Deuterated hinokitiol derivatives

Abstract

Deuterated derivatives of tropolone are disclosed that are useful for treating diseases or disorders, for example, involving deficiencies in iron transport.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 411,738, 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] Hinokitiol, a small molecule natural product, has been shown to promote transmembrane iron mobilization by reversibly forming a 3:1 complex with iron. Hinokitiol restores iron homeostasis in a variety of different model systems, including divalent metal transporter 1 (DMT1-), mitoferrin 1 (MFRN1-), and ferroportin 1 (FPN1-) deficient cells and animals. While hinokitiol is not inherently site- or direction-selective, it achieves site- and direction-selective iron mobilization by exploiting the electrochemical gradient that forms in the absence of iron transport protein function.

[0004] However, hinokitiol has important limitations that limit its potential for clinical application. We found that hinokitiol effectively mobilizes iron at low to moderate concentrations in differentiated shDMT1 monolayers, but at higher concentrations, a significant decrease in transmembrane mobilization activity was observed. A series of studies were conducted to identify derivatives of hinokitiol, such as those disclosed herein, that mobilize iron over a much broader concentration range in vitro. These compounds can also mobilize iron and treat inflammation-induced anemia in vivo.

[0005] Along the way to these improved derivatives, we observed the formation of higher-order aggregates in aqueous media due to the loss of iron mobilization at high concentrations of hinokitiol. These aggregates, in turn, limit the amount of free tropolone:iron complex available for transmembrane mobilization of iron. To understand how these complexes may interact with each other in these aggregates, we obtained several crystal structures of hinokitiol:M (M = Fe, Al, Cu) complexes. In these crystal structures, the isopropyl groups of these complexes form important van der Waals interactions that can lead to the formation of aggregates in aqueous media. Using structural isomers of hinokitiol that are less prone to aggregation, the van der Waals interactions performed by the isopropyl groups are significantly different.

[0006] Deuterium is a hydrogen isotope containing a neutron in its nucleus, doubling its atomic weight. This results in deuterated compounds with a lower zero-point energy and a reduced van der Waals radius compared to their hydrogenated counterparts. However, the literature on the effects of deuteration in pharmaceuticals has primarily focused on utilizing kinetic isotope effects to improve the pharmacokinetic profile of drugs. Some studies on deuterated materials have reported changes in boiling point and dimerization behavior, among other things. Few, if any, systematic studies have described the relationship between deuteration and changes in the biophysical behavior of pharmaceuticals. Therefore, it was unclear whether deuteration has any effect on this aggregation phenomenon, and even less whether any effect is positive or negative. Using substituted tropolones, we found that deuteration of the tropolone side chain increased both efficacy and tolerability, thereby improving their potential to act as molecular prosthetics for metal ion transporters. Summary of the Invention [Means for solving the problem]

[0007] In certain embodiments, provided herein are compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 is selected from the group consisting of H, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, —O—C1-C5 alkyl, —O-cycloalkyl, and —O-heterocycloalkyl; R 2 is selected from the group consisting of H, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, —O—C1-C5 alkyl, —O-cycloalkyl, and —O-heterocycloalkyl; R 3 is selected from the group consisting of H, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, —O—C1-C5 alkyl, —O-cycloalkyl, and —O-heterocycloalkyl; R 4 is selected from the group consisting of H, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, —O—C1-C5 alkyl, —O-cycloalkyl, and —O-heterocycloalkyl; R 5 is selected from the group consisting of H, halo, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, —O—C1-C5 alkyl, —O-cycloalkyl, and —O-heterocycloalkyl; R 1 , R 2 , R 3 , R 4 , or R 5 is C1-C5 alkyl, cycloalkyl, heterocycloalkyl, -O-C1-C5 alkyl, -O-cycloalkyl, or -O-heterocycloalkyl, at least one hydrogen atom in the C1-C5 alkyl, cycloalkyl, heterocycloalkyl, -O-C1-C5 alkyl, -O-cycloalkyl, or -O-heterocycloalkyl is replaced with a deuterium atom; R 1 , R 2 , R 3 , and R 4 At least one of them is not H.

[0008] In an additional aspect, provided herein is a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0009] In yet an additional aspect, provided herein is a method of treating a disease or condition characterized by a decrease in ferroportin, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0010] In yet a further aspect, provided herein is a method of treating a disease or condition characterized by decreased iron transport, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0011] In certain aspects, provided herein are methods for treating a disease or condition characterized by a defect or deficiency in a metal transporter, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0012] In an additional aspect, provided herein is a method of treating a disease or condition characterized by iron accumulation, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0013] In yet an additional aspect, provided herein is a method of treating a disease or condition characterized by iron maldistribution, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0014] In certain aspects, provided herein are methods of treating a neurodegenerative disorder, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure. [Brief explanation of the drawings]

[0015] [Figure 1]1 illustrates a general synthetic scheme for accessing deuterated tropolone derivatives. [Figure 2A] Figure 1 illustrates data for the evaluation of methyl-d0 and methyl-d3 tropolone. Iron mobilization by the deuterated derivatives is increased at low concentrations and remains elevated even at very high concentrations. [Figure 2B] Illustrating the data for the evaluation of methyl-d0 and methyl-d3 tropolone, the deuterated derivatives are significantly better tolerated in H9C2 cells. [Figure 2C] Illustrating data for the evaluation of methyl-d0 and methyl-d3 tropolone, the deuterated derivatives are well tolerated in K562 cells. [Figure 3A] Illustrated are the results of treating fpn-1.2KO C. elegans with various compounds for neurodegeneration scoring and iron level measurement: Treatment scheme of fpn-1.2KO;Pdat::GFP worms treated with various concentrations of DFP, Hino, and AMB-1269. Dopaminergic neurodegeneration was blindly scored by phenotypic analysis (bottom). [Figure 3B] FIG. 1 illustrates dopaminergic neurodegeneration scoring of fpn-1.2KO worms treated with DFP. [Figure 3C] Illustrates dopaminergic neurodegeneration scoring of fpn-1.2KO worms treated with Hino. [Figure 3D] FIG. 1 illustrates dopaminergic neurodegeneration scoring of fpn-1.2KO worms treated with FeM-1269. [Figure 3E] Illustrated is the treatment scheme of fpn-1.2KO;Pftn-1::GFP worms treated with various concentrations of DFP, Hino, and FeM-1269. ASI neurons expressing GFP-tagged ferritin levels (bottom). [Figure 3F] Fluorescence levels of fpn-1.2KO worms treated with DFP are shown. *P<0.05, **P<0.01, ***P<0.001, and ****P<0.0001 by one-way ANOVA. [Figure 3G]Fluorescence levels of fpn-1.2KO worms treated with Hino are shown. *P<0.05, **P<0.01, ***P<0.001, and ****P<0.0001 by one-way ANOVA. [Figure 3H] Fluorescence levels of fpn-1.2KO worms treated with FeM-1269 are shown. *P<0.05, **P<0.01, ***P<0.001, and ****P<0.0001 by one-way ANOVA. [Figure 4A] Data from flatiron mouse experiments are shown. Flatiron mice exhibit increased anxiety and decreased exploratory activity. WT and flatiron mice were subjected to an elevated plus-maze task for assessment of anxiety-like behavior, including total distance traveled and average speed throughout the maze. [Figure 4B] Data from flatiron mouse experiments are shown. Flatiron mice exhibit increased anxiety and decreased exploratory activity. WT and flatiron mice were subjected to an elevated plus maze task to assess anxiety-like behavior, including time spent in the open arms and the central zone. [Figure 4C] Data from flatiron mouse experiments are shown. Flatiron mice exhibit increased anxiety and decreased exploratory activity. WT and flatiron mice were subjected to the elevated plus maze task to assess anxiety-like behaviors, including rearing frequency and duration. *P<0.05 by Student's t-test. [Figure 4D] Figure 1 illustrates ICP-MS measurements of brain iron levels in flatiron mice after acute treatment with Hino via intraperitoneal (IP) injection. **P<0.01, ***P<0.001 by one-way ANOVA. [Figure 4E] Figure 1 illustrates ICP-MS measurements of brain iron levels in flatiron mice after chronic treatment with Hino via intraperitoneal (IP) injection. **P<0.01, ***P<0.001 by one-way ANOVA. [Figure 5]Illustrated is crystallographic data showing that hinokitiol forms a 3:1 complex with Fe(III) for transmembrane mobilization. Hinokitiol in the crystal packing structure retains isopropyl side chains from nearby neighboring complexes. [Figure 6] FIG. 1 illustrates a schematic in which deuteration is hypothesized to reduce inter-complex van der Waals interactions and restore transport ability at high concentrations for aggregation-promoting derivatives. [Figure 7A] 1 illustrates cell-free iron efflux data showing that perdeuteration of hinokitiol promotes transport of high concentrations similar to those observed with 3,5,7-tri-methyltropolone. [Figure 7B] 1 illustrates dynamic light scattering data showing that perdeuteration of hinokitiol reduces aggregation. [Figure 8A] Illustrates crystallographic data for hinokitiol showing isopropyl-isopropyl interactions. [Figure 8B] We illustrate cell-free iron efflux data showing that perdeuteration of the isopropyl isomer GT does not affect transport at high concentrations, consistent with the limited specific isopropyl-isopropyl interactions seen in the crystal structure. [Figure 9A] Dynamic light scattering data (deflection coefficients) are shown showing that perdeuteration of the methyl side chains does not significantly affect aggregation due to the lack of individual interactions and limited aggregation of the protonated parent compound. [Figure 9B] Dynamic light scattering data (average size) are shown showing that perdeuteration of the methyl side chains does not significantly affect aggregation due to the lack of individual interactions and limited aggregation of the protonated parent compound. [Figure 10A] 1 illustrates cell-free iron efflux data showing similar iron mobilization capacity between 3-methyltropolone and 3-methyl-(d3)-tropolone. [Figure 10B] 1 illustrates cell-free iron efflux data showing similar iron mobilization capacity between 4-methyltropolone and 4-methyl-(d3)-tropolone. [Figure 10C]1 illustrates cell-free iron efflux data showing similar iron mobilization capacity between 5-methyltropolone and 5-methyl-(d3)-tropolone. [Figure 10D] 1 illustrates cell-free iron efflux data showing similar iron mobilization capacity between 3,5-dimethyltropolone and 3,5-dimethyl-(d6)-tropolone. [Figure 11] 1 illustrates cell-free iron efflux data showing that perdeuteration expands the transport window of aggregating 4-n-butyl-(d9)-tropolone compared to 4-n-butyltropolone. DETAILED DESCRIPTION OF THE INVENTION

[0016] Iron is biologically essential but potentially toxic. Therefore, it is tightly regulated at the cellular and systemic levels to prevent both deficiency and excess. Iron overload can manifest in two major situations: (1) excess iron in the circulation and (2) iron accumulation in tissues. The latter can also be called maldistribution or uneven distribution of iron. Iron chelators treat iron overload by binding to iron in the blood, promoting its excretion and reducing the amount of iron in the circulation. Iron mobilizers can extract iron from tissues, thus redistributing it from sites of accumulation to sites of deficiency. Such iron mobilizers can coordinate with iron-binding proteins to restore normal iron physiology. Current treatments primarily address excess iron in the blood.

