m, 2H), 1.53-1.50 (m, 2H);13C NMR (CDCI3, 150 MHz) 567.9, 63.7, 56.3, 45.4, 43.3, 29.8.

[0145] (4-(4-Methylpiperazin-l-yl)tetrahydro-2H-pyran-4-yl)methanamine (“5e”). Compound 5e was prepared from tetrahydro-4 / 7-pyran-4-one (la) and A-methylpiperazine according to a similar procedure described for the synthesis of 5a:NMR (600 MHz, CDCh,) 54.85 (s, 4H), 3.83-3.81 (m, 2H), 3.58-3.55 (m, 2H), 2.80 (s, 2H), 2.68 (brs, 4H), 2.30 (s, 3H), 1.82-1.79 (m, 2H), 1.50-1.48 (m, 2H);13C NMR (600 MHz, CDCh,) 563.6, 56.1, 50.1, 45.7, 44.4, 35.3.

[0146] Referring now to FIG. 4, compounds consistent with embodiments of the present disclosure are prepared according to Scheme 3. In the exemplary embodiments of Scheme 3, the reagents and reaction conditions were as follows: (a) benzaldehyde, NaBHsCN, HO Ac, CH3OH, 0°C to rt, 20 h; (b) (i) LiOH H2O, CH3OH, THF, H2O, 0°C to rt, 20 h, (ii) 2 N aqueous HC1.

[0147] l-Benzylindoline-5-carboxylic Acid (“8”). Step A: To a solution of methyl indoline-5-carboxylate (“6”, 1.00 g, 5.64 mmol) in CH3OH (10 mL) was added benzaldehyde (0.68 mL, 6.77 mmol) and HO Ac (3.23 mL, 56.4 mmol) under N2 atmosphere, and the reaction mixture was stirred at room temperature for 5 h. The mixture was then cooled to 0°C, and NaBHi (0.53 g, 8.46 mmol) was then added. The reaction mixture was subsequently stirred at room temperature for an additional 20 h. After reaction completion, the reaction mixture was diluted with EtOAc (50 mL), washed with H2O (30 mL) and brine (30 mL). The organic layer was dried over anhydrous MgSC>4, fdtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (30-40% EtOAc in hexanes) to give methyl l-benzylindoline-5-carboxylate (“7”) as a colorless liquid (1.35 g, 90%): ’HNMR (600 MHz, CDCh) 57.79 (d, 1H, J= 8.28 Hz), 7.70 (s, 1H), 7.34-7.23 (m, 5H), 6.41 (d, J= 8.34 Hz, 1H), 4.34 (s, 2H), 3.83 (s, 3H), 3.46 (t, J= 8.58, Hz, 2H), 3.01 (t, J= 8.64 Hz, 2H);13C NMR (600 MHz, CDCh) 5 167.4, 155.9, 137.3, 131.0, 129.2, 128.5, 127.5, 127.3, 125.8, 118.3, 104.6, 52.5, 51.6, 51.4, 27.5.

[0148] To a solution of methyl l-benzylindoline-5-carboxylate (7, 1.35 g, 5.05 mmol) in a 1:1:1 mixture of THF / CH3OH / H2O (30 mL) was added LiOH H2O (0.61 g, 25.2 mmol), and the reaction mixture was stirred at room temperature for 24 h. After reaction completion, the mixture was concentrated under reduced pressure. The resulting residue was acidified to pH = 2 with 2N HC1, and the aqueous mixture was extracted with EtOAc (3 * 50 mL). The combined organic extractswere washed with H2O (3 x 30 mL) and brine (30 mL). The organic layer was dried over anhydrous MgSC. filtered, and concentrated under reduced pressure to give l-benzylindoline-5-carboxylic acid (8) as an off-white solid (1.15 g, 90%): 'H NMR (600 MHz, DMSO-rL) 8 12.05 (br s, 1H), 7.65 (d, J= 8.34 Hz, 1H), 7.56 (s, 1H), 7.35-7.25 (m, 5H), 6.56 (d, J= 8.34 Hz, 1H), 4.38 (s, 2H), 3.43 (t, J= 8.64 Hz, 2H), 2.95 (t, J= 8.58 Hz, 2H);13C NMR (600 MHz, DMSO-tfc,) 6 167.5, 155.6, 137.5, 130.6, 129.2, 128.5, 127.7, 127.2, 125.5, 118.3, 104.8,51.9, 50.6, 27.0.

[0149] Referring now to FIG. 5, compounds consistent with embodiments of the present disclosure are prepared according to Scheme 4. In the exemplary embodiments of Scheme 4, the reagents and reaction conditions were as follows: (a) CuCN, DMF, MW 150°C, 2 h; (b) KOH, CH3OH, H2O, rt, 16 h; (c) CH3I, NaHCO3, DMF, 25°C, (d) NaCNBH3, HOAc, 0°C to rt, 20 h; (e) LiOH H2O, CH3OH, H2O, rt, 16 h.

[0150] 6 -fluoroindoline-5-carboxylic acid (“14”). Step A: To a dissolved solution of 5-bromo-6-fluoro-177-indole (“9”, 4.02 g, 18.68 mmol) in anhydrous DMF (4 mL) was added CuCN (5.02 g, 56.06 mmol) at room temperature. The reaction mixture was heated at 150 °C for 2 h under microwave irradiation. The mixture was allowed to cool to room temperature and then filtered through celite. The resulting mother liquor was diluted with H2O (50 mL), and the aqueous mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with H2O (2 x 30 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-50% EtOAc in hexanes) to give 6-fluoro- l / 7-indole-5-carbonitrile (“10”) as brown solid (2.34 g, 78%): 'H NMR (600 MHz, acetone-rL) 8 10.88 (br s, 1 H), 8.02 (d, J= 6.3 Hz, 1 H), 7.52 (d, J= 3.0 Hz, 1 H), 7.40 (d, J= 10.3 Hz, 1 H), 6.63 (d, J = 3.0 Hz, 1 H); ESI MS m / z 160.9 [M + H]+.

[0151] Step B: To a solution of 6-fluoro-l / / -indole-5-carbonitrile (10, 0.75 g, 4.68 mmol) in CH3OH (10 mL), H2O (40 mL) was added KOH (2.10 g, 37.68 mmol) at room temperature. The reaction mixture was then heated to 100°C for 16 h. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure, and the resulting residue was diluted with H2O (50 mL). The aqueous layer was acidified with 2.0 N aqueous HC1 to about pH 1-2 and then extracted with EtOAc (2 x 50 mL), and the combined organic extracts were washed with H2O (2 x 30 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 6-fluoro-17 / -indole-5-carboxylic acid (“11”) as brown solid (0.62 g, 75%): ’H NMR (600MHz, DMSO4) 8 11.46 (br s, 1 H), 8.14 (d, J= 'll Hz, 1 H), 7.43-7.42 (m, 1 H), 7.22 (d, J = 12.0 Hz, 1 H), 7.40 (d, J= 10.3 Hz, 1 H), 6.55 (s, 1 H); ESI MS m / z 179.9 [M + H]+.

[0152] Step C: To a 0 °C cooled solution of 6-fluoro-17 / -indole-5-carboxylic acid (11, 1.60 g, 8.93 mmol) in DMF (10 mL) was added NaHCOi (3.00 g, 35.72 mmol) and CH3I (5.45 g, 38.40 mmol). The reaction mixture was stirred for 48 h at room temperature. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with H2O (2 x 20 mL), brine (30 mL), dried over Na? SO4- filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-25% EtOAc in hexanes) to give to give methyl 6-fluoro-17 / -indole-5-carboxylate (“12”) as white solid (1.50 g, 87%): 'H NMR (600 MHz, CDCI3) 88.83 (br s, 1 H), 8.28 (d,. / 7,2 Hz, 1 H), 7.26-7.25 (m, 1 H), 7.14 (d, J = 11.6 Hz, 1 H), 6.16 (t, J= 2.16 Hz, 1 H), 3.96 (s, 3 H); ESI MS m / z 193.9 [M + H]+.

[0153] Step D: To a solution of methyl 6-fluoro-17 / -indole-5-carboxylate (12, 1.30 g, 6.73 mmol) in HO Ac (10 mL) was added NaBHsCN (1.26 g, 20.18 mmol) at 0 °C. The reaction mixture was stirred for 16 h while gradually warming to room temperature. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (50 mL) and neutralized with saturated NaHCOs solution (50 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 100 mL), and the combined organic extracts were washed with H2O (2 x 50 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-30% EtOAc in hexanes) to give methyl 6-fluoroindoline-5-carboxylate (“13”) as white solid (0.77 g, 58%): ’H NMR (600 MHz, CDCI3) 87.60 (d, J= 7.2 Hz, 1 H), 6.21 (d, J= 12.0 Hz, 1 H), 4.39 (br s, 1 H), 3.85 (s, 3 H), 3.68 (t, J= 8.4 Hz, 2 H), 3.01 (t, J = 8.4 Hz, 2 H); ESI MS m z 195.8 [M + H]+.

[0154] Step E: To a solution of methyl 6-fluoroindoline-5-carboxylate (13, 0.20 g, 0.674 mmol) in CH3OH (1 mL), H2O (4 mL) was added LiOH H2O (0.024 g, 1.01 mmol) at room temperature. The reaction mixture was heated at reflux for 1 h. The mixture was allowed to cool to room temperature and was then concentrated under reduced pressure, and the resulting residue was diluted with H2O (50 mL). The aqueous mixture was acidified to pH = 2 with 2.0 N aqueous HC1 and was then extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with H2O (2 x 20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with Et2O (30 mL) to give 6-fluoroindoline-5-carboxylic acid (14) aspale yellow solid (0.130 g, 68%): 'H NMR (600 MHz, DMSO-A) 87.73 (d, J= 7.5 Hz, 1 H), 7.61 (d, J= 7.0 Hz, 2 H), 7.55 (d, J= 7.2 Hz, 1 H), 7.51 (t, J= 7.2 Hz, 2 H), 4.08 (t, J= 8.3 Hz, 2 H), 3.09 (t, 7= 8.4 Hz, 2 H (s, 3 H); ESI MS m'z 285.9 [M + H]+.

[0155] Referring now to FIG. 6, compounds consistent with embodiments of the present disclosure are prepared according to Scheme 5. In the exemplary embodiments of Scheme 5, the reagents and reaction conditions were as follows: (a) BOC2O, EtsN, CH2Q2, rt, 16 h; (b) LiOH H2O, CH3OH, H2O, rt, 16 h; (c) 3a, HBTU, 7-Pr2NEt, CH2CI2, rt, 16 h; (d) 4.0 M HC1 in 1,4-dioxane, CH2CI2, 0°C to rt, 2 h.

[0156] N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“ 19”). Step A: To a solution of l-(ter / -butoxycarbonyl)indoline-5-carboxylic acid (“17”, 0.99 g, 3.78 mmol) in CH2CI2 (25 mL) was added 4-(aminomethyl)-A, A-dimethyltetrahydro-2H-pyran-4-amine (3a, 0.71 g, 4.53 mmol), HBTU (1.72 g, 4.53 mmol), and z-Pr NEt (0.99 g, 7.56 mmol) and the mixture stirred for 16 h at room temperature and under an atmosphere of N2. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous mixture was extracted with EtOAc (3 >< 30 mL), and the combined organic extracts were washed with H2O (3 x 30 mL), brine (30 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2CI2) to give / c / 7-butyl 5-(((4-(dimethylamino)tetrahydro-2 / / -pyran-4-yl)methyl)carbamoyl)indoline-l-carboxylate (“18”) as a white solid (0.76 g, 48%); 'H NMR (600 MHz, CDCI3) 87.61 (s, 1 H), 7.54 (d, J= 8.2 Hz, 1 H), 6.84 (br s, 1 H), 4.02-4.00 (m, 2 H), 3.88-3.86 (m, 2 H), 3.68-3.67 (m, 2 H), 3.64-3.60 (m, 2 H), 3.13-3.10 (m, 2 H), 2.34 (s, 6 H), 1.92-1.87 (m, 2 H), 1.56 (s, 9 H), 1.44-1.41 (m, 2 H); ESI MS m / z 404 [M + H]+.

[0157] Step B: To a 0°C cooled solution of te / 7-butyl 5-(((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)indoline-l -carboxylate (18, 1.30 g, 3.22 mmol) in CH2CI2 (10 mL) was added 4.0 M solution of HC1 in 1,4-dioxane. The mixture was stirred for 16 h while gradually warming to room temperature. The mixture was concentrated under reduced pressure to give A-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) as a white solid (0.31 g, 32%):'HNMR (600 MHz, DMSO ) 8 10.45 (s, 1 H), 8.71 (s, 1 H), 7.84 (s, 1 H), 7.78 (d, J = 8.2 Hz, 1 H), 7.10 (d, J= 8.2 Hz, 1 H), 3.82-3.81 (m, 4 H), 3.65-3.62 (m, 2 H), 3.54 (s, 2H), 3.11 (t, J = 8.1 Hz, 2 H), 2.75-2.74 (m, 6 H), 1.91-1.89 (m, 4 H); ESIMS m / z 304 [M + H]+.

[0158] Referring now to FIG. 7, compounds consistent with embodiments of the present disclosure are prepared according to Scheme 6. In the exemplary embodiments of Scheme 6, the reagents and reaction conditions were as follows: (a) 3c, HBTU, z-Pr2NEt, CH2CI2, rt, 16 h; (b) 4.0 M HC1 in 1,4-di oxane, CH2CI2, 0°C to rt, 2 h.

[0159] N-((l-(Dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“21”). Step A: To a solution of l-( / ez7-butoxycarbonyl)indoline-5-carboxylic acid (17, 0.99 g, 3.78 mmol) in CH2CI2 (25 mb) was added l-(aminomethyl)-AA-dimethylcyclopentan-l-amine (3b, 0.71 g, 4.53 mmol), HBTU (1.72 g, 4.53 mmol), and z-Pr2NEt (0.99 g, 7.56 mmol) and the mixture stirred for 16 h at room temperature and under an atmosphere of N2. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous mixture was extracted with EtOAc (3 * 30 mL), and the combined organic extracts were washed with H2O (3 * 30 mL), brine (30 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2CI2) to give / c / 7-butyl 5-(((l-(dimethylamino)cyclopentyl)methyl)carbamoyl)indoline-l-carboxylate (“20”) as a white solid (0.732 g, 50%): ’H NMR (600 MHz, CDCI3) 8.

[0160] Step B: To a 0°C cooled solution of Zc / 7-butyl 5-(((l-(dimethylamino)cyclopentyl)methyl)carbamoyl)indoline-l -carboxylate (20, 1.24 g, 3.22 mmol) in CH2CI2 (10 mL) was added 4.0 M solution of HC1 in 1,4-dioxane. The mixture was stirred for 16 h while gradually warming to room temperature. The mixture was concentrated under reduced pressure to give A-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (21) as a white solid (0.370 g, 40%):’H NMR (600 MHz, DMSO-Je) 8.

[0161] Referring now to FIG. 8, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 7. In the exemplary embodiments of Scheme 7, the reagents and reaction conditions were as follows: (a) 8, HBTU, z-Pr2NEt, CH2CI2 or DMF, rt, 24 h.

[0162] Example 1: l-Benzyl-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“22a”). Step A: To a solution of l-benzylindoline-5-carboxylic acid (8, 0.946 g, 3.78 mmol) in DMF (25 mL) was added 4-(aminomethyl)-A(A-dimethyltetrahydro-2H-pyran-4-amine (3a, 0.718 g, 4.53 mmol), HBTU (1.72 g, 4.53 mmol), and z-Pr2NEt (0.99 g, 7.56 mmol) and the mixture stirred for 16 h at room temperature and under an atmosphere of N2. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous mixture was extracted with EtOAc (3 >< 30 mL), and the combined organic extracts were washed with H2O (3 x 30 mL), brine (30 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2Q2) to give l-benzyl-A-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (22a) as a white solid (1.04 g, 70%): ’H NMR (400 MHz, DMSO-z / 6) 87.52-7.49 (m, 2H), 7.30-7.19 (m, 5H), 6.55 (d, J= 8.34 Hz, 1H), 4.37 (s, 2H), 3.61-3.39 (m, 6H), 3.34-3.28 (m, 3H), 3.14 (t, J= 8.52 Hz, 3H), 2.63-2.27 (m, 6H), 1.60 (m, 4H); ESI MS m / z 394 [M+H]+; HPLC = 99.5 %, tR= 12.4 min.

[0163] Example 2: l-Benzyl-N-((l-(dimethylamino)cyclobutyl)methyl)indoline-5-carboxamide (“22b”). Compound 22b was prepared l-benzylindoline-5-carboxylic acid (8) and 1-(aminomethyl)-AA-dimethylcyclobutan-l -amine (3b) according to a similar procedure described for the synthesis of 22a: ’H NMR (400 MHz, acetone- r,) 87.58-7.55 (m, 2H), 7.38-7.26 (m, 5H), 6.53 (d, J= 8.34 Hz, 1H), 3.58 (m, 2H), 3.43 (m, 2H), 2.97 (m, 2H), 2.25 (s, 6H), 2.09 (m, 3H), 1.78-1.63 (m, 4H); ESI MS m / z 364 [M+H]+; HPLC = 99.7 %, tR= 12.7 min.

[0164] Example 3: l-Benzyl-N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“22c”). Compound 22c was prepared l-benzylindoline-5-carboxylic acid (8) and 1-(aminomethyl)-2V, JV-dimethylcyclopentan-l -amine (3c) according to a similar procedure described for the synthesis of 22a: ’HNMR (400 MHz, DMSO-tL) 58.22 (br s, 1H), 7.57-7.55 (m, 2H), 7.31-7.26 (m, 5H), 6.58 (d, J= 8.34 Hz, 1H), 4.35 (s, 2H), 3.52 (m, 2H), 3.28 (m, 2H), 2.94 (m, 2H), 2.77 (s, 6H), 1.86-1.66 (m, 8H); ESIMS m / z 378 [M+H]+; HPLC = 95.3 %, tR= 12.5 min.

[0165] Example 4: l-Benzyl-N-((l-(dimethylamino)cyclohexyl)methyl)indoline-5-carboxamide (“22d”). Compound 22d was prepared l-benzylindoline-5-carboxylic acid (8) and 1-(aminomethyl)- (jV-dimethylcyclohexan-l -amine (3d) according to a similar procedure described for the synthesis of 22a: ’HNMR (600 MHz, CDC13) 87.64 (m, 3H), 7.35-7.28 (m, 5H), 6.47 (d, 1H), 4.35 (s, 2H), 3.48 (t, 2H), 3.07 (t, 2H), 2.41 (br s, 6H), 1.80-1,28 (m, 10H); ESI MS m / z 392 [M+H]+; HPLC = 97.9 %, tR= 16.0 min.

[0166] Example 5: l-Benzyl-N-((3-(dimethylamino)tetrahydrofuran-3-yl)methyl)indoline-5-carboxamide (“(±)-22e”). Compound (±)-22e was prepared l-benzylindoline-5-carboxylic acid (8) and 3 -(a i nomethyl )-Af, dimethy I tetrahydrofuran-3 -amine ((±)-3e) according to a similar procedure described for the synthesis of 22a: 'H NMR (600 MHz, CDCI3) 87.61 (d, 1H), 7.60 (s, 1H), 7.36 (m, 2H), 7.30 (m, 4H), 6.45 (d, 1H), 4.38 (s, 2H), 3.12 (m, 2H), 3.91 (m, 2H), 3.78 (m, 2H), 3.53 (t, 2H), 3.08 (m, 2H), 2.77 (br s, 6H), 2.24 (m, 3H); ESI MS m / z 380 [M+H]+; HPLC = 96.4 %, tR= 15.3 min.

[0167] Example 6: l-Benzyl-N-((3-(dimethylamino)oxetan-3-yl)methyl)indoline-5-carboxamide (“22f”). Compound 22 was prepared l-benzylindoline-5-carboxylic acid (8) and 3-(aminomethyl)-A, A-dimethyloxetan-3-amine (3f) according to a similar procedure described for the synthesis of 22a: 'H NMR (400 MHz, acetone-fifc) 87.61-7.47 (m, 3H), 7.33-7.26 (m, 5H), 6.53 (d, J = 8.34 Hz, 1H), 4.36 (s, 2H), 3.47-3.36 (m, 6H), 2.97 (m, 2H), 2.28 (s, 6H), 0.91 (m, 3H); ESIMS m / z 366 [M+H]+; HPLC = 96.7 %, tR= 12.4 min.

[0168] Example 7: l-Benzyl-N-((3-(dimethylamino)tetrahydro-2H-pyran-3-yl)methyl)indoline-5-carboxamide (“(±)-22g”). Compound (±)-22g was prepared l-benzylindoline-5-carboxylic acid (8) and 3-(aminomethyl)-A, A-dimethyltetrahydro-2H-pyran-3-amine ((±)-3g) according to a similar procedure described for the synthesis of 22a:1H NMR (600 MHz, DMSO- e,) 88.18 (br s, 1H), 7.62-7.54 (m, 2H), 7.35-7.24 (m, 5H), 6.60 (d, J= 8.34 Hz, 1H), 4.40 (s, 2H), 3.86 (br s, 1H), 3.64-3.51 (m, 5H), 3.42 (t, J= 8.58 Hz, 2H), 2.97 (t, J= 8.52 Hz, 2H), 2.77 (br s, 6H), 1.96-1.88 (m, 2H), 1.69-1.68 (m, 2H);13C NMR (600 MHz, DMSO-tZ6,) 8 167.5, 154.8, 137.5, 129.1, 128.5, 128.3, 127.8, 127.2, 123.7, 104.9, 67.4, 52.1, 50.8, 37.9, 37.8, 27.3, 26.5, 20.5; ESI MS m'z 394 [M+H]+.

[0169] Referring now to FIG. 9, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 8. In the exemplary embodiments of Scheme 8, the reagents and reaction conditions were as follows: (a) benzyl bromide, K2CO3, DMF, 80°C, 16 h; (b) (i) LiOH H2O, CH3OH, THF, H2O, 0°C to rt, 20 h, (ii) 2 N aqueous HC1; (c) 3a, HBTU, z-Pr2NEt, CH2CI2, rt, 16 h.

