Compositions of antioxidant translation modulators for treating neurodegenerative disorders

Abstract

The present invention provides compositions and methods for treating disorders of the central nervous system. In some embodiments, compositions of the present invention comprise novel compounds further comprising a heterocyclic core optionally fused with a 6-membered carbocyclic ring and a non-electrophilic substituent. In one embodiment, the disorder of the central nervous system which can be treated using the present invention is Alzheimer's disease.

Description

COMPOSITIONS OF ANTIOXIDANT TRANSLATION MODULATORS FOR TREATING NEURODEGENERATIVE DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS[1] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 622,654, filed January 19, 2024, the entire contents of which are incorporated herein by reference.BACKGROUND OF THE INVENTION[2] There is a present need in the art for compositions and methods for the treatment of neurodegenerative disorders such as Alzheimer's Disease. The present invention addresses this unmet need.SUMMARY OF THE INVENTION[3] The present invention is drawn, in part, to a compound represented by the following General Formula I,General Formula I wherein X1is selected from the group consisting of O, S, NR’, BR’, CR’R”, and SiR’R”; X2is selected from the group consisting of O, S, NR’; ring A can be present or absent; ring B represents a 5-membered or 6-membered heterocyclic or carbocyclic ring; ring C represents a 5- membered or 6-membered heterocyclic or carbocyclic ring; R’, and R” are each independently selected from the group consisting of deuterium, hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, and combinations thereof, and wherein any two substituents R’ and R” may be optionally joined to form a ring; RA, RB, and Rceach independently represent mono to the maximum allowable substitution, or no substitution; and each RA, RB, and Rcisindependently a hydrogen or a substituent selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof, and wherein any two substituents RA, RB, and Rcmay be optionally joined to form a ring.[4] In one embodiment, X1is O. In one embodiment, X2is O. In one embodiment, ring A is present. In one embodiment, ring A is absent. In one embodiment, ring B is a 6-membered heterocyclic ring.[5] In one embodiment, the compound is represented by General Formula II,General Formula II wherein each of Y1to Y10is independently C, CRX, or N; and Rxis a substituent selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof.[6] In one embodiment, at least one of Y1to Y5is N.[7] In one embodiment, the compound is represented by General Formula III,General Formula III.[8] In one embodiment, each RB is an alkyoxy group.[9] The present invention is further drawn to a method of treating a CNS disorder in a subject in need thereof, the method comprising the step of: administering to the subject a compound represented by the following General Formula I,General Formula I wherein X1and X2are each independently O, S, Se, NR’, BR’, CR’R”, and SiR’R”; ring A can be present or absent; ring B represents a 5-membered or 6-membered heterocyclic or carbocyclic ring; ring C represents a 5-membered or 6-membered heterocyclic or carbocyclic ring; R’, and R” are each independently selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, and combinations thereof, and wherein any two substituents R’ and R” may be optionally joined to form a ring; RA, RB, and Rceach independently represent mono to the maximum allowable substitution, or no substitution; and each RA, RB, and Rcis independently a hydrogen or a substituent selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl,alkoxy, aryloxy, amino, silyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof, and wherein any two substituents RA, RB, and Rcmay be optionally joined to form a ring.

[0010] In one embodiment, the compound described by General Formula I facilitates Nrf2 translation. In one embodiment, the compound described by General Formula I binds to GSTM2. In one embodiment, Keapl is not affected. In one embodiment, the CNS disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Bell’s palsy, cerebral palsy, epilepsy, and multiple sclerosis.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The following detailed description of various embodiments of the invention will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings illustrative embodiments. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0012] Fig. 1 depicts target engagement and toxicity profile of the selected Nrf2 translational activators. Nrf2 translation was determined in the HEK293 cell lines containing a novel repressor. Nrf2 nuclear levels were from Keapl KO SH-SY5Y cells (left Westerns: vehicle; right Westerns: drug treatment). ECso and HO-1 levels were determined in primary neurons.

[0013] Fig. 2 depicts predicted docking and target engagement studies of MC180446 using docking studies with GSTM2 comparing MCI 80446 (upper panels) to glutathione (bottom panels). PYMOL was used for visualization.

[0014] Fig. 3 depicts binding of MC180446 to GSTM2 as determined by DARTS assay.

[0015] Fig. 4 depicts Compound 1800446 activation of a wide array of Nrf2 regulated antioxidant proteins independent of Keapl in SHSY-5Y cells as determined by unbiased global proteomics studies.

[0016] Fig. 5 depicts reduction in total ROS and mitochondrial ROS by 180446. Quantitation of individual cell total ROS intensity (n=200 cells). ** p<0.001, ****p<0.0001.

[0017] Fig. 6 depicts grouped carbonylome analysis (n=3 per group) to show the capability of MCI 80446 to reduce 4-HNE protein adducts (p<0.05 compared to untreated) produced by A|3, including tau (blue arrow). The quantitation of tau peptide containing 4-HNE adduct (bottom). Data mean±SE,*p<0.001 vs. untreated and Ab+180446.

