Methods for treating neurodegenerative diseases

Abstract

Disclosed is a method for treating a disease or condition characterized by neurodegeneration by 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 tropolone.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 411,902, filed September 30, 2022. GOVERNMENT SUPPORT

[0002] This invention was made with government support under 1R01HL140526 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0003] Uneven iron distribution is the underlying cause of many neurodegenerative diseases. For example, the most common neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are associated with iron accumulation in the brain, which 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, patients with Friedreich's ataxia have been reported to accumulate iron in mitochondria, suggesting that uneven distribution of intracellular iron also contributes to the pathology. See Non-Patent Document 1. A significant correlation between brain iron overload and neurodegeneration has also been observed in a group of inherited neurological disorders known as neurodegeneration with cerebral iron accumulation (NBIA), characterized by neurological deterioration in early adulthood and accompanied by progressive dystonia, parkinsonism, cognitive decline, and seizures.

[0004] Iron's inherent ability to act as both an electron acceptor and an electron donor makes it essential for most living organisms. Iron is required for oxidative metabolism, mitochondrial energy generation, synaptic plasticity, myelination, and neurotransmitter synthesis, so the demand for iron is particularly high in the brain, the body's most metabolically active organ. However, excess iron, especially in the form of Fe(II), is neurotoxic due to its ability to generate harmful reactive oxygen species (ROS) via the Fenton reaction of the Haber-Weiss cycle, which can cause oxidative damage and lead to cell death. Therefore, iron overload in the brain is an important yet underappreciated factor contributing to neurodegenerative diseases.

[0005] To effectively reverse iron overload in the brain, compounds are needed that enable safe, site-specific transmembrane iron mobilization by maintaining bound iron as Fe(III). Ideally, these molecules would also functionally interact with endogenous iron-binding small molecules and proteins. Currently, iron chelators such as deferasirox (DFX) and deferiprone (DFP) are promising drug candidates for protecting against iron-associated neurodegeneration. However, DFP can cause severe side effects, such as agranulocytosis, arthropathy, gastrointestinal bleeding, ocular / ototoxicity, loss of essential nutrients (zinc and copper), and neurological complications. Furthermore, DFP and other clinically approved iron chelators primarily act by removing iron already released from cells; i.e., they cannot directly transport iron across lipid bilayers. Therefore, their potential for removing iron from neurons and / or their supporting cells is limited.

[0006] As a result, there is a need for new treatments for neurodegenerative diseases that are highly specific, well tolerated, and can serve as useful therapies. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] 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 Summary of the Invention [Means for solving the problem]

[0008] In certain embodiments, the present disclosure provides a method for treating a disease or condition selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, brain iron accumulation neurodegeneration (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, 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, a hinokitiol derivative, and an iron-transporting tropolone.

[0009] In certain embodiments, the present disclosure provides a method for treating a disease or condition selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, brain iron deposition neurodegeneration (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, 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 Formulas (I), (Ia), (Ib), (Ic), (Id), (IIa), (IIb), and (IIc). [ka] [R a But 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, NO, CN, C 1~6 -Alkyl, C 1~6 -haloalkyl, and C 1~6 -substituted with a substituent selected from the group consisting of alkoxy; R b is hydrogen or methyl; with the proviso that the compound is not hinokitiol. [ka] [X represents oxygen or sulfur; R arepresents 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, or heteroalkynyl; R a ' represents hydrogen, halo, alkyl, or substituted alkyl; R b , R c , and R d is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyloxy, substituted cycloalkyloxy, heterocycloalkyloxy, substituted heterocycloalkyloxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, and heteroalkynyl; with the proviso that R a , R b , R c , and R d is not all hydrogen] [ka] [R a 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, or heteroalkynyl; R b , Rc , and R d is 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; with the proviso that R a , R b , R c , and R d is not all hydrogen] [ka] [X represents sulfur or oxygen; R a , R b , R c , and R d independently represent 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 is aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl; provided that R a , R b , R c , and R d is not all hydrogen] [ka] [R a , R b , R c , and R d independently represent 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, or substituted heteroaryl; R b , R c , and R d at least one of is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; However, R a , R b , R c , and R d is not all hydrogen] [ka] [R a 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, or heteroalkynyl; X and Y independently represent O, S, NH, or CR5R6; R2 represents -F, alkyl, haloalkyl, or alkoxy; R5 and R6 each independently represent H, (C1-C15) alkyl, or substituted (C1-C15) alkyl; However, the compound is [ka] But not].

[0010] In certain embodiments, compounds used to treat diseases or conditions characterized by neurodegeneration include pharmaceutically acceptable salts, tautomers, and isomers. The compounds can be administered as a single compound or a combination of compounds, or in combination with one or more chelating agents (examples include deferasirox (DFX) and deferiprone (DFP)). The compounds can be combined with a pharmaceutically acceptable carrier or excipient for systemic, oral, or intravenous administration to a mammal.

[0011] In certain embodiments, the disease or condition is selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, brain iron associated neurodegeneration (NBIA), beta propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, Woodhouse-Sakati syndrome, and idiopathic NBIA.

[0012] In certain embodiments, the disease or condition is selected from the group consisting of vascular dementia, tauopathy, progressive supranuclear palsy, corticobasal degeneration, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, Guam Parkinsonism-Dementia Complex, Pick's disease, and frontotemporal dementia. [Brief explanation of the drawings]

[0013] [Figure 1A] Figure 1 shows the reactivity of various Fe(III)-compound complexes to be reduced to Fe(II) as measured using the Ferrozine assay under reducing conditions. [Figure 1B] Figure 1 shows the generation of ROS in mixtures of Fe(II) with various compounds, measured using the hydroxyl radical probe 2,7-dichlorofluorescein (DCF) dye. [Figure 1C] EPR measurements of Fe(II) alone are shown. [Figure 1D] 1 shows EPR measurements of Fe(II) and hinokitiol. [Figure 2A] The structure of FeM-1269 is shown. [Figure 2B] Particle size measurements using DLS are shown as an indicator of Fe compound aggregation. [Figure 2C] Measured iron efflux from liposomes is shown. [Figure 2D] 1 shows measurements of iron efflux from FPN1-KD Caco-2 cells using hinokitiol and FeM-1269. [Figure 3A] Figure 1 shows the treatment of fpn-1.2KO C. elegans with various compounds for scoring neurodegeneration and measuring iron levels. Figure 2 shows the treatment scheme of fpn-1.2KO;Pdat::GFP worms treated with various concentrations of DFP, Hino, and AMB-1269. Dopaminergic neurodegeneration was scored blindly by phenotypic analysis. [Figure 3B] 1 shows treatment of fpn-1.2KO C. elegans with various compounds for scoring neurodegeneration and measuring iron levels. FIG. 2 shows dopaminergic neurodegeneration scoring of fpn-1.2KO worms treated with DFP. [Figure 3C] 1 shows treatment of fpn-1.2KO C. elegans with various compounds for scoring neurodegeneration and measuring iron levels. FIG. 2 shows dopaminergic neurodegeneration scoring of fpn-1.2KO nematodes treated with Hino. [Figure 3D]1 shows treatment of fpn-1.2KO C. elegans with various compounds for neurodegeneration scoring and iron level measurement. FIG. 2 shows dopaminergic neurodegeneration scoring of fpn-1.2KO nematodes treated with FeM-1269. [Figure 3E] Figure 1 shows the treatment of fpn-1.2KO C. elegans with various compounds for scoring neurodegeneration and measuring iron levels. Figure 2 shows the treatment scheme of fpn-1.2KO;Pftn-1::GFP worms treated with various concentrations of DFP, Hino, and FeM-1269. [Figure 3F] Treatment of fpn-1.2KO C. elegans with various compounds for scoring neurodegeneration and measuring iron levels is shown. ASI neurons expressing GFP-tagged ferritin levels and fluorescence levels in fpn-1.2KO worms treated with DFP (bottom) are shown. *P<0.05, **P<0.01, *** [Figure 3G] Treatment of fpn-1.2KO C. elegans with various compounds for scoring neurodegeneration and measuring iron levels is shown. The ASI neurons expressing GFP-tagged ferritin levels and fluorescence levels of fpn-1.2KO worms treated with Hino (bottom) are shown. *P<0.05, **P<0.01, *** [Figure 3H] Treatment of fpn-1.2KO C. elegans with various compounds for scoring neurodegeneration and measuring iron levels is shown. ASI neurons expressing GFP-tagged ferritin levels and fluorescence levels in fpn-1.2KO worms treated with FeM-1269 (bottom) are shown. *P<0.05, **P<0.01, *** [Figure 4A] Figure 1 shows flatiron mice exhibiting increased anxiety and decreased exploratory activity. WT and flatiron mice were subjected to the elevated plus maze test to assess anxiety-like behavior. Total distance traveled and average speed throughout the maze are shown. [Figure 4B]Figure 1 shows flatiron mice exhibiting increased anxiety and decreased exploratory activity. WT and flatiron mice were subjected to the elevated plus maze test to assess anxiety-like behavior. Time spent in the open arms and central area is shown. [Figure 4C] Flatiron mice exhibiting increased anxiety and decreased exploratory activity are shown. WT and flatiron mice were subjected to the elevated plus maze test for the assessment of anxiety-like behavior. Rearing frequency and duration are shown. *P<0.05 by Student's t-test. [Figure 4D] Figure 1 shows flatiron mice exhibiting increased anxiety and decreased exploratory activity. WT and flatiron mice were subjected to the elevated plus-maze test for assessment of anxiety-like behavior. Figure 2 shows ICP-MS measurements of brain iron levels in flatiron mice after acute treatment with Hino via intraperitoneal (IP) injection. [Figure 4E] Flatiron mice exhibiting increased anxiety and decreased exploratory activity are shown. WT and flatiron mice were subjected to the elevated plus-maze test to assess anxiety-like behavior. ICP-MS measurements of brain iron levels in flatiron mice after chronic treatment with Hino via intraperitoneal (IP) injection are shown. **P<0.01, ***P<0.001 by one-way ANOVA. [Figure 5A] Schematic representation of the ceruloplasmin phenotype of wild-type cells. [Figure 5B] FIG. 1 shows a schematic representation of the aceruloplasminemic phenotype of cells. [Figure 5C] FIG. 1 shows a schematic diagram of iron oxidation by hinokitiol and restoration of iron homeostasis in cells with an aceruloplasminemia phenotype. [Figure 6A] The cyclic voltammogram of Fe(Hino)3 is shown. [Figure 6B] Cyclic voltammograms for various Fe:Hino ratios are shown. [Figure 7A] 1 shows EPR measurements of the oxidation of Fe(II) promoted by hinokitiol. [Figure 7B]1 shows EPR measurements of Fe(II) oxidation promoted by FeM-1269. [Figure 8A] A schematic diagram of iron transfer between Fe(Hino)3 and transferrin is shown. [Figure 8B] Western blot of transferrin in the presence of increasing concentrations of Fe(Hino)3 is shown. [Figure 8C] Kinetics of iron transfer between Fe(Hino)3 and transferrin. [Figure 9] A colorimetric assay is shown that measures the percent conversion of Fe(III) to Fe(II) in the presence of a strong reducing agent. [Figure 10] A fluorometric assay is shown to measure the amount of reactive oxygen species (ROS) produced in the Fe(II)-catalyzed Fenton reaction. [Figure 11A] 1 shows measurements of dopamine oxidation in vitro in the presence of hinokitiol and Fe(II) or deferiprone (DFP) and Fe(II). [Figure 11B] Measurement of dopamine oxidation in fpn1.2KO C. elegans at day 5 after treatment with hinokitiol or deferiprone (DFP) is shown. [Figure 12A] 1 shows the amount of dopamine remaining after Fe(II)-catalyzed oxidation in the presence of hinokitiol and FeM-1269. [Figure 12B] 1 shows the amount of dopaminochrome (DAC) produced after Fe(II)-catalyzed oxidation in the presence of hinokitiol and FeM-1269. [Figure 13] A plot of absorbance versus concentration is shown for DAC versus peak area after quenching with glutathione. [Figure 14] The percent conversion of Fe(III) precomplexed with hinokitiol or dopamine to Fe(II) is shown versus time. DETAILED DESCRIPTION OF THE INVENTION

