Prodrugs of riluzole

Abstract

Provided for are prodrugs of riluzole and pharmaceutical compositions and methods of use thereof. The prodrugs have advantageous pharmacological properties for use in methods for treating glutamate-associated diseases or disorders, or other diseases or disorders, against which riluzole is known or expected to be effective, including central nervous system (CNS) disorders, neuropsychiatric disorders, and neurodegenerative disorders.

Description

PRODRUGS OF RILUZOLECROSS-REFERENCE TO RELATED APPLICATION

[0001] This international patent application claims priority to U.S. provisional patent application number 63 / 705,642, filed October 10, 2024, which is hereby incorporated by reference herein in its entirety.TECHNICAL FIELD

[0002] Provided for are prodrugs of riluzole and pharmaceutical compositions and methods of use thereof. The prodrugs have advantageous pharmacological properties for use in methods for treating glutamate-associated diseases or disorders, or other diseases or disorders, against which riluzole is known or expected to be effective, including central nervous system (CNS) disorders, neuropsychiatric disorders, and neurodegenerative disorders.BACKGROUND

[0003] Riluzole (sold under the trade name Rilutek®) is a generally non-toxic neuroprotective agent that acts in part as a glutamate modulator. Riluzole is FDA-approved for treatment of amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). Riluzole is also believed to be clinically relevant for the treatment of central nervous system (CNS) disorders such as depression / anxiety states, substance use disorders, neuropsychiatric disorders such as obsessive-compulsive disorder, and neurodegenerative disorders such as spinocerebellar ataxia. In addition, riluzole is believed to be clinically relevant for the treatment of cancers such as glioblastomas, prostate cancer, pancreatic cancer, melanoma and ovarian cancer.

[0004] The use of riluzole is constrained due to variable hepatic metabolism and a negative food effect when administered with meals. Additionally, riluzole has unfavorable pharmacokinetics / pharmacodynamics (PK / PD) and requires twice-daily dosing. These unfavorable characteristics have been improved by way of mono-, di-, and tri-peptide prodrugs of riluzole’ s primary amine group, which contain one, two, or three amine bonds respectively. Such prodrugs are taught in, for example, WO 2016 / 140878 to Wrobel et al., published September 9, 2016, corresponding to PCT / US2016 / 019773, filed February 26, 2016, which is incorporated by reference herein for its teachings on riluzole prodrugs. However, monopeptide prodrugs may undergo a spiro-cyclization process as described in Tetrahedron Letters, 2014, 55, 4193-4195 and some di-peptide prodrugs may have unsuitable cardiac liability as determined by activity in hERG assays. Certain tri-peptide prodrugs, suchas troriluzole, have low cardiac liability and are under development for neuropsychiatric and neurodegenerative disorders, among others. Advantageously, troriluzole has a PK / PD profile which allows for once-daily oral dosing. Still, the half-life is relatively short, and it would be advantageous to develop new classes of riluzole prodrugs which have even further improved PK / PD profiles for prolonged release of riluzole into the plasma of patients.

[0005] Provided for herein are prodrugs of riluzole of a new class, involving a synthetically- designed cleavage and release process which may involve two steps. These prodrug groups generally contain at least one amide bond and at least one ester bond. These prodrugs generally undergo an intramolecular process to release the active drug riluzole. The ester may be first converted to an alcohol by liver or blood esterases and lipases. The alcohol may then form a cyclic intermediate via an intramolecular nucleophilic mechanism to cleave the amide bond between riluzole and the prodrug moiety. Accordingly, prodrugs of the present invention may have improved PK / PD characteristics and improved methods of treatment for diseases associated with glutamate and / or glutamatergic activity for which riluzole treatment may be desirable or effective.SUMMARY

[0006] The disclosure relates to prodrugs of riluzole, and pharmaceutical compositions and methods of use thereof. The prodrugs contain a prodrug moiety attached to riluzole, where the prodrug moiety generally contains at least one amide bond and at least one ester bond. Advantageously, the prodrugs provide for prolonged release of riluzole for the treatment of diseases or disorders against which riluzole is known or expected to be effective. Certain non-limiting embodiments are described below, although it should be understood that these and other embodiments are provided for based upon the disclosure.

[0007] In an embodiment, provided for are riluzole prodrugs according to Formula I:or a pharmaceutically-acceptable salt thereof, whereinL is C3-C5 alkylene, C3-C5 heteroalkylene, -Q-T-, or -T-Q-, wherein L is optionally substituted at one or more positions with one or more -RL;Q is C4-C10 heterocycloalkyl or C4-C10 heteroaryl;T is C1-C4 alkyl or C2-C4 heteroalkylene;RLis, at each occurrence, independently selected from C1-C4 alkyl, C2-C4 heteroalkyl, an amino acid side chain, and carbonyl; andR4is C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5- C9 heteroaryl, each optionally substituted with one or more of -NH2, carbonyl, cyano, methyl, ethyl, propyl, hydroxyl, -O-PO3H2, -O-PCh CHa -O-SO3H, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, said C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl (which are present as optional substituents on the C1-C5 alkyl, C2- C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, more preferably on the C1-C5 alkyl or C2-C5 heteroalkyl) unsubstituted or mono-, di-, tri-, or polysubstituted with -NH2, carbonyl, cyano, methyl, ethyl, propyl, or hydroxyl; or R4is, together with the carbonyl to which it is attached, an amino acid or amino acid analogue.

[0008] In an embodiment of Formula I, RLis methyl, ethyl, propyl (including n-propyl or isopropyl), butyl (including n-butyl, s-butyl, tert-butyl, or isobutyl), or carbonyl (=0).

[0009] In some embodiments, L is a chain of between three to five atoms in length, where the chain of L may be non-cyclic or where L may comprise one or more rings. In some embodiments, L is a chain having three atoms in length and cyclization of the cleaved terminal ester as depicted in Formula I results in the release of a cyclic five-membered prodrug moiety byproduct. In some embodiments, L is a chain having four atoms in length and cyclization of the cleaved terminal ester results in the release of a six-membered prodrug moiety byproduct. In some embodiments, L is a chain having five atoms in length and cyclization of the cleaved terminal ester results in the release of a seven-membered prodrug moiety byproduct.

[0010] In an embodiment of Formula I, L is C3 heteroalkylene. In an embodiment, L is C4 heteroalkylene.

[0011] In an embodiment of Formula I, L is:, wherein RL1, RL2, RL3, RL4, and RL5are independently selected from -H, methyl, ethyl, isopropyl and an amino acid side chain.

[0012] In an embodiment of Formula I, L is Q-T, and Q is 5-membered or 6-membered heterocycloalkyl. In an embodiment, Q is:

[0013] In an embodiment of Formula I, T is C2 alkylene substituted with one or more RL. In further embodiments, T is -(C=O)-CHRL- or -(C=O)-CRL2, wherein each RLis independently selected from -H, methyl, ethyl, and isopropyl.

[0014] In an embodiment of Formula I, R4is methyl, ethyl, propyl, or butyl, optionally preceded by a linking group selected from -CH2- and -CH2-O-. In further embodiments, R4is oxane, tetrahydrofuran, pyrrolidine, pyridine, piperidine, imidazole, thiazole, dioxane, morpholine, or pyrimidine, optionally preceded by a linking group selected from -CH2- and - CH2-O-.In another aspect of the present disclosure, provided for are riluzole prodrugs according to Formula la:or a pharmaceutically acceptable salt thereof, wherein:Rla, Rlb, and R2are R’, orRlais R’ or absent, and Rlband R2combine to form C4-C10 heterocycloalkyl or C4-C10 heteroaryl;R’ is independently selected from, at each occurrence, -H, C1-C3 alkyl, C2-C3 heteroalkyl, and an amino acid side chain;R3aand R3bare independently -H, C1-C4 alkyl, and C2-C4 heteroalkyl; andR4is C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5- C9 heteroaryl, each optionally substituted with one or more of -NH2, carbonyl, cyano, methyl, ethyl, propyl, hydroxyl, -O-PO3H2, -O-PCh CHa -O-SO3H, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, said C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl (which are present as optional substituents on the C1-C5 alkyl, C2- C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, more preferably on the C1-C5 alkyl or C2-C5 heteroalkyl) unsubstituted or mono-, di-, tri-, or polysubstituted with -NH2, carbonyl, cyano, methyl, ethyl, propyl, or hydroxyl, or R4is, together with the carbonyl to which it is attached, an amino acid or amino acid analogue.

[0015] In an embodiment of Formula la, Rlaand Rlbare -H.

[0016] In an embodiment of Formula la, Rlband R2combine to form a C4-C10 heterocycloalkyl. In an embodiment, Rlband R2combine to form a C5 heterocycloalkyl or a Ce heterocycloalkyl. In an embodiment, Rlband R2combine to form a C5 heterocycloalkyl.

[0017] In an embodiment of Formula la, Rlband R2combine to form,

[0018] In an embodiment of Formula la, R2is methyl, ethyl, or propyl. In an embodiment, R2is methyl.

[0019] In an embodiment of Formula la, one of R3aand R3bis -H, and the other is methyl, ethyl, propyl, butyl. In an embodiment, R3aand R3bare methyl. In an embodiment, R3aand R3bare -H.

[0020] In an embodiment of Formula la, R4is methyl, ethyl, propyl, or butyl, optionally preceded by a linking group selected from -CH2- and -CH2-O-. In further embodiments, R4is oxane, tetrahydrofuran, pyrrolidine, pyridine, piperidine, imidazole, thiazole, dioxane, morpholine, or pyrimidine, optionally preceded by a linking group selected from -CH2- and - CH2-O-.

[0021] In another aspect, provided for are riluzole prodrugs according to Formula lb:or a pharmaceutically acceptable salt thereof, wherein:Rlais -H, C1-C3 alkyl, or C2-C3 heteroalkyl, or Rlais absent;Q is C4-C10 heterocycloalkyl or C4-C10 heteroaryl;R3aand R3bare independently -H, C1-C4 alkyl, and C2-C4 heteroalkyl;R4is C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5- C9 heteroaryl, each optionally substituted with one or more of -NH2, carbonyl, cyano, methyl, ethyl, propyl, hydroxyl, -O-PO3H2, -O-PChCCFfc -O-SO3H, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, said C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl (which are present as optional substituents on the C1-C5 alkyl, C2- C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, more preferably on the C1-C5 alkyl or C2-C5 heteroalkyl) unsubstituted or mono-, di-, tri-, or polysubstituted with -NH2, carbonyl, cyano, methyl, ethyl, propyl, or hydroxyl, or R4is, together with the carbonyl to which it is attached, an amino acid or amino acid analogue.

[0022] In an embodiment of Formula lb, Q is a 5-membered or 6-membered heterocycloalkyl.

[0023] In an embodiment of Formula lb, Q is:

[0024] In an embodiment of Formula lb, one of R3aand R3bis -H, and the other is methyl, ethyl, propyl, or butyl. In an embodiment, R3aand R3bare methyl. In an embodiment, R3aand R3bare -H.

[0025] In an embodiment of Formula lb, R4is methyl, ethyl, propyl, or butyl, optionally preceded by a linking group selected from -CH2- or -CH2-O-. In another embodiment, R4is oxane, tetrahydrofuran, pyrrolidine, pyridine, piperidine, imidazole, thiazole, dioxane, morpholine, or pyrimidine, optionally preceded by a linking group selected from -CH2- or - CH2-O-.

[0026] In further aspects, provided for are riluzole prodrugs, or pharmaceutically acceptable salts or stereoisomers thereof, selected from those described in Table 1 herein.

[0027] In another aspect, provided for are pharmaceutical compositions comprising a riluzole prodrug, and a pharmaceutically-acceptable carrier.

[0028] In further aspects, provided for are methods for treating a glutamate-associated disorders, comprising administering a therapeutically-effective amount of a riluzole prodrug, or a pharmaceutical composition comprising a therapeutically-effective amount of a riluzole prodrug, to a subject in need thereof.

[0029] In an embodiment, the glutamate-associated disorder is a central nervous system (CNS) disorder, a neuropsychiatric disorder, or a neurodegenerative disorder. In an embodiment, the glutamate-associated disorder is a central nervous system (CNS) disorder selected from depression and anxiety. In an embodiment, the glutamate-associated disorder is a neuropsychiatric disorder selected from obsessive-compulsive disorder (OCD). In an embodiment, the glutamate-associated disorder is a neurodegenerative disorder selected from spinocerebellar ataxia. In an embodiment, the spinocerebellar ataxia is selected from types 1, 2, 3, 6, 7, 8, and 10. In an embodiment, the spinocerebellar ataxia is spinocerebellar ataxia type 3. In an embodiment, the glutamate-associated disorder is cancer or a substance abuse disorder.

[0030] In further aspects, provided for are uses of a riluzole prodrug compound for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a glutamate-associated disorder. In an embodiment, the glutamate-associated disorder is a central nervous system (CNS) disorder, a neuropsychiatric disorder, or a neurodegenerative disorder. In an embodiment, the glutamate-associated disorder is a central nervous system (CNS) disorder selected from depression and anxiety. In an embodiment, the glutamate- associated disorder is a neuropsychiatric disorder selected from obsessive-compulsive disorder (OCD). In an embodiment, the glutamate-associated disorder is a neurodegenerative disorder selected from spinocerebellar ataxia. In an embodiment, the spinocerebellar ataxia is selected from types 1, 2, 3, 6, 7, 8, and 10. In an embodiment, the spinocerebellar ataxia is spinocerebellar ataxia type 3. In an embodiment, the glutamate-associated disorder is cancer or a substance abuse disorder.