[0170] Example 8: 1 -Benzyl-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l, 2,3,4-tetrahydroquinoline-6-carboxamide (“26”). Step A: To a solution of methyl 1, 2,3,4-tetrahydroquinoline-6-carboxylate (“23”, 0.510 g, 2.66 mmol) in anhydrous DMF (5 mL) was added K2CO3 (0.736 g, 5.33 mmol), and benzyl bromide (0.547 g, 3.20 mmol), and the mixture was heated to 100 °C for 16 h under an atmosphere of N2. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was diluted with H2O (50 mL), and the aqueous mixture was extracted with EtOAc (2 x 50 mL). The combined organicextracts were washed with H2O (2 x 30 mL), brine (50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% EtOAc in hexanes) to give methyl l-benzyl-l,2,3,4-tetrahydroquinoline-6-carboxylate (“24”) as a colorless liquid (0.46 g, 63%): 'H NMR (600 MHz, CDCI3) 87.69-7.67 (m, 1 H), 7.67 (s, 1 H), 7.34 (t, J= 7 A Hz, 2 H), 7.28-7.27 (m, 1 H), 7.23 (d, J= 7.6 Hz, 2 H), 6.48 (d, J = 8.4 Hz, 1 H), 4.56 (s, 2 H), 3.84 (s, 3 H), 3.44 (t, J= 5.8 Hz, 2 H), 2.84 (t, J= 6.2 Hz, 2 H), 2.04-2.00 (q, 2 H); ESI MS m / z 282 [M + H]+.

[0171] Step B: To a solution of methyl 1 -benzyl- 1,2, 3, 4-tetrahydroquinoline-6-carboxylate (24, 0.200 g, 0.748 mmol) in a mixture of THF (1 mL), CH3OH (1 mL), and H2O (0.5 mL) was added LiOH H2O (0.089 g, 3.740 mmol). The mixture was heated to 80 °C for 1 h via microwave irradiation. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (50 mL). The aqueous layer was acidified to pH = 2 with 2.0 N aqueous HC1, then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with H2O (2 x 30 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with Et2O (30 mL) to give 1 -benzyl- 1,2, 3, 4-tetrahydroquinoline-6-carboxylic acid (“25”) as white solid (0.15 g, 80%): 'H NMR (600 MHz, CDCI3) 87.74-7.73 (m, 1 H), 7.72 (s, 1 H), 7.33 (t, J= 7.3 Hz, 2 H), 7.27-7.26 (m, 1 H), 7.22 (d, J= 7.6 Hz, 2 H), 6.49 (d, J = 8.5 Hz, 1 H), 4.57 (s, 2 H), 3.45 (t, J = 5.8 Hz, 2 H), 2.85 (t, J= 6.2 Hz, 2 H), 2.05-2.01 (q, 2 H); ESI MS m / z 268 [M + H]+.

[0172] Step C: To a solution of l-benzyl-l,2,3,4-tetrahydroquinoline-6-carboxylic acid (25, 0.055 g, 0.205 mmol) in CH2Q2 (10 mL) was added 4-(aminomethyl)-V, / V-dimcthyltetrahydro-27 / -pyran-4-amine (3a, 0.039 g, 0.246 mmol), HBTU (0.093 g, 0.246 mmol), and z-P^NEt (0.052 g, 0.410 mmol). The mixture was stirred for 16 h at room temperature under an atmosphere of N2. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous mixture was extracted with EtOAc (3 x 30 mL), and the combined organic extracts were washed with H2O (3 x 30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2CI2) to give l-benzyl-f-((4-(dimethylamino)tetrahydro-27 / -pyran-4-yl)methyl)-l,2,3,4-tetrahydroquinoline-6-carboxamide (26) as white solid (0.020 g, 24%): 'H NMR (600 MHz, CDCI3) 87.51 (s, 1 H), 7.46 (d, J= 8.6 Hz, 1 H), 7.31 (t, J= 7.2 Hz, 2 H), 7.25 (t, J= 7.2 Hz, 1 H), 7.19 (d, J = 7.2 Hz, 2 H), 6.47 (d, J= 8.7 Hz, 1 H), 4.54 (s, 2 H), 3.91 (dd, J= 12.0,4.0 Hz, 2 H), 3.81 (br s, 2 H), 3.62 (t, J= 11.3 Hz, 2 H), 3.42 (t, J= 5.7 Hz, 2 H), 2.84 (t, J= 6.2 Hz, 2 H), 2.66 (br s, 6 H), 2.01-1.97 (m, 2 H), 1.92-1.87 (m, 2 H), 1.60 (d, J= 12.0 Hz, 2 H); ESIMS m / z 408 [M + H]+; HPLC = 97.4 %, tR= 15.9 min.

[0173] Referring now to FIG. 10, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 9. In the exemplary embodiments of Scheme 9, the reagents and reaction conditions were as follows: (a) benzyl bromide, K2CO3, DMF, 60°C, 16 h; (b) (i) LiOH H2O, CH3OH, THF, H2O, 0°C to rt, 20 h, (ii) 2 N aqueous HC1; (c) 3a, HBTU, z-Pr2NEt, CH2CI2, rt, 16 h.

[0174] Example 9: 1 -Benzyl -N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-lH-indole-5-carboxamide (“30”). Step A: To a solution of methyl lH-indole-5-carboxylate (“27”, 0.466 g, 2.66 mmol) in anhydrous DMF (5 mL) was added K2CO3 (0.736 g, 5.33 mmol), and benzyl bromide (0.547 g, 3.20 mmol), and the mixture was heated to 100°C for 16 h under an atmosphere of N2. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was diluted with H2O (50 mL), and the aqueous mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with H2O (2 x 30 mL), brine (50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% EtOAc in hexanes) to give methyl l-benzyl-lH-indole-5-carboxylate (“28”) as a colorless liquid (0.494 g, 70%): 'H NMR (600 MHz, CDCI3) 8.

[0175] Step B: To a solution of methyl l-benzyl-lH-indole-5-carboxylate (28, 0.198 g, 0.748 mmol) in a mixture of THF (1 mL), CH3OH (1 mL), and H2O (0.5 mL) was added LiOH H2O (0.089 g, 3.740 mmol). The mixture was heated to 80°C for 1 h via microwave irradiation. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (50 mL). The aqueous layer was acidified to pH = 2 with 2.0 N aqueous HC1, then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with H2O (2 x 30 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with Et2O (30 mL) to give 1 -benzyl- lH-indole-5-carboxylic acid (“29”) as a white solid (0.159 g, 85%): 'H NMR (600 MHz, CDCI3) 6.

[0176] Step C: To a solution of 1 -benzyl- lH-indole-5-carboxylic acid (29, 0.051 g, 0.205 mmol) in CH2O2 (10 mL) was added 4-(aminomethyl)-A, A-dimethyltetrahydro-2 / / -pyran-4-amine (3a, 0.039 g, 0.246 mmol), HBTU (0.093 g, 0.246 mmol), and z-Pr2NEt (0.052 g, 0.410 mmol). Themixture was stirred for 16 h at room temperature under an atmosphere of N2. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous mixture was extracted with EtOAc (3 x 30 mL), and the combined organic extracts were washed with H2O (3 x 30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2CI2) to give l-benzyl-V-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-lH-indole-5-carboxamide (30) as white solid (0.040 g, 50%):NMR (400 MHz, CDCh) 57.54 (s, 1 H), 7.51 (d, J= 8.2 Hz, 1 H), 8.05 (m, 2H), 7.59-7.46 (m, 3H), 7.26-7.12 (m, 4H), 6.56 (s, 1H), 5.45 (s, 2H), 3.60-3.24 (m, 6H), 2.38 (br s, 6H0, 1.63-1.49 (m, 4H); ESI MS m / z 392 [M + H]+; HPLC = 99.2 %; tR= 12.1 min.

[0177] Referring now to FIG. 11, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 10. In the exemplary embodiments of Scheme 10, the reagents and reaction conditions were as follows: (a) substituted benzaldehyde, NaBH3CN, HO Ac, CH3OH, 0°C to rt, 12-20 h; (b) (i) LiOH H2O, CH3OH, THF, H2O, 0°C to rt, 16 h, (ii) 2 N aqueous HC1; (c) 3a, HBTU, i-Pr2NEt, CH2C12, rt, 16 h.

[0178] Example 9: l-(2-Chlorobenzyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“33a”). Step A: A solution of methyl indoline-5-carboxylate (6, 0.2 g, 1.128 mmol) and 2-chlorobenzaldehyde (0.19 g, 1.354 mmol) in glacial HOAc (0.635 mL, 11.28 mmol) stirred at room temperature for 5 h under an atmosphere of N2. NaBHsCN (0.106 g, 1.692 mmol), was then added and the mixture stirred for an additional 3 h. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (20 mL) and neutralized with aqueous saturated NaHCCh solution to about pH 7. The aqueous mixture was extracted with EtOAc (2 x 30 mL), and the combined organic extracts were washed with H2O (2 x 30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2C12) to give methyl 1-(2-chlorobenzyl)indoline-5-carboxylate (“31a”) as a white solid (0.15 g, 44%): 'H NMR (600 MHz,CDC13) 87. 81 (d, J= 8.4 Hz, 1 H), 7.76 (s, 1 H), 7.34-7.32 (m, 1 H), 7.26-7.24 (m, 1 H), 6.39 (d, J = 8.6 Hz, 1 H), 4.47 (s, 2 H), 3.86 (s, 3 H), 3.59 (t, J= 8.6 Hz, 2 H), 3.10 (t, J= 8.6 Hz, 2 H); ESI MS / / Az 301 [M + H]+.

[0179] Step B: A mixture of methyl l-(2-chlorobenzyl)indoline-5-carboxylate (31a, 0.15 g, 0.497 mmol), LiOH H2O (0.059 g, 2.48 mmol), THF (1 mL), CH3OH (1 mL), and H2O (0.5 mL) was heated at 80 °C for 1 h under microwave irradiation. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous layer acidified to pH = 2 with 2.0 N aqueous HC1 and then extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with H2O (2 x 30 mL), brine (30 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The resulting residue was then triturated with Et2O (15 mL) to give l-(2-chlorobenzyl)indoline-5-carboxylic acid “32a” as white solid (0.08 g, 56%): ’HNMR (600 MHz, CD3OD) 8 7.76 (d, J= 7.5 Hz, 1 H), 7.69 (s, 1 H), 7.44-7.39 (m, 2 H), 7.29 (s, 2 H), 6.45 (d, J= 8.0 Hz, 1 H), 4.49 (s, 2 H), 3.55 (t, J= 8.6 Hz, 2 H), 3.06 (t, J= 8.6 Hz, 2 H); ESI MS m z 287 [M + H]+.

[0180] Step C: To a solution of l-(2-chlorobenzyl)indoline-5-carboxylic acid (32a, 0.06 g, 0.208 mmol) in CH2C12(6 mL) was added 4-(aminomethyl)-A, Ar-dimethyltetrahydro-2 / 7-pyran-4-amine (3a, 0.039 g, 0.25 mmol), HBTU (0.094 g, 0.25 mmol), z-Pr2NEt (0.053g, 0.416 mmol). The mixture was stirred at room temperature for 16 h. The mixture was then concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous mixture was extracted with EtOAc (3 x 30 mL), and the combined organic extracts were washed with H2O (3 x 30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2C12) to give l-(2-chlorobenzyl)-A-((4-(dimethylamino)tetrahydro-2Z / -pyran-4-yl)methyl)indoline-5-carboxamide (33a) as white solid (39 mg, 44%): ’ll NMR (600 MHz, CDCI3) 87.54 (s, 1 H), 7.51 (d, J= 8.2 Hz, 1 H), 7.40-7.39 (m, 1 H), 7.33-7.31 (m, 1 H), 7.23-7.21 (m, 2 H), 6.80 (br s, 1 H), 6.37 (d, J= 8.2 Hz, 1 H), 4.24 (s, 2 H), 3.88-3.86 (m, 2 H), 3.69 (d, J= 3.9 Hz, 2 H), 3.64-3.60 (m, 2 H), 3.55 (t, J= 8.6 Hz, 2 H), 3.08 (t, J= 8.6 Hz, 2 H), 2.38 (br s, 6 H), 1.90-1.86 (m, 2 H), 1.44 (d, J = 12.6 Hz, 2 H); ESI MS m / z 428 [M + H]+; HPLC = 98.6 %; tR= 16.6 min.

[0181] Example 10: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(2-methylbenzyl)indoline-5-carboxamide (“33b”). Compound 33b was prepared l-(2-methylbenzyl)indoline-5-carboxylic acid (“32b”) and 4-(aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine 3a according to a similar procedure described for the synthesis of 33a: H NMR (600 MHz, CDCh,) 57.54 (d, J = 10.6 Hz, 2 H), 7.28 (br s, 2 H), 7.23-7.21 (m, 2 H), 7.20-7.17 (m, 1 H), 6.74 (br s, 1 H), 6.43 (d, J = 8.1 Hz, 1 H), 4.30 (s, 2 H), 3.89 (d, J = 11.7 Hz, 2 H), 3.70 (br s, 2 H), 3.66 (t, J = 11.2 Hz, 2 H), 3.44 (t, J = 8.5 Hz, 2 H), 3.05 (t, J = 8.5 Hz, 2 H), 2.36 (s, 6 H), 1.93-1.88 (m, 2 H), 1.45 (d, J= 11.5 Hz, 2 H); ESI MS m / z 408 [M + H]+; HPLC = 96.0%; tR= 16.1 min.

[0182] Example 11: l-(3-Chlorobenzyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“33c”). Compound 33c was prepared l-(3-chlorobenzyl)indoline-5-carboxylic acid (“32c”) and 4-(aminomethyl)-7V,jV-dimethyltetrahydro-2 7-pyran-4-amine (3a) according to a similar procedure described for the synthesis of 33a: ’H NMR (600 MHz, CDCh) 57.53 (s, 1 H), 7.50 (d, J= 8.2 Hz, 1 H), 7.30 (s, 1 H), 7.26-7.25 (m, 2 H), 7.19-7.18 (m, 1 H), 6.69 (br s, 1 H), 6.39 (d, J= 8.2 Hz, 1 H), 4.29 (s, 2H), 3.87-3.83 (m, 2 H), 3.65-3.63 (m, 2 H), 3.60-3.59 (m, 2 H), 3.45 (t, J= 8.5 Hz, 2 H), 3.04 (t, J= 8.5 Hz, 2 H), 2.38 (s, 6 H), 1.89-1.85 (m, 2 H), 1.41 (m, 2 H);13C NMR (600 MHz, CDCh) 5 167.6, 154.7, 139.8, 134.5, 129.9, 129.8, 127.6, 127.5, 127.4, 125.7, 123.65, 123.6, 105.2, 64.3, 55.9, 53.2, 51.9, 39.8, 37.4, 28.7, 27.9; ESI MS m / z 428 [M + H]+; HPLC = 95.7 %; tR= 16.5 min.

[0183] Example 12: 1 -(4-methoxybenzyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“33d”). Compound 33d was prepared l-(4-methoxybenzyl)indoline-5-carboxylic acid (“32d”) and 4-(aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine (3a) according to a similar procedure described for the synthesis of 33a:JH NMR (600 MHz, CDC13) 57.52 (s, 1 H), 7.22 (d, J= 8.2 Hz, 1 H), 6.86 (t, J= 8.4 Hz, 1 H), 6.44 (d,,7= 8.6 Hz, 1 H), 4.27 (s, 1 H), 3.87-3.85 (m, 2 H), 3.80 (s, 3 H), 3.67-3.61 (m, 4 H), 3.41 (t, J = 8.5 Hz, 1 H), 3.01 (t, J= 8.4 Hz, 2 H), 2.34 (s, 6 H), 1.90-1.86 (m, 2 H), 1.43-1.41 (m, 2 H); ESIMS m / z 424 [M + H]+; HPLC = 94.8%; tR= 16.0 min.

[0184] Example 13: l-(4-(Tert-butyl)benzyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“33e”). Compound 33e was prepared l-(4-(tert-butyl)benzyl)indoline-5-carboxylic acid (“32e”) and 4-(aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine (3a) according to a similar procedure described for the synthesis of 33a:1H NMR (600 MHz, CDCh) 87.57 (d, J = 8.0 Hz, 1 H), 7.53 (s, 1 H), 7.34 (d, J= 8.2 Hz, 2 H), 7.21 (d, J = 8.2 Hz, 1 H), 6.44 (d, J= 8.3 Hz, 1 H), 4.31 (s, 1 H), 3.77 (br s, 2 H), 3.64 (t, J= 11 Hz, 1 H), 3.47 (t, J = 8.6 Hz, 2 H), 3.02 (t, J = 8.6 Hz, 2 H), 2.54 (s, 6 H), 1.92-1.88 (m, 2 H), 1.55 (br s, 2 H), 1.28 (s, 9 H); ESI MS m / z 450 [M + H]+; HPLC = 95.3%; tR= 18.0 min.

[0185] Example 14: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(4- (trifluoromethyl)benzyl)indoline-5-carboxamide (“33f’). Compound 33f was prepared from l-(4- (trifluoromethyl)benzyl)indoline-5-carboxylic acid (“32f’) and 4-(aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine (3a) according to a similar procedure described for the synthesis of 33a: ’HNMR (600 MHz, CDC13) 87.59 (d, J = 8.0 Hz, 2 H), 7.56-7.53 (m, 2 H), 7.42 (d, J = 8.0 Hz, 2 H), 6.39 (d, J = 8.0 Hz, 1 H), 4.38 (s, 2 H), 3.89-3.88 (m, 2 H), 3.72 (br s, 2 H), 3.65-3.61 (m, 2 H), 3.48 (t, J = 8.6 Hz, 2 H), 3.07 (t, J = 8.6 Hz, 2 H), 2.44 (br s, 6 H), 1.92-1.87 (m, 2 H), 1.49 (br s, 2 H); ESI MS m / z 462 [M + H]+; HPLC = 97.5%; tR= 16.9 min.

[0186] Example 15: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(4- (methylsulfonyl)benzyl)indoline-5-carboxamide (“33g”). Compound 33g was prepared from l-(4-(methylsulfonyl)benzyl)indoline-5-carboxylic acid (“32g”) and 4-(aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine (3a) according to a similar procedure described for the synthesis of 33a: 'HNMR (600 MHz, CDCI3) 87.91 (d, J= 8.2 Hz, 2 H), 7.55-7.50 (m, 4 H), 6.70 (br s, 1 H), 6.36 (d, J= 8.2 Hz, 1 H), 4.41 (s, 2 H), 3.86 (d, J= 11.7 Hz, 2 H), 3.66 (d, J= 4.0 Hz, 2 H), 3.62 (t, J= 11.0 Hz, 2 H), 3.49 (t, J= 8.5 Hz, 2 H), 3.08 (t, J= 8.5 Hz, 2 H), 3.06 (s, 3 H), 2.31 (br s, 6 H), 1.90-1.85 (m, 2 H), 1.40 (d, J= 13.2 Hz, 2 H); ESIMS m / z 472 [M + H]+; HPLC = 96.7%; tR= 14.6 min.

[0187] Referring now to FIG. 12, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 11. In the exemplary embodiments of Scheme 11, the reagents and reaction conditions were as follows: (a) substituted benzaldehyde, NaBH3CN, HO Ac, CH3OH, 0°C to rt, 12-20 h.

[0188] Example 24: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(3-methylbenzyl)indoline-5-carboxamide (“34a”). Step A: To a solution of N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19, 0.05 g, 0.164 mmol)in CH3OH (5 mL) was added m-tolualdehyde (0.023 g, 0.197 mmol) and HOAc (10 eq). The mixture was stirred at room temperature for 5 h under an atmosphere of N2. NaBHsCN (0.012 g, 0.196 mmol) was then added to the mixture continued to stir for an additional 3 h. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (10 mL) and neutralized with saturated aqueous NaHCCh solution to about pH 7. The aqueous mixture was extracted with EtOAc (2 x 30 mL), and the combined organic extracts were washed with H2O (2 x 30 mL), brine (30 mL), dried over ISfeSCL, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2CI2) to give N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l-(3 -methylbenzyl)indoline-5-carboxamide (34a) as an off-white foam (0.025 g, 37%): 'H NMR (600 MHz, CDCI3) 87.55 (s, 2 H), 7.21 (t, J = 7.5 Hz, 1 H), 7.11 (s, 1 H), 7.08 (d, J = 7.7 Hz, 2 H), 6.43 (d, J = 8.8 Hz, 1 H), 4.29 (s, 2 H), 3.90-3.88 (m, 2 H), 3.74 (br s, 2 H), 3.66 (t, J = 11.7 Hz, 2 H), 3.45 (t, J = 8.5 Hz, 2 H), 3.03 (t, J = 8.5 Hz, 2 H), 2.43 (s, 6 H), 2.33 (s, 3 H), 1.92-1.87 (m, 2 H), 1.57-1.50 (m, 2 H); ESI MS m / z 408 [M + H]+; HPLC = 75.0%; tR= 16.2 min.

[0189] Example 25: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(4-(trifluoromethyl)benzyl)indoline-5-carboxamide (“34b”). Compound 34b was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and p-tolualdehyde according to a similar procedure described for the synthesis of 34a:1H NMR (600 MHz, CDCI3) 8 7.52-7.51 (m, 2 H), 7.18 (d, J = 8.8 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 2 H), 6.81 (br s, 1 H), 6.43 (d, J = 8.8 Hz, 1 H), 4.29 (s, 2 H), 3.88-3.86 (m, 2 H), 3.69 (d, J = 4.6 Hz, 2 H), 3.65-3.61 (m, 2 H), 3.44 (t, J = 8.6 Hz, 2 H), 3.01 (t, J = 8.6 Hz, 2 H), 2.39 (br s, 6 H), 2.34 (s, 3 H), 1.91-1.86 (m, 2 H), 1.46-1.44 (m, 2 H); ESI MS m / z 408 [M + H]+; HPLC = 95.3%; tR= 16.3 min.