[0014] definition 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. Furthermore, to the extent that "including," "includes," "having," "has," "with," or variations thereof are used in any of the detailed description and / or claims, such terms are intended to be inclusive in the same manner as the term "comprising."

[0015] The term "about" or "approximately" means within an acceptable error range for a particular value 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.

[0016] "Acyl" is a term, as used herein, that 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.

[0017] As used herein, the term "administering" refers to the administration of a compound, which may be provided by oral, intralesional, intraperitoneal, intramuscular, or intravenous injection; infusion; liposome-mediated delivery; or topical, nasal, anal, vaginal, sublingual, urethral, ​​transdermal, intrathecal, ocular, or otic delivery. To achieve consistency in providing the compounds of the present invention, the compounds are preferably in unit dose 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 a compound of the present invention. Even more preferred unit dosage forms contain 5 to 50 mg of a compound of the present invention. The compounds of the present invention may be administered orally in a dose range of approximately 0.01 to 100 mg / kg, or preferably 0.1 to 10 mg / kg. Such compounds may be administered 1 to 6 times daily, more typically 1 to 4 times daily. Effective amounts are known to those skilled in the art and will also depend on the form of the compound. Those skilled in the art can routinely carry out empirical activity tests to determine the biological activity of the compound in bioassays, and thereby determine the dosage.The compound can also be delivered locally via a capsule that allows the compound to be released sustainedly over a period of time.Controlled release or sustained release compositions include formulations in lipophilic depots (e.g., fatty acids, waxes, oils).

[0018] The terms "alkenyl" or "alkenyl group" mean a group formed by removing a hydrogen from a carbon of an alkene, where the alkene is an acyclic or cyclic compound consisting solely of hydrogen and carbon atoms and containing at least one carbon-carbon double bond. An alkenyl group may contain one or more substituents.

[0019] The term "alkoxy" or "alkoxy group," as used herein, means an alkyl group, as defined herein, appended to the 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, pentyloxy, and hexyloxy. The terms "alkenyloxy," "alkynyloxy," "carbocyclyloxy," and "heterocyclyloxy" are similarly defined.

[0020] The term "alkyl," as used herein, is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl group has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), alternatively about 20 or fewer carbon atoms. In one embodiment, the term "alkyl" refers to a C1-C10 straight-chain alkyl group. In one embodiment, the term "alkyl" refers to a C1-C6 straight-chain alkyl group. In one embodiment, the term "alkyl" refers to a C3-C12 branched-chain alkyl group. In one embodiment, the term "alkyl" refers to a C3-C8 branched-chain alkyl group. Cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, alternatively about 5, 6, or 7 carbon atoms in the ring structure.

[0021] The term "alkylene" is art-recognized and, as used herein, refers to a diradical obtained by removing two hydrogen atoms from 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, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, and the like. That is, in one embodiment, a "substituted alkyl" is an "alkylene."

[0022] The term "alkylthio" as used herein refers to alkyl-S-.

[0023] The term "alkynyl," as used herein, refers to a straight- or branched-chain hydrocarbon radical 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, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0024] The term "amino" is a term of art and, as used herein, refers to both unsubstituted and substituted amines, such as those of the general formula: [ka] [In the formula, R a , R b , and R c are each independently hydrogen, alkyl, alkenyl, -(CH2) x -R d or R a and R btogether with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure; Rd represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl; and x is zero or an integer ranging from 1 to 8. In certain embodiments, R a or R b Only one of R a , R b and nitrogen together do not form an imide. a and R b are each independently hydrogen, alkyl, alkenyl, or -(CH2) x -R d In one embodiment, the term "amino" refers to -NH2.

[0025] The term "aminoacyl" is a term of art and, as used herein, refers to an acyl group substituted with one or more amino groups.

[0026] The term "aminoalkyl," as used herein, refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term "aminoalkyl" refers to an aminomethyl group.

[0027] The term "aminothionyl" as used herein refers to the analog of aminoacyl in which the O of RC(O)-- is replaced by sulfur, hence the form RC(S)--.

[0028] The term "aralkyl" or "arylalkyl" is a term of art and, as used herein, refers to an alkyl group substituted with an aryl group.

[0029] The term "aryl" is a term of art and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic hydrocarbon groups, including, for example, benzene, naphthalene, anthracene, and pyrene. The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, and the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (the rings are "fused rings"), where at least one of the rings is aromatic hydrocarbon, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. In one embodiment, the term "aryl" refers to a phenyl group.

[0030] The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0031] The term "carbocyclyl," as used herein, means a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon group containing 3 to 12 carbon atoms that is fully saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of 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.

[0032] The term "carbonyl" as used herein refers to -C(O)-.

[0033] 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 silica, and urea. In addition, auxiliary agents, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may also be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin, which is incorporated herein by reference in its entirety.

[0034] As used herein, the term "chelator" refers to a small molecule that binds very tightly to metal ions.

[0035] The term "cyano" is a term of art and as used herein refers to --CN.

[0036] The term "cycloalkylalkyl," as used herein, refers to an alkyl group substituted with one or more cycloalkyl groups.

[0037] As used herein, the term "effective amount" refers to an amount sufficient to produce a desired biological effect.

[0038] As used herein, the term "ferroportin" (FPN1) refers to the only known cellular iron transporter, which facilitates the transport of iron (ferrous iron) from storage and absorptive cells, including hepatocytes, macrophages in the liver and spleen, and intestinal epithelial cells, into the blood.

[0039] As used herein, the term "fluoroalkyl" refers to an alkyl group, as defined herein, in which some or all of the hydrogens have been replaced with fluorine.

[0040] The term "halo" is a term of art and, as used herein, refers to -F, -Cl, -Br, or -I.

[0041] The term "heteroalkyl group" means a group formed by removing a hydrogen from a carbon of a heteroalkane, where the heteroalkane is an acyclic or cyclic compound consisting solely of hydrogen atoms, saturated carbon atoms, and one or more heteroatoms. A heteroalkyl group may contain one or more substituents.

[0042] The terms "heteroaralkyl" or "heteroarylalkyl" are terms of art and, as used herein, refer to an alkyl group substituted with a heteroaryl group.

[0043] The term "heteroaryl" is a term of art and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic groups having one or more heteroatoms in the ring structure, such as pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. A "heteroaryl" may be optionally substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, and the like. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (the rings are "fused rings"), where at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl.

[0044] The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0045] The term "heteroatom" is art-recognized and includes atoms of any element other than carbon or hydrogen. Exemplary heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium, or are oxygen, nitrogen, or sulfur.

