FUNCTIONALIZED HETROARYL ENONES

EXHIBITING NRF2 ACTIVATION AND THEIR METHOD OF USE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62009151 filed June 6, 2014, which is herein incorporated by reference in its entirety.

FIELD OF INVENTION

[0002] The present invention describes compounds useful as NRF2 activators, useful for treating or preventing a disease, disorder or condition associated with an NRF2 -regulated pathway and related conditions. The present invention further describes a novel chemotype useful for treating or preventing disease, disorders, or conditions that involve oxidative stress.

BACKGROUND OF THE INVENTION

[0003] Nuclear factor erythroid-2 related factor 2 (NRF2) is a basic leucine zipper transcription factor, which regulates a transcriptional program that maintains cellular redox homeostasis and protects cells from oxidative insult. NRF2 activates transcription of its target genes through binding specifically to the antioxidant response element (ARE) found in those genes' promoters. The NRF2-regulated transcriptional program includes a broad spectrum of genes, including antioxidants, such as γ-glutamyl cysteine synthetase modifier subunit (GCLm), γ-glutamyl cysteine synthetase catalytic subunit (GCLc), heme oxygenase- 1, superoxide dismutase, glutathione reductase (GSR), glutathione peroxidase, thioredoxin, thioredoxin reductase, peroxiredoxins (PRDX), cysteine/glutamate transporter (SLC7A11), phase II detoxification enzymes NADP(H) quinone oxidoreductase 1 (NQOl), GST, UDP-glucuronosyltransferase, and several ATP- dependent drug efflux pumps, including MRP1 and MRP2.

[0004] NRF2 protects cells and multiple tissues by coordinately up-regulating ARE-related detoxification and antioxidant genes and molecules required for the defense system. NRF2- activation suppresses oxidative stress and inflammation and has been shown to be neuroprotective. Accordingly, therapeutic strategies that increase NRF2 biological activity or expression can be used to treat or prevent diseases, disorders, or conditions related to oxidative stress, including inflammatory disorders, and neurodegenerative disorders.

BRIEF SUMMARY OF THE INVENTION

[0005] The present invention is directed toward novel functionalized hetroaryl enones, compounds of formula (I),

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

Q is a member selected from the group consisting of CF ₃ , CF ₂ H, and CFH ₂ ,

R ¹ is a member selected from the group consisting of hydrogen, C e alkyl, C3.7 branched alkyl, and C3.6 cycloalkyl,

A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ , and A ⁸ are at each occurrence a member independently selected from the group consisting of N and CR ² ,

One of the set A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ , and A ⁸ must be N,

No more than one of the set A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ , and A ⁸ may be N,

R ² is at each occurrence independently selected from the group consisting of hydrogen, halogen, Cue alkyl, C ₃ _ ₇ branched alkyl, C ₃ _ ₆ cycloalkyl, Cue alkoxy, C ₃ _ ₇ branched alkoxy, CN, N0 ₂ , S0 ₂ NH ₂ , S0 ₂ R ³ , SOR ³ , NR ^4a R ^4b , SR ⁵ , -NR ^4a C(0)R ⁶ , Aryl, and Heteroaryl,

R ³ is at each occurrence independently selected from the group consisting of Cu alkyl, C ₃ . ₇ branched alkyl, and C ₃ . ₆ cycloalkyl,

R ^4a is at each occurrence independently selected from the group consisting of hydrogen, Cu ₆ alkyl, C ₃ _7 branched alkyl, and C ₃ _6 cycloalkyl,

R ^4b is at each occurrence independently selected from the group consisting of hydrogen, Cu ₆ alkyl, C ₃ _7 branched alkyl, and C ₃ _6 cycloalkyl,

R ⁵ is at each occurrence independently selected from the group consisting of hydrogen, Cu ₆ alkyl, C ₃ _7 branched alkyl, and C ₃ _6 cycloalkyl, and

R ⁶ is at each occurrence independently selected from the group consisting of hydrogen, Cu ₆ alkyl, C ₃ _7 branched alkyl, and C ₃ _6 cycloalkyl.

[0006] The compounds of the present invention include compounds having formula (II):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0007] The compounds of the present invention include compounds having formula (III): including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0008] The compounds of the present invention include compounds having formula (IV): including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes

[0009] The compounds of the present invention include compounds having formula (V):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0010] The compounds of the present invention include compounds having formula (VI):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0011] The compounds of the present invention include compounds having formula (VII):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0012] The compounds of the present invention include compounds having formula (VIII):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0013] The compounds of the present invention include compounds having formula (IX):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof. [0014] The present invention further relates to compositions comprising:

an effective amount of one or more compounds according to the present invention and an excipient.

[0015] The present invention also relates to a method for treating or preventing diseases, disorders, or conditions that involve an NRF2-regulated pathway, including, for example, those associated with an autoimmune disease, comorbidity associated with diabetes, such as retinopathy and nephropathy, bone marrow transplant for leukemia and related cancers, bone marrow deficiencies, inborn errors of metabolism, immune disorders, oxidative stress, respiratory infection, ischemia, neurodegenerative disorders, radiation injury, chemotherapy injury, neutropenia caused by chemotherapy, autoimmunity, and congenital neutropenic disorders, and dysregulated corticosteroid responsiveness, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0016] The present invention yet further relates to a method for treating or preventing diseases, disorders, or conditions that involve an NRF2 -regulated pathway, including, for example, those associated with an autoimmune disease, comorbidity associated with diabetes, such as retinopathy and nephropathy, bone marrow transplant for leukemia and related cancers, bone marrow deficiencies, inborn errors of metabolism, immune disorders, oxidative stress, respiratory infection, ischemia, neurodegenerative disorders, radiation injury, chemotherapy injury, neutropenia caused by chemotherapy, autoimmunity, and congenital neutropenic disorders, and dysregulated corticosteroid responsiveness, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0017] The present invention also relates to a method for treating or preventing diseases, disorders, or conditions that involve an NRF2 -regulated pathway, including an autoimmune disease such as acute graft-versus host disease, autoimmune inner ear disease, inflammatory bowel disease, ulcerative colitis, Crohn's disease rheumatoid arthritis, psoriasis, psoriatic arthritis, multiple sclerosis, scleroderma, lupus, ankylosing spondylitis, neutropenia, and uveitis, wherein said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0018] The present invention also relates to a method for treating or preventing diseases, disorders, or conditions that involve an NRF2 -regulated pathway, including an autoimmune disease such as acute graft-versus host disease, autoimmune inner ear disease, inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, psoriasis, psoriatic arthritis, multiple sclerosis, scleroderma, lupus, ankylosing spondylitis, neutropenia, and uveitis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0019] The present invention also relates to a method for treating or preventing disease, disorders, or conditions that involve oxidative stress such as a pulmonary inflammatory condition, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, sepsis, septic shock, meningitis, encephalitis, hemorrhage, ischemic injury, cerebral ischemia, heart ischemia, a cognitive deficit, and neurodegenerative disorders such as Alzheimer's disease (AD), Creutzfeldt- Jakob disease, Huntington's disease, Lewy body disease, Pick's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and neurofibromatosis. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.

[0020] The present invention yet further relates to a method for treating or preventing disease, disorders, or conditions that involve oxidative stress, such as a pulmonary inflammatory condition, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, sepsis, septic shock, meningitis, encephalitis, hemorrhage, ischemic injury, cerebral ischemia, heart ischemia, a cognitive deficit, and neurodegenerative disorders such as Alzheimer's disease (AD), Creutzfeldt- Jakob disease, Huntington's disease, Lewy body disease, Pick's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and neurofibromatosis wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0021] The present invention also relates to a method for treating or preventing disease, disorders, or conditions associated with oxidative stress such as a pulmonary inflammatory condition, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, sepsis, septic shock, meningitis, encephalitis, hemorrhage, ischemic injury, cerebral ischemia, heart ischemia, a cognitive deficit, and neurodegenerative disorder such as a Alzheimer's disease (AD), Creutzfeldt- Jakob disease, Huntington's disease, Lewy body disease, Pick's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and neurofibromatosis, wherein said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.

[0022] The present invention yet further relates to a method for treating or preventing disease, disorders, or conditions associated with oxidative stress, such as a pulmonary inflammatory condition, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, sepsis, septic shock, meningitis, encephalitis, hemorrhage, ischemic injury, cerebral ischemia, heart ischemia, a cognitive deficit, and neurodegenerative disorder Alzheimer's disease (AD), Creutzfeldt- Jakob disease, Huntington's disease, Lewy body disease, Pick's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and neurofibromatosis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0023] The present invention yet further relates to a method of restoring corticosteroid responsiveness in the subject, for example, in a subject that has or is at risk of developing a disease, disorder, or condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, severe asthma, acute graft versus host disease, autoimmune inner ear disease, inflammatory bowel disease, and rheumatoid arthritis wherein said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.

[0024] The present invention yet further relates to a method of restoring corticosteroid responsiveness in the subject, for example, in a subject that has or is at risk of developing a disease, disorder, or condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, severe asthma, acute graft versus host disease, autoimmune inner ear disease, inflammatory bowel disease, and rheumatoid arthritis wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0025] The present invention further relates to a method of treating or preventing a respiratory infection, for example, in a subject that has or is at risk of developing a disease, disorder, or condition selected from the group consisting of an acute respiratory infection, chronic bronchitis, cystic fibrosis, and an immunodeficiency syndrome.

[0026] The present invention further relates to a method of treating or preventing a radiation injury in the subject, for example, a radiation injury arising as a result of radiotherapy, accidental radiation exposure, or nuclear attack.

[0027] The present invention further relates to a kit for treating or preventing radiation injury, the kit comprising a therapeutically effect amount of one or more compounds according to the present invention and written instructions for use of the kit.

[0028] The present invention further relates to a device for dispersing one or more particles comprising one or more compounds according to the present invention in an amount effective to increase a NRF2 biological activity or NRF2 expression and delivering a dose of the particles to lung tissue of a subject. In some aspects, the device can be a nebulizer, a metered dose inhaler, or a dry powder inhaler.

[0029] The present invention further relates to a process for preparing the functionalized hetroaryl enones of the present invention.

[0030] These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius ( C) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Fig. 1A is a bar graph showing how compounds induce expression of Heme Oxygenase-1 (HO-1) in Beas-2B human lung epithelial cells in vitro, 6 hours post-treatment with the compounds indicated (5μΜ except for CDDO which was lOnM).

[0032] Fig. IB is a bar graph showing how compounds induce expression of Heme Oxygenase-1 (HO-1) in Beas-2B human lung epithelial cells in vitro, 6 hours post-treatment with the compounds indicated (5μΜ except for CDDO, which was lOnM).

[0033] Fig. 2A is a bar graph and Fig. 2B is a table showing how compounds induce expression of Heme Oxygenase 1 (HO-1) in human primary peripheral blood mononuclear cells (PBMC) in vitro, 6 hours post-treatment with the compounds indicated. Control compounds include VEDA-1209 and dimethyl fumarate (DMF).

[0034] Fig. 3A is a bar graph and Fig. 3B is a table showing how compounds induce expression of NAD(P)H:quinone oxidoreductase-1 (NQOl) in human primary peripheral blood mononuclear cells in vitro, 6 hours post-treatment with the compounds indicated. Control compounds include VEDA-1209 and dimethyl fumarate (DMF).

[0035] Fig. 4 is a graph showing how compounds induce expression of Heme Oxygenase 1 (HO-1) in mouse small intestine 6 hours following oral administration of the compounds indicated.