[0190] Example 26: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(3-fluorobenzyl)indoline-5-carboxamide (“34c”). Compound 34c was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3-fluorobenzaldehyde according to a similar procedure described for the synthesis of 34a: 'H NMR (600 MHz, CDC13) 87.55 (s, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.31-7.27 (m, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 7.02 (d, J = 9.6 Hz, 1 H), 6.96 (t, J = 8.4 Hz, 1 H), 6.39 (d, J = 8.2 Hz, 1 H), 4.31 (s, 2 H), 3.88-3.86 (m, 2 H), 3.71 (d, J = 4.0 Hz, 2 H), 3.64 (t, J = 10.0 Hz, 2 H), 3.46 (t, J = 8.5 Hz, 2 H), 3.04 (t, J = 8.5 Hz, 2 H), 2.38 (s, 6 H), 1.91-1.87 (m, 2 H), 1.45 (d, J = 13.0 Hz, 2 H); ESI MS m / z 412 [M + H]+; HPLC = 93.0%; tR= 15.9 min.34d

[0191] Example 27: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(2-methoxybenzyl)indoline-5-carboxamide (“34d”). Compound 34d was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 2-m ethoxybenzaldehyde according to a similar procedure described for the synthesis of 34a: 'H NMR (600 MHz, CDCh) 87.54 (d, J = 8.1 Hz, 1 H), 7.52 (s, 1 H), 7.20 (d, J = 7.1 Hz, 1 H), 6.90 (t, J = 7.6 Hz, 2 H), 6.42 (t, J = 8.3 Hz, 2 H), 4.35 (s, 2 H), 3.90 (d, J = 11.5 Hz, 2 H), 3.84 (s, 3 H), 3.75 (br s, 2 H), 3.64 (d, J = 11.5 Hz, 2 H), 3.54 (t, J = 8.6 Hz, 2 H), 3.05 (t, J = 8.6 Hz, 2 H), 2.50 (br s, 6 H), 1.92-1.87 (m, 2 H), 1.52 (d, J = 11.2 Hz, 2 H); ESI MS m / z 424 [M + H]+; HPLC = 96.0%; tR= 16.2 min.

[0192] Example 28: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(4-(methylthio)benzyl)indoline-5-carboxamide (“34e”). Compound 34e was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 4-(methylthio)benzaldehyde according to a similar procedure described for the synthesis of 34a:1H NMR (600 MHz, CDC13) 57.56-7.55 (m, 2 H), 7.21 (s, 4 H), 7.07 (br s, 1 H), 6.42 (d, J = 8.2 Hz, 1 H), 4.28 (s, 2 H), 3.90-3.88 (m, 2 H), 3.76 (d, J = 5.1 Hz, 1 H), 3.65 (t, J = 11.0 Hz, 2 H), 3.45 (t, J = 8.6 Hz, 2 H), 3.02 (t, J = 8.6 Hz, 2 H), 2.48 (br s, 6 H), 2.47 (s, 3 H), 1.92-1.87 (m, 2 H), 1.52 (d, J = 12.6 Hz, 2 H); ESI MS m / z 440 [M + H]+; HPLC = 97.7%; tR= 16.6 min.

[0193] Example 29: l-(4-Cyanobenzyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“34f”). Compound 34f was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 4-cyanobenzaldehyde according to a similar procedure described for the synthesis of 34a: 'H NMR (600 MHz, CDCh) 87.63 (s, 1 H), 7.50 (d, J = 8.1 Hz, 1 H); 7.43 (d, J = 8.1 Hz, 1 H), 6.72 (br s, 1 H), 6.35 (d, J = 8.2 Hz, 1 H), 4.37 (s, 2 H), 3.87-3.83 (m, 2 H), 3.66-3.65 (m, 2 H), 3.64-3.60 (m, 2 H), 3.47 (t, J = 8.5 Hz, 2 H), 3.07 (t, J = 8.5 Hz, 2 H), 2.32 (s, 6 H), 1.90-1.85 (m, 2 H), 1.41-1.39 (m, 2 H); ESI MS m / z 419 [M + H]+; HPLC = 97.5 %; tR= 15.6 min.

[0194] Example 30: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(pyridin-2-ylmethyl)indoline-5-carboxamide (“34g”). Compound 34g was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 2-pyridinecarboxaldehyde according to a similar procedure described for the synthesis of 34a: ’H NMR (600 MHz, CDC13) 58.57 (m, 1 H), 7.70-7.67 (m, 1 H), 7.66-7.63 (m, 3 H), 7.27 (d, J= 7.8 Hz, 1 H), 7.20-7.18 (m, 1 H), 6.40 (d, J= 8.3 Hz, 1 H), 4.47 (s, 2 H), 3.99-3.96 (m, 2 H), 3.91 (d, J = 5.7 Hz, 2 H), 3.73 (t, J= 11.5 Hz, 2 H), 3.59 (t, J= 8.6 Hz, 2 H), 3.09 (t, J= 8.5 Hz, 2 H), 2.77 (s, 6 H), 1.96-1.90 (m, 2 H), 1.73 (d, J= 12.6 Hz, 2 H); ESIMS m / z 395 [M + H]+; HPLC = 99.5 %; tR= 13.2 min.

[0195] Example 31: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(pyridin-3-ylmethyl)indoline-5-carboxamide (“34h”). Compound 34h was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3-pyridinecarboxaldehyde according to a similar procedure described for the synthesis of 34a: 'H NMR (600 MHz, CDCI3) 58.58 (s, 1 H), 8.54 (d, J = 3.8 Hz, 1 H), 7.64 (d, J = 7.7 Hz, 1 H), 7.53 (d, J = 12.0 Hz, 2 H), 7.28-7.27 (m, 1 H), 6.72 (br s, 1 H), 6.44 (d, J = 8.1 Hz, 1 H), 4.34 (s, 2 H), 3.87-3.85 (m, 2 H), 3.66 (d, J = 4.4 Hz, 2 H), 3.62 (d, J = 10.8 Hz, 2 H), 3.44 (d, J = 8.4 Hz, 2 H), 3.04 (d, J = 8.4 Hz, 2 H), 2.23 (br s, 6 H), 1.90-1.85 (m, 2 H), 1.41 (d, J = 13.2 Hz, 2 H); ESIMS m / z 395 [M + H]+; HPLC = 97.7 %; tR= 13.0 min.

[0196] Example 32: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(pyridin-4-ylmethyl)indoline-5-carboxamide (“34i”). Compound 34i was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 4-pyridinecarboxaldehyde according to a similar procedure described for the synthesis of 34a: 'H NMR (600 MHz, CDCI3) 58.57 (d, J = 5.7 Hz, 2 H), 7.68 (s, 1 H), 7.23 (d, J = 5.2 Hz, 2 H), 6.38 (d, J = 8.7 Hz, 1 H), 4.35 (s, 2 H), 3.97-3.92 (m, 4 H), 3.76 (d, J = 11.6 Hz, 2 H), 3.52 (t, J = 8.5 Hz, 2H), 3.12 (t, J = 8.5 Hz, 2 H), 2.67 (s, 6 H), 2.00-1.92 (m, 2 H), 1.65 (d, J = 13.0 Hz, 2 H); ESIMS m / z 395 [M + H]+; HPLC = 99.6 %; tR= 13.0 min.

[0197] Example 33: l-(3,4-Dichlorobenzyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“34j”). Compound 34j was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3,4-dichlorobenzaldehyde according to a similar procedure described for the synthesis of 34a:1H NMR (600 MHz, CDC13) 87.55-7.52 (m, 2 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 6.38 (d, J = 8.2 Hz, 1 H), 4.27 (s, 2 H), 3.88 (d, J = 11.4 Hz, 2 H), 3.71 (br s, 2 H), 3.63 (t, J = 10.5 Hz, 2 H), 3.46 (t, J = 8.5 Hz, 2 H), 3.06 (t, J = 8.5 Hz, 2 H), 2.41 (br s, 6 H), 1.91-1.86 (m, 2 H), 1.47 (d, J = 10.8 Hz, 2 H); ESI MS m / z 464 [M + H]+; HPLC = 97.8 %; tR= 17.1 min.

[0198] Example 34: l-(3-Chloro-2-fluorobenzyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“34k”). Compound 34k was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3-chloro-2-fluorobenzaldehyde according to a similar procedure described for the synthesis of 34a:1H NMR (600 MHz, CDCI3) 87.64 (d, J = 8.2 Hz, 2 H), 7.61 (s, 1 H), 7.44 (br s, 1 H) 7.32 (d, J = 6.9 Hz, 1 H), 7.19 (t, J = 6.9 Hz, 1 H), 7.04 (t, J = 7.8 Hz, 1 H) 6.44 (d, J = 8.3 Hz, 1 H), 4.40 (s, 1 H), 3.96-3.94 (m, 2 H), 3.86 (d, J = 5.2 Hz, 2 H), 3.72 (t, J = 11.4 Hz, 2 H), 3.53 (t, J = 8.5 Hz, 2 H), 3.07 (t, J = 8.5 Hz, 2 H), 2.63 (s, 6 H), 1.96-1.91 (m, 2 H), 1.63 (d, J = 12.8 Hz, 2 H); ESI MS m / z 446 [M + H]+; HPLC = 96.6 %; tR= 16.5 min.

[0199] Example 35: l-(3-Chloro-5-fluorobenzyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“341”). Compound 341 was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3-chloro-5-fluorobenzaldehyde according to a similar procedure described for the synthesis of 34a: 'H NMR (600 MHz, CDC13) 87.57 (s, 1 H), 7.54 (d, J = 8.2 Hz, 1 H), 7.11 (s, 1 H), 7.01 (t, J = 8.2 Hz, 1 H), 6.94 (d, J = 9.0 Hz, 1 H), 6.91 (br s, 1 H), 6.37 (d, J = 8.2 Hz, 1 H), 4.29 (s, 1 H), 3.89-3.87 (m, 2 H), 3.72 (d, J = 4.8 Hz, 2 H), 3.65 (t, J = 11.0 Hz, 2 H), 3.48 (t, J = 8.4 Hz, 2 H), 3.08 (t, J = 8.4 Hz, 2 H), 2.39 (s, 6 H), 1.92-1.87 (m, 2 H), 1.46 (d, J = 13.0 Hz, 2 H); ESIMS m / z446 [M + H]+; HPLC = 93.0 %; tR= 16.6 min.

[0200] Example 36: 1 -(Cyclobutylmethyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“34m”). Compound 34m was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and cyclobutanecarbaldehyde according to a similar procedure described for the synthesis of 34a:1H NMR (600 MHz, CDCI3) 87.52 (d, J = 7.8 Hz, 1 H), 7.48 (s, 1 H), 6.36 (d, J = 8.2 Hz, 1 H), 3.87-3.85 (m, 2 H), 3.67-3.65 (m, 2 H), 3.63-3.62 (m, 2 H), 3.45 (t, J = 8.5 Hz, 2 H), 3.12 (d, J = 7.1 Hz, 2 H), 2.99 (t, J = 8.5 Hz, 2 H), 2.66-2.61 (m, 2 H), 2.34 (s, 6 H), 2.10-2.09 (m, 2 H), 1.90-1.86 (m, 4 H), 1.77-1.74 (m, 2 H), 1.43 (d, J = 13.4 Hz, 2 H); ESI MS m / z 372 [M + H]+; HPLC = 93.4 %; tR= 16.1 min.

[0201] Example 37: l-(Cyclopentylmethyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“34n”). Compound 34n was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and cyclopentanecarbaldehyde according to a similar procedure described for the synthesis of 34a:1H NMR (600 MHz, CDC13) 57.52-7.51 (m, 1 H), 7.48 (s, 1 H), 6.36-6.33 (m, 1 H), 3.87-3.86 (m, 2 H), 3.67-3.61 (m, 4 H), 3.51 (t, J = 9.7 Hz, 2 H), 3.02 (d, J = 8.4 Hz, 4 H), 2.35 (s, 6 H), 2.25-2.21 (m, 1 H), 1.90-1.86 (m, 3 H), 1.79-1.77 (m, 3 H), 1.66-1.65 (m, 3 H), 1.58-1.57 (m, 2 H); ESIMS m / z 386 [M + H]+; HPLC = 93.0 %; tR= 16.6 min.

[0202] Example 38: l-(Cyclohexylmethyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“34o”). Compound 34o was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and cyclohexanecarbaldehyde according to a similar procedure described for the synthesis of 34a:1H NMR (600 MHz, CDCI3) 57.49 (d, I = 8.1 Hz, 1 H), 7.46 (s, 1 H), 6.64 (br s, 1 H), 6.31 (d, J = 8.2 Hz, 1 H), 3.86-3.84 (m, 2 H), 3.64-3.61 (m, 4 H), 3.49 (t, J = 8.5 Hz, 2 H), 3.02 (d, J = 8.5 Hz, 2 H), 2.92 (t, J = 7.1 Hz, 2 H), 2.31 (br s, 6 H), 1.89-1.84 (m, 2 H), 1.78-1.72 (m, 4 H), 1.69-1.66 (m, 2 H), 1.40 (d, J = 13.3 Hz, 2 H), 1.27-1.16 (m, 5 H). ESI MS m / z 400 [M + H]+; HPLC = 95.4 %; tR= 17.1 min.

[0203] Example 39: N-((4-(Dimethylamino)tetrahy dro-2H-pyran-4-yl)m ethyl)- 1 -((tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“34p”). Compound 34p was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and tetrahydro-2H-pyran-4-carbaldehyde according to a similar procedure described for the synthesis of 34a:1H NMR (600 MHz, CDC13) 87.63 (d, J = 8.2 Hz, 1 H), 7.57 (s, 1 H), 6.35 (d, J = 8.3 Hz, 1 H), 4.00-3.97 (m, 2 H), 3.95-3.93 (m, 2 H), 3.82 (br s, 2 H), 3.72 (t, J = 11.5 Hz, 2 H), 3.54 (t, J = 8.6 Hz, 2 H), 3.38 (t, J = 10.4 Hz, 2 H), 3.05 (t, J = 8.6 Hz, 2 H), 3.00 (d, J = 7.1 Hz, 2 H), 2.60 (s, 6 H), 1.93-1.90 (m, 2 H), 1.67 (d, J = 11.2 Hz, 2H), 1.60 (t, J = 12.9 Hz, 2 H), 1.37-1.33 (m, 3 H). ESI MS m / z 402 [M + H]+; HPLC = 95.7 %; tR= 14.7 min.

[0204] Example 40: l-(4,4-difluorocyclohexylmethyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran- 4-yl)methyl)indoline-5-carboxamide (“34q”). Compound 34q was prepared from N-((4- (dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 4,4-difluorocyclohexane-l-carbaldehyde according to a similar procedure described for the synthesis of 34a: *HNMR (600 MHz, CDCI3) 87.55 (d, J = 7.8 Hz, 1 H), 7.52 (s, 1 H), 6.33 (d, J = 8.2 Hz, 1 H), 3.90-3.88 (m, 2 H), 3.73 (br s, 2 H), 3.67 (t, J = 11.0 Hz, 2 H), 3.50 (t, J = 8.6 Hz, 2 H), 3.04 (t, J = 8.6 Hz, 2 H), 3.00 (d, J = 7.1 Hz, 2 H), 2.42 (s, 6 H), 2.12 (br s, 2 H), 1.90-1.85 (m, 4 H), 1.76-1.72 (m, 3 H), 1.48 (d, J = 12.2 Hz, 2 H), 1.37-1.33 (m, 2 H). ESIMS m / z 436 [M + H]+; HPLC = 93.7 %; tR= 16.0 min.

[0205] Referring now to FIG. 13, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 12. In the exemplary embodiments of Scheme 12, the reagents and reaction conditions were as follows: (a) 19, 3 -methoxybenzyl bromide, K2CO3, DMF, 100°C, 24 h.

[0206] Example 41: N-((4-(Dimethylamino)tetrahy dro-2H-pyran-4-yl)m ethyl)- 1 -(3-methoxybenzyl)indoline-5-carboxamide (“35”). To a solution of N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19, 0.055 g, 0.181 mmol) in anhydrous DMF (5.0 mL) was added 3 -methoxybenzyl bromide (0.039 g, 0.197 mmol) and K2CO3 (0.045 g, 0.328mmol). The reaction mixture was heated to 1000C for 24 h. The mixture was allowed to cool to room temperature and was then concentrated under reduced pressure. The resulting residue was diluted with H2O (10 mL) and the aqueous mixture was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with H2O (2 x 30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2CI2) to give N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l-(3-methoxybenzyl)indoline-5-carboxamide (35) as an off-white solid (0.021 g, 30%): ‘H NMR (600 MHz, CDCI3) 67.51 (d, J = 9.0 Hz, 1 H), 7.23 (d, J = 9.0 Hz, 1 H), 6.88 (t, J = 7.4 Hz, 1 H), 6.85 (s, 1 H), 6.81 (d, J = 8.2 Hz, 1 H), 6.78 (br s, 1 H), 6.42 (d, J = 8.0 Hz, 1 H), 4.29 (s, 2 H), 3.87-3.85 (m, 2 H), 3.78 (s, 3 H), 3.67 (d, J = 4.8 Hz, 2 H), 3.62 (t, J = 10.0 Hz, 2 H), 3.46 (t, J = 8.7 Hz, 2 H), 3.03 (t, J = 8.6 Hz, 2 H), 2.34 (s, 6 H), 1.90-1.87 (m, 2 H), 1.42 (d, J = 13.0 Hz, 2 H); ESI MS m / z 424 [M + H]+; HPLC = 93.7%; tR= 15.9 min.

[0207] Referring now to FIG. 14, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 13. In the exemplary embodiments of Scheme 13, the reagents and reaction conditions were as follows: (a) substituted benzyl bromide, K2CO3, DMF, 100°C, 16 h; (b) (i) LiOH H2O, CH3OH, H2O, 0°C to rt, 16 h, (ii) 2 N aqueous HC1; (c) 3a, HBTU, i-Pr2NEt, CH2CI2, rt, 16 h.

[0208] Example 42: N-((4-(Dimethylamino)tetrahy dro-2H-pyran-4-yl)m ethyl)- 1 -(2-fluorobenzyl)indoline-5-carboxamide (“38a”). Step A: To a solution of methyl indoline-5-carboxylate (6, 0.24 g, 1.35 mmol) in anhydrous DMF (2.5 mL) was added 2-fluorobenzyl bromide (0.30 g, 1.62 mmol) and K2CO3 (0.37 g, 2.70 mmol). The mixture was heated to 100°C for 16 h under an atmosphere of N2. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was diluted with H2O (20 mL) and the aqueous mixture was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with H2O (2 x 30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% EtOAc in hexanes) to give methyl l-(2-fluorobenzyl)indoline-5-carboxylate (“36a”) as a white solid (300 mg,81%): 'HNMR (600 MHz, CDC13) 87.81 (d, J = 8.3 Hz, 1 H), 7.72 (s, 1 H), 7.29 (t, J = 7.2 Hz, 1 H), 7.11-7.06 (m, 2 H), 6.45 (d, J = 8.3 Hz, 1 H), 4.42 (s, 2 H), 3.84 (s, 3 H), 3.54 (d, J = 8.6 Hz, 2 H), 3.04 (d, J = 8.6 Hz, 2 H); ESI MS m / z 286 [M + H]+.

[0209] Step B: To a solution of methyl l-(2-fluorobenzyl)indoline-5-carboxylate (36a, 0.30 g, 1.05 mmol) in a mixture of CH3OH (1 mL) and H2O (3 mL) was added LiOH H2O (0.12 g, 5.25 eq) and the mixture was heated to 80°C for 16 h. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was diluted with H2O (30 mL) and the aqueous mixture was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with H2O (2 x 20 mL), brine (30 mL), dried over Na2SCU, filtered, and concentrated under reduced pressure. The resulting solid was triturated with Et2O (20 mL) to give l-(2-fluorobenzyl)indoline-5-carboxylic acid (“37a”) as yellow solid (0.16 g, 56%): 'HNMR (600 MHz, DMSO-d6) 87.63 (d, J = 8.3 Hz, 1 H), 7.54 (s, 1 H), 7.37-7.32 (m, 2 H), 7.21-7.14 (m, 2 H), 6.57 (d, J = 8.3 Hz, 1 H), 4.42 (s, 2 H), 3.44 (d, J = 8.6 Hz, 2 H), 2.95 (d, J = 8.6 Hz, 2 H); ESI MS m / z 271 [M + H]+.

[0210] Step C: To a solution of l-(2-fluorobenzyl)indoline-5-carboxylic acid (37a, 0.06 g, 0.221 mmol) in CH2Q2 (10 mL) was added 4-(aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine (3a, 0.041 g, 0.265 mmol), HBTU (0.10 g, 0.265 mmol), and i-P^NEt (0.057 g, 0.442 mmol). The reaction mixture was allowed to stir for 16 h at room temperature under an atmosphere of N2. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous mixture was extracted with EtOAc (3 x 30 mL), and the combined organic extracts were washed with H2O (3 x 30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2CI2) to give N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l-(2-fluorobenzyl)indoline-5-carboxamide (38a) as a white solid (10 mg, 11%): 'H NMR (600 MHz, CDCI3) 87.58 (d, J = 8.2 Hz, 1 H), 7.54 (s, 1 H), 7.29-7.26 (m, 2 H), 7.10-7.04 (m, 2 H), 6.45 (d, J = 8.4 Hz, 1 H), 4.38 (s, 2 H), 3.91-3.88 (m, 2 H), 3.78 (d, J = 5.0 Hz, 2 H), 3.62 (t, J = 11.4 Hz, 2 H), 3.51 (t, J = 8.6 Hz, 2 H), 3.02 (t, J = 8.6 Hz, 2 H), 2.56 (s, 6 H), 1.92-1.87 (m, 2 H), 1.56 (d, J = 12.6 Hz, 2 H). ESI MS m / z 412 [M + H]+; HPLC = 86.1 %; tR= 15.9 min.