[0017] Iron transport throughout biological systems is achieved through the coordinated action of passive and active transport proteins. Disruptions in iron homeostasis can result from diseases induced by dysfunction in just one of these proteins. The natural product hinokitiol (β-thujaplicin) has been shown to autonomously replace the function of ion transport proteins in disease models by forming a lipophilic 3:1 complex with iron and exploiting the transmembrane concentration gradient to redistribute iron. However, hinokitiol tends to form higher-order aggregates at high concentrations, limiting its effective mobilization range. X-ray crystal structures of the complexes suggest that β-substituted isopropyl groups in neighboring complexes promote aggregation through proximity-driven attractive van der Waals interactions. Reducing these interactions while maintaining appropriate lipophilicity for transmembrane mobilization generally expands the range of mobilization efficacy, as observed in synthetic design principles for novel tropolone derivatives. Notably, these new derivatives are usually structurally distinct from the aggregating compounds, and there are no alternative means of modification to transform the aggregating compounds into ones with the same structural design but with a lower tendency to aggregate.

[0018] Deuteration of small molecules is typically used to alter pharmacokinetics through kinetic isotope effects (KIEs). The literature on the effects of deuteration on intermolecular van der Waals interactions is sparse and varied. Furthermore, while normal first-order KIEs can result in rate ratio values ​​of 1–8, the effects of noncovalent deuterium isotopes have been reported to be much milder, ranging from 1–1.5. Therefore, it is unclear whether deuteration can help address the aggregation-based loss of activity observed with tropolones such as hinokitiol, and preliminary evidence suggests that this is facilitated by the application of higher order. However, intriguing applications in supramolecular host-guest interactions, rotational barriers, chromatography, and self-association suggest that physicochemical differences that affect aggregation, albeit subtle, may be achievable through deuteration, particularly in the case of overdeuteration, where these individual effects may be amplified. Therefore, despite strong literature precedent, we decided to experimentally test whether deuteration of aggregation-prone small molecule metal mobilizers could improve the availability of active transport complexes at high concentrations through disruption of complex association. Specifically, we tested whether perdeuteration of aggregating side chains could increase the in vitro activity spectrum compared to the parent compounds while retaining much of their lipophilicity, potentially due to the effect of deuteration disrupting intercomplex van der Waals interactions, thereby reducing small molecule higher-order aggregation with minimal structural perturbation.

[0019] First, to test the application of deuteration to iron mobilization agents, we synthesized hinokitiol-d7 using Negishi coupling of 2-iodopropane-d7 to a modular bromotropolone scaffold. Hinokitiol was utilized as a highly aggregating standard, and hinokitiol-d7 was used as a comparison isotopomer containing a perdeuterated isopropyl side chain. In Fe3+ liposome efflux assays, hinokitiol-d7 had significantly higher iron transport capacity at high concentrations (50-150 μM) compared to hinokitiol, which begins to aggregate. This transport capacity was similar to that of the non-isopropyl structural isomer control, trimethyl, which aggregates less but has the same cLogP as hinokitiol, suggesting that hinokitiol-d7 also aggregates to a lesser extent. This high transport capacity level is not similar to most other derivatives and represents an interesting new development for developing improved iron mobilization agents. This lack of aggregation is supported by dynamic light scattering studies, which show that equimolar concentrations of hinokitiol-d7 with iron at 20–100 μM result in less aggregation due to the smaller photon deflection number and particle size. Interestingly, GT (γ-thujaplicin), an isopropyl structural isomer previously shown to aggregate less than hinokitiol (and with different crystal packing that limits intercomplex isopropyl proximity), shows no deuteration effect on cell-free iron transport. This suggests that deuteration of non-interacting side chains does not affect transmembrane iron transport. This is supported by non-interacting methyl and methyl-d3 variants at all ring positions, which show no significant difference in cell-free iron transport and all have low aggregation propensity. These methyl variants also showed no significant differences in shDMT1-Caco-2 monolayer transport experiments that could be performed, implying the extension of cell-free iron transport propensity to biological systems. Multiply substituted derivatives such as 3'5DiMe also show no deuteration effect as the number of deuterium substitutions increases, due to the inherent non-aggregating nature of the proton parent compound.

[0020] To support this differential deuteration effect depending on the aggregation tendency of the parent compound, the highly aggregating compound 4nBu and its perdeuterated isotopomer pair were synthesized and tested in a liposome efflux assay. Due to higher-order aggregation, 4nBu exhibits a short effective transmembrane mobilization concentration range, ceasing significant transport at 40 μM compound. Similar to hinokitiol-d7, 4nBu-d9 maintains transport levels at concentrations where the parent compound experiences higher-order aggregation limitations. Notably, in this case, this range is extended to 75 μM compound, which exhibits significant transmembrane transport of iron before declining to baseline, indicating the strategic use of deuteration as a new design principle for expanding the effective concentration range of aggregating tropolone derivatives. In certain embodiments, additional primary alkyl derivatives may be synthesized using commercially available perdeuterated halides, which are converted to the corresponding boronic acids through Grignard-promoted addition of trimethylborane and then utilized in Suzuki-Miyaura cross-coupling to the bromotropolone scaffold.

[0021] The present disclosure is based on the surprising discovery that deuteration of the side chain of tropolonoids can increase both efficacy and tolerability, thereby improving their potential to act as molecular prostheses for metal ion transporters. The compounds of the present disclosure are useful for treating diseases caused by abnormal iron distribution.

[0022] definition As used herein, the term "organic moiety" refers to a monovalent group containing one or more carbon atoms. The organic moiety may be aromatic or hydrocarbon-derived. The organic moiety may contain one or more heteroatoms, one or more units of unsaturation, and / or one or more functional groups. The organic moiety may be substituted.

[0023] As used herein, the term "alkyl" 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 has about 30 or fewer carbon atoms in its backbone (e.g., C1-C for straight chain). 30 , C3 to C for branched chains 30 ), or having about 20 or less, or 10 or less carbon atoms. In certain embodiments, the term "alkyl" refers to a C1-C 10 In certain embodiments, the term "alkyl" refers to a C1 to C6 alkyl group, for example, a C1 to C6 straight chain alkyl group. In certain embodiments, the term "alkyl" refers to a C3 to C6 alkyl group, for example, a C1 to C6 straight chain alkyl group. 12 It refers to a branched chain alkyl group. In certain embodiments, the term "alkyl" refers to a C3 to C8 branched chain alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0024] The term "cycloalkyl" refers to monocyclic, bicyclic or bridged saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Some cycloalkyls have from 5 to 12 carbon atoms in their ring structure, and some have 6 to 10 carbons in the ring structure. Preferably, cycloalkyl is a (C3-C7)cycloalkyl, which refers to a monocyclic saturated carbocyclic ring having from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings are rings in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge of 1 to 3 additional carbon atoms (i.e., of the form -(CH2) w- (where w is 1, 2, or 3) bridging group). Representative examples of bicyclic systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. Bridged or fused bicyclic cycloalkyls are attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. The cycloalkyl group is optionally substituted. In certain embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.

[0025] The term "(cycloalkyl)alkyl," as used herein, refers to an alkyl group substituted with one or more cycloalkyl groups. An example of a (cycloalkyl)alkyl is a cyclohexylmethyl group.

[0026] The term "heterocycloalkyl," 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 may contain one or more units of unsaturation, where, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system and has 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, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thiethyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl, dioxalanyl, oxazolyl, thiazolyl, triazinium, Heterocycloalkyl groups include aryl, isothiazolyl, isoxazolyl, azepine, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl. Heterocycloalkyl groups are optionally substituted with one or more substituents, described below.

[0027] As used herein, the term "(heterocycloalkyl)alkyl" refers to an alkyl group substituted with one or more heterocycloalkyl (ie, heterocyclyl) groups.

[0028] The term "alkenyl," as used herein, refers to a straight- or branched-chain hydrocarbon radical containing 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond(s) in an alkenyl group can be located at any position in the moiety and can have either the (Z) or (E) configuration about the double bond(s).

[0029] 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.

[0030] 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, "substituted alkyl" is "alkylene."

[0031] The term "amino" is a term of art and as used herein refers to both unsubstituted and substituted amines, for example, 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 b together with the N atom to which they are attached complete a heterocycle with 4 to 8 atoms in the ring structure, and R d 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 (and optionally R c ) are each independently hydrogen, alkyl, alkenyl, or -(CH2) x -R d In certain embodiments, the term "amino" refers to -NH2.

[0032] In certain embodiments, the term "alkylamino" refers to -NH(alkyl).

[0033] In certain embodiments, the term "dialkylamino" refers to -N(alkyl)2.

[0034] The term "amide," as used herein, means -NHC(=O)-, where the amide group is attached to the parent molecular moiety through a nitrogen. Examples of amides include alkylamides such as CHC(=O)N(H)- and CHCHC(=O)N(H)-.

[0035] The term "acyl" is a term of art and, as used herein, refers to any group or radical of the form RCO-, where R is any organic group, such as alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

[0036] 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.

[0037] The term "aminoacyl" is a term of art and as used herein refers to an acyl group substituted with one or more amino groups.

[0038] The term "aminothionyl" as used herein refers to the analog of aminoacyl in which the O of RC(O)-- is replaced by sulfur, thus the form RC(S)--.

[0039] The term "phosphoryl" is a term of art and as used herein generally refers to a group having the formula: [ka] where Q50 represents S or O, and R59 represents hydrogen, lower alkyl, or aryl, such as -P(O)(OMe)- or -P(O)(OH). For example, when used to substitute an alkyl, the phosphoryl group of the phosphorylalkyl has the general formula: [ka] (wherein Q50 and R59 are each independently defined above, and Q51 represents O, S, or N), for example, -OP(O)(OH)OMe or -NH-P(O)(OH)2. When Q50 is S, the phosphoryl moiety is a "phosphorothioate."

[0040] The term "aminophosphoryl," as used herein, refers to a phosphoryl group substituted with at least one amino group, as defined herein, for example, -P(O)(OH)NMe2.

[0041] The terms "azide" or "azido" as used herein refer to an -N3 group.

[0042] The term "carbonyl" as used herein refers to -C(=O)-.

[0043] The term "thiocarbonyl" as used herein refers to -C(=S)-.

