Methods of treating neurodegenerative diseases

Abstract

Disclosed is a method of treating a disease or condition characterized by neurodegeneration via administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of hinokiol, hinokiol derivatives, and iron transporter palmitol ketones.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 411,902, filed on September 30, 2022.

[0003] Government Funding Statement

[0004] This invention was made with government support under Grant 1R01HL140526 awarded by the National Institutes of Health. The government has certain rights in this invention. Background Art

[0005] Iron improper distribution is the basis of many neurodegenerative diseases. For example, the most common neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are associated with brain iron accumulation that gradually increases with age. Less common diseases, such as Friedreich's ataxia and Huntington's disease, are also characterized by abnormal iron accumulation in the brain. Specifically, it is reported that patients with Friedreich's ataxia accumulate iron in mitochondria, which suggests that improper cellular iron distribution also causes pathology. See Michael Li-Hsuan Huang, Darius JRLane and Des R. Richardson; "Mitochondrial Mayhem:The Mitochondrion as a Modulator of Iron Metabolism and Its Role in Disease"; Antioxidants & Redox Signaling, 2011, 15: 12, 3003-3019. A significant correlation between brain iron overload and neurodegeneration has also been observed in a condition called neurodegeneration with brain iron accumulation (NBIA), a group of inherited neurological disorders characterized by neurological deterioration in early adulthood as well as progressive dystonia, parkinsonism, cognitive decline, and seizures.

[0006] Iron's innate ability to act as both an electron acceptor and electron donor makes it essential for most organisms. Iron demand is particularly high in the brain, the most metabolically active organ in the body, because it is required for oxidative metabolism, mitochondrial energy production, synaptic plasticity, myelination, and neurotransmitter synthesis. However, excess iron, particularly in the Fe(II) form, is neurotoxic due to its ability to generate harmful reactive oxygen species (ROS) through the Fenton reaction of the Haber-Weiss cycle, leading to oxidative damage and consequent cell death. Therefore, brain iron overload is a key yet underappreciated factor in the development of neurodegenerative diseases.

[0007] The effective reversal of brain iron overload will need to be able to realize site-specific transmembrane iron mobilization compounds by keeping the iron of combination as Fe (III) in a safe manner. Ideally, these molecules will also be functionally engaged with endogenous iron in conjunction with small molecules and proteins. At present, iron chelators, such as deferasirox (DFX) and deferiprone (DFP), are promising drug candidates for preventing iron-related neurodegeneration. However, DFP can cause serious side effects, such as agranulocytosis, arthropathy, gastrointestinal bleeding, ophthalmology / auditory toxicity, loss of essential nutrients (zinc and copper) and neurological complications. In addition, DFP and other clinically approved iron chelators work mainly by removing the iron released from the cell; That is, they cannot directly transport iron through lipid bilayer. Therefore, their potential for removing iron from neurons and / or their supporting cells is limited.

[0008] Therefore, there is a need for new approaches to treat neurodegenerative diseases that are highly specific, well tolerated, and can serve as useful therapies. Summary of the Invention

[0009] In certain embodiments, the present disclosure relates to a method of treating a disease or condition selected from the group consisting of: an inflammatory disorder leading to abnormal inhibition of iron transporter production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of hinokitiol, hinokitiol derivatives, and iron-transporting oxalool.

[0010] In certain embodiments, the present disclosure provides a method of treating a disease or condition selected from the group consisting of an inflammatory disorder leading to abnormal inhibition of ferroportin production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by any one of Formula (I), (Ia), (Ib), (Ic), (Id), (IIa), (IIb), and (IIc):

[0011]

[0012] R a It is C 1-20 -alkyl, C 2-20 -alkenyl, C 2-20 -alkynyl, C 3-9 - cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or substituted by a substituent selected from the group consisting of halo, NO2, CN, C 1-6 -alkyl, C 1-6 -haloalkyl and C 1-6 -alkoxy; and

[0013] R b is hydrogen or methyl; provided that the compound is not hinokitiol;

[0014]

[0015] X represents oxygen or sulfur;

[0016] R a represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl; and

[0017] R a ' represents hydrogen, halo, alkyl or substituted alkyl; and Rb 、R c and R d independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkoxy, substituted cycloalkoxy, heterocycloalkoxy, substituted heterocycloalkoxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, and heteroalkynyl; provided that R a 、R b 、R c and R d It’s not all hydrogen;

[0018]

[0019] R a represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl; and

[0020] R b 、R c and R d are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, and heteroalkynyl; provided that R a 、R b 、R c and R d It’s not all hydrogen;

[0021]

[0022] X represents sulfur or oxygen;

[0023] R a 、R b 、R c and R dand independently represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, heteroalkynyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and

[0024] R a 、R b 、R c and R d At least one of is aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl; provided that R a 、R b 、R c and R d It’s not all hydrogen;

[0025]

[0026] R a 、R b 、R c and R d independently represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, heteroalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

[0027] R b 、R c and R d At least one of is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and

[0028] The condition is R a 、R b 、R c and R d Not all hydrogen; and

[0029]

[0030] R arepresents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl;

[0031] X and Y independently represent O, S, NH or CR5R6;

[0032] R2 represents -F, alkyl, haloalkyl or alkoxy; and

[0033] R5 and R6, at each occurrence, independently represent H, (C1-C15)alkyl, or substituted (C1-C15)alkyl;

[0034] Provided that the compound is not

[0035] In certain embodiments, the compound for treating a disease or illness characterized by neurodegeneration includes pharmaceutically acceptable salts, tautomers, and isomers. The compound can be administered as a single compound or a combination of the compound or in combination with one or more chelating agents (examples include deferasirox (DFX) and deferiprone (DFP)). The compound can be combined with a pharmaceutically acceptable carrier or excipient and administered systemically, orally, or intravenously to a mammal.

[0036] In certain embodiments, the disease or condition is selected from the group consisting of an inflammatory disorder leading to abnormal inhibition of ferroportin production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA.

[0037] In certain embodiments, the disease or disorder is selected from the group consisting of vascular dementia, tauopathy, progressive supranuclear palsy, corticobasal degeneration, subacute sclerosing panencephalitis parkinsonism, postencephalitis parkinsonism, Guam parkinsonism-dementia complex, Pick's disease, and frontotemporal dementia. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1ADepicted are the reactivities of various Fe(III)-compound complexes to be reduced to Fe(II) under reducing conditions, measured using the Ferrozine assay.

[0039] Figure 1B Depicted are the generation of ROS in mixtures of Fe(II) and various compounds measured using the hydroxyl radical probe 2,7-dichlorofluorescein (DCF) dye.

[0040] Figure 1C Depicted is the EPR measurement of Fe(II) alone.

[0041] Figure 1D Depicted are EPR measurements of iron(II) and hinokitiol.

[0042] Figure 2A The structure of FeM-1269 is depicted.

[0043] Figure 2B Depicted is particle size measurement using DLS as an indicator of Fe-compound aggregation.

[0044] Figure 2C Depicted are measurements of iron efflux from liposomes.

[0045] Figure 2D Depicted are measurements of iron efflux from FPN1-KD Caco-2 cells using hinokitiol and FeM-1269.

[0046] Figures 3A-3H Depicted are treatments of fpn-1.2KO Caenorhabditis elegans with various compounds for neurodegeneration scoring and iron level measurement.

[0047] Figure 3A Depicted is the treatment scheme of fpn-1.2KO;Pdat::GFP worms treated with various concentrations of DFP, hinokitiol, and AMB-1269. Dopaminergic neurodegeneration was scored blindly by phenotypic analysis.

[0048] Figure 3B Depicted are dopaminergic neurodegeneration scores of fpn-1.2KO worms treated with DFP.

[0049] Figure 3C Depicted are dopaminergic neurodegeneration scores of fpn-1.2KO worms treated with hinokitiol.

[0050] Figure 3D Depicted are dopaminergic neurodegeneration scores of fpn-1.2KO worms treated with FeM-1269.

[0051] Figure 3EDepicted is the treatment scheme of fpn-1.2KO;Pftn-1::GFP worms treated with different concentrations of DFP, hinokitiol, and FeM-1269.

[0052] Figure 3F Depicted are the levels of GFP-tagged ferritin expressed in ASI neurons (bottom panel) and the fluorescence levels of fpn-1.2KO worms treated with DFP. *P < 0.05, **P < 0.01, ***

[0053] Figure 3G Depicted are the levels of GFP-tagged ferritin expressed in ASI neurons (bottom panel) and the fluorescence levels of fpn-1.2KO worms treated with hinokitiol. *P<0.05, **P<0.01, ***

[0054] Figure 3H Depicted are the levels of GFP-tagged ferritin expressed in ASI neurons (bottom panel) and the fluorescence levels of fpn-1.2KO worms treated with FeM-1269. *P < 0.05, **P < 0.01, ***

[0055] Figures 4A-4E Depicted are Iron mice that exhibit increased anxiety and decreased exploratory activity. WT and Iron mice were subjected to an elevated plus maze task to assess anxiety-like behavior.

[0056] Figure 4A The total distance traveled and the average speed throughout the maze are depicted.

[0057] Figure 4B Time spent in the open group and central areas is depicted.

[0058] Figure 4C Rearing frequency and duration are depicted. *P<0.05 by Student's t-test.

[0059] Figure 4D Depicted are ICP-MS measurements of brain iron levels in iron mice following acute treatment with hinokitiol by intraperitoneal (IP) injection.