[0211] Example 43: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l-(3-fluorobenzyl)indoline-5-carboxamide (“38b”). Compound 38b was prepared from methyl indoline-5-carboxylate (6) and 2-fluorobenzyl bromide according to a similar procedure described for the synthesis of 38a: 'HNMR (600 MHz, CDC13) 87.55 (s, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.31-7.27 (m, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 7.02 (d, J = 9.6 Hz, 1 H), 6.96 (t, J = 8.4 Hz, 1 H), 6.39 (d, J = 8.2 Hz, 1 H), 4.31 (s, 2 H), 3.88-3.86 (m, 2 H), 3.71 (d, J = 4.0 Hz, 2 H), 3.64 (t, J = 10.0 Hz, 2 H), 3.46 (t, J = 8.5 Hz, 2 H), 3.04 (t, J = 8.5 Hz, 2 H), 2.38 (s, 6 H), 1.91-1.87 (m, 2 H), 1.45 (d, J = 13.0 Hz, 2 H); ESI MS m / z 412 [M + H]+; HPLC = 93.0 %; tR= 15.9 min.

[0212] Referring now to FIG. 15, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 14. In the exemplary embodiments of Scheme 14, the reagents and reaction conditions were as follows: (a) compound 8, HBTU, i-Pr2NEt, CH2CI2, rt, 20 h.

[0213] Example 44: (±)-l-Benzyl-N-((4-(3-fluoropyrrolidin-l-yl)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“(±)-39a”). Step A: To a solution of l-benzylindoline-5-carboxylic acid (8, 0.300 g, 1.18 mmol) in CH2CI2, (6 mL) was added (±)-(4-(3-fluoropyrrolidin-l-yl)tetrahydro-2H-pyran-4-yl)methanamine ((±)-5a, 0.263 g, 1.30 mmol), i-Pr2NEt (0.42 mL, 2.36 mmol), and HBTU (0.898 g, 2.36 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with CH2CI2, washed with 1 N aqueous NaOH solution (20 mL), 2N aqueous HC1 solution (20 mL), H2O (20 mL), brine (20 mL), dried over anhydrous MgSCU, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (7% CH3OH in CH2Q2) to give l-benzyl-N-((4-(3-fluoropyrrolidin-l-yl)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide ((±)-39a) as a white solid (0.440 g,85%): 'HNMR (CDCI3, 600 MHz) 87.52 (s, 1H), 7.50 (d, 1H, J = 8.22 Hz), 7.34-7.26 (m, 5H), 6.66 (br s, 1H), 6.43 (d, 1H, J = 8.22 Hz), 5.23-5.13 (m, 1H), 4.33 (s, 2H), 3.85-3.83 (m, 2H), 3.75-3.73 (m, 1H), 3.67-3.62 (m, 2H), 3.58-3.55 (m, 1H), 3.45 (t, 2H, J = 8.52 Hz), 3.13-2.88 (m, 5H), 2.76-2.73 (m, 1H), 2.15-2.00 (m, 2H), 1.84-1.78 (m, 2H), 1.55-1.51 (m, 2H);13C NMR (CDCI3, 600 MHz) 8 167.5, 154.9, 137.5, 129.8, 128.5, 127.6, 127.4, 127.3, 123.5, 122.9, 105.1, 93.2, 64.1, 54.7, 52.8, 52.2, 51.6, 42.6, 41.3, 38.5, 32.2, 30.2, 27.8; ESI MS m / z 438 [M + H]+; HPLC = 92.8 %; tR= 12.8 min.

[0214] Example 45: l-Benzyl-N-((4-((2-fluoroethyl)(methyl)amino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“39b”). Compound 39b was prepared from methyl indoline-5-carboxylate (6) and amine (5b) according to a similar procedure described for the synthesis of 39a: ’H NMR (600 MHz, CDCI3) 8.

[0215] Example 46: N-((4-((lR,5S)-3-Azabicyclo[3.1.0]hexan-3-yl)tetrahydro-2H-pyran-4-yl)methyl)-l-benzylindoline-5-carboxamide (“39c”). Compound 39c was prepared from methyl indoline-5 -carboxyl ate (6) and (4-((lR,5S)-3-azabicyclo[3.1,0]hexan-3-yl)tetrahydro-2H-pyran-4-yl)methanamine (5c) according to a similar procedure described for the synthesis of 39a:1H NMR (600 MHz, CDCI3) 87.51 (br s, 1H), 7.46 (br s, 1H), 7.34-7.27 (m, 5H), 6.51 (br s, 1H), 6.43 (d, 1H, J = 8.22 Hz), 4.34 (s, 2H), 3.79 (br s, 2H), 3.62-3.58 (m, 4H), 3.46 (t, 2H, J = 8.46 Hz), 3.02 (t, 2H, J = 8.46 Hz), 2.83-2.78 (m, 4H), 1.82-1.78 (m, 2H), 1.46-1.40 (m, 4H), 0.60 (br s, 1H), 0.43 (br s, 1H);13C NMR (CDCh, 150 MHz) 8 167.5, 154.9, 137.5, 129.8, 128.5, 127.6, 127.3, 127.2, 123.5, 105.1, 64.1, 54.0, 52.8, 52.1, 45.5, 41.0, 29.9, 27.8, 14.9, 6.9; ESIMS m / z 432 [M + H]+.39d

[0216] Example 47: l-Benzyl-N-((4-morpholinotetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“39d”). Compound 39d was prepared from methyl indoline-5-carboxylate (6) and (4-morpholinotetrahydro-2H-pyran-4-yl)methanamine (5d) according to a similar procedure described for the synthesis of 39a: 'H NMR (600 MHz, CDCh) 67.45 (s, 1H), 7.41 (d, 1H, J = 8.22 Hz), 7.26-7.20 (m, 5H), 6.61 (br s, 1H), 6.35 (d, 1H, J = 8.10 Hz), 4.25 (s, 2H), 3.77-3.75 (m, 2H), 3.64 (s, 4H), 3.55 (s, 4H), 3.37 (t, 2H, J = 8.40 Hz), 2.94 (t, 2H, J = 8.22 Hz), 2.57 (s, 4H), 1.79-1.75 (m, 2H), 1.37-1.35 (m, 2H);13C NMR (600 MHz, CDCh) 5 167.3, 154.9, 137.3, 129.7, 128.4, 127.5, 127.2, 127.1, 123.4, 122.7, 105.0, 67.8, 63.8, 56.3, 52.7, 51.9, 45.0, 39.7, 38.4, 29.5, 27.7; ESIMS m / z 436 [M + H]+.

[0217] Example 48: 1 -Benzyl-N-((4-(4-methylpiperazin- 1 -yl)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“39e”). Compound 39e was prepared from methyl indoline-5-carboxylate (6) and (4-(4-methylpiperazin-l-yl)tetrahydro-2H-pyran-4-yl)methanamine (5e) according to a similar procedure described for the synthesis of 39a:1H NMR (600 MHz, CDCh) 5 7.54 (s, 1H), 7.50 (d, 1H, J = 7.98 Hz), 7.34-7.30 (m, 5H), 6.69 (br s, 1H), 6.44 (d, 1H, J = 8.10 Hz), 4.33 (s, 2H), 3.84-3.82 (m, 2H), 3.64-3.61 (s, 4H), 3.45 (t, 2H, J = 8.34 Hz), 3.03 (t, 2H, J = 8.28 Hz), 2.71 (m, 4H), 2.45 (m, 4H), 2.30 (s, 3H), 1.89-1.86 (m, 2H), 1.46-1.44 (m, 2H);13C NMR (600 MHz, CDCh) 5 167.2, 154.8, 137.7, 129.7, 128.4, 127.5, 127.2, 127.1, 123.4, 122.8, 104.9, 63.9, 56.2, 56.2, 52.7, 52.0, 45.8, 44.3, 40.1, 29.8, 27.7; ESI MS m / z 449 [M + H]+.

[0218] Referring now to FIG. 16, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 15. In the exemplary embodiments of Scheme 15, the reagents and reaction conditions were as follows: (a) (i) CHsLi, THF, -78°C to rt, 1 h, (ii) NaBH4, rt, 30 min then BOC2O, rt, 16h; (b) 4.0 M HC1 solution in 1,4-dioxane, 0°C to rt, 4 h; (c) 8, HBTU, i-Pr2NEt, DMF, rt, 16 h.

[0219] Example 49: (±)-l-Benzyl-N-(l-(4-(dimethylamino)tetrahydro-2H-pyran-4-yl)ethyl)indoline-5-carboxamide (“(±)-42”). Step A: To a 0°C solution of 4-(dimethylamino)tetrahydro-2H-pyran-4-carbonitrile (2a, 7.73 g, 50.14 mmol) in anhydrous Et O (160 mL) was added a 3.0 M solution of CH Li in DME (25 mL, 75.2 mmol) dropwise. The mixture was then heated at reflux for 6 h, and then cooled to 0°C. To this mixture was added NaBTU (5.68 g, 15.0 mmol), followed by dropwise addition of CH3OH (160 mL). The mixture was stirred at room temperature for 2 h, followed by dropwise addition H2O (25 mL). The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in EtOAc (300 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SC>4, filtered, and concentrated to afford 4-(l-aminoethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine as an oil (8.25 g, crude, >99%). To a 0°C solution of 4-(l-aminoethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine (8.2 g, crude, 50.14 mmol) and EtaN (14.8 mL, 105 mmol) in CH2CI2 (100 mL) was added a solution of di-tert-butyl dicarbonate (12.71 g, 58.2 mmol) in CH2CI2 (80 mL) dropwise over a period of 15 min. The mixture was stirred at room temperature for 5 h and was washed with H2O (2 x 150 mL) and brine (150 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-30% EtOAc in hexanes) to afford (±)-tert-butyl (l-(4-(dimethylamino)tetrahydro-2H-pyran-4-yl)ethyl)carbamate (“(±)-40”) as a white solid (10.3 g, 75%), which was used as is in the next step.

[0220] Step B: To a 0°C cooled solution of (±)-tert-butyl (l-(4-(dimethylamino)tetrahydro-2H-pyran-4-yl)ethyl)carbamate ((±)-40, 1.0 g, 3.67 mmol) in CH2CI2 (10 mL) was added 4.0 M solution of HC1 in 1,4-dioxane. The mixture was stirred for 16 h while gradually warming to room temperature. The mixture was concentrated under reduced pressure to give (±)-4-(l-aminoethyl)- N, N-dimethyltetrahydro-2H-pyran-4-amine (“(±)-41”) as a white solid (0.569 g, 90%), which was used as is in the next step.

[0221] Step C: To a solution of l-benzylindoline-5-carboxylic acid (8, 0.946 g, 3.78 mmol) in DMF (25 mL) was added (±)-4-(l-aminoethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine ((±)-41, O.780 g, 4.53 mmol), HBTU (1.72 g, 4.53 mmol), and i-Pr2NEt (0.99 g, 7.56 mmol) and the mixture stirred for 16 h at room temperature and under an atmosphere of N2. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous mixture was extracted with EtOAc (3 x 30 mL), and the combined organic extracts were washed with H2O (3 x 30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reducedpressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2Q2) to give (±)-l-benzyl-N-(l-(4-(dimethylamino)tetrahydro-2H-pyran-4-yl)ethyl)indoline-5-carboxamide (“(±)-22a”) as a white solid (1.02 g, 56%).

[0222] Referring now to FIG. 17, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 16. In the exemplary embodiments of Scheme 16, the reagents and reaction conditions were as follows: (a) benzyl bromide, K2CO3, DMF, 60°C, 16 h; (b) (i) KOH, H2O, CH3OH, reflux, 10 h, (ii) 2 N aqueous HC1; (c) compound 3a, HBTU, i-Pr2NEt, CH2CI2, rt, 16 h.

[0223] Example 50: l-Benzyl-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (“46a”). Step A: To a solution of 6-fluoroindoline-5-carbonitrile (“43a”, 0.466 g, 2.66 mmol) in anhydrous DMF (5 mL) was added K2CO3 (0.736 g, 5.33 mmol), and benzyl bromide (0.547 g, 3.20 mmol), and the mixture was heated to 100 °C for 16 h under an atmosphere of N2. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was diluted with H2O (50 mL), and the aqueous mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with H2O (2 x 30 mL), brine (50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% EtOAc in hexanes) to give methyl Lbenzyl-6-fluoroindoline-5-carbonitrile (“44a”) as a colorless liquid (0.494 g, 70%), which was used as is in the next step.

[0224] Step B: To a solution of Lbenzyl-6-fluoroindoline-5-carbonitrile (44a, 0.75 g, 4.68 mmol) in CH3OH (10 mL), H2O (40 mL) was added KOH (2.10 g, 37.68 mmol) at room temperature. The reaction mixture was then heated to 100°C for 16 h. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure, and the resulting residue was diluted with H2O (50 mL). The aqueous layer was acidified with 2.0 N aqueous HC1 to about pH 1-2 and then extracted with EtOAc (2 x 50 mL), and the combined organic extracts were washed with H2O (2 x 30 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give l-benzyl-6-fluoroindoline-5-carboxylic acid (“45a”) as an off-white solid (0.62 g, 75%), which was used as is in the next step.

[0225] Step C: To a solution of l-benzyl-6-fluoroindoline-5-carboxylic acid (45a, 0.946 g, 3.78 mmol) in DMF (25 mL) was 4-(aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine (3a, 0.780 g, 4.53 mmol), HBTU (1.72 g, 4.53 mmol), and i-PrzNEt (0.99 g, 7.56 mmol) and the mixture stirred for 16 h at room temperature and under an atmosphere of N2. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous mixture was extracted with EtOAc (3 >< 30 mL), and the combined organic extracts were washed with H2O (3 x 30 mL), brine (30 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OEI in CH2Q2) to give l-benzyl-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (46a) as a white solid (1.02 g, 56%).

[0226] Example 51: l-Benzyl-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-4-fluoroindoline-5-carboxamide (“46b”). Compound 46b was prepared from 4-(aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine (3a) and 4-fluoroindoline-5-carboxylic acid (“45b”) according to a similar procedure described for the synthesis of 46a.

[0227] Referring now to FIG. 18, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 17. In the exemplary embodiments of Scheme 17, the reagents and reaction conditions were as follows: (a) substituted benzoyl chloride, i-Pr2NEt, CH2CI2, 0°C, to rt, 2-16 h.

[0228] Example 48: l-Benzoyl-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline- 5-carboxamide (47a). A solution of N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19, 0.070 g, 0.231 mmol) and i-P^NEt (0.12 mL, 0.68 mmol) in anhydrous CH2CI2 (2 mL) was cooled at 0°C for 5 min under an atmosphere of N2. Benzoyl chloride (0.026 mL, 0.227 mmol) was then added at 0°C, and the mixture stirred for 1.5 h while gradually warming to room temperature. Upon completion, the reaction was quenched with H2O and extracted with CH2CI2 (3 x 10 mL). The combined organic layers were washed successively with saturated NaHCCE (2 x 10 mL) and saturated NFLCl (2 x 10 mL), dried overanhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (10% CH3OH in CH2CI2) to afford the desired 1-benzoyl-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (47a) asan off-white solid (0.094 g, 93%); > HNMR (600 MHz, DMSO-d6) 8 10.2 (bs, 1H), 8.66 (bs, 1H), 7.85 (s, 1H), 7.8 (bs, 1H), 7.61-7.60 (m, 2H), 7.55-7.50 (m, 3H), 4.05 (t, J = 8.2 Hz, 2H), 3.89-3.85 (m, 4H), 3.67-3.63 (m, 2H) 3.14 (t, J = 8.3 Hz, 2H), 2.78 (d, J = 8.3 Hz, 6H), 1.91 (m, 4H);13C NMR (600 MHz, DMSO-d6) 8 168.9, 167.7, 145.9, 137.1, 133.5, 130.8, 129.3, 129, 127.7, 127.4, 125, 64.6, 63.7, 37.2, 37.9, 36.9, 30.1, 27.9; ESI HRMS (m / z): calc for C24H30N3O3 [M+H]+: 408.228 calculated, 408.2282 obtained; HPLC 99.2% (AUC), tR= 14.6 min.

[0229] Example 49: l-(2-Chlorobenzoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“47b”). Compound 47b was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 2-chlorobenzoyl chloride according to a similar procedure described for the synthesis of 47a:1H NMR (600 MHz, DMSO-d6): 88.19 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.44-7.33 (m, 4H), 4.05 (t, J = 8.3 Hz, 2H), 3.66 (s, 2H), 3.55 (s, 2H), 3.32 (s, 2H), 3.13 (t, J = 8.3 Hz, 2H), 2.37 (s, 6H), 1.68 (s, 2H), 1.56 (s, 2H); ESI MS m / z 442 [M+H]+; HPLC 95.6 % (AUC), tR= 14.9 min.

[0230] Example 50: N-((4-(Dimethylamino)tetrahy dro-2H-pyran-4-yl)m ethyl)- 1 -(2-fluorobenzoyl)indoline-5-carboxamide (“47c”). Compound 47c was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 2-fluorobenzolyl chloride according to a similar procedure described for the synthesis of “47a”: 'H NMR (600 MHz, DMSO-d6): 88.17 (s, 1H), 7.84 (td, J = 7.6, 1.6 Hz, 1H), 7.78 (s, 1H), 7.59 (s, 2H), 7.42-7.33 (m, 2H), 7.28 (t, J = 8.1 Hz, 1H), 3.95 - 3.87 (m, 2H), 3.70-3.62 (m, 2H), 3.55 (s, 2H), 3.43 (s, 2H), 3.16 (t, J = 8.2 Hz, 2H), 2.36 (s, 6H), 1.69 (s, 2H), 1.57 (s, 2H); ESIMS m / z 426 [M+H]+; HPLC 95.8 % (AUC), tR= 14.70 min.

[0231] Example 51: N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l-(2-methylbenzoyl)indoline-5-carboxamide (“47d”). Compound 47d was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 2-methylbenzoyl chloride according to a similar procedure described for the synthesis of 47a:rH NMR (600 MHz, DMSO-d6): 58.11 (s, 1H), 7.76 (s, 2H), 7.70 (s, 1H), 7.44-7.33 (m, 4H), 4.05 (t, J = 8.3 Hz, 2H), 3.66 (s, 2H), 3.55 (s, 2H), 3.32 (s, 2H), 3.13 (t, J = 8.3 Hz, 2H), 2.37 (s, 9H), 1.68 (s, 2H), 1.56 (s, 2H); ESIMS m / z 422 [M+H]+; HPLC 99.1 % (AUC), tR= 15.0 min.

[0232] Example 52: N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l-(2-methoxybenzoyl)indoline-5-carboxamide (“47e”). Compound 47e was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 2-methoxybenzoyl chloride according to a similar procedure described for the synthesis of 47a: 'll NMR (600 MHz, CD3OD): 58.27 (d, J = 8.2 Hz, 1H), 7.77-7.75 (m, 2H), 7.50-7.40 (m, 1H),7.36-7.33 (m, 1H), 7.17-7.08 (m, 2H), 3.98-3.83 (m, 7H), 3.71-3.67(m, 4H), 3.17 (t, J = 8.4 Hz, 2H), 2.52 (s, 6H), 1.89-1.86 (m, 2H), 1.72-1.67 (m, 2H); ESI MS m / z 438 [M+H]+; HPLC 96.4 % (AUC), tR= 14.79 min.

[0233] Example 53: N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l- (2(trifluoromethyl)benzoyl)indoline-5-carboxamide (“47f ’). Compound 47f was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 2-trifluoromethylbenzoyl chloride according to a similar procedure described for the synthesis of 47a: 'HNMR (600 MHz, CD3OD): 88.28 (d, J = 8.3Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.82-7.71(m, 4H),7.64 (d, J = 7.58 Hz, 1H), 4.31-4.26 (m, 1H), 3.88-3.84 (m, 2H), 3.71-3.67 (m, 2H), 3.67-3.65 (m, 2H), 3.20 (t, J = 8.3 Hz, 2H), 2.43 (s, 6H), 1.87-1.83 (m, 2H), 1.68-1.64 (m, 2H), ESIMS m / z 476 [M+H]+; HPLC 99.5 % (AUC), tR= 15.3 min.

[0234] Example 54: l-(3-Chlorobenzoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“47g”). Compound 47g was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3-chlorobenzoyl chloride according to a similar procedure described for the synthesis of 47a: 'HNMR (600 MHz, CDCI3): 87.71 (s, 1H), 7.54 (s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.44-7.39 (m, 2H), 6.93 (bs, 1H), 4.10 (bs, 2H), 3.87 (d, J= 11.6 Hz, 1H), 3.68 (d, J = 4.10 Hz, 1H), 3.62 (t, J = 13.0 Hz, 2H), 3.16 (t, J = 8.6 Hz, 1H), 2.33 (s, 6H), 1.93-1.88 (m, 2H), 1.40 (d, J = 13.0 Hz, 2H). ESI MS m / z 442 [M + H]+; HPLC = 94.5 % (AUC); tR= 15.6 min.

[0235] Example 55: N-((4-(Dimethylamino)tetrahy dro-2H-pyran-4-yl)m ethyl)- 1 -(3-fluorobenzoyl)indoline-5-carboxamide (“47h”). Compound 47h was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3-fluorobenzoyl chloride according to a similar procedure described for the synthesis of 47a: ’HNMR (600 MHz, CD3OD): 87.75 (bs, 1H), 7.69 (bs, 1H), 7.58-7.54 (m, 1H), 7.40-7.42 (m, 1H), 7.39-7.37 (m, 1H), 7.33-7.30 (m, 1H), 4.14 (bs, 2H), 3.87-3.83 (m, 2H), 3.70-3.66 (m, 2H), 3.64 (s,1H), 3.20 (t, J = 8.3Hz, 2H), 2.42 (s,6H), 1.86-1.82 (m,2H), 1.66-1.62 (m,2H), ESI MS m / z 426 [M+H]+; HPLC 99.5 % (AUC), tR= 14.9 min.

