Compositions and methods for preventing and / or treating mitochondrial diseases including Friedreich's ataxia

Abstract

The present invention provides therapeutic compounds, compositions (e.g., therapeutic agents or medicaments), and methods for preventing or treating mitochondrial diseases (e.g., Friedreich's ataxia) in mammalian subjects, reducing risk factors, signs, and / or symptoms associated with mitochondrial diseases (e.g., Friedreich's ataxia), and / or reducing the likelihood or severity of mitochondrial diseases (e.g., Friedreich's ataxia). The present invention also provides novel intermediates for producing the therapeutic compositions. In some cases, the intermediates themselves can be therapeutic agents or prodrugs of therapeutic agents (e.g., reduced forms of therapeutic compounds).

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 004,639, filed April 3, 2020, the contents of which are incorporated herein by reference in their entirety for any and all purposes. Technical Field

[0003] The present application generally relates to compositions and methods for preventing, ameliorating and / or treating mitochondrial diseases, such as Friedreich's ataxia, and / or reducing the severity of such diseases. In addition, the present application relates to: 1) methods for preparing novel therapeutic compounds and related intermediates (e.g., chromans (chromans), quinones, hydroquinones, benzoquinones, and hydroxybenzoquinones), and / or 2) administering an effective amount of the novel compounds disclosed herein (either by themselves or in a formulation), alone or in combination with one or more other agents, to a subject suffering from a mitochondrial disease, such as Friedreich's ataxia. Background Art

[0004] The following description is provided to aid the reader's understanding. None of the information provided or references cited are admitted to be prior art with respect to the compositions and methods disclosed herein.

[0005] Friedreich's ataxia (FA) is a fatal, monogenic, autosomal recessive disease caused by mutations in the gene encoding the nuclear-encoded mitochondrial protein frataxin. In FA, tissues of both the peripheral and central nervous systems are affected, including the dentate nucleus, Clark's column, spinocerebellar tracts, and dorsal root ganglia. Progressive degeneration of these tissues leads to worsening ataxia, which ultimately leads to the loss of independent ambulation in most patients by the third decade of life.

[0006] The FXN gene encodes the protein frataxin. Frataxin is an iron-binding protein responsible for the formation of iron-sulfur clusters. One consequence of frataxin deficiency is mitochondrial iron overload.

[0007] Partaxin is a highly conserved iron-binding protein. Human partaxin is synthesized as a 210-amino acid precursor that enters mitochondria via a mitochondrial targeting signal contained at its N-terminus. The partaxin precursor is subsequently cleaved into the mature 14 kDa protein (residues 81-210).

[0008] The symtaxins bind both Fe2+ and Fe3+ ions electrostatically and serve as iron chaperones during the assembly of Fe-S clusters. The symtaxins bind directly to the central Fe-S cluster assembly complex, which consists of the enzyme Nfs1 and the Isu scaffold protein. Nfs1 is a cysteine ​​desulfurase used to synthesize sulfur-based bioorganic derivatives, and Isu is a transient scaffold protein on which the Fe-S clusters are assembled. The symtaxins increase the efficiency of Fe-S cluster formation, which is required for the activation of the mitochondrial Kreb cycle enzyme aconitase. The symtaxins also play a role in mitochondrial iron storage and heme biosynthesis by inserting mitochondrial iron into protoporphyrins (PIX).

[0009] Loss of frataxin function leads to disrupted iron-sulfur cluster biosynthesis, mitochondrial iron overload, oxidative stress, impaired aerobic electron transport chain respiration, and cell death in the brain, spinal cord, dorsal root ganglia, and heart. Studies have also shown that frataxin protects dopaminergic neurons from MPTP-induced toxicity in a mouse model of Parkinson's disease.

[0010] Ferroptosis is an iron-dependent cell death that is biochemically distinct from apoptosis and is often accompanied by a large accumulation of iron and lipid peroxidation during the cell death process. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, leading to reduced cellular antioxidant capacity and accumulation of lipid reactive oxygen species (ROS), ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases such as tumors, neurological diseases, ischemia-reperfusion injury, renal injury, and blood diseases. Reduced expression of the FXN protein is associated with mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. Recent studies have shown that FXN, which regulates iron homeostasis and mitochondrial function, is a key regulator of ferroptosis. Therefore, ferroptosis has been identified as a therapeutic target for Friedreich's ataxia. As mentioned above, ferroptosis is associated with glutathione depletion and lipid peroxide production, and lipid peroxides are produced by the enzyme lipoxygenase (e.g., lipoxygenase-15). Therefore, targeting lipoxygenase-15 provides a therapeutic target for Friedreich's ataxia.

[0011] Mitochondrial iron overload leads to impaired mitochondrial metabolism and mitochondrial respiratory chain defects. A defective mitochondrial respiratory chain leads to increased free radical generation and oxidative damage, which may be considered a mechanism that impairs cell viability. Some evidence suggests that fraxins can detoxify ROS by activating glutathione peroxidase and increasing thiols. (See, for example, Calabrese et al., Journal of the Neurological Sciences, 233 (1): 145-162 (June 2005)).

[0012] Friedreich's ataxia occurs when the FXN gene contains expanded intronic GAA repeats. Mutated FXN genes contain expanded GAA triplet repeats in the first intron; in a few pedigrees, point mutations have also been detected. Because the defect is located in an intron, it is removed from the mRNA transcript between transcription and translation. Therefore, mutated FXN genes do not result in the production of abnormal proteins. Instead, the mutation causes gene silencing, meaning that the mutation reduces gene transcription.

[0013] Symptoms usually begin between the ages of 5 and 15, although they sometimes appear in adulthood. The first symptom to appear is usually gait disturbance, or difficulty walking. The ataxia gradually worsens and slowly spreads to the arms and trunk. Sensation in the limbs is often lost and can spread to other parts of the body. Other features include loss of tendon reflexes, especially in the knees and ankles. Most people with Friedreich's ataxia develop scoliosis, which often requires surgical intervention. Dysarthria (slowed and slurred speech) develops and can gradually worsen. Many individuals in the late stages of Friedreich's ataxia experience hearing and vision loss.

[0014] Heart disease often accompanies Friedreich's ataxia, including hypertrophic cardiomyopathy, myocardial fibrosis (the development of fibrous material in the heart muscle), and heart failure. Abnormal heart rhythms, such as tachycardia (a rapid heart rate) and heart block (impaired conduction of heart impulses within the heart), are also common. Other symptoms that may occur include chest pain, shortness of breath, and palpitations.

[0015] Many patients with Friedreich's ataxia experience a slow decline in visual acuity in the later stages of the disease. The most common ocular manifestation of Friedreich's ataxia is optic neuropathy. In some cases, severe or catastrophic vision loss occurs.

[0016] About 20% of people with Friedreich's ataxia develop carbohydrate intolerance, and 10% develop diabetes. Most individuals with Friedreich's ataxia tire easily and find that they need more rest and take longer to recover from common illnesses such as colds and flu.

[0017] The rate of progression varies from person to person. Generally, within 10 to 20 years of the first symptoms, people become wheelchair-bound, and in the later stages of the disease, individuals may become completely incapacitated. Friedreich's ataxia can shorten life expectancy, with heart disease being the most common cause of death.

[0018] The five enzyme complexes of the oxidative phosphorylation (OXPHOS) system (i.e., Complex I, Complex II, Complex III, Complex IV, and Complex V) are located in the mitochondrial membrane, and Complex I deficiency, which leads to reduced adenosine triphosphate (ATP) levels (and reduced production), is thought to be involved in Friedreich's ataxia. In fact, it has been shown that reduced expression of tataxin in cells from patients with Friedreich's ataxia increases the accumulation of non-bioavailable iron within the cell, leading to free radical production, increased cellular oxidative damage, and reduced Complex I activity and an associated decrease in intracellular ATP production (Heidari et al., Complex I and ATP Content Deficiency in Lymphocytes from Friedreich's Ataxia, Can. J. Neurol. Sci. 2009: 36: 26-31).

[0019] There is currently no cure for Friedreich's ataxia. Generally, treatment involves symptomatic treatment. Because patients with Friedreich's ataxia are at risk for developing heart disease, they are often prescribed medications such as beta-blockers, ACE inhibitors, and / or diuretics. Because damage caused by oxidative stress is believed to be associated with the progression of Friedreich's ataxia, antioxidants such as vitamin E, idebenone, and coenzyme Q10 are often co-administered to patients diagnosed with or suspected of having Friedreich's ataxia. These compounds have been used in various clinical trials.

[0020] Currently, EPI-743 (a benzoquinone compound also known as vartiquinone) is recruiting for a Phase 2 / 3 clinical trial for the treatment of Friedreich's ataxia. Vartiquinone is believed to reduce oxidative stress and improve mitochondrial function.

[0021] Omaveloxolone is a second-generation synthetic oleanane triterpenoid that is believed to exhibit antioxidant and anti-inflammatory activities. Omaveloxolone is currently in a completed Phase 2 clinical trial for the treatment of Friedreich's ataxia.

[0022] Several other therapies for Friedreich's ataxia are currently in clinical trials, but there are no FDA-approved drugs. Therefore, there remains a need for better drug candidates to address the needs of patients diagnosed with Friedreich's ataxia. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1A is a diagram of a chemical scheme for generating novel bis-fluorinated tail group intermediates used in the production of therapeutic compositions disclosed herein.

[0024] Figure 1Bis a diagram of a chemical scheme for producing tail group intermediates used in the production of the therapeutic compositions disclosed herein.

[0025] Figure 1C is a diagram of a chemical scheme for producing tail group intermediates used in the production of the therapeutic compositions disclosed herein.

[0026] Figure 2A is a diagram of a chemical scheme for generating novel bis-fluorinated tail group intermediates used in the production of therapeutic compositions disclosed herein.

[0027] Figure 2B is a diagram of a chemical scheme for producing tail group intermediates used in the production of the therapeutic compositions disclosed herein.

[0028] Figure 2C is a diagram of a chemical scheme for producing tail group intermediates used in the production of the therapeutic compositions disclosed herein.

[0029] Figure 3A is a diagram of a chemical scheme for generating novel bis-fluorinated tail group intermediates used in the production of therapeutic compositions disclosed herein.

[0030] Figure 3B is a diagram of a chemical scheme for producing tail group intermediates used in the production of the therapeutic compositions disclosed herein.

[0031] Figure 3C is a diagram of a chemical scheme for producing tail group intermediates used in the production of the therapeutic compositions disclosed herein.

[0032] Figure 4A is a diagram of a chemical scheme for generating novel bis-fluorinated tail group intermediates used in the production of therapeutic compositions disclosed herein.

[0033] Figure 4B is a diagram of a chemical scheme for producing tail group intermediates used in the production of the therapeutic compositions disclosed herein.

[0034] Figure 4C is a diagram of a chemical scheme for producing tail group intermediates used in the production of the therapeutic compositions disclosed herein.

[0035] Figure 5A is a tail group intermediate used to produce the therapeutic compositions disclosed herein (in this case, the "tail group" is the tail group 12 , as shown in the figure).

[0036] Figure 5Bis a tail group intermediate used to produce the therapeutic compositions disclosed herein (in this case, the "tail group" is the tail group 11 , as shown in the figure).

[0037] Figure 6A is a diagram of a chemical scheme for producing head group intermediates used in the production of therapeutic compositions disclosed herein.

[0038] Figure 6B is a diagram of a chemical scheme for producing head group intermediates used in the production of therapeutic compositions disclosed herein.

[0039] Figure 6C is a diagram of a chemical scheme for producing head group intermediates used in the production of therapeutic compositions disclosed herein.

[0040] Figure 6D is a diagram of a chemical scheme for producing head group intermediates used in the production of therapeutic compositions disclosed herein.

[0041] Figure 7A is a diagram of chemical schemes used to produce various compounds, some of which are intermediates used to produce the therapeutic compositions disclosed herein, and some of which are therapeutic compositions disclosed herein.

[0042] Figure 7B is a diagram of chemical schemes used to produce various compounds, some of which are intermediates used to produce the therapeutic compositions disclosed herein, and some of which are therapeutic compositions disclosed herein.

[0043] Figure 8 is a list of possible known alcohols that can be used to produce Figure 1A 、 1B , 1C, 2A, 2B, 2C, 3A, 3B, 3C, 4A, 4B, 4C, 5A and 5B as identified by the bromides shown by the general formulas 209, 209A, 209B, 219, 219a, 219b, 229, 229a, 229b, 239, 239a, 239b, 309a and 309b.

[0044] Figure 9 is a list of various possible known compounds that are represented by formula 700a and can be used to produce Figure 6A and 6B The Grignard reagent or lithiation reagent represented by the general formula 703a, 705a, or 703b. DETAILED DESCRIPTION

[0045] I. Chemical definition:

[0046] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, GAS version, Handbook of Chemistry and Physics, 7Sh Ed., inside cover. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0047] Abbreviations used herein have their conventional meaning in the field of chemistry and biology.Chemical structure as herein described and chemical formula are intended to meet the standard rules of chemical valence known in the field of chemistry.When listing a range of values, it is intended to include each value and subrange within the encompassing range.For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C5, C3-C4, C4-C6, C4-C5 and C5-C6 alkyl.When a group or part is referred to as "substituted", one or more hydrogen atoms of the group are replaced by a substituent. Possible "substituents" include, for example, one or more of the following: (i) a deuterium (D), fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom (individually, each of F, Cl, Br, and I is a "halogen," and F, Cl, Br, and I together are a "halogen group"; or (ii) a methyl, ethyl, propyl, trichloromethyl, trifluoromethyl, carbonyl (i.e., C=O), nitrile (i.e., -C≡N), hydroxyl or protected hydroxyl (i.e., -OH or -OPg, where Pg is a protecting group), alkoxy (i.e., -OR"), nitro (i.e., -NO2), or amino ( In protected or unprotected form, i.e., -NH or -NHPg, where Pg is a protecting group), each of which is independently selected for each possible position of hydrogen atom substitution. Other substituents are contemplated, such as azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carboxyl, silyl, ether, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., fluoromethyl, difluoromethyl and trifluoromethyl), cyano, and the like. Unsubstituted groups or moieties are unsubstituted.

[0048] Some compounds of the present application may exist in unsolvated forms, as well as in solvated forms, including hydrated forms. For example, solvated forms may exist because it is difficult or impossible to remove all solvents from the compound after synthesis. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present application. Some compounds of the present application may exist in a variety of crystals or amorphous forms. Some compounds of the present application may exist in various tautomeric forms. Some compounds of the present application may exist in the form of various salts. In general, all physical forms are equivalent for the purposes contemplated herein and are intended to be within the scope of the present application.

[0049] As used herein, "alkoxy" is an example of a heteroalkyl group and refers to an alkyl, cycloalkyl, heteroalkyl, or cycloheteroalkyl group attached to the terminal oxygen of the following general formula: wherein R" is an alkyl, cycloalkyl, heteroalkyl or cycloheteroalkyl group and Identifies the bond that forms the point of attachment of the alkoxy group to another compound or moiety. Each instance of an alkoxy group can independently be optionally unsubstituted ("unsubstituted alkoxy") or substituted ("substituted alkoxy") with one or more substituents. For example, a substituent can be a halogen, such as fluorine. Some non-limiting examples of fluorine-substituted alkoxy groups used herein include: fluoromethoxy ("-OCH2F"), difluoromethoxy ("-OCHF2"), and trifluoromethoxy ("-OCF3").

[0050] As used herein, "alkyl" refers to a group of straight-chain or branched saturated hydrocarbon groups having 1 to 20 carbon atoms ("C1-C 20 In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C1-C 12 In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C1-C 10 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms. atom ("C1-C2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butane (C5), tert-pentyl (C5), and n-hexyl (C6). Higher alkyl groups (e.g., C1-C6) 12 ) include n-heptyl (C7), n-octyl (C8), nonyl (C9), decyl (C 10 ), undecyl (C 11 ) and dodecyl (C 12) and the like. Each instance of an alkyl group may independently be optionally unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents; for example, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent. For example, a substituent may be a halogen, such as fluorine. Some non-limiting examples of substituted alkyl groups used herein include: fluoromethyl ("-CH2F"), difluoromethyl ("-CHF2"), and trifluoromethyl ("-CF3"). The term "alkyl" also refers to compounds in which one or more methylene groups on the alkyl chain may be replaced by heteroatoms, such as O or Si.

[0051] As used herein, "alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 12 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C 12 In some embodiments, the alkenyl group has 1-10 carbon atoms ("C2-C 10 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-C5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). The number of carbon atoms in a C2-C4 alkenyl group is not limited to the carbon atoms in the group. Examples include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. Examples of C2-C6 alkenyl groups include the aforementioned C2-C4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl groups include heptenyl (C1), octenyl (C8), octatrienyl (C8), etc. Each example of an alkenyl group can independently be unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents; for example, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent. For example, a substituent can be a halogen, such as fluorine.

[0052] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group having 2 to 12 carbon atoms, one or more carbon-carbon triple bonds ("C2-C 12In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C2-C 10 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-C5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-C4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-C3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). One or more The carbon-carbon triple bond can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Each instance of an alkynyl group can independently be optionally unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents; for example, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent. For example, a substituent can be a halogen, such as fluorine.

[0053] As used herein, "aprotic solvent" refers to an organic solvent that does not contain OH bonds or NH bonds. Non-limiting examples of aprotic solvents include acetonitrile (abbreviated as ACN or MeCN), tetrahydrofuran (THF), dioxane, dichloromethane (DCM), diethyl ether (Et2O), ethyl acetate (EtOAc), N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).

[0054] As used herein, "aryl" (sometimes abbreviated as "Ar") refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided within the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., a total of 6, 10, or 14π electrons in the cyclic array) ("C6-C 14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 In some embodiments, the aryl group has fourteen carbon atoms ("C 14 "aryl"; for example, anthracenyl). Aryl groups can be described as, for example, C6-C 10The term "aryl" refers to a non-hydrogen ring atom within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group can independently be optionally unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents; for example, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent. For example, a substituent can be a halogen, such as fluorine or chlorine. In some embodiments, 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 or protected hydroxyl (i.e., -OH or -OPg, where Pg is a protecting group), alkoxy (i.e., -OR), nitro, amino (in protected or unprotected form, i.e., -NH2 or -NHPg, where Pg is a protecting group), sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl, difluoromethyl, and trifluoromethyl), cyano, etc. Aryl groups are sometimes referred to as aromatic groups (or aromatic moieties).

[0055] As used herein, the term "arylalkyl" refers to an aryl or heteroaryl group (which may be substituted or unsubstituted) attached to a (C1-C 20 ) alkyl group (the alkyl group may be substituted or unsubstituted). The term "arylalkyl" refers to a substituted or unsubstituted group. The term "arylalkyl" also means those compounds in which one or more methylene groups in the alkyl chain of the arylalkyl group may be replaced by heteroatoms such as O, N, P, Si and S and in which the nitrogen, phosphorus and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized by one or more additional alkyl and / or aryl groups. Arylalkyl groups include, for example, benzyl (substituted or unsubstituted).

[0056] As used herein, the term "arylheteroalkyl" refers to a radical of an aryl group (which may be substituted or unsubstituted) attached to a non-cyclic stable linear or branched chain or combination thereof alkyl group, which includes at least one carbon and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized with one or more additional alkyl and / or aryl groups.