[0060] Figure 4E Depicted are ICP-MS measurements of brain iron levels in iron mice following chronic treatment with hinokitiol by intraperitoneal (IP) injection. **P<0.01, ***P<0.001 by one-way ANOVA.

[0061] Figure 5A Schematic diagram depicting the ceruloplasmin phenotype of wild-type cells.

[0062] Figure 5BSchematic diagram depicting the cellular ceruloplasminemia phenotype.

[0063] Figure 5C Schematic diagram depicting how hinokitiol oxidizes iron and restores iron homeostasis in cells with a ceruloplasmin-deficient phenotype.

[0064] Figure 6A Depicted is the cyclic voltammogram of Fe(hinokitiol)3.

[0065] Figure 6B Depicted are cyclic voltammograms for various Fe:hinokitiol ratios.

[0066] Figure 7A Depicted are EPR measurements of hinokitiol-promoted Fe(II) oxidation.

[0067] Figure 7B Depicted are EPR measurements of FeM-1269-promoted Fe(II) oxidation.

[0068] Figure 8A Schematic diagram depicting iron transfer between Fe(hinokitiol)3 and transferrin.

[0069] Figure 8B Depicted is a Western blot of transferrin in the presence of increasing concentrations of Fe(hinokitiol)3.

[0070] Figure 8C The kinetics of iron transfer between Fe(hinokitiol)3 and transferrin were depicted.

[0071] Figure 9 Depicted is a colorimetric assay that determines the percent conversion of Fe(III) to Fe(II) in the presence of a strong reducing agent.

[0072] Figure 10 Depicted is a fluorometric assay for determining the amount of reactive oxygen species (ROS) produced in the Fe(II)-catalyzed Fenton reaction.

[0073] Figure 11A Depicted are in vitro measurements of dopamine oxidation in the presence of hinokitiol and Fe(II) or deferiprone (DFP) and Fe(II).

[0074] Figure 11B Depicted are measurements of dopamine oxidation in fpn1.2 KO C. elegans five days after hinokitiol or deferiprone (DFP) treatment.

[0075] Figure 12A Depicted is the amount of dopamine remaining after Fe(II)-catalyzed oxidation in the presence of hinokitiol and FeM-1269.

[0076] Figure 12BDepicted are the amounts of dopamine pigment (DAC) produced following Fe(II)-catalyzed oxidation in the presence of hinokitiol and FeM-1269.

[0077] Figure 13 Depicted are graphs of absorbance versus concentration versus peak area of DAC after quenching with glutathione.

[0078] Figure 14 The percentage of Fe(III) pre-complexed with hinokitiol or dopamine converted to Fe(II) is plotted versus time. DETAILED DESCRIPTION

[0079] definition

[0080] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. In addition, to the extent that the terms "including," "includes," "having," "has," "with," or variations thereof are used in the detailed description and / or claims, such terms are intended to be inclusive in a manner similar to the term "comprising."

[0081] As used herein, the term "about" or "approximately" means that a particular value is within an acceptable error range as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value.

[0082] The term "acyl" as used herein refers to any group or radical of the form RCO-, where R is any organic group such as alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

[0083] As used herein, the term administration / administering means that the compound can be administered orally, by intralesional, intraperitoneal, intramuscular or intravenous injection; infusion; liposome-mediated delivery; topical, intranasal, anal, vaginal, sublingual, urethral, transdermal, intrathecal, ocular or aural delivery. In order to obtain consistency in providing the compounds of the present invention, it is preferred that the compounds of the present invention are in unit dosage form. Suitable unit dosage forms include tablets, capsules and powders in sachets or vials. Such unit dosage forms may contain 0.1 to 300 mg, preferably 2 to 100 mg of the compound of the present invention. Still further preferred unit dosage forms contain 5 to 50 mg of the compound of the present invention. The compounds of the present invention can be administered orally in a dosage range of about 0.01 to 100 mg / kg or preferably in a dosage range of 0.1 to 10 mg / kg. Such compounds can be administered 1 to 6 times a day, more typically 1 to 4 times a day. The effective amount is known to those skilled in the art; it also depends on the form of the compound. Those skilled in the art can routinely carry out empirical activity testing, to determine the biological activity of compound in bioassay, thereby determine administration dosage.Compound can be delivered locally via capsule, and described capsule allows compound to be sustained release over a period of time.Controlled release or sustained release compositions include preparations (for example: fatty acid, wax, oil) in lipophilic reservoirs.

[0084] The term "alkenyl" or "alkenyl group" means a group formed by removing a hydrogen from a carbon of an alkene, wherein an alkene is an acyclic or cyclic compound composed entirely of hydrogen and carbon atoms and contains at least one carbon-carbon double bond. An alkenyl group may contain one or more substituents.

[0085] As used herein, the term "alkoxy" or "alkoxy group" means an alkyl group, as defined herein, attached to a parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexoxy. The terms "alkenyloxy," "alkynyloxy," "carbocyclyloxy," and "heterocyclyloxy" are similarly defined.

[0086] As used herein, the term "alkyl" is a technical term and refers to a saturated aliphatic group, including straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic) group, alkyl-substituted cycloalkyl and cycloalkyl-substituted alkyl. In certain embodiments, straight-chain or branched alkyl has about 30 or less carbon atoms in its backbone (e.g., C1-C30 represents a straight chain, C3-C30 represents a branched chain), or about 20 or less carbon atoms. In one embodiment, the term "alkyl" refers to a C1-C10 straight-chain alkyl. In one embodiment, the term "alkyl" refers to a C1-C6 straight-chain alkyl. In one embodiment, the term "alkyl" refers to a C3-C12 branched-chain alkyl. In one embodiment, the term "alkyl" refers to a C3-C8 branched-chain alkyl. Cycloalkyl has about 3 to about 10 carbon atoms in its ring structure, or has about 5, 6 or 7 carbon atoms in the ring structure.

[0087] The term "alkylene" is art-recognized and, as used herein, refers to a diradical obtained by removing two hydrogen atoms of an alkyl group as defined above. In one embodiment, alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, and the like. That is, in one embodiment, "substituted alkyl" is an "alkylene".

[0088] As used herein, the term "alkylthio" refers to an alkyl-S- group.

[0089] As used herein, the term "alkynyl" means a straight or branched chain hydrocarbon group containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0090] The term "amino" is a term of art and, as used herein, refers to unsubstituted and substituted amines, such as the moiety that can be represented by the following general formula:

[0091]

[0092] where R a 、R b and R c Each independently represents hydrogen, alkyl, alkenyl, -(CH2) x —R d , or R a and R bTogether with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 atoms in the ring structure; Rd represents an aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl group; and x is zero or an integer ranging from 1 to 8. In certain embodiments, R a or R b Only one of them can be a carbonyl group, for example R a 、R b In other embodiments, R a and R b Each independently represents hydrogen, alkyl, alkenyl or -(CH2) x —R d In one embodiment, the term "amino" refers to -NH2.

[0093] The term "aminoacyl" is a term of art and, as used herein, refers to an acyl group substituted with one or more amino groups.

[0094] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term "aminoalkyl" refers to an aminomethyl group.

[0095] As used herein, the term "aminosulfonyl" refers to an analog of an aminoacyl group in which the O of RC(O)- is replaced by sulfur, thus having the form RC(S)-.

[0096] The term "aralkyl" or "arylalkyl" is a term of art and, as used herein, refers to an alkyl group substituted with an aryl group.

[0097] The term "aryl" is a technical term and, as used herein, refers to a monocyclic, bicyclic and polycyclic aromatic hydrocarbon group, such as benzene, naphthalene, anthracene and pyrene. The aromatic ring can be substituted at one or more ring positions by one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. The term "aryl" also includes polycyclic ring systems having two or more rings, wherein two or more carbon atoms are shared by two adjacent rings (the rings are "fused rings"), wherein at least one ring is, for example, an aromatic hydrocarbon, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic groups. In one embodiment, the term "aryl" refers to phenyl.

[0098] The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0099] As used herein, the term "carbocyclyl" means a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon group containing 3 to 12 carbon atoms, which is fully saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the unsaturation does not result in an aromatic ring system (e.g., phenyl). Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl, and 2-cyclopentenylmethyl.

[0100] As used herein, the term "carbonyl" refers to -C(O)-.

[0101] As used herein, the terms "carrier" and "pharmaceutically acceptable carrier" refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oils; and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silicon dioxide, urea, and the like. In addition, adjuvants, stabilizers, thickeners, lubricants, flavorings, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described by E.W. Martin in Remington's Pharmaceutical Sciences, the entire contents of which are incorporated herein by reference.

[0102] As used herein, the term "chelator" means a small molecule that binds very tightly to a metal ion.

[0103] The term "cyano" is a term of art and, as used herein, refers to -CN.

[0104] As used herein, the term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups.

[0105] As used herein, the term "effective amount" refers to an amount sufficient to produce a desired biological effect.

[0106] As used herein, the term "ferroportin" (FPN1) refers to the only known cellular iron exporter. It facilitates the export of iron (ferrous iron) from storage and absorptive cells into the blood, including hepatocytes, macrophages in the liver and spleen, and intestinal epithelial cells.

[0107] As used herein, the term "fluoroalkyl" refers to an alkyl group as defined herein wherein some or all of the hydrogens are replaced by fluorine.

[0108] The term "halo" is a term of art and, as used herein, refers to -F, -Cl, -Br, or -I.