[0044] The term "alkylphosphoryl," as used herein, refers to a phosphoryl group substituted with at least one alkyl group, as defined herein, e.g., -P(O)(OH)Me.

[0045] The term "alkylthio" as used herein refers to alkyl-S-. The term "(alkylthio)alkyl" refers to an alkyl group substituted with an alkylthio group.

[0046] The term "carboxy" as used herein means a -CO2H group.

[0047] 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. Typically, aryl groups contain 6 to 10 carbon ring atoms (i.e., (C6-C8) 10) aryl). The aromatic ring can 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, where two or more carbons are common to two adjacent rings (the rings are "fused rings"), at least one of the rings is an aromatic hydrocarbon, and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. In certain embodiments, the term "aryl" refers to a phenyl group.

[0048] The term "arylene" refers to a diradical obtained by removing two hydrogen atoms from an aryl group as defined above. In certain embodiments, arylene refers to a disubstituted arene, i.e., an arene in which two positions are substituted with substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. That is, in certain embodiments, a "substituted aryl" is an "arylene."

[0049] The term "heteroaryl" is a term of art and as used herein refers to monocyclic, bicyclic, and polycyclic aromatic groups having a total of 3 to 12 atoms and including one or more heteroatoms, such as nitrogen, oxygen, or sulfur, in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanyl, and the like. "Heteroaryl" refers to a group in which one or more ring positions can be substituted 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, etc. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings (the rings are "fused rings"), 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.

[0050] The term "heteroarylene" refers to a diradical obtained by removing two hydrogen atoms from a heteroaryl group as defined above. In certain embodiments, heteroarylene refers to a disubstituted heteroarene, i.e., a heteroarene in which two positions are substituted with substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. That is, in certain embodiments, "substituted heteroaryl" is "heteroarylene."

[0051] The term "aralkyl" or "arylalkyl" is a term of art and, as used herein, refers to an alkyl group substituted with an aryl group, where the moiety is attached to the parent molecule through the alkyl group.

[0052] The term "heteroaralkyl" or "heteroarylalkyl" is a term of art and, as used herein, refers to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through an alkyl group.

[0053] The term "alkoxy" 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.

[0054] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group.

[0055] The term "alkoxycarbonyl" means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein, represented by -C(=O)-. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

[0056] The term "alkylcarbonyl," as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

[0057] The term "arylcarbonyl," as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2-pyridinyl)carbonyl.

[0058] The terms "alkylcarbonyloxy" and "arylcarbonyloxy" as used herein mean an alkylcarbonyl group or an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples of arylcarbonyloxy include, but are not limited to, phenylcarbonyloxy.

[0059] The terms "alkenoxy" or "alkenoxyl" mean an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenoxyl include, but are not limited to, 2-propene-1-oxyl (i.e., CH2=CH-CH2-O-) and vinyloxy (i.e., CH2=CH-O-).

[0060] The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0061] The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0062] The term "carbocyclyl," as used herein, means a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing 3 to 12 carbon atoms and which 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.

[0063] The term "cyano" is a term of art and as used herein refers to --CN.

[0064] The term "halo" is a term of art and as used herein refers to -F, -Cl, -Br, or -I.

[0065] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, in which some or all of the hydrogens have been replaced with halogen atoms.

[0066] The term "hydroxy" is a term of art and as used herein refers to --OH.

[0067] The term "hydroxyalkyl," as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

[0068] The term "silyl," as used herein, includes hydrocarbyl derivatives of the silyl (HSi-) group (i.e., (hydrocarbyl)Si-), where the hydrocarbyl group is a monovalent group formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl group may be a combination of different groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM), and can be varied to provide multiple silyl groups.

[0069] The term "silyloxy" as used herein means a silyl group, as defined herein, appended to the parent molecule through an oxygen atom.

[0070] It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the valences allowed for 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.

[0071] 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 invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0072] In certain embodiments, optional substituents include, for example, halogen, haloalkyl, hydroxyl, carbonyl (such as carboxyl (—COOH), alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetic acid, or thioformic acid), alkoxyl, alkenyloxy, alkynyloxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (including alkyl- and dialkylamino), amido, amidine, imine, cyano, nitro, oxo (═O), azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, silyl, silyloxy, heterocycloalkyl, cycloalkyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group.

[0073] For purposes of this invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements (Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover).

[0074] 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 invention belongs.

[0075] 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 two or more inorganic or organic acid molecules per base molecule, such as two hydrochloric acid molecules per compound of Formula I molecule. As another example, a salt may contain less than one inorganic or organic acid molecule per base molecule, such as two tartaric acid molecules per compound of Formula I molecule.

[0076] 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 (herein incorporated by reference in its entirety).

[0077] 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.

[0078] As used herein, the term "effective amount" refers to an amount sufficient to produce a desired biological effect.

[0079] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce a desired therapeutic effect.

[0080] 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.

[0081] As used herein, the term "subject" refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, the subject is a human.

[0082] In the compounds of the present invention, atoms not specifically designated as a particular isotope are meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen in its naturally occurring isotopic composition. Also, unless otherwise specified, when a position is specifically designated as "D" or "deuterium," the position is understood to have deuterium in an abundance at least 3,340 times greater than the natural abundance of deuterium, i.e., 0.015% (i.e., at least 50.1% deuterium incorporation).

[0083] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0084] In various embodiments, compounds of the invention have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0085] Pharmaceutical Composition The compositions and methods of the present invention can be used to treat individuals in need of treatment. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents, or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for human administration, particularly for invasive administration routes (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical compositions may be in dosage unit form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilizates for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The compositions may also be present in transdermal delivery systems, e.g., skin patches. The compositions may also be present in solutions suitable for topical administration, such as lotions, creams, or ointments.

[0086] Pharmaceutically acceptable carriers can include physiologically acceptable agents that act to stabilize, increase the solubility, or enhance the absorption of compounds such as the compounds of the present invention. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low-molecular-weight proteins; or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, into which, for example, the compounds of the present invention can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and are relatively easy to prepare and administer.

[0087] As used herein, the phrase "pharmaceutically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0088] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of substances that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) celluloses and their derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0089] Pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration, including, for example, orally (e.g., as a drench such as an aqueous or non-aqueous solution or suspension, a tablet, a capsule (including sprinkle capsules and gelatin capsules), a bolus, a powder, a granule, a paste for application to the tongue), absorption through the oral mucosa (e.g., sublingually), subcutaneously, transdermally (e.g., as a patch applied to the skin), and topically (e.g., as a cream, ointment, or spray applied to the skin). The compounds may also be formulated for inhalation. In certain embodiments, the compounds may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents cited therein.

[0090] The formulations can be conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0091] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, optionally, shaping the product.

[0092] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (with a flavored base, usually sucrose and acacia or tragacanth), lyophilized tablets, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as electuaries or syrups, or as pastilles (with an inert base, e.g., gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of a compound of the present invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0093] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient can be combined with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; and (4) disintegrants, such as agar, calcium carbonate. , potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) coloring agents. For capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, etc.

[0094] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0095] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropyl methylcellulose in various proportions to provide the desired release profile, using other polymer matrices, using liposomes, and / or using microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be composed to release the active ingredient(s) only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0096] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilized products for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0097] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0098] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0099] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants which may be required.

[0100] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0101] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0102] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0103] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use and may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0104] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0105] These compositions may contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the compositions. Furthermore, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0106] In some cases, it is desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be achieved by using a liquid suspension of crystalline or amorphous material that is poorly water-soluble. In this case, the absorption rate of the drug depends on the dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0107] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0108] For use in the methods of the present invention, the active compound can be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0109] Methods of introduction can also be provided by refillable or biodegradable devices. A variety of sustained-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0110] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration without being toxic to the patient.

[0111] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts, or amides thereof, employed, the route of administration, the time of administration, the rate of excretion of the particular compound(s) employed, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health, and past medical history of the patient being treated, and similar factors well known in the medical arts.

[0112] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start by administering a pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to the concentration of a compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of a compound varies depending on the subject's weight, sex, age, and medical history. Other factors that affect the effective amount include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, other types of therapeutic agents administered together with the compound of the present invention. A larger total dose can be delivered by multiple administrations of the drug. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th ed., 1814-1882, incorporated herein by reference).

[0113] Generally, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective amount will generally depend upon the factors described above.

[0114] If necessary, the effective daily dose of the active compound can be administered as 1, 2, 3, 4, 5, 6 or more subdoses at appropriate intervals throughout the day, optionally administered separately in unit dosage forms. In certain embodiments of the present invention, the active compound can be administered two or three times a day. In a preferred embodiment, the active compound is administered once a day.

[0115] The patient receiving this treatment is any animal in need of treatment, including primates, especially humans; and other mammals, such as horses, cows, pigs, sheep, cats, and dogs; poultry; and common pets.

[0116] In certain embodiments, the compounds of the invention can be used alone or co-administered with another type of therapeutic agent.

[0117] The present disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, contemplated salts of the present invention include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carboxylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucosamine ... These include, but are not limited to, heptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenate.

[0118] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0119] Wetting agents, emulsifying agents, and lubricating agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0120] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0121] Compounds of the Disclosure In certain aspects, compounds of formula I are provided herein. [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 is selected from the group consisting of H, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, —O—C1-C5 alkyl, —O-cycloalkyl, and —O-heterocycloalkyl; R 2 is selected from the group consisting of H, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, —O—C1-C5 alkyl, —O-cycloalkyl, and —O-heterocycloalkyl; R 3 is selected from the group consisting of H, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, —O—C1-C5 alkyl, —O-cycloalkyl, and —O-heterocycloalkyl; R 4 is selected from the group consisting of H, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, —O—C1-C5 alkyl, —O-cycloalkyl, and —O-heterocycloalkyl; R 5 is selected from the group consisting of H, halo, C1-C5 alkyl, cycloalkyl, heterocycloalkyl, —O—C1-C5 alkyl, —O-cycloalkyl, and —O-heterocycloalkyl; R 1 , R2 , R 3 , R 4 , or R 5 is C1-C5 alkyl, cycloalkyl, heterocycloalkyl, -O-C1-C5 alkyl, -O-cycloalkyl, or -O-heterocycloalkyl, at least one hydrogen atom in the C1-C5 alkyl, cycloalkyl, heterocycloalkyl, -O-C1-C5 alkyl, -O-cycloalkyl, or -O-heterocycloalkyl is replaced with a deuterium atom; R 1 , R 2 , R 3 , and R 4 At least one of them is not H.