[0236] Example 56: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(3-methylbenzoyl)indoline-5-carboxamide (47i). Compound 47i was prepared from N-((4- (dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3-methylbenzoyl chloride according to a similar procedure described for the synthesis of 47a:1H NMR (600 MHz, CD3OD): 57.75 (bs, 1H), 7.65 (bs, 1H), 7.42-7.37 (m, 4H), 7.28-7.25 (m, 1H), 4.15 (t, J = 7.5 Hz, 2H), 3.89-3.85 (m, 2H), 3.70-3.67 (m, 4H), 3.21 (t, J = 8.2 Hz, 2H),2.48 (s, 6H), 2.43 (s, 3H), 1.88-1.83 (m, 2H), 1.69-1.67 (m, 2H), ESIMS m / z 422 [M+H]+; HPLC 97.56 % (AUC), tR= 15.2 min.

[0237] Example 57: N-((4-(Dimethylamino)tetrahy dro-2H-pyran-4-yl)m ethyl)- 1 -(3-methoxybenzoyl)indoline-5-carboxamide (“47j”). Compound 47j was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3-methoxybenzoyl chloride according to a similar procedure described for the synthesis of 47a:rH NMR (600 MHz, CD3OD): 57.76 (bs, 1H), 7.68 (bs, 1H), 7.56-7.52 (m, 1H), 7.44 (t, J = 8.09 Hz, 1H), 7.15-7.12 (m, 2H), 4.18 (t, J = 7.8 Hz, 2H), 3.90-3.86 (m, 2H), 3.85-3.83 (m, 3H), 3.71-3.67 (m, 4H), 3.20 (t, J = 8.3 Hz, 2H), 2.53 (s, 6H), 1.89-1.85 (m, 2H), 1.72-1.70 (m, 2H), ESIMS m / z 438 [M+H]+; HPLC 98.18 % (AUC), tR= 14.76 min.

[0238] Example 58: N-((4-(Dimethylamino)tetrahy dro-2H-pyran-4-yl)m ethyl)- 1 -(4-chlorobenzoyl)indoline-5-carboxamide (47k). Compound 47k was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 4-chlorobenzoyl chloride according to a similar procedure described for the synthesis of 47a:1H NMR (600 MHz, CD3OD): 5.

[0239] Example 59: N-((4-(Dimethylamino)tetrahy dro-2H-pyran-4-yl)m ethyl)- 1 -(4-fluorobenzoyl)indoline-5-carboxamide (“47L”). Compound 47L was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 4-fluorobenzoyl chloride according to a similar procedure described for the synthesis of 47a: 'H NMR (600 MHz, CD3OD): 58.02-7.99 (m, 1H), 7.77 (bs, 1H), 7.69-7.67 (m, 2H), 7.28-7.25 (m, 2H), 7.10-7.08 (m, 1H), 4.16 (t, J = 8.2 Hz, 2H), 3.91-3.88(m, 2H), 3.74 (s, 2H), 3.72-3.68 (m, 2H), 1.74-1.72 (m, 2H); ESI MS m / z 426 [M+H]+; HPLC 96.1 % (AUC), tR= 15.08 min.

[0240] Example 60: N-((4-(Dimethylamino)tetrahy dro-2H-pyran-4-yl)m ethyl)- 1 -(4-methylbenzoyl)indoline-5-carboxamide (“47m”). Compound 47m was prepared from N-((4- (dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 4-methylbenzoyl chloride according to a similar procedure described for the synthesis of 47a:1H NMR (600 MHz, CDCI3): 57.70 (bs, 1H), 7.53-7.45 (m, 3H), 7.26-7.28 (m, 3H), 7.03 (s,lH), 4.14 (bs, 1H), 3.91-3.89 (m, 2H),3.73-3.70 (m, 4H), 3.1 5(t, J = 8.3 Hz, 2H), 2.44 (s, 3H), 2.37 (s, 6H), 1.95-1.91 (m, 2H), 1.46-1.44 (m, 2H), ESI MS m / z 422 [M+H]+; HPLC 95.3 % (AUC), tR= 14.8 min.

[0241] Example 61: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(4-methoxybenzoyl)indoline-5-carboxamide (“47n”). Compound 47n was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 4-methoxybenzoyl chloride according to a similar procedure described for the synthesis of 47a:NMR (600 MHz, CDC13): 5.

[0242] Example 62: l-(3-Chloro-2-fluorobenzoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“47o”). Compound 47o was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3-chloro-4-fluorobenzoyl chloride according to a similar procedure described for the synthesis of 47a:!H NMR (600 MHz, CDCI3): 88.26 (d, J = 8.2 Hz, 1H), 7.96 (s, 1H), 7.80 (s, 2H), 7.67 (t, J = 6.0 Hz, 1H), 7.53 (t, J = 6.6 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 6.0 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 3.98 -3.92 (m, 5H), 3.77 (t, J = 11.6 Hz, 2H), 3.09 (t, J = 7.8 Hz, 2H), 2.61 (s, 6H), 2.04-1.93 (m, 2H), 1.63 (d, J = 12.9 Hz, 2H); ESI MS m / z 460 [M+H]+; HPLC 96.3 % (AUC), tR= 15.37 min.

[0243] Example 63: l-(2,3-Dichlorobenzoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“47p”). Compound 47p was prepared from N-((4- (dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 2,3-dichlorobenzoyl chloride according to a similar procedure described for the synthesis of 47a: 'HNMR (600 MHz, CDCh): 88.38 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.57 (dd, J = 7.7, 1.7 Hz, 1H), 7.38-7.31 (m, 2H), 6.93 (s, 1H), 3.97-3.84 (m, 4H), 3.71 (d, J = 3.4 Hz, 2H), 3.66 (t, J = 11.6 Hz, 2H), 3.22 (t, J = 7.9 Hz, 2H), 2.33 (s, 6H), 1.99-1.88 (m, 2H), 1.46-1.40 (m, 2H); ESI MS m / z 476 [M+H]+; HPLC 99.4 % (AUC), tR= 15.50 min.

[0244] Example 64: 1 -(2-Chloro-6-fluorobenzoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“47q”). Compound 47q was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 2-chloro-6-fluorobenzoyl chloride according to a similar procedure described for the synthesis of 47a:1H NMR (600 MHz, CDCh): 88.39 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.74-7.67 (m, 1H), 7.47-7.44 (m, 1H), 7.41-7.37 (m, 1H), 7.33-7.29 (m, 1H), 7.13 (t, I = 8.4 Hz, 1H), 3.98-3.85 (m, 4H), 3.77 (s, 2H), 3.68 (t, I = 11.1 Hz, 2H), 3.22 (t, I = 8.3 Hz, 2H), 2.42 (s, 6H), 1.99-1.90 (m, 2H), 1.48 (d, J = 12.3 Hz, 2H); ESI MS m / z 460 [M+H]+; HPLC 99.2 % (AUC), tR= 15.01 min.

[0245] Example 65: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -picolinoylindoline-5-carboxamide (“47r”). Compound 47r was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and pyridine-2-carbonyl chloride according to a similar procedure described for the synthesis of 47a:1H NMR (600 MHz, CDCh): 88.65 (d, J = 4.5 Hz, 1H), 8.36 (s, 1H), 7.94-7.85 (m, 2H), 7.72 (bs, 2H), 7.43 (s, 1H), 6.95 (s, 1H), 4.44 (s, 2H), 3.91 (d, J = 10.8 Hz, 2H), 3.71 (bs, 4H), 3.21 (t, J = 8.3 Hz, 2H), 2.39 (s, 6H), 1.94 (t, J = 9.2 Hz, 2H), 1.48 (s, 2H); ESI MS m / z 409 [M+H]+; HPLC 98.9 % (AUC), tR= 13.84 min.

[0246] Example 66: 1 -(3-Chloropicolinoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“47s”). Compound 47s was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3-chloropyridine-2-carbonyl chloride according to a similar procedure described for the synthesis of 47a: 'll NMR (600 MHz, CDC13): 8 8.58 (d, J = 4.5 Hz, 1H), 8.40 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.39 (dd, J = 8.2, 4.7 Hz, 1H), 6.95 (s, 1H), 3.94 (t, J = 8.4 Hz, 2H), 3.90 (d, J = 11.8 Hz, 2H), 3.71 (d, J = 3.9 Hz, 2H), 3.65 (t, J = 11.5 Hz, 2H), 3.22 (t, J = 8.4 Hz, 2H), 2.36 (s, 6H), 1.97-1.88 (m, 2H), 1.44 (d, J = 13.2 Hz, 2H); ESI MS m / z 443 [M+H]+; HPLC 99.5 % (AUC), tR= 14.27 min.

[0247] Example 67: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-l -(3-fluoropicolinoyl)indoline-5-carboxamide (“47 ’). Compound 47t was prepared from N-((4- (dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 3-fluoropyridine-2-carbonyl chloride according to a similar procedure described for the synthesis of 47a: 'HNMR (600 MHz, CDCI3): 88.51 (d, J = 3.7 Hz, 1H), 8.39 (d, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.59 (t, J = 8.7 Hz, 1H), 7.48-7.46 (m, 1H), 6.94 (s, 1H), 4.11 (t, J = 8.4 Hz, 2H), 3.91 (d, J = 11.6 Hz, 2H), 3.71 (s, 2H), 3.66 (t, J = 11.2 Hz, 2H), 3.22 (t, J = 8.4 Hz, 2H), 2.33 (s, 6H), 1.97-1.87 (m, 2H), 1.44 (d, J = 12.6 Hz, 2H); ESI MS m / z 427 [M+H]+; HPLC 98.7 % (AUC), tR= 13.94 min.

[0248] Example 68: 1 -(Bicyclofl.1. l]pentane-2-carbonyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (“47u”). Compound 47u was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and 1-bicyclo[l.l.l]pentane-2-carbonyl chloride according to a similar procedure described for the synthesis of 47a: ’H NMR (600 MHz, CDC13): 58.24 (d, J = 8.4 Hz, 1H), 7.72 (s,lH), 7.58 (d, J = 8.2 Hz, 1H), 7.01 (bs, 1H), 4.25 (t, J = 8.5 Hz, 2H), 3.91-3.90 (m, 2H), 3.73-3.72 (m, 2H), 3.67-3.63 (m, 2H), 3.26 (t, J = 8.4 Hz, 2H), 2.55 (s, 1H), 2.40 (bs, 6H), 2.28 (s, 6H), 1.97-1.90 (m, 2H), 1.47-1.45 (m, 2H), ESI MS m / z 398 [M+H]’; HPLC 97.98 % (AUC), tR= 14.4 min.

[0249] Example 69: N-((4-(Dimethylamino)tetrahy dro-2H-pyran-4-yl)m ethyl)- 1 -(spiro[3.3]heptane-2-carbonyl)indoline-5-carboxamide (“47v”). Compound 47v was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (19) and spiro[3.3]heptane-2-carbonyl chloride according to a similar procedure described for the synthesis of 47a: ' H NMR (600 MHz, CDCI3): 8 8.26 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 6.90 (bs, 1H), 4.03 (t, J = 8.5 Hz, 2H), 3.91-3.89 (m, 2H), 3.71-3.70 (m, 1H), 3.69-3.63 (m, 2H), 3.24-3.17 (m, 3H), 2.37 (s, 6H), 2.29-2.26 (m, 2H), 2.10 (t, J = 7.3 Hz, 2H), 1.98-1.90 (m, 4H), 1.87-1.82 (m, 2H), 1.68 (bs, 2H), 1.45-1.43 (m, 2H); ESI MS m / z 426 [M+H]+; HPLC 99.5 % (AUC), tR= 15.5 min.

[0250] Referring now to FIG. 19, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 18. In the exemplary embodiments of Scheme 18, the reagents and reaction conditions were as follows: (a) benzoyl chloride, NaH, THF, 0°C, to rt, 16 h; (b) (i) LiOH H2O, CH3OH, H2O, reflux, 1 h, (ii) 2 N aqueous HC1; (c) compound 3a, HBTU, i-Pr2NEt, CH2CI2, rt, 16 h.

[0251] Example 72: 1 -Benzoyl-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (“50”). Step A: To a 0 °C cooled solution of methyl 6-fluoroindoline-5-carboxylate (13, 0.09 g, 0.471 mmol) in THF (10 mb) was added NaH (0.016 g, 0.706 mmol), and the mixture was allowed to stir for 30 min at room temperature. Benzoyl chloride (0.079 g, 0.565 mmol) was then added dropwise, and the mixture was stirred at room temperaturefor an additional 16 h. The mixture was cooled to 0 °C and carefully quenched with slow dropwise addition of H2O (50 mL). The aqueous mixture was extracted with EtOAc (2 x 20 mL), and the combined organic extracts were washed with H2O (2 x 10 mL), brine (30 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% EtOAc in hexanes) to give methyl l-benzoyl-6-fluoroindoline-5-carboxylate (“48”) as a white solid (0.06 g, 43%):1H NMR (600 MHz, CDCh) 57.82 (d, J = 7.1 Hz, 1 H), 7.57-7.56 (m, 2 H), 7.53 (d, J = 7.3 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 2 H), 4.15 (t, J = 8.2 Hz, 2 H), 3.92 (s, 3 H), 3.13 (t, J = 8.2 Hz, 2 H); ESI MS m / z 300 [M + H]+.

[0252] Step B: To a solution of methyl l-benzoyl-6-fluoroindoline-5-carboxylate (48, 0.20 g, 0.674 mmol) in a mixture of CH3OH (1 mL) and H2O (4 mL) was added LiOH H2O (0.024 g, 1.01 mmol). The mixture was heated at reflux for 1 h, then concentrated under reduced pressure. The resulting residue was diluted with H2O (50 mL), and the aqueous mixture was acidified to pH = 2 with 2.0 N aqueous HC1. The aqueous mixture was extracted with EtOAc (2 x 30 mL), and the combined organic extracts were washed with H2O (2 x 20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was then triturated with Et2O (30 mL) to give l-benzoyl-6-fluoroindoline-5-carboxylic acid (“49”) as pale yellow solid (0.130 g, 68%): 'H NMR (600 MHz, DMSO-d6) 87.73 (d, J = 7.5 Hz, 1 H), 7.61 (d, J = 7.0 Hz, 2 H), 7.55 (d, J = 7.2 Hz, 1 H), 7.51 (t, J = 7.2 Hz, 2 H), 4.08 (t, J = 8.3 Hz, 2 H), 3.09 (t J = 8.4 Hz, 2 H (s, 3 H); ESI MS m / z 285 [M + H]+.

[0253] Step C: To a solution of l-benzoyl-6-fluoroindoline-5-carboxylic acid (49, 0.946 g, 3.78 mmol) in DMF (25 mL) was 4-(aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine (3a, 0.780 g, 4.53 mmol), HBTU (1.72 g, 4.53 mmol), and i-Pr2NEt (0.99 g, 7.56 mmol) and the mixture stirred for 16 h at room temperature and under an atmosphere of N2. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous mixture was extracted with EtOAc (3 x 30 mL), and the combined organic extracts were washed with H2O (3 x 30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2CI2) to give 1 -benzoyl -N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (50) as a white solid (1.02 g, 56%): ’H NMR (600 MHz, CDCI3) 6.

[0254] Referring now to FIG. 20, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 19. In the exemplary embodiments ofScheme 19, the reagents and reaction conditions were as follows: (a) compound 3a, HBTU, i-Pr2NEt, CH2CI2, rt, 16 h; (b) substituted benzoyl chloride, i-PnNEt, CH2CI2, 0°C, to rt,4-16 h.

[0255] Example 73: l-(2-Chlorobenzoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (“52a”). Step A: To a solution of 6-fluoroindoline-5-carboxylic acid (14, 0.946 g, 3.78 mmol) in DMF (25 mL) was 4-(aminomethyl)-N, N-dimethyltetrahydro-2H-pyran-4-amine (3a, 0.780 g, 4.53 mmol), HBTU (1.72 g, 4.53 mmol), and i-PnNEt (0.99 g, 7.56 mmol) and the mixture stirred for 16 h at room temperature and under an atmosphere of N2. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (30 mL). The aqueous mixture was extracted with EtOAc (3 x 30 mL), and the combined organic extracts were washed with H2O (3 x 30 mL), brine (30 mL), dried over ISfeSCU, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2CI2) to give lN-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamid (“51”) as a white solid (1.02 g, 56%).

[0256] Step B: To a 0°C cooled solution of N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (“51”, 0.070 g, 0.231 mmol) and i-Pr2NEt (0.12 mL, 0.68 mmol) in anhydrous CH2CI2 (2 mL) was added 2-chlorobenzoyl chloride (0.040 g, 0.227 mmol) and the mixture stirred at room temperature for 1.5 h. The mixture was diluted with additional CH2CI2 (30 mL) and washed with saturated aqueous NaHCOs (2 >< 10 mL) and saturated NH4CI (2 x 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (10% CH3OH in CH2CI2) to afford l-(2-chlorobenzoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (52a) as an off-white solid (0.030g, 64%):JH NMR (600 MHz, CDCI3): 58.14 (d, J = 13.3 Hz, 1H), 7.98 (t, J = 7.4 Hz, 1H), 7.50-7.40 (m, 5H), 3.90-3.88 (m, 4H), 3.73-3.62 (m, 4H), 3.15 (t, J = 8.2 Hz, 2H), 2.35 (s, 6H), 1.92 (t, J = 9.6 Hz. 2H), 1.48(d, J = 13.0 Hz, 2H); ESI MS m / z 460 [M+H]+; HPLC >99 % (purity), tR= 14.8 min.

[0257] Example 74: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoro- 1 -(2-fluorobenzoyl)indoline-5-carboxamide (“52b”). Compound 52b was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (51) and 2-fluorobenzolyl chloride according to a similar procedure described for the synthesis of 52a: 'H NMR (600 MHz, CDC13): 88.10 (d, J = 12.0 Hz, 1H), 7.93 (t, J = 7.5 Hz, 1H), 7.50-7.45 (m, 3H), 7.30-7.28 (m, 1H), 7.19 (t, J = 9.0 Hz, 1H), 4.03 (bs, 2H), 3.90-3.88 (m, 2H), 3.72 (bs, 2H), 3.64 (t, J = 10.5 Hz, 2H), 3.16 (t, J = 8.1 Hz, 2H), 2.35 (s, 6H), 1.91 (bs, 2H), 1.48-1.46 (m, 2H); ESIMS m / z 444 [M+H]+; HPLC >99 % (purity), tR= 14.7 min.

[0258] Example 75: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoro- 1 -(2-methylbenzoyl)indoline-5-carboxamide (“52c”). Compound 52c was prepared N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (51) and 2-methylbenzoyl chloride according to a similar procedure described for the synthesis of 52a: 'H NMR (600 MHz, CDCI3): 87.86-7.85 (m, 1H), 7.57-7.55 (m, 1H), 7.37-7.33 (m, 5H), 4.11 (t, J = 7.7 Hz, 2H), 3.77 (d, J = 4.7 Hz, 2H), 3.66 (t, J = 10.5 Hz, 2H), 3.08 (t, J = 8.3 Hz, 2H), 2.40 (s, 2H) 1.96-1.91 (m, 2H), 1.52 (d, J = 13.3 Hz, 2H); ESI MS m / z 440 [M+H]+; HPLC 94.0 % (purity), tR= 15.0 min.

[0259] Example 76: l-(2-Chloro-6-fluorobenzoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (“52d”). Compound 52d was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (51) and 2-chloro-6-fluorobenzoyl chloride according to a similar procedure described for the synthesis of 52a: 'HNMR (600 MHz, CDC13): 88.15 (d, J = 13.30 Hz, 1H), 7.94 (d, J = 7.54 Hz, 1H), 7.47 (bs, 1H), 7.42-7.39 (m, 1H), 7.31 (d, J = 8.29 Hz, 1H), 7.14 (t, J = 8.29 Hz, 1H), 3.96-3.89 (m, 4H), 3.73 (s, 2H), 3.67-3.63 (m, 2H), 3.20 (t, J = 8.34 Hz, 2H), 2.36 (s, 6H), 1.95-1.91 (m, 2H), 1.49- 1.47 (m, 2H); ESI MS m / z 478 [M+H]+; HPLC 94.4 % (purity), tR= 15.4 min.

[0260] Example 77: l-(3-Chloro-2-fluorobenzoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (“52e”). Compound 52e was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (51) and 3-chloro-2-fluorobenzolyl chloride according to a similar procedure described for the synthesis of 52a: ’H NMR (600 MHz, CDCI3): 88.09 (d, J = 13.64 Hz, 1H), 7.94 (d, J = 7.64 Hz, 1H), 7.56-7.54 (m, 1H), 7.45 (bs, 1H), 7.39-7.37 (m, 1H), 7.24 (t, J = 7.83 Hz, 1H), 4.02-4.00 (m, 2H), 3.90-3.88 (m, 2H), 3.72 (s, 2H), 3.66-3.62 (m, 2H), 3.18 (t, J = 8.23 Hz, 2H), 2.35 (s, 6H), 1.94-1.90 (m, 2H), 1.48-1.46 (m, 2H): ESI MS m / z 478 [M+H]+; HPLC 90.4 % (purity), tR= 15.5 min.

[0261] Example 78: l-(2,3-Dichlorobenzoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (“52f ’). Compound 52f was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (51) and 2,3-di chlorobenzolyl chloride according to a similar procedure described for the synthesis of 52a: 'H NMR (600 MHz, CDCI3): 88.12 (d, J = 13.2 Hz, 1H),7.93 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 4.0 Hz, 1H), 7.45-7.31 (m, 3H), 3.96-3.89 (m, 4H), 3.72-3.62 (m, 4H), 3.17 (t, J = 8.1 Hz, 2H), 2.35 (s, 6H) 1.92 (bs, 2H), 1.48-1.47 (m, 2H); ESI MS m / z 494 [M+H]+; HPLC 92.0 % (purity), tR= 15.4 min.