[0018] Fig. 7 depicts PK profile of single-dose study of MCI 80446. Plasma concentration-time profile (left figure). The table shows a non-compartmental model analysis for MC- 180446 in male mice (n=3) after intravenous and oral administration.DETAILED DESCRIPTIONDefinitions

[0019] 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. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

[0020] As used herein, each of the following terms has the meaning associated with it in this section.

[0021] The articles “a” and “an” are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0022] The term “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1 %, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0023] The term “abnormal” when used in the context of organisms, tissues, cells or components thereof, refers to those organisms, tissues, cells or components thereof that differ in at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) from those organisms, tissues, cells or components thereof that display the “normal” (expected) respective characteristic. Characteristics which are normal or expected for one cell or tissue type, might be abnormal for a different cell or tissue type.

[0024] An “allele” refers to one specific form of a genetic sequence (such as a gene) within a cell, an individual or within a population, the specific form differing from other forms of the same gene in the sequence of at least one, and frequently more than one, variant sites within the sequence of the gene. The sequences at these variant sites that differ between different alleles are termed “variants.” “polymorphisms,” or “mutations.”

[0025] As used herein the terms “alteration,” “defect,” “variation,” or “mutation,” refers to a mutation in a gene in a cell that affects the function, activity, expression (transcription or translation) or conformation of the polypeptide that it encodes. Mutations encompassed by the present invention can be any mutation of a gene in a cell that results in the enhancement or disruption of the function, activity, expression or conformation of the encoded polypeptide, including the complete absence of expression of the encoded protein and can include, for example, missense and nonsense mutations, insertions, deletions, frameshifts and premature terminations. Without being so limited, mutations encompassed by the present invention may alter splicing the mRNA (splice site mutation) or cause a shift in the reading frame (frameshift).

[0026] The term “amplification” refers to the operation by which the number of copies of a target nucleotide sequence present in a sample is multiplied.

[0027] The terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In certain non-limiting embodiments, the patient, subject or individual is a human.

[0028] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0029] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0030] As used herein, the term “diagnosis” refers to the determination of the presence of a disease or disorder. In various embodiments of the present invention, methods for making a diagnosis are provided which permit determination of the presence of a particular disease or disorder.

[0031] A disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.

[0032] To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject.

[0033] As used herein, the terms “therapy” or “therapeutic regimen” refer to those activities taken to alleviate or alter a disorder or disease state, e.g., a course of treatment intended to reduce or eliminate at least one sign or symptom of a disease or disorder using pharmacological, surgical, dietary and / or other techniques. A therapeutic regimen may include a prescribed dosage of one or more drugs or surgery. Therapies will most often be beneficial and reduce or eliminate at least one sign or symptom of the disorder or disease state, but in some instances the effect of a therapy will have non-desirable or side-effects. The effect of therapy will also be impacted by the physiological state of the subject, e.g., age, gender, genetics, weight, other disease conditions, etc.

[0034] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs or symptoms of a disease or disorder, for the purpose of diminishing or eliminating the severity and / or frequency of those signs or symptoms.

[0035] The terms “effective amount” and “pharmaceutically effective amount” refer to a sufficient amount of an agent to provide the desired biological result. That result can be reduction and / or alleviation of a sign, symptom, or cause of a disease or disorder, or any otherdesired alteration of a biological system. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0036] A “therapeutically effective amount” refers to that amount which provides a therapeutic effect for a given disease or disorder and administration regimen. In particular, “therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate the severity and / or frequency of at least one sign or symptom of the disease or disorder, or prolong the survival of the subject being treated, which may be a human or non-human animal.Determination of a therapeutically effective amount is within the skill of the person skilled in the art.

[0037] As used herein, the term “pharmaceutical composition” refers to a mixture of at least one compound of the invention with other chemical components and entities, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.

[0038] “Pharmaceutically acceptable” refers to those properties and / or substances which are acceptable to the patient from a pharmacological / toxicological point of view and to the manufacturing pharmaceutical chemist from a physical / chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability. “Pharmaceutically acceptable carrier” refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered.

[0039] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and notinjurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0040] The term “nutritional composition” may be a food product intended for human consumption, for example, a beverage, a drink, a bar, a snack, an ice cream, a dairy product, for example a chilled or a shelf-stable dairy product, a fermented dairy product, a drink, for example a milk-based drink, an infant formula, a growing-up milk, a confectionery product, a chocolate, a cereal product such as a breakfast cereal, a sauce, a soup, an instant drink, a frozen product intended for consumption after heating in a microwave or an oven, a ready-to-eat product, a fast food or a nutritional formula.

[0041] The term “solvate” in accordance with this invention should be understood as meaning any form of the active compound in accordance with the invention in which said compound isbonded by a non-covalent bond to another molecule (normally a polar solvent), including especially hydrates and alcoholates.