DETAILED DESCRIPTION OF THE INVENTION

[0036]The functionalized hetroaryl enones of the present invention are capable of treating or preventing diseases, disorders, or conditions that involve an NRF2 -regulated pathway, for example those associated with an autoimmune disease, comorbidity associated with diabetes such as retinopathy and nephropathy, bone marrow transplant for leukemia and related cancers, bone marrow deficiencies, inborn errors of metabolism, immune disorders, oxidative stress, respiratory infection, ischemia, neurodegenerative disorders, radiation injury, chemotherapy injury, neutropenia caused by chemotherapy, autoimmunity, and congenital neutropenic disorders, and dysregulated corticosteroid responsiveness. It has been discovered that nuclear factor erythroid 2- related factor 2 (NRF2) plays a central role in protecting cells from oxidative stress and inflammation by increasing several cytoprotective pathways. Such cytoprotective pathways include antioxidant enzymes, which scavenge and decompose free radicals, Phase II enzymes, which detoxify electrophiles, and the proteasome system, which removes damaged proteins. NRF2 -deficient mice are more sensitive to oxidative stress and show an increase in susceptibility and severity to several inflammatory disorders, including chronic obstructive pulmonary disease (COPD), asthma, radiation-induced normal tissue injuries, and neurodegenerative diseases. Activation of NRF2 protects mice from these and related disorders by suppressing oxidative stress and inflammation. Accordingly, NRF2 is a potential drug target for treating disorders related to oxidative stress and from autoimmune diseases by suppressing inflammation.

[0037] The functionalized hetroaryl enones of the present invention activate NRF2 and increase antioxidant and anti-inflammatory defenses in mouse tissues. As provided in more detail herein below, the presently disclosed compounds can be used for treating or preventing diseases, disorders, or conditions associated with NRF2-regulated pathways, including, but not limited to an autoimmune disease, comorbidity associated with diabetes, such as retinopathy and nephropathy, bone marrow transplant for leukemia and related cancers, bone marrow deficiencies, inborn errors of metabolism, and other immune disorders, oxidative stress, respiratory infection, ischemia, neurodegenerative disorders, radiation injury, neutropenia caused by chemotherapy, autoimmunity, and congenital neutropenic disorders, and for restoring a corticosteroid responsiveness.

[0038] NRF2-mediated activation of antioxidant response element (ARE) is a central part of molecular mechanisms governing the protective function of phase II detoxification and antioxidant enzymes against oxidative stress and inflammation. By "NRF2 polypeptide" is meant a protein or protein variant, or fragment thereof, that comprises an amino acid sequence substantially identical to at least a portion of GenBank Accession No. AAB32188 (human nuclear factor erythroid 2- related factor 2) and that has an NRF2 biological activity (e.g., activation of target genes through binding to antioxidant response element (ARE), regulation of expression of antioxidants and xenobiotic metabolism genes).

[0039] NRF2 is sequestered in the cytoplasm by its repressor, Keap. Modification of cysteine residues in Keapl by a variety of inducers, specifically Michael acceptors, results in a conformational change that renders Keapl to dissociate from NRF2, thereby inducing translocation of NRF2 to the nucleus. By "Keapl polypeptide" is meant a polypeptide comprising an amino acid sequence having at least 85% identity to GenBank Accession No. NP 987096.1. By "Keapl nucleic acid molecule" is meant a nucleic acid molecule that encodes a Keapl polypeptide or fragment thereof. Representative NRF2-regulated gene functions are summarized in Table 1

Table 1 : NRF2-regulated Gene Functions

Heat shock proteins (HSP70) proteosome Chaperone activity; Enhance the recognition, members repair, and removal of damaged proteins

MRP1 Enhance toxin export via the multidrug response transporter

Leukotriene B4 12- Inhibits cytokine mediated inflammation hydroxydehydrogenase

CD36, MARCO (scavenger receptors) i) Enhances phagocytosis of bacteria.

ii) Maintenance of tissue homeostasis and resolution of inflammatory lesions by clearance of apoptotic cells.

Suppress NF-KB signaling Regulates redox dependent innate immune, as well as adaptive immune response

[0040] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.

[0041] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.

[0042] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs.

[0043] The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term "about" is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise.

[0044] For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, parameters, quantities, characteristics, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about" even though the term "about" may not expressly appear with the value, amount or range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are not and need not be exact, but may be approximate and/or larger or smaller as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art depending on the desired properties sought to be obtained by the presently disclosed subject matter. For example, the term" about," when referring to a value can be meant to encompass variations of, in some embodiments, ± 100% in some embodiments ± 50%, in some embodiments ± 20%, in some embodiments ± 10%, in some embodiments ± 5%, in some embodiments ±1 %, in some embodiments ± 0.5%, and in some embodiments ± 0.1 % from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.

[0045] Further, the term "about" when used in connection with one or more numbers or numerical ranges, should be understood to refer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries above and below the numerical values set forth. The recitation of numerical ranges by endpoints includes all numbers, e.g., whole integers, including fractions thereof, subsumed within that range (for example, the recitation of 1 to 5 includes 1,2,3,4, and 5, as well as fractions thereof, e.g., 1.5,2.25,3.75,4.1, and the like) and any range within that range.

[0046] It should be understood that 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

[0047] As used herein, the term "halogen" shall mean chlorine, bromine, fluorine and iodine.

[0048] As used herein, unless otherwise noted, "alkyl" and/or "aliphatic" whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. Ci_ ₆ ) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl -containing substituent. Non- limiting examples of alkyl groups include methyl, ethyl, n-propyl, z ^' o-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Alkyl groups can be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1 -chloroethyl, 2-hydroxyethyl, 1 ,2-difluoroethyl, 3-carboxypropyl, and the like. In substituent groups with multiple alkyl groups such as (Ci_ ₆ alkyl) ₂ amino, the alkyl groups may be the same or different.

[0049] As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent group, refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain. Alkenyl and alkynyl groups can be optionally substituted. Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1- propenyl (also 2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of substituted alkenyl groups include 2-chloroethenyl (also 2-chlorovinyl), 4-hydroxybuten-l-yl, 7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-3,5-dien-2-yl, and the like. Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-l-yl, and 2-methyl-hex-4-yn-l -yl. Nonlimiting examples of substituted alkynyl groups include, 5-hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl, 5-hydroxy-5- ethylhept-3-ynyl, and the like.

[0050] As used herein, "cycloalkyl," whether used alone or as part of another group, refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionally substituted. Nonlimiting examples of cycloalkyl groups include: cyclopropyl, 2 -methyl -cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5- dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-l-yl, octahydropentalenyl, octahydro-lH-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-lH-fluorenyl. The term "cycloalkyl" also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, l,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0051] "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF ₃ , -CF ₂ CF ₃ ). Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

[0052] The term "alkoxy" refers to the group -O-alkyl, wherein the alkyl group is as defined above. Alkoxy groups optionally may be substituted. The term C ₃ -C ₆ cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). C ₃ -C ₆ cyclic alkoxy groups optionally may be substituted.

[0053] The term "aryl," wherein used alone or as part of another group, is defined herein as a an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Aryl rings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms. Non-limiting examples of aryl groups include: phenyl, naphthylen-l-yl, naphthylen-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2- (N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-feri-butylphenyl, 3-methoxyphenyl, 8- hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-l-yl, and 6-cyano-naphthylen-l -yl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-l,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.

[0054] The term "arylalkyl" or "aralkyl" refers to the group -alkyl-aryl, where the alkyl and aryl groups are as defined herein. Aralkyl groups of the present invention are optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1 -phenylethyl, 2-phenylethyl, 3- phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

[0055] The terms "heterocyclic" and/or "heterocycle" and/or "heterocylyl," whether used alone or as

part of another group, are defined herein as one or more ring having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and wherein further the ring that includes the heteroatom is non-aromatic. In heterocycle groups that include 2 or more fused rings, the non-heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocycle groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heterocycle group can be oxidized. Heterocycle groups can be optionally substituted.

[0056] Non-limiting examples of heterocyclic units having a single ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-lH- azepinyl, 2,3-dihydro-lH-indole, and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclic units having 2 or more rings include: hexahydro-lH-pyrrolizinyl, 3a,4,5, 6,7,7a- hexahydro-lH-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-lH-indolyl, 1,2,3,4- tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-lH- cycloocta[b]pyrrolyl.

[0057] The term "heteroaryl," whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused rings, the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H- cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted. Non-limiting examples of heteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl, triazinyl, thiazolyl, lH-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2- phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non- limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-i ]pyrimidinyl, 7H- pyrrolo[2,3-i ]pyrimidinyl, pyrido[2,3-i ]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, lH-indolyl, 4,5,6,7-tetrahydro-l-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8- hydroxy-quinolinyl, and isoquinolinyl.

[0058] One non- limiting example of a heteroaryl group as described above is Ci-C ₅ heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S). Examples of Ci-C ₅ heteroaryl include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-l -yl, lH-imidazol-2-yl, lH-imidazol-4-yl, isoxazolin- 5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0059] Unless otherwise noted, when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R ² and R ³ taken together with the nitrogen (N) to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The ring can be saturated or partially saturated and can be optionally substituted.

[0060] For the purposed of the present invention fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring. For example, 1,2,3,4- tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclic unit. 6,7-Dihydro cyclopentapyrimidine having the formula:

is, for the purposes of the present invention, considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1, 2,3,4 -tetrahydro- [l,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroaryl unit.

[0061] Whenever a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for "alkyl" and "aryl."

[0062] 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 below. The substituents are 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 single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. The term "substituted" is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as "substituted" any number of the hydrogen atoms may be replaced. For example, difluoromethyl is a substituted Ci alkyl; trifluoromethyl is a substituted Ci alkyl; 4 rydroxyphenyl is a substituted aromatic ring; (N,N-dimethyl-5-amino)octanyl is a substituted Cg alkyl; 3-guanidinopropyl is a substituted C3 alkyl; and 2-carboxypyridinyl is a substituted heteroaryl.

[0063] The variable groups defined herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups will be so indicated.