[0262] Example 79: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoro- 1 -picolinoylindoline-5-carboxamide (“52g”). Compound 52g was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (51) and pyridine-2-carbonyl chloride according to a similar procedure described for the synthesis of 52a:1H NMR (600 MHz, CDC13): 58.66 (d, J = 4.7 Hz, 1H), 8.12 (d, J = 13.0 Hz, 1H), 7.96-7.88 (m, 2H), 7.45 (d, J = 4.5 Hz, 2H), 4.50 (t, J = 6.6 Hz, 2H), 3.91 (d, J = 11.6 Hz, 2H), 3.75 (s, 2H), 3.65 (dt, J = 1.8 Hz, J = 10.2 Hz, 2H), 3.18 (t, J = 8.4 Hz, 2H), 2.39 (s, 6H), 1.96-1.87 (m, 2H), 1.51 (d, J = 12.4 Hz, 2H); ESI MS m / z 427 [M+H]+; HPLC 93.9 % (purity), tR= 14.05 min.

[0263] Example 80: l-(3-Chloropicolinoyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (“52h”). Compound 52h was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (51) and 3-chloropicolinoyl chloride according to a similar procedure described for the synthesis of 52a:1H NMR (600 MHz, CDCI3): 88.59 (dd, J = 4.7, 1.2 Hz, 1H), 8.16 (d, J = 13.3 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.87 (dd, J = 8.2, 1.2 Hz, 1H), 7.46 (bs, 1H), 7.41 (dd, J = 8.2, 4.7 Hz, 1H), 3.98 (t, J = 8.5 Hz, 2H), 3.90 (dt, J = 11.6, 4.0 Hz, 2H), 3.73 (d, J = 4.6 Hz, 2H), 3.65 (dt, J = 9.6, 2.4 Hz, 2H), 3.19 (t, J = 8.4 Hz, 2H), 2.36 (s, 6H), 1.96-1.88 (m, 2H), 1.48 (d, J = 13.1 Hz, 2H); ESI MS m / z 461 [M+H]+; HPLC 94.6 % (purity), tR= 14.30 min.

[0264] Example 81: N-((4-(Dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoro-l-(3-fluoropicolinoyl)indoline-5-carboxamide (“52i”). Compound 52i was prepared from N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-6-fluoroindoline-5-carboxamide (51) and 3-fluoropicolinoyl chloride according to a similar procedure described for the synthesis of 52a:1H NMR (600 MHz, CDC13): 58.51 (d, J = 4.2 Hz, 1H), 8.15 (d, J = 13.4 Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.61 (t, J = 8.7 Hz, 1H), 7.51-7.46 (m, 2H), 4.15 (t, J = 8.4 Hz, 2H), 3.90 (d, J = 11.5 Hz, 2H), 3.73 (d, J = 3.3 Hz, 2H), 3.65 (t, J = 10.6 Hz, 2H), 3.19 (t, J = 8.3 Hz, 2H), 2.36 (s, 6H), 1.95-1.88 (m, 2H), 1.49 (d, J = 13.6 Hz, 2H); ESI MS m / z 445 [M+H]+; HPLC 92.3 % (purity), tR= 14.08 min.

[0265] Referring now to FIG. 21, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 20. In the exemplary embodiments of Scheme 20, the reagents and reaction conditions were as follows: (a) compound 3c, HBTU, i-PnNEt, CH2CI2, rt, 16 h; (b) 1 N HC1 in Et2O, CH2CI2, 0°C to rt, 2 h; (e) substituted benzoyl chloride, i-PnNEt, CH2CI2, 0°C, to rt,4-16 h.

[0266] Example 82: l-Benzoyl-N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“55a”). A solution of N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“54”, 0.070 g, 0.231 mmol) in anhydrous CH2CI2 (2 mL) containing i-Pr2NEt (0.12 mL, 0.68 mmol) was stirred at 0°C for 5 min. Benzoyl chloride (0.227 mmol) was then added at 0°C, and the mixture was stirred at room temperature for 1.5 h. Upon completion, the reaction was extracted with CH2CI2 (3 >< 10 mL), and the combined organic layers were washed successively with saturated NaHCCh (2 x 10 mL) and saturated NH4Q (2 x 10 mL). The organic phase was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (10% MeOH in CH2CI2) to afford 1-benzoyl-N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (55a) as a white solid (50%): 'H NMR (600 MHz, DMSO-D6): d 10.49 (bs, 1H), 8.66 (bs, 1H), 7.82 (s, 1H), 7.57 -7.46 (d, m 6H), 4.02 (t, J = 8.1 Hz, 2H), 3.57 (d, J = 6.0 Hz, 2H), 3.09 (t, J = 8.2 Hz, 2H), 2.46 (s, 6H), 1.89-1.69 (m, 8H), ESI MS m / z 392 [M+H]+; HPLC 95.6 % (purity), tR= 15.1 min.

[0267] Example 83: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-(2-phenylacetyl)indoline-5-carboxamide (55b). Compound 55b was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and phenylacetyl chloride according to a similar procedure described for the synthesis of 55a:1H NMR (600 MHz, CDCh): 8 10.56 (bs, 1H), 8.68 (t, J = 6.1 Hz, 1H), 8.10-8.08 (m, 1H), 7.82-7.77 (m, 2H), 7.35-7.24 (m, 5H), 4.24 (t, J = 8.4 Hz, 2H), 3.88 (s, 2H), 3.61 (d, J = 6.2 Hz, 2H), 3.21-3.18 (m, 2H), 2.79 (d, J = 4.9 Hz, 6H), 1.92-1.73 (m, 8H); ESI MS m / z 406 [M+H]+; HPLC 95.4 % (purity), tR= 15.3 min.

[0268] Example 84: l-(2-Chlorobenzoyl)-N-((l -(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (55c). Compound 55c was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 2-chlorobenzoyl chloride according to a similar procedure described for the synthesis of 55a:JH NMR (600 MHz, CDCh): 8 8.38 (d, J = 8.2 Hz, 1H), 7.76-7.40 (m, 7H), 3.87 (bs, 2H), 3.43-3.17 (m, 4H), 2.27 (s, 6H), 1.86-1.46 (m, 8H); ESI MS m / z 426 [M+H]+; HPLC 97.18 % (purity), tR= 15.5 min.

[0269] Example 85: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-(2-fluorobenzoyl)indoline-5-carboxamide (“55d”). Compound 55d was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 2-fluorobenzoyl chloride according to a similar procedure described for the synthesis of 55a:1H NMR (600 MHz, CDCh): 88.33 (bs, 1H), 7.77-7.16 (m, 7H), 3.99 (bs, 2H), 3.49 (bs, 2H), 3.18( t, J = 7.8 Hz, 2H), 2.33 (s, 6H), 1.86-1.44 (m, 8H); ESI MS m / z 410 [M+H]+; HPLC 97.6 % (purity), tR= 15.1 min.

[0270] Example 86: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-(2-(trifluoromethyl)benzoyl)indoline-5-carboxamide (“55e”). Compound 55e was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 2-trifluorobenzoyl chloride according to a similar procedure described for the synthesis of 55a:1H NMR (600 MHz, CDC13): 88.37- 8.36 (m, 1H), 7.84 - 7.44 (m, 6H), 7.05 (bs, 1H), 3.79 (bs, 2H), 3.47-3.46 (m, 2H), 3.2 -3.16 (m, 2H), 3.29 (s, 6H), 1.88-1.48 (m, 8H); ESI MS m / z 460 [M+H]+; HPLC 96.0 % (purity), tR= 15.2 min.

[0271] Example 87: N-((l-(Dimethylamino)cy cl opentyl)m ethyl)- 1 -(2-methylbenzoyl)indoline-5-carboxamide (“55f”). Compound 55f was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 2-methylbenzoyl chloride according to a similar procedure described for the synthesis of 55a: 'H NMR (600 MHz, CDCh): 8 7.75 (bs, 1H), 7.57 (bs, 1H), 7.38-7.33 (m, 4H), 7.01 (bs, 1H), 4.14 (bs, 2H), 3.47 (bs, 2H), 3.17 (t, J = 8.6 Hz, 2H), 2.30 (s, 6H), 1.85-1.45 (m, 8H); ESI MS m / z 406 [M+H]+; HPLC 99.0 % (purity), tR= 15.5 min.

[0272] Example 88: l-(3-Chlorobenzoyl)-N-((l -(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“55g”). Compound 55g was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 3-chlorobenzoyl chloride according to a similar procedure described for the synthesis of 55a:JH NMR (600 MHz, CDCh): 5 7.77 (bs, 1H), 7.57 (bs, 2H), 7.50 -7.41 (m, 3H), 7.01 (bs, 2H), 4.13 (bs, 2H), 3.47 (bs, 2H), 3.19 (t, J = 8.2 Hz, 2H), 2.31 (s, 6H), 1.86-1.44 (m, 8H); ESIMS m / z 426 [M+H]+; HPLC 95.3 % (purity), tR= 15.3 min.

[0273] Example 89: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-(3-fluorobenzoyl)indoline-5-carboxamide (“55h”). Compound 55h was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 3-fluorobenzoyl chloride according to a similar procedure described for the synthesis of 55a:1H NMR (600 MHz, CDCI3): 8 7.78 (bs, 1H), 7.61 (bs, 1H), 7.48 -7.10 (m, 6H), 4.13 (bs, 2H), 3.48 (bs, 2H), 3.20 (t, J = 8.2 Hz, 2H), 2.32 (s, 6H), 1.87-1.44 (m, 8H); ESIMS m / z 410 [M+H]+; HPLC 95.2 % (purity), tR= 14.9 mm.

[0274] Example 90: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-(3-methylbenzoyl)indoline-5-carboxamide (“55i”). Compound 55i was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 3 -methylbenzoyl chloride according to a similar procedure described for the synthesis of 55a: 'H NMR (600 MHz, CDCI3): 8 7.72 (bs, 1H), 7.55 (bs, 2H), 7.40 -7.33 (m, 4H), 6.96 (bs, 1H), 4.14 (bs, 2H), 3.44 (bs, 2H), 3.18 (t, J = 8.2 Hz, 2H), 2.43 (s, 3H), 2.22 (s, 6H), 1.85-1.42 (m, 8H); ESIMS m / z 406 [M+H]+; HPLC 96.0 % (purity), tR= 15.1 min.

[0275] Example 91: l-(4-Chlorobenzoyl)-N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“55j”). Compound 55j was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide(54) and 4-chlorobenzoyl chloride according to a similar procedure described for the synthesis of 55a:JH NMR (600 MHz, CD3OD): 5 7.76 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.98 (bs, 2H), 4.13 (bs, 2H), 3.46 (bs, 2H), 3.19 (t, J = 8.2 Hz, 2H), 2.29 (bs, 6H), 1.84-1.43 (m, 8H); ESIMS m / z 426 [M+H]+; HPLC 95.8 % (purity), tR= 15.7 min.

[0276] Example 92: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-(4-fluorobenzoyl)indoline-5-carboxamide (“55k”). Compound 55k was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 4-fluorobenzoyl chloride according to a similar procedure described for the synthesis of 55a:1H NMR (600 MHz, CDCI3): 8 7.77 (bs, 1H), 7.61-7.59 (m, 4H), 7.18-7.15 (m, 3H), 4.15 (bs, 2H), 3.47 (bs, 2H), 3.19 (t, J = 8.2 Hz, 2H), 2.31 (s, 6H), 1.86-1.44 (m, 8H); ESIMS m / z 410 [M+H]+; HPLC 95.6 % (purity), tR= 14.8 min.

[0277] Example 93: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-(3-fluoropicolinoyl)indoline-5-carboxamide (“55L”). Compound 55L was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 4-m ethylbenzoyl chloride according to a similar procedure described for the synthesis of 55a:JH NMR (600 MHz, CDCI3): 8 7.77 (s, 1H), 7.67 (bs, 2H), 7.50 (d, J = 7.8 Hz, 2H),7.35 (d, J = 7.9 Hz, 2H), 4.16 (t, J = 7.8 Hz,2H), 3.60 (s, 2H), 3.20 (t, J = 8.2 Hz, 2H), 2.51 (s, 6H), 2.44 (s, 3H), 1.82-1.76 (m, 8H); ESI MS m / z 406 [M+H]+; HPLC 97.0 % (purity), tR= 15.4 min.

[0278] Example 94: l-(2-Chloro-6-fluorobenzoyl)-N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“55m”). Compound 55m was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 2-chloro-6-fluorobenzoyl chloride according to a similar procedure described for the synthesis of 55a:XH NMR (600 MHz, CDC13): 88.39 (d, J = 8.3 Hz, 1H), 7.79-7.74 (m, 2H), 7.40-7.11 (m, 4H), 3.94-3.86 (m, 2H), 2.35 (s, 6H), 1.89-1.49 (m, 8H); ESI MS m / z 444 [M+H]+; HPLC 96.7 % (purity), tR= 15.1 min.

[0279] Example 95: l-(3-Chloro-2-fluorobenzoyl)-N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“55n”). Compound 55n was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 3-chloro-2-fluorobenzoyl chloride according to a similar procedure described for the synthesis of 55a: 'll NMR (600 MHz, CDCI3): 88.32 (d, J = 8.2 Hz, 1H), 7.79-7.21 (m, 6H), 3.98 (t, J = 7.98 Hz, 2H), 3.50 (s, 2H), 3.20 (t, J = 8.21 Hz, 2H), 2.34 (s, 6H), 1.68-1.48 (m, 8H); ESIMS m / z 444 [M+H]+; HPLC 99.0 % (purity), tR= 15.7 min.

[0280] Example 96: l-(2,3-Dichlorobenzoyl)-N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“55o”). Compound 55o was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 2,3-dichlorobenzoyl chloride according to a similar procedure described for the synthesis of 55a:JH NMR (600 MHz, CDCh): 5 8.37 (d, J = 8.3 Hz, 1H), 7.77-7.32 (m, 6H), 3.94-3.21 (m, 6H), 2.30 (s, 6H), 1.85-1.84 (m, 8H); ESI MS m / z 461 [M+H]+; HPLC 99.0 % (purity), tR= 15.9 min.

[0281] Example 97: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-picolinoylindoline-5-carboxamide (“55p”). Compound 55p was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and pyridine-2-carbonyl chloride according to a similar procedure described for the synthesis of 55a: 'H NMR (600 MHz, CD3OD): 8 8.66 (d, J = 4.3 Hz, 1H), 8.30 (bs, 1H), 8.03 (t, J = 7.4Hz, 1H), 7.83-7.81 (m, 3H), 7.58 (bs, 1H), 4.31 (t, J = 8.1 Hz, 2H), 3.69 (bs, 2H), 3.24 (t, J = 8.4 Hz, 2H), 2.74 (s, 6H), 1.91-1.82 (m, 8H); ESI MS m / z 393 [M+H]+; HPLC 99.0 % (purity), tR= 14.2 min.

[0282] Example 98: l-(3-Chloropicolinoyl)-N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (55q). Compound 55q was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 3-chloropicolinoyl chloride according to a similar procedure described for the synthesis of 55a:1H NMR (600 MHz, CD3OD): 5 8.62-8.61 (m, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.09 - 8.08 (m, 1H), 8.83-8.82 (m, 2H), 7.59 -7.57 (m, 1H), 3.93 (t, J = 8.4 Hz, 2H), 3.69 (bs, 2H), 3.26 (t, J = 8.4 Hz, 2H), 2.74 (s, 6H), 1.91-1.81 (m, 8H); ESI MS m / z 427 [M+H]+; HPLC 96.7 % (purity), tR= 14.4 min.

[0283] Example 99: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-(3-fluoropicolinoyl)indoline-5-carboxamide (“55r”). Compound 55r was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 3-fluoropicolinoyl chloride according to a similar procedure described for the synthesis of 55a:JH NMR (600 MHz, CD3OD): 8 8.52 (d, J = 4.6 Hz, 1H), 8.30 (d, J = 9.0 Hz, 1H), 7.86 -7.64 (m, 4H), 4.07 (t, J = 8.4 Hz, 2H), 3.60 (s, 2H), 3.25 (t, J = 8.3 Hz, 2H), 2.46 (s, 6H), 1.82-1.73 (m, 8H); ESIMS m / z 411 [M+H]+; HPLC 98.7 % (purity), tR= 14.4 min.

[0284] Example 100: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-(3-methylpicolinoyl)indoline- 5-carboxamide (“55s”). Compound 55s was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 3-methylpicolinoyl chloride according to a similar procedure described for the synthesis of 55a:JH NMR (600 MHz, CD3OD): 8 8.47-8.46 (m, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.87-7.77 (m, 3H), 7.48-7.46 (m, 1H), 3.91 (t, J = 8.4 Hz, 2H), 3.63 (s, 2H), 3.23 (t, J = 8.4 Hz, 2H), 2.57 (s, 6H), 2.43 (s, 3H), 1.84-1.79 (m, 8H); ESI MS m / z 407 [M+H]+; HPLC 99.01 % (purity), tR= 14.2 min.

[0285] Example 101: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-isonicotinoylindoline-5-carboxamide (55t). Compound 55t was prepared from N-((l- (dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and pyridine-4-carbonyl chloride according to a similar procedure described for the synthesis of 55a:1H NMR (600 MHz, CD3OD): 8 8.75-8.74 (m, 1H), 8.25 (bs, 1H), 7.80 (bs, 1H), 7.64-7.59 (m, 3H), 6.59-6.58 (m, 1H), 4.01 (bs,1H), 3.62-3.58 (m, 2H), 3.24 (t, J = 8.2 Hz, 2H), 3.04 (t, J= 8.5 Hz, 2H), 2.60 (s, 6H), 1.81-1.77 (m, 8H); ESI MS m / z 393 [M+H]+; HPLC 97.2 % (purity), tR= 13.2 min.

[0286] Example 102: l-(3-Bromo-4-fluorobenzoyl)-N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“55u”). Compound 55u was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 3-bromo-4-fluorobenzoyl chloride according to a similar procedure described for the synthesis of 55a:NMR (600 MHz, CD3OD): 57.83-7.80 (m, 2H), 7.63 -7.50 (m, 3H), 7.22 (t, J = 8.3 Hz, 1H), 4.13 (s, 2H), 3.50 -3.49 (m, 2H), 3.20 (t, J = 8.2 Hz, 2H), 2.35 (s, 6H), 1.88-1.47 (m, 8H); ESI MS m / z 490 [M+H]+; HPLC 96.1 % (purity), tR= 15.8 min.

[0287] Example 103: l-(2-Bromo-3-methylbenzoyl)-N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“55v”). Compound 55v was prepared fromN-((l -(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide(54) and 2-bromo-3-methylbenzoyl chloride according to a similar procedure described for the synthesis of 55a:1H NMR (600 MHz, CDCI3): 88.39 (d, J = 8.4 Hz 1H), 7.77-7.72 (m, 2H), 7.34-7.28 (m, 3H), 7.21-7.19 (m, 1H), 3.94-3.77 (m, 2H), 3.48-3.42 (m, 2H), 3.19-3.18 (m, 2H), 2.48 (s, 3H), 2.31 (s, 6H), 1.85-1.46 (m, 8H); ESI MS m / z 486 [M+H]+; HPLC 95.0 % (purity), tR= 15.7 min.

[0288] Example 104: N-((l-(Dimethylamino)cyclopentyl)methyl)-l-(indoline-2-carbonyl)indoline-5-carboxamide (“55w”). Compound 55w was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and 2-indoline-carbonyl chloride according to a similar procedure described for the synthesis of 55a:JH NMR (600 MHz, CDCh): 5 8.23 (t, J = 8.3 Hz, 1H), 7.80 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H),7.69 (d, J = 8.0 Hz, 1H), 7.50-7.49 (m, 1H), 7.30-7.27 (m, 1H), 7.17 (s, 1H), 7.12-7.09 (m, 1H), 4.63 (t, J = 8.3 Hz, 2H), 3.62 (s, 2H), 3.37-3.33 (m, 4H), 2.55 (s, 6H), 1.83-1.78 (m, 8H); ESI MS m / z 432 [M+H]+; HPLC 96.3 % (purity), tR= 15.8 min.

[0289] Example 105: l-(Cyclohexanecarbonyl)-N-((l- (dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“55x”). Compound 55x was prepared fromN-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and cyclohexane carbonyl chloride according to a similar procedure described for the synthesis of 55a: H NMR (600 MHz, CDCh): 5 10.41 (s, 1H), 8.66 (t, J = 6.0 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.77 (d, J = 8.20 Hz, 1H), 4.22 (t, J = 7.9 Hz, 2H), 3.61 (d, J = 6.0 Hz, 2H), 3.18 (t, J = 8.2 Hz, 2H), 2.79 (d, J = 4.90 Hz, 6H), 2.57 (bs, 1H), 1.93-1.63 (m, 12H), 1.43-1.17 (m, 6H); ESIMS m / z 398 [M+H]+; HPLC 98.9 % (purity), tR= 15.7 min.

[0290] Example 106: l-Butyryl-N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (“55y”). Compound 55y was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)indoline-5-carboxamide (54) and butyryl chloride according to a similar procedure described for the synthesis of 55a: 'H NMR (600 MHz, CDCh): 8 10.48 (bs, 1H), 8.65 (t, J = 6.0 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.81 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 4.14 (t, J = 8.4 Hz, 2H), 3.61 (d, I = 6.2 Hz, 2H), 3.18 (t, J = 8.2 Hz, 2H), 2.79 (d, I = 4.9 Hz, 2H), 2.46 (t, I= 7.0 Hz, 2H), 1.92-1.59 (m, 10H), 0.95 (t, J = 7.9 Hz, 3H); ESI MS m / z 358 [M+H]+; HPLC 95.0 % (purity), tR= 14.7 min.

[0291] Referring now to FIG. 22, GlyT2 inhibitor compounds according to some embodiments of the present disclosure are prepared according to Scheme 21. In the exemplary embodiments of Scheme 21, the reagents and reaction conditions were as follows: (a) compound 3c, HBTU, i-PnNEt, CH2CI2, rt, 16 h; (b) 1 N HC1 in Et2O, CH2CI2, 0°C to rt, 2 h; (e) substituted benzoyl chloride, i-Pr2NEt, CH2CI2, 0°C, to rt,4-16 h.