[0057] As used herein, the term "benzyl group" refers to a group of the formula:

[0058]

[0059] wherein each A1 is independently H, D, F, Cl, Br, I, -CH3, -OCH3, -CH2CH3, -OCH2CH3, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, nitrile (-C≡N), hydroxyl / phenol (i.e., -OH or -OPg, where Pg is a protecting group), or nitro (-NO2). If each A1 is H, the benzyl group is unsubstituted. If at least one A1 is not H, the benzyl group is substituted.

[0060] As used herein, the term "carbocyclic ring" or "carbocycle" refers to a ring formed by connected carbon atoms. The carbocyclic ring can be independently optionally unsubstituted (e.g., "unsubstituted cycloalkyl") or substituted (e.g., "substituted cycloalkyl") with one or more substituents. For example, a substituent can be a halogen, such as fluorine. A cycloalkyl group comprises a carbocyclic ring. An aryl group, such as benzene, comprises a carbocyclic ring. The carbocyclic ring can comprise 3 carbon atoms ("C3 carbocycle"), 4 carbon atoms ("C4 carbocycle"), 5 carbon atoms ("C5 carbocycle"), 6 carbon atoms ("C6 carbocycle"), 7 carbon atoms ("C7 carbocycle"), or 8 carbon atoms ("C8 carbocycle"). The carbocyclic ring can be aromatic and thus comprise 6 carbon atoms ("C6 carbocycle"), 10 carbon atoms ("C 10 carbocycle") or 14 carbon atoms ("C 14 carbon ring").

[0061] As used herein, "chiral chromatography" refers to the separation of racemic mixtures, and sometimes mixtures of diastereomers, using a chiral column (ie, a chiral stationary phase) to obtain optically enriched or optically pure products from the chromatographic separation.

[0062] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon radical having 3 to 12 ring carbon atoms ("C3-C 12 In some embodiments, the cycloalkyl group has 3 to 10 ring carbon atoms ("C3-C 10In some embodiments, cycloalkyl groups have 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, cycloalkyl groups have 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, cycloalkyl groups have 4 to 6 ring carbon atoms ("C4-C6 cycloalkyl"). In some embodiments, cycloalkyl groups have 5 to 6 ring carbon atoms ("C5-C6 cycloalkyl"). In some embodiments, cycloalkyl groups have 5 to 7 ring carbon atoms ("C5-C7 cycloalkyl"). In some embodiments, cycloalkyl groups have 6 to 7 ring carbon atoms ("C6-C7 cycloalkyl"). Cycloalkyl groups can be described, for example, as C 4-C7 yuan cycloalkyl, wherein the term "yuan" refers to the non-hydrogen ring atoms within the moiety. Exemplary C3-C6 cycloalkyl groups include but are not limited to cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6) and the like. Exemplary C3-C7 cycloalkyl groups include but are not limited to the C3-C6 cycloalkyl groups mentioned above as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7) and cycloheptatrienyl (C7), bicyclo [2.1.1] hexane (C6), bicyclo [3.1.1] heptane (C7) and the like. Exemplary C3-C 10 The cycloalkyl groups include, but are not limited to, the C3-C7 cycloalkyl groups mentioned above, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As illustrated in the above examples, in certain embodiments, the cycloalkyl group is either a monocyclic ring ("monocyclic cycloalkyl"), or contains a fused, bridged or spirocyclic ring system, such as a bicyclic ring system ("bicycloalkyl"), and may be saturated or may be partially unsaturated. Non-limiting examples of bicyclic cycloalkyl groups include 1-ethylbicyclo[1.1.1]pentane, 1-ethylbicyclo[2.2.2]octane and (3r,5r,7r)-1-ethyladamantane. "Cycloalkyl" also includes a ring system in which a cycloalkyl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the cycloalkyl ring and in this case, the number of carbons continues to represent the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may independently be optionally unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. For example, a substituent may be a halogen such as fluorine.

[0063] As used herein, "cycloheteroalkyl" refers to a radical of a cycloalkyl radical (wherein the heteroatom replaces a carbon atom in the ring) that contains at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen, phosphorus, and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized with additional alkyl and / or aryl groups. The heteroatoms O, N, P, S, and Si may be placed at any position of the cycloheteroalkyl radical, but typically each heteroatom is attached to at least two carbon atoms of the cycloalkyl radical.

[0064] As used herein, the term "heteroalkyl" refers to a non-cyclic stable linear or branched chain, or combinations thereof, comprising at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen, phosphorus, and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized with additional alkyl and / or aryl groups. The heteroatoms O, N, P, S, and Si may be placed at any position in the heteroalkyl group, but typically each heteroatom is attached to at least two carbon atoms of the cycloalkyl group. Exemplary heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-CH2-P(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two heteroatoms can be consecutive, for example, -CH2-NH-OCH3, -CH2CH2-SS-CH2CH3, and -CH2-O-Si(CH3)3. Each instance of a heteroalkyl group can independently be optionally unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents; for example, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent. For example, a substituent can be a halogen, such as fluorine.

[0065] As used herein, the term "heteroaryl" refers to a group of aromatic heterocyclic rings containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. As used herein, the term "heteroaryl" refers to a substituted or unsubstituted group. For example, a substituent may be a halogen, such as fluorine. A heteroaryl group may be fused to one or two rings, such as a cycloalkyl, aryl, or a second heteroaryl ring. The point of attachment of the heteroaryl group to the molecule may be on the heteroaryl, cycloalkyl, heterocycloalkyl, or aryl ring, and the heteroaryl group may be attached through a carbon or heteroatom. Examples of heteroaryl groups include imidazolyl, furanyl, pyrrolyl, thienyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, indolizinyl, imidazopyridinyl, pyrazolyl, triazolyl, oxazolyl, tetrazolyl, benzimidazolyl, benzisothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridinyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, or benzo(b)thienyl, each of which can be optionally substituted. The aromatic heterocycle can be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy or protected hydroxy (i.e., -OH or -OPg, where Pg is a protecting group), alkoxy (i.e., -OR), nitro, amino (in protected or unprotected form, i.e., -NH2 or -NHPg, where Pg is a protecting group), thiol, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, etc. Heteroaryl groups are sometimes referred to as heteroaromatic groups (or moieties).

[0066] As used herein, the term "heterocyclic ring" or "heterocycle" refers to a ring of atoms of at least two different elements, one of which is carbon. Reference may also be made to the Oxford Dictionary of Biochemistry and Molecular Biology, Oxford University Press, Oxford, 1997, as evidence that the term "heterocyclic ring" is a well-known term in the field of organic chemistry. Heterocyclic rings may be aliphatic (e.g., tetrahydrofuran) or aromatic (e.g., pyridine). Heterocyclic rings may be substituted or unsubstituted.

[0067] As used herein, the term "hydrate" refers to a compound that is associated with water. The number of water molecules contained in a hydrate of a compound may (or may not) be proportional to the number of compound molecules in the hydrate.

[0068] As used herein, the term "pharmaceutically acceptable salt" refers to salts of therapeutically active compounds that can be prepared with relatively nontoxic acids or bases, depending on the specific substituents present on the compounds described herein. When the compounds of the present application contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present application contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine (NEt3), trimethylamine, tripropylamine, tromethamine, and the like, wherein the salt includes, for example, the protonated form of the organic base (e.g., [HNEt3] +). Salts derived from pharmaceutically acceptable inorganic acids include salts of boric acid, carbonic acid, hydrohalic acid (hydrobromic acid, hydrochloric acid, hydrofluoric acid or hydroiodic acid), nitric acid, phosphoric acid, sulfamic acid and sulfuric acid. Salts derived from pharmaceutically acceptable organic acids include salts of aliphatic hydroxy acids (e.g., citric acid, gluconic acid, glycolic acid, lactic acid, lactobionic acid, malic acid and tartaric acid), aliphatic monocarboxylic acids (e.g., acetic acid, butyric acid, formic acid, propionic acid and trifluoroacetic acid), amino acids (e.g., aspartic acid and glutamic acid), aromatic carboxylic acids (e.g., benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, gentisic acid, hippuric acid and triphenylacetic acid), aromatic hydroxy acids (e.g., o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene-

[0014] Examples of the present invention include, for example, benzoic acid, benzoic acid, benzophenone, benzoic acid ... In some embodiments, the pharmaceutically acceptable counterion is selected from the group consisting of acetate, benzoate, benzenesulfonate, bromide, camphorsulfonate, chloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, methanesulfonate, methylsulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate. In some embodiments, the salt is tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, maleate, trifluoroacetate, hydrochloride, or toluenesulfonate. Also included are salts of amino acids, such as arginine, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, for example, Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present application may contain both basic and acidic functional groups, allowing the compounds to be converted into base addition salts or acid addition salts or to exist in the form of zwitterions. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in the current art.

[0069] As used herein, the term "protecting group" or "Pg" refers to a chemical group that reacts with a functional group in a molecule and binds thereto (at least for a period of time) to prevent the functional group (e.g., -OH, -NH2, -SH) from participating in the reaction of the molecule, but the chemical group can be subsequently removed to regenerate the functional group. Reference may be made to: Oxford Dictionary of Biochemistry and Molecular Biology, Oxford University Press, Oxford, 1997, as evidence that protecting groups are generally recognized terms in the field of organic chemistry. Reference is also made to Greene's Protective Groups in Organic Synthesis, 4th edition, 2007, John Wiley & Sons, Inc., which is considered to be a primary reference for studying the suitability of various protecting groups (e.g., protecting groups for hydroxyl or amine groups (i.e., Pg)) for organic synthesis reactions.

[0070] As used herein, the term "solvate" refers to a form of a compound that is associated with a solvent, typically by a solvolysis reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, acetone, hexane, DMSO, THF, diethyl ether, and the like.

[0071] As used herein, the term "tautomer" refers to compounds that are interchangeable forms of a particular compound structure and differ in the displacement of hydrogen atoms and electrons. Thus, the two structures can reach equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they can be rapidly interconverted by treatment with acid or base. Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a target compound.

[0072] II. Other definitions:

[0073] It should be noted that certain aspects, modes, implementations, variations, and features of the technology will be described in detail below at varying levels in order to provide a substantial understanding of the present application. Definitions of certain terms used in this specification are provided below. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which the technology belongs.

[0074] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the content clearly dictates otherwise. For example, reference to "a cell" includes reference to two or more cells, and so forth.

[0075] As used herein, "administering" or "administration" of an agent (i.e., a therapeutic agent) or drug to a subject includes any route of introducing or delivering a compound to a subject to achieve its intended function. Administration can be performed by any suitable route, such as oral administration. Administration can be performed subcutaneously. Administration can be performed intravenously. Administration can be performed intraocularly. Administration can be administered systemically. Alternatively, administration can be performed topically, intranasally, intraperitoneally, intradermally, ophthalmologically, intrathecally, intracerebroventricularly, via ionophoresis, transmucosally, intravitreally, or intramuscularly. Administration includes self-administration and administration by another person.

[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 silicon dioxide, silicon dioxide particles (nanoparticles or microparticles), urea, and the like. In addition, adjuvants, stabilizers, thickeners, lubricants, flavorings, and coloring agents may be used. Examples of other suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, EW Martin, which is incorporated herein by reference in its entirety.

[0077] As used herein, the phrase "delaying the onset of" means that in a statistical sample, one or more symptoms of a condition, symptom, disorder or indication is delayed, hindered or caused to occur more slowly than normal in the treated sample relative to an untreated control sample.

[0078] As used herein, the term "effective amount" refers to an amount sufficient to achieve the desired therapeutic and / or prophylactic effect, for example, an amount that reduces, ameliorates, prevents, or delays the onset of physiological symptoms of mitochondrial disease (e.g., Friedreich's ataxia). In the context of therapeutic or prophylactic applications, in some embodiments, the amount of the composition administered to a subject will depend on the type and severity of the disease and individual characteristics, such as general health, age, sex, weight, and tolerance to drugs. In some embodiments, it will also depend on the extent, severity, and type of the disease. One skilled in the art will be able to determine an appropriate dosage based on these and other factors. The composition can also be administered in combination with one or more additional therapeutic compounds (so-called "co-administration," where, for example, the additional therapeutic compounds can be administered simultaneously, sequentially, or separately). For example, the one or more additional therapeutic compounds can be a beta-blocker, ACE inhibitor, and / or diuretic for treating patients at risk for heart disease or heart failure. The one or more additional therapeutic compounds can be, for example, a Szeto-Schiller peptide, such as SS-20 or SS-31 (also known as lamiptide or bendavia).

[0079] In the methods described herein, a therapeutic compound, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, can be administered to a subject having one or more signs, symptoms, or risk factors for a mitochondrial disease (e.g., Friedreich's ataxia); for example, muscle weakness (particularly in the arms and legs), loss of coordination, impaired motor control, impaired vision, impaired hearing, slurred speech, curvature of the spine, diabetes, cardiac and / or ophthalmic disorders or conditions. For example, a "therapeutically effective amount" of a therapeutic compound includes reducing or eliminating the presence, frequency, or severity of one or more signs, symptoms, or risk factors for a mitochondrial disease (e.g., Friedreich's ataxia). In some embodiments, a therapeutically effective amount reduces or alleviates the physiological effects of a mitochondrial disease (e.g., Friedreich's ataxia) and / or risk factors for a mitochondrial disease (e.g., Friedreich's ataxia), and / or delays the progression or onset of a mitochondrial disease (e.g., Friedreich's ataxia).

[0080] As used herein, "inhibit" or "inhibiting" means to reduce an objectively measurable amount or degree as compared to a control. In one embodiment, inhibit or inhibiting means to reduce by at least a statistically significant amount as compared to a control. In one embodiment, inhibit or inhibiting means to reduce by at least 5% as compared to a control. In each separate embodiment, inhibit or inhibiting means to reduce by at least 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 33%, 40%, 50%, 60%, 67%, 70%, 75%, 80%, 90%, 95% or 99% as compared to a control.

[0081] As used herein, the term "concurrent" therapeutic use refers to the administration of at least two active ingredients by the same route at the same time or substantially the same time.

[0082] As used herein, the term "separate" therapeutic use refers to the simultaneous or essentially simultaneous administration of at least two active ingredients by different routes.

[0083] As used herein, the term "sequential" therapeutic use refers to the non-simultaneous administration of at least two active ingredients, whether by the same or different routes of administration. More specifically, sequential use refers to the complete administration of one of the active ingredients before the start of administration of the other active ingredient(s). Thus, one of the active ingredients may be administered minutes, hours, or days prior to the administration of the other active ingredient(s). Simultaneous treatment is not encompassed within this definition.

[0084] As used herein, "subject" refers to a living animal. In various embodiments, the subject is a mammal. In various embodiments, the subject is a non-human mammal, including but not limited to a mouse, rat, hamster, guinea pig, rabbit, sheep, goat, cat, dog, pig, minipig, horse, cow, or non-human primate. In certain embodiments, the subject is a human.

[0085] As used herein, the term "treating" or "treatment" or "alleviation" refers to therapeutic treatment in which the goal is to alleviate, relieve or slow down (slow down) the targeted pathological condition or disorder. For example, but not limitation, a subject is successfully "treated" for a mitochondrial disease (such as Friedreich's ataxia) if the subject shows an observable and / or measurable reduction in one or more signs and symptoms of a mitochondrial disease (such as Friedreich's ataxia) (such as, but not limited to, muscle weakness (particularly in the arms and legs), loss of coordination, impaired motor control, impaired vision, impaired hearing, slurred speech, spinal curvature, diabetes, heart and / or ophthalmological disorders or conditions) after receiving an effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof (such as a hydrochloride, acetate, citrate, trifluoroacetate, benzoate, oxalate or methanesulfonate, stereoisomer, mixture of stereoisomers, tautomer, hydrate and / or solvate) according to the methods described herein. It should also be understood that the treatment modalities described for various medical conditions are intended to mean "substantially," which includes full treatment, but also includes less than full treatment, and wherein some biologically or medically relevant result is achieved. Treating Friedreich's ataxia, as used herein, in some embodiments, also refers to treating signs and symptoms associated with decreased frataxin activity or frataxin expression levels that are characteristic of Friedreich's ataxia.

[0086] As used herein, "prevention" or "preventing" a disease or condition, such as a mitochondrial disease, such as Friedreich's ataxia, refers to a result that, in a statistical sample, shows a reduced occurrence of the disease or condition in the treated sample relative to an untreated control sample, or shows a delayed onset of one or more symptoms of the disease or condition relative to an untreated control sample. Such prevention is sometimes referred to as prophylactic treatment. As used herein, prevention of a mitochondrial disease (such as Friedreich's ataxia) includes preventing or delaying the onset of a mitochondrial disease (such as Friedreich's ataxia), preventing, delaying or slowing the progression or advancement of a mitochondrial disease (such as Friedreich's ataxia). As used herein, prevention of Friedreich's ataxia also includes preventing the recurrence of one or more signs or symptoms of Friedreich's ataxia.

[0087] III. Chirality / Stereochemistry Considerations:

[0088] The compounds described herein may include one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers (i.e., stereoisomers). Chiral centers in the illustrated structures (including the claims) may be identified herein with an asterisk (*). For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962) and; Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., University of Notre Dame Press, University of Notre Dame, IN 1972). The disclosure of the present application also encompasses compounds described herein as individual isomers substantially free of other isomers and, alternatively, as mixtures of various isomers.

[0089] As used herein, an enantiomerically pure compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess); since purity is a relative term, it is extremely difficult to achieve 100% purity. In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is therefore present in enantiomeric excess of the "R" form. With respect to amino acids (more commonly described in terms of "D" and "L" enantiomers), it should be understood that for "D"-amino acids, the configuration is "R" and for "L"-amino acids, the configuration is "S". In some embodiments, 'substantially free' refers to: (i) a sample of the "R" form of the compound containing less than 2% of the "S" form; or (ii) a sample of the "S" form of the compound containing less than 2% of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or greater than 99.9% by weight of a specifically identified enantiomer (e.g., compared to the other enantiomers). In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0090] In the compositions provided herein, enantiomerically pure compounds can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure "R" form compound can comprise about 90% excipients and about 10% enantiomerically pure "R" form compound. In certain embodiments, the enantiomerically pure "R" form compound in such a composition can, for example, comprise at least about 95% by weight of the "R" form compound and up to about 5% by weight of the "S" form compound based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure "S" form compound can comprise about 90% excipients and about 10% enantiomerically pure "S" form compound. In certain embodiments, the enantiomerically pure "S" form compound in such a composition can, for example, comprise at least about 95% by weight of the "S" form compound and up to about 5% by weight of the "R" form compound based on the total weight of the enantiomers of the compound. In certain embodiments, the active ingredient can be formulated to be substantially free of or free of excipients or carriers.

[0091] IV. Pharmaceutical composition, route of administration and dosing:

[0092] In some embodiments, the present application relates to pharmaceutical compositions. In some embodiments, the composition comprises a compound of the present application and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises multiple compounds of the present application and a pharmaceutically acceptable carrier. The pharmaceutical composition can be a medicament.

[0093] In certain embodiments, the pharmaceutical compositions of the present application further comprise at least one additional therapeutic agent in addition to one or more compounds of the present application. The at least one additional therapeutic agent may be an agent useful for treating a mitochondrial disease, such as Friedreich's ataxia. Thus, in some embodiments, the pharmaceutical compositions of the present application may be prepared, for example, by combining one or more compounds of the present application with a pharmaceutically acceptable carrier and, optionally, one or more additional therapeutic agents.

[0094] The pharmaceutical compositions of the present application contain an effective amount of a therapeutic compound (or multiple therapeutic compounds) as described herein, and may optionally be dispensed in a pharmaceutically acceptable carrier. The components of the pharmaceutical composition are also capable of being mixed with the compounds of the present application in a manner that does not significantly impair the desired drug efficacy.