[0031] In another aspect, provided for are methods of releasing riluzole into the plasma of a patient in need thereof, comprising: administering a riluzole prodrug or a pharmaceutical composition comprising a riluzole prodrug to the patient. In an embodiment, administering the riluzole prodrug causes the ester group of the prodrug (-O-(C=O))- to be cleaved to form a terminal reactive hydroxy group, and wherein the terminal reactive hydroxy group subsequently reacts intramolecularly to release riluzole into the plasma of the patient. In an embodiment, the intramolecular reaction is a cyclization reaction. In an embodiment, the cyclization reaction forms a 5, 6, or 7-membered ring which may be monocyclic if no ring is present on the parent prodrug moiety, or polycyclic such as bicyclic if one or more rings are present on the parent prodrug moiety.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIGs. 1 A-1D depict PK / PD curves for Compound 1 and riluzole from Compound 1 in mice. Plasma concentrations of Compound 1 after IV (FIG. 1 A) and PO (FIG. IB) administration, and the released riluzole after IV (FIG. 1C) and PO (FIG. ID) administration are shown on a logarithmic scale in ng / mL as a function of time (hours) on a linear scale.

[0033] FIG. 2 depicts an overlay of the FIG. IB and FIG. ID PK / PD curves to compare prodrug exposure and decomposition to the prolonged release of riluzole.

[0034] FIGs. 3A-3D depict PK / PD curves for Compound 13 and riluzole from Compound 13 in mice. Plasma concentrations of Compound 13 after IV (FIG. 3 A) and PO (FIG. 3B)administration, and the released riluzole after IV (FIG. 3C) and PO (FIG. 3D) administration are shown on a logarithmic scale in ng / mL as a function of time (hours) on a linear scale.

[0035] FIGs. 4A-4D depict PK / PD curves for Compound 24 and riluzole from Compound 24 in mice. Plasma concentrations of Compound 24 after IV (FIG. 4A) and PO (FIG. 4B) administration, and the released riluzole after IV (FIG. 4C) and PO (FIG. 4D) administration are shown on a logarithmic scale in ng / mL as a function of time (hours) on a linear scale.DETAILED DESCRIPTION

[0036] Provided for herein are riluzole prodrugs having improved PK / PD properties, including prodrugs having at least one amide bond and at least one ester bond in the prodrug group. The prodrug group generally is bound to the primary amine of riluzole by a peptide- like amide bond. The structure of riluzole (sold under the trade name Rilutek®) is shown below for reference:Riluzole

[0037] Advantageously, prodrugs of the present invention may provide for prolonged or enhanced release of riluzole into plasma of a patient. For example, the improved PK / PD properties may include advantageous Cmax, AUC, half-life, or other properties. The prodrugs generally have a prodrug moiety forming an amide bond with the -NFL group of riluzole. The prodrugs generally contain at least one amide bond and at least one ester.

[0038] For example, these prodrugs may undergo a release process involving conversion of the terminal ester (see, e.g., the right-most ester group (-O-(C=O)-) of Formulae I, la, and lb) to a hydroxyl followed by an intramolecular cyclization or other mechanism causing release of riluzole from the prodrug moiety. As will be described herein, the riluzole release characteristics of these prodrugs may provide for prolonged exposure to riluzole after administration. The variability in plasma concentration of the drug active riluzole is expected to be reduced. Prodrugs having prolonged half-life compared with riluzole can be considered as suitable for once-daily dosing, whereas riluzole generally requires twice-daily dosing.

[0039] Accordingly, embodiments of the present disclosure include prodrugs of riluzole, and pharmaceutical compositions and methods of use thereof. For example, provided for are compositions comprising a prodrug of riluzole and one or more pharmaceutically acceptableexcipients. Also provided for are methods of treating a disease indication associated with riluzole or glutamate modulation, comprising administering a therapeutically effective amount of a prodrug of riluzole to a patient or subject in need thereof.

[0040] Several disease indications associated with riluzole or glutamate modulation are contemplated, including but not limited to central nervous system (CNS) disorders, such as neurodegenerative disorders, neuropsychiatric disorders, pain, etc. These include, but are not limited to, bipolar disorder, treatment resistant and major depression, obsessive-compulsive disorder, general anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive disorders, dementia, agitation, apathy, psychoses, post-traumatic stress disorders, irritability, disinhibition, learning disorders, memory loss, personality disorders, bipolar disorders, Rett syndrome, eating disorders, conduct disorder, pain disorders, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, delirium, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, substance use disorders (such as alcohol or other drug addiction), tinnitus, mental retardation, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, hereditary spinocerebellar ataxia, spinocerebellar ataxia, sporadic ataxia, episodic ataxia, Friedreich Ataxia, Multisystem Atrophy, ataxia associated with anti-GAD antibodies and onconeural antigen, essential tremor, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, Progressive Supranuclear Palsy, Dementia with Lewy Bodies, and Huntington's disease.

[0041] “Neuropsychiatric disorders” could also include neurodegenerative or neurologic disorders including: Alzheimer's disease, limbic-predominant age-related TDP-43 encephalopathies (LATE), dementia, vascular dementia, mixed dementia, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis (ALS), pseudobulbar affect, agitation in Alzheimer's disease, dementia, cerebellar ataxia, hereditary ataxias, multiple sclerosis, Progressive Supranuclear Palsy, pain disorders, neuropathic pain, neuropathies, stroke, seizure, Fragile X, etc.

[0042] The neuropsychiatric symptoms may include anxiety, depression, obsessive compulsive disorder, stress, fatigue, feelings of panic, fear, uneasiness, problems in sleeping, cold or sweaty hands and / or feet, shortness of breath, heart palpitations, social phobia, fear of public speaking, an inability to be still and calm, dry mouth, numbness or tingling in the hands or feet, nausea, muscle tension, dizziness, apathy, elation, disinhibition, irritability, wandering, and the like. Additionally, neuropsychiatric symptoms could include: delusions,hallucinations, disorganized thinking or speech, derailment of focal topic or loose associations, incoherence, grossly disorganized or abnormal motor behavior (including catatonia), negative symptoms — reduced emotional expression, avolition, alogia, anhedonia, asociality, dyskinesias (including tardive dyskinesia), anhedonia and dysphoria, anger and aggression, or symptoms of dissociation, or some combination of these.

[0043] In particular embodiments, the prodrugs are useful in methods of treating ataxias. Ataxias generally cause gait dysfunction, altered speech, impaired coordination, imbalance, difficulty in locomotion, and other related symptoms. Ataxias are typically classified into hereditary and non-hereditary ataxias and typically affect the cerebellum, posterior column, pyramidal tracts, and basal ganglia, and may lead to decreased motoneuron function. In some embodiments, the ataxia is spinocerebellar ataxia (SC A), including types 1, 2, 3, 6, 7, 8, and 10. In some embodiments, the spinocerebellar ataxia is type 3 (i.e., SCA3). U.S. Patent Publication No. 2021 / 0023061 Al, published January 28, 2021, corresponding to U.S. Application No. 16 / 762,165 filed November 11, 2018 as PCT / US2018 / 060232 is incorporated by reference herein for its teachings on SCAs and its disclosure on and experimental examples demonstrating the effective treatment of SCAs with tripeptide prodrugs of riluzole.

[0044] In further particular embodiments, the prodrugs are useful in methods of treating obsessive-compulsive disorder (OCD). OCD is a chronic neuropsychiatric disorder having symptoms of intrusive thoughts or obsessions and repetitive behaviors (i.e., compulsions). Approximately 0.5% of US adults have OCD symptoms characterized as severe, with approximately 1% of adults overall having diagnosed OCD symptoms. Over half of patients are non-responsive to existing first-line treatments including cognitive behavioral therapy, selective serotonin reuptake inhibitors, and atypical antipsychotics. OCD is believed to be associated with glutamatergic hyperactivity and thus may be treated with a glutamate modulator such as riluzole.

[0045] A phase 2 / 3 study demonstrated that troriluzole (i.e., a tripeptide prodrug of riluzole) administered once daily as adjunctive therapy in OCD patients with inadequate response to standard of care showed consistent numerical improvement over placebo on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at all study timepoints (weeks 4 to 12). While the primary outcome measure at week 12 (p = 0.22 at week 12) was not met, it was significant at week 8 (p < 0.05). This study corresponds to ClinicalTrials.gov ID NCT03299166, last updated September 19, 2024. Based upon the improved PK / PD characteristics of prodrugswhich deliver the same drug active as tripeptide troriluzole, prodrugs of riluzole in the present invention are expected to have a similar or enhanced effect in OCD patients.

[0046] The disease indications associated with riluzole or glutamate modulation further include cancers. For example, these cancers may include glioblastomas, prostate cancer, pancreatic cancer, melanoma and ovarian cancer. In further embodiments, cancers may include Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinomas, Childhood cancers, AIDS-Related Cancers, Kaposi Sarcoma, AIDS-Related Lymphoma, Primary CNS Lymphoma, Anal Cancer, Astrocytomas, Atypical Teratoid / Rhabdoid Tumor, Basal Cell Carcinoma, Skin Cancer (Nonmelanoma), Bile Duct Cancer, Bladder Cancer, Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Stem Glioma, Atypical Teratoid / Rhabdoid Tumor, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma, Ependymoma, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Non-Hodgkin Lymphoma, Carcinoid Tumor, Gastrointestinal Carcinoma, Cardiac (Heart) Tumors, Primary Lymphoma, Cervical Cancer, Cholangiocarcinoma, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Neoplasms, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma, Mycosis Fungoides and Sezary Syndrome, Ductal Carcinoma In Situ (DCIS), Embryonal Tumors, Endometrial Cancer, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Eye Cancer, Intraocular Melanoma, Retinoblastoma, Fallopian Tube Cancer, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor, Ovarian, Testicular, Gestational Trophoblastic Disease, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer, Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma, Kidney, Renal Cell, Wilms Tumor, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Acute Lymphoblastic (ALL), Acute Myeloid (AML), Chronic Lymphocytic (CLL), Chronic Myelogenous (CML), Hairy Cell, Lip and Oral Cavity Cancer, Liver Cancer (Primary), Lung Cancer, Non-Small Cell, Small Cell, Lymphoma, Hodgkin, Non-Hodgkin, Macroglobulinemia, Waldenstrom, Male Breast Cancer, Melanoma, Merkel Cell Carcinoma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma / Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplasia Syndromes,Myelodysplastic / Myeloproliferative Neoplasms, Myelogenous Leukemia, Chronic (CML), Myeloid Leukemia, Acute (AML) Myeloma, Multiple, Myeloproliferative Neoplasms, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer, Low Malignant Potential Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm / Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Primary Peritoneal Cancer, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Rhabdomyosarcoma, Uterine, Small Intestine Cancer, Soft Tissue Sarcoma, Sqamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic, Stomach (Gastric) Cancer, T-Cell Lymphoma, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Unknown Primary, Ureter and Renal Pelvis, Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenstrom Macroglobulinemia, and Wilms Tumor, among others which may be treated with riluzole.

[0047] In various embodiments, the riluzole prodrugs are compounds according to Formula I:Formula I or a pharmaceutically-acceptable salt thereof, whereinL is C3-C5 alkylene, C3-C5 heteroalkylene, -Q-T-, or -T-Q-, wherein L is optionally substituted at one or more positions with one or more -RL;Q is C4-C10 heterocycloalkyl or C4-C10 heteroaryl;T is C1-C4 alkyl or C2-C4 heteroalkylene;RLis, at each occurrence, independently selected from C1-C4 alkyl, C2-C4 heteroalkyl, carbonyl, an amino acid side chain, or any other substituent as described herein; andR4is C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5- C9 heteroaryl, each optionally substituted with one or more of -NH2, carbonyl, cyano, methyl, ethyl, propyl, hydroxyl, methyl, ethyl, propyl, -O-PO3H2, -O-PO3(CH3)2, -O-SO3H, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, any other substituent as described herein, wherein said C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl (which are present as optional substituents on the C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, more preferably on the C1-C5 alkyl or C2-C5 heteroalkyl) are optionally further substituted (i.e., unsubstituted, mono- , di-, tri-, or poly-substituted) with one or more of halogen, methyl, ethyl, propyl, nitro, -NH2, carbonyl, cyano, hydroxyl, -O-PO3H2, -O-PCh CHa or -O-SO3H.

[0048] In an embodiment of Formula I, L is C3-C4 alkylene, C3-C4 heteroalkylene, -Q-T-, or - T-Q. In an embodiment, L is C4 alkylene or C4 heteroalkylene. In an embodiment, L is C3 alkylene or C3 heteroalkylene. In an embodiment, L is C5 alkylene or C5 heteroalkylene.

[0049] In an embodiment of Formula I, RLis methyl, ethyl, propyl (including n-propyl or isopropyl), butyl (including n-butyl, s-butyl, tert-butyl, or isobutyl), or carbonyl.

[0050] In an embodiment of Formula I, L is:, wherein RL1, RL2, RL3, RL4, and RL5are independently selected from -H, methyl, ethyl, and isopropyl.

[0051] In an embodiment of Formula I, L is Q-T, and Q is 5-membered or 6-memberedCH2- groups with one or more RL. In some embodiments, T is C2 alkylene substituted with one or more RL. In some embodiments wherein L is -Q-T-, T is -(C=O)-CHRL- or -(C=O)- CRL2 wherein each RLis independently selected from -H, methyl, ethyl, and isopropyl.