[0046] The term "heterocyclyl," as used herein, refers to radicals of non-aromatic ring systems, including but not limited to monocyclic, bicyclic, and tricyclic rings, which may be fully saturated or which contain one or more units of unsaturation, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, having from 3 to 12 atoms including at least one heteroatom, e.g., nitrogen, oxygen, or sulfur. For illustrative purposes, and not to be construed as limiting the scope of the invention, examples of heterocycles are listed below: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, azetyl, oxetanyl, oxetyl, thietanyl, thiethyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl, furyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl, tetrazolyl. , pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, indolyl, benzotriazolyl, naphthyridinyl, azepine, azetidinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl, and tetrahydrofuranyl.

[0047] The term "heterocycloalkylalkyl," as used herein, refers to an alkyl group substituted with one or more heterocycloalkyl (ie, heterocyclyl) groups.

[0048] The term "hydroxy" is a term of art and as used herein refers to --OH.

[0049] As used herein, the term "inhibit" refers to a reduction in an objectively measurable amount or extent. In various embodiments, "inhibit" refers to a reduction of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to a relevant control. In one embodiment, "inhibit" refers to a 100 percent reduction, i.e., cessation or elimination.

[0050] As used herein, the term "neurodegeneration associated with brain iron deposition" or "NBIA" has its common meaning in the art and refers to a group of rare inherited neurological disorders characterized by abnormal accumulation of iron in the basal ganglia. The characteristic clinical symptoms of NBIA are related to physical muscle function and are characterized by progressive movement disorders including dystonia, choreoathetosis, stiffness of the arms and legs, and parkinsonism. Most forms of NBIA are accompanied by eye disease. The most common problems are retinal degeneration and optic nerve atrophy. Generalized loss of brain cells and tissue is also frequently observed, a condition referred to as cerebral and cerebellar atrophy. Onset of NBIA ranges from infancy to adulthood. Progression can be rapid or slow with long periods of stability. In some embodiments, the NBIA is caused by a disease gene selected from PANK2, PLA2G6, COASY, FA2H, ATP13A2, C2orf37, WDR45, C19ORFf12, CP, FTL, GTPBP2, CRAT, and REPS1. In some embodiments, the NBIA is beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, Woodhouse-Sakati syndrome, and idiopathic NBIA. Subtypes of NBIA are "beta-propeller protein-associated neurodegeneration" and pantothenate kinase-associated neurodegeneration (PKAN).

[0051] As used herein, the term "pharmaceutically acceptable salt" includes salts derived from inorganic or organic acids, including, for example, 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 salt-containing molecules is not 1:1. For example, a salt may contain multiple inorganic or organic acid molecules per molecule of base, such as two hydrochloric acid molecules per molecule of a compound of Formula Ia or Ib. As another example, a salt may contain less than one inorganic or organic acid molecule per molecule of base, such as two molecules of a compound of Formula Ia or Ib per molecule of tartaric acid.

[0052] As used herein, the term "subject" refers to a mammal. In various embodiments, the subject is a mammal, including a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, the subject is a human.

[0053] It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the allowed valence of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

[0054] The term "substituted" is also contemplated to include all permissible substituents of organic compounds. Broadly speaking, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and 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 the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0055] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce a desired therapeutic effect.

[0056] The term "thiocarbonyl" as used herein refers to -C(S)-.

[0057] As used herein, the term "treating" means preventing, halting or slowing the progression of, or eliminating a disease or condition in a subject. In one embodiment, "treating" means halting or slowing the progression of, or eliminating a disease or condition in a subject. In one embodiment, "treating" means reducing at least one objective manifestation of a disease or condition in a subject.

[0058] Certain compounds contained in the compositions of the present disclosure may exist in particular geometric or stereoisomeric forms. In addition, the compounds of the present disclosure may also be optically active. The present disclosure contemplates that all such compounds are within the scope of the present invention, including cis and trans isomers, (R) and (S) enantiomers, diastereoisomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present disclosure.

[0059] For example, if a particular enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by separation of the diastereomers so formed by fractional crystallization or chromatographic techniques well known in the art, followed by recovery of the pure enantiomers.

[0060] For purposes of this disclosure, chemical elements are identified according to the CAS version of the Periodic Table of the Elements, found inside the cover of the Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0061] Other chemical terms herein are used in accordance with conventional usage in the art as exemplified by The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco (incorporated herein by reference). Unless otherwise defined, 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.

[0062] compound 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 of either. [ka] [R a But 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, NO, CN, C 1~6 -Alkyl, C 1~6 -haloalkyl, and C 1~6 -substituted with a substituent selected from the group consisting of alkoxy; R b is hydrogen or methyl; with the proviso that the compound is not hinokitiol. [ka] [X represents oxygen or sulfur; R arepresents 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, or heteroalkynyl; R a ' represents hydrogen, halo, alkyl, or substituted alkyl; R b , R c , and R d is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyloxy, substituted cycloalkyloxy, heterocycloalkyloxy, substituted heterocycloalkyloxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, and heteroalkynyl; with the proviso that R a , R b , R c , and R d But not all hydrogen; R a ' is hydrogen or R a ' is a halo or R a ' is alkyl or substituted alkyl; R a , R b , R c , and R dat least one of is selected from the group consisting of halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyloxy, substituted cycloalkyloxy, heterocycloalkyloxy, substituted heterocycloalkyloxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl; 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. [ka] [R a 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, or heteroalkynyl; R b , R c , and R d is 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; with the proviso that R a , R b , R c , and R d is not all hydrogen] [ka] [X represents sulfur or oxygen; R a , R b , R c , and R d independently represent 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 is aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl; provided that R a , R b , R c , and R d is not all hydrogen] [ka] [R a , R b , R c , and R dindependently represent 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, or substituted heteroaryl; R b , R c , and R d at least one of is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; However, R a , R b , R c , and R d are not all hydrogen] or [ka] [R a 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, or heteroalkynyl; X and Y independently represent O, S, NH, or CR5R6; R2 represents -F, alkyl, haloalkyl, or alkoxy; R5 and R6 each independently represent H, (C1-C15) alkyl, or substituted (C1-C15) alkyl; However, the compound is [ka] But not].

[0063] In certain embodiments, the compound is [ka] is selected from.

[0064] In certain embodiments, the compound is [ka] is selected from.

[0065] In certain embodiments, the compound is [ka] is selected from.

[0066] In certain embodiments, the compound is [ka] is selected from.

[0067] In certain embodiments, the compound is [ka] is selected from.

[0068] In certain embodiments, the compound is [ka] is selected from.

[0069] In certain embodiments, the compound is [ka] is selected from.

[0070] In certain embodiments, the compound is [ka] is selected from.

[0071] In certain embodiments, the compound is [ka] is selected from.

[0072] In certain embodiments, the compound is [ka] [ka] is selected from.

[0073] In certain embodiments, the compound is [ka] is selected from.

[0074] In certain embodiments, the compound is [ka] is selected from.

[0075] In certain embodiments, the compound is [ka] is selected from.

[0076] In certain embodiments, the compound is [ka] is selected from.

[0077] In certain embodiments, the compound is [ka] is selected from.

[0078] In certain embodiments, the compound is [ka] is selected from.

[0079] In certain embodiments, the compound is [ka] is selected from.

[0080] In certain embodiments, the compound is [ka] is selected from.

[0081] In certain embodiments, the compound is [ka] is selected from.

[0082] In certain embodiments, the compound is [ka] is selected from.

[0083] In certain embodiments, the compound is [ka] is selected from.

[0084] In certain embodiments, the compound is [ka] is selected from.

[0085] In certain embodiments, the compound is [ka] is selected from.

[0086] In certain embodiments, the compound is [ka] is selected from.

[0087] In certain embodiments, the compound is [ka] is selected from.

[0088] In certain embodiments, the compound is [ka] is selected from.

[0089] In certain embodiments, the compound is [ka] is selected from.

[0090] In certain embodiments, the compound is [ka] [ka] [ka] [ka] is selected from.

[0091] In certain embodiments, the compound is [ka] is selected from.

[0092] In certain embodiments, the compound is [ka] is selected from.

[0093] In certain embodiments, the compound is [ka] is selected from.

[0094] In certain embodiments, the compound is [ka] [ka] is selected from.

[0095] In certain embodiments, the compound is [ka] [ka] is selected from.

[0096] In certain embodiments, the compound is [ka] [ka] is selected from.

[0097] In certain embodiments, the compound is [ka] [ka] [ka] is selected from.

[0098] In certain embodiments, the compound is [ka] is.

[0099] In certain embodiments, the compound is [ka] is.

[0100] In certain embodiments, the compound is [ka] is.

[0101] In certain embodiments, the compound is [ka] is.

[0102] In certain embodiments, the compound is [ka] is.

[0103] In certain embodiments, the compound is [ka] is.

[0104] In certain embodiments, the compound is [ka] is.

[0105] In certain embodiments, the compound is [ka] is.

[0106] In certain embodiments, the compound is [ka] is.

[0107] In certain embodiments, the compound is [ka] is.

[0108] In certain embodiments, the compound is [ka] is.