[0109] The term "heteroalkyl" means a group formed by removing a hydrogen from a carbon of a heteroalkane, wherein the heteroalkane is an acyclic or cyclic compound consisting entirely of hydrogen atoms, saturated carbon atoms, and one or more heteroatoms. The heteroalkyl group may contain one or more substituents.

[0110] The term "heteroaralkyl" or "heteroarylalkyl" is a term of art and, as used herein, refers to an alkyl group substituted with a heteroaryl group.

[0111] The term "heteroaryl" is a term of art and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic radicals having one or more heteroatoms in the ring structure, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, etc. "Heteroaryl" can be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, thiol, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic radical, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, and the like. The term "heteroaryl" also includes polycyclic ring systems having two or more rings in which two or more carbon atoms are common to two adjacent rings (the rings are "fused rings"), wherein at least one ring is an aromatic group having one or more heteroatoms in the ring structure, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl.

[0112] The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0113] The term "heteroatom" is art-recognized and includes atoms of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium, or oxygen, nitrogen, or sulfur.

[0114] As used herein, the term "heterocyclyl" refers to a radical of a non-aromatic ring system, including but not limited to monocyclic, bicyclic and tricyclic rings, which may be fully saturated or may contain one or more units of unsaturation, provided, for the avoidance of doubt, that the unsaturation does not result in an aromatic ring system, and having from 3 to 12 atoms, including at least one heteroatom such as nitrogen, oxygen or sulfur. For purposes of illustration, which should not be construed as limiting the scope of the present disclosure, the following are examples of heterocycles: aziridine, aziridinyl, oxiranyl, thiol, thipropylene, bis-oxiranyl, bis-aziridinyl, azetidinyl, oxetanyl, oxetanyl, thiol, thiol, diazetidinyl, dioxetanyl, dioxetanyl, dithiol, dithiol, furanyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazole, benzotriazole, benzothiophene, benzoimidazolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, indolyl, benzotriazolyl, naphthyridinyl, azepine, azetidinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl, and tetrahydrofuranyl.

[0115] As used herein, the term "heterocycloalkylalkyl" refers to an alkyl group substituted with one or more heterocycloalkyl (ie, heterocyclyl) groups.

[0116] The term "hydroxy" is a term of art and, as used herein, refers to -OH.

[0117] As used herein, the term "inhibit" means to reduce an objectively measurable amount or degree. In various embodiments, "inhibit" means to reduce by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% compared to a relevant control. In one embodiment, "inhibit" means to reduce by 100%, i.e., to stop or eliminate.

[0118] As used herein, the expression "neurodegeneration with brain iron accumulation" or "NBIA" has its ordinary meaning in the art and refers to a group of rare, inherited neurological disorders characterized by abnormal iron accumulation in the basal ganglia. The hallmark clinical manifestations of NBIA relate to muscle function and are characterized by progressive movement disorders, including dystonia, choreoathetosis, arm stiffness, and parkinsonism. Most forms of NBIA involve ocular disease. The most common problems are retinal degeneration and optic atrophy. Generalized loss of brain cells and tissue, conditions known as cerebral and cerebellar atrophy, is also frequently observed. The onset of NBIA ranges from infancy to adulthood. In cases of long-term stability, progression can be rapid or slow. In some embodiments, NBIA is caused by a disease gene selected from the group consisting of: PANK2, PLA2G6, COASY, FA2H, ATP13A2, C2orf37, WDR45, C19ORFf12, CP, FTL, GTPBP2, CRAT, and REPS1. In some embodiments, NBIA is beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA. Subtypes of NBIA are "beta-propellant protein-associated neurodegeneration" and pantothenate kinase-associated neurodegeneration (PKAN).

[0119] As used herein, the term "pharmaceutically acceptable salt" includes salts derived from inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. Pharmaceutically acceptable salt forms may include forms in which the ratio of molecules comprising the salt is not 1:1. For example, the salt may contain more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of Formula Ia or Ib compound. As another example, the salt may contain less than one inorganic or organic acid molecule per molecule of base, such as two molecules of Formula Ia or Ib compound per molecule of tartaric acid.

[0120] As used herein, the term "subject" refers to a mammal. In various embodiments, the subject is a mammal and includes mice, rats, rabbits, cats, dogs, pigs, sheep, horses, cows, or non-human primates. In one embodiment, the subject is a human.

[0121] It is understood that "substituted" or "substituted by" includes the implicit proviso that such substitution complies with the permitted valencies of the substituted atom and substituent and that the substitution results in a stable compound, e.g., the compound does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination or other reaction.

[0122] The term "substituted" is also intended to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include those described above, for example, herein. Permissible substituents can be one or more substituents and are the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms (such as nitrogen) can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy heteroatom valences. This disclosure is not intended to be limited in any way by the permissible substituents of organic compounds.

[0123] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce the desired therapeutic effect.

[0124] As used herein, the term "thiocarbonyl" refers to -C(S)-.

[0125] As used herein, the term "treating" means preventing a disease or disorder in a subject, halting or slowing the progression of the disease or disorder, or eliminating the disease or disorder. In one embodiment, "treating" means halting or slowing the progression of a disease or disorder in a subject, or eliminating the disease or disorder. In one embodiment, "treating" means reducing at least one objective manifestation of a disease or disorder in a subject.

[0126] Certain compounds contained in the compositions of the present disclosure can exist in specific geometric or stereoisomeric forms. In addition, compounds of the present disclosure can also be optically active. The present disclosure contemplates all such compounds, including cis and trans isomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, their racemic mixtures and their other mixtures, which all fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in a substituent (such as an alkyl). All such isomers and mixtures thereof are intended to be included in the present disclosure.

[0127] For example, if a specific enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers so formed by fractional crystallization or chromatographic means well known in the art, and the pure enantiomers can then be recovered.

[0128] For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th edition, 1986-87, inside cover.

[0129] Other chemical terms used herein are used according to conventional usage in the art, as exemplified by the McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco, which is incorporated herein by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0130] Compound

[0131] In some aspects, the present disclosure provides a compound represented by Formula (I), (Ia), (Ib), (Ic), (Id), (IIa), (IIb), or (IIc), or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0132]

[0133] R a It is C 1-20 -alkyl, C 2-20 -alkenyl, C 2-20 -alkynyl, C 3-9 - cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or substituted by a substituent selected from the group consisting of halo, NO2, CN, C 1-6 -alkyl, C 1-6 -haloalkyl and C 1-6 -alkoxy; and

[0134] R b is hydrogen or methyl; provided that the compound is not hinokitiol;

[0135]

[0136] X represents oxygen or sulfur;

[0137] R a represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl;

[0138] R a ' represents hydrogen, halo, alkyl or substituted alkyl; and R b 、R c and R d independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkoxy, substituted cycloalkoxy, heterocycloalkoxy, substituted heterocycloalkoxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, and heteroalkynyl; provided that R a 、R b 、R c and R d It’s not all hydrogen;

[0139] R a ' is hydrogen, R a ' is a halo group, or R a ' is alkyl or substituted alkyl;

[0140] R a 、R b 、R c and R d at least one of which is selected from the group consisting of halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkoxy, substituted cycloalkoxy, heterocycloalkoxy, substituted heterocycloalkoxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and

[0141] R a 、R a '、R b 、R c and R d at least one of which is selected from the group consisting of: methyl, ethyl, n-propyl, and isopropyl;

[0142]

[0143] R a represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl;

[0144] R b 、R c and R d are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, and heteroalkynyl; provided that R a 、R b 、R c and R d It’s not all hydrogen;

[0145]

[0146] X represents sulfur or oxygen;

[0147] R a 、R b 、R c and R d and independently represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, heteroalkynyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and

[0148] R a 、R b 、R c and R d At least one of is aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl; provided that R a 、R b 、R c and R d It’s not all hydrogen;

[0149]

[0150] R a 、R b 、R c and R d independently represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, heteroalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

[0151] R b 、R c and R d At least one of is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and

[0152] The condition is R a 、R b 、R c and R d not all hydrogen; or

[0153]

[0154] R a represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl;

[0155] X and Y independently represent O, S, NH or CR5R6;

[0156] R2 represents -F, alkyl, haloalkyl or alkoxy; and

[0157] R5 and R6, at each occurrence, independently represent H, (C1-C15)alkyl, or substituted (C1-C15)alkyl;

[0158] Provided that the compound is not

[0159] In one embodiment, the compound is selected from:

[0160]

[0161] In one embodiment, the compound is selected from:

[0162]

[0163] In one embodiment, the compound is selected from:

[0164]

[0165] In one embodiment, the compound is selected from:

[0166] In one embodiment, the compound is selected from:

[0167]

[0168] In one embodiment, the compound is selected from:

[0169]

[0170]

[0171] In one embodiment, the compound is selected from:

[0172] In one embodiment, the compound is selected from:

[0173] In one embodiment, the compound is selected from:

[0174]

[0175] In one embodiment, the compound is selected from:

[0176]

[0177]

[0178] In one embodiment, the compound is selected from:

[0179]

[0180] In one embodiment, the compound is selected from:

[0181]

[0182] In one embodiment, the compound is selected from:

[0183]

[0184]

[0185] In one embodiment, the compound is selected from:

[0186]

[0187] In one embodiment, the compound is selected from:

[0188]

[0189] In one embodiment, the compound is selected from:

[0190]

[0191] In one embodiment, the compound is selected from:

[0192] In one embodiment, the compound is selected from:

[0193]

[0194] In one embodiment, the compound is selected from:

[0195] In one embodiment, the compound is selected from:

[0196]

[0197] In one embodiment, the compound is selected from:

[0198] In one embodiment, the compound is selected from:

[0199]

[0200] In one embodiment, the compound is selected from:

[0201]

[0202]

[0203] In one embodiment, the compound is selected from:

[0204] In one embodiment, the compound is selected from:

[0205] In one embodiment, the compound is selected from:

[0206]

[0207] In one embodiment, the compound is selected from:

[0208] In one embodiment, the compound is selected from:

[0209]

[0210]

[0211]

[0212]

[0213] In one embodiment, the compound is selected from:

[0214]

[0215]

[0216] In one embodiment, the compound is selected from:

[0217]

[0218] In one embodiment, the compound is selected from:

[0219]

[0220]

[0221] In one embodiment, the compound is selected from:

[0222]

[0223]

[0224]

[0225] In one embodiment, the compound is selected from:

[0226]

[0227]

[0228] as well as

[0229]

[0230] In one embodiment, the compound is selected from:

[0231]

[0232]

[0233]

[0234] as well as In one embodiment, the compound is selected from:

[0235]

[0236]

[0237]

[0238] as well as In one embodiment, the compound is

[0239] In one embodiment, the compound is

[0240] In one embodiment, the compound is

[0241] In one embodiment, the compound is

[0242] In one embodiment, the compound is

[0243] In one embodiment, the compound is:

[0244] In one embodiment, the compound is:

[0245] In one embodiment, the compound is:

[0246]

[0247] In one embodiment, the compound is:

[0248]

[0249] In one embodiment, the compound is:

[0250]

[0251] In one embodiment, the compound is:

[0252]

[0253] Treatment of neurodegenerative diseases

[0254] Ceruloplasminemia is a rare autosomal recessive genetic disease caused by mutations in the gene encoding ceruloplasmin (Cp), resulting in a deficiency or inactivity of the multi-copper oxidase glycoprotein. In the absence of this protein, iron (II) cannot be oxidized to iron (III) and cannot bind to transferrin. This ultimately leads to a decrease in holotransferrin, which is responsible for circulating iron throughout the body and shows an increase in intracellular iron. EPR results show that hinokitiol and FeM-1269 can mimic ferroxidase activity by promoting the oxidation of Fe (II) to Fe (III). In addition, it was shown that hinokitiol can transfer iron to transferrin, thereby maintaining the system in homeostasis. It was also shown that Fe (III) bound to hinokitiol showed the ability to reduce Fenton chemistry, which promotes neurodegeneration. These observations collectively support the use of hinokitiol, FeM-1269 and other similarly acting oxalools as molecular repair agents for ceruloplasmin to restore ferroxidase activity, thereby restoring systemic iron by increasing holotransferrin levels and increasing iron (III). In certain embodiments, brain iron and holo-transferrin concentrations can be tested in ceruloplasmin knockout mice (CpKO) before and after treatment with hinokitiol. In other embodiments, iron (III) concentrations in blood and plasma samples from ceruloplasmin knockout mice (CpKO) can be measured using ICP-MS and EPR.

[0255] In certain embodiments, the generation of holo-transferrin can be measured using gel shift assay, and described gel shift assay can separate apo-transferrin from holo-transferrin, thereby indicating that iron is loaded onto protein.In certain embodiments, the recovery of iron (III) concentration can be measured with cell assay, iron-specific binding dye and / or the ICP-MS paired with EPR with plasma ceruloplasmin knocking out.In other embodiments, the oxidative stress in the cell can be monitored via QT-PCR with ROS specific primers.

[0256] Treatment of neurodegenerative diseases comprises administering any of the compounds disclosed herein to a mammal in need thereof. One skilled in the art will administer the compound by a method consistent with the mammal's medical history. Diseases or conditions treated include, but are not limited to, inflammatory disorders leading to abnormal inhibition of ferroportin production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, idiopathic NBIA, vascular dementia, tauopathy, progressive supranuclear palsy, corticobasal degeneration, subacute sclerosing panencephalitis parkinsonism, postencephalitis parkinsonism, Guam parkinsonism-dementia complex, Pick's disease, and frontotemporal dementia.

[0257] Example

[0258] Having now generally described the disclosure, the disclosure will be more readily understood by reference to the following, which is included merely for the purpose of illustrating certain aspects and embodiments of the disclosure and is not intended to limit the disclosure.

[0259] Example 1 Effect of Hinokitiol on Dopamine Oxidation

[0260] To measure the ability of hinokitiol to act as a "safe channel" for neuronal iron mobilization, the reactivity of iron (III) complexed with dopamine, DFP, and hinokitiol was measured and characterized using the ferroxine assay (33). Iron (III) was pre-complexed with dopamine, hinokitiol, or DFP in HEPES buffer, then added to a 96-well plate containing ferroxine and a reducing agent and monitored via absorbance at 562 nm using a plate reader. When iron (III) was complexed with dopamine and DFP, a strong conversion of iron (II) under reducing conditions was observed, while complexation with hinokitiol significantly reduced the conversion of iron (III) ( Figure 1A In a similar manner, the use of the ROS probe 2,7-dichlorofluorescein (DCF) showed that ROS production induced by Fe(II) was greatly reduced in the presence of hinokitiol compared with dopamine and DFP ( Figure 1B The ability of the iron species generated by the combination of hinokitiol and Fe(II) to auto-oxidize Fe(II) was examined by using electron paramagnetic resonance (EPR). When Fe(II) binds to hinokitiol, a signal at g'=4.3 was observed ( Figure 1D), indicating the presence of a high-spin Fe(III)-hinokitiol complex in an octahedral geometry. This peak was not observed when only Fe(II) was present ( Figure 1C ), which indicates that Fe(II) did not spontaneously oxidize during the measurement period. In vitro data show that when iron is kept as Fe 3+ In this regard, hinokitiol outperformed DFP. To perform this assay, an iron(II) solution was prepared in degassed 1:1 MeOH:H2O with a reducing agent. After acquiring the Fe(II) spectrum at 77 K, the solution was allowed to warm to room temperature and hinokitiol was added at a concentration of 3:1. A spectrum was obtained in which a g' value of 4.3 was observed.

[0261] FeM-1269 is a more effective and less toxic derivative ( Figure 2A ), less aggregated than hinokitiol ( Figure 2B ), and in liposomes ( Figure 2C ) and Caco-2 cells ( Figure 2D ) can transport iron over a wider concentration range than hinokitiol.

[0262] To detect dopamine oxidation and ROS generation, the fluorescent probe 2,7-dichlorofluorescein (DCF) was used, in which dopamine was pre-complexed with Fe(II) and monitored via a plate reader for one hour, followed by the addition of small molecules such as hinokitiol or DFP, and evidence that hinokitiol alleviated dopamine oxidation was observed ( Figure 11A To further explore this, FPN1.2KO C. elegans were plated on NGM plates seeded with OP50 at the L4 life stage and then grown to day four, treated with the small molecule hinokitiol or DFP, and then collected and homogenized on day five. The lysates were used in 96-well plates containing 2,7-dichlorofluorescein (DCF) to detect ROS. Hinokitiol can restore wild-type levels of ROS in vivo ( Figure 11B ).

[0263] To monitor dopamine oxidation, an in vitro assay using LC-MS was developed by monitoring dopamine concentrations via mass spectrometry. 100 μM dopamine samples were prepared and then treated with control, hinokitiol, or FeM-1269. Both hinokitiol and FeM-1269 showed evidence of mitigating dopamine oxidation ( Figure 12A ). In addition, this was monitored via LC-MS to see the concentration of DAC produced during this same process. Similarly, hinokitiol and FeM-1269 reduced the amount of dopamine that was oxidized to form DAC ( Figure 12B To determine the quantitative linearity of the assay, peak intensities were plotted against increasing DAC concentrations, with an R2 value of 0.9738.

[0264] Finally, to determine the affinity of the complexation, the small molecules were pre-complexed with iron(III) and then introduced into a plate reader with a strong reducing agent and ferroxine dye to determine the affinity of the complex. Hinokitiol has a strong affinity for binding to Fe(III), while the dopamine control does not bind strongly to Fe(II) ( Figure 14 )

[0265] Example 2 - Effects of Hinokitiol in a C. elegans Neurodegeneration Model

[0266] Hinokitiol and FeM-1269 confer neuroprotective abilities. A replicated NBIAfpn-1.2KO C. elegans strain was generated using CRISPR / Cas9-mediated knockout and then mated with the Pdat::GFP strain to produce the fpn-1.2KO strain (fpn-1.2KO; Pdat::GFP) with GFP-labeled dopaminergic neurons. The genotypes of the strains were verified by genotyping PCR and Sanger sequencing. All strains used had been backcrossed with N2 at least three times. To treat C. elegans with small molecules, day 4 adult worms were transferred to NGM containing small molecules. The worms were transferred to NGM containing freshly inoculated small molecules until the seventh day, at which time they were imaged using a confocal microscope with GFP fluorescence. Scoring was performed in a blinded study, where the integrity of dopaminergic neurons was observed to reflect neurodegeneration. This mutant strain showed dopaminergic neurodegeneration ( Figures 3B-3D ) and elevated neuronal ferritin levels ( Figures 3F-3H ), which is a readout of intracellular iron levels. Figure 3A ) and reported neurodegeneration scoring methods (35, 36), it was found that DFP did not confer neuroprotection at all administered concentrations ( Figure 3B ), while hinokitiol showed efficacy at low concentrations (0.05-0.1 μM) ( Figure 3C Interestingly, FeM-1269 showed efficacy at concentrations as low as 0.05 μM and at the highest concentration (25 μM) ( Figure 3D ). These results demonstrate the potential of hinokitiol and FeM-1269, and more broadly, iron-transporting fusholones, to treat neurodegenerative disorders. The hinokitiol derivative FeM-1269 may have the potential to increase the therapeutic index of hinokitiol. Furthermore, to link neuroprotection to iron mobilization capacity, an fpn-1.2KO line was created using GFP-tagged ferritin (ftn-1) to measure iron levels in representative ASI neurons ( Figure 3E ).and Figure 1B Consistently, DFP failed to reduce the fluorescence level at all applied concentrations ( Figure 3F), indicating that DFP did not mobilize iron from fpn-1.2KO ASI neurons. On the other hand, treatment of fpn-1.2KO worms with hinokitiol and FeM-1269 caused a significant decrease in fluorescence levels from 0.1 μM and 0.05 μM concentrations, respectively ( Figures 3G-3H ), which may be associated with the release of intracellular iron from ASI neurons. These data further support the conclusion that hinokitiol and FeM-1269 have the ability to protect neurons from iron-induced neurodegeneration.