[0052] In an embodiment, L comprises one or more amino acids or amino acid analogues, or portions of an amino acid. The amino acids may be a natural or synthetic amino acid, and amino acid analogues may be based upon a natural or synthetic amino acid, differing at one or more atoms therefrom. In an embodiment, the amino acid analogue contains a substitution of its primary chain amino group with a functionality capable of forming an ester. In an embodiment, natural amino acids may include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, asparagine / aspartic acid, and glutamine / glutamic acid. Likewise, as described herein, RLmay be, or may include, a side chain of any such amino acid.

[0053] In some embodiments, L together with the carbonyl to which it is attached comprises a natural or synthetic amino acid. In some embodiments, said amino acid is proline, sarcosine, a piperidine amino acid, an azetidine amino acid, or a valine amino acid.

[0054] In some embodiments, L is a chain of between three to five atoms in length, where the chain of L may be non-cyclic or where L may comprise one or more rings. In some embodiments, L is a chain having three atoms in length and cyclization of the cleaved terminal ester as depicted in Formula I results in the release of a cyclic five-membered prodrug moiety byproduct. In some embodiments, L is a chain having four atoms in length and cyclization of the cleaved terminal ester results in the release of a six-membered prodrug moiety byproduct. In some embodiments, L is a chain having five atoms in length and cyclization of the cleaved terminal ester results in the release of a seven-membered prodrug moiety byproduct. In various embodiments, the cyclization forming a 5, 6, or 7-membered ring may form such a ring which is monocyclic if no ring is present in L on the parent prodrug moiety, or polycyclic such as bicyclic if one or more rings are present on the parent prodrug moiety (i.e., where L is -Q-T- or -T-Q-).

[0055] In an embodiment of Formula I, R4is methyl, ethyl, propyl (including n-propyl or isopropyl), butyl (including n-butyl, s-butyl, tert-butyl, or isobutyl), optionally preceded by an alkylene (such as -CH2-) or heteroalkylene (such as -CH2-O-) linking group. In further embodiments, R4is oxane, tetrahydrofuran, pyrrolidine, pyridine, piperidine, imidazole, thiazole, dioxane, morpholine, or pyrimidine, optionally preceded by an alkylene (such as - CH2-) or heteroalkylene (such as -CH2-O-) linking group.

[0056] In further embodiments, R4may be, including with the carbonyl to which it is attached, be an amino acid or amino acid analogue (such as an analogue having its primary chain amine replaced with a hydroxyl group). The amino acid may be a natural or syntheticamino acid. In an embodiment, natural amino acid may include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, asparagine / aspartic acid, and glutamine / glutamic acid.

[0057] In further embodiments, the riluzole prodrug of Formula I is a compound according to Formula la:or a pharmaceutically acceptable salt thereof, wherein:Rla, Rlb, and R2are R’, orRlais R’ or absent, and Rlband R2combine to form C4-C10 heterocycloalkyl or C4-C10 heteroaryl, optionally substituted with any substituent described herein;R’ is independently selected from, at each occurrence, -H, C1-C3 alkyl, and C2-C3 heteroalkyl;R3aand R3bare R”, orR3ais R” and R3aand R2combine to form C4-C10 heterocycloalkyl or C4-C10 heteroaryl, optionally substituted with any substituent described herein;R” is independently selected from, at each occurrence, -H, C1-C4 alkyl, and C2-C4 heteroalkyl;R4is C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5- C9 heteroaryl, each optionally substituted with one or more of -NH2, carbonyl, cyano, methyl, ethyl, propyl, hydroxyl, -O-PO3H2, -O-PChCCFfc -O-SO3H, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, or any other substituent as described herein, wherein said C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl (which are present as optional substituents on the C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, more preferably on the C1-C5 alkyl or C2-C5 heteroalkyl) are optionally further substituted (i.e., unsubstituted, mono-, di-, tri-, orpoly-substituted) with one or more of halogen, methyl, ethyl, propyl, nitro, -NH2, carbonyl, cyano, hydroxyl, -O-PO3H2, -O-PCh CHa or -O-SO3H.

[0058] In an embodiment of Formula la, Rlaand Rlbare -H.

[0059] In an embodiment, where Rlband R2combine to form a heterocycloalkyl or heteroaryl, Rlamay be absent. For example, where the heterocycloalkyl contains an unsaturated bond to the position Rlais connected at, or where heteroaryl is present, Rlamay be absent.

[0060] In an embodiment of Formula la, Rlaand R2combine to form a C4-C10 heterocycloalkyl. In an embodiment, Rlaand R2combine to form a C5 heterocycloalkyl or a Ce heterocycloalkyl. In an embodiment, Rlaand R2combine to form a C5 heterocycloalkyl. Inmore -CH2- groups with any substituent as described herein.

[0061] In an embodiment of Formula la, R2is methyl, ethyl, or propyl (including isopropyl or n-propyl). In an embodiment of Formula la, R2is methyl.

[0062] In an embodiment of Formula la, one of R3aand R3bis -H, and the other is methyl, ethyl, propyl (including n-propyl or isopropyl), butyl (including n-butyl, s-butyl, tert-butyl, or isobutyl). In another embodiment, R3aand R3bare both methyl. In further embodiments, R3aand R3bare both -H.

[0063] In an embodiment of Formula la, R4is methyl, ethyl, propyl (including n-propyl or isopropyl), butyl (including n-butyl, s-butyl, tert-butyl, or isobutyl), optionally preceded by an alkylene (such as -CH2-) or heteroalkylene (such as -CH2-O-) linking group. In further embodiments, R4is oxane, tetrahydrofuran, pyrrolidine, pyridine, piperidine, imidazole, thiazole, dioxane, morpholine, or pyrimidine, optionally preceded by an alkylene (such as - CH2-) or heteroalkylene (such as -CH2-O-) linking group.

[0064] In further embodiments, R4may be, including with the carbonyl to which it is attached, be an amino acid or amino acid analogue (such as an analogue having its primary chain amine replaced with a hydroxyl group). The amino acid may be a natural or synthetic amino acid. In an embodiment, natural amino acid may include alanine, arginine, asparagine,aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, asparagine / aspartic acid, and glutamine / glutamic acid.

[0065] In further embodiments, the riluzole prodrug of Formula I is a compound according to Formula lb:Formula lb or a pharmaceutically acceptable salt thereof, wherein:Rlais -H, C1-C3 alkyl, or C2-C3 heteroalkyl, or Rlais absent;Q is C4-C10 heterocycloalkyl or C4-C10 heteroaryl, optionally substituted with any substituent as described herein;R3aand R3bare independently -H, C1-C4 alkyl, and C1-C4 heteroalkyl;R4is C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5- C9 heteroaryl, each optionally substituted with one or more of -NH2, carbonyl, cyano, methyl, ethyl, propyl, hydroxyl, -O-PO3H2, -O-PChCCFfc -O-SO3H, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, or any other substituent as described herein, wherein said C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl (which are present as optional substituents on the C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, more preferably on the C1-C5 alkyl or C2-C5 heteroalkyl) are optionally further substituted (i.e., unsubstituted, mono-, di-, tri-, or poly-substituted) with one or more of halogen, methyl, ethyl, propyl, nitro, -NH2, carbonyl, cyano, hydroxyl, -O-PO3H2, -O-PChCCFfe or -O-SO3H.

[0066] In an embodiment of Formula lb, Q is a 5-membered or 6-membered

[0067] In an embodiment of Formula lb, one of R3aand R3bis -H, and the other is methyl, ethyl, propyl (including n-propyl or isopropyl), butyl (including n-butyl, s-butyl, tert-butyl, or isobutyl). In another embodiment, R3aand R3bare both methyl. In further embodiments, R3aand R3bare both -H.

[0068] In an embodiment of Formula lb, R4is methyl, ethyl, propyl (including n-propyl or isopropyl), butyl (including n-butyl, s-butyl, tert-butyl, or isobutyl), optionally preceded by an alkylene (such as -CEE-) or heteroalkylene (such as -CH2-O-) linking group. In further embodiments, R4is oxane, tetrahydrofuran, pyrrolidine, pyridine, piperidine, imidazole, thiazole, dioxane, morpholine, or pyrimidine, optionally preceded by an alkylene (such as - CH2-) or heteroalkylene (such as -CH2-O-) linking group.

[0069] In further embodiments, R4may be, including with the carbonyl to which it is attached, be an amino acid or amino acid analogue (such as an analogue having its primary chain amine replaced with a hydroxyl group). The amino acid may be a natural or synthetic amino acid. In an embodiment, natural amino acid may include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, asparagine / aspartic acid, and glutamine / glutamic acid.

[0070] In further embodiments, the prodrugs according to Formula I, Formula la, and / or Formula lb are a compound selected from the group consisting of those shown in Table 1 below:Table 1 : Exemplary prodrugs of riluzole

[0071] The term “substituted” is used throughout the specification. The term “substituted” is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein. That is, the moiety may be “substituted” with one or more substituents. The substituents are generally capable of replacing one or two hydrogen atoms of a single moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit. For example, a substituted unit that requires a singlehydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, a spiro ring, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. In some cases, specific groups or substituents are recited; in other cases, the term “substituent” may be used generally to encompass the substituents described below.