[0109] Treatment of neurodegenerative diseases Aceruloplasminemia is a rare autosomal recessive disorder caused by mutations in the gene encoding ceruloplasmin (Cp), resulting in a missing or inactive multicopper oxidase glycoprotein. Without this protein, iron(II) cannot be oxidized to iron(III) and cannot bind to transferrin. This ultimately reduces holotransferrin, which is involved in the circulation of iron throughout the body, leading to increased intracellular iron. Our EPR results demonstrate that hinokitiol and FeM-1269 can mimic ferroxidase activity by promoting the oxidation of Fe(II) to Fe(III). Furthermore, we have also shown that hinokitiol's ability to transfer iron to transferrin allows for the maintenance of system homeostasis. We have also shown that hinokitiol-bound Fe(III) can attenuate the pro-neurodegenerative Fenton reaction. Collectively, these observations support the use of Hino, FeM-1269, and other similarly acting tropolones as molecular prosthetics of ceruloplasmin to restore ferroxidase activity, resulting in increased holo-transferrin levels and increased iron(III) levels, leading to systemic iron restoration. In certain embodiments, brain iron and holo-transferrin concentrations before and after treatment with hinokitiol can be examined in ceruloplasmin knockout mice (CpKO). In further embodiments, iron(III) concentrations in blood and plasma samples from ceruloplasmin knockout mice (CpKO) can be measured by ICP-MS coupled with EPR.

[0110] In certain embodiments, holo-transferrin production can be measured using a gel shift assay, which can separate apo-transferrin from holo-transferrin and indicate iron loading into the protein. In certain embodiments, recovery of iron(III) concentration can be measured with cellular assays using ceruloplasmin knockout, iron-specific binding dyes, and / or ICP-MS combined with EPR. In further embodiments, intracellular oxidative stress can be monitored by QT-PCR using ROS-specific primers.

[0111] Treatment of neurodegenerative diseases involves administering any one of the compounds disclosed herein to a mammal in need thereof. One skilled in the art would administer the compound in a manner consistent with the mammal's medical history. Diseases or conditions to be treated include, but are not limited to, inflammatory diseases leading to abnormal suppression of ferroportin production, neurodegeneration associated with brain iron deposition (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, Woodhouse-Sakati syndrome, idiopathic NBIA, vascular dementia, tauopathy, progressive supranuclear palsy, corticobasal degeneration, subacute sclerosing panencephalitis parkinsonism, postencephalitic parkinsonism, Guam Parkinsonism-dementia complex, Pick's disease, and frontotemporal dementia. [Example]

[0112] The present disclosure, having been generally described herein, 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 present disclosure and is not intended to limit the present disclosure.

[0113] Example 1 - Effect of Hinokitiol on Dopamine Oxidation To measure the ability of hinokitiol as a "safe passage" for iron mobilization from neurons, the reactivity of Fe(III) complexed with dopamine, DFP, and hinokitiol was measured using the ferrozine assay and described (33). Iron(III) was precomplexed with either dopamine, hinokitiol, or DFP in HEPES buffer, then added to a 96-well plate containing ferrozine and a reducing agent, and absorbance at 562 nm was monitored using a plate reader. When Fe(III) was complexed with dopamine and DFP, robust conversion to Fe(II) was observed under reducing conditions, whereas complexation with hinokitiol significantly reduced Fe(III) conversion (Figure 1A). Using a similar method, using the ROS probe 2,7-dichlorofluorescein (DCF), it was shown that Fe(II)-induced ROS production was significantly reduced in the presence of hinokitiol compared to dopamine and DFP (Figure 1B). The ability of hinokitiol to autoxidize Fe(II) was assessed by detecting the iron species generated by the binding of hinokitiol to Fe(II) using electron paramagnetic resonance (EPR). A signal at g' = 4.3 was observed when Fe(II) was bound by hinokitiol (Figure 1D), suggesting the presence of a high-spin Fe(III)-Hino complex with an octahedral structure. This peak was not observed when Fe(II) alone was present (Figure 1C), suggesting that Fe(II) was not spontaneously oxidized during the measurements. In vitro data also demonstrated that the iron was converted to Fe 3+ This shows that hinokitiol is superior to DFP in maintaining the Fe(II) as a marker. To perform this assay, a solution of iron(II) was prepared with a reducing agent in degassed 1:1 MeOH:HO. After acquiring the Fe(II) spectrum at 77 K, the solution was warmed to room temperature and hinokitiol was added at a concentration of 3:1. A spectrum was acquired in which a g' value of 4.3 was observed.

[0114] A more effective and less toxic derivative, FeM-1269 (Figure 2A), aggregated less than hinokitiol (Figure 2B) and was able to deliver iron over a wider concentration range compared to hinokitiol in liposomes (Figure 2C) and Caco-2 cells (Figure 2D).

[0115] To examine dopamine oxidation and ROS production, we used the fluorescent probe 2,7-dichlorofluorescein (DCF). Dopamine was precomplexed with Fe(II) and monitored for 1 hour using a plate reader. After the addition of small molecules such as Hino or DFP, we found evidence that hinokitiol attenuated dopamine oxidation (Figure 11A). To further investigate this, FPN1.2KO C. elegans were plated on NGM plates seeded with OP50 at the L4 stage, grown until day 4, treated with the small molecules Hino or DFP, and then harvested and homogenized on day 5. ROS was detected using lysates in 96-well plates containing 2,7-dichlorofluorescein (DCF). Hinokitiol was able to restore wild-type levels of ROS in vivo (Figure 11B).

[0116] To monitor dopamine oxidation, we developed an in vitro assay using LC-MS by monitoring dopamine concentration via mass spectrometry hits. 100 μM dopamine samples were prepared and then treated with either control, hino, or FeM-1269. Evidence was obtained that both hino and FeM-1269 attenuated dopamine oxidation (Figure 12A). This was further monitored by LC-MS to confirm the concentration of DAC produced in the same process. Similarly, hino and FeM-1269 reduced the amount of dopamine oxidized to form DAC (Figure 12B). To measure the linearity of the quantitative assay, peak intensities were plotted against increasing DAC concentrations, yielding an R value of 0.9738.

[0117] Finally, to measure the affinity of the complexation, small molecules were precomplexed with iron(III) and then introduced into a plate reader along with a strong reducing agent and ferrozine dye to measure the affinity of the complex. Hino has a strong affinity for binding to Fe(III), whereas the dopamine control does not bind to Fe(II) as strongly (Figure 14).

[0118] Example 2 - Effects of Hinokitiol in a C. elegans Neurodegeneration Model The ability of hinokitiol and FeM-1269 to confer neuroprotection. To recapitulate NBIA, an fpn-1.2KO C. elegans line was generated using CRISPR / Cas9-mediated knockout and then crossed with a Pdat::GFP line to generate an fpn-1.2KO line with GFP-tagged dopaminergic neurons (fpn-1.2KO;Pdat::GFP). The genotype of the line was confirmed by genotyping PCR and Sanger sequencing. All lines used were backcrossed to N2 at least three times. To treat C. elegans with small molecules, day 4 adult worms were transferred to NGM containing the small molecules. The worms were transferred to freshly seeded NGM containing the small molecules, and on day 7, the worms were imaged using a confocal microscope with GFP fluorescence. Scoring was performed in a blinded experiment, where the integrity of dopaminergic neurons was observed to reflect neurodegeneration. This mutant line exhibited dopaminergic neurodegeneration (Figure 3B-D) and elevated neuronal ferritin levels, an indicator of intracellular iron levels (Figure 3F-H). Using a specific treatment scheme (Figure 3A) and reported neurodegeneration scoring methods (35, 36), DFP was found to have no neuroprotective effect at all administered concentrations (Figure 3B), whereas hinokitiol demonstrated efficacy at low concentrations (0.05-0.1 μM) (Figure 3C). Interestingly, FeM-1269 demonstrated efficacy at concentrations as low as 0.05 μM and at its highest concentration (25 μM) (Figure 3D). These results suggest that hinokitiol and FeM-1269, and more broadly, iron-transporting tropolones, may have the potential to treat neurodegenerative disorders. FeM-1269, a hinokitiol derivative, may have the potential to increase the therapeutic index of hinokitiol. To further correlate the neuroprotective effect with iron mobilization, we generated the fpn-1.2KO line with GFP-tagged ferritin (ftn-1) and measured iron levels in representative ASI neurons (Figure 3E). Consistent with Figure 1B, DFP failed to reduce the fluorescence level at any dose (Figure 3F), suggesting 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 at concentrations of 0.1 μM and 0.05 μM, respectively, strongly reduced the fluorescence level (Figure 3G-H), 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.

[0119] Example 3 - Effects of Hinokitiol in the Flatiron Mouse Neurodegeneration Model In parallel with C. elegans, we used flatiron mice, a key animal model of FPN1 deficiency due to the H32R mutation in FPN1 (34, 35). These mice were subjected to ICP-MS and behavioral testing, and blood samples and tissues were collected and analyzed. Furthermore, behavior was assessed by the elevated plus maze, search maze, and daily monitoring. Due to the accumulation of iron in the brain (Figure 3D-E), these mice exhibited elevated anxiety levels (Figure 4A-C). To determine dose-dependence, these mice were subjected to a single IP injection to assess acute administration, followed by chronic treatment with IP injections of 10 mg / kg for 1 week. Acute administration of hinokitiol dose-dependently reduced brain iron levels (Figure 4D). Similar effects were observed after chronic administration of 10 mg / kg hinokitiol 7 days later (Figure 4E). Collectively, these data sets suggest that hinokitiol has the ability to cross the blood-brain barrier and mobilize accumulated iron in the brain of flatiron mice.