[0267] Example 3 - Effects of Hinokitiol in the Flatiron Mouse Neurodegeneration Model

[0268] In parallel with C. elegans, the iron mouse, a leading animal model of FPN1 deficiency due to the H32R mutation of FPN1, was used (34, 35). These mice were subjected to ICP-MS and behavioral studies, in which blood samples and tissues were collected and submitted for analysis. In addition, behavior was assessed by elevated plus maze, exploratory maze, and daily monitoring. Due to iron accumulation in the brain ( Figures 3D-3E ), these mice showed elevated anxiety levels ( Figures 4A-4C To determine dose dependence, these mice were given a single IP injection to assess acute administration, followed by chronic treatment via IP injection of 10 mg / kg for one week. Acute administration of hinokitiol resulted in a dose-dependent decrease in brain iron levels ( Figure 4D Similar effects were observed after long-term administration of 10 mg / kg hinokitiol 7 days later ( Figure 4E Together, these data sets indicate that hinokitiol has the ability to penetrate the blood-brain barrier to mobilize brain iron accumulated in iron-bearing mice.

[0269] Example 4 - Cyclic Voltammetry of Hinokitiol-Iron Complex

[0270] The redox potential decreases with increasing hinokitiol concentration. These were obtained at a scan rate of 100 mV / s using a Hg electrode, Ag / AgCl reference, and graphite auxiliary, using 0.1 μM Tris buffer in 1:1 MeOH:H2O (pH=7.2) and 100 μM Fe(NO3)3. The data for these experiments are shown in Figure 6A-Figure 6B middle.

[0271] Example 5 - EPR of Hinokitiol-Iron Complex

[0272] To perform this assay, an iron (II) solution was prepared in degassed 1:1 MeOH:H2O with a reducing agent. After obtaining the Fe (II) spectrum at 77 K, the solution was allowed to warm to room temperature and hinokitiol was added at a concentration of 3:1. A spectrum was obtained in which a g' = 4.3 value was observed. The data for these experiments are shown in Figures 7A-7B middle.

[0273] Example 6 - Transferrin-Hinokiol Iron Transfer Kinetics

[0274] For the kinetic experiments, 4 μM human apo-Tf was incubated with 64 μM Fe(hinokitiol)3 complex. The reaction was stopped with sample buffer at several time points. The samples were run using the same conditions as above. After the run, the gel was stained with RAPIDStain (G-biosciences 786-31) according to the manufacturer's instructions. The formation of different Fe-Tf species was quantified by measuring the band density using ImageLab 4.1 (Bio-Rad) and expressed as a function of mole fraction. The data for these experiments are shown in Figure 8B-Figure 8C middle.

[0275] Example 7 - Colorimetric / Fluorescent Iron(II) Conversion Assay

[0276] For the colorimetric assay: Small molecules are pre-complexed with Fe(III) at a 3:1 ratio and then placed in a 96-well plate compatible with a plate reader. A solution containing HEPES buffer, ferrozine dye, and a reducing agent is then added to the wells, and the absorbance at 562 nm is recorded over several hours.

[0277] For the fluorescence assay: freshly prepared solutions of iron (II) and iron (III) were placed in a 96-well plate compatible with a plate reader, then the ROS dye 2,7-dichlorofluorescein (DCF) was added to the plate and fluorescence was monitored at 488 nm. The data for these experiments are shown in Figure 9 and Figure 10 middle.

[0278] Example 8 - Synthesis and Characterization of Compounds of the Present Disclosure

[0279] The compounds of the present disclosure have been previously synthesized and characterized. See, for example, WO 2021 / 076938 (PCT / US2020 / 056048), WO 2021 / 076945 (PCT / US2020 / 056056), and US 2021 / 0163393 (USSN 17 / 046,608), the contents of which are expressly incorporated herein by reference.

[0280] Example 9 - Ligand-promoted iron (III) efflux from liposomes

[0281] Preparation of POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine):cholesterol liposomes:

[0282] Prepare a 1M buffer solution of MES and Tris by dissolving 121.14 grams of Tris base and 213.25 grams of MES hydrate in 500 mL of MilliQ water and adjusting to pH 7.0 with 18M HCl solution before adding the total volume of the solution to 1 L. Prepare a 500 mM FeCl solution by dissolving 0.811 grams of anhydrous FeCl in 10 mL of 0.1 M HSO aqueous solution. Prepare an internal buffer in a 50 mL falcon tube by adding 25 mL of MilliQ water, 1.61 g of sodium citrate, 1.5 mL of the above-mentioned FeCl solution, and 2.5 mL of 1 M MES / Tris HCl buffer (pH 7.0). Finally, add additional MilliQ HO to a final volume of 50 mL. The prepared internal buffer will be a solution of 15 mM FeCl, 125 mM sodium citrate, and 50 mM MES / Tris HCl (pH 7.0) at a final concentration.

[0283] A lipid solution was prepared by dissolving 206.9 mg of POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and 8.6 mg of cholesterol in 10 mL of ethanol.

[0284] Lipid solution and internal buffer solution are loaded into 10mL Luer lock syringe independently, for being loaded into the new barrel on Precision Nanosystems NanoAssembler, to prepare the unilamellar liposome with following parameter: the internal buffer of 7.5mL cumulative volume, 1.5:1 mixing ratio: lipid solution, 8mL / min flow velocity, ambient temperature, 0.35mL starting waste and the final waste of 0.05mL.Harvested 7.5mL liposome, for purifying on the Sephadex G-50 post of long 6 inches, 1 inch in diameter, described post is moistened with 600mM sodium ascorbate and 50mM MES / Tris HCl pH 7.0 buffer.This buffer is also used as post running buffer.Crude liposome solution is carefully loaded onto on the Sephadex top with the running buffer of minimum volume, makes it enter matrix, and in the situation that continuously adds running buffer, runs this post.Collect and be observed as the eluted liposome of milky turbid solution, until free iron begins to elute (observe as dark purple), and merge fraction and be used for phosphorus quantitative.

[0285] Determination of phosphorus content:

[0286] The phosphorus content of the eluted liposomes was determined by the method outlined below. 10 μL of the liposome eluate and a running buffer blank were added to a 5 mL glass vial containing 450 μL of 8.9 M aqueous H2SO4. The mixture was heated to 225°C for 25 minutes in an aluminum heating block to hydrolyze POPC and allowed to cool for 5 minutes. 200 μL of 30% aqueous hydrogen peroxide was added to each vial and heated to 225°C for 25 minutes. After cooling, phosphorus content was determined using the Abcam phosphate assay kit, where the buffer-subtracted phosphorus level was determined based on a phosphate standard curve included in the kit. Liposomes were diluted to 1 mM phosphate in running buffer for the assay following dilution performed during the interpretation of the phospholipid digestion.

[0287] Determination of ligand iron transport rate constant:

[0288] The determination of the rate at which small molecule ligands release (transport) ferric iron from liposomes was performed in a clear bottom black 384-well plate on a Spectramax i3x, with the instrument set to read the absorbance at 562 nm in kinetic mode every 60 seconds for 120 minutes. 1 μL of a serially diluted DMSO stock solution of the small molecule ligand was added to the wells in triplicate to a final concentration of 40, 20, 10, 5, 2.5, and 1.25 μM of the ligand in a final volume of 80 μL, followed by 1 μL of an aqueous solution of 100 mM ferroxine to a final concentration of 1 mM ferroxine. 78 μL of liposomes diluted to 1 mM phosphorus in running buffer were added to the wells as quickly as possible (using a digital repeat multichannel pipette), and kinetic readings were started as quickly as possible after the liposomes were added to all wells. Typically, eight compounds at six concentrations were tested in triplicate simultaneously.

[0289] After the kinetic reading is completed, the equation Y = (Y0-Y Max ) (-kX) +Y Max Data from a single read were fitted to a single-association regression, where Y is the absorbance value and X is the time in minutes. For each compound concentration, the k values for the individual replicates of three runs were averaged. The ability of a ligand to release iron from liposomes at a given concentration is represented by the rate k. The rate k is considered the efflux rate, and ligands were ranked by the efflux rate they affect at a 10 μM ligand concentration.