[0072] As used herein, the term “substituent” may generally encompass various chemical moieties which may be feasibly coupled with the described compound at various positions. A person of skill in the art will generally appreciate which substituents are feasible at a particular position. In various embodiments, compounds or substituents of compounds are “optionally substituted” at any position with “substituent(s)” or “substituent(s) as described herein”. Thus, it is generally contemplated that the formulae and compounds of the present invention may be substituted in any viable manner. While various substituents are included under the definition of “optionally substituted,” and like terms it should be appreciated that a person skilled in the art would recognize which positions are viable for substitution, and at those positions, which substituents would be viable. Unless stated clearly stated otherwise in the context, the term “optionally substituted” encompasses one or more, e.g. 1, 2, 3, 4 or more, independently selected substituents selected from: -F, -Cl, -Br, -I, -CN, -Ci-6-alkyl, - CF3, -CF2H, -CFH2, -CF2C1, -CFC12, -Ci.6-alkylene-CF3, -Ci-6-alkylene-CF2H, -Ci-6- alkylene-CFH2, -Ci-6-alkylene-O-CF3, -Ci-6-alkylene-O-CF2H, -Ci-6-alkylene-O-CFH2, -Ci-6- alkylene-NH-Ci-6-alkylene-CF3, -Ci-6-alkylene-N(Ci-6-alkyl)-Ci-6-alkylene-CF3, -C(=O)-Ci-6- alkyl, -Ci-6-alkylene-C(=O)-Ci-6-alkyl, -C(=O)OH, -Ci-6-alkylene-C(=O)-OH, -C(=O)-OCi-6- alkyl, -Ci-6-alkylene-C(=O)-OCi-6-alkyl, -C(=O)O-Ci-6-alkylene-CF3, -C(=O)-NH2, -Ci-6- alkylene-C(=O)-NH2, -C(=O)-NH(Ci-6-alkyl), -Ci.6-alkylene-C(=O)-NH(Ci-6-alkyl), -C(=O)- N(Ci-6-alkyl)2, -Ci.6-alkylene-C(=O)-N(Ci-6-alkyl)2, -C(=O)-NH(OH), -Ci-6-alkylene-C(=O)- NH(OH), -OH, -Ci-6-alkylene-OH, =0, -OCF3, -OCF2H, -OCFH2, -OCF2C1, -OCFC12, -O-Ci- 6-alkyl, -Ci-6-alkylene-O-Ci-6-alkyl, -O-Ci-6-alkylene-O-Ci-6-alkyl, -O-Ci-6-alkylene-NH2, - O-Ci-6-alkylene-NH-Ci-6-alkyl, -O-Ci-6-alkylene-N(Ci-6-alkyl)2, -O-C(=O)-Ci-6-alkyl, -Ci-6- alkylene-O-C(=O)-Ci-6-alkyl, -O-C(=O)-O-Ci-6-alkyl, -Ci.6-alkylene-O-C(=O)-O-Ci-6-alkyl, -O-C(=O)-NH(Ci-6-alkyl), -Ci.6-alkylene-O-C(=O)-NH(Ci-6-alkyl), -O-C(=O)-N(Ci-6-alkyl)2, -Ci-6-alkylene-O-C(=O)-N(Ci-6-alkyl)2, -O-S(=O)2-NH2, -Ci-6-alkylene-O-S(=O)2-NH2, -O- S(=O)2-NH(Ci-6-alkyl), -Ci.6-alkylene-O-S(=O)2-NH(Ci-6-alkyl), -O-S(=O)2-N(Ci-6-alkyl)2, - Ci-6-alkylene-O-S(=O)2-N(Ci-6-alkyl)2, -NH2, -NO, -NO2, -Ci-6-alkylene-NH2, -NH(CI-6- alkyl), -N(3-14-membered cycloalkyl)(Ci-6-alkyl), -N(Ci-6-alkyl)-Ci-6-alkylene-OH, -N(H)- Ci-6-alkylene-OH, -Ci-6-alkylene-NH(Ci-6-alkyl), -N(Ci-6-alkyl)2, -Ci-6-alkylene-N(Ci-6-alkyl)2, -NH-C(=O)-Ci-6-alkyl, -Ci-6-alkylene-NH-C(=O)-Ci.6-alkyl, -NH-C(=O)-O-CI-6- alkyl, -Ci-6-alkylene-NH-C(=O)-O-Ci-6-alkyl, -NH-C(=O)-NH2, -Ci-6-alkylene-NH-C(=O)- NH2, -NH-C(=O)-NH(Ci-6-alkyl), -Ci-6-alkylene-NH-C(=O)-NH(Ci.6-alkyl), -NH-C(=O)- N(Ci-6-alkyl)2, -Ci-6-alkylene-NH-C(=O)-N(Ci-6-alkyl)2, -N(Ci-6-alkyl)-C(=O)-Ci.6-alkyl, - Ci-6-alkylene-N(Ci-6-alkyl)-C(=O)-Ci-6-alkyl, -N(Ci-6-alkyl)-C(=O)-O-Ci.6-alkyl, -Ci-6- alkylene-N(Ci-6-alkyl)-C(=O)-O-Ci-6-alkyl, -N(Ci-6-alkyl)-C(=O)-NH2, -Ci-6-alkylene-N(Ci- 6-alkyl)-C(=O)-NH2, -N(Ci-6-alkyl)-C(=O)-NH(Ci-6-alkyl), -Ci-6-alkylene-N(Ci-6-alkyl)- C(=O)-NH(Ci-6-alkyl), -N(Ci-6-alkyl)-C(=O)-N(Ci.6-alkyl)2, -Ci-6-alkylene-N(Ci-6-alkyl)- C(=O)-N(Ci-6-alkyl)2, -NH-S(=O)2OH, -Ci-6-alkylene-NH-S(=O)2OH, -NH-S(=O)2-CI-6- alkyl, -Ci-6-alkylene-NH-S(=O)2-Ci-6-alkyl, -NH-S(=O)2-O-Ci-6-alkyl, -Ci-6-alkylene-NH- S(=O)2-O-Ci-6-alkyl, -NH-S(=O)2-NH2, -Ci-6-alkylene-NH-S(=O)2-NH2, -NH-S(=O)2- NH(Ci-6-alkyl), -Ci-6-alkylene-NH-S(=O)2-NH(Ci.6-alkyl), -NH-S(=O)2N(Ci-6-alkyl)2, -Ci-6- alkylene-NH-S(=O)2N(Ci-6-alkyl)2, -N(Ci-6-alkyl)-S(=O)2-OH, -Ci-6-alkylene-N(Ci-6-alkyl)- S(=O)2-OH, -N(Ci-6-alkyl)-S(=O)2-Ci-6-alkyl, -Ci-6-alkylene-N(Ci-6-alkyl)-S(=O)2-Ci-6-alkyl, -N(Ci-6-alkyl)-S(=O)2-O-Ci-6-alkyl, -Ci-6-alkylene-N(Ci-6-alkyl)-S(=O)2-O-Ci-6-alkyl, -N(Ci- 6-alkyl)-S(=O)2-NH2, -Ci-6-alkylene-N(Ci-6-alkyl)-S(=O)2-NH2, -N(Ci-6-alkyl)-S(=O)2- NH(Ci-6-alkyl), -Ci-6-alkylene-N(Ci-6-alkyl)-S(=O)2-NH(Ci-6-alkyl), -N(Ci-6-alkyl)-S(=O)2- N(Ci-6-alkyl)2, -Ci-6-alkylene-N(Ci-6-alkyl)-S(=O)2-N(Ci-6-alkyl)2, -SH, =S, -SF5, -SCF3, - SCF2H, -SCFH2, -S-Ci-6-alkyl, -Ci-6-alkylene-S-Ci-6-alkyl, -S(=O)-Ci-6-alkyl, -Ci-6-alkylene- S(=O)-Ci-6-alkyl, -S(=O)2-Ci-6-alkyl, -Ci-6-alkylene-S(=O)2-Ci-6-alkyl, -S(=O)2-OH, -Ci-6- alkylene-S(=O)2-OH, -S(=O)2-O-Ci-6-alkyl, -Ci-6-alkylene-S(=O)2-O-Ci-6-alkyl, -S(=0)2- NH2, -Ci-6-alkylene-S(=O)2-NH2, -S(=O)2-NH(Ci-6-alkyl), -Ci-6-alkylene-S(=O)2-NH(Ci-6- alkyl), -S(=O)2-N(Ci-6-alkyl)2, -Ci-6-alkylene-S(=O)2-N(Ci-6-alkyl)2, 3-14-membered cycloalkyl, -Ci-6-alkylene-(3-14-membered cycloalkyl), 3 to 14-membered heterocycloalkyl, -Ci-6-alkylene-(3 to 14-membered heterocycloalkyl), -phenyl, -Ci-6-alkylene-phenyl, 5 to 14- membered heteroaryl, -Ci-6-alkylene-(5 to 14-membered heteroaryl), -O-(3- 14-membered cycloalkyl), -O-(3 to 14-membered heterocycloalkyl), -O-phenyl, -O-(5 to 14-membered heteroaryl), -C(=O)-(3- 14-membered cycloalkyl), -C(=O)-(3 to 14-membered heterocycloalkyl), -C(=O)-phenyl, -C(=O)-(5 to 14-membered heteroaryl), -S(=O)2-(3- 14- membered cycloalkyl), -S(=O)2-(3 to 14-membered heterocycloalkyl), -S(=O)2-phenyl, and - S(=O)2-(5 to 14-membered heteroaryl). In cases where a listing of optional substituents are presented in a grouping in a given embodiment, any optional substituents from the preceding list not included in said grouping are further contemplated in additional variants of said given embodiment.

[0073] As used herein with respect to a substituting group, and unless otherwise stated, the terms “monosubstituted”, "di substituted", "tri substituted", "polysubstituted" and the like means chemical structures defined herein, wherein the respective moiety is substituted with one or more substituents, meaning that one or more hydrogen atoms of said moiety are each independently replaced with a substituent. For example, -Ci-6-alkyl that may be polysubstituted with -F includes -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, and the like. Likewise, -Ci-6-alkyl that may be polysubstituted with substituents independently of one another selected from -F and -Cl includes -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, -CH2CI, - CHCh, -CCh, -CH2CCI3, CCI2CCI3, -CHC1F, -CCIF2, -CCI2CF3, -CF2CCI3, -CCIFCCLF, and the like. Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected. Likewise, substituents present at the same site may be the same or different (i.e., they are independently selected). In general, where a moiety is “optionally substituted”, monosubstitution, di substitution, tri substitution, and / or polysubstitution are contemplated. The term tetrasubstituted may also be utilized to indicate that four substituents are present. In various embodiments, polysubstituted means that the group or moiety is substituted with two or more substituents. The number of substituents may be as high as the valency of the group or moiety permits. In some embodiments, polysubstituted means that two, three, four, five, six, or seven substituents are present. In some embodiments, polysubstituted means that two, three, four, or five substituents are present. In some embodiments, polysubstituted means that two, three, or four substituents are present.

[0074] The term “heteroatom(s)” as used herein means an atom selected from nitrogen, which in some cases can be quatemized or present as an oxide; oxygen; and sulfur, including oxidized sulfurs including, sulfoxide and sulfone, and in some cases sulfonate. In certain instances, the compounds and / or synthetic intermediates may include other heteroatoms such as boron, phosphorous, and silicon.

[0075] In the various embodiments described herein, the compound is a prodrug compound according to Formula I, Formula la, or Formula lb. In various embodiments described herein, the compound is a prodrug compound according to Formula I. In various embodiments described herein, the compound is a prodrug compound according to Formula la. In various embodiments described herein, the compound is a prodrug compound according to Formula lb. In further embodiments, the compound is a prodrug compound according to one or more of Formula I, Formula la, and / or Formula lb.

[0076] In this disclosure, where compositions or processes are described as having, including, or comprising specific components or steps, it is contemplated that said compositions or processes also may consist essentially of, or consist of, the recited components or steps. Where a composition or process consists essentially of a number of recited components or steps, it is contemplated that the composition or process may include additional components or steps which are routine or which do not materially alter the composition or process. The order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0077] The use of the singular herein includes the plural, and the use of the plural includes the singular, unless specifically stated otherwise or clear from the context. In addition, the use of the term “about” before a quantitative value should be taken to include the specific quantitative value itself unless specifically stated otherwise. Where the term “about” is used without any other specific description before a quantitative value, values within 10% of the quantitative value are generally contemplated.

[0078] As used herein, the term “halogen” means chlorine, bromine, fluorine, and iodine. It is specifically contemplated that the term “halogen” may be replaced by any one or more of chlorine, bromine, fluorine, or iodine in any described embodiment. Likewise, where any embodiment recites one of chlorine, bromine, fluorine, or iodine, alternative, analogous embodiments reciting one other of chloring, bromine, fluorine, or iodine are contemplated.

[0079] As used herein, the symbol and abbreviation “fBu”, such as in a chemical formula ortext shorthand, means “tert-butyl” and is represented by the formula:CHs . As used herein, the abbreviation “Me” such as in a chemical formula or text shorthand, means “methyl” and is represented by the formula -CH3. As used herein, the abbreviation “Et” such as in a chemical formula or text shorthand, means “ethyl” and is represented by the formula - CH2-CH3. As used herein, the chemical abbreviation -OPO3H2 represents a phosphate group, ohaving the structure OH . As used herein, the chemical abbreviation -O-SO3H o- &5-0 — S II — OH? II represents a sulfate group, having the structure o

[0080] As used herein, the term “alkyl” or refers to straight and branched carbon chains. The term may be preceded by a range of carbon atoms (e.g., C1-C10 alkyl) which means that the straight or branched chain may include from 1 to 10 carbon atoms, not accounting for those which may also be present in a substituent to the carbon chain at any position. It should be appreciated that while a range of atom numbers is given for the purposes of defining embodiments of the present invention, a small number of additional atoms outside of the range (such as one, two, three, or four) may be contemplated in other embodiments of the present invention. Alkyl groups may also contain one or more (e.g., one, two, or three) unsaturations such as double or triple bonds, which may be alternatively referred to as alkenyl or alkynyl groups, respectively. That is, the term “alkyl” where recited encompasses unsaturated alkenyl and alkynyl groups, however “alkenyl” and / or “alkynyl,” where specifically recited, do not encompass saturated “alkyl” groups. Any alkyl group may be further indicated as “saturated” meaning that it does not encompass unsaturated alkenyl and alkynyl groups, in other words that it does not encompass a carbon-carbon double or triple bond. Alkyl groups may generally be substituted at one or more positions to replace a hydrogen atom with a different atom or constituent atom of another group. One example of a substituted alkyl group is “hydroxyalkyl” which contains one or more hydroxyl (-OH) substituents. As would be apparent from the context, in some cases “alkyl” is also intended to encompass internal linking groups which bridge two substituents. Such internal alkyl linking groups may be alternatively referred to as alkylene groups, which are bivalent saturated aliphatic radicals such as in the context of linking groups. An example of an alkylene group is methylene, i.e., -CH2-.

[0081] As used herein, the term “heteroalkyl” refers to straight and branched carbon chains including at least one heteroatom independently selected from S, N, or O. For example, “C2- C10 heteroalkyl” means linear or branched chain of two to ten atoms where at least one of the atoms is a heteroatom (such as S, N, or O) while the other atoms are carbon. Branched groups may include one or more C or heteroatoms (e.g., methyl, ethyl, propyl, carbonyl, hydroxyl, amine, etc.). In some embodiments, a heteroalkyl may contain one, two, three, or four heteroatoms. It should be appreciated that while a range of atom numbers is given for the purposes of defining embodiments of the present invention, a small number of additional atoms outside of the range (such as one, two, three, or four) may be contemplated in other embodiments of the present invention. Heteroalkyl groups may also contain one or more (e.g., one, two, or three) unsaturations such as double or triple bonds, which may be alternatively referred to as heteroalkenyl or heteroalkynyl groups, respectively. That is, theterm “heteroalkyl” where recited encompasses unsaturated heteroalkenyl and heteroalkynyl groups, however the terms “heteroalkenyl” and / or “heteroalkynyl,” where specifically recited, do not intend to encompass fully saturated “heteroalkyl” groups. Any heteroalkyl group may be further indicated as “saturated” meaning that it does not encompass unsaturated alkenyl and alkynyl groups. Heteroalkyl groups may generally be substituted at one or more positions to replace a hydrogen atom or lone electron pair with a different atom or constituent atom of another group. One specific type of heteroalkyl is an “alkoxy” group containing one or more oxygen atoms in the chain. As would be apparent from the context, in some cases “heteroalkyl” is also intended to encompass internal linking groups which bridge two substituents (such as various heteroalkylene groups).

[0082] As used herein, the term “cycloalkyl” refers to one or more rings of carbon atoms. For example, “C4-C7 cycloalkyl” means one or more rings having between 4 to 7 carbon atoms total (by way of non-limiting example, cyclobutyl having 4 carbon atoms, cyclohexyl having 6 carbon atoms, norbomane having 7 carbon atoms as a bridged ring system, and spiro[2.3]hexane having 6 carbon atoms as a spiro system). It should be appreciated that while a range of atom numbers is given for the purposes of defining embodiments of the present invention, a small number of additional atoms outside of the range (such as one, two, three, or four) may be contemplated in other embodiments of the present invention.Cycloalkyl groups may also contain one or more (e.g., one, two, or three) unsaturations such as double bonds. Cycloalkyl groups may generally be substituted at one or more positions to replace a hydrogen atom with a different atom or constituent atom of another group. As would be apparent from the context, in some cases “cycloalkyl” is also intended to encompass internal linking groups which bridge two substituents.