[0064] The following are non-limiting examples of substituents which can substitute for hydrogen atoms on a moiety: halogen (chlorine (CI), bromine (Br), fluorine (F) and iodine(I)), -CN, -NO ₂ , oxo (=0), -OR ⁷ , -SR ⁷ , -N(R ⁷ ) ₂ , -NR ⁷ C(0)R ⁷ , -S0 ₂ R ⁷ , -S0 ₂ OR ⁷ , -S0 ₂ N(R ⁷ ) ₂ , -C(0)R ⁷ , - C(0)OR ⁷ , -C(0)N(R ⁷ ) ₂ , d. ₆ alkyl, d_ ₆ haloalkyl, d_ ₆ alkoxy, C ₂ . ₈ alkenyl, C ₂ . ₈ alkynyl, C ₃ _i ₄ cycloalkyl, aryl, heterocycle, or heteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups is optionally substituted with 1 -10 (e.g., 1-6 or 1 -4) groups selected independently from halogen, -CN, -N0 ₂ , oxo, and R ⁷ ; wherein R ⁷ , at each occurrence, independently is hydrogen, -OR ⁸ , -SR ⁸ , -C(0)R ⁸ , -C(0)OR ⁸ , - C(0)N(R ⁸ ) ₂ , -S0 ₂ R ⁸ , -S(0) ₂ OR ⁸ , -N(R ⁸ ) ₂ , -NR ⁸ C(0)R ⁸ , Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₂ _ ₈ alkenyl, C ₂ _8 alkynyl, cycloalkyl (e.g., C ₃ _6 cycloalkyl), aryl, heterocycle, or heteroaryl, or two R ⁷ units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle has 3 to 7 ring atoms; wherein R ⁸ , at each occurrence, independently is hydrogen, Ci_6 alkyl, Ci_6 haloalkyl, C ₂ .g alkenyl, C ₂ .g alkynyl, cycloalkyl (e.g., C ₃ _ ₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R ⁸ units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

[0065] In some embodiments, the substituents are selected from

i) -OR ⁹ ; for example, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ ;

ii) -C(0)R ⁹ ; for example, -COCH ₃ , -COCH ₂ CH ₃ , -COCH ₂ CH ₂ CH ₃ ;

iii) -C(0)OR ⁹ ; for example, -C0 ₂ CH ₃ , -C0 ₂ CH ₂ CH ₃ , -C0 ₂ CH ₂ CH ₂ CH ₃ ;

iv) -C(0)N(R ⁹ ) ₂ ; for example, -CONH ₂ , -CONHCH ₃ , -CON(CH ₃ ) ₂ ;

v) -N(R ⁹ ) ₂ ; for example, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NH(CH ₂ CH ₃ );

vi) halogen: -F, -CI, -Br, and -I;

vii) -CH _e X _g ; wherein X is halogen, m is from 0 to 2, e+g =3; for example, -CH ₂ F, -CHF ₂ , -CF ₃ , -CC1 ₃ , or -CBr ₃ ;

viii) -S0 ₂ R ⁹ ; for example, -S0 ₂ H; -S0 ₂ CH ₃ ; -S0 ₂ C ₆ H ₅ ;

ix) Ci-6 linear, branched, or cyclic alkyl;

x) Cyano

xi) Nitro;

xii) N(R ⁹ )C(0)R ⁹ ;

xiii) Oxo (=0);

xiv) Heterocycle; and

xv) Heteroaryl.

wherein each R ⁹ is independently hydrogen, optionally substituted Ci_ ₆ linear or branched alkyl (e.g., optionally substituted Q-4 linear or branched alkyl), or optionally substituted C ₃ . ₆ cycloalkyl (e.g optionally substituted C ₃ - ₄ cycloalkyl); or two R ⁹ units can be taken together to form a ring comprising 3-7 ring atoms. In certain aspects, each R ⁹ is independently hydrogen, Ci_ ₆ linear or branched alkyl optionally substituted with halogen or C ₃ . ₆ cycloalkyl or C ₃ . ₆ cycloalkyl.

[0066] At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci_6 alkyl" is specifically intended to individually disclose Ci, C ₂ , C ₃ , C4, C ₅ , Ce, C -C6, C -C5, C -C ₄ , C ₁ -C3, C ₁ -C ₂ , C ₂ -C6, C ₂ -C5, C ₂ -C i, C ₂ -C ₃ , C ₃ -C6, C ₃ -C5, C3-C ₄ , C ₄ -C6, C ₄ -C5, and C5-C6, alkyl.

[0067] For the purposes of the present invention the terms "compound," "analog," and "composition of matter" stand equally well for the NRF2 activators described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms "compound," "analog," and "composition of matter" are used interchangeably throughout the present specification.

[0068] Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.

[0069] Pharmaceutically acceptable salts of compounds of the present teachings, which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation. 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 NaHC0 ₃ , Na ₂ C0 ₃ , KHC0 ₃ , K ₂ C0 ₃ , Cs ₂ C0 ₃ , LiOH, NaOH, KOH, NaH ₂ P0 ₄ , Na ₂ HP0 ₄ , and Na ₃ P0 ₄ . 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, 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.

[0070] When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(R ⁸ ) ₂ , each R ⁸ may be the same or different than the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0071] The terms "treat" and "treating" and "treatment" as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer.

[0072] As used herein, "therapeutically effective" and "effective dose" refer to a substance or an amount that elicits a desirable biological activity or effect.

[0073] As used herein, the term "effective amount" of a therapeutic agent refers to the amount of the agent necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of an agent may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue or cell, and the like. More particularly, the term" effective amount" refers to an amount sufficient to produce the desired effect, e.g., to reduce or ameliorate the severity, duration, progression, or onset of a disease, disorder, or condition, or one or more symptoms thereof; prevent the advancement of a disease, disorder, or condition, cause the regression of a disease, disorder, or condition; prevent the recurrence, development, onset or progression of a symptom associated with a disease, disorder, or condition, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.

[0074] As used herein, the term "in combination with" is meant the administration of a compound of

the disclosure with one or more therapeutic agents either simultaneously, sequentially, or a combination thereof. Therefore, a cell or a subject administered a combination of a compound of the disclosure can receive a compound of the disclosure and one or more therapeutic agents at the same time (i.e., simultaneously) or at different times (i.e., sequentially, in either order, on the same day or on different days), so long as the effect of the combination of both agents is achieved in the cell or the subject. When administered sequentially, the agents can be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes or longer of one another. In other embodiments, agents administered sequentially, can be administered within 1, 5, 10, 15, 20 or more days of one another. Where the compound of the disclosure and one or more therapeutic agents are administered simultaneously, they can be administered to the cell or administered to the subject as separate pharmaceutical compositions, each comprising either a compound of the disclosure or one or more therapeutic agents, or they can contact the cell as a single composition or be administered to a subject as a single pharmaceutical composition comprising both agents.

[0075] When administered in combination, the effective concentration of each of the agents to elicit a particular biological response may be less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be needed if the agent was administered as a single agent. The effects of multiple agents may, but need not be, additive or synergistic. The agents may be administered multiple times.

[0076] Except when noted, the terms "subject" or "patient" are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term "subject" or "patient" as used herein means any mammalian patient or subject to which the compounds of the invention can be administered. In an exemplary embodiment of the present invention, to identify subject patients for treatment according to the methods of the invention, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.

[0077] The subject treated by the presently disclosed methods in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term "subject." Accordingly, a "subject" can include a human subject for medical purposes, such as for treating an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal subject for medical, veterinary purposes, or developmental purposes. Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like. An animal may be a transgenic animal. In some embodiments, the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Further, a "subject" can include a patient afflicted with or suspected of being afflicted with a condition or disease. Thus, the terms "subject" and "patient" are used interchangeably herein.

[0078] Methods of Treating an Autoimmune Disease

[0079] In some embodiments, the presently disclosed subject matter provides a method for treating or preventing an autoimmune disease, disorder or condition associated with an NRF2-regulated pathway, the method comprising administering a compound of the disclosure to the subject in an amount effective to increase an NRF2 biological activity or NRF2 expression, thereby treating or preventing the autoimmune disease, disorder, or condition. Without wishing to be bound to anyone particular theory, it is believed that the presently disclosed compounds act as potent immunomodulators, which upon activation of the NRF2 signaling pathway, protect a subject from an autoimmune disease by suppressing inflammation. [0080] In some embodiments, the autoimmune disease is a member selected from the group consisting of acute graft-versus host disease, autoimmune inner ear disease, inflammatory bowel disease, rheumatoid arthritis, psoriasis, psoriatic arthritis, multiple sclerosis, scleroderma, lupus, ankylosing spondylitis, neutropenia, and uveitis. Again, without wishing to be bound to anyone particular theory, it is believed that these diseases are mainly mediated by Thl and Thl7 inflammation and activating the NRF2 pathway can suppress these inflammatory mediators.

[0081] In other embodiments, the presently disclosed subject matter provides compositions and methods for treating or preventing a comorbidity associated with diabetes including, but not limited to, retinopathy and nephropathy. As used herein, the term "comorbidity" includes either the presence of one or more disorders (or diseases) in addition to a primary disease or disorder, or the effect of such additional disorders or diseases on a subject. "Comorbidity" can include (i) a medical condition existing simultaneously, but independently with another condition in a subject; and/or (ii) a medical condition in a subject that causes, is caused by, or is otherwise related to another condition in the same subject.

[0082] In yet other embodiments, the presently disclosed subject matter provides compositions and methods for improving the outcome for bone marrow transplant for leukemia and related cancers and treating bone marrow deficiencies, inborn errors of metabolism, and immune disorders. Activating NRF2 also is thought to stimulate hematopoiesis (Merchant, AA, et al.) as well as the redox-sensitive transcription factor NRF2 regulates murine hematopoietic stem cell survival independently of ROS levels, Blood 2011; 118(25):6572-6579.

[0083] Methods of Treating a Disease or Condition Associated with Oxidative Stress

[0084] Methods of treating a disease, disorder, or condition associated with oxidative stress are disclosed in International PCT Patent Application Publication No. W02007/005879, which is incorporated herein by reference in its entirety. Oxidative Stress describes the level of oxidative damage caused by reactive oxygen species (ROS) in a cell, tissue, or organ. Reactive oxygen species (e.g., free radicals, reactive anions) are generated in endogenous metabolic reactions. Exogenous sources of reactive oxygen species include exposure to cigarette smoke and environmental pollutants. Reactions between free radicals and cellular components result in the alteration of macromolecules, such as polyunsaturated fatty acids in membrane lipids, essential proteins, and DNA. Oxidative stress results when the formation of free radicals exceeds antioxidant activity. Accordingly, by "oxidative stress" is meant cellular damage or a molecular alteration in response to a reactive oxygen species. By disease or disorder related to oxidative stress" is meant any pathology characterized by an increase in oxidative stress. Oxidative stress is implicated in a variety of disease states, including Alzheimer's disease, Parkinson's disease, inflammatory diseases, neurodegenerative diseases, heart disease, HIV disease, chronic fatigue syndrome, hepatitis, cancer, autoimmune diseases, and aging. [0085] In some embodiments, the presently disclosed subject matter provides a method for treating a disease, disorder, or condition associated with oxidative stress. Mammals having reduced levels of NRF2 are particularly susceptible to tissue damage associated with oxidative stress, including pulmonary inflammatory conditions, sepsis, and neuronal cell death associated with ischemic injury. NRF2 provides protection against oxidative stress and reduces neuronal cell death associated with ischemic injury. Accordingly, agents that increase the expression or biological activity of Nfr2 are useful for preventing and treating diseases or disorders associated with increased levels of oxidative stress or reduced levels of antioxidants, including pulmonary inflammatory conditions, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), emphysema, sepsis, septic shock, ischemic injury, including cerebral ischemia and heart ischemia, cognitive deficits, and neurodegenerative disorders.

[0086] Oxidative Stress and Pulmonary Disorders

[0087] Oxidative stress is involved in the pathogenesis of pulmonary diseases, including asthma, COPD, and emphysema. By "pulmonary inflammatory condition" is meant any disease, disorder, or condition characterized by an increase in airway inflammation, intermittent reversible airway obstruction, airway hyperreactivity, excessive mucus production, or an increase in cytokine production (e.g., elevated levels of immunoglobulin E and Th2 cytokines). In particular, increased NRF2 activation is associated with a decrease in airway remodeling (Rangasamy, T., et al., Disruption of NRF2 enhances susceptibility to severe airway inflammation and asthma in mice. J. Exp. Med. 2005, 202, 47-59). Airway remodeling occurs as a result of the proliferation of fibroblasts. Increased remodeling is associated with several pulmonary diseases, such as COPD, asthma and interstitial pulmonary fibrosis (IPF). Compounds and strategies that increase NRF2 biological activity or expression are useful for preventing or decreasing fibrosis and airway remodeling in lungs as a result of COPD, asthma and IPF.