[0042] The term “inhibit,” as used herein, means to suppress or block an activity or function by at least about ten percent relative to a control value. In various embodiments, the activity is suppressed or blocked by at least 50% compared to a comparator value, or by at least 55%, or by at least 60%, or by at least 65%, or by at least 70%, or by at least 75%, or by at least 80%, or by at least 85%, or by at least 90%, or by at least 95%.

[0043] The term “label” when used herein refers to a detectable compound or composition that is conjugated directly or indirectly to a probe to generate a “labeled” probe. The label may be detectable by itself (e.g. radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable (e.g., avidin-biotin). In some instances, primers can be labeled to detect a PCR product.

[0044] By the term “specifically binds,” as used herein with respect to an antibody, is meant an antibody which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample. For example, an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more species. However, such cross-species reactivity does not itself alter the classification of an antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, such cross reactivity does not itself alter the classification of an antibody as specific. In some instances, the terms “specific binding” or “specifically binding,” can be used in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope “A”, the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled “A” and the antibody, will reduce the amount of labeled A bound to the antibody.

[0045] As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation isplaced on the maximum number of amino acids that can comprise a protein or peptide’s sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or any combination thereof.

[0046] As used herein, “polynucleotide” includes cDNA, RNA, DNA / RNA hybrid, antisense RNA, ribozyme, genomic DNA, synthetic forms, and mixed polymers, both sense and antisense strands, and may be chemically or biochemically modified to contain non-natural or derivatized, synthetic, or semi-synthetic nucleotide bases. Also, contemplated are alterations of a wild type or synthetic gene, including but not limited to deletion, insertion, substitution of one or more nucleotides, or fusion to other polynucleotide sequences.

[0047] Also disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This conceptapplies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0048] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, / / -propyl, isopropyl, n-butyl, isobutyl, s- butyl, / -butyl, / / -pentyl, isopentyl, -pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.

[0049] The terms “amine” or “amino” as used herein are represented by the formula NA1A2A3, where A1, A2, and A3can be, independently, hydrogen or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0050] The term “halide” as used herein refers to the halogens fluorine, chlorine, bromine, and iodine.

[0051] The term “hydroxyl” as used herein is represented by the formula — OH.

[0052] The term “nitro” as used herein is represented by the formula — NO2.

[0053] The term “nitrile” as used herein is represented by the formula — CN.

[0054] The term “thiol” as used herein is represented by the formula — SH.

[0055] The term “heterocyclyl” or the like terms refer to cyclic structures including a heteroatom. Thus, “heterocyclyl” includes both aromatic and non-aromatic ring structures with one or more heteroatoms. Non-limiting examples of heterocyclic includes, pyridine, isoquinoline, methylpyrrole and thiophene etc. “Heteroaryl” specifically denotes an aromatic cyclic structure including a heteroatom.

[0056] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.Compounds of the Invention

[0057] In part, the present invention discloses novel compounds comprising a heterocyclic core optionally fused with a 6-membered carbocyclic ring and a non-electrophilic substituent. These compounds may be useful in methods of treating disorders of the central nervous system.

[0058] In one aspect, the present invention relates to a compound represented by the following General Formula I,General Formula I whereinX1is selected from the group consisting of O, S, NR’, BR’, CR’R”, and SiR’R”;X2is selected from the group consisting of O, S, NR’; ring A can be present or absent; ring B represents a 5-membered or 6-membered heterocyclic or carbocyclic ring; ring C represents a 5-membered or 6-membered heterocyclic or carbocyclic ring;R’, and R” are each independently selected from the group consisting of deuterium, hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, and combinations thereof, and wherein any two substituents R’ and R” may be optionally joined to form a ring;RA, RB, and Rceach independently represent mono to the maximum allowable substitution, or no substitution; and each RA, RB, and Rcis independently a hydrogen or a substituent selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof, and wherein any two substituents RA, RB, and Rcmay be optionally joined to form a ring.

[0059] In one embodiment, X1is O. In one embodiment, X1is S. In one embodiment, X1is NR’. In one embodiment, X1is BR’. In one embodiment, X1is CR’R”. In one embodiment, X1is SiR’R”. In one embodiment, X2is O. In one embodiment, X2is S. In one embodiment, X2is NR’.

[0060] In one embodiment, ring A is present. In one embodiment, ring A is absent.

[0061] In one embodiment, ring B is a 5-membered heterocyclic ring. In one embodiment, ring B is a 6-membered heterocyclic ring. In one embodiment, ring B is a 5-membered carbocyclic ring. In one embodiment, ring B is a 6-membered carbocyclic ring.

[0062] In one embodiment, ring C is a 5-membered heterocyclic ring. In one embodiment, ring C is a 6-membered heterocyclic ring. In one embodiment, ring C is a 5-membered carbocyclic ring. In one embodiment, ring C is a 6-membered carbocyclic ring.

[0063] In one embodiment, the compound is represented by General Formula II,General Formula II wherein each of Y1to Y10is independently C, CRX, or N;Rxis a substituent selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof.