[0095] As described above, an "effective amount" refers to any amount of an active compound (or multiple active compounds; alone or in combination) sufficient to achieve the desired biological effect. In combination with the teachings provided herein, by selecting among various active compounds and weighting factors (e.g., potency, relative bioavailability, patient weight, severity of adverse side effects, and mode of administration), an effective prophylactic (i.e., preventive) or therapeutic treatment regimen can be planned that does not cause a large amount of unnecessary toxicity and effectively treats a specific condition or disease in a specific subject. The effective amount for any particular indication can vary depending on factors such as the disease or disease being treated, the specific compound of the present application being administered, the size of the subject, or the severity of the disease or disease. The effective amount can be determined in preclinical trials and / or clinical trials by methods familiar to physicians and clinicians. Those skilled in the art can empirically determine the effective amount of a specific compound of the present application and / or other one or more therapeutic agents without the need for unnecessary experimentation. A maximum dose, i.e., the highest safe dose based on certain medical judgment, can be used. Multiple doses per day can be considered to achieve appropriate systemic compound levels. Appropriate systemic levels can be determined, for example, by measuring the patient's peak or sustained plasma levels of the drug. "Dose" and "dosage" are used interchangeably herein. A dose can be administered by oneself, by another person, or by means of a device such as a pump.

[0096] For any compound described herein, a therapeutically effective amount can be initially determined from an animal model. It is also possible to determine a therapeutically effective dose from human data of compounds tested in humans and known compounds (e.g., other related active agents) that exhibit similar pharmacological activity. Parenteral administration may require a higher dosage. The dosage applied can be adjusted according to the relative bioavailability and effectiveness of the administered compound. It is within the capabilities of those skilled in the art to adjust the dosage to achieve maximum efficacy according to the above-mentioned methods and other methods well known in the art.

[0097] Compounds for therapy or prevention (alone or formulated in pharmaceutical compositions) can be tested in appropriate animal model systems. Suitable animal model systems include, but are not limited to, rats, mice, chickens, cows, monkeys, rabbits, pigs, mini-pigs, etc., prior to testing in human subjects. In in vivo testing, any animal model system known in the art can be used prior to administration to human subjects.

[0098] The dosage, toxicity and therapeutic efficacy of any therapeutic compound, composition (such as preparation or medicament), other therapeutic agent or its mixture can be determined by standard pharmaceutical procedures in cell culture or experimental animals, for example, to determine LD50 (the dose that is lethal to 50% of the population) and ED50 (the dose that is therapeutically effective to 50% of the population). The dose ratio of toxic effect to therapeutic effect is the therapeutic index, and it can be expressed as the ratio LD50 / ED50. Compounds that exhibit high therapeutic indexes are advantageous. Although compounds that exhibit toxic side effects can be used, it should be noted that a delivery system that targets such compounds to infected tissue sites should be designed to minimize potential damage to uninfected cells and thereby reduce side effects.

[0099] The data obtained from cell culture assays and animal studies can be used to formulate a dosage range for human use. The dosage of such compounds can be within a circulating concentration range that includes an ED50 with very little or no toxicity. The dosage can vary within this range according to the dosage form employed and the route of administration employed. For any compound used in the method, the therapeutically effective dose can initially be estimated from the cell culture assay. The dosage can be formulated in an animal model to achieve a circulating plasma concentration range as determined in cell culture, including an IC50 (i.e., the test compound concentration that achieves half-maximal inhibition of symptoms). This type of information can be used to accurately determine a dosage useful to humans. For example, the level in plasma can be measured with high performance liquid chromatography.

[0100] In some embodiments, the range of an effective amount of a therapeutic compound disclosed herein, sufficient to achieve a therapeutic or preventive effect, can be from about 0.000001 mg / kg body weight / day to about 10,000 mg / kg body weight / day. Suitably, the dosage range is from about 0.0001 mg / kg body weight / day to about 100 mg / kg body weight / day. For example, the dosage can be 1 mg / kg body weight or 10 mg / kg body weight every day, every two days, or every three days, or within the range of 1-10 mg / kg per week, every two weeks, or every three weeks. In some embodiments, the single dose range of a therapeutic compound disclosed herein is 0.001-10,000 micrograms / kg body weight. In some embodiments, the range of a therapeutic compound disclosed herein dissolved or suspended in a carrier is 0.2 to 2000 micrograms / delivered microliters.

[0101] Exemplary treatment regimens may entail administration once a day, twice a day, three times a day, or once a week. In therapeutic applications, relatively high doses are sometimes required at relatively short intervals until the progression of the disease is slowed or terminated, or until the subject exhibits partial or complete improvement in disease symptoms. Thereafter, a prophylactic regimen may be administered to the patient.

[0102] In some embodiments, a therapeutically effective amount of a therapeutic compound disclosed herein can be defined as the concentration of the compound present at the target tissue, 10 -12 to 10 -6 mole, for example about 10 -7 Molar. This concentration can be delivered by a systemic dose of 0.001 to 100 mg / kg or an equivalent dose based on body surface area. The dosage schedule should be optimized to maintain therapeutic concentrations at the target tissue, for example, by a single daily or weekly administration, but also including continuous administration (e.g., oral, systemic, topical, subcutaneous, parenteral infusion, or transdermal application).

[0103] In some embodiments, the intravenous or subcutaneous administration of the compound (alone or in preparation) may be generally 0.01 μg / kg / day to 20 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the compound (alone or in preparation) may be generally 0.01 μg / kg / day to 100 μg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the compound (alone or in preparation) may be generally 0.1 μg / kg / day to 1 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the compound (alone or in preparation) may be generally 10 μg / kg / day to 2 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the compound (alone or in preparation) may be generally 500 μg / kg / day to 5 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the compound (alone or in preparation) may be generally 1 mg / kg / day to 20 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of the compound (alone or formulated) may typically be 1 mg / kg / day to 10 mg / kg / day.

[0104] Typically, the daily oral dose of the compound (alone or prepared) will be about 0.01 micrograms / kg / day to 100 micrograms / kg / day for a human subject. In some embodiments, the daily oral dose of the compound (alone or prepared) will be about 1 microgram / kg / day to 100 micrograms / kg / day or about 10 micrograms / kg / day to 75 micrograms / kg / day for a human subject, or an oral dose of the expected compound (alone or prepared) within the range of 0.1 to 50 micrograms / kg in one or more daily administrations will produce a therapeutic result. Depending on the mode of administration, the dosage can be appropriately adjusted to achieve the desired local or systemic drug level. For example, it is expected that intravenous administration will be a lower dose of one to several orders of magnitude per day. If the response in the subject is insufficient at such a dose, an even higher dose (or an effective higher dose by a different, more localized delivery route) can be used to the extent that the patient's tolerance allows. Multiple doses per day are considered to achieve appropriate systemic compound levels.

[0105] For use in therapy, an effective amount of the compound (alone or in a formulation) can be administered to a subject by any mode of delivery of the compound to the desired surface. Administration of the pharmaceutical composition can be accomplished by any means known to those skilled in the art. Routes of administration include, but are not limited to, oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, ophthalmic, intrathecal, intracerebroventricular, iontophoretic, transmucosal, intravitreal, or intramuscular administration. Administration includes self-administration, administration by another person, and administration by a device.

[0106] The formulations of the present application can be administered in a pharmaceutically acceptable solution, which may generally contain pharmaceutically acceptable concentrations of salt (eg, NaCl or sodium phosphate), a buffer, a protective agent, a compatible carrier, an adjuvant, and optionally other therapeutic ingredients.

[0107] The therapeutic compounds disclosed herein can be delivered to a subject in a formulation or medicament (i.e., a pharmaceutical composition). Formulations and medicaments can be prepared, for example, by dissolving or suspending the therapeutic compounds disclosed herein in water or a carrier (i.e., a pharmaceutically acceptable carrier). For example, the formulations and medicaments of the present application can be administered in a pharmaceutically acceptable solution, which can typically contain pharmaceutically acceptable concentrations of salt, a buffer, a protective agent, a compatible carrier, an adjuvant, and optionally other therapeutic ingredients.

[0108] Pharmaceutical composition (such as preparation or medicament) can comprise carrier, and carrier can be the solvent or dispersion medium containing such as water, ethanol, polyol (such as glycerol, propylene glycol and liquid polyethylene glycol etc.) and its applicable mixture.For example, can by using the coating of such as lecithin, by keeping required particle size and by using surfactant to keep suitable fluidity when being dispersed.The effect of preventing microorganism can be realized by various antibacterial and antifungal agents, such as paraben, chlorobutanol, phenol, ascorbic acid, thimerosal etc. Glutathione and other antioxidants can be included to prevent oxidation.In many cases, it is advantageous to include isotonic agent in the composition, such as sugar, polyol such as mannitol, sorbitol or sodium chloride.The extended absorption of injectable composition can be realized by including the agent of delayed absorption, such as aluminum monostearate or gelatin in the composition.

[0109] Solutions or suspensions (e.g., formulations or medicaments) for parenteral, intradermal, subcutaneous, or intraocular administration may contain the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; an antibacterial agent, such as benzyl alcohol or methyl paraben; an antioxidant, such as ascorbic acid or sodium bisulfite; a chelating agent, such as ethylenediaminetetraacetic acid; a buffer, such as acetate, citrate, or phosphate, and an agent for adjusting tonicity, such as sodium chloride or glucose. The pH can be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be packaged in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic. For the convenience of the patient or treating physician, the formulation may be provided for administration alone or in a kit containing all necessary equipment (e.g., drug vials, diluent vials, syringes, and needles) for a course of treatment (e.g., 2, 3, 4, 5, 6, 7 days or longer).

[0110] Systemic formulations include those designed for administration by injection (eg, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0111] For intravenous and other parenteral administration routes, the compounds of the present application can be formulated as lyophilized preparations, liposome-sandwich or -encapsulated lyophilized preparations of active compounds, lipid complexes in aqueous suspensions, or salt complexes. The lyophilized preparations are generally reconstituted in a suitable aqueous solution, such as sterile water or physiological saline, shortly before administration.

[0112] Pharmaceutical compositions (e.g., formulations or medicaments) suitable for injection may include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). Compositions for administration by injection will generally be sterile and should be liquid to the extent that easy syringability exists. They should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0113] Sterile injectable solutions (e.g., formulations or medicaments) can be prepared by incorporating the active compound in the desired amount with one or a combination of the ingredients enumerated above in an appropriate solvent (as needed), followed by filtration sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the desired other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical preparation methods include vacuum drying and freeze drying, which can produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution thereof.

[0114] The therapeutic compound or pharmaceutical composition, when intended for systemic delivery, can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion (e.g., by intravenous injection or via a pump to meter the dosage over a prescribed period of time). Injectable formulations can be presented in unit dosage form, for example, in ampoules or multi-dose containers with added protective agents. The composition can be in the form of a suspension, solution, or emulsion, for example, in an oily or aqueous vehicle, and can contain formulating agents, such as suspending agents, stabilizers, and / or dispersants.

[0115] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compound in water-soluble form. In addition, suspensions of the therapeutic compound can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the therapeutic compound to prepare highly concentrated solutions.

[0116] For oral administration, the compounds can be readily formulated by combining one or more active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the present application to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like for oral ingestion by the subject being treated. Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, or stearates; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint, methyl salicylate, or orange flavoring.

[0117] Pharmaceutical formulations for oral use can be obtained as solid excipients, optionally grinding the resulting mixture, and processing the granular mixture, after adding a suitable adjuvant (if desired), to obtain tablets or dragee cores. Suitable excipients are particularly fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; Cellulose formulations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate, can be added. Optionally, oral formulations can also be prepared in physiological saline or buffer such as EDTA, for neutralizing internal acidic conditions, or can be used without any carrier.

[0118] In addition, it is specifically contemplated that the oral dosage forms described above may be chemically modified so that oral delivery of the derivative is effective. Generally, the chemical modification contemplated is the addition of at least one moiety to the one or more therapeutic agents, one or more ingredients, and / or one or more excipients, wherein the moiety permits (a) inhibition of acid hydrolysis; and (b) absorption from the stomach or intestine into the bloodstream. Also desired is an increase in the overall stability of the one or more therapeutic agents, one or more ingredients, and / or one or more adjuvants and an increase in the in vivo circulation time. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts", In: Enzymes as Drugs, eds. Hocenberg and Roberts, Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that may be used are poly-1,3-dioxolane and poly-1,3,6-trioxocane.As indicated above, for pharmaceutical uses, polyethylene glycols (PEG) of various molecular weights are suitable.

[0119] For formulations of one or more therapeutic agents, one or more ingredients and / or one or more excipients, the release site may be the stomach, small intestine (duodenum, jejunum or ileum) or large intestine. Those skilled in the art have available formulations that will not dissolve in the stomach but will release the substance elsewhere in the duodenum or intestine. Preferably, the release will avoid the deleterious effects of the gastric environment by protecting the compound (or derivative) of the present application or by releasing the bioactive substance outside the gastric environment (e.g., in the intestine).

[0120] A coating or mixture of coatings can also be applied to tablets that are not intended to protect against the stomach. This can include sugar coatings, or coatings that make the tablet easier to swallow. Capsules can consist of a hard shell (e.g., gelatin) for delivering dry therapeutics (e.g., powders); for liquid forms, a soft gelatin shell can be used. The shell material for cachets can be thick starch or other edible paper. For pills, lozenges, molded tablets, or tablets, wet kneading techniques can be used.

[0121] The therapeutic compound or pharmaceutical composition can be included in the formulation as fine multiparticulates in the form of granules or pellets having a particle size of about 1-2 mm. The formulation of the material for capsule administration can also be as a powder, a lightly compressed plug, or even as a tablet. The therapeutic compound or pharmaceutical composition can be prepared by compression.

[0122] Coloring agents and flavoring agents may be included. For example, the compound or pharmaceutical composition (or derivative) of the present application may be formulated and then further included in an edible product, such as a refrigerated beverage containing coloring agents and flavoring agents.

[0123] Inert materials may be used to dilute or increase the volume of a therapeutic compound or pharmaceutical composition. These diluents may include carbohydrates, particularly mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextran, and starch. Certain inorganic salts may also be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents are STARCH and

[0124] Disintegrants may be included in the formulation of the therapeutic compound or composition to form a solid dosage form. Materials used as disintegrants include, but are not limited to, starch, including the commercial starch-based disintegrant Explotab. Sodium starch glycolate, Sodium carboxymethylcellulose, super-branched starch, sodium alginate, gelatin, orange peel, acidic carboxymethylcellulose, natural sponge, and bentonite can all be used. Another form of disintegrant is an insoluble cation exchange resin. Powdered gums can be used as disintegrants and binders, and these can include powdered gums such as agar, karaya gum, or tragacanth gum. Alginic acid and its sodium salt can also be used as a disintegrant.

[0125] Binders can be used to bind the therapeutic agent together to form a hard tablet and include materials from natural products such as gum arabic, astragalus, starch and gelatin. Others include methylcellulose (MC), ethylcellulose (EC) and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) can both be used in alcoholic solutions to granulate the therapeutic agent.

[0126] Anti-friction agents may be included in the therapeutic formulation to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these may include, but are not limited to; stearic acid, including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols (PEG) of various molecular weights, Carbowax TM 4000 and 6000.

[0127] Glidants may be added to improve the flow characteristics of the drug during formulation and to aid rearrangement during compression. Glidants may include starch, talc, fumed silica, and hydrated aluminosilicates.

[0128] In order to help therapeutic compounds or compositions to dissolve in water environments, surfactants can be added as wetting agents. Surfactants can include anionic detergents, such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Operable cationic detergents can include benzalkonium chloride and benzethonium chloride. Potential nonionic detergents that can be included in the preparation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10,50 and 60, glyceryl monostearate, polysorbate 40,60,65 and 80, sucrose fatty acid esters, methylcellulose and carboxymethyl cellulose. These surfactants can be present in the preparation of the compound of the application or derivatives as a mixture alone or in different ratios.

[0129] Pharmaceutical formulations that can be used orally include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol). Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate and an optional stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, a stabilizer can be added. Microspheres formulated for oral administration can also be used. Such microspheres are well defined in the art. All formulations for oral administration should be doses suitable for such administration.

[0130] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0131] For topical administration, the compounds can be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well known in the art. Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0132] For administration by inhalation, the compound or composition (e.g., medicament) used herein can be conveniently delivered in the form of aerosol spray from a pressurized package or atomizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In some embodiments, the preparation, medicament or therapeutic compound can be delivered in the form of aerosol spray from a pressurized container or disperser or atomizer containing a suitable propellant (e.g., gas, such as carbon dioxide). Such methods include those described in U.S. Patent No. 6,468,798. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. For example, capsules and boxes such as gelatin used in inhalers or insufflators can be formulated as powder mixtures and suitable powder bases, such as lactose or starch, containing therapeutic compounds.

[0133] Nasal delivery of the therapeutic compound or pharmaceutical composition of the present application is also contemplated. Nasal delivery allows the therapeutic compound or pharmaceutical composition of the present application to pass directly through the bloodstream after administration to the nose without depositing the product in the lungs. Formulations for nasal delivery include formulations containing dextran or cyclodextran.

[0134] For nasal administration, a useful device is a rigid vial with a metered-dose sprayer attached. In some embodiments, the metered dose is delivered by drawing the pharmaceutical composition of the present application solution into a chamber of a specified volume, wherein the chamber has an aperture sized to atomize the aerosol formulation by forming a spray when the liquid in the chamber is compressed. The chamber is compressed to administer the therapeutic compound or pharmaceutical composition. In a specific embodiment, the chamber is arranged in a piston-like arrangement. Such devices are commercially available.

[0135] Alternatively, a plastic squeeze bottle is used whose hole or opening is sized to atomize the aerosol formulation by forming a spray when squeezed. The opening is usually present at the top of the bottle, and the top is usually tapered to partially fit into the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation for administering a measured amount of the therapeutic compound or pharmaceutical composition.

[0136] Alternatively, the therapeutic compound or pharmaceutical composition may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.

[0137] Pulmonary delivery of the compounds disclosed herein (or salts thereof) is also contemplated herein. The compound or pharmaceutical composition is delivered to the lungs of a mammal upon inhalation and crosses the lung epithelial lining into the bloodstream. Other reports on inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(Suppl 5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (α1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (α-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-γ and tumor necrosis factor α) and Platz et al., U.S. Pat. No. 5,284,656 (granulocyte colony-stimulating factor; incorporated by reference). Methods and compositions for pulmonary delivery of drugs for systemic effect are described in U.S. Pat. No. 5,451,569, issued Sep. 19, 1995 to Wong et al. (incorporated by reference).

[0138] Contemplated for use in the practice of the present technology are various mechanical devices designed to deliver therapeutic products transpulmonary, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0139] Some specific examples of commercially available equipment suitable for the practice of the present technology are the Ultravent manufactured by Mallinckrodt, Inc., St. Louis, Mo. TM Nebulizer; Acorn manufactured by Marquest Medical Products, Englewood, Colo. Nebulizer; manufactured by Glaxo Inc., Research Triangle Park, North Carolina Metered-dose inhalers; and manufactured by Fisons Corp., Bedford, Mass. Powder inhaler.