[0122] In certain embodiments, R 1 is selected from the group consisting of methyl, ethyl, propyl, and butyl. 1 is selected from the group consisting of CD3, C2D5, C3D7, and C4D9. 1 teeth, [ka] In yet further embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] In additional embodiments, R 1 teeth, [ka] In yet further embodiments, R 1 teeth, [ka] In yet further embodiments, R 1 teeth, [ka] is.

[0123] In certain embodiments, R 1 is selected from the group consisting of -OMe, -OEt, -OPr, and -OBu. 1 is selected from the group consisting of -OCD3, -OC2D5, -OC3D7, and -OC4D9. 1 teeth, [ka] In yet further embodiments, R 1 teeth, [ka] is.

[0124] In certain embodiments, R 2 is selected from the group consisting of methyl, ethyl, propyl, and butyl. 2 is selected from the group consisting of CD3, C2D5, C3D7, and C4D9. 2 teeth, [ka] In yet further embodiments, R 2 teeth, [ka] In certain embodiments, R 2 teeth, [ka] In additional embodiments, R 2 teeth, [ka] In yet further embodiments, R 2 teeth, [ka] In yet further embodiments, R 2 teeth, [ka] is.

[0125] In certain embodiments, R 2 is selected from the group consisting of -OMe, -OEt, -OPr, and -OBu. 2 is selected from the group consisting of -OCD3, -OC2D5, -OC3D7, and -OC4D9. 2 teeth, [ka] In yet further embodiments, R 2 teeth, [ka] is.

[0126] In certain embodiments, R 3 is selected from the group consisting of methyl, ethyl, propyl, and butyl. 3 is selected from the group consisting of CD3, C2D5, C3D7, and C4D9. 3 teeth, [ka] In yet further embodiments, R 3 teeth, [ka] In certain embodiments, R3 teeth, [ka] In additional embodiments, R 3 teeth, [ka] In yet further embodiments, R 3 teeth, [ka] In yet further embodiments, R 3 teeth, [ka] is.

[0127] In certain embodiments, R 3 is selected from the group consisting of -OMe, -OEt, -OPr, and -OBu. 3 is selected from the group consisting of -OCD3, -OC2D5, -OC3D7, and -OC4D9. 3 teeth, [ka] In yet further embodiments, R 3 teeth, [ka] is.

[0128] In certain embodiments, R 4 is selected from the group consisting of methyl, ethyl, propyl, and butyl. 4 is selected from the group consisting of CD3, C2D5, C3D7, and C4D9. 4 teeth, [ka] In yet further embodiments, R 4 teeth, [ka] In certain embodiments, R 4 teeth, [ka] In additional embodiments, R 4 teeth, [ka] In yet further embodiments, R 4 teeth, [ka] In yet further embodiments, R 4 teeth, [ka] is.

[0129] In certain embodiments, R 4 is selected from the group consisting of -OMe, -OEt, -OPr, and -OBu. 4 is selected from the group consisting of -OCD3, -OC2D5, -OC3D7, and -OC4D9. 4 teeth, [ka] In yet further embodiments, R 4 teeth, [ka] is.

[0130] In certain embodiments, R 5 is H. In additional embodiments, R 5is halo. In yet further embodiments, R 5 is F. In yet further embodiments, R 5 is selected from the group consisting of methyl, ethyl, propyl, and butyl. 5 is selected from the group consisting of CD3, C2D5, C3D7, and C4D9. 5 teeth, [ka] In yet further embodiments, R 5 teeth, [ka] In yet further embodiments, R 5 teeth, [ka] In certain embodiments, R 5 teeth, [ka] In additional embodiments, R 5 teeth, [ka] In yet further embodiments, R 5 teeth, [ka]

[0131] In certain embodiments, R 5 is selected from the group consisting of -OMe, -OEt, -OPr, and -OBu. 5 is selected from the group consisting of -OCD3, -OC2D5, -OC3D7, and -OC4D9. 5 teeth, [ka] In yet further embodiments, R 5 teeth, [ka] is.

[0132] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0133] In a further embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0134] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0135] In an additional aspect, provided herein is a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition further comprises an additional therapeutic agent selected from the group consisting of an iron mobilizing agent and deferiprone.

[0136] Treatment method In yet a further aspect, provided herein are methods of treating a disease or condition characterized by a decrease in ferroportin, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure. In certain embodiments, the disease or condition characterized by a decrease in ferroportin is age-related induced ferroportin disease.

[0137] In yet a further aspect, provided herein is a method of treating a disease or condition characterized by decreased iron transport, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0138] In certain aspects, provided herein are methods for treating a disease or condition characterized by a defect or deficiency in a metal transporter, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0139] In an additional aspect, provided herein are methods of treating a disease or condition characterized by iron accumulation, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure. In certain embodiments, the iron accumulation is iron accumulation in the brain.

[0140] In yet an additional aspect, provided herein are methods of treating a disease or condition characterized by iron maldistribution, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure. In certain embodiments, the iron maldistribution is cerebral iron maldistribution.

[0141] In certain embodiments, the disease or condition is selected from the group consisting of anemia of inflammation, iron overload, thalassemia, hemochromatosis, atransferrinemia, myelodysplasia, hypochromic microcytic anemia, ferroportin disease, transfusional iron overload, and aceruloplasminemia.

[0142] In certain aspects, provided herein are methods for treating a neurodegenerative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure. In certain embodiments, the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, and spinal muscular atrophy. In further embodiments, the neurodegenerative disorder is neurodegeneration with brain iron accumulation (NBIA). In still further embodiments, the NBIA is selected from the group consisting of 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 (also known as Parkinson's disease 9 (PARK9)), neuroferritinopathy, Woodhouse-Sakati syndrome, and idiopathic NBIA.

[0143] In certain embodiments, the methods of the present disclosure further comprise administering to the subject an effective amount of an additional therapeutic agent selected from the group consisting of an iron mobilizing agent and deferiprone. [Example]

[0144] The invention will now be generally described, but will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to be limiting thereof.

[0145] Example 1 - Preparation of Boronic Acid Derivatives Magnesium turnings (1 equiv.) was added to an oven-dried 40 mL vial containing a stir bar, and the vial was then evacuated with N2 three times. To a second oven-dried 40 mL vial containing a stir bar under N2, the deuterated alkyl halide and dry Et2O were added. The second vial was mixed briefly, and then the mixture was added dropwise to the Mg-containing vial. A third oven-dried vial containing a stir bar was placed under N2 and trimethyl borate (1.2 equiv.) and dry Et2O were added, while the Grignard reagent was allowed to form over 2 h. The third vial was then cooled to -78 °C, and the Grignard reagent was added dropwise over 10 min. The solution was stirred at -78 °C for 20 min, then warmed to 23 °C over 1 h. 1 M HCl solution was added, and the solution was allowed to stir at 23 °C for 30 min. The reaction was then extracted with EtO (2 × 6 mL), washed with brine (10 mL), and dried over NaSO. 0.5 mL of dry dioxane was added to the dried solution, and the ether was removed under a stream of N. The crude boronic acid in dioxane was directly utilized in the Suzuki-Miyuara coupling with a bromotropolone coupling partner.

[0146] Example 2 - Synthesis of Bromotropolone Scaffold Alpha Bromotropolone Scaffold [ka] An oven-dried, two-necked round-bottom flask was fitted with a condenser and evacuated and backfilled with N three times. Anhydrous KCO (3 equiv.), tropolone (1 equiv.), and 18-crown-6 (0.1 equiv.) were added, followed by MeCN. MeI (5 equiv.) was then added, and the reaction was refluxed for 5 h. The reaction was cooled and then filtered through a Celite pad, rinsing with MeCN. The filtrate was then concentrated in vacuo and purified by flash column chromatography to give the methyl-protected alpha-bromotropolone 1a. 1H NMR (500 MHz, CDCl3) d 7.28 - 7.18 (m, 2H), 7.10 (ddd, J = 10.8, 9.8, 1.0 Hz, 1H), 6.91 - 6.84 (m, 1H), 6.77 (dd, J = 9.9, 0.8 Hz, 1H), 3.94 (s, 3H). 13 C NMR (126 MHz, CDCl3) 180.2, 165.1, 136.5, 136.5, 132.7, 127.8, 112.3, 56.1 HRMS (ESI+) C8H8O2 [M+H] calculated: 137.0603, found: 137.0603

[0147] [ka] To a 40 mL chemical vial containing a stir bar was added the previous product (1 equivalent), followed by NBS (1.2 equivalents) (recrystallized from water) and CCl4. The reaction was then heated at 90°C for 3 hours. The reaction was then rinsed into a separatory funnel with DCM, washed with saturated sodium thiosulfate, and then extracted three times with DCM. The combined organic extracts were then washed with brine, dried over MgSO4, and then concentrated under vacuum. The product was then purified by flash chromatography to yield alpha-bromotropolone scaffold 1b. 1 H NMR (500 MHz, CDCl3) d 8.19 (dd, J = 9.5, 1.0 Hz, 1H), 7.15 (ddd, J = 10.8, 9.9, 1.0 Hz, 1H), 6.79 (dt, J = 9.9, 0.7 Hz, 1H), 6.68 (ddd, J = 10.4, 9.5, 0.7 Hz, 1H), 3.96 (d, J = .8 Hz, 3H) 13 C NMR (126 MHz, CDCl3) d 174.0, 162.9, 140.0, 138.0, 133.0, 125.4, 112.4, 56.9 HRMS (ESI+) calculated for C8H7O2Br [M+H]: 214.9708, found: 214.9717

[0148] Beta-bromotropolone scaffold [ka] A large round-bottom flask was fitted with an addition funnel and evacuated and backfilled with N2 three times. KOtBu (1.5 equiv.) and pentane were added to the flask. The solution was then cooled to 0 °C in an ice bath. 1,3-Cyclohexadiene was then added (1 equiv.) via syringe. CHBr3 (1.2 equiv.) was then added via addition funnel over 1 h. The reaction was then stirred at 0 °C for 1 h, then warmed to room temperature, and stirred for an additional 1 h. Water was then added to the round-bottom flask and stirred. The reaction was then transferred to a separatory funnel, extracted three times with hexane, dried over MgSO4, and concentrated in vacuo. The product was then purified by flash chromatography to give the desired intermediate 2a as an oil. 1 H NMR (500 MHz, CDCl3) d 5.92 (app. d, J = 2.9 Hz, 2H), 2.14 (dd, J = 10.4, 2.2 Hz, 1H), 2.08-2.01 (m, 3H), 1.95-1.90 (m, 2H) 13 C NMR (126 MHz, CDCl3) d 130.1, 122.2, 39.6, 29.6, 27.7, 21.0, 17.8 HRMS (ESI+) calculated for C7H8Br2 [M+H]: 249.8993, found: 249.8996