[0290] Example 10 - Evaluation of the ability of shDMT1-Caco2 ligands to transport Fe(III) 55 Fe transport assay

[0291] Materials and methods:

[0292] Cells: DMT1-deficient Caco-2 cells (alternative names: “shDMT1” or “4A” cells) were obtained from Grillo et al., Science, 2017, and were cryopreserved in liquid nitrogen until use.

[0293] Reagents and supplies: 55 FeCl3 was obtained from PerkinElmer (Boston, MA). Iron (III) chloride (FeCl3) hexahydrate was obtained from Sigma. Dulbecco's Modified Eagle Medium (DMEM), fetal bovine serum (FBS), L-glutamine, MEM non-essential amino acids, penicillin-streptomycin, G418, formic acid, methanol, high-purity water, ammonium formate, and dimethyl sulfoxide (DMSO) were purchased from Fisher Scientific. Propranolol, atenolol, and amoxicillin were purchased from Sigma-Aldrich Chemical Co. (St Louis, MO). Scintillation cocktail was obtained from Research Product International, Inc. (Mount Prospect, IL). Stericup filtration system (PES membrane, 0.22 μm pore size) was purchased from Fisher Scientific. Corning item number 3378 24-well transwell insert plate.

[0294] Test Articles: The known compounds hinokitiol and deferiprone were purchased from Sigma. They were tested side by side with the small molecule ligands disclosed in this application. DMSO stock solutions of hinokitiol or test article were prepared (10 mM, 1,000 times the 10 μM dose level). A 25 mM stock solution of deferiprone in DMSO was prepared. When not in use, the DMSO stock solutions were stored at or below -20°C.

[0295] Prepare growth medium according to the following table:

[0296]

[0297]

[0298] Prepare apical culture medium (serum-free DMEM, 10 mM MES, pH 6.5). Before each experiment, add 200 nM 55 Prepare freshly prepared apical master mix medium with Fe. For propranolol and atenolol negative control wells, use 200 nM non-radioactive iron.

[0299] Basolateral culture medium was serum-free DMEM, 10 mM HEPES, 2% bovine serum albumin (BSA) (pH 7.4).

[0300] For each experiment, cells were seeded into 24-well transwell plates (0.5 mL, 50,000 cells / mL) with growth medium. 1 mL of growth medium was loaded onto the basolateral paired plate. After 12-24 hours, the top chamber and basolateral chamber were replaced with growth medium. The top culture medium was replaced 3 times per week for 21-28 days, including a culture medium replacement 48 hours before the assay date.

[0301] On the day of determination, TEER value was measured and average TEER value was obtained. Individual wells with TEER value lower than the average value of all wells>35% were excluded. For qualified wells, the top chamber (twice) and the basolateral chamber (once) were washed with PBS. The basolateral paired plate was then filled with 1mL basolateral culture medium. By adding downward along the side wall of the top hole, 300 μL of the top test master mixture of the test article with the specified dose level was added to each well. Each dose was tested in triplicate. The plate was incubated (5% CO2 and 90% humidity, 37°C) for the specified time point. At each specified time point, the basolateral supernatant was gently mixed by pipetting, and 200 μL of the basolateral supernatant was transferred to a scintillation vial. 5mL of scintillation cocktail was added to each scintillation counting vial. For each scintillation vial, radioactivity (CPM) was determined using a liquid scintillation counter LS6500. The counting time for each vial was 5 minutes.

[0302] Data processing:

[0303] All raw CPM values were divided by the mean of the blank DMSO solution to obtain the fold change above the DMSO value. The mean and standard deviation were calculated for each compound at each concentration level and each measurement time point to give the fold change (FC) value. For rank-ordered compounds, the FC value of the ligand at the 4-hour time point was further divided by the fold change (FC) value of hinokitiol (positive control compound) at an equimolar concentration to obtain the FC (normalized fold change) value.

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[0340] Incorporated by Reference

[0341] All U.S. patents and U.S. and PCT patent application publications mentioned herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference in its entirety. In the event of a conflict, the present application, including any definitions herein, will control.

[0342] Equivalent solutions

[0343] While specific embodiments of the present invention have been discussed, the above description is illustrative and not restrictive. Many variations of the present invention will become apparent to those skilled in the art upon reading this specification and the appended claims. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and this specification, along with such variations.

Claims

1. A method for treating a disease or condition selected from the group consisting of: an inflammatory disorder leading to abnormal inhibition of iron transporter production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of hinokitiol, a hinokitiol derivative, and an iron-transporting oxalool, or a pharmaceutically acceptable salt thereof.

2. A method for treating a disease or condition selected from the group consisting of an inflammatory disorder leading to abnormal inhibition of ferroportin production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure according to Formula (Ia) or a pharmaceutically acceptable salt thereof: in: X represents oxygen or sulfur; R a represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl; R a ' represents hydrogen, halo, alkyl or substituted alkyl; and R b 、R c and R d independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkoxy, substituted cycloalkoxy, heterocycloalkoxy, substituted heterocycloalkoxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, and heteroalkynyl; provided that R a 、R b 、R c and R d Not all hydrogen.

3. The method of claim 2, wherein R a 'It's hydrogen.

4. The method of claim 2, wherein R a ' is a halo group.

5. The method of claim 2, wherein R a ' is an alkyl group or a substituted alkyl group.

6. The method of any one of claims 2 to 5, wherein R a 、R b 、R c and R d At least one of the following is selected from the group consisting of: halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkoxy, substituted cycloalkoxy, heterocycloalkoxy, substituted heterocycloalkoxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl.

7. The method of any one of claims 2 to 6, wherein R a 、R a '、R b 、R c and R d At least one of the following is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.

8. The method of claim 2 or 3, wherein the compound is represented by Formula Ib: in: R a represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl; and R b 、R c and R d independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, and heteroalkynyl; The condition is R a 、R b 、R c and R d Not all hydrogen.

9. The method of any one of claims 2 to 8, wherein: Each occurrence of heterocycloalkyl is independently selected from the group consisting of: n is independently at each occurrence an integer selected from 0 to 5, inclusive; R 2b is independently at each occurrence hydrogen, alkyl, substituted alkyl, heteroalkyl, hydroxy, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, and substituted alkynyl; and R 2 Each instance of independently represents -F, alkyl, haloalkyl, or alkoxy; or R 2 The two geminal examples of represent a carbonyl group.

10. The method of any one of claims 2 to 9, wherein R a It represents -F, -CF3, (C2-C15)alkyl or substituted (C1-C15)alkyl.

11. The method of claim 10, wherein: R b 、R c and R d independently represent hydrogen, (C1-C15)alkyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, (C1-C15)alkylene-R1, 3-12-membered cycloalkyl-R1, or 3-12-membered heterocycloalkyl-R1; and R1, at each occurrence, independently represents halo, alkyl, alkoxy or hydroxy.

12. The method of claim 8, wherein R a 、R b 、R c and R d At least one of them is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.

13. The method of any one of claims 11-12, wherein the compound is selected from the group consisting of:

14. The method of claim 13, wherein the compound is 15. The method of claim 13, wherein the compound is 16. The method of claim 11, wherein the compound is selected from the group consisting of:

17. The method of claim 11, wherein the compound is 18. The method of any one of claims 2 to 9, wherein R a represents -Cl, -F, -CF3, (C2-C15)alkyl or substituted (C1-C15)alkyl.

19. The method of claim 18, wherein R a Indicates –F.

20. The method of any one of claims 18-19, wherein: R b 、R c and R d independently represent hydrogen, halo, (C1-C15)alkyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, (C1-C15)alkylene-R1, 3-12-membered cycloalkyl-R1, or 3-12-membered heterocycloalkyl-R1; and R1, at each occurrence, independently represents halo, alkyl, alkoxy or hydroxy.

21. The method of claim 20, wherein the compound is selected from the group consisting of:

22. The method of any one of claims 2 to 9, wherein: R b 、R c and R d R2 independently represents hydrogen or 3-12 membered heterocycloalkyl optionally substituted by one or two instances of R2; wherein the heterocycloalkyl group comprises one or two oxygen atoms, one or two nitrogen atoms, one or two sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms; and Each instance of R2 independently represents -F, alkyl, haloalkyl, carbonyl, or alkoxy.

23. The method of claim 22, wherein the compound is selected from the group consisting of:

24. The method of claim 23, wherein the compound is 25. The method of claim 22, wherein: The heterocycloalkyl group contains one or two nitrogen atoms; and at least one of the nitrogen atoms is N(R 2b )express; R 2b independently represents hydrogen, -C(O)R5 or -C(O)OR5; and R5 independently represents hydrogen, alkyl or substituted alkyl.

26. The method of any one of claims 2 to 9, wherein: R b 、R c and R d independently represents hydrogen or –OR 3 ; and R3 independently represents (C1-C15)alkyl, 3-12-membered cycloalkyl or bicycloalkyl, 3-12-membered heterocycloalkyl or heterobicycloalkyl, wherein the heterocycloalkyl or heterobicycloalkyl contains one or two oxygen atoms, one or two nitrogen atoms, one or two sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms.

27. The method of claim 26, wherein the compound is:

28. The method of claim 26, wherein the compound is selected from the group consisting of:

29. The method of claim 26, wherein each instance of R3 is optionally substituted with R4; and R4 independently represents alkyl, halogen-substituted alkyl, alkoxy, or hydroxy.