[0140] All such devices require the use of a formulation suitable for dispensing the compounds of the present invention. Typically, each formulation is specific to the type of device used and may involve the use of an appropriate propellant material in addition to conventional diluents, adjuvants, and / or carriers useful in therapy. In addition, the use of liposomes, microcapsules, microspheres, nanoparticles, nanospheres, inclusion compounds, or other types of carriers is contemplated. Depending on the type of chemical modification or the type of device employed, the chemically modified compounds of the present invention may also be prepared in different formulations.

[0141] For example, a formulation suitable for use with a nebulizer, whether jet or ultrasonic, can contain a compound (or derivative) of the present application dissolved in water at a concentration of about 0.01 to 50 mg of the bioactive compound per mL of solution. The formulation can also contain a buffer and a simple sugar (e.g., for inhibitor stabilization and regulating osmotic pressure). The nebulizer formulation can also contain a surfactant to reduce or prevent surface-induced aggregation of the compound of the present application caused by the atomized solution when forming an aerosol.

[0142] Preparations for metered dose inhaler devices generally include a fine powder containing the compound (or derivative) of the present application suspended in a propellant with the help of a surfactant. The propellant can be any conventional material used for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane, or a combination thereof. Suitable surfactants include sorbitol trioleate and soy lecithin. Oleic acid can also be used as a surfactant.

[0143] The formulation for dispersion from a powder inhaler device may comprise a fine dry powder containing the compound (or derivative) of the present application and may further comprise a bulking agent, such as lactose, sorbitol, sucrose, or mannitol, in an amount that facilitates dispersion of the powder from the device (e.g., 50 to 90% by weight of the formulation). The compound (or derivative) of the present application may advantageously be prepared in the form of particles or nanoparticles having an average particle size of less than 10 microns (μm), most preferably 0.5 to 5 μm, for most effective delivery to the deep lung.

[0144] Nasal delivery of the pharmaceutical compositions of the present application is also contemplated. Nasal delivery allows the pharmaceutical compositions of the present application to pass directly through the bloodstream after administering the therapeutic product to the nose, without having to deposit the product in the lungs. Formulations for nasal delivery include formulations containing dextran or cyclodextran.

[0145] For nasal administration, a useful device is a rigid vial with a metered-dose sprayer attached. In one embodiment, the metered dose is delivered by inhaling the pharmaceutical composition of the present application into a chamber of defined volume, wherein the chamber has an aperture sized to atomize the aerosol formulation by forming a spray when the liquid in the chamber is compressed. The chamber is pressed to administer the pharmaceutical composition of the present application. In a specific embodiment, the chamber is arranged in a piston-like manner. Such devices are commercially available.

[0146] Alternatively, a plastic squeeze bottle is used whose hole or opening is sized to atomize the aerosol formulation by forming a spray when squeezed. The opening is usually present at the top of the bottle, and the top is usually tapered to partially fit into the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation for administering a measured dose of the medication.

[0147] The compound, when intended for systemic delivery, can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations can be presented in unit dosage form, for example, in ampoules or multidose containers optionally with the addition of a protective agent. The formulation can be delivered from an IV bag for injection via a syringe or via a pen-type injector device. The formulation / composition can be in the form of a suspension, solution or solution, for example, in an oily or aqueous vehicle, and can include formulating agents, such as suspending agents, stabilizers and / or dispersants.

[0148] Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In addition, suspensions of the active compound can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound in order to prepare highly concentrated solutions.

[0149] Alternatively, the active compound may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.

[0150] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0151] For ophthalmic or intraocular indications, any suitable mode of delivering therapeutic compounds or pharmaceutical compositions to the eye or surrounding area of ​​the eye can be used. For ophthalmic preparations, generally see Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, NY (1993) and also see Havener, WH, Ocular Pharmacology, CV Mosby Co., St. Louis (1983). Non-limiting examples of pharmaceutical compositions suitable for intraocular or periocular administration include, but are not limited to, eye inserts, mini-tablets, and topical preparations, such as eye drops, ointments, and in situ gels. In one embodiment, contact lenses are coated with a pharmaceutical composition comprising a therapeutic compound disclosed herein. In some embodiments, a single dose comprises 0.1 ng to 5000 μg, 1 ng to 500 μg, or 10 ng to 100 μg of a therapeutic compound or pharmaceutical composition administered to the eye.

[0152] Eye drops can comprise a sterile liquid formulation that can be applied directly to the eye. In some embodiments, the eye drops comprise at least one therapeutic compound disclosed herein and may further comprise one or more protective agents. In some embodiments, the optimal pH of the eye drops is equal to the pH of tear fluid and is approximately 7.4.

[0153] In situ gel is a viscous liquid that, when subjected to the influence of external factors (such as the presence of suitable pH, temperature and electrolyte), demonstrates the ability of experiencing sol-to-gel. This characteristic causes the outflow of medicine from the surface of the eyeball to slow down, and the bioavailability of active ingredients increases. Polymers commonly used in in situ gel preparations include but are not limited to gellan gum, poloxamer, silicone-containing preparations and cellulose acetate phthalate. In some embodiments, therapeutic compounds are formulated as in situ gel (as pharmaceutical composition).

[0154] For topical ophthalmic administration, the therapeutic compound or pharmaceutical composition can be formulated as a solution, gel, ointment, cream, suspension, etc. as is well known in the art. Ointments are semisolid dosage forms for external use (e.g., topical use for the eyes or skin). In some embodiments, the ointment comprises a solid or semisolid hydrocarbon base having a melting or softening point close to the core temperature of the human body. In some embodiments, the ointment applied to the eye breaks down into droplets that reside in the conjunctival sac for a longer period of time, thereby increasing bioavailability.

[0155] Ocular inserts are solid or semisolid dosage forms that do not suffer from the drawbacks of traditional ophthalmic drug forms. They are less susceptible to defense mechanisms such as egress through the nasolacrimal duct, exhibit the ability to remain in the conjunctival sac for extended periods, and are more stable than conventional dosage forms. They also offer advantages such as precise dosing of one or more therapeutic compounds, slow release of one or more therapeutic compounds at a constant rate, and limited systemic absorption of one or more therapeutic compounds. In some embodiments, the ocular insert comprises one or more therapeutic compounds as disclosed herein and one or more polymeric materials. Polymeric materials may include, but are not limited to, methylcellulose and its derivatives (e.g., hydroxypropyl methylcellulose (HPMC)), ethylcellulose, polyvinylpyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethyl chitosan, gelatin, and various mixtures of the aforementioned polymers. The ocular insert may comprise silicon dioxide. The ocular insert may comprise liposomes, nanoparticles, or microparticles (as described in more detail below) that may contain degradable or biodegradable polymers.

[0156] Microtablets are biodegradable solid drug forms that convert into gels after application to the conjunctival sac, thereby prolonging the contact time of the active ingredient (i.e., the therapeutic compound disclosed herein) with the surface of the eyeball, thereby improving the bioavailability of the therapeutic compound. The advantages of microtablets include easy application to the conjunctival sac, resistance to defense mechanisms such as tearing or outflow through the nasolacrimal duct, longer contact with the cornea due to the presence of mucoadhesive polymers, and gradual release of the active ingredient from the formulation instead of application due to expansion of the outer carrier layer. The microtablet may contain one or more therapeutic compounds disclosed herein and one or more polymers. Non-limiting examples of polymers suitable for use in microtablet formulations include cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose, ethyl cellulose, acrylates (e.g., polyacrylic acid and its cross-linked forms), Or carbomer, chitosan and starch (such as drum dried waxy corn starch). In some embodiments, the mini-tablet further comprises one or more excipients. Non-limiting examples of excipients include mannitol and magnesium stearate.

[0157] Ophthalmic or intraocular preparations and medicaments may contain non-toxic auxiliary substances, such as antibacterial components that are harmless when used, such as thimerosal, benzalkonium chloride, methyl and propyl parabens, benzyldodecyl ammonium bromide, benzyl alcohol or phenylethyl alcohol; buffer components, such as sodium chloride, sodium borate, sodium acetate, sodium citrate or sodium gluconate buffer; and other conventional ingredients, such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitate, ethylenediaminetetraacetic acid, etc.

[0158] In some embodiments, the viscosity of the ophthalmic preparation comprising one or more therapeutic compounds is increased to improve contact with the cornea and intraocular bioavailability. Viscosity can be increased by adding a high molecular weight hydrophilic polymer that does not diffuse through the biofilm and forms a three-dimensional network in water. The limiting examples of this type of polymer include polyvinyl alcohol, poloxamate, hyaluronic acid, carbomer and polysaccharides, cellulose derivatives, gellan gum and xanthan gum.

[0159] In some embodiments, the ophthalmic formulation can be injected into the eye, for example, as a sol-gel. In some embodiments, the ophthalmic formulation is a reservoir formulation, such as a controlled release formulation. Such controlled release formulations can comprise particles, such as microparticles or nanoparticles.

[0160] In addition to the above-mentioned preparations, the therapeutic compounds disclosed herein can also be formulated as a depot preparation. Such long-acting preparations can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, e.g., a sparingly soluble salt.

[0161] The pharmaceutical composition may also contain a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0162] For example, applicable liquid or solid drug formulation form can be the aqueous solution or saline solution for sucking, microencapsulation, be rolled into spiral (encochleated), be coated on microscopic gold particles, be included in liposomes, atomized aerosol, be used for implanting the pellet of skin, or be dried on the sharp object to be scratched into skin.Pharmaceutical composition also comprises the preparation of granule, powder, tablet, coated tablet, (micro) capsule, suppository, syrup, emulsion, suspensoid, cream, drop or active compound prolonged release, in described preparation, excipient and additive and / or adjuvant, for example disintegrant, adhesive, coating agent, swelling agent, lubricant, flavoring, sweetener or solubilizing agent are usually used as described above.Pharmaceutical composition can be applicable to multiple drug delivery system.For the brief overview of drug delivery method, referring to Langer R, Science 249:1527-33 (1990).

[0163] One or more therapeutic agents specifically include, but are not limited to, compounds of the present application and can be provided in the form of particles. As used herein, particles refer to nanoparticles or microparticles (or larger particles in some cases), which can be composed in whole or in part of compounds of the present application or one or more other therapeutic agents as described herein. The particles can contain one or more therapeutic agents in a core surrounded by a coating (including but not limited to an enteric coating). One or more therapeutic agents can also be dispersed throughout the particles. One or more therapeutic agents can also be adsorbed into the particles. The particles can have release kinetics of any order, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to one or more therapeutic agents, the particles can also include any of those materials conventionally used in the fields of pharmacy and medicine, including but not limited to erodible, non-erodible, biodegradable or non-biodegradable materials or combinations thereof. The particles can be microcapsules containing the compounds of the present application in the form of a solution or semi-solid. The particles can be almost any shape.

[0164] Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for delivering one or more therapeutic agents. Such polymers can be natural or synthetic polymers. Polymers are selected according to the time period of release as needed. Particularly interesting bioadhesive polymers include the bioerodible hydrogels described in Sawhney HS et al. (1993) Macromolecules 26:581-7, whose teachings are incorporated herein. These include polyhyaluronic acid, casein, gelatin, gelatin, polyanhydrides, polyacrylic acid, alginate, chitosan, polyethylene glycol (PEG), polyvinyl alcohol (PVA), poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(lactic-co-glycolic acid) (PLGA), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and poly(ε-caprolactone), or mixtures of two or more of the foregoing.

[0165] The therapeutic compound or other therapeutic agent or mixture thereof can be formulated in a carrier system. The carrier can be a colloidal system. The carrier or colloidal system can be a liposome, a phospholipid bilayer vehicle. In one embodiment, the therapeutic compound or other therapeutic agent or mixture thereof can be encapsulated in a liposome while maintaining the integrity of the therapeutic compound or other therapeutic agent or mixture thereof. Those skilled in the art will appreciate that there are various methods to prepare liposomes. (See Lichtenberg, et al., Methods Biochem. Anal., 33: 337-462 (1988); Anselem, et al., Liposome Technology, CRC Press (1993)). Liposomal formulations can delay clearance and increase cellular uptake (see Reddy, Ann. Pharmacother., 34 (7-8): 915-923 (2000)). For example, the active agent can also be loaded into particles prepared from pharmaceutically acceptable ingredients, including but not limited to soluble, insoluble, permeable, impermeable, biodegradable or gastric retention polymers or liposomes. Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles, and viral vector systems.

[0166] The carrier can also be a polymer, such as a biodegradable, biocompatible polymer matrix. In one embodiment, the therapeutic compound or other therapeutic agent or a mixture thereof can be embedded in a polymer matrix while maintaining the integrity of the composition. The polymer can be a microparticle or nanoparticle that encapsulates one or more therapeutic agents. The polymer can be natural, such as a polypeptide, protein or polysaccharide, or synthetic, such as poly-α-hydroxy acid. Examples include carriers such as collagen, fibronectin, elastin, cellulose acetate, nitrocellulose, polysaccharides, fibrin, gelatin and combinations thereof. In one embodiment, the polymer is polylactic acid (PLA) or polylactic / glycolic acid (PLGA). The polymer matrix can be prepared and separated in a variety of forms and sizes, including microspheres and nanospheres. Polymer formulations can lead to an extended duration of therapeutic action. (See Reddy, Ann.Pharmacother., 34(7-8):915-923(2000)). Polymer formulations for human growth hormone (hGH) have been used in clinical trials. (See Kozarich and Rich, Chemical Biology, 2:548-552 (1998)).

[0167] Examples of sustained-release polymer microsphere formulations are described in PCT Publication WO 99 / 15154 (Tracy et al.), U.S. Patent Nos. 5,674,534 and 5,716,644 (both to Zale et al.), PCT Publication WO 96 / 40073 (Zale et al.), and PCT Publication WO 00 / 38651 (Shah et al.). U.S. Patent Nos. 5,674,534 and 5,716,644 and PCT Publication WO 96 / 40073 describe polymer matrices containing erythropoietin particles stabilized by salt to prevent aggregation.

[0168] In some embodiments, the therapeutic compound or other therapeutic agent or its mixture is prepared with a carrier that will protect the therapeutic compound or other therapeutic agent or its mixture from rapid clearance from the body, such as a controlled release formulation, including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such materials can be directly prepared using known techniques. The materials can also be commercially available from Alza and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to specific cells with monoclonal antibodies to cell-specific antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0169] One or more therapeutic compounds may be included in a controlled release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the mode and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, wherein non-immediate release formulations include, but are not limited to, sustained release formulations and delayed release formulations. The term "sustained release" (also referred to as "extended release") is used in its traditional sense to refer to a pharmaceutical formulation that provides a gradual release of the drug over an extended period of time and preferably, although not necessarily, results in a constant blood drug level over an extended period of time. The term "delayed release" is used in its traditional sense to refer to a pharmaceutical formulation in which there is a time delay between the administration of the formulation and the release of the drug therefrom. "Delayed release" may or may not include the gradual release of the drug over the delayed period of time, and therefore may or may not be "sustained release."

[0170] Use long-term sustained release implant or reservoir preparation can be particularly suitable for treating chronic diseases.Term " implant " and " reservoir preparation " are intended to include single composition (such as mesh) or the composition (such as the fibrous mesh being made of a few independent web materials) or a plurality of independent compositions comprising multiple components, wherein a plurality of compositions keep local and provide the long-term sustained release produced from the gathering of a plurality of compositions. " long-term " release, as used herein, means that implant or reservoir preparation are constructed and arranged to deliver the active component that provides treatment or prevention level and continue at least 2 days. In some embodiments, implant or reservoir preparation are constructed and arranged to deliver the active component that provides treatment or prevention level and continue at least 7 days. In some embodiments, implant or reservoir preparation are constructed and arranged to deliver the active component that provides treatment or prevention level and continue at least 14 days. In some embodiments, implant or reservoir preparation are constructed and arranged to deliver the active component that provides treatment or prevention level and continue at least 30 days. In some embodiments, implant or reservoir preparation are constructed and arranged to deliver the active component that provides treatment or prevention level and continue at least 60 days. In some embodiments, the implant or reservoir formulation is constructed and arranged to deliver an active ingredient that provides treatment or prevention levels for at least 90 days. In some embodiments, the implant or reservoir formulation is constructed and arranged to deliver an active ingredient that provides treatment or prevention levels for at least 180 days. In some embodiments, the implant or reservoir formulation is constructed and arranged to deliver an active ingredient that provides treatment or prevention levels for at least one year. In some embodiments, the implant or reservoir formulation is constructed and arranged to deliver an active ingredient that provides treatment or prevention levels for 15-30 days. In some embodiments, the implant or reservoir formulation is constructed and arranged to deliver an active ingredient that provides treatment or prevention levels for 30-60 days. In some embodiments, the implant or reservoir formulation is constructed and arranged to deliver an active ingredient that provides treatment or prevention levels for 60-90 days. In some embodiments, the implant or reservoir formulation is constructed and arranged to deliver an active ingredient that provides treatment or prevention levels for 90-120 days. In some embodiments, the implant or reservoir formulation is constructed and arranged to deliver an active ingredient that provides treatment or prevention levels for 120-180 days. In some embodiments, long-term sustained release implants or reservoir formulations are well known to those of ordinary skill in the art and include some release systems described above. In some embodiments, such implants or reservoir formulations can be administered surgically. In some embodiments, such implants or reservoir formulations can be administered topically or by injection.

[0171] Those skilled in the relevant art will appreciate that other suitable modifications and adaptations of the compositions and methods described herein will be apparent from the description of the technology contained herein based on information known to those skilled in the art and may be made without departing from the scope of this application or any embodiment thereof.

[0172] V. Compounds and compositions useful for treating mitochondrial diseases such as Friedreich's ataxia and their combinations Intermediates of Guan

[0173] (a) Therapeutic compound (i.e., agent)

[0174] In some embodiments, the present application relates to novel compounds and compositions (including the compounds) that can be used to treat mitochondrial diseases, such as Friedreich's ataxia, in mammalian subjects. The compounds and compositions can be formulated in any manner suitable for administration to a subject. Various possible modes of administration have been discussed previously. The compounds and compositions can, for example, be formulated as tablets (for oral administration) or as solutions for subcutaneous or intravenous injection. In some embodiments, the compounds and compositions can be used to prepare medicaments.