[0120] Example 4 - Cyclic voltammetry of hinokitiol-iron complex The redox potential decreased with increasing hinokitiol concentration. These were acquired at a scan rate of 100 mV / s using a Hg electrode, an Ag / AgCl reference electrode, and a graphite auxiliary electrode, with 0.1 M Tris buffer and 100 μM Fe(NO) in 1:1 MeOH:HO at pH 7.2. Data from these experiments are shown in Figures 6A-6B.

[0121] Example 5 - EPR of Hinokitiol-Iron Complex To perform this assay, a solution of iron(II) was prepared with a reducing agent in degassed 1:1 MeOH:HO. After acquiring the Fe(II) spectrum at 77 K, the solution was warmed to room temperature and hinokitiol was added at a concentration of 3:1. A spectrum was acquired in which a g' value of 4.3 was observed. The data from these experiments are shown in Figures 7A-7B.

[0122] Example 6 - Kinetics of transferrin-hinokitiol iron transfer In kinetic experiments, 4 μM human apo-Tf was incubated with 64 μM Fe(Hino)3 complex. The reaction was stopped at several time points using sample buffer. Samples were run using the same conditions as above. After electrophoresis, 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 band density using ImageLab 4.1 (Bio-Rad) and expressed as a function of molar fraction. Data from these experiments are shown in Figure 8B-C.

[0123] Example 7 - Colorimetric / fluorimetric iron(II) conversion assay Colorimetric assay: Small molecules were precomplexed with Fe(III) in 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 was then added to the wells, and the absorbance at 562 nm was reported over several hours.

[0124] Fluorometric assay: Solutions of iron(II) and iron(III) were freshly prepared and placed in a 96-well plate compatible with a plate reader. The ROS dye 2,7-dichlorofluorescein (DCF) was then added to the plate, and fluorescence monitoring at 488 nm was observed. Data from these experiments are shown in Figures 9 and 10.

[0125] Example 8 - Synthesis and characterization of compounds of the present disclosure The compounds of the present disclosure have been previously synthesized and characterized, see, e.g., WO2021 / 076938 (PCT / US2020 / 056048), WO2021 / 076945 (PCT / US2020 / 056056), and US2021 / 0163393 (USSN 17 / 046,608), the contents of each of which are expressly incorporated herein by reference.

[0126] Example 9 - Ligand-facilitated Fe(III) efflux assay from liposomes Preparation of POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine):cholesterol liposomes : A 1M buffer of MES and Tris was prepared by dissolving 121.14 grams of Tris base and 213.25 grams of MES hydrate in 500 mL of MilliQ water, adjusting the pH to 7.0 with 18 M HCl solution, and bringing the total volume of the solution to 1 L. A 500 mM solution of FeCl3 was prepared by dissolving 0.811 grams of anhydrous FeCl3 in 10 mL of 0.1 M aqueous H2SO4. The internal buffer was prepared in a 50 mL Falcon tube by combining 25 mL of MilliQ water, 1.61 g of sodium citrate, 1.5 mL of the above FeCl3 solution, and 2.5 mL of 1 M MES / Tris HCl buffer (pH = 7.0), and finally adding additional MilliQ HO to a final volume of 50 mL. The prepared internal buffer solution contains final concentrations of 15 mM FeCl3, 125 mM sodium citrate, and 50 mM MES / Tris HCl, pH 7.0.

[0127] A lipid solution is 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.

[0128] The lipid solution and inner buffer were independently loaded into 10 mL Luer-Lock syringes and loaded into a fresh cartridge on a Precision Nanosystems NanoAssembler to prepare unilamellar liposomes using the following parameters: total volume 7.5 mL, inner buffer:lipid solution ratio 1.5:1, flow rate 8 mL / min, ambient temperature, initial waste volume 0.35 mL, and final waste volume 0.05 mL. 7.5 mL of liposomes were collected and purified on a 6-inch long, 1-inch diameter Sephadex G-50 column pre-wetted with 600 mM sodium ascorbate and 50 mM MES / Tris HCl pH 7.0 buffer. This buffer also served as the column running buffer. The crude liposome solution was carefully loaded onto the top of the Sephadex with a minimal amount of running buffer to allow it to penetrate the matrix, and the column was operated by continuously adding running buffer. The eluted liposomes, observed as a milky, cloudy solution, are collected until free iron begins to elute (observed as a deep purple color), and the fractions are pooled for phosphorus quantification.

[0129] Determination of phosphorus content : The phosphorus content of the eluted liposomes was measured using the process outlined below. 10 μL of liposome eluate and a running buffer blank were added to a 5 mL glass vial containing 450 μL of 8.9 M aqueous H2SO4, and the mixture was heated to 225 °C for 25 minutes in an aluminum heat block to hydrolyze the POPC, followed by 5 minutes of cooling. 200 μL of 30% aqueous hydrogen peroxide was added to each vial and heated to 225 °C for 25 minutes. After cooling, the phosphorus content was measured using an Abcam phosphate assay kit, where buffer-subtracted phosphorus levels were measured against a phosphate standard curve included in the kit. Liposomes were diluted to 1 mM phosphate in running buffer for use in the assay, accounting for the dilution that occurred during phospholipid digestion.

[0130] Determination of the iron transport rate constant of the ligand : The rate at which small molecule ligands release (transport) ferric iron from liposomes was determined in a black, clear-bottom 384-well plate using a Spectramax i3x in kinetics mode, set to read absorbance at 562 nm every 60 seconds for 120 minutes. 1 μL of serially diluted DMSO stock solutions of small molecule ligands were added to triplicate wells to obtain final concentrations of 40, 20, 10, 5, 2.5, and 1.25 μM ligand in a final volume of 80 μL. Then, 1 μL of 100 mM aqueous Ferrozine solution was added to obtain a final concentration of 1 mM Ferrozine. 78 μL of liposomes diluted to 1 mM phosphate in running buffer were added to the wells as quickly as possible (using a digital repeater multichannel pipette). After liposomes were added to all wells, kinetic readings were initiated as quickly as possible. Typically, eight compounds were tested in triplicate at six concentrations.

[0131] Once the kinetic readings are complete, the individual readings are calculated using the formula Y = (Y - Y Max ) (-kX) +Y Max (Y is the absorbance value at 562 and X is time in minutes) are fitted to a single phase association regression. The k values ​​from the individual replicates are averaged from the triplicate determinations for each compound concentration. The ability of a ligand to liberate iron from within the liposomes is represented by the rate k at a given concentration. The rate k is considered as the efflux rate, and ligands are ranked by the efflux rate at a 10 μM ligand concentration that results in efflux of ferric iron.

[0132] Example 10 - shDMT1-Caco2 to evaluate the ability of ligands to transport Fe(III) 55 Fe transport assay Materials and Methods : Cells: DMT1-deficient Caco-2 cells (also known as "shDMT1" or "4A" cells) were from Grillo et al. Science, 2017 and were cryopreserved in liquid nitrogen before use.

[0133] Reagents and consumables: 55FeCl3 was obtained from PerkinElmer (Boston, MA). Iron(III) chloride (FeCl3) hexahydrate was obtained from Sigma. Dulbecco's modified Eagle's 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 carbutamide were obtained from Sigma-Aldrich Chemical Company (St Louis, MO). Scintillation cocktail was obtained from Research Products International Co. (Mount Prospect, IL). Stericup filter systems (PES membrane, 0.22 μm pore size) were purchased from Fisher Scientific. Corning item number 3378 24-well Transwell insert plates.

[0134] Test articles: The known compounds hinokitiol and deferiprone were purchased from Sigma. They will be tested in parallel with the small molecule ligands disclosed in this application. DMSO stocks (10 mM, which is 1,000 times the 10 μM dose level) of hinokitiol or test article were prepared. A 25 mM stock solution of deferiprone in DMSO was prepared. The DMSO stock solution was stored at -20°C or below between uses.

[0135] Growth medium was prepared according to the table below. Apical medium (serum-free DMEM, 10 mM MES, pH 6.5) was prepared. The apical master mix medium was prepared by adding 200 nM of 55 Freshly prepared with Fe added. For negative control propranolol and atenolol wells, 200 nM non-radioactive iron was used.

[0136] The basolateral medium was serum-free DMEM, 10 mM HEPES, 2% bovine serum albumin (BSA), pH 7.4.

[0137] For each experiment, cells were seeded into 24-well Transwell plates (0.5 mL, 50,000 cells / mL) with growth medium. The basolateral counterpart was loaded with 1 mL of growth medium. After 12–24 h, both the apical and basolateral chambers were replaced with growth medium. The apical medium was replaced three times a week for 21–28 days, including a medium change just 48 h before the assay day.

[0138] TEER values ​​were measured on the day of the assay, and an average TEER value was obtained. Individual wells with TEER values ​​>35% lower than the average of all wells were excluded. For eligible wells, the apical (twice) and basolateral (once) chambers were washed with PBS. The basolateral counterpart plate was then filled with 1 mL of basolateral medium. 300 μL of apical assay master mix containing the indicated dose level of test article was added per well by adding it down the side of the apical well. Each dose was tested in triplicate. The plate was incubated (37°C, 5% CO2, and 90% humidity) until the indicated time points. At each indicated time point, the basolateral supernatant was gently mixed by pipetting, and 200 μL of the basolateral supernatant was transferred to a scintillation vial. 5 mL of scintillation cocktail was added to each scintillation counting vial. Radioactivity (CPM) for each scintillation vial was measured using an LS6500 liquid scintillation counter. The counting time per vial was 5 minutes.