[0064] In one embodiment, at least one of Y1to Y5is N. In one embodiment, at least one of Y6to Y10is N.

[0065] In one embodiment, the compound is represented by General Formula III,General Formula III.

[0066] In one embodiment, each RB in General Formula III is an alkoxy group.

[0067] In another aspect, the present invention relates to a method of treating a CNS disorder in a subject in need thereof, the method comprising the step of:administering to the subject a compound represented by the following General FormulaGeneral Formula I whereinX1and X2are each independently O, S, Se, NR’, BR’, CR’R”, and SiR’R”; ring A can be present or absent; ring B represents a 5-membered or 6-membered heterocyclic or carbocyclic ring; ring C represents a 5-membered or 6-membered heterocyclic or carbocyclic ring;R’, and R” are each independently selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, and combinations thereof, and wherein any two substituents R’ and R” may be optionally joined to form a ring;RA, RB, and Rceach independently represent mono to the maximum allowable substitution, or no substitution; and each RA, RB, and Rcis independently a hydrogen or a substituent selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof, and wherein any two substituents RA, RB, and Rcmay be optionally joined to form a ring.

[0068] In one embodiment, X1is O. In one embodiment, X1is S. In one embodiment, X1is NR’. In one embodiment, X1is BR’. In one embodiment, X1is CR’R”. In one embodiment, X1is SiR’R”. In one embodiment, X2is O. In one embodiment, X2is S. In one embodiment, X2is NR’.

[0069] In one embodiment, ring A is present. In one embodiment, ring A is absent.

[0070] In one embodiment, ring B is a 5-membered heterocyclic ring. In one embodiment, ring B is a 6-membered heterocyclic ring. In one embodiment, ring B is a 5-membered carbocyclic ring. In one embodiment, ring B is a 6-membered carbocyclic ring.

[0071] In one embodiment, ring C is a 5-membered heterocyclic ring. In one embodiment, ring C is a 6-membered heterocyclic ring. In one embodiment, ring C is a 5-membered carbocyclic ring. In one embodiment, ring C is a 6-membered carbocyclic ring.

[0072] In one embodiment, the compound facilitates Nrf2 translation. In one embodiment, the compound increases Nr£2 translation. In one embodiment, the compound decreases Nrf2 translation. In one embodiment, the compound does not affect Nrf2 translation.

[0073] In one embodiment, the compound binds to GSTM2.

[0074] In one embodiment, the method does not affect Keapl . In one embodiment, the method does affect Keapl.

[0075] In one embodiment, the CNS disorder is Alzheimer's disease. In one embodiment, the CNS disorder is Parkinson’s disease. In one embodiment, the CNS disorder is Huntington’s disease. In one embodiment, the CNS disorder is Bell’s palsy. In one embodiment, the CNS disorder is cerebral palsy. In one embodiment, the CNS disorder is epilepsy. In one embodiment, the CNS disorder is multiple sclerosis.Salts

[0076] Certain compounds of the Formula (I) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. The term “salts” embraces addition salts of free acids or free bases which are compounds of the invention. The term “pharmaceutically acceptable salt” refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of this invention. 1

[0077] All such salts are within the scope of this invention, and references to compounds of the Formula (I) include the salt forms of the compounds. The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[0078] Acid addition salts (mono- or di-salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(lS)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1 ,2-di sulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-Llactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthal ene-2-sulfonic, naphthalene- 1 ,5-disulfonic, l-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, Lpyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)- Ltartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins. One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is the hydrochloride salt. Where the compounds of the formula (I) contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I). The compounds of theinvention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art.

[0079] Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, pivalic, propionic, furoic, mucic, isethionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, |3-hydroxybutyric, salicylic, galactaric, camphorosulfonic and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention. Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0080] Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transistion metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’ -dibenzylethylenediamine, chlooprocaine, choline, diethanolamine, ethylenediamine, tromethamine, meglumine (N-methylglucamine) and procaine.Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts.

[0081] All of these salts may be prepared by conventional means from the corresponding compound according to Formula I by reacting, for example, the appropriate acid or base with the compound according to Formula I. Preferably the salts are in crystalline form, and preferably prepared by crystallization of the salt from a suitable solvent. The person skilled in the art will know how to prepare and select suitable salt forms for example, as described in Handbook of Pharmaceutical Salts: Properties, Selectin and Use by P. H. Stahl and C. G. Wermuth (Wiley- VCH 2002).Solvates

[0082] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention. In one embodiment, the pharmaceutically acceptable solvates of the compounds of the invention include the hydrate thereof. In one embodiment, said crystalline form of the compounds of formula (I) is a cocrystal or coformer. Such a cocrystal or coformer may be prepared using water-soluble molecules such as saccharin, caffeine, nicotinamide or carboxylic acids. Coformers may be prepared as described in Emami S et al (2018) BioImpacts 8(4), 305-320, the techniques of which are herein incorporated by reference. It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention. As used herein "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.N-Oxides