[0175] In some embodiments, the present application relates to a compound represented by formula AB, or a pharmaceutically acceptable salt, stereoisomer, stereoisomer mixture, tautomer, hydrate and / or solvate thereof, wherein A is a head group of formula 1 or 2:

[0176]

[0177] and B is a tail group of formula 3, 4, 5, 6, 7, 8, 9, 10 or 11:

[0178]

[0179] Wherein, each Q is independently of the formula -(CR 12 R 13 )-, O or Si(CH3)2, provided that each O and each Si(CH3)2 is not directly bonded to O or Si(CH3)2; each of R1 and R2 is independently H, D or C1-C6 alkyl, or R1 and R2 together form a 5-membered heterocyclic ring or a 6-membered heterocyclic ring; R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy; each W is independently C (carbon) or N (nitrogen) and wherein for each use The bond between each W may be a single bond or a double bond and further provided that if a single bond, each C (carbon) atom will have a hydrogen atom attached thereto, except for one of R4, R5, R6 or R7; and wherein (i) if W is C (carbon), each of R4, R5, R6 and R7 attached thereto is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, and (ii) if W is N (nitrogen), each of R4, R5, R6 and R7 attached thereto is independently absent or selected from H, D or C1-C6 alkyl; L is absent or is -(CR 12 R 13 )-; each X is independently of the formula -(CR 12 R 13 )-group; each Y is independently absent or of the formula -(CR 12 R 13 )-group; each Z is independently of the formula -(CR 14 )-; each of R8 and R9 is independently H, D, F, Cl, Br, I, C1-C4 alkyl or C1-C8 alkoxy, or a group of the formula -(CR8R9)-, -(CR8R9) or -(CR8R9R 10 ) of the group R8 and R9 together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic ring or heterocyclic ring; each R8 ', R9 ' and R 10 R ' is independently Cl, Br, I, C1-C4 alkyl or C1-C4 alkoxy, or R8' and R9' together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic ring or heterocyclic ring; R 10 is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy; each R 12 、R 13 and R 14 are independently H, D, F, Cl, Br, I, C1-C8 alkyl, C1-C8 alkoxy, C3-C6 cycloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C6-C 14 Aryl or -NR 22 R 23 , or -(CR 12 R 13 )- 12 and R 13 Together they form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring; R 20 It is H, D, F, C1-C 12 Alkyl or C3-C6 cycloalkyl; each R 21 R is independently H, D, F, Cl, Br, I or C1-C4 alkyl; 22 and R23 Each of which is independently H, D, C1-C4 alkyl, or -NR 22 R 23 The group R 22 and R 23 together to form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; m is 0 or 1; n is an integer from 0 to 12, inclusive (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12); p is an integer from 0 to 12, inclusive (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and *** indicates the point of attachment of A to B and ** indicates the point of attachment of B to A; and further provided that: (i) R8, R9, or R 10 At least one of: (a) is F or (b) is a group containing at least one fluorine atom; or (ii) is a group of the formula -(CR8R9)-, -(CR8R9) or -(CR8R9R 10 ) at least one R8 and R9 of the group together form a 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic ring; or (iii) the compound of formula AB has a calculated LogD of 2 to 7, inclusive. In some embodiments, if B is 7, then n cannot be 0. In some embodiments, B is 9, each of m and n is independently 0 or 1, provided that if m + n = 2, then L is absent, and R8, R9, or R 10 is F. In some embodiments, B is 9, m+n=0, 1 or 2, provided that if m+n=2, then L is absent, and R8, R9 and R 10 Each of is F.

[0180] Any combination of head groups 1 and 2 (i.e., "A") and tail groups 3, 4, 5, 6, 7, 8, 9, 10, or 11 (i.e., "B") is permitted. In some embodiments, A is 1 and B is 3, 4, 9, or 10. In some embodiments, A is 1 and B is 5, 6, 7, or 8. In some embodiments, A is 1 and B is 3, 5, 7, or 9. In some embodiments, A is 1 and B is 4, 6, 8, or 10. In some embodiments, A is 1 and B is 11. In some embodiments, A is 2 and B is 3, 4, 9, or 10. In some embodiments, A is 2 and B is 5, 6, 7, or 8. In some embodiments, A is 2 and B is 3, 5, 7, or 9. In some embodiments, A is 2 and B is 4, 6, 8, or 10. In some embodiments, A is 2 and B is 11. In some embodiments, A is 1 and B is 3. In some embodiments, A is 1 and B is 4. In some embodiments, A is 1 and B is 5. In some embodiments, A is 1 and B is 6. In some embodiments, A is 1 and B is 7. In some embodiments, A is 1 and B is 8. In some embodiments, A is 1 and B is 9. In some embodiments, A is 1 and B is 10. In some embodiments, A is 1 and B is 11. In some embodiments, A is 2 and B is 3. In some embodiments, A is 2 and B is 4. In some embodiments, A is 2 and B is 5. In some embodiments, A is 2 and B is 6. In some embodiments, A is 2 and B is 7. In some embodiments, A is 2 and B is 8. In some embodiments, A is 2 and B is 9. In some embodiments, A is 2 and B is 10. In some embodiments, A is 2 and B is 11.

[0181] Generally, for compounds AB, any combination of head group 1 and tail group 3, 4, 5, 6, 7, 8, 9, 10, or 11, in combination with any possible values ​​of m and n, is permitted; provided that: (i) if B is 3, one of m or n is 1; (ii) if B is 5, m is not 0; (iii) if B is 7, n is not 0; (iv) if B is 9, m + n = 0 or 1; and in some embodiments, R8, R9, and R 10is selected from the group consisting of H, D, F, -CH3, CH2F, CHF2, and CF3. For example, in some embodiments, A is 1, B is 3, m is 1, and n is 0, or A is 1, B is 3, m is 0, and n is 1, or A is 1, B is 3, m is 1, and n is 1. In some embodiments, A is 1, B is 4, m is 0, and n is 0, or A is 1, B is 4, m is 1, and n is 0, or A is 1, B is 4, m is 1, and n is 1, or A is 1, B is 4, m is 0, and n is 1. In some embodiments, A is 1, B is 5, m is 1, and n is 0, or A is 1, B is 5, m is 1, and n is 1. In some embodiments, A is 1, B is 6, m is 0, and n is 0, or A is 1, B is 6, m is 1, and n is 0, or A is 1, B is 6, m is 1, and n is 1, or A is 1, B is 6, m is 0, and n is 1. In some embodiments, A is 1, B is 7, m is 0, and n is 1, or A is 1, B is 7, m is 1, and n is 1. In some embodiments, A is 1, B is 8, m is 0, and n is 0, or A is 1, B is 8, m is 1, and n is 0, or A is 1, B is 8, m is 1, and n is 1, or A is 1, B is 8, m is 0, and n is 1. In some embodiments, A is 1, B is 9, m is 0, and n is 0, or A is 1, B is 9, m is 1, and n is 0, or A is 1, B is 9, m is 0, and n is 1. In some embodiments, A is 1, B is 10, m is 0, and n is 0, or A is 1, B is 10, m is 1, and n is 0, or A is 1, B is 10, m is 1, and n is 1, or A is 1, B is 10, m is 0, and n is 1.

[0182] In some embodiments (ie, any of the previously cited embodiments of AB), the group represented by L is absent. In some embodiments (ie, any of the previously cited embodiments of AB), the group represented by L is -(CR 12 R 13In some embodiments, L is -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CD(CD3))-, -(CF(CH3))-, -(CH(CF3))-, -(CF(CF3))-, -(C(CH3)2)-, -(C(CD3)2)-, -(C(CF3)2)-, -(CH(OCH3))-, -(CD(OCD3))-, -(CF(OCH3))-, -(CH(OCF3))-, -(CF(OCF3))-, - (C(OCH3)2)-, -(C(OCD3)2)-, -(C(OCF3)2)-, -(C(CH3)(CF3))-, -(C(CD3)(CF3))-, -(CH(CH2CH3))-, -(CD(CD2CD3))-, -( CF(CH2CH3))-, -(CH(CH2CF3))-, -(CH(CF2CF3))-, -(CF(CF2CF3))-, -(C(CH2CH3)2)-, -(C(CD2CD3)2)- or -(C(CF2CF3)2)-. In some embodiments, L is -(CH2)-, -(CD2)-, -(CF2)-, -(CH(CH3))-, -(CD(CD3))-, -(CF(CF3))-, -(C(CH3)2)-, -(C(CD3)2)-, -(C(CF3)2)-, -(CH(OCH3))-, -(CD(OCD3))-, -(CF(OCF3))-, or -(C(OCH3)2)-. In some embodiments, L is -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-. In some embodiments, L is -(CH2)-, -(CD2)-, or -(CF2)-. In some embodiments, L is -(CH2)-. In some embodiments, L is -(CD2)-. In some embodiments, L is -(CF2)-. In some embodiments, L is -(CHF)-. In some embodiments, L is -(CR 12 R 13 )-and where R 12 and R 13 Together they form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring.

[0183] In some embodiments of the compound represented by AB, each X and each Y is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CD(CD3))-, -(CF(CH3))-, -(CH(CF3))-, -(CF(CF3))-, -(C(CH3)2)-, -(C(CD3)2)-, -(C(CF3)2)-, -(CH(OCH3))-, -(CD(OCD3))-, -(CF(OCH3))-, -(CH(OCF3))-, -(CF( OCF3))-, -(C(OCH3)2)-, -(C(OCD3)2)-, -(C(OCF3)2)-, -(C(CH3)(CF3))-, -(C(CD3)(CF3))-, -(CH(CH2CH3))-, -(CD(CD2CD3)) -, -(CF(CH2CH3))-, -(CH(CH2CF3))-, -(CH(CF2CF3))-, -(CF(CF2CF3))-, -(C(CH2CH3)2)-, -(C(CD2CD3)2)- or -(C(CF2CF3)2)-. In some embodiments, each X and each Y is independently -(CH2)-, -(CD2)-, -(CF2)-, -(CH(CH3))-, -(CD(CD3))-, -(CF(CF3))-, -(C(CH3)2)-, -(C(CD3)2)-, -(C(CF3)2)-, -(CH(OCH3))-, -(CD(OCD3))-, -(CF(OCF3))-, or -(C(OCH3)2)-. In some embodiments, each X and each Y is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-. In some embodiments, each X and each Y is independently -(CH2)-, -(CD2)-, or -(CF2)-. In some embodiments, each X and each Y is -(CH2)-. In some embodiments, each X and each Y is -(CD2)-. In some embodiments, each X and each Y is -(CF2)-. In some embodiments, each X and each Y is -(CHF)-. In some embodiments, at least one X or one Y is -(CD2)-, -(CF2)-, or -(CHF)-. In some embodiments, at least one of X and Y is -(CR 12 R 13 )-, where R 12 and R 13Together they form a 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic ring. In some embodiments, each of X and Y is -(CR 12 R 13 )-, where for the formula -(CR 12 R 13 )-each group, each R 12 and R 13 Together they form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring.

[0184] In some embodiments of compounds represented by AB, each X is -(CH2)-. In some embodiments, each X is -(CD2)-. In some embodiments, each X is -(CF2)-. In some embodiments, each X is -(CHF)-. In some embodiments, each Y is -(CH2)-. In some embodiments, each Y is -(CD2)-. In some embodiments, each Y is -(CF2)-. In some embodiments, each Y is -(CHF)-. In some embodiments, at least one X is -(CD2)-, -(CF2)-, or -(CHF)-. In some embodiments, at least one X or one Y is -(CD2)-, -(CF2)-, or -(CHF)-.

[0185] In some embodiments of compounds represented by AB, each Z is independently -(CH)-, -(CD)-, -(CF)-, or -(C(CH3))-. In some embodiments, each Z is -(CH)-. In some embodiments, each Z is -(CD)-. In some embodiments, each Z is -(CF)-. In some embodiments, each Z is -(C(CH3))-. In some embodiments, at least one Z is -(CD)- or -(CF)-.

[0186] In some embodiments of the compound represented by AB, each Q is of the formula -(CR 12 R 13 In some embodiments, each Q is a group of formula -(CH2)-. In some embodiments, p is >2 and at least one Q is O and the other Q is -(CH2)-. In some embodiments, p>2 and is represented by -(Q) p - represents a group containing at least one ethylene oxide moiety (i.e., at least one group of formula -OCH2CH2-). In some embodiments, p>3 and is represented by -(Q) p - represents a group containing at least one propylene oxide moiety (i.e., at least one group of the formula -OCH2CH2CH2-). In some embodiments, the group represented by -(Q) p- represents a group of formula -(OCH2CH2) s -, wherein s is 1, 2, 3, 4, 5 or 6. In some embodiments, -(Q) p - represents a group of formula -(OCH2CH2CH2) t -, wherein t is 1, 2, 3 or 4.

[0187] In some embodiments of the compound represented by AB, wherein A is 1, each of R1 and R2 is independently H, D, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH(CH3)2, -CD2CD3, -CD(CD3)2, -CF2CH3, -CF(CH3)2, -CH2CF3, -CH(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2C D3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, or -OCH2CH2CH3; and R3 is H, D, Cl, F, -CH3, -OCH 3. -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, -CH(CH3)2, -CD2CD3, -CD(CD3)2, -CF2CH3, -CF(CH3)2, -CH2CF3, -CH(CF3)2, - CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -OCF2CF3, - OCH(CF3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH 2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, -OCH2C H2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2.In some embodiments, wherein A is 1, each of R1 and R2 is independently H, D, -CH3, -CD3, -CH2F, -CHF2, -CF3, -C(CH3)3, -C(CD3)3, -C(CF3)3, -CH2CH3, or -CH(CH3)2; and R3 is H, D, Cl, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments, wherein A is 1, each of R1 and R2 is independently H, -CH3, -CH2F, -CHF2, -CF3, -C(CH3)3, -C(CF3)3, -CH2CH3, or -CH(CH3)2; and R3 is H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments, wherein A is 1, each of R1 and R2 is H, -CH3, or -CF3; and R3 is H, F, -CH3, -OCH3, -CF3, or -OCF3. In some embodiments, wherein A is 1, each of R1 and R2 is -CH3 or -CH2CH3; and R3 is H, F, or -CH3. In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; and R3 is H. In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; and R3 is F. In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; and R3 is -CH3. In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; and R3 is -OCH3. In some embodiments, wherein A is 1, at least one of R1, R2, and R3 contains at least one fluorine atom. In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; R3 is H, F, CH3, or -OCH3, and at least one of R8 and R9 contains a fluorine atom. In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; R3 is H, F, CH3, or -OCH3, and each of R8 and R9 contains a fluorine atom. In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; R3 is H, F, CH3 or -OCH3, and R8, R9 and R. 10Each of contains a fluorine atom. In some embodiments, wherein A is 1: (i) at least one of R1, R2, and R3 contains at least one fluorine atom; and / or (ii) at least one of R8 and R9 contains a fluorine atom. In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; R3 is H, F, CH3, or -OCH3, and each of R8 and R9 is a fluorine atom. In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; R3 is H, F, CH3, or -OCH3, and R8, R9, and R 10 In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; R3 is H, F, CH3 or -OCH3, and R8, R9 and R 10 In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; R3 is H, F, CH3 or -OCH3, and R8, R9 and R 10 In some embodiments, wherein A is 1, each of R1 and R2 is -CH3; R3 is H, F, CH3 or -OCH3, and R8, R9 and R 10 Each of them is a fluorine atom.

[0188] In some embodiments of compounds represented by AB, wherein A is 1, (i) R3 is H, D, Cl, F, -CH3, -OCH3, -CD3, -OCD3, -CF3, -OCF3, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2; and (ii) each of R1 and R2 is -CH3 or together form a 5- or 6-membered heterocyclic ring. In some embodiments, wherein A is 1, (i) R3 is H, D, F, -CH3, -OCH3, -CF3, or -OCF3; and (ii) R1 and R2 together form a 5- or 6-membered heterocyclic ring. In some embodiments, wherein A is 1; (i) R3 is H, F, -CH3 or -OCH3, and (ii) R1 and R2 together form a 5- or 6-membered heterocyclic ring. In some embodiments, wherein A is 1; (i) R3 is H; and (ii) R1 and R2 together form a 5- or 6-membered heterocyclic ring. In some embodiments, wherein A is 1; (i) R3 is -CH3; and (ii) R1 and R2 together form a 5- or 6-membered heterocyclic ring. In some embodiments of the compound represented by AB, wherein A is 1; (i) R3 is -OCH3; and (ii) R1 and R2 together form a 5- or 6-membered heterocyclic ring. In some embodiments of the compound represented by AB, wherein A is 1; (i) R3 is F; and (ii) R1 and R2 together form a 5- or 6-membered heterocyclic ring.

[0189] In some embodiments of the compound represented by AB, A is a head group of formula 1A or 1B:

[0190]

[0191] In some embodiments of 1A or 1B, R3 is H, F, -CH3, or -OCH3. In some embodiments of 1A or 1B, R3 is H. In some embodiments of 1A or 1B, R3 is F. In some embodiments of 1A or 1B, R3 is -CH3. In some embodiments of 1A or 1B, R3 is -OCH3.

[0192] In some embodiments of the compound represented by AB, wherein A is 2, R3 is H, D, F, Cl, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, -CH(CH3)2, -CD2CD3, -CD(CD3)2, -CF2CH3, CF(CH3)2, -CH2CF3, -CH(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, - OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -OCF2CF3, -OCH(CF3)2, -OCF2(CF3), -OCF(CF 3)2, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH2CH2CH3, -CH( CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, - OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF 2CF2CF3 or -OCF(CF2CF3)2; and wherein if W is C (carbon), each of R4, R5, R6 and R7 attached thereto may independently be H, D, F, Cl, Br, I, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3 or -CH(CH3)2, and wherein if W is N (nitrogen), each of R4, R5, R6 and R7 attached thereto may independently be absent or be H, D, methyl, ethyl, isopropyl or tert-butyl.In some embodiments, wherein A is 2, R3 is H, D, Cl, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2; and wherein if W is C (carbon), each of R4, R5, R6, and R7 attached thereto is independently H, D, F, Cl, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2, and wherein if W is N (nitrogen), each of R4, R5, R6, and R7 attached thereto is independently absent or is H, D, methyl, or ethyl. In some embodiments, wherein A is 2, R3 is H, F, -CH3, -OCH3, -CF3, or -OCF3; and wherein if W is C (carbon), each of R4, R5, R6, and R7 attached thereto is independently H, F, -CH3, -OCH3, -CF3, or -OCF3, and wherein if W is N (nitrogen), each of R4, R5, R6, and R7 attached thereto is independently absent or is H or methyl. In some embodiments, wherein A is 2, each W is C (carbon) and each of R4, R5, R6, and R7 is independently H, D, Cl, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, or -OCF3. In some embodiments, wherein A is 2, each W is C (carbon) and each of R4, R5, R6, and R7 is independently H, F, -CH3, -OCH3, -CF3, or -OCF3. In some embodiments, wherein A is 2, each W is C (carbon) and each of R4, R5, R6 and R7 is independently H, F, -CH3 or -OCH3. In some embodiments, wherein A is 2, each W is C (carbon) and each of R4, R5, R6 and R7 is H. In some embodiments, wherein A is 2, each W is C (carbon) and each of R4, R5, R6 and R7 is F. In some embodiments, wherein A is 2, each W is C (carbon) and each of R4, R5, R6 and R7 is -CH3.

[0193] In some embodiments of the compound represented by AB, each R8 and R9 is independently H, D, F, Cl, Br, I, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH(CH3)2, -CD2CD3, -CD(CD3)2, -CF2CH3, -CF(CH3)2, -CH2CF3, -CH(CH2F)2, -CH(CF3)2, -CF2CF3, -CF(CF3)2, -C (CH3)3, -C(CD3)3, -C(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD 3. -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some embodiments of the compounds represented by AB, each R8 and R9 is independently H, F, -CH3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH(CH3)2, -CF2CH3, -CH2CF3, -CH(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CF3)3, -CH2CH2CH3, -CH(CH2F)2, -CH(CH2CH3)2, -CF2CF2CF3, or -CF(CF2CF3)2. In some embodiments of the compounds represented by AB, each R8 and R9 is independently H, F, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH(CH2F)2, -CH(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, or -C(CF3)3. In some embodiments of the compound represented by AB, each R8 and R9 are independently H, F, -CH3, -CF3, -CH2CH3 or -CH(CH2F)2. In some embodiments of the compound represented by AB, each R8 and R9 are independently H, F, -CH3, -CH2F, -CHF2 or -CF3. In some embodiments of the compound represented by AB, each R8 and R9 are H. In some embodiments of the compound represented by AB, each R8 and R9 are F. In some embodiments of the compound represented by AB, one of R8 and R9 is F and the other of R8 and R9 is H. In some embodiments of the compound represented by AB, each R8 and R9 are -CH3. In some embodiments of the compound represented by AB, each R8 and R9 are -CH2F. In some embodiments of the compound represented by AB, each R8 and R9 are -CF3.In some embodiments of the compound represented by AB, at least one of R8 and R9 is -CF3. In some embodiments of the compound represented by AB, at least one of R8 and R9 is F. In some embodiments of the compound represented by AB, at least one of R8 and R9 is -CH2F.