[0139] Data Processing : All raw CPM values ​​were divided by the mean value of the blank DMSO solution to obtain the fold change above the DMSO value. The mean and standard deviation of each compound at each concentration level and time point were calculated to obtain a fold change (fc) value. To rank the compounds, the fc value of the ligand at the 4-hour time point was further divided by the fold change (fc) value of hinokitiol (a positive control compound) at equimolar concentration to obtain an FC (normalized fold change) value. References

[0140] 1.RJ Ward, FA Zucca, JH Duyn, RR Crichton, L. Zecca, The role of iron in brain aging and neurodegenerative disorders. Lancet Neurol 13, 1045-1060 (2014). 2.BB Muhoberac, R. Vidal, Abnormal iron homeostasis and neurodegeneration. Frontiers in aging neuroscience 5, 32 (2013). 3.RM Uranga, GA Salvador, Unraveling the Burden of Iron in Neurodegeneration: Intersections with Amyloid Beta Peptide Pathology. Oxid Med Cell Longev 2018, 2850341 (2018). 4.L. Balejcikova, K. Siposova, P. Kopcansky, I. Safarik, Fe(II) formation after interaction of the amyloid beta-peptide with iron-storage protein ferritin. J Biol Phys 44, 237-243 (2018). 5.J. S. Cristovao, R. Santos, C. M. Gomes, Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer’s Disease. Oxid Med Cell Longev 2016, 9812178 (2016). 6.C. Cheignon et al., Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol 14, 450-464 (2018). 7.H. Jiang, J. Wang, J. Rogers, J. Xie, Brain Iron Metabolism Dysfunction in Parkinson’s Disease. Mol Neurobiol 54, 3078-3101 (2017). 8.A. P. Lan, J. Chen, Z. F. Chai, Y. Hu, The neurotoxicity of iron, copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 29, 665-678 (2016). 9.S. Chiang, D. S. Kalinowski, P. J. Jansson, D. R. Richardson, M. L. Huang, Mitochondrial dysfunction in the neuro-degenerative and cardio-degenerative disease, Friedreich’s ataxia. Neurochemistry international 117, 35-48 (2018). 10.F. Lupoli, T. Vannocci, G. Longo, N. Niccolai, A. Pastore, The role of oxidative stress in Friedreich’s ataxia. FEBS letters 592, 718-727 (2018). 11.M. Muller, B. R. Leavitt, Iron dysregulation in Huntington’s disease. Journal of neurochemistry 130, 328-350 (2014). 12.S. Agrawal, J. Fox, B. Thyagarajan, J. H. Fox, Brain mitochondrial iron accumulates in Huntington’s disease, mediates mitochondrial dysfunction, and can be removed pharmacologically. Free radical biology & medicine 120, 317-329 (2018). 13.A. Gregory, S. Hayflick, Neurodegeneration with Brain Iron Accumulation Disorders Overview. 14.P. Hogarth, Neurodegeneration with brain iron accumulation: diagnosis and management. J Mov Disord 8, 1-13 (2015). 15.M. C. Kruer et al., Neuroimaging features of neurodegeneration with brain iron accumulation. AJNR Am J Neuroradiol 33, 407-414 (2012). 16.E. Madsen, J. D. Gitlin, Copper and iron disorders of the brain. Annu Rev Neurosci 30, 317-337 (2007). 17.B. Todorich, X. Zhang, B. Slagle-Webb, W. E. Seaman, J. R. Connor, Tim-2 is the receptor for H-ferritin on oligodendrocytes. Journal of neurochemistry 107, 1495-1505 (2008). 18.G. A. Salvador, Iron in neuronal function and dysfunction. Biofactors 36, 103-110 (2010). 19.S. J. Dixon, B. R. Stockwell, The role of iron and reactive oxygen species in cell death. Nat Chem Biol 10, 9-17 (2014). 20.G. A. Salvador, R. M. Uranga, N. M. Giusto, Iron and mechanisms of neurotoxicity. Int J Alzheimers Dis 2011, 720658 (2010). 21.H. M. Schipper, Brain iron deposition and the free radical-mitochondrial theory of ageing. Ageing Res Rev 3, 265-301 (2004). 22.R. C. Hider, Y. Ma, F. Molina-Holgado, A. Gaeta, S. Roy, Iron chelation as a potential therapy for neurodegenerative disease. Biochemical Society transactions 36, 1304-1308 (2008). 23.G. Abbruzzese et al., A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica 96, 1708-1711 (2011). 24.D. Devos et al., Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal 21, 195-210 (2014). 25.N. Parakh et al., Neurological Complications and Cataract in a Child With Thalassemia Major Treated With Deferiprone. J Pediatr Hematol Oncol 37, 433-444 (2015). 26.N. Mobarra et al., A Review on Iron Chelators in Treatment of Iron Overload Syndromes. International Journal of Hematology-Oncology and Stem Cell Research 10, 239-247 (2016). 27.F. N. Al-Refaie, B. Wonke, A. V. Hoffbrand, Deferiprone-associated myelotoxicity. European journal of haematology 53, 298-301 (1994). 28.A. S. Grillo et al., Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals. Science 356, 608-616 (2017). 29.M. T. Nunez, P. Chana-Cuevas, New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases. Pharmaceuticals (Basel) 11 (2018). 30.J. L. Hamilton, M. I. Ul-Haq, A. L. Creagh, C. A. Haynes, J. N. Kizhakkedathu, Iron Binding and Iron Removal Efficiency of Desferrioxamine Based Polymeric Iron Chelators: Influence of Molecular Size and Chelator Density. Macromol Biosci 17 (2017). 31.G. Crisponi et al., A Speciation Study on the Perturbing Effects of Iron Chelators on the Homeostasis of Essential Metal Ions. PloS one 10, e0133050 (2015). 32. S. Ekaputri et al., A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages. Proceedings of the National Academy of Sciences 119, e2121400119 (2022). 33. Y. Sun, AN Pham, TD Waite, Elucidation of the interplay between Fe(II), Fe(III), and dopamine with relevance to iron solubilization and reactive oxygen species generation by catecholamines. J Neurochem 137, 955-968 (2016). 34.IE Zohn et al., The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood 109, 4174-4180 (2007). 35.A. Donovan et al., The iron exporter ferroportin / Slc40a1 is essential for iron homeostasis. Cell metabolism 1, 191-200 (2005).

[0141] Incorporation by Reference All U.S. patents and published U.S. and PCT patent applications mentioned herein are incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0142] equivalent While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

1. 1. A method for treating a disease or condition selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, neurodegeneration associated with brain iron deposition (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, Woodhouse-Sakati syndrome, and idiopathic NBIA, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of hinokitiol, a hinokitiol derivative, and an iron-transporting tropolone, or a pharmaceutically acceptable salt thereof.

2. 1. A method of treating a disease or condition selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, neurodegeneration associated with brain iron deposition (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, 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. 【Chemical 1】 [In the formula, X represents oxygen or sulfur; R ａ 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, or heteroalkynyl; R ａ ' represents hydrogen, halo, alkyl, or substituted alkyl; R ｂ , R ｃ , and R ｄ is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyloxy, substituted cycloalkyloxy, heterocycloalkyloxy, substituted heterocycloalkyloxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, and heteroalkynyl; with the proviso that R ａ , R ｂ , R ｃ , and R ｄ But it's not all hydrogen.

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

4. R ａ 3. The method of claim 2, wherein ' is halo.

5. R ａ 3. The method of claim 2, wherein ' is alkyl or substituted alkyl.

6. R ａ , R ｂ , R ｃ , and R ｄ is selected from the group consisting of halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyloxy, substituted cycloalkyloxy, heterocycloalkyloxy, substituted heterocycloalkyloxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl.

7. R ａ , R ａ ', R ｂ , R ｃ , and R ｄ 7. The method of claim 2, wherein at least one of is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl.

8. 4. The method of claim 2 or 3, wherein the compound has formula Ib. 【Chemistry 2】 [In the formula, R ａ 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, or heteroalkynyl; 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; However, R ａ , R ｂ , R ｃ , and R ｄ But it's not all hydrogen.

9. Each occurrence of heterocycloalkyl independently represents 【Chemistry 3】 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; R ２ each occurrence independently represents -F, alkyl, haloalkyl, or alkoxy; or R ２ 9. The method of any one of claims 2 to 8, wherein the two geminal occurrences of represent carbonyl.

10. R ａ But -F, -CF ３ , (C2-C15) alkyl, or substituted (C1-C15) alkyl.

11. R ｂ , R ｃ , and R ｄ are independently hydrogen, (C1-C15) alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, (C1-C15) alkylene-R １ , 3- to 12-membered cycloalkyl-R １ , or 3- to 12-membered heterocycloalkyl-R １ represents; R １ 11. The method of claim 10, wherein each occurrence independently represents halo, alkyl, alkoxy, or hydroxyl.

12. R ａ , R ｂ , R ｃ , and R ｄ 9. The method of claim 8, wherein at least one of is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl.