[0088] The lungs of NRF2 ^{" "} mice exhibit a defective antioxidant response that leads to worsened asthma, exacerbates airway inflammation and increases airway hyperreactivity (ARR). By "antioxidant response" is meant an increase in the expression or activity of a NRF2 regulated gene. Exemplary NRF2 regulated genes are described herein (see Table 1). Critical host factors that protect the lungs against oxidative stress determine susceptibility to asthma or act as modifiers of risk by inhibiting associated inflammation. NRF2 -regulated genes in the lungs include almost all of the relevant antioxidants, such as heme oxygenase-1 (HO-1), γ-glutamyl cysteine synthase (γ- GCS), and several members of the GST family. Methods for increasing Nrf-2 expression or biological activity are, therefore, useful for treating pulmonary diseases associated with oxidative stress, inflammation, and fibrosis. Such diseases include, but are not limited to, chronic bronchitis, emphysema, inflammation of the lungs, pulmonary fibrosis, interstitial lung diseases, and other pulmonary diseases or disorders characterized by subepithelial fibrosis, mucus metaplasia, and other structural

alterations associated with airway remodeling.

[0089] Ischemia and Neurodegenerative Disease

[0090] NRF2 protects cells and multiple tissues by coordinately up-regulating ARE-related detoxification and antioxidant genes and molecules required for the defense system in each specific environment. A role has been identified for NRF2 as a neuroprotectant molecule that reduces apoptosis in neural tissues following transient ischemia. By "ischemic injury" is meant any negative alteration in the function of a cell, tissue, or organ in response to hypoxia. By "reperfusion injury" is meant any negative alteration in the function of a cell, tissue, or organ in response restore of blood flow following transient occlusion.

[0091] Accordingly, in some embodiments, the presently disclosed subject matter provides compositions and methods for treating a variety of disorders involving cell death, including but not limited to, neuronal cell death. In one embodiment, agents that increase NRF2 expression or biological activity are useful for treating or preventing a disease or disorder characterized by increased levels of cell death, including ischemic injury (caused by, e.g., a myocardial infarction, a stroke, or a reperfusion injury, brain injury, stroke, and multiple infarct dementia, a secondary exsanguination or blood flow interruption resulting from any other primary diseases), as well as neurodegenerative disorders (e.g., Alzheimer's disease (AD) Creutzfeldt- Jakob disease, Huntington's disease, Lewy body disease, Pick's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and neurofibromatosis). By "neurodegenerative disorder" is meant any disease or disorder characterized by increased neuronal cell death, including neuronal apoptosis or neuronal necrosis.

[0092] Methods for Reversing Corticosteroid Resistance and Treating Respiratory Infections

[0093] Methods for reversing corticosteroid resistance and treating respiratory infections are disclosed in International PCT Patent Application Publication No. W020111094598, which is incorporated herein by reference in its entirety. By "corticosteroid resistance" is meant having diminished corticosteroid sensitivity. Chronic obstructive pulmonary disease (COPD) is characterized by a progressive decrease in lung function and encompasses both chronic bronchitis and emphysema. COPD is the fifth leading cause of death worldwide. Tobacco exposure is the major risk factor for COPD development in industrialized countries. Patients with COPD have frequent symptomatic exacerbations, which are primarily due to exposure to bacterial or viral infections or environmental pollutants. These exacerbations are a major cause of morbidity, mortality, and

healthcare costs.

[0094] Among the bacterial causes of exacerbations, nontypeable Haemophilus influenzae (NTHI) is the most prevalent, and Pseudomonas aeruginosa (PA) becomes important in severe COPD. Patients with advanced COPD experience, on average, two to three periods of exacerbation annually. Clinical and animal studies have shown that cigarette smoking causes defective bacterial phagocytosis by alveolar macrophages resulting in bacterial colonization and enhanced inflammation in lungs. Currently, there are no proven therapies that can inhibit bacterial colonization and prevent infectious COPD exacerbations. Current treatments for COPD are of limited benefit. Corticosteroids are highly effective anti-inflammatory drugs for asthma, but they have little therapeutic benefit in COPD because of diminished corticosteroid sensitivity. High doses of inhaled corticosteroids are widely used to manage COPD; but they reduce exacerbations by only about 20% to 25% and do not alter disease progression or survival. High doses of systemic corticosteroids are used to treat acute severe COPD exacerbations, but they reduce length of hospitalization by only 9%.

[0095] Corticosteroid resistance due to inactivation of histone deacetylase (HDAC) 2 is a barrier to effective treatment of chronic obstructive pulmonary disease (COPD). The presently disclosed subject matter is based, at least in part, on the discovery that S-nitrosylation is a key posttranslational modification responsible for inactivation of HDAC2 in COPD alveolar macrophages that can be reversed by targeting transcription factor nuclear factor erythroid 2- related factor 2 (NRF2). Sulforaphane, a small-molecule activator of NRF2, restores the function of HDAC2 by denitrosylation in a glutathione-dependent manner, thereby augmenting deacetylation of histones in the interleukin-8 promoter and glucocorticoid receptor in alveolar macrophages from patients with COPD. In contrast to nitric oxide synthase inhibition alone, sulforaphane treatment reestablishes the repressive effect of corticosteroid on cytokine production in alveolar macrophages from patients with COPD. Sulforaphane restores HDAC2 function and corticosteroid sensitivity in alveolar macrophages from cigarette smoke -exposed mice. Thus, NRF2 is a novel drug target to reverse corticosteroid resistance in COPD and other corticosteroid- resistant inflammatory diseases (e.g., severe asthma, acute graft-versus host disease, autoimmune inner ear disease, inflammatory bowel diseases, and rheumatoid arthritis).

[0096] Patients with chronic obstructive pulmonary disease (COPD) have pulmonary innate immune dysfunction largely due to defective macrophage phagocytic ability by unknown mechanisms. This condition results in periodic bacterial infection and colonization that cause acute exacerbation of COPD, a major source for morbidity and mortality. The presently disclosed subject matter is further based, at least in part, on the discovery that activation of transcription factor NRF2 by sulforaphane treatment restores bacterial recognition, phagocytic ability and clearance of clinical isolates nontypeable Haemophilus influenza (NTHI) and Pseudomonas aeruginosa (PA) by alveolar macrophages from patients with COPD. Molecular studies reveal NRF2 improves macrophage phagocytic ability by direct transcriptional upregulation of class A scavenger receptor MARCO and was independent of its antioxidant function. Sulforaphane treatment restored phagocytic ability of alveolar macrophages by increasing MARCO and inhibited bacterial colonization (NTHI or PA) and inflammation in the lungs of wild-type mice after 6 months of chronic exposure to cigarette smoke. These findings identify increasing MARCO by targeting NRF2 as a therapeutic approach to improve anti-bacterial defenses and suggest that this pathway can be targeted for preventing bacterial exacerbations in COPD.

[0097] Accordingly, agents that increase the expression or biological activity of Nfr2 (e.g compounds of the disclosure) are useful for reversing corticosteroid resistance, as well as for treating respiratory infections, particularly those associated with chronic obstructive pulmonary disease, emphysema, and related conditions. Therefore, the presently disclosed subject matter provides compositions for reversing corticosteroid resistance that comprise an agent that increases NRF2 activity, alone or in combination with a corticosteroid (e.g., dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate, budesonide, prednisone, prednisolone, and methylprednisolone).

[0098] In other embodiments, the presently disclosed subject matter provides compositions for treating a bacterial infection, particularly for bacterial infections that occur in a subject having or at risk of developing COPD, in subjects having chronic bronchitis, in smokers, and in subjects having cystic fibrosis or having an immunodeficiency syndrome that reduces or otherwise compromises the efficacy of the subject's immune system.

[0099] Conditions associated with corticosteroid resistance include, but are not limited to, corticosteroid resistance in COPD, asthma, including severe asthma, acute graft-versus host disease, autoimmune inner ear disease, inflammatory bowel diseases, rheumatoid arthritis, as well as bacterial infections, including those associated with COPD and related conditions (e.g., smoking, chronic bronchitis).

[0100] By "pulmonary inflammatory condition" also is meant any pathological condition that increases mononuclear cells (monocytes/macrophages, lymphocytes), neutrophils, and fibroblasts in the lungs. Exemplary pulmonary inflammatory conditions include, but are not limited to, bacterial, viral, or fungal pulmonary infections, environmental pollutants (e.g., particulate matter, automobile exhaust, allergens), chronic obstructive pulmonary disease, asthma, acute lung injury/acute respiratory distress syndrome or inflammation.

[0101] By "restoring corticosteroid responsiveness" is meant increasing the anti -inflammatory action of corticosteroids in subjects having reduced sensitivity to corticosteroid treatment. The restoration need not be complete, but can be an increase in sensitivity of at least about 10%, 25%, 30%, 50%, 75% or more.

[0102] By "reversing corticosteroid insensitivity" is meant re-establishing the repressive effect of corticosteroids on cytokine production in subjects having reduced sensitivity to corticosteroid treatment, thereby reducing the levels required for efficacy to those closer to levels typically used in subjects that are not corticosteroid insensitive. [0103] By "respiratory infection" is meant any infection affecting the respiratory system (e.g., lungs and associated tissues). Exemplary respiratory infections include, but are not limited to, infections with a Gram negative or positive bacteria (e.g., Pseudomonas aeruginosa, nontypeable Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumonia, Staphylococcus aureus), or a virus (e.g. Pvhinovirus, coronovirus, influenza A and B, parainfluenza, Adenovirus, and Respiratory syncytial virus).

[0104] Methods for Treating Radiation Damage

[0105] Radiation injury can occur from external irradiation, either when the entire body is irradiated or when only part of the body is irradiated. Radiation injury may occur in connection with radiotherapy, during an accidental exposure to radioactivity, e.g., nuclear fallout from a nuclear accident, or in connection with a nuclear attack.

[0106] Accidental exposure or nuclear attack also can cause internal radiation exposure due to widespread radioactive particles released in the environment. Radiation exposure causes short term and/or long term disorders. Clinical components of the acute radiation syndrome include hematopoietic, gastrointestinal, and cerebrovascular syndromes that occur within days to a few weeks following radiation exposure. Long term disorders, such as lung fibrosis, following radiation exposure are typically associated with tissue damage.

[0107] Health effects after radiation exposure are caused by damage to rapidly dividing normal cells.

Therapies directed toward preventing and mitigating injuries caused by unintentional (e.g., nuclear accidents or attack) or intentional (e.g., cancer treatment) radiation exposure are vital to addressing such health effects.

[0108] In the case of whole body exposure to high doses of radiation, acute radiation syndrome can appear within minutes or days after radiation exposure. At doses between 2 Gy and 6 Gy, the hematopoietic system is significantly damaged leading to immunosuppression, infection, and bleeding. Without appropriate therapy, death may result within 60 days. At doses higher than 6 Gy, significant damage to the gut occurs, which results in severe nausea, vomiting, diarrhea, ulceration of the intestinal mucosa, and systemic infection leading to sepsis. At these doses, death may occur within two to four weeks. Doses higher than 20 Gy cause significant damage to the central nervous system and cardiovascular system that may result in death within two days.

[0109] In the case of curative intent, such as eliminating a tumor and/or preventing cancer reoccurrence, the radiation dose for a solid epithelial tumor ranges from about 60 Gy about 80 Gy. During palliative treatment, however, such as relieving suffering by shrinking a tumor in the brain or esophagus, cancer patients are exposed to about 20 Gy to about 40 Gy in 2 Gy fractions. Radiotherapy can cause both acute and late side effects. Depending on the area of the body treated, the acute and late health effects after radiotherapy include permanent damage to salivary glands (e.g., dry mouth and loss of taste), damage to mucosal areas (e.g., oral mucositis, GI mucositis and esophagitis), damage to lungs (e.g., pneumonitis and fibrosis) and damage to the brain (e.g., memory loss).