[0292] Example 107: l-Benzoyl-N-((l-(dimethylamino)cyclopentyl)methyl)-6-fluoroindoline-5-carboxamide (“58a”). A solution of N-((l-(dimethylamino)cyclopentyl)methyl)-6-fluoroindoline-5-carboxamide (“57”, 0.070 g, 0.231 mmol) in anhydrous CH2CI2 (2 mL) containing DIPEA (0.12 mL, 0.68 mmol) was stirred at 0°C for 5 min to liberate the free amine. Benzoyl chloride (0.227 mmol) was then added at 0°C, and the mixture was stirred at room temperature for 1.5 h. Upon completion, the reaction was extracted with CH2CI2 (3 x 10 mL), and the combined organic layers were washed successively with saturated NaHCO (2 ^ 10 mL) and saturated NH4Q (2 x 10 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (10% MeOH in CH2CI2) to afford l-benzoyl-N-((l-(dimethylamino)cyclopentyl)methyl)-6-fluoroindoline-5-carboxamide (58a): ' H NMR (600 MHz, CD3OD): 87.72-7.53 (m, 7H), 4.17 (t, J = 8.0 Hz, 2H), 3.80 (s, 2H), 3.18 (t, J = 8.2 Hz, 2H), 3.01 (s, 6H), 2.12-2.09 (m, 2H), 1.97-1.90 (m, 6H); ESI MS m / z 410 [M+H]+; HPLC 95 % (purity), tR= 15.3 min.

[0293] Example 108: N-((l-(Dimethylamino)cyclopentyl)methyl)-6-fluoro-l-(2-phenylacetyl)indoline-5-carboxamide (“58b”). Compound 58b was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)-6-fluoroindoline-5-carboxamide (57) and phenylacetyl chloride according to a similar procedure described for the synthesis of 58a:rH NMR (600 MHz, CDCh): 5 10.23 (s, 1H), 7.83 (d, J = 12.0 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.35-7.25 (m, 5H), 4.27 (t, J = 8.5 Hz, 2H), 3.89 (s, 2H), 3.60 (d, J = 7.60 Hz, 2H), 3.17 (t, J = 7.8 Hz, 2H), 2.81 (d, J = 7.9 Hz, 6H), 1.95-1.73 (m, 8H); ESI MS m / z 424 [M+H]+; HPLC 94.0 % (purity), tR= 15.7 min.

[0294] Example 109: l-(2-Chlorobenzoyl)-N-((l-(dimethylamino)cyclopentyl)methyl)-6-fluoroindoline-5-carboxamide (“58c”). Compound 58c was prepared from N-((l- (dimethylamino)cyclopentyl)methyl)-6-fluoroindoline-5-carboxamide (57) and 2-chlorobenzoyl chloride according to a similar procedure described for the synthesis of 58a:1H NMR (600 MHz, CDCh): 58.15-8.13 (m, 1H), 7.94-7.92 (m, 1H), 7.51-7.41 (m, 5H), 3.90 (bs, 2H), 3.51 (bs, 2H), 3.16 (t, J = 8.2 Hz, 2H), 2.29 (s, 6H), 1.67-1.59 (m, 8H); ESI MS m / z 444 [M+H]+; HPLC 95.0 % (purity), tR= 15.4 min.58d

[0295] Example 110: N-((l-(Dimethylamino)cyclopentyl)methyl)-6-fluoro-l-(2-methylbenzoyl)indoline-5-carboxamide (58d). Compound 58d was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)-6-fluoroindoline-5-carboxamide (57) and 2-methylbenzoyl chloride according to a similar procedure described for the synthesis of 58a:1H NMR (600 MHz, CDCh): 87.88 (d, J = 7.6 Hz, 1H), 7.53 (bs, 2H), 7.38-7.33 (m, 4H), 4.13 (bs, 2H), 3.52 -3.51 (m, 2H), 3.10 (t, J = 8.2 Hz, 2H), 2.43 (s, 3H), 2.32 (s, 6H), 1.87-1.49 (m, 8H); ESI MS m / z 424 [M+H]+; HPLC 95.0 % (purity), tR= 15.7 min.

[0296] Example 111: 1 -(Cyclohexanecarbonyl)-N-(( 1 -(dimethylamino)cyclopentyl)methyl)-6-fluoroindoline-5-carboxamide (“58e”). Compound 58e was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)-6-fluoroindoline-5-carboxamide (57) and cyclohexane carbonyl chloride according to a similar procedure described for the synthesis of 58a: 'H NMR (600 MHz, CDCh): 8 10.58 (s, 1H), 8.52 (bs, 1H), 7.87 (t, J = 12.5 Hz, 1H), 7.53 (d, J = 7.4Hz, 1H), 4.25 (t, J = 8.4 Hz, 2H), 3.60 (d, J = 6.3 Hz, 2H), 3.14 (t, J = 8.3 Hz, 2H), 2.79 (d, J = 5.0 Hz, 6H), 2.58-2.50 (m, 3H). 1.93-1.66 (m, 12H), 1.43-1.17 (m, 6H); ESIMS m / z 416 [M+HT; HPLC 95.6 % (purity), tR= 16.3 min.

[0297] Example 112: 1 -Butyryl-N-(( 1 -(dimethylamino)cy clopentyl)methyl)-6-fluoroindoline-5-carboxamide (“58f”). Compound 58f was prepared from N-((l-(dimethylamino)cyclopentyl)methyl)-6-fluoroindoline-5-carboxamide (57) and butyryl chloride according to a similar procedure described for the synthesis of 58a:1H NMR (600 MHz, CDCh): 8 10.45 (s, 1H), 8.50 (bs, 1H), 7.86 (d, J = 12.5 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 4.17 (t, J = 8.5 Hz, 2H), 3.60 (d, J = 6.40 Hz, 2H), 3.14 (t, J = 8.30 Hz, 2H), 2.80 (d, J = 4.90 Hz, 6H), 2.47 (t, J = 7.1 Hz, 2H), 1.92-1.57 (m, 10H), 0.94 (t, J = 7.4 Hz, 3H); ESI MS m / z 376 [M+H]+; HPLC 97.7 % (purity), tR= 15.0 min.

[0298] Example 113: Expression and functional analysis of GlyT2 in Xenopus laevis oocytes. Stock solutions of 50 mM ORG25543, and 20 mM RPI-GLYT2-82 (l-Benzoyl-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)indoline-5-carboxamide (47a)) were dissolved in dimethyl sulfoxide (DMSO) and diluted in frog Ringer’s solution (96 mM NaCl, 2 mM KC1, 1 mM MgCh, 1.8 mM CaCh, 5 mM HEPES, pH 7.5) to desired concentrations. Final solutions included less than 0.001% DMSO, a concentration that had no effect on transporter function. Human GlyT2a wild type (herein referred to as hGlyT2) were subcloned into the plasmid oocyte transcription vector(pOTV). Purified plasmid DNAs were linearized with Spel (New England Biolabs, Catalogue number R3133S). Complementary RNA was transcribed by the T7 RNA polymerase using the mMESAGE mMACHINE T7 kit (Ambion, Cat# AMI 344). Stage V Xenopus laevis oocytes were detached from the lobe by digestion with 2 mg / mL collagenase A (Boehringer, Mannheim, Germany). Defolliculated stage V oocytes were injected with 20 ng of cRNA encoding hGlyT2 (Drummond Nanoinject, Drummond Scientific Co., Broomall, PA, USA). The oocytes were stored at 18°C in frog Ringer’s solution, which was supplemented with 2.5 mM sodium pyruvate, 0.5 mM theophylline, 50 mg / mL gentamicin and 100 mg / mL tetracycline for 3-6 days, until transporter expression was adequate for measurement using the two-electrode voltage clamp technique. Wholecell glycine transport currents were recorded at -60 mV using a Geneclamp 500 amplifier (Axon Instruments, Foster City, CA, USA) with a Powerlab 2 / 25 chart recorder (AD Instruments, Sydney, Australia). LabChart version 8 software (AD Instruments, Sydney, Australia) was used to process and visualize current traces. Glycine concentration (1-300 mM) dependent transport currents were measured for GlyT2 (n = 5). Cumulative inhibitor concentration-dependent transport current responses were measured for ORG25543 (0.3-300 nM) and new inhibitors (0.01-10 mM). The substrate EC50 for hGlyT2 was applied and then increasing concentrations of inhibitor were coapplied.

[0299] Example 114: Electrophysiology data analysis. Data was analyzed using GraphPad Prism 10 (version 4.0, GraphPad Software, San Diego, USA). Currents for each cell were normalized to the current generated by a maximal substrate concentration to account for the difference in transporter expression between cells, n refers to biological samples and not technical replicates. The EC50 for glycine transport by hGlyT2 was determined using the Equation 1 below:Elmax = [Gly] / (ECso + [Gly]) (Equation 1)where I is the change in current from baseline (nA), and Imax is the current generated by a maximal glycine concentration as determined by Michaelis-Menten kinetics.

[0300] Example 115: Reversibility and transport recovery assessment via a washout time course assay. Reversibility was determined by using the previously determined IC50. Transport recovery data was generated via a cellular washout time course assay using the two-electrode voltage-clamp assay previously described. This protocol provides measurable time course data with which to accurately compare relative levels of reversibility and surmountability for newly synthesizedcompounds. The assay protocol involves application of the EC50 concentration of glycine to oocytes to determine the maximal current. The glycine EC50 for hGlyT2 was applied and then the IC50 of the inhibitor was co-applied until the current plateaued. The cell was then continuously perfused with frog Ringer's solution to wash out the inhibitor from the bath solution. Every 5 min, glycine (EC50) was re-applied for 1 min, and repeated for a total wash period of 30 min or until complete transporter recovery. Transport recovery is presented as Vlmax, where Imax is the current produced by glycine in the absence of inhibitor.Table 1: GlyT2 IC50 and washout half-life for select compounds.The IC50 values for inhibitors were determined using Equation 2 below:VIEC50 = Bottom + (Top- Bottom) / (l+10(x-logIC5o)) (Equation 2)

[0301] Example 116: Referring now to FIG. 23, compound 47a (RPI-GLYT2-82) consistent with embodiments of the present disclosure has been demonstrated to be a non-competitive inhibitor of GlyT2. Glycine concentration-dependent transport currents were measured in the absence and presence of increasing concentrations of compound 47a (RPI-GLYT2-82) and fit to Equation 3 below:I / I3oo / [Gly] = [Gly] / (ECso + [Gly]) (Equation 3)

[0302] Compound 47a caused a concentration dependent reduction in the maximal rate of transport with no significant change in the EC50 for glycine, indicating a non-competitive mechanism of inhibition of transport. There was no statistically significant difference in the glycine EC50 values across all four conditions (p = 0.49) but there was a statistically significant reduction in Imaxbetween 0 nM RPI-GLYT2-82 (mean Imax ± SEM= 1.07 ± 0.01) and the Imax at 600 nM RPI-GLYT2-82 (mean Imax± SEM= 0.76 ± 0.04) (p < 0.0001) and also the Imaxat 1.8 pM RPI-GLYT2-82 (mean Imax ± SEM= 0.39 ± 0.02) (p < 0.0001). Data was analysed using nonlinear regression.In Vitro ADME Assay Information

[0303] Example 117: Kinetic Solubility Assay. Kinetic aqueous solubility determination in PBS (pH 7.4) was conducted using UV detection (230 nm). Aqueous solubility (pM) was determined by comparing the peak area of the principal peak in a calibration standard (200 pM) containing organic solvent (methanol / water, 60 / 40, v / v) with the peak area of the corresponding peak in a buffer sample. In addition, chromatographic purity (%) was defined as the peak area of the principal peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard. A chromatogram of the calibration standard of each test compound, along with a UV / VIS spectrum with labeled absorbance maxima, was generated. The standards used for the kinetic solubility study were amiodarone and propranolol.

[0304] Example 118: Thermodynamic Solubility in PBS. Thermodynamic aqueous solubility determination in PBS (pH 7.4) (shake flask, flask Standard Curve Range 1 mM - 2 mM) was conducted using UV detection (230 nm). UV detection A chromatogram of the testcompound (200 pM) along with a UV / VIS spectrum with labeled absorbance maxima, was generated. Aqueous solubility (pM) was determined by comparing the peak area of the principal peak in a calibration standard (200 pM) containing organic solvent (methanol / water, 60 / 40, v / v) with the peak area of the corresponding peak in a buffer sample. In addition, chromatographic purity (%) was defined as the peak area of the principal peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard. A chromatogram of the calibration standard of each test compound, along with a UV / VIS spectrum with labeled absorbance maxima, was generated.

[0305] Example 119: CYP Inhibition Assay. Inhibition potential (IC50 values) results against the human cytochrome P450 (CYP) isoforms 2C9, 2C19, 2D6, and 3A4, were run. Each recombinant human CYP isoform was tested with a standard positive and negative control, using fluorometric detection for measuring CYP activity. The measured IC50 values for the respective standard inhibitors were all within expected ranges for each isoform (see below).IC50 Concentrations of Standard CYP Inhibitors:CYP Inhibitor IC50 (pM):2C9 Sulfaphenazole IC50 = 3.4 pM2C19 Oxybutynin IC5o= 9.5 pM2D6 Quinidine ICso= 0.058 pM3A4 Ketoconazole IC50 = 0.0084 pM

[0306] Pre-formulated NADPH regenerating solutions, recombinant CYP isoforms 2C19 and 3A4 (Lot# 3007790 and 2276593 respectively), 3-[2-(N, N-diethyl-N-methylamino)ethyl]-7-methoxy-4-methylcoumarin (AMMC), 3 -cyano-7-ethoxy coumarin (CEC) and 7-benzyloxy-4-trifluorom ethylcoumarin (BFC) were obtained from Corning Life Sciences (Bedford, MA).Recombinant CYP isoform 2D6 (Lot # 49242) was obtained from Invitrogen (Carlsbad, CA). CYP isoform 2C9 (Lot # 0446966-1) was obtained from Cayman Chemical (Ann Arbor, MI). 7-methoxy-4-trifluoromethylcoumarin (MFC), trans-2-phenylcyclopropylamine HC1 (TCP), sulfaphenazole (SFZ), ketoconazole (KTZ) and quinidine (QDN) were obtained from Sigma (St. Louis, MO). All solvents and buffers were obtained from commercial sources and used without further purification.

[0307] Cytochrome P450 Inhibition (HPLC-UV / VIS and HPLC-MS / MS detection): Test compound was prepared as a 10 mM stock solution in acetonitrile. Four human P450 isoforms cDNA-expressed in insect cell microsomes (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) were tested for inhibition by test compound using fluorescence-based assays. Nine serial dilutions (concentrations from 0-100 mM) using each test compound stock solution were prepared in black microtiter plates, in duplicate. This dilution series was incubated at 37°C with the individual CYP isoforms and a standard fluorogenic probe substrate for each respective isoform. The concentration of the probe substrate added was at or near the Kmvalue for each CYP isoform. Reaction mixtures contained potassium phosphate buffer, pH 7.4 and the NADPH-regenerating system. The final reaction volume was 0.20 mL and the reaction was terminated with 75 mL of stop solution (0.5 M Tris base in acetonitrile) after the appropriate incubation time (15-45 min). Fluorescence measurements were made at the appropriate excitation and emission wavelengths. Duplicate control wells with no test compound, duplicate blank wells containing stop solution prior to adding isoform, and a dilution series in duplicate containing a standard inhibitor for each isoform were also conducted. IC50 values were calculated using a non-linear regression of the data using the four-parameter logistic model (dose response equation) fit with XLFit 5.2 from IDBSSoftware (Emeryville, CA), supported by linear interpolation of data points at concentrations indicating inhibition levels approximately 50% of the uninhibited rate. Peak areas corresponding to the metabolite of each substrate were recorded. The percentage of control activity was thencalculated by comparing the peak area obtained in the presence of the test compound to that obtained in the absence of the test compound. Subsequently, the percent inhibition was calculated by subtracting the percent control activity from 100 for each compound. IC50 values (concentration causing a half-maximal inhibition of control values) were determined by non-linear regression analysis of the concentration-response curve using Hill equation curve fitting.

[0308] Example 120: Plasma Protein Binding Assay. Plasma protein binding (PPB) was conducted using equilibrium dialysis of plasma with HPLC-UV / Vis detection.

[0309] Mean Plasma Protein Binding of Control Propranolol in Human, Rat, and Mouse Plasma:

[0310] The peak areas of the test compound in the buffer and test samples were used to calculate percent binding and recovery according to the following Equations 4 and 5:(Equation 4)(Equati on 5 )Area-where Areap= Peak area of analyte in protein matrix; Areab = Peak area of analyte in buffer; Areac = Peak area of analyte in control sample.

[0311] Example 121: Metabolic Stability in Liver Microsomes. The results of metabolic stability determinations for compounds consistent with embodiments of the present disclosure and testosterone (positive control) were conducted in the presence of human, rat, and mouse liver microsomes. Values shown below are percent of parent remaining after a 30 min incubation. All measurements were done in duplicate. Assay results for testosterone were within an acceptable range. Mixed-gender human liver microsomes (Lot# 1710084), male Sprague-Dawley rat liver microsomes (Lot# 1610290), and male CD-I mouse liver microsomes (Lot# 1710069) microsomes (Lot# 1510193) were used. The reaction mixture, minus NADPH, was prepared as described below. The test article was added into the reaction mixture at a final concentration of 1 mM. The control compound, testosterone, was run simultaneously with the test article in a separate reaction. An aliquot of the reaction mixture (without cofactor) was equilibrated in a shaking water bath at 37°C for 3 min. The reaction was initiated by the addition of cofactor, and the mixturewas incubated in a shaking water bath at 37°C. Aliquots (100 mb) were withdrawn at 0, 10, 20, 30, and 60. Test article and testosterone samples were immediately combined with 400 pL of ice-cold 50 / 50 acetonitrile (ACN) / H20 containing 0.1% formic acid and internal standard to terminate the reaction. The samples were then mixed and centrifuged to precipitate proteins. All samples were assayed by LC-MS / MS using electrospray ionization. The peak area response ratio (PARR) to internal standard was compared to the PARR at time 0 to determine the percent remaining at each time point. Half-lives were calculated using GraphPad software, fitting to a single-phase exponential decay equation.

[0312] Intrinsic Clearance (microsomes, S9, cryopreserved hepatocytes, recombinant CYP, recombinant UGT) metabolic stability, expressed as percent of the parent compound remaining, was calculated by comparing the peak area of the compound at the time point relative to that at time-0. The half-life (T1 / 2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming the first-order kinetics. The apparent intrinsic clearance (CLint, in pL / min / pmol, pL / min / mg or pL / min / Mcell) was calculated according to the following Formula II:(Formula II)

[0313] Example 122: Mouse %Brain Tissue Homogenate Binding. Mouse %brain tissue homogenate binding in PBS (pH 7.4) was conducted using equilibrium dialysis with HPLC-MS-MS detection. In each experiment and if applicable, the respective reference compound was tested concurrently with select GlyT2 inhibitors, and the data were compared with historical values."Kinetic solubility measured in PBS (pH= 7.4). ^Microsomal intrinsic clearance (CLmt); H = human; R = rat; M = mouse. "Plasma stability, % of parent drug remaining after a 120-minute incubation in respective plasma, H = human, M = mouse:d%PPB = plasma protein binding; H = human, R = rat, M = mouse.Table 2: In Vitro ADME Profile for compound 22a."Thermodynamic solubility measured in PBS (pH= 7.4). ^Microsomal intrinsic clearance (CLmt); H = human; R = rat; M = mouse. "Plasma stability, % of parent drug remaining after a 120-minutc incubation in respective plasma, H = human, M = mouse;J%PPB = plasma protein binding; H = human, R = rat, M = mouse.Table 3: In Vitro ADME Profile for compound 47a (RPI-GLYT2-82).

[0314] Example 123: Mouse PK Study and Tn Vivo Exposure Studies.

[0315] Plasma Pharmacokinetics (PK). PK studies were performed in male ICR mice following intraperitoneal (i.p.) administration The serial plasma samples were collected at 1, 2, 4, 6 and 24 hours(h) after i.p. administration from three animals at each time point.

[0316] Equipment: Agilent Poroshell 120 EC-C18 column (2.7 pm, 3.0 x 50 mm; Agilent Technologies, Inc., USA), Animal cage (Allentown, USA), BD® lithium heparin tube (BD®, USA), Centrifuge 5810R (Eppendrof, Germany), Centrifuge tube (50 m; Labcon, USA), Disposal syringe (1 mL, Terumo Corporation, Japan), Electronic scale (0-1000 g; Tanita Corporation, Japan), Gilson pipettes (# P200 Neo-PION Micro Pipette; Gilson, France), Goldenrod animal lancet (4 mm, Goldenrod Corporation, USA), LC-MS / MS Triple Quad™ 5500+ (SCIEX, USA), Microcentrifuge tubes 1.5 mL click-cap (Treff AG, Switzerland), Pipette (# P200 Gilson, France), Pipettetips (Costar, USA), Polypropylene 96-well round U-bottom deep well plates and silicone microplate lids (StorPlate-96 U and StorMat-96; PerkinElmer Inc., USA), RAININ pipettes (E4 Multi E12-50XLS+, E12-300XLS, Refurbished Rainin E4™ XLS™ electronic 12 channel pipette, 30-300 pL, E4 Pipette Multi E12-1200XLS+, and EA6-300XLS; RAININ, USA), and Stop watch (Casio, China).

[0317] Dosing vehicle: 5% Solutol® HS-15 / 95% PBS.

[0318] Dosing Solution Analysis: The dosing solutions were analyzed by LC-MS / MS. The measured dosing solution concentrations are shown in Table 1 above. The dosing solutions were diluted into mouse blood and analyzed in triplicate. All concentrations are expressed as mg / mL. The nominal dosing level was used in all calculations.

[0319] Species and strain: mouse; male ICR.

[0320] Number: 3 animals.