[0149] [ka] To a 40 mL chemical vial was added 2a (1 equiv.), followed by a solution containing 1:1 tBuOH:HO, NMO (2 equiv.), and freshly distilled pyridine (2.5 equiv.). OsO (0.03 equiv.) was then added from a 40 mg / mL solution in HO. The reaction was then heated to 100 °C and vigorously stirred for 3 h. The reaction was then cooled and poured into aqueous sodium thiosulfate solution and quenched overnight. The crude product was then added to a separatory funnel and extracted five times with EtO. The organic extract was washed with saturated aqueous CuSO, water, and brine, then dried over MgSO, and concentrated in vacuo. The crude product was then purified by flash column chromatography to give the desired product 2b as a brown solid. 1 H NMR (500 MHz, CD3OD) d 3.77 (ddd, J = 5.6, 3.0, 1.9 Hz, 1H), 3.5 (t, J = 2.8 Hz, 1H), 2.12-2.03 (m, 1H), 2.03-1.96 (m, 1H), 1.85 (dd, J = 11.1, 2.6 Hz, 1H), 1.70-1.54 (m, 2H), 1.41-1.26 (m, 1H). 13 C NMR (126 MHz, CD3OD) d 69.5, 67.8, 37.2, 34.2, 29.1, 26.6, 16.7 HRMS(ESI+)C7H 10 Calculated value for O2Br2[M+Na]: 306.8945, Found: 306.8948

[0150] [ka] An oven-dried, three-necked round-bottom flask was equipped with a stir bar and placed under N2. DCM (200 mL) and DMSO (4 equiv.) were added, and the reaction was cooled to -65 °C using an immersion condenser. After cooling, TFAA (4 equiv.) was added via syringe over 10 min. After 15 min, a solution of 2b (1 equiv.) in DMSO (10 mL) was added over 10 min. The reaction was allowed to proceed for 2 h, and then NEt3 (7 equiv.) was added over 10 min. The reaction was allowed to proceed for 2 h and then warmed to room temperature. The reaction was then quenched with 200 mL of 2 M HCl, transferred to a separatory funnel, and extracted three times with DCM. The combined organic layers were then washed three times with water, then once with brine, then dried over MgSO4, and concentrated in vacuo. This mixture containing 2c was then carried on to the next step without purification.

[0151] [ka] An oven-dried, two-necked round-bottom flask was fitted with a condenser and evacuated and backfilled with N three times. Anhydrous KCO (3 equiv.), a mixture of 2c (1 equiv.), and 18-crown-6 (0.1 equiv.) were added, followed by MeCN. MeI (5 equiv.) was then added, and the reaction was refluxed for 5 h. The reaction was cooled and then filtered through a Celite pad, rinsing with MeCN. The filtrate was then concentrated in vacuo and purified by flash column chromatography to give the methyl-protected beta-bromotropolone. 1 H NMR (500 MHz, CDCl3) d 7.63 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 11.4, 2.0 Hz, 1H), 6.79 (dd, J = 11.4, 10.1 Hz, 1H), 6.59 (d, J = 10.1 Hz, 1H), 3.90 (s, 3H) 13 C NMR (126 MHz, CDCl3) d 177.2, 165.3, 139.3, 136.9, 132.5, 131.6, 111.0, 56.5 HRMS (ESI+) calculated for C7H5O2Br [M+H]: 219.9708, found: 219.9704

[0152] Gamma-bromotropolone scaffold [ka] The gamma-bromotropolone scaffold was synthesized following the same procedure as the beta-bromotropolone scaffold, using 1,4-cyclohexadiene instead of 1,3-cyclohexadiene in the first step, to give the following intermediates: [ka] 1 H NMR (500 MHz, CDCl3) d 5.50 (s, 2H), 2.47 (d, J = 17.5 Hz, 2H), 2.10 (d, J = 17.5 Hz, 2H), 1.91 (dd, J = 5.3, 2.4 Hz, 2H) 13 C NMR (126 MHz, CDCl3) d 122.6, 38.5, 25.1, 21.1 HRMS (ESI+) calculated for C7H8Br2 [M+H]: 249.8993, found: 249.9005 [ka] 1 H NMR (500 MHz, CD3OD) d 3.66-3.59 (m, 2H), 2.17 (dtd, J = 15.3, 6.6, 3.1 Hz, 1H), 1.99-1.90 (m, 2H), 1.76 (ddd, J = 15.2, 4.7, 1.8 Hz, 2H) 13 C NMR (126 MHz, CD3OD) d 68.3, 40.2, 28.4, 28.0 HRMS(ESI+)C7H 10 Calculated for O2Br2 [M+H]: 265.8942, Found: 265.8941

[0153] [ka] As above, it was used in the next step without purification. [ka] 1 H NMR (500 MHz, CDCl3) d 7.38 (dd, J = 13.1, 2.0 Hz, 1H), 7.36 (dd, J = 11.0, 2.0 Hz, 1H), 6.95 (d, J = 13.0 Hz, 1H), 6.46 (d, J = 10.9 Hz, 1H), 3.88 (s, 3H) 13 C NMR (126 MHz, CDCl3) d 179.5, 164.8, 140.1, 136.1, 134.4, 122.6, 111.6, 56.5 HRMS (ESI+) calculated for C7H5O2Br2 [M+H]: 214.9708, found: 214.9710

[0154] 1,3-Dibromotropolone scaffold [ka] The synthesis is the same as the procedure listed for 1A. [ka] To an oven-dried vial containing a stir bar was added 30 mL of CCl4 and the methyl-protected tropolone from the previous step (1 gram, 7.3 mmol). N-bromosuccinimide (2.1 equivalents) was added in two portions, after which the vial was capped, sealed with electrical tape, and heated to 90°C overnight. The reaction was then rinsed into a separatory funnel with DCM, washed with saturated sodium thiosulfate, and then extracted three times with DCM. The combined organic extracts were then washed with brine, dried over MgSO4, and then concentrated under vacuum. The product was then purified by flash chromatography to give the desired product. 1 H NMR (500 MHz, CDCl3) δ 8.45 (d, 1H), 7.46 (d, 1H), 6.54 (d, 1H), 3.94 (s, 3H) 13 C NMR (126 MHz, CDCl3) δ 173.3, 161.9, 142.8, 137.0, 134.5, 119.5, 111.5, 56.9

[0155] 1,3,5-tribromotropolone scaffold [ka] To an oven-dried 40 mL vial containing a stir bar was added 30 mL of CCl4 and tropolone (1 gram, 8.1 mmol). N-Bromosuccinimide (3.2 equivalents) was added in three portions, after which the vial was capped, sealed with electrical tape, and heated to 90°C overnight. The reaction was then rinsed into a separatory funnel with DCM, washed with saturated sodium thiosulfate, and then extracted three times with DCM. The combined organic extracts were then washed with brine, dried over MgSO4, and concentrated under vacuum to give the pure product, which was used directly in the next step. 1 H NMR (500 MHz, CDCl3) δ 8.34 (s, 2H) 13 C NMR (126 MHz, CDCl3) δ 164.4, 144.0, 124.3, 118.0

[0156] [ka] An oven-dried, two-necked round-bottom flask was fitted with a condenser and evacuated and backfilled with N three times. Anhydrous KCO (16.97 g, 123 mmol, 3 equiv.), 7a (5 g, 41 mmol, 1 equiv.), and 18-crown-6 (1.08 g, 4.1 mmol, 0.1 equiv.) were added, followed by MeCN (250 mL). MeI (29.1 g, 205 mmol, 5 equiv.) was then added, and the reaction was refluxed for 3 h. The reaction was cooled and then filtered through a Celite pad, rinsing with acetone. The filtrate was then concentrated in vacuo and purified by flash column chromatography to give the product as a yellow solid. 1 H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 7.95 (s, 1H), 4.01 (s, 3H)

[0157] Example 3 - General Procedure for Derivatives Containing α'-Fluorine / α-Substitution [ka] The benzyl-protected α-bromotropolone scaffold was prepared as previously described (4). To a mixture of this scaffold in DMSO, dry CsF (1.5 equiv.) was added under N2 atmosphere. The mixture was stirred at 110 °C for 8 h under N2. The reaction was cooled to 25 °C and brine was added. The aqueous mixture was extracted with EtOAc, and the combined organic layers were washed with brine and then dried over Na2SO4. The solution was concentrated and purified by silica gel chromatography to give the product.

[0158] The resulting residue was then deprotected using TFA at 50°C to give the α-fluorotropolone scaffold, as previously described. Briefly, the residue was dissolved in TFA, and the mixture was stirred at 50°C for 1 hour. The mixture was concentrated under vacuum, and the crude product was used in the next step.

[0159] To a solution of the crude product in CCl4 at 25 °C under N2, NBS (1.3 equiv.) was added slowly. The mixture was heated to 80 °C for 3 h. After that, the mixture was cooled to 25 °C and water was added. The aqueous mixture was extracted 3x with dichloromethane, and the combined organics were washed with brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness to give the fluoro / bromo intermediates as a crude mixture, which was used in the next step without purification.

[0160] The intermediate was then reprotected using the methyl protection procedure described previously (4). Briefly, the crude residue was resuspended in MeCN, to which KCO (3 equiv.) and 18-crown-6 (0.1 equiv.) were added under N. MeI (4 equiv.) was then added dropwise, and the reaction was heated to 85 °C and continued for 12 h. After cooling, the mixture was filtered, and the residue was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give the desired methylated fluoro / bromotropolone scaffold. This scaffold was then used in GP1 and subsequently GP2 to give the desired α-fluoro / α-substituted derivatives.

[0161] Example 4 - General procedure for derivatives containing α'-fluorine / α,γ-substitution [ka] The methyl-protected α-fluoro / α-substituted derivatives were obtained as shown above after GP1. To a solution of this product in CHCl3 at 25°C under N2, NBS (1.3 equiv.) was slowly added. The mixture was heated to 80°C for 3 hours. The mixture was then cooled to 25°C, and water was added. The aqueous mixture was extracted 3x with dichloromethane, and the combined organics were washed with brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness to give the α-fluoro / α-substituted / γ-bromo intermediates, which were purified by silica gel chromatography. The purified products were used in GP1 and subsequently in GP2 to give the α-fluoro / α,γ-substituted derivatives.

[0162] Example 5 - General procedure for derivatives containing α'-fluorine / γ-substitution [ka] The γ-bromotropolone scaffold was synthesized as described in Example 2. This scaffold was then used in GP1 to obtain the protected coupling product. Subsequently, this product was redissolved in CHCl3, and NBS (1.3 equiv.) was slowly added at 25°C under N2. The mixture was heated to 80°C for 3 hours. The mixture was then cooled to 25°C, and water was added. The aqueous mixture was extracted 3x with dichloromethane, and the combined organics were washed with brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness to afford the α'-bromo / γ-substituted intermediate, which was purified by silica gel chromatography. The purified product was used in the α'-fluorination procedure as previously described.