[0110] Toxic effects of radiation are initiated by oxidative stress, which causes cell death, tissue damage, and promotes inflammation. Agents that can inhibit oxidative stress (anti-oxidants), cell death (anti-apoptotic agents or cell survival factors), and inflammation (anti-inflammatory agents) are potential drugs to limit radiation injuries. "Radioprotectants" are agents that protect from radiation damage when administered prior to radiation exposure. "Radiomitigators" are agents that reduce the radiation damage when administered after radiation exposure. In an emergency scenario, radiomitigators that are effective after radiation exposure (e.g., 24 h after radiation exposure) are promising drug candidates.

[0111] Methods for treating radiation damage are disclosed in International PCT Patent Application No. W02010/059245, which is incorporated herein by reference in its entirety. By "radiation injury" is meant any cell, tissue, or organ damage associated with exposure to ionizing radiation. Examples of radiation injury include, but are not limited to, hematopoietic syndrome, gastrointestinal syndrome, cerebrovascular syndrome, cerebrospinal injury, pulmonary effects, sepsis, renal failure, pneumonitis, mucositis, enteritis, fibrosis, skin injuries, neutropenia, and an effect on a soft tissue.

[0112] Accordingly, in some embodiments, the presently disclosed subject matter provides compositions and methods that are useful for treating or preventing radiation injury. The presently disclosed subject matter is based, at least in part, on the discovery that compounds that activate NRF2 protect against cell and tissue damage associated with radiation exposure, and reduce mortality in response to such injury.

[0113] Radiation Injury:

[0114] Clinical components of acute radiation syndrome include hematopoietic, gastrointestinal, and cerebrovascular syndromes that occur within days or weeks of exposure. The hematopoietic syndrome, which is characterized by hypoplasia or aplasia of the bone marrow, occurs in connection with significant partial-body or whole-body radiation exposures. These hematopoietic changes result in pancytopenia, predisposition to infection, bleeding, and poor wound healing. Any one of these effects of radiation on hematopoiesis can be fatal. Gastrointestinal syndrome is characterized by abdominal pain, diarrhea, and nausea and vomiting and predispose patients to infection. Radiation induces loss of intestinal crypts and breakdown of the mucosal barrier. Cutaneous injury from thermal or radiation burns is characterized by loss of epidermis and dermis. Injuries to the skin may cover small areas, but extend deep into the soft tissue, even reaching underlying muscle and bone.

[0115] Mechanism of radiation injury

[0116] ROS and electrophiles generated by irradiation are key players in causing acute and chronic pathological injury. ROS induce oxidative damage to biomolecules and causes apoptosis of hematopoietic cells, endothelial cells and epithelial cells. Depletion of hematopoietic cells in a subject results in an impaired immune response and predisposes the subject to secondary infections. The increased death of endothelial cells and epithelial cells results in a loss of mucosal barrier and tissue injury. Loss of intestinal or lung mucosal barrier leads to translocation of bacteria into systemic circulation and causes systemic inflammation and sepsis. Tissue injury causes local inflammation leading to tissue remodeling and fibrosis. In sum, irradiation increases oxidative stress, apoptosis, and inflammation leading to multiorgan injury, which is often lethal. Therapies directed toward blocking ROS-induced deleterious effects mitigates and treats radiation injury.

[0117] In other embodiments, the presently discloses subject matter provides compositions and methods that are useful for treating or preventing chemotherapy injury. By "chemotherapy injury", it is meant injury or side effects resulting from administering chemotherapy drugs to a patient, such as a cancer patient and the like. The presently disclosed subject matter is based, at least in part, on the discovery that compounds that activate NRF2 protect against cell and tissue damage associated with chemotherapy exposure.

[0118] Methods of Treating Neutropenia

[0119] Accordingly, in some embodiments, the presently disclosed subject matter provides a method for treating of preventing neutropenia caused by chemotherapy, autoimmunity diseases, and in subjects having a congenital neutropenic disorder. Neutropenia is a condition in which the number of neutrophils in the bloodstream is decreased. Neutrophils are a type of white blood cell, also known as polymorphonuclear leukocytes. Neutropenia can affect the body's ability to fight an infection. As provided hereinabove, activating NRF2 also is thought to stimulate hematopoiesis (Merchant, AA, et al.) The redox-sensitive transcription factor NRF2 regulates murine hematopoietic stem cell survival independently of ROS levels, Blood 2011; 118, 25, 6572-6579.

[0120] The NRF2 activators

[0121] The NRF2 activators of the present invention are functionalized hetroaryl enones, and include all enantiomeric and diastereomeric forms and pharmaceutically accepted salts thereof having the formula:

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

Q is a member selected from the group consisting of CF ₃ , CF ₂ H, and CFH ₂ , R ¹ is a member selected from the group consisting of hydrogen, C e alkyl, C3.7 branched alkyl, and C3.6 cycloalkyl,

A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ , and A ⁸ are at each occurrence a member independently selected from the group consisting of N and CR ² ,

One of the set A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ , and A ⁸ must be N,

No more than one of the set A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ , and A ⁸ may be N,

R ² is at each occurrence independently selected from the group consisting of hydrogen, halogen, Cue alkyl, C ₃ _ ₇ branched alkyl, C ₃ _ ₆ cycloalkyl, Cue alkoxy, C ₃ _ ₇ branched alkoxy, CN, N0 ₂ , S0 ₂ NH ₂ , S0 ₂ R ³ , SOR ³ , NR ^4a R ^4b , SR ⁵ , -NR ^4a C(0)R ⁶ , Aryl, and Heteroaryl,

R ³ is at each occurrence independently selected from the group consisting of Cue alkyl, C ₃ . ₇ branched alkyl, and C ₃ . ₆ cycloalkyl,

R ^4a is at each occurrence independently selected from the group consisting of hydrogen, Cue alkyl, C ₃ _7 branched alkyl, and C ₃ . ₆ cycloalkyl,

R ^4b is at each occurrence independently selected from the group consisting of hydrogen, Cue alkyl, C ₃ _7 branched alkyl, and C ₃ _6 cycloalkyl,

R ⁵ is at each occurrence independently selected from the group consisting of hydrogen, C ₆ alkyl, C ₃ _7 branched alkyl, and C ₃ _6 cycloalkyl, and

R ⁶ is at each occurrence independently selected from the group consisting of hydrogen, Cu ₆ alkyl, C ₃ _7 branched alkyl, and C ₃ _6 cycloalkyl.

[0122] The compounds of the present invention include compounds having formula (II):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0123] The compounds of the present invention include compounds having formula (III):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0124] The compounds of the present invention include compounds having formula (IV):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof. [0125] The compounds of the present invention include compounds having formula (V):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0126] The compounds of the present invention include compounds having formula (VI):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0127] The compounds of the present invention include compounds having formula (VII):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0128] The compounds of the present invention include compounds having formula (VIII):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0129] The compounds of the present invention include compounds having formula (IX):

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

[0130] In some embodiments CF ₃ .

[0131] In some embodiments CF ₂ H.

[0132] In some embodiments CFH ₂ .

[0133] In some embodiments R ¹ is hydrogen.

[0134] In some embodiments R ¹ is Ci_ ₆ alkyl.

[0135] In some embodiments R ¹ is C ₃ . ₇ branched alkyl [0136] In some embodiments R is C3.6 cycloalkyl.

[0137] In some embodiments A ¹ is N.

[0138] In some embodiments A ¹ is CR ² .

[0139] In some embodiments A ² is N.

[0140] In some embodiments A ² is CR ² .

[0141] In some embodiments A ³ is N.

[0142] In some embodiments A ³ is CR ² .

[0143] In some embodiments A ⁴ is N.

[0144] In some embodiments A ⁴ is CR ² .

[0145] In some embodiments A ⁵ is N.

[0146] In some embodiments A ⁵ is CR ² .

[0147] In some embodiments A ⁶ is N.

[0148] In some embodiments A ⁶ is CR ² .

[0149] In some embodiments A ⁷ is N.

[0150] In some embodiments A ⁷ is CR ² .

[0151] In some embodiments A ⁸ is N.

[0152] In some embodiments A ⁸ is CR ²

[0153] In some embodiments R ² is hydrogen.

[0154] In some embodiments R ² is halogen.

[0155] In some embodiments R ² is Ci_6 alkyl.

[0156] In some embodiments R ² is C3.7 branched alkyl.

[0157] In some embodiments R ² is C3.6 cycloalkyl.

[0158] In some embodiments R ² is Ci_6 alkoxy.

[0159] In some embodiments R ² is C3.7 branched alkoxy.

[0160] In some embodiments R ² is CN.

[0161] In some embodiments R ² is N0 ₂ .

[0162] In some embodiments R ² is S0 ₂ NH ₂ .

[0163] In some embodiments R ² is S0 ₂ R ³ .

[0164] In some embodiments R ² is SOR ³ .

[0165] In some embodiments R ² is NR ^4a R ^4b .

[0166] In some embodiments R ² is SR ⁵ .

[0167] In some embodiments R ² is -NR ^4a C(0)R ⁶ .

[0168] In some embodiments R ² is aryl.

[0169] In some embodiments R ² is heteroaryl.

[0170] In some embodiments R ³ is Ci_6 alkyl.

[0171] In some embodiments R ³ is C3.7 branched alkyl.

[0172] In some embodiments R ³ is C3.6 cycloalkyl. [0173] In some embodiments drogen.

[0174] In some embodiments

[0175] In some embodiments

[0176] In some embodiments

[0177] In some embodiments irogen.

[0178] In some embodiments

[0179] In some embodiments

[0180] In some embodiments

[0181] In some embodiments ' is hydrogen.

[0182] In some embodiments ' is Ci_6 alkyl.

[0183] In some embodiments ' is C ₃ .7 branched alkyl.

[0184] In some embodiments ' is C ₃ _6 cycloalkyl.

[0185] In some embodiments ' is hydrogen.

[0186] In some embodiments ' is Ci_6 alkyl.

[0187] In some embodiments

[0188] In some embodiments ' is C ₃ .6 cycloalkyl.

[ [0u1i8o9j']j F rouri t uhiec p puurrppoosseess o 0f1 ucmonstrat tiinngg tthhee mmaanmnieeri i 1n11 w WhJ ich the compounds of the present invention are named and referred to herein, the compound hhaavviing the formula:

has the chemical name l -(3-methoxy-pyridin-2-yl)-3-(2-trifluoromethyl-phenyl)-prope none.

[0190] For the purposes of the present invention, a compound depicted by the racemic formula will stand equally well for either of the two enantiomers or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.

[0191] Compounds of the present invention include compounds having the formula (I) or a pharmaceutically acceptable salt form thereof:

wherein non-limiting examples of A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ , A, and R ¹ are defined herein below in Table 2.

Table 2: Exemplary compounds of the formula (I) 2 CF ₃ CH N CH CH CH CH CH CH CH ₃

3 CF ₃ CH CH N CH CH CH CH CH CH ₃

4 CF ₃ CH CH CH N CH CH CH CH CH ₃

5 CF ₃ CH CH CH CH N CH CH CH CH ₃

6 CF ₃ CH CH CH CH CH N CH CH CH ₃

7 CF ₃ CH CH CH CH CH CH N CH CH ₃

8 CF ₃ CH CH CH CH CH CH CH N CH ₃

9 CI N CH CH CH CH CH CH CH CH ₃

10 CI CH N CH CH CH CH CH CH CH ₃

11 CI CH CH N CH CH CH CH CH CH ₃

12 CI CH CH CH N CH CH CH CH CH ₃

13 CI CH CH CH CH N CH CH CH CH ₃

14 CI CH CH CH CH CH N CH CH CH ₃

15 CI CH CH CH CH CH CH N CH CH ₃

16 CI CH CH CH CH CH CH CH N CH ₃

[0192] In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. The compounds of the invention may contain any of the substituents, or combinations of substituents, provided herein.