[0083] As used herein, the term “heterocycloalkyl” refers to one or more rings including at least one heteroatom independently selected from S, N, or O. For example, C4-C7 heterocycloalkyl means one or more rings having between 4 and 7 atoms total, where at least one atom is a heteroatom other than C, such as S, N, or O. In some embodiments, a heterocycloalkyl may contain one, two, three, or four heteroatoms. It should be appreciated that while a range of atom numbers is given for the purposes of defining embodiments of the present invention, a small number of additional atoms outside of the range (such as one, two, three, or four) may be contemplated in other embodiments of the present invention.oII OH o Heterocycloalkyl groups may also contain phosphorous such as in the group: " Heterocycloalkyl groups may also contain one or more (e.g., one, two, or three) unsaturations such as double bonds. Heterocycloalkyl groups may generally be substituted at one or more positions to replace a hydrogen atom or lone electron pair with a different atom or constituent atom of another group. As would be apparent from the context, in some cases “heterocycloalkyl” is also intended to encompass internal linking groups which bridge two substituents.

[0084] Non-limited examples of saturated and unsaturated heterocycloalkyl include azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxane, di oxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiazolidine, thietane, thiirane, thiolane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1- dioxothiacyclohexane, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 7- azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, hexahydro-lH- pyrrolizine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, and octahydropyrrolo[l,2-a]pyrazine. N-containing heterocycloalkyl rings may be alkylated at the N, such as in N-methyl, N-ethyl, N-propyl, etc. substituted variants. Further heterocycloalkyls in the meaning of the invention are described in Paquette, Leo A. "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C.W. and Scriven, E. "Comprehensive Heterocyclic Chemistry" (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566. When the heterocycloalkyl contains no nitrogen as ring member, it is typically bonded through carbon. When the heterocycloalkyl contains nitrogen as ring member, it may be bonded through nitrogen or carbon. Unless specified otherwise, a “heterocycloalkyl” may include between 3 - 10 carbon atoms / heteroatoms, or in some cases preferably 4 - 6 carbon atoms / heteroatoms.

[0085] As used herein, the term “heteroaryl” means an aromatic ring system including at least one heteroatom independently selected from S, N, or O. Included are unsaturated,aromatic monocyclic rings and unsaturated, polycyclic rings. For example, C5-C10 heteroaryl means one or more rings having between 5 and 10 atoms total, where at least one atom is a heteroatom other than C, such as S, N, or O. In some embodiments, a heteroaryl may contain one, two, three, or four heteroatoms. It should be appreciated that while a range of atom numbers is given for the purposes of defining embodiments of the present invention, a small number of additional atoms outside of the range (such as one, two, three, or four) may be contemplated in other embodiments of the present invention. Heteroaryl groups may generally be substituted at one or more positions to replace a hydrogen atom or lone electron pair with a different atom or constituent atom of another group. As would be apparent from the context, in some cases “heteroaryl” is also intended to encompass internal linking groups which bridge two substituents.

[0086] As used herein, the term “compound” or “prodrug compound” includes all enantiomeric forms, diastereomeric forms, stereoisomers, salts, solvates, and esters thereof. Also encompassed are all isotopic variants having natural or enriched isotopic content such as deuterated compounds or other isotopically enriched forms. Where a particular enantiomer, diastereomer, or other stereoisomer is shown specifically, all other possible enantiomers, diastereomers, or other stereoisomers are contemplated (which may be represented by chemical structures which do not show specific stereochemical configurations).

[0087] Non-limiting examples of heteroaryl include benzimidazole, benzisoxazole, benzoazole, benzodioxole, benzofuran, benzothiadi azole, benzothiazole, benzothiophene, carbazole, cinnoline, dibenzofuran, furane, furazane, imidazole, imidazopyridine, indazole, indole, indolizine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, oxindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and [l,2,4]triazolo[4,3-a]pyrimidine. Unless specified otherwise, a “heteroaryl” group may include between 5 - 8 carbon atoms / heteroatoms, or in some cases preferably 5 - 6 carbon atoms / heteroatoms. The “heteroaryl” can be a single ring or a fused ring system.

[0088] In various embodiments, a number of atoms in a particular group or substituent is denoted by a range (e.g. C1-C10 alkyl). It is specifically intended that each and every individual numbers of atoms in the range are contemplated, as are each and every subcombination of numbers within the ranges. For example “C1-C10” in the context of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and others would include Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, and C10 groups, as well as sub-combinations such as C1-C9, Ci-Cs, C1-C7,C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C10, C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C3-C10, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, c4-c5, C5-C1O, C5-C9, C5-C8, C5-C7, C5-C6, C6-C10, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, c7-c8, c8- C10, C8-C9, and C9-C10. Other ranges given herein likewise include the individual numbers and all sub-combinations.

[0089] The prodrug compounds described herein may contain one or more chiral centers, and may therefore include optical isomers, i.e. enantiomers, and diastereomers. The compounds may be obtained as racemic mixtures or enantiomerically pure R and S stereoisomers and pharmaceutically acceptable salts thereof. Cis- and trans- isomers of alkenes and imines or other double-bonded species are also contemplated. Certain stereoisomers may be obtained by standard techniques known in the art such as asymmetric synthesis, diastereomeric recrystallization, kinetic resolution, chromatographic or other separation techniques, etc. Chromatographic techniques may include column chromatography, thin-layer chromatography, and high-performance liquid chromatography (HPLC), and may incorporate chiral columns which generally have a chiral stationary phase. Chromatographic and other separation techniques are well-known in the art and standard procedures may be followed to obtain enantiomerically-pure or diastereomerically-pure compounds.

[0090] Pharmaceutically-acceptable salts of compounds of the present teachings can be formed using organic and inorganic bases, or organic and inorganic acids. Both mono and polyanionic salts, or mono and polycationic salts, are contemplated, depending on the number of charges available on the compound. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl -tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCCh, Na2CO3, KHCO3, K2CO3, CsCCh, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, trifluoroacetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic,pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids. Pharmaceutically-acceptable salts may also include halide salts, such as salts containing chloride, bromide, or iodide ions. A non-limiting example is a halide salt of an amine, such as -NH3+C1-.

[0091] In each of the embodiments disclosed herein, the compositions and methods may be utilized with or on a subject in need of such treatment, which may also be referred to as “in need thereof’, means that the subject has been identified as having a need for the particular method or treatment.

[0092] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, or prevent, or any combination thereof, an unwanted condition, disorder or disease of a subject or patient.

[0093] As used herein, the term “patient” and “subject” are interchangeable and may be taken to mean any living organism, which may be treated with compounds of the present invention. As such, the terms “patient” and “subject” may include, but are not limited to, any nonhuman mammal, primate or human. In some embodiments, the “patient” or “subject” is an adult, child, infant, or fetus. In some embodiments, the “patient” or “subject” is a human. In some embodiments, the “patient” or “subject” is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans.

[0094] The terms “therapeutically effective amount” or “therapeutic dose” or “effective amount” as used herein are interchangeable and may refer to the amount of an active agent or pharmaceutical compound or composition that elicits a clinical, biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinical professional. A clinical, biological or medical response may include, for example, one or more of the following: (1) preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display pathology or symptoms of the disease, condition or disorder, (2) inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptoms of the disease, condition or disorder or arresting further development of the pathology and / or symptoms of the disease, condition or disorder, and (3) ameliorating a disease, condition or disorder in an individual that is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder or reversing the pathology and / or symptoms experience or exhibited by the individual.

[0095] The terms “treat,” “treated,” or “treating” may be taken to mean prophylaxis of a specific disorder, disease or condition, alleviation of the symptoms associated with a specific disorder, disease or condition and / or prevention of the symptoms associated with a specific disorder, disease or condition. In some embodiments, the term refers to slowing the progression of the disorder, disease or condition or alleviating the symptoms associated with the specific disorder, disease or condition. In some embodiments, the term refers to alleviating the symptoms a disease or condition. In some disorder, disease or condition. In some embodiments, the term refers to restoring function which was impaired or lost due to a specific disorder, disorder or condition.

[0096] Another aspect of the disclosure is a pharmaceutical composition comprising a compound of Formula I, Formula la, or Formula lb with a pharmaceutically acceptable adjuvant, carrier, or diluent. Further aspects of the disclosure are method for treating a glutamate-associated disorder in a subject in need thereof by administration of a prodrug compound according to Formula I, Formula la, or Formula lb. In some embodiments, the administration route may oral. In other embodiments, the administration route may be intravenous or other parenteral route, or any other appropriate route.

[0097] Riluzole is known to have glutamate modulatory activity and the riluzole prodrugs disclosed herein may be useful for treatment of various “glutamate-associated disorders” or other disorders for which riluzole has a known role. Such disorders may be encompassed by the term “glutamate-associated disorder”. Such disorders may be related to the glutamatergic system and the prodrugs may be useful in various glutamatergic dysfunctions or related indications. The glutamate-associated disorders for which the riluzole prodrugs are useful include, but are not limited to, central nervous system (CNS) disorders such as depression / anxiety states, neuropsychiatric disorders such as obsessive-compulsive disorder or substance use disorder, and neurodegenerative disorders such as spinocerebellar ataxia, as well as related conditions such as those disclosed herein. The riluzole prodrugs may also be useful in any other disorder where glutamate modulation is relevant or where riluzole has a known role, including various cancers including but not limited to melanoma, ovarian cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, lung cancer, renal cancer, colorectal cancer, skin cancer, brain cancer, and leukemia, among other cancers disclosed herein.

[0098] Compounds are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of one or more of a compound of Formula I, Formula la, or Formula lb, or pharmaceutically acceptable salt(s) thereof, and a pharmaceutically acceptable carrier, further optionally containing conventional excipients. A therapeutically effectiveamount is the amount needed to provide a meaningful patient benefit as determined by practitioners in that art. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including capsules, tablets, lozenges, and powders as well as liquid suspensions, syrups, elixirs, and solutions. Solid compositions may by formed in timed or sustained released formulations. Compositions are made using common formulation techniques and conventional excipients (such as binding and wetting agents) and / or vehicles (such as water and alcohols).

[0099] The disclosure and methods encompass all conventional modes of administration including oral, parenteral, intranasal, sublingual, topical, and transdermal methods. Typically, the daily dose may be 0.01-100 mg / kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, should be determined by a physician using sound medical judgement. Advantageously, the riluzole prodrug may be given once-per-day orally as a unit dosage. The once-per-day oral unit dosage may be about 500 mg, or about 400 mg, or about 350 mg, or about 300 mg, or about 250 mg, or about 200 mg, or about 150mg, or about 125 mg, or about 100 mg, or about 75 mg, or about 50 mg, or about 30 mg, or about 20 mg, or about 10 mg.

[0001] Among other routes of administration, the standard routes of administration described by the FDA are contemplated herein (see, FDA Routes of Administration; accessible from the official FDA website). These routes include auricular (otic), buccal, conjunctival, cutaneous, dental, electro-osmosis, endocervical, endosinusial, endotracheal, enteral, epidural, extra amniotic, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra- amniotic, intra-arterial, intra-articular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavemous, intracavitary, intracerebral, intracisternal, intracorneal, intracoronal, dental, intracoronary, intracorporus cavemosum, intradermal, intradiscal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intratubular, intratumor, intratympanic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous drip, intraventricular, intravesical, intravitreal, iontophoresis, irrigation, laryngeal, nasal, nasogastric, not applicable, occlusive dressing technique, ophthalmic, oral, oropharyngeal, parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual,submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, urethral, and / or vaginal.

[0100] In some embodiments, the route of administration for compounds of Formula I, Formula la, or Formula lb may be oral. In other embodiments, the administration route may be intravenous or other parenteral. In other embodiments, the administration route may be intranasal or inhalant.

[0101] The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating, or other function.

[0102] Pharmaceutical compositions may comprise one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0103] While oral administration is preferred in some embodiments, compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportionsand compacted in the shape and size desired. The powders and tablets can contain up to 99% of the compound.

[0104] Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and / or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.

[0105] Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, ion exchange resins, benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, pol oxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

[0106] Liquid carriers can be used in preparing solutions for oral or parenteral administration (such as intravenous, intramuscular, or other injections), including suspensions, emulsions, syrups, elixirs, and additionally for inhaled delivery. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodiumcarboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.

[0107] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile injectable solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[0108] Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be further sub-divided to contain appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.

[0109] When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the pharmaceutical composition formulated, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.

[0110] In some cases it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath- operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal orintrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.

[0111] Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

[0112] The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.EXPERIMENTAL

[0113] General methods: Reagents and chemicals were purchased from multiple suppliers including Sigma-Aldrich chemical company (Milwaukee, WI), Astatech (Bristol,PA) and TCI America (Portland, OR). Solvents and bulk reagents were purchased from Fisher Scientific. All purchased reagents and chemicals were used as is directly from the container. All reactions were carried out under an inert atmosphere in a fume hood.XH NMR spectra were taken on a Varian 400 MHz NMR using tetramethylsilane (TMS) as internal standard (5 = 0.00 ppm) with peaks reported downfield from TMS. In instances where multiple signals are observed due to the presence of rotational isomers, the multiplicity of the ’H NMR signal is designated as ‘m’. LCMS data were determined with a Waters Alliance 2695 HPLC / MS (Waters Symmetry C18, 4.6 x 75 mm, 3.5 pm) with a 2996 diode array detector from 210-400 nm; the solvent system is 5-95% acetonitrile in water (with 0.1% TFA) over nine minutes using a linear gradient, retention times are in minutes. Mass spectrometry was performed on a Waters ZQ using electrospray in positive mode. Preparative reversed phase HPLC was performed on a Waters Sunfire column (19 x 50 mm, C18, 5 pm) with a 10 min mobile phase linear gradient of 10% acetonitrile / water to 90% acetonitrile / water (with 0.1% TFA) using 214 and 254 nm as detection wavelengths. Injection and fraction collection were performed with a Gilson 215 liquid handling apparatus using Trilution LC software. Product fractions were combined and lyophilized. Normal phase chromatography was carried out on a Teledyne ISCO Combiflash® Rf instrument eluted with the indicated solvents and gradients.