[0083] Compounds of the formula (I) containing an amine function may also form N-oxides. Where a compound contains several amine functions, one or more than one nitrogen atom maybe oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience. More particularly, N-oxides can be made by the procedure of L . W. Deady (Syn. Commun. 1977, 7 , 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as di chi oromethane.ProdrugsIt will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All such prodrugs of compounds of the invention are included within the scope of the invention. Examples of pro-drug functionality suitable for the compounds of the present invention are described in Drugs of Today, 19, 9 , 1983, 499-538 and in Topics in Chemistry, Chapter 31, pp. 306-316 and in “Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moi eties”, for example as described by H. Bundgaard in “Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. Also included within the scope of the compound and various salts of the invention are polymorphs thereof.Enantiomers

[0084] Where chiral centers are present in compounds of formula (I), the present invention includes within its scope all possible enantiomers and diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methodsor by stereospecific or asymmetric syntheses. The invention also extends to any tautomeric forms or mixtures thereof.Isotopes

[0085] The subject invention also includes all pharmaceutically acceptable isotopically- labelled compounds which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as 2H (D) and H (T), carbon, such as 1 1C, 1 C and 14C, chlorine, such as 6CI, fluorine, such as 18F, iodine, such as 123 1 , 125 1 and 1 1 1, nitrogen, such as 1 N and 1 N, oxygen, such as 1 0 , 170 and 180 , phosphorus, such as 2P, and sulfur, such as S. Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors. The detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase) etc. The radioactive isotopes tritium, i.e. H (T), and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. 2H (D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 1 1C, 18F, 1 0 and 1 N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.

[0086] Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically- labelled reagents in place of the non-labelled reagent previously employed.Purity

[0087] Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are given on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.Admini strati on / Dosage / Formulations

[0088] The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either before or after the onset of cancer. Further, several divided dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0089] Administration of the compositions of the present invention to a patient, such as a mammal, (e.g., human), may be carried out using known procedures, at dosages and for periods of time effective to treat cancer in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a cancer in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily. In another example, the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 mg / kg to about 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to assess the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0090] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without generating excessive side effects in the patient.

[0091] In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

[0092] A medical professional, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start with a dosage of the compound of the invention in the pharmaceutical composition at a level that is lower than the level required to achieve the desired therapeutic effect, and then increase the dosage over time until the desired effect is achieved.

[0093] In particular embodiments, it is advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. “Dosage unit form” as used herein refers to a physically discrete unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect, in association with the required pharmaceutical vehicle. The dosage unit forms of the invention can be selected based upon (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound for the treatment of cancer in a patient.

[0094] In one embodiment, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

[0095] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), vegetable oils, and suitable mixtures thereof . The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In some embodiments, itis useful to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be achieved by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In one embodiment, the pharmaceutically acceptable carrier is DMSO, alone or in combination with other carriers.

[0096] The therapeutically effective amount or dose of a compound of the present invention depends on the age, sex and weight of the patient, the current medical condition of the patient and the severity of the cancer in the patient being treated. The skilled artisan is able to determine appropriate doses depending on these and other factors.

[0097] The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

[0098] Doses of the compound of the invention for administration may be in the range of from about 1 pig to about 10,000 mg, from about 20 pg to about 9,500 mg, from about 40 pg to about 9,000 mg, from about 75 pg to about 8,500 mg, from about 150 pg to about 7,500 mg, from about 200 pg to about 7,000 mg, from about 3050 pg to about 6,000 mg, from about 500 pg to about 5,000 mg, from about 750 pg to about 4,000 mg, from about 1 mg to about 3,000 mg, from about 10 mg to about 2,500 mg, from about 20 mg to about 2,000 mg, from about 25 mg to about 1,500 mg, from about 30 mg to about 1,000 mg, from about 40 mg to about 900 mg, from about 50 mg to about 800 mg, from about 60 mg to about 750 mg, from about 70 mg to about 600 mg, from about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0099] In some embodiments, the dose of a compound of the invention is from about 1 mg to about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dosage of a second compound as described elsewhere herein is less than about 1,000 mg, or less than about 800 mg, or less thanabout 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

[0100] The compounds for use in the method of the invention may be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0101] In one embodiment, the compositions of the invention are administered to the patient from about one to about five times per day or more. In various embodiments, the compositions of the invention are administered to the patient, 1-7 times per day, 1-7 times every two days, 1-7 times every 3 days, 1-7 times every week, 1-7 times every two weeks, and 1-7 times per month. . It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from individual to individual depending on many factors including, but not limited to, age, the disease or disorder to be treated, the severity of the disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosing regime and the precise dosage and composition to be administered to any patient is determined by the medical professional taking all other factors about the patient into account.

[0102] In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the inhibitor of the invention is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.The dose reduction during a drug holiday includes from 10%-l 00%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0103] Once improvement of the patient’s condition has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced to a level at which the improved disease is retained. In some embodiments, a patient may require intermittent treatment on a long-term basis, or upon any recurrence of the disease or disorder.