[0194] In some embodiments of the compound represented by AB, the formula -(CR8R9)-, -(CR8R9) or -(CR8R9R 10 ) wherein at least one R8 and R9 of the group of formula (I) together form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring selected from the group of formula (s) 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 and 47:

[0195]

[0196] wherein # indicates the point of attachment of the carbocyclic or heterocyclic ring to the rest of the compound. In some embodiments of the compound represented by AB, the formula -(CR8R9)-, -(CR8R9) or -(CR8R9R 10 ) each R8 and R9 of a group together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring selected from groups of formula 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47:

[0197]

[0198] wherein # indicates the point of attachment of the carbocyclic or heterocyclic ring to the rest of the compound. In some embodiments of the compound represented by AB, the formula -(CR8R9) or -(CR8R9R 10 ) each R8 and R9 of a group together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring selected from groups of formula 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47:

[0199]

[0200] wherein # indicates the point of attachment of the carbocycle or heterocycle to the rest of the compound.

[0201] In some embodiments, each of R8', R9' and R 10 ' is independently C1-C4 alkyl. In some embodiments, each of R8', R9' and R 10' is independently C1-C4 alkoxy. In some embodiments, each R8', R9' and R 10 ' is independently methyl, ethyl or tert-butyl. In some embodiments, each R8', R9' and R 10 ' is methyl. In some embodiments, each of R8', R9' and R 10 ' is methoxy. In some embodiments, each of R8', R9' and R 10 ' is ethyl. In some embodiments, each of R8', R9' and R 10 In some embodiments, R8' and R9' together form a 4-membered, 5-membered, or 6-membered carbocyclic or heterocyclic ring.

[0202] In some embodiments of compound AB, R 10 Is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, -CH(CH3)2, -CD2CD3, -CD(CD3)2, -CF2CH3, CF(CH3)2, -CH2CF3, -CH( CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OCF2CF3, -OCD(CD3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CF2CF3, -CF(CF2CF3)2, -C(CH2CH3)3, -C(CD2CD3)3, -C(CF2CF3)3, -OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CF2CF3, or -OCF(CF2CF3)2. In some embodiments of compound AB, R 10 is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3 or -CH(CH3)2. In some embodiments of compound AB, R 10is H, D, F, -CH3, -CH2F, -CHF2 or -CF3. In some embodiments of compound AB, R 10 It is R 10 is H, F, -CH3, -OCH3, -CF3 or -OCF3. In some embodiments of compound AB, R 10 is H, D or F. In some embodiments of compound AB, R 10 Is -CH3 or -CF3. In some embodiments of compound AB, R 10 Is H or -CH3. In some embodiments of compound AB, R 10 Is H or -CF3. In some embodiments of compound AB, R 10 is H. In some embodiments of compound AB, R 10 is D. In some embodiments of compound AB, R 10 is F. In some embodiments of compound AB, R 10 In some embodiments of compound AB, R 10 In some embodiments of compound AB, R 10 Does not exist.

[0203] In some embodiments of compound AB, R 12 、R 13 or R 14 Each instance of is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH(CH2CH3)2, -C(CH3)3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2CH3, -OCH(CH2CH3)2, or -OC(CH3)3. In some embodiments of compound AB, R 12 、R 13 or R 14 Each instance of is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3 or -CH(CH3)2. In some embodiments of compound AB, R 12 、R 13 or R 14Each instance of is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3 or -OCF3. In some embodiments of compound AB, R 12 、R 13 and R 14 Each instance of is independently H, F, -CH3, -OCH3, -CF3, -OCF3, -CH2CH3 or -OCH2CH3. In some embodiments of compound AB, R 12 、R 13 or R 14 Each instance of is independently H, D, F, -CH3, -CD3 or -CF3. In some embodiments of compound AB, R 12 、R 13 or R 14 Each instance of is independently H, D, F or -CH3. In some embodiments of compound AB, R 12 、R 13 or R 14 Each instance of is independently H or F. In some embodiments of compound AB, R 12 、R 13 or R 14 Each instance of is H. In some embodiments of compound AB, R 12 、R 13 or R 14 Each instance of is D. In some embodiments of compound AB, R 12 、R 13 or R 14 Each instance of is F. In some embodiments of compound AB, R 12 、R 13 or R 14 Each instance of is -CH3. In some embodiments of compound AB, R 12 、R 13 and R 14 Each instance of is independently H, F, -CH3, -OCH3, -CF3, -OCF3, -CH2CH3 or -OCH2CH3; provided, however, that for the formula -(CR 12 R 13 )-at least one group, R 12 and R 13 Together they form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring.

[0204] In some embodiments of compound AB, R 20is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In some embodiments of compound AB, R 20 is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3. In some embodiments of compound AB, R 20 is H, D, F, -CH3, -CD3, -CH2F, -CHF2 or -CF3. In some embodiments of compound AB, R 20 is H, D, F, -CH3, -CD3, -CH2F, -CHF2 or -CF3. In some embodiments of compound AB, R 20 is H, D, F or -CH3. In some embodiments of compound AB, R 20 is -CH3, -CD3, -CH2F, -CHF2 or -CF3. In some embodiments of compound AB, R 20 is H, F or -CH3. In some embodiments of compound AB, R 20 is H. In some embodiments of compound AB, R 20 In some embodiments of compound AB, R 20 In some embodiments of compound AB, R 20 It's F.

[0205] In some embodiments of compound AB, each R 21 R is independently H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3 or -C(CH3)3. In some embodiments of compound AB, each R 21 In some embodiments of compound AB, each R 21In some embodiments of compound AB, each R 21 In some embodiments of compound AB, each R 21 In some embodiments of compound AB, each R 21 is H. In some embodiments of compound AB, each R 21 It's F.

[0206] In some embodiments of compound AB, m is 0. In some embodiments of compound AB, m is 1. In some embodiments of compound AB, n is 0. In some embodiments of compound AB, n is 1. In some embodiments of compound AB, n and m are both 0. In some embodiments of compound AB, one of n and m is 0 and the other is 1. In some embodiments of compound AB, n and m are both 1. In some embodiments of compound AB, (i) m is 0 and n is 0; (ii) m is 0 and n is 1, 2, or 3; or (iii) m is 1 and n is 0, 1, 2, or 3.

[0207] In some embodiments of compound AB, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments of compound AB, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of compound AB, n is 0, 1, 2, 3, or 4. In some embodiments of compound AB, n is 2. In some embodiments of compound AB, n is 3. In some embodiments of compound AB, n is 4. In some embodiments of compound AB, n is 5. In some embodiments of compound AB, n is 6. In some embodiments of compound AB, n is 7. In some embodiments of compound AB, n is 8. In some embodiments of compound AB, n is 9. In some embodiments of compound AB, n is 10. In some embodiments of compound AB, n is 11. In some embodiments of compound AB, n is 12.

[0208] In some embodiments of compound AB, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments of compound AB, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments of compound AB, p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments of compound AB, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of compound AB, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of compound AB, p is 0. In some embodiments of compound AB, p is 1. In some embodiments of compound AB, p is 2. In some embodiments of compound AB, p is 3. In some embodiments of compound AB, p is 4. In some embodiments of compound AB, p is 5. In some embodiments of compound AB, p is 6. In some embodiments of compound AB, p is 7. In some embodiments of compound AB, p is 8. In some embodiments of compound AB, p is 9. In some embodiments of compound AB, p is 10. In some embodiments of compound AB, p is 11. In some embodiments of compound AB, p is 12. In some embodiments of compound AB, p is 13. In some embodiments of compound AB, p is 14. In some embodiments of compound AB, p is 15. In some embodiments of compound AB, p is 16. In some embodiments of compound AB, p is 17. In some embodiments of compound AB, p is 18. In some embodiments of compound AB, p is 19. In some embodiments of compound AB, p is 20.

[0209] In some embodiments of compound AB, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 、R 12 、R 13 、R 14 、R 20 or R 21 In some embodiments of compound AB, at least one group of formula R8, R9, R 10 、R 20 or R 21 In some embodiments of compound AB, at least one group of formula R8, R9 or R 10 At least one group in contains at least one fluorine atom. In some embodiments of compound AB, the formula -(CR8R9)-, -(CR8R9) or -(CR8R9R10 ) at least one R8 and R9 of the group together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic ring or heterocyclic ring. In some embodiments of compound AB, the formula -(CR8R9) or -(CR8R9R 10 ) group together form a 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic ring. In some embodiments of compound AB, each R8 and R9 of the group of formula -(CR8R9) together form a 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic ring.

[0210] In some embodiments, Compound AB has the formula referred to herein as Compound X:

[0211]

[0212] wherein each of R1' and R2' is independently C1-C3 alkyl; R3' is H, D, F, -CH3, -CF3, -OCH3 or -OCF3; each Z is independently H, D or F; a is 1, 2, 3, 4, 5, 6, 7, 9 or 9; and R 30 、R 31 and R 32 Each of is independently H, D or F, provided that R 30 、R 31 or R 32 In some embodiments of compound X, at least one of R1' and R2' is F. In some embodiments of compound X, each of R1' and R2' is methyl. In some embodiments of compound X, each of R1' and R2' is ethyl. In some embodiments of compound X, R3' is H or -CH3. In some embodiments of compound X, R3' is -CH3. In some embodiments of compound X, a is 3, 4, 5, 6, 7, or 8. In some embodiments of compound X, a is 3, 4, 5, 6, or 7. In some embodiments of compound X, a is 4, 5, 6, 7, 8, or 9. In some embodiments of compound X, a is 4, 5, 6, 7, or 8. In some embodiments of compound X, a is 4, 5, 6, or 7. In some embodiments of compound X, a is 1. In some embodiments of compound X, a is 2. In some embodiments of compound X, a is 3. In some embodiments of compound X, a is 4. In some embodiments of compound X, a is 5. In some embodiments of compound X, a is 6. In some embodiments of compound X, a is 7. In some embodiments of compound X, a is 8. In some embodiments of Compound X, a is 9. In some embodiments of Compound X, each Z is H. In some embodiments of Compound X, R 30 、R 31and R 32 Each of them is F.

[0213] In some embodiments, compound AB has the formula referred to herein as Y:

[0214]

[0215] wherein each of R1' and R2' is independently C1-C3 alkyl; R3' is H, D, F, -CH3, -CF3, -OCH3 or -OCF3; b is 1, 2 or 3; and R 33 and R 34 Each of the R 33 and R 34 In some embodiments of compound Y, at least one of R1' and R2' is selected from F, -CH2F, -CHF2, and -CF3. In some embodiments of compound Y, each of R1' and R2' is methyl. In some embodiments of compound Y, each of R1' and R2' is ethyl. In some embodiments of compound Y, R3' is H or -CH3. In some embodiments of compound Y, b is 1. In some embodiments of compound Y, b is 2. In some embodiments of compound Y, b is 3. In some embodiments of compound Y, each Z is H. In some embodiments of compound Y, R 33 and R 34 Each of them is F.

[0216] In some embodiments, compound AB has the formula referred to herein as Z:

[0217]

[0218] wherein each of R1′ and R2′ is independently C1-C3 alkyl; R3′ is H, D, F, -CH3, -CF3, -OCH3, or -OCF3; and u is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, each of R1′ and R2′ is independently -CH3 or -CH2CH3, and R3′ is H or -CH3. In some embodiments, each of R1′, R2′, and R3′ is -CH3. In some embodiments, u is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, u is 1, 2, 3, 4, 5, or 6. In some embodiments, u is 2, 3, 4, 5, 6, 7, or 8. In some embodiments, u is 2, 3, 4, 5, 6, or 7. In some embodiments, u is 3, 4, 5, 6, or 7. In some embodiments, u is 3, 4, 5, or 6. In some embodiments, u is 4, 5, 6, or 7. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments of Z, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, u is 6. In some embodiments, u is 7. In some embodiments, u is 8. In some embodiments, each of R1' and R2' is independently -CH3 or -CH2CH3, R3' is -CH3, u is 2, 3, 4, 5, 6, 7, or 8, and Z has a calculated LogD of 2 to 7, inclusive.

[0219] In some embodiments, Compound AB has the formula referred to herein as Compound B:

[0220]

[0221] In some embodiments, Compound AB has the formula referred to herein as Compound C:

[0222]

[0223] In some embodiments, Compound AB has the formula referred to herein as Compound E:

[0224]

[0225] In some embodiments, Compound AB has the formula referred to herein as Compound F:

[0226]

[0227] In some embodiments, Compound AB has the formula referred to herein as Compound G:

[0228]

[0229] In some embodiments, Compound AB has the formula referred to herein as Compound 1:

[0230]

[0231] In some embodiments, Compound AB has the formula referred to herein as Compound J:

[0232]

[0233] In some embodiments, Compound AB has the formula referred to herein as Compound K:

[0234]

[0235] In some embodiments, Compound AB has the formula referred to herein as Compound M:

[0236]

[0237] In some embodiments, Compound AB has the formula referred to herein as Compound N:

[0238]

[0239] In some embodiments, Compound AB has the formula referred to herein as Compound O:

[0240]

[0241] In some embodiments, Compound AB has the formula referred to herein as Compound P:

[0242]

[0243] In some embodiments, Compound AB has the formula referred to herein as Compound Q:

[0244]

[0245] As illustrated in Examples 12-15 and Table 1 below, certain compounds disclosed herein exhibit a significant degree of potency in the BSO assay (Example 12) and the rotenone ATP assay (Example 13) and / or the alternative rotenone oxymeter assay (Example 15; each of the rotenone ATP and rotenone oxymeter assays provides information on whether the compound under investigation has Complex I bypass capability). For example, the potency and efficacy of Compound C disclosed herein are similar to those of vatiquinone in ameliorating Friedreich's ataxia in a cell-based assay (see Example 12; BSO assay). However, unlike vatiquinone, Compound C is also effective in rescuing cells exhibiting induced Complex I deficiency in both the rotenone ATP assay (Example 13) and the rotenone oxymeter assay (Example 15). In fact, in contrast, although some currently available therapeutic agents such as vartiquinone, idebenone, or omaviron may exhibit good or fairly good activity in one or the other of the BSO assay or the rotenone ATP (or rotenone oxygraph assay; see: Table 1 below), none of them are active in both assays, suggesting that many of the compounds disclosed herein (e.g., Compounds B to I and K) may be better therapeutic agents than compounds currently being evaluated in clinical trials as therapeutic agents for treating mitochondrial diseases such as Friedreich's ataxia. Therefore, it is believed that the therapeutic compounds disclosed herein may prove to be superior agents for treating mitochondrial diseases such as Friedreich's ataxia. The above-mentioned compounds can be used to prepare compositions, such as medicaments. The compounds (e.g., Compounds B to I and K) or compositions thereof can therefore be used to treat or prevent mitochondrial diseases such as Friedreich's ataxia.

[0246] It is noteworthy that compound J (calculated LogD of 1.79) was not as effective in any of the BSO assays, rotenone ATP, or rotenone oxygraph assays; see: Table 1 below. However, it is noteworthy that according to: Erb et al., Features of Idebenone and Related Short-Chain Quinones that Rescue ATP Levels under Conditions of Imparied Mitochondrial Complex I, PLoS One, (April 2012) 7(4):e36153, quinone compounds with calculated LogD values ​​less than 1.9 are poor at rescuing ATP levels in cells impaired by complex I, and a calculated LogD window of 2 to 7 (inclusive) is suggested to be preferred. This LogD value may also explain the poor performance of compound J in the BSO assay.

[0247] (b) Other derivatives / therapeutic agents

[0248] In some embodiments, the present application also provides a therapeutic compound of formula CB (defined below), which can be prepared by reducing a therapeutic compound of formula AB. This reduced form of the compound of formula AB is also considered to be suitable for treating mitochondrial diseases, such as Friedreich's ataxia or other ataxias (e.g., ataxia with vitamin E deficiency (AVED)), because other compounds with a hydroquinone structure, such as vitamin E, have also been shown to be clinically relevant to ataxia (see: Imounan et al., Clinical and Genetic Study of Friedreich's ataxia and Ataxia with Vitamin E Deficiency in 44 Moroccan Families, World Journal of Neuroscience, 2014, 4, 299-305; and Abeti et al., Calcium Deregulation: Novel Insights to Understand Friedreich's ataxia Pathophysiology, Frontiers in Cellular Neuroscience: doi: 10.3398 / fncel.2018.00264). For example, it is believed that the therapeutic compound of formula CB can itself be considered a therapeutic agent or, alternatively, a prodrug form of the therapeutic agent of formula AB. Specifically, the therapeutic compound of formula AB is believed to be active in affecting the in vivo concentration of reactive oxygen species (ROS) (e.g., internal and external mitochondrial concentrations) and can indeed actively cycle in vivo between a reduced form (the compound of formula CB) and an oxidized form (the compound of formula AB); indeed, such cycling is discussed in the literature, for example, in Erb et al., PLoSone (April 2012) 7(4):e36153. The compound of formula AB can, for example, be converted to the compound of formula CB, as described in Examples 11A and 11B below. Alternatively, the compound of formula CB is provided as an intermediate in the production of the compound of formula AB, as described, for example, in Examples 1-10 below.