[0114] Compounds of formula I can be synthesized through multistep conventional organic synthesis, executable by those skilled in the art, from commercially available 6- (trifluoromethoxy)benzothiazol-2-amine (riluzole). The illustration of examples, but not the limitation, of the synthesis of compounds of formula I is detailed below.

[0115] Compounds of formula I that incorporate an initial functionalization of riluzole with a natural or an unnatural amino acid can be synthesized according to Scheme 1.Scheme 1

[0116] Acylation of riluzole with a carboxylic acid, including but not limited to a protected natural or unnatural amino acid, can be achieved with the appropriate carboxylic acidand a coupling reagent such as hexafluorophosphate azabenzotri azole tetramethyl uronium (HATU) to provide intermediate- 1 (Int-1). Suitable protecting groups in instances where the carboxylic acid is an amino acid include, but are not limited to A-Boc, TV-Fmoc and A-Cbz. The protecting group associated with the riluzole-aminoamide can be removed to provide intermediate-2 (Int-2), which can be further functionalized through A -acylation with a substituted or unsubstituted glycolic acid derivative (Int-3) to provide examples of compounds of formula I. In instances where the RIVcomponent of Int-3 is derived from an amino acid, the amino group can be protected with a suitable protecting group including, but not limited to N- Boc and removed on completion of the coupling of Int-3 with Int-2 using standard deprotection conditions.

[0117] As shown in Scheme 1 and in other schemes herein, R1represents at least one variable substituent which may, for example, be a substituent according to variables Rlaand / or Rlb(see, e.g., Formula la). R1may alternatively form a portion of a ring (shown in a dashed line) along with the nitrogen adjacent to the atom to which R1is bound. Where a ring is formed with said nitrogen, the hydrogen atom depicted in Scheme 1 is not present. In additional cases where a ring is not formed with said nitrogen, the hydrogen atom may remain on the nitrogen or instead another substituent according to variable R’ as described herein may be present (see, e.g., Formula la), such as methyl or others. In Scheme 1 and other schemes herein, “R111” represents at least one variable substituent which may, for example, be a substituent according to variables R3aand / or R3b(see, e.g., Formula la). In Scheme 1 and other schemes herein, “RIV” represents a variable substituent which may, for example, be a substituent according to variable R4(see, e.g., Formula I and Formula la).Synthesis of functionalized riluzole intermediates (Int-2):

[0118] Int-2a-(R): (R)-A-(6-(Trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2- carboxamide hydrochloride saltlnt-2a-(R)

[0119] To a mixture of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (riluzole, 2.0 g, 8.54 mmol, 1.0 eq.), Boc D-proline (2.0 g, 9.4 mmol, 1.1 eq.) and HATU (3.6 g, 9.4 mmol, 1.1 eq.) in 25 mL of DMF was added A,A-diisopropylethylamine (3.5 mL, 20 mmol, 2.3 eq.) and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with ethyl acetate (x2). The combined organic extracts were dried(MgSCU), filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography (SiCh, eluting with a linear gradient of 0-100% ethyl acetate / hexanes) to provide 1.8 g (4.2 mmol) of (R)- / c77-butyl 2-(6-(trifluoromethoxy)benzo[d]thiazol-2- ylcarbamoyl)pyrrolidine-l -carboxylate as a white solid which was redissolved in methanol (10 mL). A 4 M solution of HCI in 1,4-di oxane (20 mL) was added and the mixture was stirred at room temperature 2 hours. The solvent was removed in vacuo to provide 1.46 g (4.0 mmol, 46%) of (R)-A-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide hydrochloride as an off-white solid. ’H NMR (400 MHz, Methanol-t / p 6 = 7.88 (s, 1H), 7.82 (d, 1H), 7.37 (d, 1H), 4.58 (t, 1H), 3.57 - 3.32 (m, 2H), 2.66 - 2.49 (m, 1H), 2.27 - 2.04 (m, 3H). LCMS m / z = 332.2 [M+H]+

[0120] Int-2a-(S): (S)-A-(6-(Trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2- carboxamide hydrochloride salt

[0121] (S)-A-(6-(Trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide hydrochloride salt (Int-2a-(S)) was synthesized in a similar manner to Int-2a-(R) from riluzole and Boc-L-proline.

[0122] Int-2b: 2-(Methylamino)-A-(6-(trifluoromethoxy)benzo[d]thiazol-2- yDacetamide hydrochloride saltlnt-2b

[0123] 2-(Methylamino)-A-(6-(trifluorom ethoxy )benzo[d]thiazol-2-yl)acetamide hydrochloride salt (Int-2b) was synthesized in a similar manner to Int-2a-(R) from riluzole and Boc-sarcosine. ’H NMR (400 MHz, Methanol-^) 8 = 7.90 (s, 1H), 7.82 (d, 1H), 7.44 - 7.30 (m, 1H), 4.18 (s, 2H), 2.84 (s, 3H); LCMS: 3.65 min, m / z = 306.7 [M+H]+.

[0124] Int-2c-(R): (R)-2 -Amino-3 -methyl-A-(6-(trifluorom ethoxy )benzo[d]thiazol-2- yDbutanamide hydrochloride salt.

[0125] (R)-2-Amino-3-methyl-7V-(6-(trifluoromethoxy)benzo[d]thiazol-2- yl)butanamide hydrochloride salt (Int-2c-(R)) was synthesized in a similar manner to Int-2a- (R) from riluzole and Boc-D-valine. ‘HNMR (400 MHz, DMSO-tL) 8 = 13.17 (bs, 1H), 8.68 - 8.51 (m, 3H), 8.19 (d, 1H), 7.88 (d, 1H), 7.59 - 7.33 (m, 1H), 4.04 (t, 1H), 2.40 - 2.08 (m, 1H), 1.20 - 0.91 (m, 6H); LCMS: 4.10 min, m / z = 334.65 [M+H]+.

[0126] Int-2c-(S): (S)-2-Amino-3 -methyl-A-(6-(trifluorom ethoxy )benzo[d]thiazol-2- yDbutanamide hydrochloride salt.lnt-2c (S)

[0127] (S)-2-Amino-3 -methyl-7V-(6-(trifluorom ethoxy )benzo[d]thiazol-2- yl)butanamide hydrochloride salt (Int-2c-(S)) was synthesized in a similar manner to Int-2a-(R) from riluzole and Boc-L-valine.

[0128] Int-2d-(R): (R)-A-(6-(Trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2- carboxamide hydrochloride saltlnt-2d (R)

[0129] (R)-A-(6-(Trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide hydrochloride salt (Int-2d-(R)) was synthesized in a similar manner to Int-2a-(R) from riluzole and Boc-D-pipecolic acid. ’H NMR (400 MHz, DMSO-tL) 6 = 13.17 (bs, 1H), 9.40 (bs, 1H), 9.09 (bs, 1H), 8.19 (bs, 1H), 7.88 (d, 1H), 7.47 (d, 1H), 4.12 (m, 1H), 3.45 - 3.24 (m, 1H), 2.99 (d, 1H), 2.29 (d, 1H), 1.95 - 1.45 (m, 5H); LCMS: 3.94 min, m / z = 346.4 [M+H]+.

[0130] Int-2d-(S): (S)-A-(6-(Trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2- carboxamide hydrochloride saltlnt-2d (S)

[0131] (S)-A-(6-(Trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide hydrochloride salt (Int-2d-(S)) was synthesized in a similar manner to Int-2a-(R) from riluzole and Boc-L-pipecolic acid.

[0132] Int-2e-(R): (R)-A-(6-(Trifluorom ethoxy )benzo[d]thiazol-2-yl)azetidine-2- carboxamide hydrochloride saltlnt-2e (R)

[0133] (R)-7V-(6-(Trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide hydrochloride salt (Int-2e-(R)) was synthesized in a similar manner to Int-2a-(R) from riluzole and Boc-(R)-azetidine-2-carboxylicacid. ’H NMR (400 MHz, DMSO-tL) 5 = 9.40 (bs, 1H), 9.19 (bs, 1H), 8.25 - 8.16 (m, 1H), 7.93 - 7.84 (m, 1H), 7.52 - 7.42 (m, 1H), 5.28 - 5.05 (bs, 1H), 4.51 - 4.43 (m, 1H), 4.12 - 3.70 (m, 1H), 2.85 - 2.55 (m, 2H); LCMS: 3.96 min, m / z =318.4 [M+H]+.

[0134] Int-2e-(S): (S)-7V-(6-(Trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2- carboxamide hydrochloride saltlnt-2e (S)

[0135] (S)-7V-(6-(Trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide hydrochloride salt (Int-2e-(S)) was synthesized in a similar manner to Int-2a-(R) from riluzole and Boc-(S)-azetidine-2-carboxylicacid.

[0136] Int-2f-(S): (S)-7V-(6-(Trifluorom ethoxy )benzo[d]thiazol-2-yl)morpholine-3- carboxamide hydrochloride saltn - ( )

[0137] (S)-7V-(6-(Trifluoromethoxy)benzo[d]thiazol-2-yl)morpholine-3-carboxamide hydrochloride salt (Int-2f-(S)) was synthesized in a similar manner to Int-2a-(R) from riluzole and Boc-(S)-morpholine-2-carboxylicacid. 'HNMR (400 MHz, Methanol-t / 4) 5 = 7.89 (d, 1H), 7.81 (d, 1H), 7.40 (ddd, 1H), 4.49 - 4.35 (m, 2H), 4.12 - 4.01 (m, 1H), 3.94 - 3.78 (m, 2H), 3.55 - 3.46 (m, 1H), 3.41 - 3.32 (m, 1H); LCMS: 3.63 min, m / z = 348.3 [M+H]+.

[0138] General procedure for the synthesis of substituted (9-acyl glycolic acids (Int-3) via acid chloride mediated acylation of a substituted glycolic acid benzyl ester (Scheme 2),Scheme 2

[0139] To a solution of the (un) substituted glycolic acid benzyl ester (A) (1.0 eq.), N,N- diisopropylethylamine (1.5 eq.) and 7V,7V-dimethylaminopyridine (0.2 eq.) in methylene chloride at 0 °C was added the acid chloride (1.5 eq.) and the mixture was stirred at 0 °C for 1 h. The mixture was diluted with methylene chloride and washed with 1 M aqueous HC1, followed by saturated brine. The organic phase was dried over MgSCU, and the solvent was removed in vacuo. The resulting O-acyl glycolic acid benzyl ester (B) as a solution in methanol was stirred under a hydrogen atmosphere in the presence of 10% palladium on charcoal (50% wet with water) for 2 h. The mixture was filtered through Celite® and the pad was washed with methanol. The combined filtrate was evaporated in vacuo to provide the O-acyl glycolic acid (Int-3).

[0140] Exemplary synthesis of (S)-2-acetoxy-3 -methylbutanoic acid (Int-3a).Aa lnt-3a

[0141] To a solution of benzyl (S)-2-hydroxy-3-methylbutanoate (0.50 g, 2.4 mmol), 7V,7V-diisopropylethylamine (0.46 g, 0.65 mL, 3.6 mmol) and 7V,7V-dimethylaminopyridine (59 mg, 0.48 mmol) in methylene chloride (10 mL) at 0 °C was added acetyl chloride (0.25 mL, 3.6 mmol) and the mixture was stirred at 0 °C for 1 h. The mixture was diluted with methylene chloride (50 mL) and washed with 1 M aqueous HC1 (25 mL), followed by saturated brine (25 mL). The organic phase was dried over MgSCL, and the solvent was removed in vacuo. The resulting (S)-benzyl 2-acetoxy-3-methylbutanoate in methanol (10 mL) containing 10% Pd / C (50% wet with water, 50 mg) was purged with hydrogen gas via balloon and adaptor and then stirred under a hydrogen atmosphere for 2 h. The mixture was filtered through Celite® and the pad was washed with methanol. The combined filtrate was evaporated in vacuo to provide (S)- 2-acetoxy-3 -methylbutanoic acid (Int-3a) (0.2 g, 1.3 mmol, 53%).XH NMR (300 MHz, Chloroforms / ) 5 = 4.87 (d, 1H), 2.26 (dquin, 1H), 2.15 (s, 3H), 1.03 (d, 3H), 1.01 (d, 3H).

[0142] General procedure for the synthesis of substituted (9-acyl glycolic acids (Int-3) via EDC / carboxylic acid mediated acylation of a substituted glycolic acid benzyl ester (Scheme ILScheme 3

[0143] To a mixture of the (un) substituted glycolic acid benzyl ester (A) (1.0 eq), the carboxylic acid (1.1 eq.) and 7V,7V-dimethylaminopyridine (0.1 eq.) in methylene chloride was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 eq.) and the mixture was stirred at room temperature for 16 h. The mixture was diluted with methylene chloride and washed with 0.5 M aqueous HC1, followed by saturated aqueous sodium bicarbonate solution. The organic phase was dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified by chromatography to provide the ( -acyl glycolic acid benzyl ester (B) which was subjected to hydrogenation in the presence of 10% palladium on charcoal (50% wet with water). The mixture was filtered through Celite® and the pad was washed with methanol. The combined filtrate was evaporated in vacuo to provide the ( -acyl glycolic acid (Int-3).