[0104] Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LDso (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LDso and EDso. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the EDso with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0105] In one embodiment, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat or prevent cancer in a patient.

[0106] Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. 1

[0107] Routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0108] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.Oral Administration

[0109] For oral administration, suitable forms include tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions formulated for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0110] For oral administration, the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose orhydroxypropylmethylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).

[0111] Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a “granulation.” For example, solvent-using “wet” granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.

[0112] Melt granulation involves the use of materials that are solid or semi-solid at room temperature (i.e., having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium. The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e., drug) by forming a solid dispersion or solid solution.

[0113] U.S. Patent No. 5,169,645 discloses directly compressible wax-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) melt.The present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention, and a further layer providing for the immediate release of a medication for treatment of G-protein receptor-related diseases or disorders. Using a wax / pH-sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.Parenteral AdministrationFor parenteral administration, the compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used.Additional Administration FormsAdditional dosage forms of this invention include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820.Additional dosage forms of this invention also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.Controlled Release Formulations and Drug Delivery Systems

[0114] In one embodiment, the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

[0115] The term sustained release refers to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a day, a week, or a month or more and should be a release which is longer that the same amount of agent administered in bolus form. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

[0116] For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use the method of the invention may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.

[0117] In one embodiment of the invention, the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

[0118] The term pulsatile release refers to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profdes of the drug after drug administration.

[0119] The term immediate release refers to a drug formulation that provides for release of the drug immediately after drug administration.

[0120] As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

[0121] As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours,about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.EXPERIMENTAL EXAMPLES

[0122] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0123] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples therefore, specifically point out the preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.Mechanism, Pharmacology, and Pharmacokinetics of MC180446:

[0124] MCI 80446 was identified as the lead compound following screening studies and a hit- to-lead campaign and was chosen based on its ability to: A) increase Nrf2 translation, B) enhance Nrf2 levels independent of Keapl, C) bind to GSTM2, D) activate canonical downstream targets, E) reduce tau carbonylation, F) lack of in vitro toxicity, and G) brain penetrance. Significantly, the promiscuous electrophilic chaicone moiety was eliminated and database searching has identified significant chemical space within the MCI 80446 scaffold that provides novel compounds (Figure 1).

[0125] Docking studies performed with GSTM2 predicted that the affinity of MCI 80446 (logP=4.20, Mcule docking score: -8.4) is better than that seen with 180441 (logP=5.49, docking score: -7.2) and even higher than the known ligand glutathione (docking score: -5.2). An active site model examining all interactions within 5 A suggested that MCI 80466 binds within a cleft occupied by glutathione and forms multiple H-bond JC-TC and van der Waals interactions with the top of the predicted pocket (Figure 2, upper panels). Glutathione, by contrast, formed bindinginteractions only with the bottom of the pocket (Figure 2, lower panels). MCI 80466 appeared to be positioned to prevent the binding of glutathione.

[0126] To experimentally confirm MC180446 binding to GSTM2, Drug Affinity Response Target Stability (DARTS) was performed. This technology is typically used to detect drug interactions on the proteins responsible for binding. DARTS is based on the concept that some drugs can protect the target protein from degradation by proteases when mixed in a solution and was recently applied to uncover the binding of a promising anti-cancer drug. The same approach was used for MCI 80446. Specifically, 3 different concentrations (0.01 pM, 0.1 pM, and 1 pM) of MCI 80446 were used to interact with purified GSTM2. Trypsin was added and incubated for 3 hours at 37 °C. Interacting peptides were identified by gel electrophoresis liquid chromatography-mass spectroscopy (GelLCMS) as described in art. The analysis confirmed the binding of MCI 80446 to GSTM2 at all three escalating doses. As expected, in control containing GSTM2 but no MCI 80446, GSTM2 was not protected against trypsin digestion (Figure 3). Mechanistic studies were performed on MCI 80446 to show it activates Nr£2 translation and increases nuclear Nrf2 levels with ECso of 65nM (Figure 1) and EC90 of 567 nM. To further delineate the effect of MCI 80446 on the downstream targets of Nrf2, global proteomics studies were performed on SH-SY5Y cells (n=3 biological replicates) treated with vehicle,A|3 (100 pM) and A[3 (100 pM) + MC180446 (10 pM) for 24 hr as described in art. The volcano plot comparing A|3 with A[3 showed an extensive increase in antioxidant response in cells treated with 180446 but without altering Keapl levels (Figure 4). Notably, apigenin and dimethyl fumarate showed much lower levels of the same antioxidant proteins (approx.3 folds) compared to 180446. Next, the ROS levels in the parallel group were analyzed using DCFDA and Mitosox immunohistochemistry and showed a significant ROS reduction by 180446 (Figure 5). To determine the effect of the 180446 on 4-HNE protein adducts, a carbonylome (4-HNE protein adduct quantitation) study (n=3 per group) was performed as described in art. The data demonstrated that 180446 reduced 49 HNE protein adducts of lysine, arginine, or histidine, including Tau, by at least 2 folds with p<0.05 compared to the A|3 treatment (Figure 6). Studies to determine drug-like properties showed that because of its lower lipophilicity, MCI 80446 demonstrated better aqueous solubility (12.2 pM vs. 3.2 pM), similar protein binding (98% vs. 99.7%), and greater stability in mouse (ti / 2 = 2.8 min vs. < 2 min) and human (ti / 2 = 22.6 min vs. 11.1 min) liver microsomes compared to MCI 80441. MCI 80446 does not inhibit the three majorCyp450s (3A4, 2D6, 2C9) and is not an hERG blocker at concentrations up to 10 pM in a FluxOR® assay using HEK293 cells stably transfected with hERG (Kvl 1.1).