13. The compound is 【Chemistry 4】 The method according to any one of claims 11 to 12, wherein the compound is selected from the group consisting of:

14. The compound is 【Chemistry 5】 The method of claim 13, wherein

15. The compound is 【Chemistry 6】 The method of claim 13, wherein

16. The compound is 【Chemistry 7】 12. The method of claim 11 , selected from the group consisting of:

17. The compound is 【Chemistry 8】 The method of claim 11, wherein

18. R ａ -Cl, -F, -CF ３ , (C2-C15) alkyl, or substituted (C1-C15) alkyl.

19. R ａ The method of any one of claims 18, wherein represents -F.

20. R ｂ , R ｃ , and R ｄ are independently hydrogen, halo(C1-C15)alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, (C1-C15)alkylene-R １ , 3- to 12-membered cycloalkyl-R １ , or 3- to 12-membered heterocycloalkyl-R １ represents; R １ The method of any one of claims 18 to 19, wherein each occurrence independently represents halo, alkyl, alkoxy, or hydroxyl.

21. The compound is 【Chemistry 9】 21. The method of claim 20, selected from the group consisting of:

22. R ｂ , R ｃ , and R ｄ are independently hydrogen or one or two R ２ represents a 3- to 12-membered heterocycloalkyl optionally substituted with the heterocycloalkyl 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 atoms, nitrogen atoms, and sulfur atoms; R ２ The method of any one of claims 2 to 9, wherein each occurrence of independently represents -F, alkyl, haloalkyl, carbonyl, or alkoxy.

23. The compound is 【Chemistry 10】 23. The method of claim 22, selected from the group consisting of:

24. The compound is 【Chemistry 11】 24. The method of claim 23, wherein:

25. The heterocycloalkyl contains one or two nitrogen atoms; at least one of the nitrogen atoms is N(R ２ｂ ) is represented by; R ２ｂ are independently hydrogen, —C(O)R ５ , or —C(O)OR ５ represents; R ５ 23. The method of claim 22, wherein independently represent hydrogen, alkyl, or substituted alkyl.

26. R ｂ , R ｃ , and R ｄ are independently hydrogen or -OR ３ represents; R ３ independently represent (C1-C15) alkyl, 3-12 cycloalkyl or bicycloalkyl, 1 or 2 oxygen atoms, 1 or 2 nitrogen atoms, 1 or 2 sulfur atoms, or any combination of two atoms selected from the group consisting of oxygen atoms, nitrogen atoms, and sulfur atoms.

27. The compound is 【Chemistry 12】 27. The method of claim 26, wherein:

28. The compound is 【Chemistry 13】 27. The method of claim 26, selected from the group consisting of:

29. R ３ Each entity of R ４ optionally substituted with R ４ 27. The method of claim 26, wherein independently represents alkyl, halogen-substituted alkyl, alkoxy, or hydroxy.

30. R ａ But -CH ３ The method according to any one of claims 2 to 10, wherein

31. R ｂ , R ｃ , and R ｄ are independently hydrogen, (C1-C15) alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, (C1-C15) alkylene-R １ , 3- to 12-membered cycloalkyl-R １ , or 3- to 12-membered heterocycloalkyl-R １ represents; R １ 31. The method of claim 30, wherein each occurrence independently represents halo, alkyl, alkoxy, or hydroxy.

32. The compound is 【Chemistry 14】 32. The method of claim 31 , selected from the group consisting of:

33. R ｂ , R ｃ , and R ｄ are independently hydrogen or one or two R ２ represents a 3- to 12-membered heterocycloalkyl optionally substituted with The heterocycloalkyl 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 atoms, nitrogen atoms, and sulfur atoms; R ２ 31. The method of claim 30, wherein each occurrence of independently represents -F, alkyl, haloalkyl, carbonyl, or alkoxy.

34. The compound is 【Chemistry 15】 34. The method of claim 33, selected from the group consisting of:

35. The heterocycloalkyl contains one or two nitrogen atoms; at least one of the nitrogen atoms is N(R ２ｂ ) is represented by; R ２ｂ are independently hydrogen, —C(O)R ５ , or —C(O)OR ５ represents; R ５ 34. The method of claim 33, wherein independently represent hydrogen, alkyl, or substituted alkyl.

36. R ｂ , R ｃ , and R ｄ are independently hydrogen or -OR ３ represents; R ３ independently represent (C1-C15) alkyl, 3- to 12-membered cycloalkyl or bicycloalkyl, 3- to 12-membered heterocycloalkyl or heterobicycloalkyl 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 atoms, nitrogen atoms, and sulfur atoms.

37. R ３ Each entity of R ４ optionally substituted with R ４ 37. The method of claim 36, wherein independently represents alkyl, halogen-substituted alkyl, alkoxy, or hydroxy.

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

39. R ｂ , R ｃ , and R ｄ are independently hydrogen, (C1-C15) alkyl, —F, or —CF ３ The method of claim 38, wherein

40. The compound is 【Chemistry 16】 40. The compound of claim 38 or 39, selected from the group consisting of:

41. The compound is 【Chemistry 17】 40. The method of claim 39, selected from the group consisting of:

42. R ｂ , R ｃ , and R ｄ are independently hydrogen, (C1-C15) alkyl, —Cl, —F, or —CF ３ The method of claim 38, wherein

43. The compound is 【Chemistry 18】 43. The method of claim 42, wherein:

44. R ｂ , R ｃ , and R ｄ independently represent hydrogen, 3- to 12-membered cycloalkyl, or 3- to 12-membered heterocycloalkyl, each optionally being substituted by one or two R ２ is substituted with; the heterocycloalkyl 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 atoms, nitrogen atoms, and sulfur atoms; R ２ 39. The method of claim 38, wherein each occurrence of independently represents -F, alkyl, haloalkyl, carbonyl, or alkoxy.

45. The compound is 【Chemistry 19】 【Chemistry 20】 45. The method of claim 44, selected from the group consisting of:

46. The compound is 【Chemical 21】 46. ​​The method of claim 45, wherein:

47. The compound is 【Chemical formula 22】 46. ​​The method of claim 45, selected from the group consisting of:

48. The compound is 【Chemical 23】 45. The method of claim 44, selected from the group consisting of:

49. R ｂ is a halo; R ｃ and R ｄ independently represent hydrogen, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, cycloalkyloxy, or heterocycloalkyloxy; Each cycloalkylheterocycloalkyl, cycloalkyloxy, or heterocycloalkyloxy is selected from one or two R ２ optionally substituted with; the heterocycloalkyl 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 atoms, nitrogen atoms, and sulfur atoms; R ２ 39. The method of claim 38, wherein each occurrence of independently represents -F, alkyl, haloalkyl, carbonyl, or alkoxy.

50. The compound is 【Chemistry 24】 50. The method of claim 49, selected from the group consisting of:

51. The heterocycloalkyl contains one or two nitrogen atoms; at least one of the nitrogen atoms is N(R ２ｂ ) is represented by; R ２ｂ are independently hydrogen, —C(O)R ５ , or —C(O)OR ５ represents; R ５ 45. The method of claim 44, wherein independently represent hydrogen, alkyl, or substituted alkyl.

52. The compound is 【Chemistry 25】 52. The method of claim 51 , selected from the group consisting of:

53. R ｂ , R ｃ , and R ｄ are independently hydrogen or -OR ３ represents; R ３ independently represent (C1-C15) alkyl, 3- to 12-membered cycloalkyl or bicycloalkyl, or 3- to 12-membered heterocycloalkyl or heterobicycloalkyl 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 atoms, nitrogen atoms, and sulfur atoms.

54. The compound is 【Chemical Formula 26】 54. The method of claim 53, selected from the group consisting of:

55. The compound is 【Chemical 27】 51. The method of claim 50, wherein:

56. R ３ Each entity of R ４ optionally substituted with R ４ 54. The method of claim 53, wherein independently represents alkyl, halogen-substituted alkyl, alkoxy, or hydroxy.

57. The compound is 【Chemical Formula 28】 54. The method of claim 53, selected from the group consisting of:

58. R ｂ , R ｃ , and R ｄ are independently hydrogen or -alkyl-R ３ or —O-alkyl-R ３ represents; R ３ independently represent aryl, substituted aryl, 3- to 12-membered cycloalkyl or bicycloalkyl, or 3- to 12-membered heterocycloalkyl or heterobicycloalkyl 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 atoms, nitrogen atoms, and sulfur atoms.

59. The compound is 【Chemical 29】 59. The method of claim 58, selected from the group consisting of:

60. R ａ 40. The method of claim 38 or 39, wherein ' is halo or alkyl.

61. The compound is 【Chemistry 30】 59. The method of claim 58, wherein:

62. 1. A method for treating a disease or condition selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, neurodegeneration associated with brain iron deposition (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, Woodhouse-Sakati syndrome, and idiopathic NBIA, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure represented by Formula IIa, IIb, or IIc, or a pharmaceutically acceptable salt thereof. 【Chemical 31】 [In the formula, R ａ 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, or heteroalkynyl; X and Y are independently O, S, NH, or CR ５ R ６ represents; R ２ represents -F, alkyl, haloalkyl, or alkoxy; R ５ and R ６ represents independently at each occurrence H, (C1-C15) alkyl, or substituted (C1-C15) alkyl; However, the compound is 【Chemical 32】 But not.

63. 62. The method of claim 61, wherein the compound is represented by Formula IIa or IIb.