[0163] Briefly, to a mixture of this scaffold in DMSO was added dry CsF (1.5 equiv.) under N2 atmosphere. The mixture was stirred at 110 °C under N2 for 8 h. The reaction was cooled to 25 °C and brine was added. The aqueous mixture was extracted with EtOAc, and the combined organic layers were washed with brine and then dried over Na2SO4. The solution was concentrated and purified by silica gel chromatography to give the protected product. This product was then deprotected using GP2 to give the desired final product.

[0164] Example 6 - Procedure for α-perdeuterated furan derivatives [ka] The benzyl-protected α-bromotropolone scaffold used in the Heck coupling was prepared as described in Example 2.

[0165] Preparation of 2'3'-dideuterofuran-d6(a) (based on the synthesis from J. Org. Chem. 2007, 72, 19, 7253-7259) [ka] LiAlD4 was suspended in THF and refluxed for 30 min. After cooling to -55 °C using an immersion condenser, a solution of succinic anhydride-d4 in THF was added dropwise over 30 min. The solution was warmed to 25 °C over 90 min and then cooled to -15 °C for 15 min. A 6 M HCl solution was added slowly, and the solution was warmed to 25 °C and stirred for 20 min. The reaction mixture was washed with brine, and the organics were extracted 3x with Et2O. The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was purified by fractional distillation (BP 65 °C) to give the desired product.

[0166] This product was then dissolved in dichloromethane and cooled to −78° C. using an immersion chiller for 2 h. A solution of cold DIBAL-D in DCM (4° C.) was slowly added and the reaction allowed to proceed for 2 h. The reaction was quenched by slowly adding MeOD and saturated Rochelle's salt, and the reaction was warmed to 25° C., causing a precipitate to form. The solid was resuspended in dichloromethane, and the filtrate was concentrated to give the crude lactol, which was used immediately in the next step without purification.

[0167] A three-neck flask was charged with the solution of TsOH in quinoline, and a distillation apparatus was assembled. 2 M aqueous NaOH was frozen around the bottom of the receiver flask. The quinoline solution was immersed in a wax bath at 190 °C, and the receiver flask was maintained at -78 °C in a dry ice / acetone bath. The crude product from the previous step was added dropwise to the quinoline solution, and the solution was heated to 210 °C for 1 h. The collected liquid was quickly removed from the apparatus and purified by distillation (BP 54 °C) to give the final desired product.

[0168] 2'3'-dideuterofuran-d6(a) and the benzyl-protected α-bromotropolone scaffold were used in the Heck coupling as described in Example 2.

[0169] Briefly, to a solution of a (5 equiv.) and benzyl-protected α-bromotropolone scaffold in dioxane in a pressure flask, K2CO3 (2 equiv.), Ph3P (0.20 equiv.), and Pd(OAc)2 (0.10 equiv.) were added under Ar in a glovebox. The mixture was then heated to 110 °C for 2 h, after which the reaction was cooled and water was added. The mixture was extracted 2x with EtOAc, and the combined organics were washed with brine and dried over Na2SO4. The crude product was concentrated in vacuo and purified by silica gel chromatography to give the racemic Heck coupling intermediate (b).

[0170] To a solution of intermediate (b) in MeOD was added Rh(PPh3)3Cl under N2. The reaction flask was evacuated and refilled with D23x, and the mixture was stirred under D2 (1 atm) for 4 h. The reaction mixture was filtered through Celite, rinsing with MeOH, and then concentrated under vacuum to give the desired product as a racemic mixture. The mixture was resolved using chiral SFC with a DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 mm) as the stationary phase. The separated enantiomers were then used separately in the final step to give the desired product.

[0171] The enantiomers were separately dissolved in neat TFA and heated at 50°C for 2 hours with stirring. The reaction mixture was cooled and then concentrated under vacuum to give the crude products. The residues were separately purified by preparative HPLC using Nano-micro Kromasil C18 (100mm*30mm, 8mm) as the stationary phase to give the final desired products as pure enantiomers.

[0172] Example 7 - General procedure for preparing derivatives via Csp2-Csp3 bond formation In general, the perdeuterated derivatives were synthesized as follows: The bromotropolone scaffold was synthesized as described above. An oven-dried 8 mL vial containing a stir bar and the vial containing the crude boronic acid were brought into an Ar-filled glovebox. Inside the glovebox, all solid components were added first: bromotropolone scaffold (0.5 mmol, 1 equiv.), Pd(dba) (0.05 mmol, 0.1 equiv.), P(o-tol) (0.1 mmol, 0.2 equiv.), and AgO (0.75 mmol, 1.5 equiv.). An additional 0.5 mL of dry dioxane was then added to the crude boronic acid mixture (total of 1 mL of dioxane), and then the boronic acid in dioxane was added to the chemical vial using a micropipettor. For polybrominated scaffolds, equivalent amounts of reagents per bromide were used. For example, for the tribromotropolone scaffold, Pd(dba) (0.15 mmol, 0.3 equiv.), P(o-tol) (0.3 mmol, 0.6 equiv.), and AgO (2.25 mmol, 4.5 equiv.) were used in a total of 3 mL of dry dioxane. For the dibromotropolone scaffold, Pd(dba) (0.1 mmol, 0.2 equiv.), P(o-tol) (0.2 mmol, 0.4 equiv.), and AgO (1.5 mmol, 3 equiv.) were used in a total of 2 mL of dry dioxane. The vial was then capped, removed from the glovebox, and stirred at 85 °C for 36 h. The crude reaction was then passed through a silica plug, rinsing with EtOAc, and then concentrated under vacuum. The mixture was then dissolved in HPLC-grade MeOH (5 mL) and subsequently purified by preparative HPLC on an Agilent 1200 Series HPLC equipped with a Waters Sunfire OBD Prep Column (100 Å, 5 μm, 30 mm × 150 mm) using MeCN and HO as the mobile phase at a flow rate of 40 mL / min and monitoring at 238 nm. The purified material was collected and then concentrated in vacuo, using additional MeCN to azeotrope residual water as needed.

[0173] Another method for forming a C-C bond between sp2 and sp3 centers involves using Grignard reagents to generate Kumada couplings starting from haloalkane counterparts (J. Organomet. Chem. 1997, 532, 1, 271-273; Bioorg. Med. Chem. 2007, 15, 22, 7144-7165; Adv. Synth. Catal. 2019, 361, 19, 4468-4473). 2-Hydroxy-4-(isopropyl-d7)-cyclohepta-2,4,6-trien-1-one and 2-hydroxy-5-(isopropyl-d7)-cyclohepta-2,4,6-trien-1-one can be prepared in a similar manner using perdeuterated haloalkanes.

[0174] Acid deprotection of the methyl ether coupling product An 8 mL chemical vial was equipped with a stir bar. The purified material from GP1 was dissolved in dioxane (0.11 M) and added to the vial. Next, 20% H2SO4 solution was added (0.11 M, equal volume to dioxane). This was then heated to 100 °C and stirred for 3 hours. The reaction mixture was then diluted with water and extracted three times with ether. The combined organic extracts were then dried over Na2SO4 and concentrated in vacuo to give the final product.

[0175] Example 8 - Characterization data for selected compounds [ka] 2-Hydroxy-3-methylcyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.55 - 7.51 (m, 1H), 7.35 (dd, J = 10.3, 1.2 Hz, 1H), 7.32 - 7.27 (m, 1H), 6.97 (td, J = 9.8, 1.2 Hz, 1H), 2.48 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.5, 167.6, 139.9, 138.1, 135.8, 127.4, 121.2, 22.2. HRMS (ESI+) calculated for C8H8O2 [M+H]: 137.0603, found: 137.0602

[0176] [ka] 2-Hydroxy-4-methylcyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.30-7.24 (m, 3H), 6.92 (m, 1H), 2.47 (s, 3H) 13 C NMR (126 MHz, CDCl3) δ 170.8, 170.7, 149.9, 136.7, 129.7, 125.7, 121.9, 27.2 HRMS (ESI+) calculated for C8H8O2 [M+H]: 137.0603, found: 137.0607

[0177] [ka] 2-Hydroxy-5-methylcyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.32 - 7.26 (m, 4H), 2.45 (s, 3H) 13 C NMR (126 MHz, CDCl3) δ 170.7, 138.4, 123.9, 25.9 HRMS (ESI+) C8H8O2 [M+H] calculated: 137.0603, found: 137.0600

[0178] [ka] 2-Hydroxy-3-(methyl-d3)cyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.52 (d, 1H), 7.35 (d, 1H), 7.29 (t, 1H), 6.97 (t, 1H) 2 H NMR (500 MHz, CDCl3) δ 2.45 13 C NMR (126 MHz, CDCl3) δ 172.5, 167.5, 140.5, 137.8, 135.7, 127.3, 121.2 HRMS (ESI+) calculated for C8H5D3O2 [M+H]: 140.0791, found: 140.0793

[0179] [ka] 2-Hydroxy-4-(methyl-d3)cyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.30-7.24 (m, 3H), 6.92 (m, 1H) 2 H NMR (500 MHz, CDCl3) δ 2.46 13 C NMR (126 MHz, CDCl3) δ 170.8, 170.7, 149.9, 136.8, 129.8, 125.7, 122.0 HRMS (ESI+) calculated for C8H5D3O2 [M+H]: 140.0791, found: 140.0796

[0180] [ka] 2-Hydroxy-5-(methyl-d3)cyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.32 - 7.26 (m, 4H) 2 H NMR (500 MHz, CDCl3) δ 2.39 13 C NMR (126 MHz, CDCl3) δ 170.7, 138.5, 124.0 HRMS (ESI+) calculated for C8H5D3O2 [M+H]: 140.0791, found: 140.0794

[0181] [ka] 2-Hydroxy-1,3,5-trimethylcyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CD3CN) δ 7.39 (s, 2H), 2.38 (s, 3H), 2.37 (s, 6H) 13 C NMR (126 MHz, CD3CN) δ 167.8, 140.1, 136.8, 135.0, 26.2, 21.5

[0182] [ka] 2-Hydroxy-4-(isopropyl-d7)-cyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.30-7.24 (m, 3H), 6.95 (m, 1H) 2 H NMR (500 MHz, CDCl3) δ 2.90, 1.27 13 C NMR (126 MHz, CDCl3) δ 170.8, 170.7, 149.9, 136.5, 129.7, 125.6, 121.5,

[0183] [ka] 2-Hydroxy-5-(isopropyl-d7)-cyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.32 - 7.26 (m, 4H) 2 H NMR (500 MHz, CDCl3) δ 2.92, 1.26 13 C NMR (126 MHz, CDCl3) δ 170.7, 144.0, 138.2, 124.1