[0144] Exemplary synthesis of 2-(T(7c / 7-butoxycarbonyl )-L-valyl )oxy lacetic acid(Int-3b)

[0145] To a mixture of benzyl 2-hydroxyacetate (Ab) (0.5 g, 3.0 mmol), Boc-L-valine (0.63 g, 2.9 mmol), and 7V,7V-dimethylaminopyridine (37 mg, 0.3 mmol) in methylene chloride (15 mL) was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g, 3.6 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was diluted with methylene chloride (10 mL) and washed with 0.5 M aqueous HC1 (10 mL), followed by saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, eluting with a linear gradient of 0 to 30% ethyl acetate / hexanes) to provide 2-(benzyloxy)-2-oxoethyl (terLbutoxycarbonyl)-L-valinate (Bb) (0.92 g, 2.5 mmol, 87%) as a colorless oil. ’H NMR (400MHz, Chloroforms / ) 5 = 7.47 - 7.29 (m, 5H), 5.20 (s, 2H), 5.00 (d, 1H), 4.92 - 4.50 (m, 2H), 4.34 (dd, 1H), 2.35 - 2.17 (m, 1H), 1.51 - 1.40 (m, 9H), 1.01 (d, 3H), 0.93 (d, 3H); LCMS: 5.57 min, m / z = 266.6 [M+H-Boc]+.

[0146] 2-(Benzyloxy)-2-oxoethyl (tert-butoxycarbonyl)-L-valinate (Bb) (0.67 g, 1.8 mmol) was dissolved in ethyl acetate (30 mL) and placed under nitrogen atmosphere and palladium on activated carbon (10 wt. %, 180 mg) was added to the solution. A vacuum was applied, followed by hydrogen balloon. After repeating three times, the mixture was stirred under a hydrogen atmosphere (balloon) for 16 h. The mixture was filtered through Celite® andthe pad was washed with ethyl acetate (20 mL). The combined filtrate was concentrated in vacuo and dried under high vacuum to provide 2-(((te / 7-butoxycarbonyl)-L-valyl)oxy)acetic acid (Int-3b) (0.45 g, 89%) as a colorless oil.XH NMR (400 MHz, Chloroform-t / ) 5 = 5.03 (d, 1H), 4.88 - 4.61 (m, 2H), 4.28 (dd, 1H), 2.35 - 2.15 (m, 1H), 1.46 (s, 9H), 1.09 - 0.88 (m, 6H); LCMS: 4.05 min, m / z = 176.5 [M+H-Boc]+.

[0147] General procedure for the synthesis of compounds of formula I via HATU mediated coupling of Int-2 with Int-3 (Scheme 4),Scheme 4

[0148] To a mixture of Int-2 (1.0 eq.), Int-3 (1.0 eq.) and A,A-diisopropylethylamine (3.0 eq.) in DMF was added hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU, 1.0 eq.) and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate and washed with water (2 X) followed by 1 M aqueous HC1. The organic phase was dried over MgSCL, filtered and the solvent was removed in vacuo. The residue was purified by chromatography to provide compounds of formula I.

[0149] Exemplary synthesis of (S)-3-methyl-l-oxo-l-((R)-2-((6-(tri fluoromethoxy )benzo[d]thiazol-2-yl)carbamoyl)pyrrolidin-l-yl)butan-2-yl acetate (Compound 1).

[0150] To a mixture of (R)-A-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine- 2-carboxamide hydrochloride salt (Int-2a(R)) (219 mg, 0.59 mmol), (S)-2-acetoxy-3- methylbutanoic acid (Int-3a) (95 mg, 0.59 mmol) and MA-diisopropylethylamine (0.23 g, 0.32 ml, 1.8 mmol) in DMF (2 mL) was added hexafluorophosphate azabenzotri azole tetramethyl uronium (HATU, 0.22 g, 0.59 mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate (30 mL) and washed with water (2 X 30 mL) followed by 1 M aqueous HC1 (25 mL). The organic phase was dried over MgSCL, filteredand the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, eluting with a linear gradient of 20-80% ethyl acetate / hexanes) to provide (S)-3-methyl- 1 -oxo- 1 -((R)-2-((6-(trifluorom ethoxy )benzo[d] thiazol-2-yl)carbamoyl)pyrrolidin- 1 -yl)butan- 2-yl acetate (Compound 1, 190 mg, 68%) as a viscous oil. 'H NMR (400 MHz, Methanol-t / 4) 5 = 7.89-7.81 (m, 1H), 7.78 (d, 1H), 7.33 (m, 1H), 5.00 (d, 1H), 4.66 (dd, 1H), 4.59 (s, 1H), 4.05 - 3.96 (m, 1H), 3.76 - 3.59 (m, 1H), 2.33-1.98 (m, 5H), 2.10 (s, 3H), 1.04 (m, 6H).

[0151] Characterization data for Compound 1 and other compounds synthesized according to a similar protocol is shown below in Table 2.Table 2: Characterization Data for Exemplary Riluzole ProdrugsEXAMPLESGeneral methods:

[0152] Assessment of compound stability in Simulated Gastric Fluid (SGF) and Simulated Intestinal Fluid (SIF):

[0153] Preparation of Simulated Gastric Fluid (2 mL): 4 mg of sodium chloride and 6.4 mg of pepsin were dissolved in 140 pL of 1.2 N aqueous HC1 with vortexing. Once the mixture appeared milky white, water (1.86 mL) was added to provide a homogeneous solution of a total volume of 2 mL. The initial pH of the blank SGF solution was measured to approximately pH 1.4. Once the test compound solution was added, the final pH of the SGF was adjusted to pH 1.2.

[0154] Preparation of Simulated Intestinal Fluid (2 mL): 13.6 mg monobasic potassium phosphate was added to 0.5 mL water. Then 154 pL of 0.2 N aqueous NaOH and 1.0 mL of water were added to the mixture. Finally, 20 mg of pancreatin was added slowly with stirring to the solution immediately prior to utilization of the solution and water (about 0.346 mL) was added to bring the total volume to 2 mL. Once the test compound solution was added, the final pH of the SIF was adjusted to pH 6.8.

[0155] Incubation: For each test compound, samples at a final concentration of 1 pM (final organic solvent concentration of 0.5%, v / v) were prepared in respective blank simulated gastric fluid with pepsin (pH 1.2) and simulated intestinal fluid with pancreatin (pH 6.8). All samples were incubated at 37 °C on a 150-RPM orbital shaker, and aliquots were removed at pre-determined time points (0, 30, 60, 120 and 180 minutes). Samples were precipitated with three volumes of acetonitrile containing an internal standard and centrifuged for 10 min at 2000 g before LC-MS / MS analysis of the supernatant solutions.

[0156] Data Analysis: Percent of parent compound remaining was determined relative to 0-minute incubation samples for each compound based on peak area ratios, from which the degradation half-life was calculated based on the natural log of % compound remaining vs. time plot.Assessment of Compound Stability in Blood Plasma:

[0157] Sample Preparation / Incubation: For each test compound, samples at a final concentration of 2 pM (final organic solvent concentration of 0.5%, v / v) were prepared in blank plasma of the selected species. All samples were incubated at 37 °C on a 150-RPM orbital shaker, and aliquots were removed at pre-determined time points (0, 30, 60, 120 and 240 minutes). All incubated plasma samples were prepared as follows for bioanalysis. Three volumes of acetonitrile containing internal standard were added to one volume of plasma toprecipitate proteins. Samples were centrifuged (3000 g for 10 min) and supernatant removed for analysis by LC-MS / MS.

[0158] Data Analysis: Percent of parent compound remaining is determined relative to 0-minute incubation samples based on the peak area ratios, from which the degradation halflife is calculated based on the natural log of % compound remaining vs. time plot.Example P. Stability andPK / PD of Compound 1

[0159] Compound 1 was prepared and its stability and pharmacokinetic / pharmacodynamic (PK / PD) properties were investigated. Compound 1 has an ester functionality stable to gut transport and first passage through the liver followed by cleavage by blood and liver borne esterases and lipases to provide an intermediate alcohol which is suitably disposed for cleavage and release of riluzole, as depicted in Scheme 4 below. The alcohol-containing dipeptide from compound 1 is highly conformationally biased so when the alcohol is formed it cyclizes to a morpholine dione in a time-dependent manner and then releases riluzole. Since the morpholine dione thus produced contains an ester functionality, it would be expected to cleave quickly itself by the action of esterases, which would form a non-toxic substituted proline analog for clearance from the body.Scheme 4: Exemplary mechanism of riluzole release from compound 1.As shown in Table 3 below, the stability of compound 1 was investigated in plasma (mouse, rat, dog, monkey, and human; indicated as % remaining after 4 hours), simulated gastric fluid (SGF; indicated as % remaining after 2 hours), simulated intestinal fluid (SIF; indicated as % remaining after 2 hours). As can be seen from the results, compound 1 is relatively stable in plasma from five species and in simulated gastric and intestinal fluids. This indicates that the prodrug should be suitable for administration and prolonged release of riluzole into the plasma of patients.Table 3: In vitro stability data for compound 1.

[0160] Compound 1 was administered orally (PO) or intravenously (IV) to CD-I mice in a vehicle of 10% DMA, 30% PEG300, and 60% H2O. The plasma concentrations of compound 1 and riluzole released from compound 1 were collected at various time points after administration from plasma as shown in FIGs. 1 A-1D. Corresponding PK / PD data is shown in Tables 4 - 7 below. Compound 1 has good oral bioavailability (%F = 62) and converts to riluzole in a regular manner over time (FIGs. 1 A-1D). In FIG. 2 the levels of riluzole and compound 1 upon oral administration of compound 1 are overlaid upon each other showing an excellent regular rate of conversion of compound 1 to riluzole (Tmax 2.0 hrs).Table 4: Compound 1 PK / PD parameters; Compound 1 administered intravenously at dosage of 5,0 mg / kg, dose volume of 5,0 mL / kgTable 5: Compound 1 PK / PD parameters; Compound 1 administered PO at dosage of 20.0 mg / kg dose volume of 20,0 mL / kgTable 6: Riluzole PK / PD parameters; Compound 1 administered intravenously at dosage of 5,00 mg / kg (equivalent to 2,48 mg / kg dose of riluzole) dose volume of 5,0 mL / kg,Table 7: Riluzole PK / PD parameters; Compound 1 administered PO at dosage of 20.00 mg / kg (equivalent to 9,90 mg / kg dose of riluzole), dose volume of 20,0 mL / kg,Example 2: Stability of Structurally Diverse Prodrugs of RiluzoleAs shown in Table 8 below, the stability of exemplary prodrugs of riluzole was investigated in plasma (mouse and human; indicated as % remaining after 4 hours), simulated gastric fluid (SGF; indicated as % remaining after 2 hours), and simulated intestinal fluid (SIF; indicated as % remaining after 2 hours).Table 8: Stability data for exemplary prodrugs of riluzole.Example 3: PK / PD of Compound 13

[0161] Compound 13 was administered orally (PO) or intravenously to CD-I mice in a vehicle of 10% DMA, 30% PEG300, and 60% H2O. The plasma concentrations of compound 13 and riluzole released from compound 13 were collected at various time points after administration from plasma as shown in FIGs. 3 A-3D. Corresponding PK / PD data is shown in Tables 9- 12 below. Compound 13 is quickly and efficiently converted to riluzole following IV or PO administration (FIGs. 3 A-3D). Compared with the Compound 1 PK / PD results, it can be seen that the prodrug is decomposed faster for compound 13, yet riluzole concentrations are generally maintained over a similar time period. At the 20.00 mg / kg oral dosage, the AUCinf for released riluzole was 8542 hr*ng / mL for compound 1, compared with 6692 hr*ng / mL for compound 13. Overall, these results demonstrate that prodrugs have advantageous release profiles for improved delivery of riluzole.Table 9: Compound 13 PK / PD parameters; Compound 13 administered intravenously at dosage of 5,0 mg / kg, dose volume of 5,0 mL / kg,Table 10: Compound 13 PK / PD parameters; Compound 13 administered PO at dosage of dose volume of 20.0 mL / kg.Table 11 : Riluzole PK / PD parameters; Compound 13 administered intravenously at dosage of 5,00 mg / kg (equivalent to 2,72 mg / kg dose of riluzole), dose volume of 5,0 mL / kg,Table 12: Riluzole PK / PD parameters; Compound 13 administered PO at dosage of 20.00 mg / kg (equivalent to 10.9 mg / kg dose of riluzole), dose volume of 20.0 mL / kg.Example 4: PK / PD of Compound 24Compound 24 was administered orally (PO) or intravenously (IV) to CD-I mice in a vehicle of 10% DMA, 30% PEG300, and 60% H2O. The plasma concentrations of compound 24 and riluzole released from compound 24 were collected at various time points after administration from plasma as shown in FIGs. 4A-4D. Corresponding PK / PD data is shown in Tables 13-16 below. Compound 24 is quickly and efficiently converted to riluzole following IV or PO administration (FIGs. 4A-4D). As observed with the compound 13 PK / PD results, it can be seen that the prodrug (compound 24) is rapidly decomposed, and riluzole concentrations are generally maintained over a similar time period. At the 20.00 mg / kg oral dosage, the AUCinf for released riluzole was 9394 hr*ng / mL for compound 24. These results further demonstrate that prodrugs have advantageous release profiles for improved delivery of riluzole.Table 13: Compound 24 PK / PD parameters; Compound 24 administered intravenously at dosage of 5,0 mg / kg, dose volume of 5,0 mL / kg,Table 14: Compound 24 PK / PD parameters; Compound 24 administered PO at dosage of 20,0 mg / kg dose volume of 20,0 mL / kg,Table 15: Riluzole PK / PD parameters; Compound 24 administered intravenously at dosage of 5,00 mg / kg (equivalent to 2,89 mg / kg dose of riluzole), dose volume of 5,0 mL / kg,Table 16: Riluzole PK / PD parameters; Compound 24 administered PO at dosage of 20.00 mg / kg (equivalent to 11.6 mg / kg dose of riluzole), dose volume of 20,0 mL / kg,INCORPORATON BY REFERENCE

[0162] The entire disclosure of each of the patent documents, including certificates of correction, patent application documents, scientific articles, governmental reports, websites, and other references referred to herein is incorporated by reference herein in its entirety for all purposes. In case of a conflict in terminology, the present specification controls.EQUIVALENTS

[0163] The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are to be considered in all respects illustrative rather than limiting on the invention described herein. In the various embodiments of the present invention, where the term comprises is used with respect to the recited components or steps of the platforms or methods, it is also contemplated that the platforms and methods consist essentially of, or consist of, the recited components or steps. Furthermore, the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0164] In the specification, the singular forms also include the plural forms, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification will control.