PROCESS

[0193] The present invention further relates to a process for preparing the NRF2 activators of the present invention.

[0194] Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein. [0195] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., H or 13, C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

[0196] Preparation of the compounds can involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.

[0197] The reactions or the processes described herein can be carried out in suitable solvents which

can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

[0198] The compounds of these teachings can be prepared by methods known in the art of organic chemistry. The reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature. For example, compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes below.

GENERAL SYNTHETIC SCHEMES FOR PREPARATION OF COMPOUNDS.

[0199] The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus may be produced by one of the following reaction schemes.

[0200] Compounds of formula (I) may be prepared according to the process outlined in Scheme 1.

Base, Solvent

[0201] A suitably substituted compound of formula (1), a known compound or compound prepared by known methods wherein X is a leaving group such as chlorine, bromine, iodine, methanesulfonate, toluenesulfonate and the like, is reacted a compound of the formula (2), a known compound or a compound prepared by known methods, wherein M is a metal such as sodium, lithium, potassium, and the like, in the presence of an organic solvent such as tetrahydrofuran, 1 ,4-dioxane, methanol, ethanol, Ν,Ν-dimethylformamide, N, N-dimethyl acetamide, dichloromethane, 1 ,2-dichloroethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (3). A compound of the formula (3) is reacted with a compound of the formula (4) wherein Y is a halogen, in the presence of an organic solvent such as tetrahydrofuran, 1 ,4-dioxane, Ν,Ν-dimethylformamide, N, N-dimethyl acetamide, dichloromethane, 1 ,2-dichloroethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (5). A compound of the formula (5) is then reacted with a compound of the formula (6), a known compound or a compound prepared by known methods, in the presence of a base such as sodium hydride, potassium hydride, lithium diisopropyl amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and the like, in the presence of an organic solvent such as tetrahydrofuran, 1 ,4-dioxane, Ν,Ν-dimethylformamide, N, N-dimethyl acetamide, dichloromethane, 1 ,2-dichloroethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (I).

[0202] The Examples provided below provide representative methods for preparing exemplary compounds of the present invention. The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds of the present invention.

EXAMPLE 1

[0203] Example 1 provides methods for preparing representative compounds of formula (1). The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare additional compounds of the present invention.

[0204]Example 1 : Synthesis of l -(3-methoxy-pyridin-2-yl)-3-(2-trifluoromethyl-phenyl)- propenone (CVA-130034)

[0205] Step 1 : Synthesis of 3-methoxy-2-cyanopyridine: Sodium methoxide (0.41g, 7.5mmol) was dissolved in 10 mL anhydrous Ν,Ν-dimethylformamide in a 25 mL round bottom flask under a nitrogen atmosphere and cooled to 4 °C with an ice water bath. 3-Chloro-2-cyanopyridine (1.01 g, 7.2mmol) was added, the ice water bath was removed, and the reaction was warmed to 25 °C. After 2 hours, the reaction was concentrated under vacuum and ethyl acetate was added to the residue and the mixture was filtered to remove the precipitate. The resulting filtrate was then concentrated on a rotary evpaorator to obtain the desired product as a white solid that was used without further purification (0.88g, 88% yield). 'H-NMR (400MZ, CDCI ₃ ) δ 8.22 (1H, dd, J = 7.4 and 1.6 Hz), 7.90 (1H, dd, J = 7.5 and 7.3 Hz), 7.73 (1H, dd, J = 7.73 and 1.6 Hz), 3.92 (3H, s). MS (M+H): 135.

[0206] Step 2: Synthesis of l -(3-methoxy-pyridin-2-yl)-ethanone: 3-Methoxy-2-cyanopyridine (0.88g, 6.5mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) in a 3-neck flask under a nitrogen atmosphere. The reaction was cooled to 0 °C, and a solution of methyl magnesium iodide in tetrahydrofuran (3M, 4.3 ml, 12.8mmol) was added. The reaction was stirred at 0 °C for 2 hours and then quenched with 50 mL of water at 0 °C. The pH was adjusted to 7 with 2N HC1, and the resulting solution was extracted with ethyl acetate (3 x 50 mL)), the combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to provide the crude product. Silica gel chromatography (ISCO RediSep 80 gram column, gradient of 0 - 100% ethyl acetate in hexane over 26 minutes) provided the product as a colorless oil (0.79g, 79% yield). ^l U-

NMR (400Mz, CDCI ₃ ) δ 8.42 (1H, dd, J = 7.7 and 1.4 Hz), 7.63 (1H, dd, J = 7.6 and 1.4 Hz), 7.61 (1H, dd, J = 7.7 and 152.

[0207] Step 3: Synthesis of l-(3-methoxy-pyridin-2-yl)-3-(2-trifluoromethyl-phenyl)-prop enone: l-(3-methoxy-pyridin-2-yl)-ethanone (0.04 g, 0.26mmol) was dissolved in anhydrous methanol (5 mL) and a solution of lithium hydroxide (1.2 mg, 0.05mmol) in anhydrous methanol (1.75 mL) was added. After 30 minutes, 2-trifluoromethyl-benzaldehyde (0.0356 mL 0.27mmol) was added, and the reaction was allowed to stir for 18 hours. The reaction was then concentrated on a rotary evaporator and the crude product was purified by silica gel chromatography (Isco RediSep 12gram column, gradient of 0 - 100%) ethyl acetate in hexane over 10 minutes) to provide the desired product (0.043 g, 54% yield) as a yellow solid. 'H-NMR (400MZ, CDCI ₃ ) δ 8.33 (1H, dd, J = 4.4 and 1.3 Hz), 8.09 (1H, dd, J = 15.9 and 2.1 Hz), 7.90 (1H, d, J = 7.7 Hz), 7.73 (1H, d, J = 7.7 Hz), 7.71 (1H, d, J = 15.9 Hz),7.60 (1H, t, J = 7.6 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.47, (1H, dd, J = 8.6 and 4.4 Hz), 7.41 (1H, dd, J = 8.6 and 1.3 Hz), 3.96 (3H, s). (M+H): 308.

[0208] Example 2: Synthesis of l -(4-methoxypyridin-3-yl)-3-(2-trifluoromethyl-phenyl)- propenone

(CVA-130031)

[0209] Step 1. Synthesis of l -(4-chloropyridin-3-yl)-ethanol: Prepared as described in Busto et al. (Adv. Synthesis Catal. 2006, 348, 2626-2632) starting with 4-chloropyridine hydrochloride (2.5 g, 17 mmol). The desired product was isolated by silica gel chromatography (ISCO RediSep 120gram column, gradient of 0 - 10% ethyl acetate in hexane over 20 minutes) and obtained as a yellow solid (0.25 g, 25% yield). 'H-NMR (400MZ, CDCI ₃ ) δ 8.74 (1H, s), 8.35 (1H, d, J = 7.4 Hz), 7.20 (1H, d, J = 7.4 Hz), 5.24 (1H, q, J = 6.5 Hz, 2.07 (1H, s), 1.49 (3H, d, J = 6.5 Hz). MS (M+/M+2): 157/159.

[0210] Step 2: Synthesis of l-(4-chloropyridin-3-yl)-ethanone hydrochloride: Prepared as described in Busto et al. (Adv. Synthesis Catal. 2006, 348, 2626-2632) starting with l-(4- chloropyridin-3-yl)-ethanol (0.25 g, 1.54 mmol) and chromium trioxide (0.48 g, 4.8 mmol). The desired product was isolated as a hydrochloride salt in the form of a white solid (0.28 g, 98%> yield). 'H-NMR (400MZ, d ₆ -DMSO) δ 9.10 (1H, s), 8.82 (1H, d, J = 6.2 Hz), 8.17 (1H, d, J = 6.2 Hz, 2.75 (3H, s), MS M+/M+2): 155/157.

[0211] Step 3: Synthesis of l-(4-methoxypyridin-3-yl)-ethanone: l-(4-chloropyridin-3-yl)- ethanone hydrochloride (0.25 g, 1.30 mmol) and sodium methoxide (0.16 g, 2.93 mmol) were stirred in anhydrous methanol (10 mL) at reflux for 1 hour under a nitrogen atmosphere. The reaction was cooled to room temperature and water (5 mL) was added. The resulting mixture was concentrated on a rotary evaporator to remove methanol and the resulting aqueous mixture was partitioned between dichloromethane (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product (0.15 g, 76% yield) was obtained as a yellow liquid and used without further purification. 'H-NMR (400Mz, CDCI ₃ ) δ 8.75 (1H, s), 8.51 (1H, d, J = 5.9 Hz), 6.83 (1H, d, J = 5.9 Hz), 3.92 (3H, s), 2.55 (3H, s), MS (M+H): 152. [0212] Step 4: Synthesis of l-(4-(methoxypyridin-3-yl)-3-(2-trifluoromethoxy-phenyl)- propenone: Prepared from l -(4-methoxypyridin-3-yl)-ethanone (23.4 mg, 0.15 mmol) lithium hydroxide (0.8 mg, 0.032 mmol) and 2-trifluoromethyl-benzaldehyde (0.021 mL, 0.16 mmol) in anhydrous methanol (1.5 mL) using the procedure described in Example 1, Step 3. Total reaction time was 24 hours. The crude product was purified by silica gel chromatography (ISCO RediSep 12gram column, 5% methanol, 95% ethyl acetate) to provide the desired product as a yellow solid (38 mg, 83% yield). ¾-NMR (400MZ, CDC1 ₃ ) δ 8.74 (1H, s), 8.64 (1H, d, J = 5.9 Hz), 7.97 (1H, dd, J = 15.8 and 2.0 Hz), 7.80 (1H, d, J = 7.7 Hz), 7.75 (1H, d, J = 7.7 Hz), 7.62 (1H, t, J = 7.5 Hz), 7.53 (1H, t, J = 7.5 Hz), 7.25 (1H, d, J = 15.8 Hz), 6.66 (1H, d, J = 5.9 Hz), 3.98 (3H, s). MS (M+H): 308.

[0213] Example 3. Synthesis of l-(3-methoxy-pyridin-4-yl)-3-(2-trifluoromethyl-phenyl)- propenone (CVA- 130037).

[0214] Step 1 : Synthesis of 3 -methoxy-4-cyanopyridine: Prepared from 3 -chloro-4-cyanopyridine (0.51 g, 8.7mmol), sodium methoxide (0.21 g, 8.8mmol) and anhydrous N,N-dimethylformamide (10 mL) using the procedure described in Example 1. Step 1. The resulting product (a colorless oil, 0.46 g, 92% yield) was used without further purification. 'H-NMR (400MZ, CDC1 ₃ ) δ 8.52

(1H, s), 8.40 (1H, d, J = 4.8 Hz), 7.47 (1H, d, J = 4.8 Hz), 4.09 (3H, s). MS (M+H): 135.