[0127] A pilot pharmacokinetics study was performed on a single IV and PO dose ofMCI 80446 in male C57BL / 6J mice. Mice (n=3) were given a single 2 mg / kg IV or 5 mg / kg oral dose of MCI 80446. Blood was collected from 5 min to 8 h post-dose (IV) or from 15 min to 8 hrs (PO). Brain tissue was also collected from 15 min to 2 hr post IV and PO doses. Plasma and brain concentrations of MCI 80446 were measured by HPLC-MS / MS, and PK parameters were calculated (Figure 7). MC 180446 has a rapid distribution and a moderate elimination rate after an IV dose of 2mg / kg. The half-life of the IV dose was 1.6 hr. After an oral dose of 5 mg / kg in mice, the Cmax was 0.14 pg / ml at ~0.5hr. The observed half-life after oral dosing is ~4 h, suggesting that absorption still occurs after eight hours. This could be due to slow dissolution, precipitation, or slow stomach emptying. The bioavailability of the oral dose is 98%, which indicates good absorption in a gastrointestinal system with minimal first-pass metabolism. Brain concentrations are higher by 3-fold than plasma concentrations. Using fraction unbound in plasma (fup = 0.02) and fraction unbound in microsomes (fum = 0.158), unbound brain concentrations are predicted to be about 7-fold higher than unbound plasma concentrations.Synthesis of MCI 80446

[0128] Inventive Compound MC180446 (2-(benzo[d]oxazol-2-yl)-3-(5,6-dimethoxypyridin-3- yl)-l-(4-ethoxyphenyl)propan-l-one) can be synthesized by the following steps.

[0129] Step 1 - Synthesis of 2-(benzo[d]oxazol-2-yl)-l-(4-ethoxyphenyl)ethan-l-one

[0130] A solution of 4’ -ethoxy acetophenone (3.21 g, 19.53 mmol) in anhydrous toluene (40 mb) was degassed by bubbling nitrogen through it. 2-Chlorobenzoxazole (0.74 mL, 6.51 mmol) was added, and the reaction solution was cooled to 0 °C in an ice bath. A solution of NaHMDS (1.0 M in THF, 19.5 mL, 19.53 mmol) was added dropwise to the cold reaction mixture. After dropwise addition was complete, the reaction was stirred at 0°C for 3 hours. It was then allowedto warm to RT with stirring overnight. In the morning, the reaction solution was cooled to 0°C in an ice bath, quenched with saturated aqueous ammonium chloride and stirred until the solution had changed color from orange to yellow. The aqueous layer was separated and extracted with EtOAc twice. All of the organic solutions were combined, dried over anhydrous Na2SC>4, and concentrated. The crude product was purified by column chromatography on silica gel using 100% DCM until the excess unreacted acetophenone had eluted. The solvent system was then changed to 10% EtOAc in DCM to elute off the titled compound as a yellow solid (1.42 g, 78%) 'H NMR (400 MHz, CDCh) 5 7.99 (m, 2H), 7.76 (m, 1H), 7.55 (m, 1H), 7.38 (m, 2H), 6.95 (m, 2H), 4.62 (bs, 1H), 4.10 (q, J = 7.0 Hz, 2H), 1.45 (t, J = 6.96 Hz, 3H).; MS(ESI): m / z 282.1 [(M+H)+],

[0131] Step 2 - Synthesis of (E)-2-(benzo[d]oxazol-2-yl)-3-(5,6-dimethoxypyridin-3-yl)-l-(4- ethoxyphenyl)prop-2-en- 1 -one

[0132] Piperidine (130 uL, 1 .316 mmol) was added to a solution of 2-(benzo[d]oxazol-2-yl)-l- (4-ethoxyphenyl)ethan-l-one (296 mg, 1.053 mmol) and 5,6-dimethoxynicotinaldehyde (198 mg, 1.184 mmol) in anhydrous pyridine (4 mL). This solution was stirred at 100°C for 4 hours. It was then cooled to RT and concentrated down. The residue was dissolved into DCM, washed with 10% aqueous copper sulfate solution (3X) and water (2X), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel using 0 to 50% EtOAc in hexanes to afford the titled compound as a tannish-yellow solid (242 mg, 53%). ’H NMR (400 MHz, CDCh) 5 8.04 (d, J = 8.84 Hz, 2H), 7.94 (s, 1H), 7.89 (d, J = 1.64 Hz, 1H), 7.69 (bd, J = 6.84 Hz, 1H), 7.52 (bd, J =7.04 Hz, 1H), 7.31 (m, 2H), 7.03 (d, J =1 .96 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 4.08 (q, J = 7.0 Hz, 2H), 4.00 (s, 3H), 3.58 (s, 3H), 1 .42 (t, J = 6.96 Hz, 3H.; MS(ESI): m / z 431.2 [(M+H)+],