[0184] [ka] 2-Hydroxy-4-butylcyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.30-7.24 (m, 3H), 6.92 (dd, 1H), 2.63 (dd, 2H), 1.64 (m, 2H), 1.38 (tq, 1H), 0.94 (t, 1H) 13 C NMR (126 MHz, CDCl3) δ 170.9, 170.5, 154.6, 136.9, 129.4, 125.2, 122.1, 41.0, 33.4, 22.2, 13.8

[0185] [ka] 2-Hydroxy-4-(butyl-d9)cyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.30-7.24 (m, 3H), 6.92 (m, 1H) 2 H NMR (500 MHz, CDCl3) δ 2.57, 1.56, 1.30, 0.87 13C NMR (126 MHz, CDCl3) δ 170.9, 170.7, 154.6, 136.9, 129.4, 125.2, 122.1

[0186] [ka] 2-Hydroxy-1,3-dimethylcyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.43 (s, 1H), 7.26 (d, 1H), 7.16 (d, 1H), 2.40 (s, 3H), 2.37 (s, 3H) 13 C NMR (126 MHz, CDCl3) δ 171.9, 166.4, 141.3, 137.7, 137.5, 136.0, 121.4, 26.0, 22.3

[0187] [ka] 2-Hydroxy-1,3-(dimethyl-d6)cyclohepta-2,4,6-trien-1-one 1 H NMR (500 MHz, CDCl3) δ 7.43 (s, 1H), 7.26 (d, 1H), 7.16 (d, 1H) 2 H NMR (500 MHz, CDCl3) δ 2.41, 2.37 13 C NMR (126 MHz, CDCl3) δ 171.9, 166.2, 141.4, 137.7, 137.5, 136.0, 121.3

[0188] Example 9 - Preparation of Liposomes Liposomes were prepared as previously described (AS Grillo et al. Science, 356, 608-615 (2017)). Lipid films were generated by adding 200 μL of 4 mg / mL recrystallized cholesterol in chloroform to 960 μL of a 25 mg / mL POPC solution in chloroform (Avanti Polar Lipids 850457C). After evaporation under a nitrogen stream, the film was placed under high vacuum for 18 hours to ensure quantitative solvent removal. The lipid film was rehydrated by adding 1 mL of intraliposomal buffer (15 mM FeCl3, 125 mM citrate, 50 mM MES / TRIS pH 7.0) to the lipid film and vortexing thoroughly to form a solution of multilamellar vesicles (MLVs). The liposomes were then extruded through an Avanti Lipids extruder (Avanti Polar Lipids 610023) using a 0.2 mm membrane (Whatman 800281) to filter the MLV suspension 21 times to ensure uniform large unilamellar vesicles (LUVs). The LUVs were subjected to size exclusion chromatography using a 20 cm column of Sephadex® G-50 Medium resin hydrated in extraliposomal buffer (600 mM sodium ascorbate, 50 mM MES / TRIS pH 7.0). Separation of LUVs from extravesicular Fe was easily visualized on the column, and the most concentrated fraction of LUVs was collected.

[0189] Example 10 - Liposome Quantification Total phosphorus determination was performed using the Bartlett assay. Briefly, the LUV suspension was diluted 10-fold in extraliposomal buffer, and 10 μL of this solution, along with 10 μL of extraliposomal buffer for background, was then placed into three 7 mL vials. 450 mL of 8.9 M H2SO4 was then added, and the mixture was heated at 225 °C for 25 minutes in the open air. After cooling, 150 mL of 30% H2O2 was added, and the mixture was further heated at 225 °C for 30 minutes in the open air. The samples were then cooled completely and diluted with 3.9 mL of Milli-Q water. 500 mL of 2.5% w / v ammonium molybdate was then added, the samples were then vortexed, and 500 mL of 10% w / v ascorbic acid was then added. The samples were then revortexed, capped, and heated at 100 °C for 7 minutes. The samples were allowed to cool completely and then read at A820 and compared to a phosphorus standard curve to determine total phosphorus.

[0190] Example 11 - Liposome Ejection Assay The data from this experiment are shown in Figure 2A.

[0191] A 16 mL liposome suspension was made with the following components: 160 mL of ferrozine solution (100x stock solution, 50 mM in extraliposomal buffer), LUV suspension (to a final concentration of 1 mM phosphorus), and up to 16 mL of extraliposomal buffer. Using a multichannel pipettor, 195 mL of liposome suspension was then added to a 96-well plate (NUM). The plate was then placed in a plate reader and equilibrated at 37°C for 5 minutes before being read for a baseline measurement. After this equilibration, compounds were added at the designated concentrations (40x stock solutions in DMSO) using a multichannel pipettor, and the plate was then incubated at 37°C for 40 minutes. A562 readings were taken every minute, and the plate was mixed at 220 rpm. Total iron excretion was determined by the ferrocene-iron complex signal. These experiments were performed in triplicate with a minimum of two biological replicates.

[0192] Example 12 - H9C2 Toxicity Assay The data from this experiment are shown in Figure 2B.

[0193] H9C2 cells (ATCC CRL-1446) were cultured in T175 culture flasks (Thermofisher) in DMEM medium supplemented with 10% FBS (Gemini 900-108), 1% penicillin-streptomycin (Gibco 15140-122), and 1% MEM non-essential amino acids (Corning 25-025-Cl) at 37°C / 5% CO2 for at least five passages. Cell pellets were centrifuged and diluted to 5x10 cells. 5 A solution of 100 cells / mL was obtained. A 96-well compound plate containing 40x DMSO solutions of the desired test compounds across the desired concentration range was prepared using a 100 mM DMSO stock solution. Using a multichannel micropipettor, 3.34 μL of each stock solution was added to 297 μL of cell culture medium in the 96-well plate and gently mixed by pipetting up and down. 3x80 μL of each prepared compound solution was added to consecutive rows in a 96-well tissue culture plate, with the top and bottom rows filled with cell culture medium to reduce evaporation. Subsequently, 20 μL of 5x10 5 The cells / mL solution was adjusted so that each well contained 1x10 4 A micropipette was used to add the cells to each well. After incubating the plate at 37°C / 5% CO2 for 4 days, cell viability was measured using AlamarBlue reagent according to the assay protocol. Briefly, 10 μL of AlamarBlue reagent was added to each well, and the plate was then incubated for 3 hours. Cell viability was determined by fluorescent signal (Em555 / Ex585) using a microplate reader (BioTek Synergy H1 Hybrid Reader) and comparison with puromycin- and DMSO-treated wells as positive and negative controls, respectively.

[0194] Example 13 - K562 Toxicity Assay The data from this experiment are shown in Figure 2C.

[0195] K562 cells (ATCC CCL-243) were cultured in T175 culture flasks (Thermofisher) in IMDM (Iscove's Modified Dulbecco's Medium, ATCC 30-2005) supplemented with 10% FBS (Gemini 900-108), 1% penicillin-streptomycin (Gibco 15140-122), and 1% MEM non-essential amino acids (Corning 25-025-Cl) at 37°C / 5% CO2 for at least five passages. Cell pellets were centrifuged and diluted to a concentration of 1.25 x 10 cells. 6 A solution of 100 cells / mL was obtained. A 96-well compound plate containing 40x DMSO solutions of the desired test compounds across the desired concentration range was prepared using a 100 mM DMSO stock solution. Using a multichannel micropipettor, 3.34 μL of each stock solution was added to 297 μL of cell culture medium in the 96-well plate and gently mixed by pipetting up and down. 3x80 μL of each prepared compound solution was added to the 96-well plate in consecutive rows, with the top and bottom rows filled with cell culture medium to reduce evaporation. Subsequently, 20 μL of 1.25x10 6 The cells / mL solution was adjusted so that each well contained 2.5x10 4 A micropipette was used to add the cells to each well. After incubating the plate at 37°C / 5% CO2 for 4 days, cell viability was measured using AlamarBlue reagent according to the assay protocol. Briefly, 10 μL of AlamarBlue reagent was added to each well, and the plate was then incubated for 3 hours. Cell viability was determined by fluorescent signal (Em555 / Ex585) using a microplate reader (BioTek Synergy H1 Hybrid Reader) and comparison with puromycin- and DMSO-treated wells as positive and negative controls, respectively.

[0196] Example 14 - C. Elegans Experimental Procedure The data from this experiment are shown in Figures 3A-3H. C. elegans strains: BY200 vtIs1[pdat-1::gfp;rol-6]V NES277 fpn-1.2-KO V;vtIs1[pdat-1::gfp;rol-6]V GA631 wuIs177[ftn-1p::GFP+lin-15(+)]X NES281 fpn-1.2-KO V;wuIs177[ftn-1p::gfp+lin-15(+)]X

[0197] Analysis of dopaminergic neurodegeneration Strains BY200 and NES277 were grown on standard NGM plates. At 1 day of age, worms were transferred to NGM plates containing vehicle (DMSO) or various concentrations of deferiprone (DFP), hinokitiol (Hino), and FeM-1269. Worms were passaged daily and imaged on day 7 using a Zeiss AxioImager microscope equipped with DIC and fluorescence. Data analysis was performed blindly according to a previously described protocol (R. Nass, D.H. Hall, D.M. Miller, R.D.Blakely, Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans. Proceedings of the National Academy of Sciences 99, 3264-3269 (2002)).

[0198] Measurement of ferritin fluorescence GA631 and NES281 strains were grown on regular NGM plates. At 1 day of age, worms were transferred to NGM plates containing vehicle (DMSO) or various concentrations of DFP, Hino, and FeM-1269. Worms were passaged daily and imaged on day 5 using a Zeiss LSM880 at 20x magnification, focusing on the head. Fluorescence intensity was quantified blindly using ImageJ.

[0199] Example 15 - Procedure for measuring brain iron levels in flatiron mice The data from this experiment are shown in Figures 4A-E.

[0200] animal control This study was conducted in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (Bethesda, MD, USA). The protocol (protocol number: PRO00010742) was approved by the University of Michigan's Committee on Use and Care of Animals (UCUCA). Flatiron (ffe / +) mice were provided by IEZohn (Children's National Medical Center, Washington, DC). All mice used in these studies were on the 129S6 / SvEvTac background. Weanling mice were fed a diet (TD120518; Harlan Teklad, Indianapolis, IN, USA) as previously reported (YASeo, J.A. Elkhader, M. Wessling-Resnick, Distribution of manganese and other biometals in flatiron mice. Biometals 29, 147-155 (2016); YASeo, M. Wessling-Resnick, Ferroportin deficiency impairs manganese metabolism in flatiron mice. FASEB J 29, 2726-2733 (2015)).