30. The method of any one of claims 2 to 10, wherein R a Indicates –CH3.

31. The method of claim 30, wherein: R b 、R c and R d independently represent hydrogen, (C1-C15)alkyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, (C1-C15)alkylene-R1, 3-12-membered cycloalkyl-R1, or 3-12-membered heterocycloalkyl-R1; and R1, at each occurrence, independently represents halo, alkyl, alkoxy or hydroxy.

32. The method of claim 31 , wherein the compound is selected from the group consisting of:

33. The method of claim 30, wherein: R b 、R c and R d R2 independently represents hydrogen or 3-12 membered heterocycloalkyl optionally substituted by one or two instances of R2; wherein the heterocycloalkyl group comprises one or two oxygen atoms, one or two nitrogen atoms, one or two sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms; and each instance of R2 independently represents -F, alkyl, haloalkyl, carbonyl, or alkoxy.

34. The method of claim 33, wherein the compound is selected from the group consisting of:

35. The method of claim 33, wherein: The heterocycloalkyl group contains one or two nitrogen atoms; and at least one of the nitrogen atoms is N(R 2b )express; R 2b independently represents hydrogen, -C(O)R5 or -C(O)OR5; and R5 independently represents hydrogen, alkyl or substituted alkyl.

36. The method of claim 30, wherein: R b 、R c and R d independently represents hydrogen or –OR 3 ; and R3 independently represents (C1-C15)alkyl, 3-12 membered cycloalkyl or bicycloalkyl, 3-12 membered heterocycloalkyl or heterobicycloalkyl, wherein the heterocycloalkyl or heterobicycloalkyl contains one or two oxygen atoms, one or two nitrogen atoms, one or two sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms.

37. The method of claim 36, wherein each instance of R3 is optionally substituted with R4; and R4 independently represents alkyl, halogen-substituted alkyl, alkoxy, or hydroxy.

38. The method of any one of claims 2 to 10, wherein R a Represents hydrogen.

39. The method of claim 38, wherein R b 、R c and R d independently represents hydrogen, (C1-C15)alkyl, -F or -CF3.

40. The compound of claim 38 or 39, wherein the compound is selected from the group consisting of:

41. The method of claim 39, wherein the compound is selected from the group consisting of:

42. The method of claim 38, wherein R b 、R c and R d independently represents hydrogen, (C1-C15)alkyl, -Cl, -F or -CF3.

43. The method of claim 42, wherein the compound is 44. The method of claim 38, wherein: R b 、R c and R d R2 independently represents hydrogen, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl, each of which is optionally substituted by one or two instances of R2; wherein the heterocycloalkyl group comprises one or two oxygen atoms, one or two nitrogen atoms, one or two sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms; and Each instance of R2 independently represents -F, alkyl, haloalkyl, carbonyl, or alkoxy.

45. The method of claim 44, wherein the compound is selected from the group consisting of:

46. The method of claim 45, wherein the compound is:

47. The method of claim 45, wherein the compound is selected from the group consisting of:

48. The method of claim 44, wherein the compound is selected from the group consisting of:

49. The method of claim 38, wherein: R b is a halo group; R c and R d independently represent hydrogen, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, cycloalkoxy or heterocycloalkoxy, Each cycloalkylheterocycloalkyl, cycloalkoxy, or heterocycloalkoxy is optionally substituted with one or two instances of R2; wherein the heterocycloalkyl group comprises one or two oxygen atoms, one or two nitrogen atoms, one or two sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms; and Each instance of R2 independently represents -F, alkyl, haloalkyl, carbonyl, or alkoxy.

50. The method of claim 49, wherein the compound is selected from the group consisting of:

51. The method of claim 44, wherein: The heterocycloalkyl group contains one or two nitrogen atoms; and at least one of the nitrogen atoms is N(R 2b )express; R 2b independently represents hydrogen, -C(O)R5 or -C(O)OR5; and R5 independently represents hydrogen, alkyl or substituted alkyl.

52. The method of claim 51, wherein the compound is selected from the group consisting of:

53. The method of claim 38, wherein: R b 、R c and R d independently represents hydrogen or –OR 3 ; and R3 independently represents (C1-C15)alkyl, 3-12 membered cycloalkyl or bicycloalkyl, or 3-12 membered heterocycloalkyl or heterobicycloalkyl, wherein the heterocycloalkyl or heterobicycloalkyl contains one or two oxygen atoms, one or two nitrogen atoms, one or two sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms.

54. The method of claim 53, wherein the compound is selected from the group consisting of:

55. The method of claim 50, wherein the compound is:

56. The method of claim 53, wherein each instance of R3 is optionally substituted with R4; and R4 independently represents alkyl, halogen-substituted alkyl, alkoxy, or hydroxy.

57. The method of claim 53, wherein the compound is selected from the group consisting of:

58. The method of claim 38, wherein: R b 、R c and R d independently represents hydrogen or -alkyl-R3 or -O-alkyl-R3; and R3 independently represents an aryl group, a substituted aryl group, a 3-12 membered cycloalkyl or bicycloalkyl group, or a 3-12 membered heterocycloalkyl or heterobicycloalkyl group containing one or two oxygen atoms, one or two nitrogen atoms, one or two sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms.

59. The method of claim 58, wherein the compound is selected from the group consisting of:

60. The method of claim 38 or 39, wherein R a ' is a halo group or an alkyl group.

61. The method of claim 58, wherein the compound is 62. A method of treating a disease or condition selected from the group consisting of an inflammatory disorder leading to abnormal inhibition of ferroportin production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure represented by Formula IIa, Formula IIb, or Formula IIc, or a pharmaceutically acceptable salt thereof: in: R a represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl; X and Y independently represent O, S, NH or CR5R6; R2 represents -F, alkyl, haloalkyl or alkoxy; and R5 and R6, at each occurrence, independently represent H, (C1-C15)alkyl, or substituted (C1-C15)alkyl; Provided that the compound is not 63. The method of claim 61, wherein the compound is represented by Formula IIa or Formula IIb.

64. The method of claim 63, wherein R a Represents hydrogen.

65. The method of claim 64, wherein the compound is selected from the group consisting of:

66. The method of claim 64, wherein the compound is 67. A method of treating a disease or condition selected from the group consisting of an inflammatory disorder leading to aberrant inhibition of ferroportin production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure according to Formula (Ic) or a pharmaceutically acceptable salt thereof: in: X represents sulfur or oxygen; R a 、R b 、R c and R d independently represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, heteroalkynyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R a 、R b 、R c and R d At least one of is aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and The condition is R a 、R b 、R c and R d Not all hydrogen.

68. The method of claim 67, wherein R a 、R b 、R c and R d At least one of is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

69. The method of claim 67, wherein R b 、R c and R d At least one of is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

70. The compound of claim 67, which is represented by formula (Id): in: R a 、R b 、R c and R d independently represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, heteroalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R b 、R c and R d At least one of is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and The condition is R a 、R b 、R c and R d Not all hydrogen.

71. The method of any one of claims 67 to 70, wherein: R b 、R c and R d Each of which is an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group, represented by Formula II: Each of A, B, C, D and E independently represents CH, N or CR; For each instance of Formula II, the total number of nitrogen atoms in A, B, C, D, and E is 0, 1, or 2; and Each instance of R independently represents halo, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxy, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkoxy, substituted cycloalkoxy, cyano, amino, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl.

72. The method of claim 71, wherein each instance of R independently represents chloro, fluoro, bromo, iodo, cyano, trifluoromethyl, amino, hydroxy, (C1-C12)alkyl, (C3-C12)cycloalkyl, (C1-C12)alkoxy, (C3-12)cycloalkyloxy, or (C3-C12)heterocycloalkyl; and The heterocycloalkyl group contains one or two oxygen atoms, one or two nitrogen atoms, one or two sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms.

73. The method of claim 71 or 72, wherein: R a 、R b and R d represents hydrogen; and R c represents an aryl, substituted aryl, heteroaryl or substituted heteroaryl group according to formula II.

74. The compound of claim 73, wherein the compound is selected from the group consisting of:

75. The method of claim 71 or 72, wherein: R a 、R c and R d represents hydrogen; and R b represents an aryl, substituted aryl, heteroaryl or substituted heteroaryl group according to formula II.

76. The method of claim 75, wherein the compound is selected from the group consisting of:

77. The method of claim 71 or 72, wherein: R a 、R b and R c represents hydrogen; and R d represents an aryl, substituted aryl, heteroaryl or substituted heteroaryl group according to formula II.

78. The method of claim 77, wherein the compound is selected from the group consisting of:

79. The method of claim 78, wherein the compound is selected from the group consisting of:

80. The method of claim 71 or 72, wherein: R a represents an alkyl group; R b 、R c and R d One and only one of represents an aryl, substituted aryl, heteroaryl or substituted heteroaryl according to formula II; and R b 、R c and R d The two in represent hydrogen.

81. The method of claim 80, wherein the compound is selected from the group consisting of:

82. The method of claim 80 or 81, wherein: R a represents an aryl, substituted aryl, heteroaryl or substituted heteroaryl group according to formula II; R b 、R c and R d One and only one of represents an alkyl group; and R b 、R c and R d The two in represent hydrogen.

83. The method of claim 82, wherein the compound is selected from the group consisting of:

84. The method of claim 71 or 72, wherein: R a represents an aryl, substituted aryl, heteroaryl or substituted heteroaryl group according to formula II; and R b 、R c and R d Each of represents hydrogen.