[0249] Therefore, in some embodiments, the present application relates to a compound represented by Formula CB, or a pharmaceutically acceptable salt, stereoisomer, stereoisomer mixture, tautomer, hydrate and / or solvate thereof, wherein C is a head group of Formula 13 or 14:

[0250]

[0251] and B is a tail group of formula 3, 4, 5, 6, 7, 8, 9, 10 or 11:

[0252]

[0253] Wherein, each Q is independently of the formula -(CR 12 R 13 )-, O or Si(CH3)2, provided that each O and each Si(CH3)2 is not directly bonded to O or Si(CH3)2; each of R1 and R2 is independently H, D or C1-C6 alkyl, or R1 and R2 together form a 5-membered heterocyclic ring or a 6-membered heterocyclic ring; R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy; each W is independently C (carbon) or N (nitrogen), and wherein for each use The bond between each W may be a single bond or a double bond, and further provided that if it is a single bond, then each C (carbon) atom will have a hydrogen atom attached thereto, except for one of R4, R5, R6 or R7; and wherein (i) if W is C (carbon), then each of R4, R5, R6 and R7 attached thereto is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, and (ii) if W is N (nitrogen), then each of R4, R5, R6 and R7 attached thereto is independently absent or selected from H, D or C1-C6 alkyl; L is absent or is -(CR 12 R 13 )-; each X is independently of the formula -(CR 12 R 13 )-group; each Y is independently absent or of the formula -(CR 12 R 13 )-group; each Z is independently of the formula -(CR 14 )-; each of R8 and R9 is independently H, D, F, Cl, Br, I, C1-C4 alkyl or C1-C8 alkoxy, or a group of the formula -(CR8R9)-, -(CR8R9) or -(CR8R9R 10 ) of the group R8 and R9 together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic ring or heterocyclic ring; each R8 ', R9 ' and R 10 R ' is independently Cl, Br, I, C1-C4 alkyl or C1-C4 alkoxy, or R8' and R9' together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic ring or heterocyclic ring; R 10 is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy; each R 12 、R 13 and R 14are independently H, D, F, Cl, Br, I, C1-C8 alkyl, C1-C8 alkoxy, C3-C6 cycloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C6-C 14 Aryl or -NR 22 R 23 , or -(CR 12 R 13 )-group R 12 and R 13 together to form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring; each R 19 are independently H, C1-C4 alkyl, (unsubstituted or substituted) benzyl, R 24 C(O)-、R 24 OC(O)-、R 24 R 25 NC(O)-or(R 24 O)(R 25 O)P(O)-;R 20 It is H, D, F, C1-C 12 Alkyl or C3-C6 cycloalkyl; each R 21 R is independently H, D, F, Cl, Br, I or C1-C4 alkyl; 22 and R 23 Each of which is independently H, D, C1-C4 alkyl; or -NR 22 R 23 The group R 22 and R 23 Together they form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring; R 24 and R 25 Each of the following is independently H, D, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, heteroarylheteroalkyl, or T, wherein T is -(CH2) w -(O) x -[(CH2CH2)-O] q -R 26 ; R 26is H, methyl, ethyl, isopropyl or tert-butyl; m is 0 or 1; n is an integer from 0 to 12 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12), inclusive; p is an integer from 0 to 20, inclusive (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); q is 0, 1, 2, 3, 4 or 5; x is 0 or 1; w is 0, 1 or 2; provided that if x is 0, then w is 0; and if w is 0, then x is 0; and *** indicates the point of attachment of C to B and ** indicates the point of attachment of B to C; and further provided that: (i) R8, R9 or R 10 At least one of: (a) is F or (b) is a group containing at least one fluorine atom; or (ii) is a group of the formula -(CR8R9)-, -(CR8R9) or -(CR8R9R 10 ) at least one R8 and R9 of the group together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring; or (iii) the compound of formula CB is the hydroquinone form of the corresponding quinone, which has a calculated LogD of 2 to 7, inclusive; or (iv) at least one R 19 It is R 24 C(O)-、R 24 OC(O)-、R 24 R 25 NC(O)-or(R 24 O)(R 25 In some embodiments, if B is 7, then n cannot be 0. In some embodiments, B is 9, and each of m and n is independently 0 or 1, provided that if m+n=2, then L is absent, and R8, R9, or R 10 In some embodiments, at least one of B is F. In some embodiments, B is 9, m+n=0, 1, or 2, provided that if m+n=2, then L is absent, and R8, R9, and R 10 Each of them is F.

[0254] Any combination of head groups 13 and 14 (i.e., "C") and tail groups 3, 4, 5, 6, 7, 8, 9, 10, or 11 (i.e., "B") is permitted. In some embodiments, C is 13 and B is 3, 4, 9, or 10. In some embodiments, C is 13 and B is 5, 6, 7, or 8. In some embodiments, C is 13 and B is 3, 5, 7, or 9. In some embodiments, C is 13 and B is 4, 6, 8, or 10. In some embodiments, C is 13 and B is 11. In some embodiments, C is 14 and B is 3, 4, 9, or 10. In some embodiments, C is 14 and B is 5, 6, 7, or 8. In some embodiments, C is 14 and B is 3, 5, 7, or 9. In some embodiments, C is 14 and B is 4, 6, 8, or 10. In some embodiments, C is 14 and B is 11. In some embodiments, C is 13 and B is 3. In some embodiments, C is 13 and B is 4. In some embodiments, C is 13 and B is 5. In some embodiments, C is 13 and B is 6. In some embodiments, C is 13 and B is 7. In some embodiments, C is 13 and B is 8. In some embodiments, C is 13 and B is 9. In some embodiments, C is 13 and B is 10. In some embodiments, C is 13 and B is 11. In some embodiments, C is 14 and B is 3. In some embodiments, C is 14 and B is 4. In some embodiments, C is 14 and B is 5. In some embodiments, C is 14 and B is 6. In some embodiments, C is 14 and B is 7. In some embodiments, C is 14 and B is 8. In some embodiments, C is 14 and B is 9. In some embodiments, C is 14 and B is 10. In some embodiments, C is 14 and B is 11.

[0255] Generally, for compound CB, any combination of head group 1 and tail group 3, 4, 5, 6, 7, 8, 9, 10, or 11, in combination with any possible values ​​of m and n, is permitted; provided that: (i) if B is 3, one of m or n is 1; (ii) if B is 5, m is not 0; (iii) if B is 7, n is not 0; (iv) if B is 9, m + n = 0 or 1; and in some embodiments, R8, R9, and R 10is selected from the group consisting of H, D, F, -CH3, CH2F, CHF2, and CF3. For example, in some embodiments, C is 13, B is 3, m is 1, and n is 0, or C is 13, B is 3, m is 0, and n is 1, or C is 13, B is 3, m is 1, and n is 1. In some embodiments, C is 13, B is 4, m is 0, and n is 0, or C is 13, B is 4, m is 1, and n is 0, or C is 13, B is 4, m is 1, and n is 1, or C is 13, B is 4, m is 0, and n is 1. In some embodiments, C is 13, B is 5, m is 1, and n is 0, or C is 13, B is 5, m is 1, and n is 1. In some embodiments, C is 13, B is 6, m is 0 and n is 0, or C is 13, B is 6, m is 1 and n is 0, or C is 13, B is 6, m is 1 and n is 1, or C is 13, B is 6, m is 0 and n is 1. In some embodiments, C is 13, B is 7, m is 0 and n is 1, or C is 13, B is 7, m is 1 and n is 1. In some embodiments, C is 13, B is 8, m is 0 and n is 0, or C is 13, B is 8, m is 1 and n is 0, or C is 13, B is 8, m is 1 and n is 1, or C is 13, B is 8, m is 0 and n is 1. In some embodiments, C is 13, B is 9, m is 0 and n is 0, or C is 13, B is 9, m is 1 and n is 0, or C is 13, B is 9, m is 0 and n is 1. In some embodiments, C is 13, B is 10, m is 0 and n is 0, or C is 13, B is 10, m is 1 and n is 0, or C is 13, B is 10, m is 1 and n is 1, or C is 13, B is 10, m is 0 and n is 1.

[0256] In some embodiments (ie, any of the previously cited embodiments of CB), the group represented by L is absent. In some embodiments (ie, any of the previously cited embodiments of CB), the group represented by L is -(CR 12 R 13In some embodiments, L is -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CD(CD3))-, -(CF(CH3))-, -(CH(CF3))-, -(CF(CF3))-, -(C(CH3)2)-, -(C(CD3)2)-, -(C(CF3)2)-, -(CH(OCH3))-, -(CD(OCD3))-, -(CF(OCH3))-, -(CH(OCF3))-, -(CF(OCF3))-, - (C(OCH3)2)-, -(C(OCD3)2)-, -(C(OCF3)2)-, -(C(CH3)(CF3))-, -(C(CD3)(CF3))-, -(CH(CH2CH3))-, -(CD(CD2CD3))-, -( CF(CH2CH3))-, -(CH(CH2CF3))-, -(CH(CF2CF3))-, -(CF(CF2CF3))-, -(C(CH2CH3)2)-, -(C(CD2CD3)2)- or -(C(CF2CF3)2)-. In some embodiments, L is -(CH2)-, -(CD2)-, -(CF2)-, -(CH(CH3))-, -(CD(CD3))-, -(CF(CF3))-, -(C(CH3)2)-, -(C(CD3)2)-, -(C(CF3)2)-, -(CH(OCH3))-, -(CD(OCD3))-, -(CF(OCF3))-, or -(C(OCH3)2)-. In some embodiments, L is -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-. In some embodiments, L is -(CH2)-, -(CD2)-, or -(CF2)-. In some embodiments, L is -(CH2)-. In some embodiments, L is -(CD2)-. In some embodiments, L is -(CF2)-. In some embodiments, L is -(CHF)-. In some embodiments, L is -(CR 12 R 13 )-and where R 12 and R 13 Together they form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring.

[0257] In some embodiments of the compound represented by CB, each X and each Y is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CD(CD3))-, -(CF(CH3))-, -(CH(CF3))-, -(CF(CF3))-, -(C(CH3)2)-, -(C(CD3)2)-, -(C(CF3)2)-, -(CH(OCH3))-, -(CD(OCD3))-, -(CF(OCH3))-, -(CH(OCF3))-, -(CF( OCF3))-, -(C(OCH3)2)-, -(C(OCD3)2)-, -(C(OCF3)2)-, -(C(CH3)(CF3))-, -(C(CD3)(CF3))-, -(CH(CH2CH3))-, -(CD(CD2CD3)) -, -(CF(CH2CH3))-, -(CH(CH2CF3))-, -(CH(CF2CF3))-, -(CF(CF2CF3))-, -(C(CH2CH3)2)-, -(C(CD2CD3)2)- or -(C(CF2CF3)2)-. In some embodiments, each X and each Y is independently -(CH2)-, -(CD2)-, -(CF2)-, -(CH(CH3))-, -(CD(CD3))-, -(CF(CF3))-, -(C(CH3)2)-, -(C(CD3)2)-, -(C(CF3)2)-, -(CH(OCH3))-, -(CD(OCD3))-, -(CF(OCF3))-, or -(C(OCH3)2)-. In some embodiments, each X and each Y is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-. In some embodiments, each X and each Y is independently -(CH2)-, -(CD2)-, or -(CF2)-. In some embodiments, each X and each Y is -(CH2)-. In some embodiments, each X and each Y is -(CD2)-. In some embodiments, each X and each Y is -(CF2)-. In some embodiments, each X and each Y is -(CHF)-. In some embodiments, at least one of X and Y is -(CR 12 R 13 )-, where R 12 and R 13 Together they form a 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic ring. In some embodiments, each X and each Y is -(CR 12 R 13)-, where for the formula -(CR 12 R 13 )-each group, each R 12 and R 13 Together they form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring.

[0258] In some embodiments of the compound represented by CB, each X is -(CH2)-. In some embodiments, each X is -(CD2)-. In some embodiments, each X is -(CF2)-. In some embodiments, each X is -(CHF)-. In some embodiments, each Y is -(CH2)-. In some embodiments, each Y is -(CD2)-. In some embodiments, each Y is -(CF2)-. In some embodiments, each Y is -(CHF)-. In some embodiments, at least one X is -(CD2)-, -(CF2)-, or -(CHF)-. In some embodiments, at least one X or one Y is -(CD2)-, -(CF2)-, or -(CHF)-.

[0259] In some embodiments of compounds represented by CB, each Z is independently -(CH)-, -(CD)-, -(CF)-, or -(C(CH3))-. In some embodiments, each Z is -(CH)-. In some embodiments, each Z is -(CD)-. In some embodiments, each Z is -(CF)-. In some embodiments, each Z is -(C(CH3))-. In some embodiments, at least one Z is -(CD)- or -(CF)-.

[0260] In some embodiments of the compound represented by CB, each Q is of the formula -(CR 12 R 13 In some embodiments, each Q is a group of formula -(CH2)-. In some embodiments, p>2 and at least one Q is O and the other Q is -(CH2)-. In some embodiments, p>2 and is represented by -(Q) p - represents a group containing at least one ethylene oxide moiety (i.e., at least one group of the formula -OCH2CH2-). In some embodiments, p>3 and the group represented by -(Q)p- comprises at least one propylene oxide moiety (i.e., at least one group of the formula -OCH2CH2CH2-). In some embodiments, the group represented by -(Q)p- comprises at least one propylene oxide moiety (i.e., at least one group of the formula -OCH2CH2CH2-). p - represents a group of formula -(OCH2CH2) s -, wherein s is 1, 2, 3, 4, 5 or 6. In some embodiments, -(Q) p - represents a group of formula -(OCH2CH2CH2)t -, wherein t is 1, 2, 3 or 4.

[0261] In some embodiments of the compound represented by CB, wherein C is 13, each of R1 and R2 is independently H, D, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH(CH3)2, -CD2CD3, -CD(CD3)2, -CF2CH3, -CF(CH3)2, -CH2CF3, -CH(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2 CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, or -OCH2CH2CH3; and R3 is H, D, Cl, F, -CH3, -OC H3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, -CH(CH3)2, -CD2CD3, -CD(CD3)2, -CF2CH3, -CF(CH3)2, -CH2CF3, -CH(CF3)2, - CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -OCF2CF3, - OCH(CF3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH 2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, -OCH2C H2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2.In some embodiments, wherein C is 13, each of R1 and R2 is independently H, D, -CH3, -CD3, -CH2F, -CHF2, -CF3, -C(CH3)3, -C(CD3)3, -C(CF3)3, -CH2CH3, or -CH(CH3)2; and R3 is H, D, Cl, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments, wherein C is 13, each of R1 and R2 is independently H, -CH3, -CH2F, -CHF2, -CF3, -C(CH3)3, -C(CF3)3, -CH2CH3, or -CH(CH3)2; and R3 is H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments, wherein C is 13, each of R1 and R2 is H, -CH3, or -CF3; and R3 is H, F, -CH3, -OCH3, -CF3, or -OCF3. In some embodiments, wherein C is 13, each of R1 and R2 is -CH3 or -CH2CH3; and R3 is H, F, or -CH3. In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; and R3 is H. In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; and R3 is F. In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; and R3 is -CH3. In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; and R3 is -OCH3. In some embodiments, wherein C is 13, at least one of R1, R2, and R3 contains at least one fluorine atom. In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; R3 is H, F, CH3, or -OCH3, and at least one of R8 and R9 contains a fluorine atom. In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; R3 is H, F, CH3, or -OCH3, and each of R8 and R9 contains a fluorine atom. In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; R3 is H, F, CH3 or -OCH3 and R8, R9 and R. 10Each of contains a fluorine atom. In some embodiments, wherein C is 13: (i) at least one of R1, R2 and R3 contains at least one fluorine atom; and / or (ii) at least one of R8 and R9 contains a fluorine atom. In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; R3 is H, F, CH3 or -OCH3 and each of R8 and R9 is a fluorine atom. In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; R3 is H, F, CH3 or -OCH3 and R8, R9 and R 10 In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; R3 is H, F, CH3 or -OCH3 and R8, R9 and R 10 In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; R3 is H, F, CH3 or -OCH3, and R8, R9 and R 10 In some embodiments, wherein C is 13, each of R1 and R2 is -CH3; R3 is H, F, CH3 or -OCH3, and R8, R9 and R 10 Each of them is a fluorine atom.

[0262] In some embodiments of the compound represented by CB, wherein C is I3, (i) R3 is H, D, Cl, F, -CH3, -OCH3, -CD3, -OCD3, -CF3, -OCF3, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2; and (ii) R1 and R2 together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments, wherein C is I3, (i) R3 is H, D, F, -CH3, -OCH3, -CF3, or -OCF3; and (ii) R1 and R2 together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments, wherein C is 13; (i) R3 is H, F, -CH3 or -OCH3, and (ii) R1 and R2 together form a 5-membered or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by CB, wherein C is 13; (i) R3 is H; and (ii) R1 and R2 together form a 5-membered or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by CB, wherein C is 13; (i) R3 is H; and (ii) R1 and R2 together form a 5-membered or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by CB, wherein C is 13; (i) R3 is -CH3; and (ii) R1 and R2 together form a 5-membered or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by CB, wherein C is 13; (i) R3 is -OCH3; and (ii) R1 and R2 together form a 5-membered or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by CB, wherein C is 13; (i) R3 is F; and (ii) R1 and R2 together form a 5- or 6-membered carbocyclic or heterocyclic ring.

[0263] In some embodiments of the compound represented by CB, C is a head group of formula 13A or 13B:

[0264]

[0265] In some embodiments of 13A or 13B, R3 is H, F, -CH3, or -OCH3. In some embodiments of 13A or 13B, R3 is H. In some embodiments of 13A or 13B, R3 is F. In some embodiments of 13A or 13B, R3 is -CH3. In some embodiments of 13A or 13B, R3 is -OCH3.

[0266] In some embodiments of the compound represented by CB, wherein C is I4, R3 is H, D, F, Cl, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, -CH(CH3)2, -CD2CD3, -CD(CD3)2, -CF2CH3, CF(CH3)2, -CH2CF3, -CH(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -OCF2CF3, -OCH(CF3)2, -OCF2(CF3), -OCF(CF 3)2, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH2CH2CH3, -CH( CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, - OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF 2CF2CF3 or -OCF(CF2CF3)2; and wherein if W is C (carbon), each of R4, R5, R6 and R7 attached thereto can independently be H, D, F, Cl, Br, I, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3 or -CH(CH3)2, and wherein if W is N (nitrogen), each of R4, R5, R6 and R7 attached thereto is independently absent or is H, D, methyl, ethyl, isopropyl or tert-butyl.In some embodiments, wherein C is 14, R3 is H, D, Cl, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3 )2;And if W is C (carbon), then each of R4, R5, R6 and R7 attached thereto is independently H, D, F, Cl, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -CH2CH3 or -CH(CH3)2, and if W is N (nitrogen), then each of R4, R5, R6 and R7 attached thereto is independently absent or is H, D, methyl or ethyl. In some embodiments, wherein C is I4, R3 is H, F, -CH3, -OCH3, -CF3 or -OCF3; and if W is C (carbon), then each of R4, R5, R6 and R7 attached thereto is independently H, F, -CH3, -OCH3, -CF3 or -OCF3, and if W is N (nitrogen), then each of R4, R5, R6 and R7 attached thereto is independently absent or is H or methyl. In some embodiments, wherein C is 14, each W is C (carbon) and each of R4, R5, R6 and R7 is independently H, D, Cl, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3 or -OCF3. In some embodiments, wherein C is 14, each W is C (carbon) and each of R4, R5, R6 and R7 is independently H, F, -CH3, -OCH3, -CF3 or -OCF3. In some embodiments, wherein C is 14, each W is C (carbon) and each of R4, R5, R6 and R7 is independently H, F, -CH3, -OCH3, -CF3 or -OCF3. In some embodiments, wherein C is 14, each W is C (carbon) and each of R4, R5, R6 and R7 is independently H, F, -CH3 or -OCH3. In some embodiments, wherein C is 14, each W is C (carbon) and each of R4, R5, R6 and R7 is H. In some embodiments, wherein C is 14, each W is C (carbon) and each of R4, R5, R6 and R7 is F. In some embodiments, where C is 14, each W is C (carbon) and each of R4, R5, R6 and R7 is -CH3.

[0267] In some embodiments of the compound represented by CB, each R8 and R9 is independently H, D, F, Cl, Br, I, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH(CH3)2, -CD2CD3, -CD(CD3)2, -CF2CH3, -CF(CH3)2, -CH2CF3, -CH(CH2F)2, -CH(CF3)2, -CF2CF3, -CF(CF3)2, -C (CH3)3, -C(CD3)3, -C(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD 3. -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some embodiments of the compounds represented by CB, each R8 and R9 are independently H, F, -CH3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH(CH3)2, -CF2CH3, -CH2CF3, -CH(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CF3)3, -CH2CH2CH3, -CH(CH2F)2, -CH(CH2CH3)2, -CF2CF2CF3, or -CF(CF2CF3)2. In some embodiments of the compounds represented by CB, each R8 and R9 are independently H, F, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH(CH2F)2, -CH(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, or -C(CF3)3. In some embodiments of the compound represented by CB, each R8 and R9 are independently H, F, -CH3, -CF3, -CH2CH3 or -CH(CH2F)2. In some embodiments of the compound represented by CB, each R8 and R9 are independently H, F, -CH3, -CH2F, -CHF2 or -CF3. In some embodiments of the compound represented by CB, each R8 and R9 are H. In some embodiments of the compound represented by CB, each R8 and R9 are F. In some embodiments of the compound represented by CB, one of R8 and R9 is F and the other of R8 and R9 is H. In some embodiments of the compound represented by CB, each R8 and R9 are -CH3. In some embodiments of the compound represented by CB, each R8 and R9 are -CH2F. In some embodiments of the compound represented by CB, each R8 and R9 are -CF3.In some embodiments of the compound represented by CB, at least one of R8 and R9 is F. In some embodiments of the compound represented by CB, at least one of R8 and R9 is -CH2F.