[0321] Male ICR mice weighing 30 ± 5 g were provided by BioLasco Taiwan Co., Ltd. Animals were acclimated for 3 days prior to use and were confirmed to be in good health. The animals were housed in animal cages with a space allocation of 30 x 19 x 13 cm. All animals were maintained in a controlled temperature (20 - 24°C) and humidity (30% - 70%) environment with 12-h light / dark cycles. Free access to standard lab diet [MFG (Oriental Yeast Co., Ltd., Japan)] and autoclaved tap water were granted.

[0322] Plasma Sample Collection from Mice (Serial Sampling). Blood aliquots were collected via facial vein ( about 0.05 mL) for the first four time points or cardiac puncture (about 0.3 mL) for the last time-point from mice in tubes coated with lithium heparin, mixed gently, and centrifuged at 2,500 xg for 15 minutes at 4°C, within 1 h of collection. The plasma samples were then harvested and kept frozen at <-70°C until further processing. The plasma samples were processed using acetonitrile (ACN) precipitation and analyzed by LC-MS / MS.

[0323] The exposure levels (ng / mL) of compound in plasma samples were then determined by LC-MS / MS. Plots of plasma concentrations (mean ± SD) vs. time for compound 47a (RPLGLYT2-82) were constructed. The fundamental PK parameters after IP administration were obtained from the NCA of the plasma data using WinNonlin (best-fit mode).

[0324] In Vivo Plasma-Brain Level (PBL) Study. A plasma and brain PK study was performed in male C57BL / 6 mice following intraperitoneal (i.p.) administration of select compound. The brain and plasma samples were collected at 0.5 and 2 hours (h) after TP administration from three alternative animals at each time point.

[0325] Equipment: 0-1000 g Electronic scale (Tanita Corporation, Japan), Animal cage (Allentown, USA), Agilent Poroshell 120 EC-C18 column (2.7 pm, 3.0 x 50 mm; Agilent Technologies, Inc., USA), BD® lithium heparin tube (BD®, USA), Centrifuge 5810R (Eppendrof, Germany), Disposal syringe (1 mb, Terumo Corporation, Japan), Gilson pipettes (# P200 Neo-PION Micro Pipette; Gilson, France), Goldenrod Animal Lancet (4 mm, Goldenrod Corporation, USA), LC-MS / MS Triple Quad™ 5500+ (SCIEX, USA), Microcentrifuge tubes 1.5 mL click-cap (Treff AG, Switzerland), NEPHELOstar® microplate reader (BMGLabTech, Germany), Pipetman (# P200 Gilson, France), Pipette tips (Costar, USA), Polypropylene 96-well round U-bottom deep well plates and silicone microplate lids (StorPlate-96 U and StorMat-96; PerkinElmer Inc., USA), RAININ pipettes (E4 Multi E12-50XLS+, E12-300XLS, Refurbished Rainin E4™ XLS™ electronic 12 channel pipette, 30-300 pL, E4 Pipette Multi E12-1200XLS+, and EA6-300XLS; RAININ, USA), and Stop watch (Casio, China).

[0326] Dosing vehicle: 5% Solutol® HS-15 / 95% PBS.

[0327] Dosing Solution Analysis: The dosing solutions were analyzed by LC-MS / MS. The measured dosing solution concentrations are shown in Table 1 above. The dosing solutions were diluted into mouse blood and analyzed in triplicate. All concentrations are expressed as mg / mL. The nominal dosing level was used in all calculations.

[0328] Species and strain: mouse; male C57BL / 6.

[0329] Number: 6 animals.

[0330] Male C57BL / 6 mice weighing 22 ± 2 g were provided by BioLasco Taiwan Co., Ltd.Animals were acclimated for 3 days prior to use and were confirmed to be in good health. The animals were housed in animal cages with a space allocation of 30 x 19 x 13 cm. All animals were maintained in a controlled temperature (20 - 24°C) and humidity (30% - 70%) environment with 12-h light / dark cycles. Free access to standard lab diet [MFG (Oriental Yeast Co., Ltd., Japan)] and autoclaved tap water were granted.

[0331] Plasma Sample Collection from Mice (Parallel). Animals were terminated under inhalant euthanasia with CO2 for blood collection by cardiac puncture. Blood aliquots (about 0.3 mL) were collected in tubes coated with lithium heparin, mixed gently, then kept on ice and centrifugedat 2,500 xg for 15 minutes at 4°C, within 1 h of collection. The plasma was then harvested and kept5 frozen at <-70°C until further processing.

[0332] Brain Sample Collection from Mice. Immediately after the blood sampling, the whole brain was quickly removed, rinsed with cold saline (0.9 % NaCl), blotted with dry gauze, weighed, andstored at <-70°C until further processing within 1 h of collection. Each brain sample washomogenized in 0.2 mL of cold PBS, pH 7.4 on ice. The brain homogenate from each brain was0 then stored at < -70°C until further processing.

[0333] Referring now to FIG. 24 and Table 4 identified therein, PK data is provided for compound22a, represented as the mean ± standard deviation. For Study 1, a dose group including 3 drug naive adult male ICR mice was used. For Study 2, two dose groups of 3 drug naive adult male ICR mice were used for plasma and brain drug concentration determination at the 30 min and 120 min time5 points. Data for the 30 min time points are shown. Test article vehicle: 5% DMSO / 5% Solutol®HS-15 / 90%.

[0334] Referring now to Table 5 below, PK data is provided for compound 47a (RPI-GLYT2-82), represented as the mean ± standard deviation. For Study 1, a dose group of 3 drug naive adult maleICR mice was used. For Study 2, two dose groups of 3 drug naive adult male ICR mice were used0 for plasma and brain drug concentration determination at the 30 min and 120 min time points. Datafor the 30 min time points are shown. Test article vehicle: 5% DMSO / 5% Solutol® HS-15 / 90%.Table 5: Mouse In Vivo Exposure Data for 47a (RPI-GLYT2-82) Upon Intraperitoneal (i.p.)Dosing.5

[0335] Referring now to Table 6 below, PK data is provided for compound 47a (RPLGLYT2-82), represented as the mean ± standard deviation. Male C57BL6 mice (3 per group) were used. Data for the 30 min time points are shown. Test article vehicle: 5% DMSO / 5% Solutol® HS-15 / 90%.5 Table 6: Mouse In Vivo Exposure Data for 47a (RPLGLYT2-82) Upon Oral (p.o.) Dosing.

[0336] Example 123: Referring now to FIGs. 25 and 26, the behavioral effects of GlyT2 Inhibitor compounds consistent with embodiments of the present disclosure were tested In Vivo utilizing the Chronic Constriction Injury (CCI) and Partial Nerve Ligation Mouse Models of Neuropathic 10 Pain (PSNL). The CCI model of peripheral mononeuropathy was originally developed to offer a model that, unlike the existing neuroma model employing complete deafferentation, retained some intact peripheral nerve connections. Thus, CCI better replicated clinical neuropathic pain syndromes, as opposed to deafferentation pain, and generated common clinical symptoms of hyperalgesia, allodynia, and possible dysesthesia that are absent upon total deafferentation. In this 15 model, the sciatic nerve is loosely constricted with chromic-infused catgut ligatures, or more recently, with a polyethylene cuff. The CCI model replicates pain conditions wherein compression and strangulation of a nerve bundle results in damaged nerve fibers lying alongside intact nerves. The original ligature-CCI model is a mixed neuropathic / inflammatory pain model, as the chromium / pyrogallol infusion in the catgut introduces a strong inflammatory component, while the 20 cuff-CCI is an exclusively neuropathic pain model. The PSNL model was first developed for use in rats and later adapted for use in mice. The sciatic nerve is partially injured such that 1 / 3 to 1 of the nerve is tightly ligated with a silk suture. Animals rapidly exhibit pain-related behaviors such as allodynia and hyperalgesia to both thermal and mechanical stimuli, as well as spontaneous pain-like behaviors.

[0337] Referring specifically to FIG. 25, the behavioral effects of compound 22a on CCI Mice are shown. Analgesic effects of compound 22a in CCI mice are shown in (A). A single 0.4 gram-force von Frey filament, determined to elicit a response rate of 15% in naive mice, was used. The filament was applied to the plantar surface of the left hind paw until it bent for a duration of up to 5 sec. A positive response was recorded if a mouse flinched, licked, or vigorously shook the hind paw. The % response to 10 separate applications of the filament, with 20-sec intervals between applications, was recorded as the allodynia score. Motor coordination assessment via rotarod performance accelerating from 4 -40 rpm for 180 sec is shown in (B). Data shown as mean ± SEM. Two-way ANOVA with Dunnett’s multiple comparison post hoc test was conducted between mice administered saline and every other group. Significance is denoted as: * = p < 0.05, ** = p < 0.01, and *** = p < 0.001.

[0338] Referring specifically to FIG. 26, the behavioral effects of compound 47a (RPI-GLYT2-82) on CCI and PSNL Mice are shown. As shown in (a), compound 47a (RPI-GLYT2-82) reduced response rate to von Frey stimulus in CCI mice. Two-way ANOVA with Dunnett’s multiple comparison post hoc test was conducted between mice administered vehicle and every other group. ANOVA showed significant effects of time (p < 0.001; F (5, 149) = 27.3) and treatment (p < 0.001; F (3, 28) = 48.3), and an interaction effect (p < 0.001; F (21, 196) = 6.30). Both 50 and 100 mg / kg (i.p.) doses demonstrated efficacy against mechanical allodynia, significant at 2 and 3 hours postinjection compared to vehicle (p < 0.01 & p < 0.001). The 50 mg / kg dose was also significant at 30 minutes (p < 0.01). Both doses peaked at 3 hours, with 30% and 42% reductions, respectively. As shown in (b), compound 47a (RPI-GLYT2-82) reduced response rate to von Frey stimulus in PSNL mice. Two-way ANOVA showed significant main effects of time (p < 0.001; F (4, 46) = 12.7) and treatment (p < 0.001; F (2, 13) = 20.8), and an interaction effect (p < 0.001; F (14, 91) = 5.86). A 50 mg / kg (i.p.) dose reduced mechanical allodynia, significant at 90 minutes and 2-hours post-injection compared to vehicle (p < 0.05). This effect peaked at 90 mins, with 22.5% reductions. As shown in (c), compound 47a (RPI-GLYT2-82) reduced response rate to acetone stimulus in CCI mice. Two-way ANOVA with Dunnett’s multiple comparison post hoc test was conducted between CCI model mice administered vehicle and every other group. ANOVA showed significant main effects of time (p < 0.0001; F (4, 93) = 25.8) and treatment (p < 0.0001; F (3, 26) = 21.8, along with an interaction effect (p < 0.0001; F (11, 93) = 4.4). Both 50 and 100 mg / kg (i.p.) doses demonstrated efficacy in reducing cold allodynia, significant between 0.5 and 6-hours postinjection compared to vehicle (p < 0.05-0.001). Gabapentin was also significant at 1-6 hours (p<0.05-0.001). Alltreatments peaked by the 2-hour time point, with 59%, 62% and 75% reductions, respectively. As shown in (d), compound 47a (RPI-GLYT2-82) caused a transient reduction in rotarod performance at 250 mg / kg. As shown in (e), compound 47a (RPLGLYT2-82) produced transient forelimb muscle weakness at 250 mg / kg but not at 50 mg / kg, 30 min post-injection which was recovered at the 60-minute time point. As shown in (f), compound 47a (RPI-GLYT2-82) produced transient sedation at maximal dose. As shown (g) - (i), compound 47a (RPI-GLYT2-82) (50 mg / kg and 250 mg / kg) was examined against positive morphine control (10 mg / kg) and vehicle (saline). Activity of compounds using whole-body plethysmography, measuring (g) respiratory frequency, (h) minute volume, and (i) tidal volume. Two-way ANOVA with Dunnett’s multiple comparison post-hoc test conducted between mice administered saline and every other group. As shown in (h), compound 47a (RPI-GLYT2-82) did not increase preference in a conditioned place preference paradigm. Compound 47a (RPI-GLYT2-82) (50 and 150 mg / kg) was compared to positive morphine control (10 mg / kg) and vehicle (5% Solutol, 95% PBS). One-way ANOVA with Dunnett’s multiple comparison post-hoc test conducted between mice administered vehicle and every other group. Data shown as mean ± SEM. Significance is denoted as: *, p < 0.05; **, p < 0.01; ***, p < 0.001. n = biological replicates.

[0339] Systems and methods of the present disclosure advantageously provide a class of competitive and reversible GlyT2 inhibitors that demonstrate a differentiated pharmacological profile from earlier inhibitors, e.g., ORG25543. ORG25543 and genetic GlyT2 knockout paradigms can elicit neuromotor or excitatory adverse effects. To overcome these challenges, SAR- and SKR-driven hit-to-lead campaigns were used to design improved, competitive and reversible GlyT2 inhibitors with improved drug-like characteristics and demonstrates a differentiated pharmacological profile.

[0340] Compounds consistent with embodiments of the present disclosure provide potent anti-allodynic efficacy in two gold-standard preclinical models of neuropathic pain, the CCI and PSNL mouse models. Moreover, in the mouse CPP paradigm, these compounds lack rewarding properties, further supporting its role as a non-addictive analgesic. The compounds display favorable oral bioavailability, metabolic stability, reversibility, and overall drug-like properties, thereby overcoming limitations of earlier tool compounds. One exemplary compound, referred to herein as compound 47a or “RPI-GLYT2-82,” exhibits potent anti-allodynic efficacy in the CCI and PSNLmouse models. Unlike ORG25543 and genetic GlyT2 knockout paradigms, RPI-GLYT2-82 does not elicit neuromotor or excitatory adverse effects.

[0341] Restoring glycinergic neurotransmission in these pathways will reduce mechanical hypersensitivity and allodynia and multiple lines of experimental evidence support this hypothesis. The compounds described herein are shown to possess properties useful for safe, efficacious, and orally bioavailable non-opioid analgesics for the treatment of neuropathic pain.

[0342] Although the invention has been described and illustrated with respect to exemplary embodiments thereof, it should be understood by those skilled in the art that the foregoing and various other changes, omissions and additions may be made therein and thereto, without parting from the spirit and scope of the present invention.

Claims

CLAIMSWhat is claimed is:

1. A glycine transporter 2 (GlyT2) inhibitor compound comprising a structure according to Formula (I):wherein:Ri and R2 are each independently hydrogen or Ci-Ce alkyl, or Ri and R2 together with a carbon atom to which they are attached form a 3-, 4-, 5- or 6- membered heterocycle; and combinations thereof;R3 and R4 are each independently hydrogen, deuterium, Ci-Cnalkyl, or R3 and R4 together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered carbocycle or heterocycle; and combinations thereof;Rs, Re, and R7 are selected from the group consisting of:hydrogen; halogen; deuterium; Ci-Cnalkyl; cycloalkyl; aryl or heteroaryl; -OR12, -NR12R13, -NR C(O)RI2, -S(O)RI2, -SO2R12, -CN, -C(0)Ri2, -C(O)NRi2Ri3, C(0)Ri2, or -NRI2C(S)RI3; 4-, 5- or 6- membered heterocycle containing one to two heteroatoms including oxygen, nitrogen and sulfur; and combinations thereof;Rs and R9 are selected from the group consisting of:hydrogen; halogen; deuterium; Ci-Cnalkyl; cycloalkyl; Rs and R9 together with the carbon atom to which they are attached form a 3-, 4-,5- or 6-membered carbocycle or heterocycle; aryl; heteroaryl; -OR12, - NR12R13, -NRC(0)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(0)Ri2, - C(O)NRi2Ri3, C(0)Ri2, or -NRI2C(S)RI3; 4-, 5- or 6- membered heterocycle containing one to two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; oxo or thio; and combinations thereof;Rio is selected from the group consisting of:hydrogen; halogen; deuterium; Ci-Cnalkyl; cycloalkyl; C5-C12 fused or spirocarbocycle or heterocycle; aryl; heteroaryl, -OR12, -NR12R13, - NR C(0)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)RI2, -C(O)NRi2Ri3, C(0)Ri2, or -NRi2C(S)Ri3; 4-, 5- or 6- membered heterocycle containing one to two heteroatoms including oxygen, nitrogen and sulfur; and combinations thereof;R11 is selected from the group consisting of:hydrogen; halogen; deuterium; gew-di alkyl; gem-dihalo, -OR12, - NR12R13, -NRC(0)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(0)Ri2, - C(O)NRi2Ri3, C(0)Ri2, or -NRi2C(S)Ri3; 4-, 5- or 6- membered heterocycle containing one to two heteroatoms including oxygen, nitrogen and sulfur; oxo or thio; and combinations thereof;R12 is selected from the group consisting of:hydrogen; halogen; Ci-Cnalkyl, Ci-Cnalkenyl, Ci-Cnalkynyl, C3-C7 cycloalkyl, or C4-C7 cycloalkylalkyl; aryl; heteroaryl; and combinations thereof;R13 is selected from the group consisting of:hydrogen; halogen; Ci-C„ alkyl, Ci-Cnalkenyl, Ci-Cnalkynyl, C3-C7 cycloalkyl, or C4-C7 cycloalkylalkyl; and combinations thereof, andA is a ring selected from a group consisting of:3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl,4-, 5-, 6-, 7-, or 8-membered heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;and combinations thereof.

2. The compound according to claim 1, wherein:the Ri and R2 heterocycle is substituted from 1 to 10 times with Rn;the R3 and R4 Ci-Cnalkyl is substituted from 1 to 10 times with Rn;the R3 and R4 carbocycle or heterocycle is substituted from 1 to 10 times with Rn;the Rs and R9 carbocycle or heterocycle is substituted from 1 to 10 times with Rn;the Rs, Re, and R7 Ci-Cnalkyl is substituted from 1 to 10 times with Rn;the R5, Re, and R7 cycloalkyl is substituted from 1 to 10 times with Rn;the Rs, Re, and R7 aryl or heteroaryl is substituted from 1 to 10 times with R;the R5, Re, and R74-, 5- or 6- membered heterocycle is substituted from 1 to 10 times with Rn;the Rs and R9 Ci-Cnalkyl is substituted from 1 to 10 times with Rn;the Rs and R9 cycloalkyl is substituted from 1 to 10 times with Rn;the Rs and R9 aryl or heteroaryl is substituted from 1 to 10 times with Rn;the Rs and R94-, 5- or 6- membered heterocycle is substituted from 1 to 10 times with Rn;the Rio Ci-Cn alkyl is substituted from 1 to 10 times with Rn;the Rio cycloalkyl is substituted from 1 to 10 times with Rn;the Rio C5-C12 fused or spirocarbocycle or heterocycle is substituted from 1 to 10 times with RH;the Rio aryl and heteroaryl is substituted from 1 to 10 times with Rn;the Rio 4-, 5- or 6- membered heterocycle is substituted from 1 to 10 times with Rn;the RH 4-, 5- or 6- membered heterocycle is substituted from 1 to 10 times with R12;the R12 Ci-Cn alkyl, Ci-Cnalkenyl, Ci-Cnalkynyl, C3-C7 cycloalkyl, or C4-C7 cycloalkylalkyl is substituted from one to eleven times with R13;the R12 aryl or heteroaryl is independently substituted from 1 to 7 times with R13;the A 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl is substituted from 1 to 12 times with R12;the A 4-, 5-, 6-, 7-, or 8-membered heterocycle is substituted from 1 to 10 times with R12,or combinations thereof.

3. The compound according to claim 1, wherein Ri and R2 are each individually CH3.

4. The compound according to claim 1, wherein:Ri and R2 are each individually CH3; andA is a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl or a 4-, 5-, 6- or 7-membered heterocycle containing a heteroatom including oxygen, nitrogen, and sulfur.

5. The compound according to claim 4, wherein the A 3-, 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered heterocycle are each substituted from one to ten times with R12.

6. The compound according to claim 1, wherein:Ri and R2 are each individually CH3; andA includes one or more of:

7. The compound according to claim 6, wherein R3 and R4 are each independently hydrogen, deuterium, or CH3.

8. The compound according to claim 7, wherein R3 and R4 are each independently hydrogen.

9. The compound according to claim 8, wherein R5, Re, and R7 are each independently hydrogen or fluorine.

10. The compound according to claim 9, wherein Rs and R9 are each independently hydrogen, deuterium, or oxo.

11. The compound according to claim 1, wherein:R5 and Re are each independently hydrogen or fluorine; andR7 is hydrogen.

12. The compound according to claim 11, wherein Rio is Ci-Cnalkyl, cycloalkyl, aryl,or heteroaryl.

13. The compound according to claim 12, wherein Rw is aryl or heteroaryl.

14. The compound according to claim 13, wherein Rio is aryl.

15. The compound according to claim 12, wherein:the Rio Ci-Cn alkyl is substituted from 1 to 10 times with Rn;the Rio cycloalkyl is substituted from 1 to 10 times with Rn;the Rio aryl is substituted from 1 to 10 times with Rn,-ORi2, -NR12R13, -NR C(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)Ri2, -C(O)NRI2R13, C(O)RI2, or -NRI2C(S)RI3;the Rio heteroaryl is substituted from 1 to 10 times with Rn,-ORi2, -NR12R13, -NR C(O)Ri2, -S(O)Ri2, -SO2R12, -CN, -C(O)Ri2, -C(O)NR12RI3, C(O)RI2, or - NRI2C(S)R13;or combinations thereof.

16. The compound according to claim 1, wherein:Ri and R2 are each individually CH3;A includes one or more of:R3and R4 are each independently hydrogen;R5, Re, are each independently hydrogen or fluorine;R7 is hydrogen;Rs and R9 are each independently hydrogen, deuterium, or oxo; andRio is aryl.

17. The compound according to claim 16, wherein Rs and R9 are oxo.

18. The compound according to claim 16, wherein the Rio aryl is substituted from 1 to 10 times with Rn.

19. A pharmaceutical composition including an amount of a compound according to claim 1 effective to produce a predetermined peak plasma concentration of the compound in a target.

20. A pharmaceutically acceptable salt of the compound according to claim 16.

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