[0215] Step 2: Synthesis of l -(3-methoxy-pyridin-4-yl)-ethanone: Prepared from 3-methoxy-4- cyanopyridine(0.46 g, 3.4mmol), methyl magnesium iodide (3M in tetrahydrofuran, 2.24 mL, 6.72 mmol) and anhydrous tetrahydrofuran (10 mL) using the procedure described in Example 1, Step 2. The crude reaction mixture was purified by silica gel chromatography (ISCO RediSep 40 gram column, 50%> ethyl acetate, 50%> hexane) to provide the desired product as a yellow oil (0.38 g,

75% yield). ¾-NMR (400Mz, CDC1 ₃ ) δ 8.48 (1H, s), 8.35 (1H, d, J = 4.8 Hz), 7.49 (1H, d, J = 4.8 Hz), 4.04 (3 +H): 152.

[0216] Step 3: Synthesis of l -(3-methoxy-pyridin-4-yl)-3-(2-trifluoromethyl-phenyl)-prope none: Prepared from l -(3-methoxy-pyridin-4-yl)-ethanone (55.1 mg, 0.36 mmol), lithium hydroxide (1.75 mg, 0.073mmol) and 2-trifluoromethyl-benzaldehyde (0.039 mL, 0.37mmol) in anhydrous methanol (3 mL) using the procedure described in Example 1, Step 3. Total reaction time was 24 hours. The crude product was purified by silica gel chromatography (ISCO RediSep 12gram column, 5% methanol, 95% ethyl acetate) to provide the desired product as a yellow solid (67.1 mg, 57% yield). 'H-NMR (400MZ, CDC1 ₃ ) δ 8.50 (1H, s), 8.40 (1H, d, J = 4.3 Hz), 7.89 (1H, dd, J = 15.8 and 1.9 Hz), 7.78 (1H, d, J = 7.8 Hz), 7.72 (1H, d, J = 7.8 Hz), 7.61 (1H, t, J = 7.5 Hz), 7.52 (1H, t, J = 7.5 Hz), 7.40 (1H, d, J = 4.4 Hz), 7.16 (1H, d, J = 15.8 Hz), 3.98 (3H, s). MS (M+H): 308.

[0217] Example 4: Synthesis of l-(2-methoxy-pyridin-3-yl)-3-(2-trifluoromethyl-phenyl)- propenone (CVA- 130030).

[0218] Step 1 : Synthesis of l -(2-methoxy-pyridin-3-yl)-ethanone: Sodium methoxide (0.065 g, 1.2mmol) and l -(2-chloropyridin-3-yl)-ethanone (0.063 gm, 0.4mmol) were stirred in 1.5mL anhydrous methanol in a 7 mL vial under a nitrogen atmosphere for 4 hours. The reaction was cooled to room temperature and 0.5mL of H ₂ 0 was added. The mixture was concentrated on a rotary evaporator to remove methanol and the resulting aqueous mixture was partitioned between dichloromethane (20 mL) and water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to provide the crude product as an orange oil (0.032 g, 53% yield), which was used without further purification. 'H-NMR (400MZ, CDC1 ₃ ) δ

8.33 (1H, dd, J = 4.8 and 2.0 Hz), 8.13 (1H, ds, J = 7.5 and 2.0 Hz), 7.00 (1H, dd, J = 7.5 and 4.8 Hz), 4.08 (3H, s), +H): 152.

[0219] Step 2: Synthesis of l -(2-methoxy-pyridin-3-yl)-3-(2-trifluoromethyl-phenyl)-prope none: Prepared from l-(2-methoxy-pyridin-3-yl)-ethanone (0.029 g, 0.19mmol), lithium hydroxide (0.001 g, 0.04 mmol) and 2-trifluoromethyl-benzaldehyde (0.026 mL, 0.196 mmol) in anhydrous methanol (1.5mL) using the procedure described in Example 1, Step 3. Total reaction time was 48 hours. The crude product was purified by silica gel chromatography (ISCO RediSep 12 gram column, 40%> ethyl acetate, 60%> hexane) to provide the desired product as a yellow solid (0.029 g, 49% yield). 'H-NMR (400MZ, CDC1 ₃ ) δ 8.36 (1H, dd, J = 4.8 and 2.0 Hz), 8.08 (1H, dd, J = 7.4 and 2.0 Hz), 8.05 (1H, dd, J = 15.6 and 2.2 Hz), 7.83 (1H, d, J = 7.8 Hz), 7.75 (1H, d, J = 7.8 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.53 (1H, d, J = 7.5 Hz), 7.47 (1H, d, J = 15.7 Hz), 7.05 (1H, dd, J = 7.4 and 4.8 Hz), 4.09 (3H, s). MS (M+H): 308.

[0220] Example 5: Synthesis of l-(2-methoxy-phenyl)-3-(3-trifluoromethyl-pyridin-2-yl)- propenone (CVA-130032)

[0221] Step 1 : Synthesis of l -(2-methoxy-phenyl)-3-(3-trifluoromethyl-pyridin-2-yl)-prope none: Prepared from l -(2-methoxy-phenyl)-ethanone (0.066 mL, 0.48mmol), lithium hydroxide (1.2 mg, 0.01 mmol) and 3-trifluoromethyl-pyridine-2-carboxaldehyde (85 mg, 0.49 mmol) in anhydrous methanol (4 mL) using the procedure described in Example 1, Step 3. Total reaction time was 24 hours. The crude product was purified by silica gel chromatography (ISCO RediSep 12gram column, gradient of 0 - 100% ethyl acetate in hexane over 18 minutes)) to provide the desired product as a yellow oil that hardened upon standing (77mg, 53% yield). 'H-NMR (400MZ, CDCI ₃ ) δ 8.82 (1H, d, J = 4.3 Hz), 8.12 (1H, d, J= 15.0 Hz), 8.01 (1H, dd, J = 8.0 and 1.6 Hz), 7.93 (1H, d, J = 15.0 Hz), 7.70 (1H, dd, J = 7.6 and 1.6 Hz), 7.53 (1H, t, J = 7.4 Hz), 7.71 (1H, dd, J = 7.5 and 4.6 Hz), 7.07 (1H, t, J = 7.5 Hz), 7.02 (1H, d, J = 8.1 Hz), 3.93 (3H, s). MS (M+H): 308.

[0222] Example 6: Synthesis of l-(2-methoxy-phenyl)-3-(4-trifluoromethyl-pyridin-3-yl)- propenone (CVA- 130020).

[0223] Step 1 : Synthesis of l -(2-methoxy-phenyl)-3-(4-trifluoromethyl-pyridin-3-yl)-prope none: Prepared from l -(2-methoxy-phenyl)-ethanone (0.086 mL, 0.63mmol), lithium hydroxide (3.0 mg, 0.1 mmol) and 4-trifluoromethyl-pyridine-3-carboxaldehyde (111 mg, 0.64 mmol) in anhydrous methanol (4 mL) using the procedure described in Example 1, Step 3. Total reaction time was 24 hours. The crude product was purified by silica gel chromatography (ISCO RediSep 12 gram column, gradient of 0 - 100%) ethyl acetate in hexane over 18 minutes) to provide the desired product as a yellow oil that hardened upon standing (104mg, 54%> yield). 'H-NMR (400MZ, CDCI ₃ ) δ 8.99 (1H, s), 8.70 (1H, d, J = 5.5 Hz), 7.81 (1H, dd, J = 15.8 and 2.0 Hz), 7.63 (1H, dd, J = 7.6 and 1.8 Hz), 7.51 (1H, d, J = 7.6 Hz), 7.46 (1H, dt, J = 8.4 and 1.8 Hz), 7.42 (1H, d, J = 15.8 Hz), 7.00 (1H, t, J = 7.6 Hz), 6.94 (1H, d, J = 8.4 Hz), 3.94 (3H, s). MS (M+H): 308.

[0224] Example 7: Synthesis of l-(2-methoxy-phenyl)-3-(3-trifluoromethyl-pyridin-4-yl)- propenone (CVA- 130036).

[0225] Step 1 : Synthesis of 3-trifluoromethyl-pyridine-4-carboxaldehyde: (3-trifluoromethyl- pyridin-4-yl)-methanol (0.07 g, 0.395mmol) was dissolved in anhydrous dichloromethane (10 mL). To this was added manganese dioxide (0.103 g, 1.19mmol). The resulting mixture was stirred at reflux for 4 hours. The mixture was then cooled to room temperature and filtered through Celite. The resulting filtrate was concentrated on a rotary evaporator to yield the desired product as a yellow oil (0.029 g, 42% yield), which was used without further purification. ^l H-

NMR (400Mz, CDC1 ₃ ) δ 10.36 (1H, s), 9.03 (1H, s), 8.84 (1H, d, J = 5.7 Hz), 7.80 (1H, d, J

Hz).

[0226] Step 2: Synthesis of l -(2-methoxy-phenyl)-3-(3-trifluoromethyl-pyridin-4-yl)-prope none: Prepared from l -(2-methoxy-phenyl)-ethanone (0.015 mL, O. l lmmol), lithium hydroxide (0.6 mg, 0.023 mmol) and 3-trifluoromethyl-pyridine-4-carboxaldehyde (20 mg, 0.11 mmol) in anhydrous methanol (2 mL) using the procedure described in Example 1, Step 3. Total reaction time was 24 hours. The crude product was purified by silica gel chromatography (ISCO RediSep 12 gram column, gradient of 0 - 100% ethyl acetate in hexane over 18 minutes) to provide the desired product as a yellow solid (5.2 mg, 15% yield). 'H-NMR (400MZ, CDCI ₃ ) δ 8.87 (1H, s), 8.76 (1H, d, J = 5.2 Hz), 7.77 (1H, dd, J = 15.8 and 2.0 Hz), 7.62 (1H, dd, J = 7.6 and 1.8 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.46 (1H, dt, J = 7.6 and 1.8 Hz), 7.42 (1H, d, J = 15.8 Hz), 7.00 (lh, t, J = 7.6 Hz), 6.94 (1H, d, J = 8.3 Hz), 3.85 (3H, s). MS (M+H): 308.

[0227] Example 8: Synthesis of l-(2-methoxy-phenyl)-3-(2-trifluoromethyl-pyridin-3-yl)- propenone (CVA-130033).

[0228] Step 1 : Synthesis of (2-trifluoromethyl-pyridin-3-yl)-methanol: Sodium borohydride (0.35 g, 9.1mmol) was suspended in anhydrous tetrahydrofuran (20 mL). The stirred mixture was cooled in an ice bath and treated dropwise with a solution of methyl nicotinate (1.00 g, 0.46mmol) in anhydrous tetrahydrofuran (20 mL). The resulting reaction mixture was stirred at 4 °C for 16 hours. Methanol (5 mL) was added to quench remaining sodium borohydride, followed by 15%> aqueous sodium hydroxide (25 mL). The resulting mixture was stirred at 25 °C for 30 minutes, then concentrated on a rotary evaporator to remove tetrahydrofuran and methanol. The resulting aqueous mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give the desired product as yellow oil (0.61 g, 75%> yield), which was used without further purification. 'H-NMR

(400Mz, CDCI ₃ ) δ 8.64 (1H, d, J = 4.5 Hz), 8.17 (1H, d, J = 8.0 Hz), 7.57 (1H, dd, J = 8.0 and 4.5 Hz), 4.98 (2H, s), 1.99 (1H, s). MS (M+H): 178.

[0229] Step 2: Synthesis of 2-trifluoromethyl-pyridine-3-carboxaldehyde: Prepared from (2- trifluoromethyl-pyridin-3-yl)-methanol (0.05 g, 0.28 mmol), manganese dioxide (0.7 g, 8.0 mmol) and anhydrous dichloromethane (10 mL) using the procedure described for Example 7, Step 1. The desired product was isolated as a yellow oil (0.035 g, 71% yield) by concentration of the filtrate on a rotary evaporator and used without further purification. 'H-NMR (400MZ, CDCI ₃ ) δ 10.40 (1H, s), 8.8 J = 8.0 and 4.7 Hz).