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

65. The compound is 【Chemical 33】 65. The compound of claim 64, selected from the group consisting of:

66. The compound is 【Chemical 34】 65. The method of claim 64, wherein:

67. 1. A method of treating a disease or condition selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, neurodegeneration associated with brain iron deposition (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, 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. 【Chemistry 35】 [In the formula, X represents sulfur or oxygen; R ａ , R ｂ , R ｃ , and R ｄ independently represent 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; However, R ａ , R ｂ , R ｃ , and R ｄ But it's not all hydrogen.

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

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

70. 68. The compound of claim 67, represented by formula (Id): 【Chemical 36】 [In the formula, R ａ , R ｂ , R ｃ , and R ｄ independently represent 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, or substituted heteroaryl; R ｂ , R ｃ , and R ｄ at least one of is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; However, R ａ , R ｂ , R ｃ , and R ｄ But it's not all hydrogen.

71. R is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. ｂ , R ｃ , and R ｄ Each of the following is represented by Formula II: 【Chemical 37】 wherein each of A, B, C, D, and E independently represents CH, N, or CR; for each occurrence of Formula II, the total number of nitrogen atoms present in A, B, C, D, and E is 0, 1, or 2; each occurrence 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. each occurrence of R independently represents chloro, fluoro, bromo, iodo, cyano, trifluoromethyl, amino, hydroxy, (C1-C12) alkyl, (C3-C12) cycloalkyl, (C1-C12) alkoxy, (C3-C12) cycloalkoxy, or (C3-C12) heterocycloalkyl; 72. The method of claim 71, wherein the heterocycloalkyl 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 atoms, nitrogen atoms, and sulfur atoms.

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

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

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

76. The compound is 【Chemical 39】 76. The method of claim 75, selected from the group consisting of:

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

78. The compound is 【Chemistry 40】 78. The method of claim 77, selected from the group consisting of:

79. The compound is 【Chemistry 41】 79. The method of claim 78, selected from the group consisting of:

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

81. The compound is 【Chemistry 42】 81. The method of claim 80, selected from the group consisting of:

82. R ａ represents an aryl, substituted aryl, heteroaryl, or substituted heteroaryl according to Formula II; R ｂ , R ｃ , and R ｄ represents alkyl; R ｂ , R ｃ , and R ｄ 82. The method of claim 80 or 81, wherein two of represent hydrogen.

83. The compound is 【Chemistry 43】 83. The method of claim 82, selected from the group consisting of:

84. R ａ represents an aryl, substituted aryl, heteroaryl, or substituted heteroaryl according to Formula II; R ｂ , R ｃ , and R ｄ 73. The method of claim 71 or 72, wherein each of represents hydrogen.

85. The compound is 【Chemical 44】 85. The method of claim 84, selected from the group consisting of:

86. R ａ , R ｂ , R ｃ , and R ｄ 68. The method of claim 67, wherein at least one of is aryloxy, substituted aryloxy, heteroaryloxy, or substituted heteroaryloxy.

87. R ｂ , R ｃ , and R ｄ 68. The method of claim 67, wherein at least one of is aryloxy, substituted aryloxy, heteroaryloxy, or substituted heteroaryloxy.

88. R is aryloxy, substituted aryloxy, heteroaryloxy, or substituted heteroaryloxy. ｂ , R ｃ , and R ｄ 88. The method of claim 86 or 87, wherein each of is represented by formula IId: 【Chemistry 45】 wherein each of A, B, C, D, and E independently represents CH, N, or CR; For each occurrence of Formula IId, the total number of nitrogen atoms present in A, B, C, D, and E is 0, 1, or 2; each occurrence 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. each occurrence of R independently represents chloro, fluoro, bromo, iodo, cyano, trifluoromethyl, amino, hydroxy, (C1-C12) alkyl, (C3-C12) cycloalkyl, (C1-C12) alkoxy, (C3-C12) cycloalkoxy, or (C3-C12) heterocycloalkyl; 89. The method of claim 88, wherein the heterocycloalkyl 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 atoms, nitrogen atoms, and sulfur atoms.

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

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

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

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

94. R ａ represents an aryl, substituted aryl, heteroaryl, or substituted heteroaryl according to formula IId; R ｂ , R ｃ , and R ｄ 90. The method of claim 88 or 89, wherein each of represents hydrogen.

95. The compound is 【Chemistry 46】 93. The method of claim 91 or 92, selected from the group consisting of:

96. R is heteroaryl or substituted heteroaryl ｂ , R ｃ , and R ｄ each of which is represented by formula IIe: 【Chemistry 47】 A' represents O or S; B', C', and D' each independently represent CH, N, or CR; each occurrence 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. R is heteroaryl or substituted heteroaryl ｂ , R ｃ , and R ｄ Each of the following is represented by formula IIf: 【Chemistry 48】 wherein C' represents O or S; A', B', and D' each independently represent CH, N, or CR; each occurrence 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. R is heteroaryl or substituted heteroaryl ｂ , R ｃ , and R ｄ Each of the formulas is represented by formula IIg. 【Chemistry 49】 D' represents O or S; A', B', and C' each independently represent CH, N, or CR; each occurrence 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. R is heteroaryl or substituted heteroaryl ｂ , R ｃ , and R ｄ Each of the formulas is represented by formula IIh. 【Chemistry 50】 [B' represents O or S; A', C', and D' each independently represent CH, N, or CR; each occurrence 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. each occurrence of R independently represents chloro, fluoro, bromo, iodo, cyano, trifluoromethyl, amino, hydroxy, (C1-C12) alkyl, (C3-C12) cycloalkyl, (C1-C12) alkoxy, (C3-C12) cycloalkoxy, or (C3-C12) heterocycloalkyl; 100. The method of any one of claims 97-99, wherein the heterocycloalkyl 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 atoms, nitrogen atoms, and sulfur atoms.

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

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

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

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

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

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

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

108. The compound or tautomer is 【Chemistry 51】 The method of any one of claims 101 to 107, selected from the group consisting of:

109. 1. A method for treating a disease or condition selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, neurodegeneration associated with brain iron deposition (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, Woodhouse-Sakati syndrome, and idiopathic NBIA, comprising administering to a subject in need of said treatment a therapeutically effective amount of a compound having the structure of formula (I) or a salt thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 52】 [In the formula, R ａ But 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, NO ２ , C.N., C. １～６ -Alkyl, C １～６ -haloalkyl, and C １～６ -substituted with a substituent selected from the group consisting of alkoxy; R ｂ is hydrogen or methyl; with the proviso that the compound is not hinokitiol.

110. The following structure: 【Chemistry 53】 and pharmaceutically acceptable salts thereof.

111. R ａ But C １～４ -Alkyl, C ２～４ -alkenyl, C ２～４ -alkynyl, or C ３～４ -cycloalkyl; with the proviso that the compound is not hinokitiol.

112. R ａ but, 【Chemical 54】 The method of any one of claims 109 to 110, selected from the group consisting of:

113. R ａ but, 【Chemistry 55】 The method of any one of claims 109 to 110, selected from the group consisting of:

114. R ａ but, 【Chemical Formula 56】 The method of any one of claims 109 to 110, selected from the group consisting of:

115. 1. A method for treating a disease or condition selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, neurodegeneration associated with brain iron deposition (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, Woodhouse-Sakati syndrome, and idiopathic NBIA, comprising administering to a subject in need of said treatment a therapeutically effective amount of a compound having a structure selected from the following, or a pharmaceutically acceptable salt thereof: 【Chemical 57】 【Chemistry 58】 【Chemical 59】 【Chemistry 60】

116. The compound is 【Hua 61】 or a pharmaceutically acceptable salt thereof.

117. The compound is 【Hua 62】 or a pharmaceutically acceptable salt thereof.

118. The compound is 【Chemistry 63】 or a pharmaceutically acceptable salt thereof.

119. The compound is 【Hua 64】 【Chemistry 65】 or a pharmaceutically acceptable salt thereof.

120. 1. A method for treating a disease or condition selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, neurodegeneration associated with brain iron deposition (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, Woodhouse-Sakati syndrome, and idiopathic NBIA, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure selected from the group consisting of: 【Hua 66】 【Hua 67】

121. 1. A method for treating a disease or condition selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, neurodegeneration associated with brain iron deposition (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, Woodhouse-Sakati syndrome, and idiopathic NBIA, comprising administering to a subject in need of said treatment a therapeutically effective amount of a compound having a structure selected from the group consisting of: 【Chemistry 68】 【Chemical Formula 69】

122. 1. A method for treating a disease or condition selected from the group consisting of inflammatory diseases leading to abnormal suppression of ferroportin production, neurodegeneration associated with brain iron deposition (NBIA), beta-propeller 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), aceruloplasminemia, Kufor-Rakeb syndrome, Parkinson's disease 9 (PARK9), neuroferritinopathy, 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: 【Chemistry 70】 【Chemical Formula 71】 【Chemical Formula 72】

123. 123. The method of any one of claims 1 to 122, further comprising administering to the subject a therapeutically effective amount of a chelating agent.

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

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

126. 126. The method of any one of claims 1 to 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-associated dementia, COVID-associated neurodegeneration, mood disorders, depression, and bipolar disorder.

127. 127. The method of any one of claims 1 to 126, wherein the disease or condition is selected from the group consisting of vascular dementia, tauopathy, progressive supranuclear palsy, corticobasal degeneration, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, Guam Parkinsonism-Dementia Complex, Pick's disease, and frontotemporal dementia.

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

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

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

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

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

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