[0201] elevated cross maze This technique has been widely used in mice to test anxiety-like behavior and motor activity (AA W Alf, CA Frye, The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2, 322-328 (2007)). The elevated plus maze consists of two open arms and two closed arms extending from a central zone platform. Each mouse was placed in the central zone facing the open arms and allowed to explore the maze for 5 minutes. The time spent and frequency of entries in the three areas of the apparatus, i.e., the open arms, the closed arms, and the central zone, as well as the total distance traveled throughout the maze, the frequency and duration of rearing behavior were recorded and analyzed using EthoVision XT (Noldus).

[0202] Inductively coupled plasma mass spectrometry (ICP-MS) measurement of brain Fe levels To characterize the acute and chronic effects of Hino on iron mobilization and distribution, we administered Hino to flatiron mice and their WT littermates via intraperitoneal (IP) injection. After 4 hours or 1 week, the mice were euthanized, their brains were harvested, and iron content was measured by ICP-MS. (Y.A. Soe, J.A. Elkhader, M. Wessling-Resnick, "Distribution of manganese and other biometals in flatiron mice." Biometals 29, 147-155 (2016); Y.A. Soe, M. Wessling-Resnick, "Ferroportin deficiency impairs manganese metabolism in flatiron mice." FASEB J 29, 2726-2733 (2015)).

[0203] Example 16 - Dynamic Light Scattering Experiments Dynamic light scattering was performed on a Malvern Zetasizer Nano using disposable cuvettes. Samples were evaluated in the same buffer as for liposome extrusion studies (50 mM MES / TRIS, pH 7.0, using either 1 M MES or 1 M TRIS solutions). A defined concentration of compound (1000X in DMSO) and equimolar FeCl3 (1000X in 1 M HCl) were added to this buffer. After addition, the compounds were vortexed for 30 seconds, sonicated for 1 minute, and then vortexed for an additional 30 seconds before equilibrating in the Zetasizer at 37°C for 5 minutes. All standard parameters were used, and each graph represents a minimum of 30 10-second measurements. Count rate analysis utilized raw count rates and accounted for differences in attenuator position between samples.

[0204] Incorporation by Reference All U.S. patents and U.S. and PCT patent application publications referred to 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.

[0205] 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 disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

1. Compound of formula I 【Chemistry 1】 or a pharmaceutically acceptable salt thereof During the ceremony, R １ H, C １ ~C ５ Alkyl, cycloalkyl, heterocycloalkyl, -O-C １ ~C ５ Selected from the group consisting of alkyl, -O-cycloalkyl, and -O-heterocycloalkyl, R ２ is selected from H, C １ to C ５ alkyl, cycloalkyl, heterocycloalkyl, -O-C １ to C ５ alkyl, -O-cycloalkyl, and -O-heterocycloalkyl R ３ H, C １ ~C ５ Alkyl, cycloalkyl, heterocycloalkyl, -O-C １ ~C ５ Selected from the group consisting of alkyl, -O-cycloalkyl, and -O-heterocycloalkyl, R ４ H, C １ ~C ５ Alkyl, cycloalkyl, heterocycloalkyl, -O-C １ ~C ５ Selected from the group consisting of alkyl, -O-cycloalkyl, and -O-heterocycloalkyl, R ５ H, Halo, C １ ~C ５ Alkyl, cycloalkyl, heterocycloalkyl, -O-C １ ~C ５ Selected from the group consisting of alkyl, -O-cycloalkyl, and -O-heterocycloalkyl, R １ , R ２ , R ３ , R ４ , or R ５ However, C １ ~C ５ Alkyl, cycloalkyl, heterocycloalkyl, -O-C １ ~C ５ If C is alkyl, -O-cycloalkyl, or -O-heterocycloalkyl, １ ~C ５ Alkyl, cycloalkyl, heterocycloalkyl, -O-C １ ~C ５ At least one hydrogen atom in the alkyl, -O-cycloalkyl, or -O-heterocycloalkyl is replaced by a deuterium atom, R １ , R ２ , R ３ , and R ４ A compound or a pharmaceutically acceptable salt thereof, wherein at least one of the atoms is not H.

2. R １ is selected from the group consisting of methyl, ethyl, propyl, and butyl, or R 1 is, 【Chemistry 2】 is, or R 1 is, 【Transformation 3】 is, or R 1 is, 【Chemistry 4】 is, or R1 is selected from the group consisting of -OMe, -OEt, -OPr, and -OBu, or R 1 is, 【Transformation 5】 The compound according to claim 1.

3. R １ CD ３ , C ２ D ５ , C ３ D ７ , and C ４ D ９ Selected from the group consisting of, R 1 is, 【Transformation 6】 is, or R 1 is, 【Transformation 7】 is, or R 1 is, 【Transformation 8】 is, or R1 is selected from the group consisting of -OCD3, -OC2D5, -OC3D7, and -OC4D9, or R 1 is, 【Chemistry 9】 The compound according to claim 1.

4. R ２ is selected from the group consisting of methyl, ethyl, propyl, and butyl, or R2 is, 【Chemistry 10】 is, or R2 is, 【Chemistry 11】 is, or R2 is, 【Chemistry 12】 is, or R2 is selected from the group consisting of -OMe, -OEt, -OPr, and -OBu, or R2 is, 【Chemistry 13】 The compound according to claim 1.

5. R ２ CD ３ , C ２ D ５ , C ３ D ７ , and C ４ D ９ Selected from the group consisting of, R2 is, 【Chemistry 14】 is, or R2 is, 【Chemistry 15】 is, or R2 is, 【Chemistry 16】 is, or R2 is selected from the group consisting of -OCD3, -OC2D5, -OC3D7, and -OC4D9, or R2 is, 【Chemistry 17】 The compound according to claim 1.

6. R ３ is selected from the group consisting of methyl, ethyl, propyl, and butyl, or R 3 is, [Chemistry 18] is, or R 3 is, 【Chemistry 19】 is, or R 3 is, 【Chemistry 20】 is, or R3 is selected from the group consisting of -OMe, -OEt, -OPr, and -OBu, or R 3 is, 【Chemistry 21】 The compound according to claim 1.

7. R ３ CD ３ , C ２ D ５ , C ３ D ７ , and C ４ D ９ Selected from the group consisting of, R 3 is, 【Chemistry 22】 is, or R 3 is, 【Chemistry 23】 is, or R 3 is, 【Chemistry 24】 is, or R3 is selected from the group consisting of -OCD3, -OC2D5, -OC3D7, and -OC4D9, or R 3 is, 【Chemistry 25】 The compound according to claim 1.

8. R4 is selected from the group consisting of methyl, ethyl, propyl, and butyl, or R 4 is, 【Chemistry 26】 is, or R 4 is, 【Chemistry 27】 is, or R 4 is, 【Chemistry 28】 is, or R4 is selected from the group consisting of -OMe, -OEt, -OPr, and -OBu, or R 4 is, 【Chemistry 29】 The compound according to claim 1.

9. R ４ CD ３ , C ２ D ５ , C ３ D ７ , and C ４ D ９ Selected from the group consisting of, R 4 is, 【Transformation 30】 is, or R 4 is, 【Chemistry 31】 is, or R 4 is, 【Chemistry 32】 is, or R4 is selected from the group consisting of -OCD3, -OC2D5, -OC3D7, and -OC4D9, or R 4 is, 【Transformation 33】 The compound according to claim 1.

10. R ５ is H, or R 5 is a halo, or R5 is selected from the group consisting of methyl, ethyl, propyl, and butyl, or R 5 is, 【Transformation 34】 is, or R 5 is, 【Chemistry 35】 is, or R 5 is, 【Transformation 36】 is, or R 5 is selected from the group consisting of -OMe, -OEt, -OPr, and -OBu, or R 5 is, 【Chemistry 37】 The compound according to claim 1.

11. R ５ is F, or R 5 is selected from the group consisting of CD 3, C 2 D 5, C 3 D 7, and C 4 D 9, or R 5 is, 【Transformation 38】 is, or R 5 is, 【Chemistry 39】 is, or R 5 is, 【Chemistry 40】 is, or R 5 is selected from the group consisting of -OCD 3, -OC 2 D 5, -OC 3 D 7, and -OC 4 D 9, or R 5 is, 【Chemistry 41】 The compound according to claim 1.

12. The aforementioned compound, 【Chemistry 42】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

13. The aforementioned compound, 【Chemistry 43】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

14. The aforementioned compound, 【Chemistry 44】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

16. The pharmaceutical composition according to claim 15, further comprising a further therapeutic agent selected from the group consisting of iron mobilizers and deferipron.

17. A composition for treating a disease or condition characterized by a decrease in ferroportin, comprising a compound according to any one of claims 1 to 14.

18. The composition according to claim 17, wherein the disease or condition characterized by the decrease in ferroportin is age-related induced ferroportin disease.

19. The composition according to claim 17, administered in combination with a further therapeutic agent selected from the group consisting of iron mobilizers and deferipron.

20. A composition for treating a disease or condition characterized by reduced iron transport, or a disease or condition characterized by defects or deficiencies in iron transporters, or a disease or condition characterized by iron accumulation, or a disease or condition characterized by abnormal iron distribution, comprising a compound according to any one of claims 1 to 14.

21. The aforementioned iron accumulation is iron accumulation in the brain, or The composition according to claim 20, wherein the abnormal distribution of iron is an abnormal distribution of iron in the brain.

22. The composition according to claim 20, wherein the disease or condition is selected from the group consisting of inflammatory anemia, iron overload, thalassemia, hemochromatosis, atransferrinemia, myelodysplasia, hypochromic microcytic anemia, ferroportin disease, transfusion iron overload, and aceruloplasminemia.

23. The composition according to claim 20, administered in combination with a further therapeutic agent selected from the group consisting of iron mobilizers and deferipron.

24. A composition for treating neurodegenerative disorders, comprising a compound according to any one of claims 1 to 14.

25. The composition according to claim 24, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body dementia, and spinal muscular atrophy.

26. The composition according to claim 24, wherein the neurodegenerative disorder is neurodegeneration with cerebral iron accumulation (NBIA).

27. The composition according to claim 26, wherein the NBIA is selected from the group consisting of beta-propeller protein-related neurodegeneration (BPAN), pantothenate kinase-related neurodegeneration (PKAN), PLA2G6-related neurodegeneration (PLAN), mitochondrial membrane protein-related neurodegeneration (MPAN), fatty acid hydroxylase-related neurodegeneration (FAHN), COASY protein-related neurodegeneration (CoPAN), aceruloplasminemia, Kufor-Rakeb syndrome (also known as Parkinson's disease 9 (PARK9)), neuroferritinopathy, Woodhouse-Sakatai syndrome, and idiopathic NBIA.

28. The composition according to claim 24, administered in combination with a further therapeutic agent selected from the group consisting of iron mobilizers and deferipron.

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