[0165] All percentages and ratios used herein, unless otherwise indicated, are by weight.

Claims

CLAIMS1. A riluzole prodrug according to Formula I:Formula I or a pharmaceutically-acceptable salt thereof, whereinL is C3-C5 alkylene, C3-C5 heteroalkylene, -Q-T-, or -T-Q-, wherein L is unsubstituted or mono-, di-, tri-, or polysubstituted at one or more positions with one or more -RL;Q is C4-C10 heterocycloalkyl or C4-C10 heteroaryl;T is C1-C4 alkyl or C2-C4 heteroalkylene;RLis, at each occurrence, independently selected from C1-C4 alkyl, C2-C4 heteroalkyl, an amino acid side chain, and carbonyl; andR4is C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5- C9 heteroaryl, each unsubstituted or mono-, di-, tri-, or polysubstituted with -NH2, carbonyl, cyano, methyl, ethyl, propyl, hydroxyl, -O-PO3H2, -O-PO3(CH3)2, -O-SO3H, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, said C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl unsubstituted or mono-, di-, tri-, or polysubstituted with -NH2, carbonyl, cyano, methyl, ethyl, propyl, or hydroxyl; or R4is, together with the carbonyl to which it is attached, an amino acid or amino acid analogue.

2. A riluzole prodrug according to claim 1, wherein RLis methyl, ethyl, propyl (including n-propyl or isopropyl), butyl (including n-butyl, s-butyl, tert-butyl, or isobutyl), or carbonyl.

3. A riluzole prodrug according to claim 1, wherein L is C3 heteroalkylene, C4 heteroalkylene.

4. A riluzole prodrug according to claim 1, wherein L is C4 heteroalkylene.

5. A riluzole prodrug according to claim 1, wherein L is:wherein RL1, RL2, RL3, RL4, and RL5are independently selected from -H, methyl, ethyl, isopropyl and an amino acid side chain.

6. A riluzole prodrug according to claim 1, wherein L is Q-T, and Q is a 4-membered, 5- membered, or 6-membered heterocycloalkyl.

7. A riluzole prodrug according to claim 6, wherein, Q is:

8. A riluzole prodrug according to claim 6 or claim 7, wherein T is C2 alkylene mono-, di-, tri-, or polysubstituted with RL.

9. A riluzole prodrug according to claim 8, wherein T is -(C=O)-CHRL- or -(C=O)- C(RL)2, wherein each RLis independently selected from -H, methyl, ethyl, and isopropyl.

10. A riluzole prodrug according to claim 1, wherein R4is methyl, ethyl, propyl, or butyl, connected directly or through a linking group selected from -CH2- and -CH2-O-.

11. A riluzole prodrug according to claim 1, wherein R4is oxane, tetrahydrofuran, pyrrolidine, pyridine, piperidine, imidazole, thiazole, dioxane, morpholine, or pyrimidine connected directly or through a linking group selected from -CH2- and -CH2-O-.

12. A riluzole prodrug according to Formula la:Formula la or a pharmaceutically acceptable salt thereof, wherein:Rla, Rlb, and R2are R’, orRlais R’ or absent, and Rlband R2combine to form C4-C10 heterocycloalkyl or C4-C10 heteroaryl;R’ is independently selected from, at each occurrence, -H, C1-C3 alkyl, C2-C3 heteroalkyl, and an amino acid side chain;R3aand R3bare independently -H, C1-C4 alkyl, and C2-C4 heteroalkyl; andR4is C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5- C9 heteroaryl, each unsubstituted or mono-, di-, tri-, or polysubstituted with -NH2, carbonyl, cyano, methyl, ethyl, propyl, hydroxyl, -O-PO3H2, -O-PO3(CH3)2, -O-SO3H, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, said C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl unsubstituted or mono-, di-, tri-, or polysubstituted with -NH2, carbonyl, cyano, methyl, ethyl, propyl, or hydroxyl;, or R4is, together with the carbonyl to which it is attached, an amino acid or amino acid analogue.

13. A riluzole prodrug according to claim 12, wherein Rlaand Rlbare -H.

14. A riluzole prodrug according to claim 12, wherein Rlband R2combine to form a C4- C10 heterocycloalkyl.

15. A riluzole prodrug according to claim 14, wherein Rlband R2combine to form a C4 heterocycloalkyl, C5 heterocycloalkyl, or Ce heterocycloalkyl.

16. A riluzole prodrug according to claim 14 or claim 15, wherein Rlband R2combine to form a C5 heterocycloalkyl.

17. A riluzole prodrug according to claim 15, wherein Rlband R2combine to form18. A riluzole prodrug according to claim 12, wherein R2is methyl, ethyl, or propyl.

19. A riluzole prodrug according to claim 18, wherein R2is methyl.

20. A riluzole prodrug according to claim 12, wherein one of R3aand R3bis -H, and the other is methyl, ethyl, propyl, butyl.

21. A riluzole prodrug according to claim 12, wherein R3aand R3bare methyl.

22. A riluzole prodrug according to claim 12, wherein R3aand R3bare -H.

23. A riluzole prodrug according to claim 12, wherein R4is methyl, ethyl, propyl, or butyl, connected directly or through a linking group selected from -CH2- and -CH2-O-.

24. A riluzole prodrug according to claim 12, wherein R4is oxane, tetrahydrofuran, pyrrolidine, pyridine, piperidine, imidazole, thiazole, dioxane, morpholine, or pyrimidine, connected directly or through a linking group selected from -CH2- and -CH2-O-.

25. A riluzole prodrug according to Formula lb:or a pharmaceutically acceptable salt thereof, wherein:Rlais -H, C1-C3 alkyl, or C2-C3 heteroalkyl, or Rlais absent;Q is C4-C10 heterocycloalkyl or C4-C10 heteroaryl;R3aand R3bare independently -H, C1-C4 alkyl, and C2-C4 heteroalkyl;R4is C1-C5 alkyl, C2-C5 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5- C9 heteroaryl, each optionally substituted with -NH2, carbonyl, cyano, methyl, ethyl, propyl, hydroxyl, -O-PO3H2, -O-PCh CHa -O-SO3H, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl, said C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or C5-C9 heteroaryl unsubstituted or mono-, di-, tri-, or polysubstituted with -NH2, carbonyl, cyano, methyl, ethyl, propyl, or hydroxyl, orR4is, together with the carbonyl to which it is attached, an amino acid or amino acid analogue.

26. A riluzole prodrug according to claim 25, wherein Q is a 4-membered, 5-membered, or 6-membered heterocycloalkyl.

27. A riluzole prodrug according to claim 26, wherein Q is:

28. A riluzole prodrug according to claim 25, wherein one of R3aand R3bis -H, and the other is methyl, ethyl, propyl, or butyl.

29. A riluzole prodrug according to claim 25, wherein R3aand R3bare methyl.

30. A riluzole prodrug according to claim 25, wherein R3aand R3bare -H.

31. A riluzole prodrug according to claim 25, wherein R4is methyl, ethyl, propyl, or butyl, connected directly or through a linking group selected from -CH2- or -CH2-O-.

32. A riluzole prodrug according to claim 25, wherein R4is oxane, tetrahydrofuran, pyrrolidine, pyridine, piperidine, imidazole, thiazole, dioxane, morpholine, or pyrimidine, connected directly or through a linking group selected from -CH2- or -CH2-O-.

33. A riluzole prodrug, or a pharmaceutically acceptable salt thereof, selected from:

34. A method for treating a glutamate-associated disorder, comprising administering a therapeutically-effective amount of a riluzole prodrug according to any one of claims 1 - 33 to a subject in need thereof.

35. A method according to claim 34, wherein the glutamate-associated disorder is a central nervous system (CNS) disorder, a neuropsychiatric disorder, or a neurodegenerative disorder.

36. A method according to claim 35, wherein the glutamate-associated disorder is a central nervous system (CNS) disorder selected from depression and anxiety.

37. A method according to claim 35, wherein the glutamate-associated disorder is a neuropsychiatric disorder selected from obsessive-compulsive disorder (OCD).

38. A method according to claim 35, wherein the glutamate-associated disorder is a neurodegenerative disorder selected from spinocerebellar ataxia.

39. A method according to claim 38, wherein the spinocerebellar ataxia is selected from types 1, 2, 3, 6, 7, 8, and 10.

40. A method according to claim 39, wherein the spinocerebellar ataxia is spinocerebellar ataxia type 3.

41. A method according to claim 34, wherein the glutamate-associated disorder is cancer.

42. A method according to claim 41, wherein the cancer is glioblastoma, prostate cancer, pancreatic cancer, melanoma or ovarian cancer.

43. A method according to claim 34, wherein the glutamate-associated disorder is a substance use disorder.

44. A pharmaceutical composition comprising a riluzole prodrug according to any one of claims 1 - 33, and a pharmaceutically-acceptable carrier.

45. A method for treating a glutamate-associated disorder, comprising administering a therapeutically-effective amount of a pharmaceutical composition according to claim 44 to a subject in need thereof.

46. A method according to claim 45, wherein the glutamate-associated disorder is a central nervous system (CNS) disorder, a neuropsychiatric disorder, or a neurodegenerative disorder.

47. A method according to claim 46, wherein the glutamate-associated disorder is a central nervous system (CNS) disorder selected from depression and anxiety.

48. A method according to claim 46, wherein the glutamate-associated disorder is a neuropsychiatric disorder selected from obsessive-compulsive disorder (OCD).

49. A method according to claim 46, wherein the glutamate-associated disorder is a neurodegenerative disorder selected from spinocerebellar ataxia.

50. A method according to claim 49, wherein the spinocerebellar ataxia is selected from types 1, 2, 3, 6, 7, 8, and 10.

51. A method according to claim 50, wherein the spinocerebellar ataxia is spinocerebellar ataxia type 3.

52. A method according to claim 45, wherein the glutamate-associated disorder is cancer.

53. A method according to claim 52, wherein the cancer is glioblastoma, prostate cancer, pancreatic cancer, melanoma or ovarian cancer.

54. A method according to claim 45, wherein the glutamate-associated disorder is a substance use disorder.

55. The use of a compound according to any one of claim 1 to 33 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a glutamate-associated disorder.

56. The use of claim 55, wherein the glutamate-associated disorder is a central nervous system (CNS) disorder, a neuropsychiatric disorder, or a neurodegenerative disorder.

57. The use of claim 56, wherein the glutamate-associated disorder is a central nervous system (CNS) disorder selected from depression and anxiety.

58. The use of claim 56, wherein the glutamate-associated disorder is a neuropsychiatric disorder selected from obsessive-compulsive disorder (OCD).

59. The use of claim 56, wherein the glutamate-associated disorder is a neurodegenerative disorder selected from spinocerebellar ataxia.

60. The use of claim 59, wherein the spinocerebellar ataxia is selected from types 1, 2, 3, 6, 7, 8, and 10.

61. The use of claim 60, wherein the spinocerebellar ataxia is spinocerebellar ataxia type 3.

62. The use of claim 55, wherein the glutamate-associated disorder is cancer.

63. The use of claim 62, wherein the cancer is glioblastoma, prostate cancer, pancreatic cancer, melanoma or ovarian cancer.

64. The use of claim 55, wherein the glutamate-associated disorder is a substance use disorder.

65. A method of releasing riluzole into the plasma of a patient in need thereof, comprising administering to the patient a riluzole prodrug according to any one of claims 1-33.

66. The method of claim 65, wherein administering the riluzole prodrug causes the ester group of the prodrug to be cleaved to form a terminal reactive hydroxy group, and wherein the terminal reactive hydroxy group subsequently reacts intramolecularly to release riluzole into the plasma of the patient.

67. The method of claim 66, wherein the intramolecular reaction is a cyclization reaction.

68. The method of claim 67, wherein the cyclization reaction forms a 5, 6, or 7-membered ring.

69. The method of claim 65, wherein the patient in need thereof is suffering from a central nervous system (CNS) disorder, a neuropsychiatric disorder, a neurodegenerative disorder, a cancer, or a substance abuse disorder, and wherein administering the riluzole prodrug to the patient contacts the plasma of the patient with a therapeutically effective amount of riluzole.

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