[0133] Step 3 - Sy03nthesis of 2-(benzo[d]oxazol-2-yl)-3-(5,6-dimethoxypyridin-3-yl)-l-(4- ethoxyphenyl)propan- 1 -one

[0134] (E)-2-(benzo[d]oxazol-2-yl)-3-(5,6-dimethoxypyridin-3-yl)-l-(4-ethoxyphenyl)prop-2- en-l-one (200 mg, 0.4646 mmol) was dissolved into EtOAc (10 mL, previously dried over anhydrous Na2SO4). 10% Pd / C (23 mg, previously washed with anhydrous MeOH and dried) was added and the reaction was hydrogenated using a balloon at RT overnight. The reaction solution was fdtered through a plug of celite and concentrated down. The crude product was purified by column chromatography on silica gel using 0 to 50% EtOAc in hexanes to afford the titled compound as a tan solid (121 mg, 60%)). 'H NMR (400 MHz, dmso-de) 8 8.05 (d, J = 8.96 Hz, 2H), 7.69 (m, 2H), 7.49 (d, J = 1.84 Hz, 1H), 7.35 (m, 2H), 7.24 (d, J 1.84 = Hz, 1H), 7.02 (d, J = 8.96 Hz, 2H), 5.71 (t, J = 7.72 Hz, 1H), 4.10 (q, J = 6.92 Hz, 2H), 3.75 (s, 3H), 3.64 (s, 3H), 3.40 (m, 2H), 1.32 (t, J = 6.96 Hz, 3H).; MS(ESI): m / z 433.2 [(M+H)+],

[0135] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMSWhat is claimed is:

1. A compound represented by the following General Formula I,General Formula I whereinX1is selected from the group consisting of O, S, NR’, BR’, CR’R”, and SiR’R”;X2is selected from the group consisting of O, S, NR’; ring A can be present or absent; ring B represents a 5-membered or 6-membered heterocyclic or carbocyclic ring; ring C represents a 5-membered or 6-membered heterocyclic or carbocyclic ring;R’, and R” are each independently selected from the group consisting of deuterium, hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, and combinations thereof, and wherein any two substituents R’ and R” may be optionally joined to form a ring;RA, RB, and Rceach independently represent mono to the maximum allowable substitution, or no substitution; and each RA, RB, and Rcis independently a hydrogen or a substituent selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof, and wherein any two substituents RA, RB, and Rcmay be optionally joined to form a ring.

2. The compound of claim 1, wherein X1is O.

3. The compound of claim 1, wherein X2is O.

4. The compound of claim 1, wherein ring A is present.

5. The compound of claim 1, wherein ring A is absent.

6. The compound of claim 1, wherein ring B is a 6-membered heterocyclic ring.

7. The compound of claim 1, wherein the compound is represented by General Formula II,General Formula II wherein each of Y1to Y10is independently C, CRX, or N; andRxis a substituent selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof.

8. The compound of claim 7, wherein at least one of Y1to Y3is N.

9. The compound of claim 1, wherein the compound is represented by General Formula III,General Formula III.

10. The compound of claim 9, wherein each RB is an alkyoxy group.

11. A method of treating a CNS disorder in a subject in need thereof, the method comprising the step of administering to the subject a compound represented by the following General Formula I,General Formula I whereinX1and X2are each independently O, S, Se, NR’, BR’, CR’R”, and SiR’R”; ring A can be present or absent; ring B represents a 5-membered or 6-membered heterocyclic or carbocyclic ring; ring C represents a 5-membered or 6-membered heterocyclic or carbocyclic ring;R’, and R” are each independently selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, and combinations thereof, and wherein any two substituents R’ and R” may be optionally joined to form a ring;RA, RB, and Rceach independently represent mono to the maximum allowable substitution, or no substitution; and each RA, RB, and Rcis independently a hydrogen or a substituent selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof, and wherein any two substituents RA, RB, and Rcmay be optionally joined to form a ring.

12. The method of treating a CNS disorder of claim 11, wherein the compound described by General Formula I facilitates Nrf2 translation.

13. The method of treating a CNS disorder of claim 11, wherein the compound described by General Formula I binds to GSTM2.

14. The method of treating a CNS disorder of claim 11, wherein Keapl is not affected.

15. The method of treating a CNS disorder of claim 11, wherein the CNS disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Bell’s palsy, cerebral palsy, epilepsy, and multiple sclerosis.

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