85. The method of claim 84, wherein the compound is selected from the group consisting of:

86. The method of claim 67, wherein R a 、R b 、R c and R d At least one of the groups is an aryloxy group, a substituted aryloxy group, a heteroaryloxy group, or a substituted heteroaryloxy group.

87. The method of claim 67, wherein R b 、R c and R d At least one of the groups is an aryloxy group, a substituted aryloxy group, a heteroaryloxy group, or a substituted heteroaryloxy group.

88. The method of claim 86 or 87, wherein: R b 、R c and R d Each of which is an aryloxy group, a substituted aryloxy group, a heteroaryloxy group or a substituted heteroaryloxy group, represented by Formula IId Each of A, B, C, D and E independently represents CH, N or CR; For each instance of Formula IId, the total number of nitrogen atoms in A, B, C, D, and E is 0, 1, or 2; and Each instance of R independently represents halo, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxy, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkoxy, substituted cycloalkoxy, cyano, amino, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl.

89. The method of claim 88, wherein each instance of R independently represents chloro, fluoro, bromo, iodo, cyano, trifluoromethyl, amino, hydroxy, (Ci-Ci2)alkyl, (C3-Ci2)cycloalkyl, (Ci-Ci2)alkoxy, (C3-12)cycloalkoxy, or (C3-Ci2)heterocycloalkyl; and the heterocycloalkyl group contains one or two oxygen atoms, one or two nitrogen atoms, one or two sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms.

90. The method of claim 88 or 89, wherein: R a 、R b and R d represents hydrogen; and R c represents an aryloxy group, a substituted aryloxy group, a heteroaryloxy group or a substituted heteroaryloxy group according to formula IId.

91. The method of claim 88 or 89, wherein: R a 、R c and R d represents hydrogen; and R b represents an aryloxy group, a substituted aryloxy group, a heteroaryloxy group or a substituted heteroaryloxy group according to formula IId.

92. The method of claim 88 or 89, wherein: R a 、R b and R c represents hydrogen; and R d represents an aryloxy group, a substituted aryloxy group, a heteroaryloxy group or a substituted heteroaryloxy group according to formula IId.

93. The method of claim 88 or 89, wherein: R a represents an alkyl group; R b 、R c and R d One and only one of represents an aryloxy, substituted aryloxy, heteroaryloxy or substituted heteroaryloxy according to formula IId; and R b 、R c and R d The two in represent hydrogen.

94. The method of claim 88 or 89, wherein: R a represents an aryl, substituted aryl, heteroaryl or substituted heteroaryl group according to formula IId; and R b 、R c and R d Each of represents hydrogen.

95. The method of claim 91 or 92, wherein the compound is selected from the group consisting of:

96. The method of any one of claims 67 to 70, wherein: R b 、R c and R d Each of is a heteroaryl group or a substituted heteroaryl group, represented by Formula IIe: A' represents O or S; Each of B', C' and D' independently represents CH, N or CR; and Each instance of R independently represents halo, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxy, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkoxy, substituted cycloalkoxy, cyano, amino, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl.

97. The method of any one of claims 67 to 70, wherein: R b 、R c and R d Each of is a heteroaryl or substituted heteroaryl, represented by Formula IIf: C' represents O or S; Each of A', B' and D' independently represents CH, N or CR; and Each instance of R independently represents halo, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxy, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkoxy, substituted cycloalkoxy, cyano, amino, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl.

98. The method of any one of claims 67-70, wherein: R b 、R c and R d Each of is a heteroaryl group or a substituted heteroaryl group, represented by Formula IIg: D' represents O or S; Each of A', B' and C' independently represents CH, N or CR; and Each instance of R independently represents halo, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxy, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkoxy, substituted cycloalkoxy, cyano, amino, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl.

99. The method of any one of claims 57-60, wherein: R b 、R c and R d Each of is a heteroaryl group or a substituted heteroaryl group, represented by Formula IIh: B' represents O or S; Each of A', C' and D' independently represents CH, N or CR; and Each instance of R independently represents halo, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxy, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkoxy, substituted cycloalkoxy, cyano, amino, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl.

100. The method of any one of claims 97-99, wherein each instance of R independently represents chloro, fluoro, bromo, iodo, cyano, trifluoromethyl, amino, hydroxy, (Ci-Ci2)alkyl, (C3-Ci2)cycloalkyl, (Ci-Ci2)alkoxy, (C3-12)cycloalkoxy, or (C3-Ci2)heterocycloalkyl; and the heterocycloalkyl group contains one or two oxygen atoms, one or two nitrogen atoms, one or two sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms.

101. The method of any one of claims 97 to 100, wherein: R a 、R b and R d represents hydrogen; and R c represents a heteroaryl or substituted heteroaryl according to any one of formulae IIe-IIh.

102. The method of any one of claims 97-100, wherein: R a 、R c and R d represents hydrogen; and R b represents a heteroaryl or substituted heteroaryl according to any one of formulae IIe-IIh.

103. The method of any one of claims 97-100, wherein: R a 、R b and R c represents hydrogen; and R d represents a heteroaryl or substituted heteroaryl according to any one of formulae IIe-IIh.

104. The method of any one of claims 97-100, wherein: R a and R c represents hydrogen; R b represents a halo group, an alkyl group or a substituted alkyl group. R d represents a heteroaryl or substituted heteroaryl according to any one of formulae IIe-IIh.

105. The method of any one of claims 97-100, wherein: R a represents a halo group or an alkyl group; R b 、R c and R d One and only one of represents a heteroaryl or substituted heteroaryl according to any one of Formulae IIe-IIh; and R b 、R c and R d The two in represent hydrogen.

106. The method of any one of claims 97 to 100, wherein: R a represents a heteroaryl or substituted heteroaryl according to any one of formulae IIe-IIh; R b 、R c and R d One and only one of represents an alkyl group; and R b 、R c and R d The two in represent hydrogen.

107. The method of any one of claims 97 to 100, wherein: R a represents a heteroaryl or substituted heteroaryl according to any one of Formulae IIe-IIh; and R b 、R c and R d Each of represents hydrogen.

108. The method of any one of claims 101-107, wherein the compound or tautomer is selected from the group consisting of:

109. A method of treating a disease or condition selected from the group consisting of an inflammatory disorder leading to abnormal inhibition of ferroportin production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof: or its salt; wherein R a It is C 1-20 -alkyl, C 2-20 -alkenyl, C 2-20 -alkynyl, C 3-9 - cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or selected from halo, NO2, CN, C 1-6 -alkyl, C 1-6 -haloalkyl and C 1-6 -substituted with a substituent consisting of an alkoxy group; and R b is hydrogen or methyl; provided that the compound is not hinokitiol.

110. The method of claim 109, selected from the group consisting of: and pharmaceutically acceptable salts thereof.

111. The method of any one of claims 109-110, wherein R a It is C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl or C 3-4 -cycloalkyl; provided that the compound is not hinokitiol.

112. The method of any one of claims 109-110, wherein R a Selected from the group consisting of:

113. The method of any one of claims 109-110, wherein R a Selected from the group consisting of:

114. The method of any one of claims 109-110, wherein R a Selected from the group consisting of:

115. A method of treating a disease or condition selected from the group consisting of an inflammatory disorder resulting in aberrant inhibition of ferroportin production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure selected from the group consisting of:

116. The method of claim 115, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

117. The method of claim 115, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

118. The method of claim 115, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

119. The method of claim 115, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

120. A method of treating a disease or condition selected from the group consisting of an inflammatory disorder leading to aberrant inhibition of ferroportin production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure selected from the group consisting of: as well as 121. A method of treating a disease or condition selected from the group consisting of an inflammatory disorder leading to aberrant inhibition of ferroportin production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure selected from the group consisting of: as well as 122. A method of treating a disease or condition selected from the group consisting of an inflammatory disorder leading to aberrant inhibition of ferroportin production, neurodegeneration with brain iron accumulation (NBIA), beta-propellant protein-associated neurodegeneration (BPAN), pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), COASY protein-associated neurodegeneration (CoPAN), ceruloplasminemia, Kufer-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinosis, Woodhouse-Sakati syndrome, and idiopathic NBIA, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of: as well as 123. The method of any one of claims 1-122, further comprising administering to the subject a therapeutically effective amount of a chelating agent.

124. The method of claim 123, wherein the chelating agent is deferasirox or deferiprone or a combination thereof.

125. The method of any one of claims 1-124, wherein the disease or condition is ceruloplasminemia.

126. The method of any one of claims 1-125, wherein the disease or condition is selected from the group consisting of Huntington's disease, amyotrophic lateral sclerosis (ALS), schizophrenia, brain injury, stroke, ischemia, multiple sclerosis, epilepsy, spongiform encephalopathy, frontotemporal lobar degeneration, pugilistic encephalitis, AIDS-related dementia, COVID-related neurodegeneration, affective disorders, depression, and bipolar disorder.

127. The method of any one of claims 1-126, wherein the disease or disorder is selected from the group consisting of vascular dementia, tauopathy, progressive supranuclear palsy, corticobasal degeneration, subacute sclerosing panencephalitis parkinsonism, postencephalitis parkinsonism, Guam parkinsonism-dementia complex, Pick's disease, and frontotemporal dementia.

128. The method of any one of claims 1 to 127, wherein the compound is administered systemically.

129. The method of any one of claims 1 to 128, wherein the compound is administered orally.

130. The method of any one of claims 1 to 128, wherein the compound is administered intravenously.

131. The method of any one of claims 1 to 130, wherein the subject is a mammal.

132. The method of claim 131, wherein the subject is a human.

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