[0230] Step 3: Synthesis of l -(2-methoxy-phenyl)-3-(2-trifluoromethyl-pyridin-3-yl)-prope none: Prepared from l -(2-methoxy-phenyl)-ethanone (0.026 mL, 0.16mmol), lithium hydroxide (0.8 mg, 0.03 mmol) and 2-trifluoromethyl-pyridine-3-carboxaldehyde (28 mg, 0.16 mmol) in anhydrous methanol (2 mL) using the procedure described in Example 1, Step 3. Total reaction time was 24 hours. The crude product was purified by reversed phase chromatography (Phenomenex Gemini C-18 5 mcron column, gradient of 10 - 100%) acetonitrile in water with 0.1 %> formic acid over 10 minutes) to provide the desired product as a yellow solid (17 mg, 35% yield). 'H-NMR (400MZ,

CDCI ₃ ) δ 8.71 (1H, d, J = 4.9 Hz), 8.12 (1H, d, J = 8.1 Hz), 7.93 (1H, dd, J = 15.8 and 2.0 Hz), 7.68 (1H, dd, J = 7.6 and 1.8 Hz), 7.56 (1H, dd, J = 8.0 and 4.6 Hz), 7.55 (1H, d, J = 7.4 Hz), 7.54 (1H, dt, J = 7.4 and 1.9 Hz), 7.36 (1H, d, J = 15.8 Hz), 7.09 (1H, t, J = 7.6 Hz), 7.03 (1H, d, J = 8.2), 3.03 (3H, s). MS (M+H): 308.

Example 9: Synthesis of l -(6-methoxy-pyridin-2-yl)-3-(2-chloro-phenyl)-propenone (CVA- 130035).

Step 1 : Synthesis of l-(6-methoxy-pyridin-2-yl)-3-(2-methoxy-phenyl)-propenone: Prepared from l-(3-methoxy-pyridin-2-yl)-ethanone (Step 2, Example 1, 0.049 g, 0.31 mmol), lithium hydroxide (1.7 mg, 0.07 mmol) and 2-chloro-pyridine-3-carboxaldehyde (0.036 mL, 0.32 mmol) in anhydrous methanol (4 mL) using a the procedure described in Example 1, Step 3. Total reaction time was 24 hours. The crude product was purified by reversed phase chromatography (Phenomenex Gemini C-18 5 micron column, gradient of 10 - 100%) acetonitrile in water with 0.1%) formic acid over 10 minutes) to provide the desired product as a yellow solid (57 mg, 67%> yield). 'H-NMR (400MZ, CDCI ₃ ) δ 8.35 (1H, dd, J = 4.5 and 1.2 Hz), 8.07 (1H, d, J = 16.0 Hz), 7.73 (1H, d, J = 7.5 Hz), 7.71 (1H, d, J = 7.5 Hz), 7.60 (1H, d, J = 16.0 Hz), 7.49 (1H, t, J = 7.6 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.25, (1H, dd, J = 8.6 and 4.5 Hz), 7.20 (1H, dd, J = 8.6 and 1.2 Hz), 3.96 (3H, s). MS (M+H): 274.

Example 10. Synthesis of l-(2-methoxy-pyridin-4-yl)-3-(2-chloro-phenyl)-propenone (CVA- 130038).

Step 1: Synthesis of l-(2-methoxy-pyridin-4-yl)-3-(2-chloro-phenyl)-propenone: Prepared from l-(3-methoxy-pyridin-4-yl)-ethanone (Step 2, Example 3, 0.045 g, 0.30 mmol), lithium hydroxide (1.4 mg, 0.06 mmol) and 2-chloro-pyridine-3-carboxaldehyde (0.034 mL, 0.31 mmol) in anhydrous methanol (4 mL) using the procedure described in Example 1, Step 3. Total reaction time was 24 hours. The crude product was purified by reversed phase chromatography (Phenomenex Gemini C-18 5 micron column, gradient of 10 - 100% acetonitrile in water with 0.1% formic acid over 10 minutes) to provide the desired product as a yellow solid (45 mg, 55% yield). ¾-NMR (400MZ, CDCI ₃ ) δ 8.49 (1H, s), 8.33 (1H, dd, J = 4.4 and 1.3 Hz), 8.09 (1H, dd, J = 15.9 and 2.1 Hz), 7.90 (1H, d, J = 7.7 Hz), 7.72 (1H, d, J = 7.7 Hz), 7.71 (1H, d, J = 15.9 Hz), 7.58 (1H, t, J = 7.5 Hz), 7.51 (1H, t, J = 7.5 Hz), 7.46 (1H, dd, J = 8.6 and 4.4 Hz), 7.41 (1H, dd, J = 8.6 and 1.3 Hz), 3.96 (3H, s). MS (M+H): 274.

FORMULATIONS

[0231] The present invention also relates to compositions or formulations which comprise the NRF2 activators according to the present invention. In general, the compositions of the present invention comprise an effective amount of one or more functionalized hetroaryl enones and salts thereof according to the present invention which are effective for providing for treating or preventing a disease, disorder or condition associated with an NRF2 -regulated pathway and related conditions; and one or more excipients. In addition, the compositions of the present invention comprise an effective amount of one or more functionalized hetroaryl enones and salts thereof according to the present invention which are effective for providing for treating or preventing a disease, disorder or condition associated that involve oxidative stress; and one or more excipients.

[0232] For the purposes of the present invention the term "excipient" and "carrier" are used interchangeably throughout the description of the present invention and said terms are defined herein as, "ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition."

[0233] 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 to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.

[0234] The present teachings also provide pharmaceutical compositions that include at least one compound described herein and 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.

[0235] 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. The compounds can be formulated in conventional manner, for example, in a manner similar to that used for known NRF2 activators. 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 proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99 % of the compound.

[0236] 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.

[0237] 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, and ion exchange resins. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, 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.

[0238] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and 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 a 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 sodium carboxymethyl 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.

[0239] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[0240] 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 sub-divided in unit dose(s) containing 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 unit dosage form can contain from about 1 mg/kg of compound to about 500 mg/kg of compound, and can be given in a single dose or in two or more doses. 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.

[0241] 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 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.

[0242] 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 or intrabronchial 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.

[0243] 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.

[0244] 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.

[0245] Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[0246] Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

[0247] Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

[0248] Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[0249] To increase the effectiveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For example, other active compounds (i.e., other active ingredients or agents) effective in treating the target disease can be administered with compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein.

[0250] Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human subject. The present teachings accordingly provide methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings including its pharmaceutically acceptable salt) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with pharmaceutically acceptable carriers. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder.

[0251] Non-limiting examples of compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more functionalized hetroaryl enones according to the present invention and one or more excipients; from about 0.01 mg to about 100 mg of one or more functionalized hetroaryl enones according to the present invention and one or more excipients; and from about 0.1 mg to about 10 mg of one or more functionalized hetroaryl enones according to the present invention; and one or more excipients.

PROCEDURES

[0252] The following procedures can be utilized in evaluating and selecting compounds as NRF2 activators.

[0253] Potency of compounds of the disclosure to activate the expression of NRF2 -regulated cytoprotective genes in human lung epithelial cells, human primary peripheral blood mononuclear cells and in mouse small intestine and spleen.

[0254] To investigate the potency of compounds of the disclosure to activate NRF2, the expression of antioxidant genes, Hemeoxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQOl), two well characterized transcriptional targets of NRF2, were measured as surrogate markers. By "marker" is meant any protein or polynucleotide having an alteration in expression level or activity that is associated with a disease, disorder, or condition. It has been previously shown that oxidants or small molecule activators of NRF2 increase HO-1 and NQOl in cells or tissues of wild-type, but not in NRF2-deficient mice. Osburn, W.O., et al. Genetic or pharmacologic amplification of NRF2 signaling inhibits acute inflammatory liver injury in mice. Toxicol. Sci. 2008, 104(1), 218-227.

[0255] In the presently disclosed subject matter, to screen novel NRF2 activators in Beas-2B cells, Beas-2B cells (ATCC, Manassas, VA) were treated with compounds of the disclosure, or positive control compounds 2-trifluoromethyl-2-'methoxychalcone (TMC; VEDA-1209), 2-cyano-3,12- dioxo-oleana- 1,9(1 l)-dien-28-oic acid (CDDO) or dimethyl fumarate (DMF). The compounds were dissolved in dimethyl sulfoxide and the final concentration was made in Dulbecco's Modified Eagle Medium (DMEM) medium with 10% Fetal Bovine Serum and 1% Penicillin- Streptomycin. The cells were incubated for 6 hours at 37°C, 5% CO ₂ . Dimethyl sulfoxide was the negative, vehicle control. Following incubation, medium was removed and cells were lysed by adding 350 μL· of RLT buffer from RNeasy Mini Kit (Qiagen, Valencia, CA). RNA isolation from lysed cells was completed using the RNeasy mini kit. cDNA synthesis was executed from the extracted RNA using Applied Biosystems High Capacity cDNA Reverse Transcription Kit followed by real time PCR using Applied Biosystems Master Mix and HO-1 probe (Hs00157965_ml). Relative fold change (RFC) in HO-1 niRNA is calculated relative to the dimethyl sulfoxide control. Exemplary results of compounds of the disclosure are described in Figs. 1A and IB.

[0256] To screen Nrf2 activators in peripheral blood mononuclear cells (PMBC), uncharacterized cryopreserved human PBMC (Cellular Technology Limited, Shaker Heights, OH; CTL) were thawed and washed with lx CTL -Anti Aggregate Wash in RPMI 1640. The cells were spun at 330g for 10 minutes at room temperature, re-suspended in wash solution and counted. The cells were spun again using the same conditions and re-suspended in CTL Test Medium with 1% L- glutamine. Cells were plated and allowed to adhere in an incubator at 37°C, 5% CO ₂ . Cells were treated with the compounds of the disclosure or positive controls and analyzed by quantitative RT- PCR as described above (Beas-2B assay description). Exemplary results of compounds of the disclosure are described in Figs. 2A and 2B. Figs. 3A and 3B describe exemplary results for compounds of the disclosure using the same procedure, except that NQOl probe (Hs00168547_ml) was used. Relative fold change (RFC) in NQOl mRNA (RFC) is shown, relative to the dimethyl sulfoxide control.

[0257] In vivo potency of identified lead compounds to activate NRF2 using mouse models: The efficacy of compounds of the disclosure to activate the NRF2 pathway were evaluated in mouse models. C57BL/6 male mice at age 7-8 weeks were dosed by oral gavage with lmg or 5mg of each compound. The analogs were dissolved in SEDDS (10% ethanol: 90%> Sesame oil/Cremophor El (55:35 w/w)) which was used as the vehicle control. After 6 hours the mice were euthanized by C0 ₂ overdose and the small intestine or spleen was isolated and stored in RNAlater to conserve for gene expression analysis. A piece of each small intestine or spleen (approximately 15 mg) was cut and homogenized in 400 μΕ of RLT buffer from RNeasy Mini Kit (Qiagen, Valencia, CA) RNA was isolated from the homogenized tissue using RNeasy mini kit. cDNA synthesis was executed from the extracted RNA using Applied Biosystems High Capacity cDNA Reverse Transcription Kit followed by real time PCR using Applied Biosystems Master Mix and HO-1 probe (Mm00516005_ml). Exemplary results of compounds of the disclosure are described in Fig. 4.