[0268] In some embodiments of the compound represented by CB, the formula -(CR8R9)-, -(CR8R9) or -(CR8R9R 10 ) wherein at least one R8 and R9 of the group of formula (I) together form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring selected from the group of formula (s) 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 and 47:

[0269]

[0270] wherein # indicates the point of attachment of the carbocyclic or heterocyclic ring to the rest of the compound. In some embodiments of the compound represented by CB, the formula -(CR8R9)-, -(CR8R9) or -(CR8R9R 10 ) each R8 and R9 of a group together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring selected from groups of formula 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47:

[0271]

[0272] wherein # indicates the point of attachment of the carbocyclic or heterocyclic ring to the rest of the compound. In some embodiments of the compound represented by CB, the formula -(CR8R9) or -(CR8R9R 10 ) each R8 and R9 of a group together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring selected from groups of formula 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47:

[0273]

[0274] wherein # indicates the point of attachment of the carbocycle or heterocycle to the rest of the compound.

[0275] In some embodiments, each of R8', R9' and R 10 ' is independently C1-C4 alkyl. In some embodiments, each of R8', R9' and R 10 ' is independently C1-C4 alkoxy. In some embodiments, each R8', R9' and R 10' is independently methyl, ethyl or tert-butyl. In some embodiments, each R8', R9' and R 10 ' is methyl. In some embodiments, each of R8', R9' and R 10 ' is methoxy. In some embodiments, each of R8', R9' and R 10 ' is ethyl. In some embodiments, each of R8', R9' and R 10 In some embodiments, R8' and R9' together form a 4-membered, 5-membered, or 6-membered carbocyclic or heterocyclic ring.

[0276] In some embodiments of Compound CB, R 10 Is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, -CH(CH3)2, -CD2CD3, -CD(CD3)2, -CF2CH3, CF(CH3)2, -CH2CF3, -CH( CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OCF2CF3, -OCD(CD3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC(CD3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CF2CF3, -CF(CF2CF3)2, -C(CH2CH3)3, -C(CD2CD3)3, -C(CF2CF3)3, -OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments of compound CB, R 10 is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3 or -CH(CH3)2. In some embodiments of compound CB, R 10 Is H, D, F, -CH3, -CH2F, -CHF2 or -CF3. In some embodiments of compound CB, R 10Is H, F, -CH3, -OCH3, -CF3 or -OCF3. In some embodiments of compound CB, R 10 is H, D or F. In some embodiments of compound CB, R 10 Is -CH3 or -CF3. In some embodiments of compound CB, R 10 Is -H or -CH3. In some embodiments of compound CB, R 10 Is H or -CF3. In some embodiments of compound CB, R 10 Is H. In some embodiments of Compound CB, R 10 is D. In some embodiments of compound CB, R 10 is F. In some embodiments of compound CB, R 10 In some embodiments of compound CB, R 10 In some embodiments of compound CB, R 10 Does not exist.

[0277] In some embodiments of Compound CB, R 12 、R 13 or R 14 Each instance of is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH(CH2CH3)2, -C(CH3)3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2CH3, -OCH(CH2CH3)2, or -OC(CH3)3. In some embodiments of compound CB, R 12 、R 13 or R 14 Each instance of is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3 or -CH(CH3)2. In some embodiments of compound CB, R 12 、R 13 or R 14 Each instance of is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3 or -OCF3. In some embodiments of compound CB, R 12 、R 13 and R 14Each instance of is independently H, F, -CH3, -OCH3, -CF3, -OCF3, -CH2CH3 or -OCH2CH3. In some embodiments of compound CB, R 12 、R 13 or R 14 Each instance of is independently H, D, F, -CH3, -CD3 or -CF3. In some embodiments of compound CB, R 12 、R 13 or R 14 Each instance of is independently H, D, F or -CH3. In some embodiments of compound CB, R 12 、R 13 or R 14 Each instance of is independently H or F. In some embodiments of compound CB, R 12 、R 13 or R 14 Each instance of is H. In some embodiments of compound CB, R 12 、R 13 or R 14 Each instance of is D. In some embodiments of compound CB, R 12 、R 13 or R 14 Each instance of is F. In some embodiments of compound CB, R 12 、R 13 or R 14 Each instance of is -CH3. In some embodiments of compound CB, each R 12 、R 13 and R 14 are independently H, F, -CH3, -OCH3, -CF3, -OCF3, -CH2CH3 or -OCH2CH3; provided, however, that for the formula -(CR 12 R 13 )-at least one group, R 12 and R 13 Together they form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring.

[0278] In some embodiments of compound CB, at least one R 19 is H. In some embodiments of compound CB, each R 19 is H. In some embodiments of compound CB, at least one R 19 In some embodiments of compound CB, each R 19 In some embodiments of compound CB, at least one R 19is a (unsubstituted or substituted) benzyl group. In some embodiments of compound CB, each R 19 is an (unsubstituted or substituted) benzyl group.

[0279] In some embodiments of compound CB, at least one R 19 It is R 24 C(O)- or R 24 OC(O)-, where R 24 Is H, -CH3, -CD3, -CF3, -CH2CH3 or -CH(CH3)2. In some embodiments of compound CB, each R 19 It is R 24 C(O)- or R 24 OC(O)-, where R 24 is H, -CH3, -CD3, -CF3, -CH2CH3 or -CH(CH3)2. In some embodiments of compound CB, at least one R 19 It is R 24 C(O)- or R 24 OC(O)-, where R 24 Is T. In some embodiments of compound CB, wherein R 24 is T and T may be -(CH2)0-(O)0-[(CH2CH2)-O] q -R 26 、-(CH2)1-(O)1-[(CH2CH2)-O] q -R 26 or -(CH2)2-(O)1-[(CH2CH2)-O] q -R 26 , where R 26 Is H, methyl, ethyl or tert-butyl. In some embodiments of compound CB, wherein R 24 is T, q is 1. In some embodiments of compound CB, wherein R 24 is T, q is 2. In some embodiments of compound CB, wherein R 24 is T, q is 3. In some embodiments of compound CB, wherein R 24 is T, q is 4. In some embodiments of compound CB, wherein R 24 It is T, q is 5.

[0280] In some embodiments of compound CB, at least one R 19 It is R 24 R 25 NC(O)-or(R 24 O)(R 25O)P(O)-, where R 24 and R 25 Each of R is independently H, -CH3, -CD3, -CF3, -CH2CH3 or -CH(CH3)2. In some embodiments of compound CB, each R 19 It is R 24 R 25 NC(O)-or(R 24 O)(R 25 O)P(O)-, where R 24 and R 25 Each of R is independently H, -CH3, -CD3, -CF3, -CH2CH3 or -CH(CH3)2. In some embodiments of compound CB, at least one R 19 It is R 24 R 25 NC(O)-or(R 24 O)(R 25 O)P(O)-, where R 24 and R 25 Together they form a 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic ring. In some embodiments of compound CB, each R 19 It is R 24 R 25 NC(O)-or(R 24 O)(R 25 O)P(O)-, where R 24 and R 25 Together they form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring.

[0281] In some embodiments of compound CB, at least one R 19 It is R 24 R 25 NC(O)-or(R 24 O)(R 25 O)P(O)-, and where R 24 and R 25 At least one of is T. In some embodiments of compound CB, each R 19 It is R 24 R 25 NC(O)-or(R 24 O)(R 25 O)P(O)- and where R 24 and R 25 At least one of is T. In some embodiments of compound CB, at least one R 19 It is R 24 R 25 NC(O)-or(R24 O)(R 25 O)P(O)- and where R 24 and R 25 Each of is T. In some embodiments of compound CB, each R 19 It is R 24 R 25 NC(O)-or(R 24 O)(R 25 O)P(O)- and R 24 and R 25 Each of is T. In some embodiments of compound CB, wherein R 24 and / or R 25 One or more of them is T and T can be -(CH2)0-(O)0-[(CH2CH2)-O] q -R 26 、-(CH2)1-(O)1-[(CH2CH2)-O] q -R 26 or -(CH2)2-(O)1-[(CH2CH2)-O] q -R 26 , where R 26 Is H, methyl, ethyl or tert-butyl. In some embodiments of compound CB, wherein R 24 and R 25 At least one of is T, and for each T, q is 1. In some embodiments of compound CB, wherein R 24 and R 25 At least one of is T, and for each T, q is 2. In some embodiments of compound CB, wherein R 24 and R 25 At least one of is T, and for each T, q is 3. In some embodiments of compound CB, wherein R 24 and R 25 At least one of is T, and for each T, q is 4. In some embodiments of compound CB, wherein R 24 and R 25 At least one of is T, and for each T, q is 5.

[0282] In some embodiments of Compound CB, R 20In some embodiments of compound CB, R 20 is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3. In some embodiments of compound CB, R 20 Is H, D, F, -CH3, -CD3, -CH2F, -CHF2 or -CF3. In some embodiments of compound CB, R 20 Is H, D, F, -CH3, -CD3, -CH2F, -CHF2 or -CF3. In some embodiments of compound CB, R 20 Is H, D, F or -CH3. In some embodiments of compound CB, R 20 is -CH3, -CD3, -CH2F, -CHF2 or -CF3. In some embodiments of compound CB, R 20 Is H, F or -CH3. In some embodiments of compound CB, R 20 Is H. In some embodiments of Compound CB, R 20 In some embodiments of compound CB, R 20 In some embodiments of compound CB, R 20 It's F.

[0283] In some embodiments of Compound CB, each R 21 R is independently H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3 or -C(CH3)3. In some embodiments of compound CB, each R 21 R is independently H, D, F, -CH3, -CD3, -CH2F, -CHF2 or -CF3. In some embodiments of compound CB, each R 21In some embodiments of compound CB, each R 21 In some embodiments of compound CB, each R 21 In some embodiments of compound CB, each R 21 is H. In some embodiments of compound AB, each R 21 It's F.

[0284] In some embodiments of Compound CB, R 27 Is H. In some embodiments of Compound CB, R 27 In some embodiments of compound CB, R 27 In some embodiments of compound CB, R 27 It is tert-butyl.

[0285] In some embodiments of compound CB, m is 0. In some embodiments of compound CB, m is 1. In some embodiments of compound CB, n is 0. In some embodiments of compound CB, n is 1. In some embodiments of compound CB, n and m are both 0. In some embodiments of compound CB, one of n and m is 0 and the other is 1. In some embodiments of compound CB, n and m are both 1. In some embodiments of compound CB, (i) m is 0 and n is 0; (ii) m is 0 and n is 1, 2, or 3; or (iii) m is 1 and n is 0, 1, 2, or 3.

[0286] In some embodiments of Compound CB, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments of Compound CB, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of Compound CB, n is 0, 1, 2, 3, or 4. In some embodiments of Compound CB, n is 2. In some embodiments of Compound CB, n is 3. In some embodiments of Compound CB, n is 4. In some embodiments of Compound CB, n is 5. In some embodiments of Compound CB, n is 6. In some embodiments of Compound DB, n is 7. In some embodiments of Compound CB, n is 8. In some embodiments of Compound CB, n is 9. In some embodiments of Compound CB, n is 10. In some embodiments of Compound CB, n is 11. In some embodiments of Compound CB, n is 12.

[0287] In some embodiments of compound CB, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments of compound CB, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments of compound CB, p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments of compound CB, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of compound CB, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of compound CB, p is 0. In some embodiments of compound CB, p is 1. In some embodiments of compound CB, p is 2. In some embodiments of compound CB, p is 3. In some embodiments of compound CB, p is 4. In some embodiments of compound CB, p is 5. In some embodiments of compound CB, p is 6. In some embodiments of compound CB, p is 7. In some embodiments of compound CB, p is 8. In some embodiments of compound CB, p is 9. In some embodiments of compound CB, p is 10. In some embodiments of compound CB, p is 11. In some embodiments of compound CB, p is 12. In some embodiments of compound CB, p is 13. In some embodiments of compound CB, p is 14. In some embodiments of compound CB, p is 15. In some embodiments of compound CB, p is 16. In some embodiments of compound CB, p is 17. In some embodiments of compound CB, p is 18. In some embodiments of compound CB, p is 19. In some embodiments of compound CB, p is 20.

[0288] In some embodiments of compound CB, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 、R 12 、R 13 、R 14 、R 20 or R 21 At least one group of contains at least one fluorine atom. In some embodiments of compound CB, the formulas R8, R9, R 10 、R 20 or R 21 In some embodiments of compound CB, at least one group of formula R8, R9 or R 10 At least one group in contains at least one fluorine atom. In some embodiments of compound CB, the formula is -(CR8R9)-, -(CR8R9) or -(CR8R9R 10) at least one R8 and R9 of the group together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic ring or heterocyclic ring. In some embodiments of compound CB, the formula -(CR8R9) or -(CR8R9R 10 ) at least one of the R8 and R9 of the group of formula -(CR8R9) together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic ring or heterocyclic ring. In some embodiments of compound CB, each R8 and R9 of the group of formula -(CR8R9) together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic ring or heterocyclic ring. In some embodiments of compound CB, at least one R 19 It is R 24 C(O)-、R 24 OC(O)-、R 24 R 25 NC(O)-or(R 24 O)(R 25 In some embodiments of compound CB, at least one R 19 It is R 24 C(O)-. In some embodiments of compound CB, at least one R 19 It is R 24 OC(O)-. In some embodiments of compound CB, at least one R 19 It is R 24 R 25 NC(O)-. In some embodiments of compound CB, at least one R 19 Yes (R 24 O)(R 25 O)P(O)-.

[0289] In some embodiments, Compound CB has the formula referred to herein as Compound X':

[0290]

[0291] wherein each of R1' and R2' is independently C1-C3 alkyl; R3' is H, D, F, -CH3, -CF3, -OCH3 or -OCF3; each Z is independently H, D or F; a is 1, 2, 3, 4, 5, 6 or 7; and R 30 、R 31 and R 32 Each of is independently H, D or F, provided, however, that R 30 、R 31 or R 32In some embodiments of compound X', at least one of R1' and R2' is F. In some embodiments of compound X', each of R1' and R2' is methyl. In some embodiments of compound X', each of R1' and R2' is ethyl. In some embodiments of compound X', R3' is H or -CH3. In some embodiments of compound X', a is 3, 4, or 5. In some embodiments of compound X', a is 1. In some embodiments of compound X', a is 2. In some embodiments of compound X', a is 3. In some embodiments of compound X', a is 4. In some embodiments of compound X', a is 5. In some embodiments of compound X', a is 6. In some embodiments of compound X', a is 7. In some embodiments of compound X', each Z is H. In some embodiments of compound X', R 30 、R 31 and R 32 Each of them is F.

[0292] In some embodiments, compound CB has the formula referred to herein as Y':

[0293]

[0294] wherein each of R1' and R2' is independently C1-C3 alkyl; R3' is H, D, F, -CH3, -CF3, -OCH3 or -OCF3; b is 1, 2 or 3; and R 33 and R 34 Each of the R 33 and R 34 In some embodiments of compound Y', at least one of R1' and R2' is selected from F, -CH2F, -CHF2, and -CF3. In some embodiments of compound Y', each of R1' and R2' is methyl. In some embodiments of compound Y', each of R1' and R2' is ethyl. In some embodiments of compound Y', R3' is H or -CH3. In some embodiments of compound Y', b is 1. In some embodiments of compound Y', b is 2. In some embodiments of compound Y', b is 3. In some embodiments of compound Y', each Z is H. In some embodiments of compound Y', R 33 and R 34 Each of them is F.

[0295] In some embodiments, compound CB has the formula referred to herein as Z':

[0296]

[0297] wherein each of R1′ and R2′ is independently C1-C3 alkyl; R3′ is H, D, F, -CH3, -CF3, -OCH3, or -OCF3; and u is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, each of R1′ and R2′ is independently -CH3 or -CH2CH3 and R3′ is H or -CH3. In some embodiments, each of R1′, R2′, and R3′ is -CH3. In some embodiments, u is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, u is 1, 2, 3, 4, 5, or 6. In some embodiments, u is 2, 3, 4, 5, 6, 7, or 8. In some embodiments, u is 2, 3, 4, 5, 6, or 7. In some embodiments, u is 3, 4, 5, 6, or 7. In some embodiments, u is 3, 4, 5, or 6. In some embodiments, u is 4, 5, 6, or 7. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments of Z, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, u is 6. In some embodiments, u is 7. In some embodiments, u is 8. In some embodiments, each of R1' and R2' is independently -CH3 or -CH2CH3, R3' is -CH3, u is 2, 3, 4, 5, 6, 7, or 8, and Z has a calculated LogD of 2 to 7, inclusive.

[0298] In some embodiments, Compound CB has the formula referred to herein as (22):

[0299]

[0300] In some embodiments, Compound CB has the formula referred to herein as (28):

[0301]

[0302] In some embodiments, Compound CB has the formula referred to herein as (31):

[0303]

[0304] In some embodiments, Compound CB has the formula referred to herein as (34):

[0305]

[0306] In some embodiments, Compound CB has the formula referred to herein as (37):

[0307]

[0308] In some embodiments of Compound CB, the compound has the formula referred to herein as (43):

[0309]

[0310] In some embodiments of Compound CB, the compound has the formula referred to herein as (46):

[0311]

[0312] In some embodiments of Compound CB, the compound has the formula referred to herein as (49):

[0313]

[0314] In some embodiments, Compound CB has the formula referred to herein as (50):

[0315]

[0316] In some embodiments, Compound CB has the formula referred to herein as (51):

[0317]

[0318] In some embodiments of Compound CB, the compound has the formula referred to herein as (52):

[0319]

[0320] In some embodiments, Compound CB has the formula referred to herein as (53):

[0321]

[0322] In some embodiments of Compound CB, the compound has the formula referred to herein as (54):

[0323]

[0324] VI. Methods for preparing therapeutic compounds and related intermediates

[0325] In some embodiments, the present application relates to methods for producing the novel compositions disclosed herein. Suitable methods are generally Figure 1A 、 1B , 1C, 2A, 2B, 2C, 3A, 3B, 3C, 4A, 4B, 4C, 5A, 5B, 6A, 6B, 6C, 6D, 7A and 7B. Specific examples of using this method to produce various intermediates and therapeutic compounds can be found in Examples 1-10 below. Figure 1A 、 1B The general synthetic schemes described in Schemes 1-12 (hereinafter in the Examples section) and Examples 1-10 are closely consistent with those described in Schemes 1-12 (hereinafter in the Examples section) and the related descriptions in Examples 1-10. General methods for reducing certain therapeutic compounds of Formula AB to compounds of Formula CB can be found in Examples 11A and 11B. However, while these examples demonstrate the ease of interconversion between oxidized and reduced forms, the reduced forms (i.e., compounds of Formula CB) are provided according to the disclosed synthetic methods, whereby the reduced forms are converted to the oxidized forms (i.e., compounds of Formula AB), as disclosed in Examples 1-10. Therefore, the reduced forms (i.e., compounds of Formula CB) are more readily obtained as intermediates in the disclosed synthetic pathways to compounds of Formula AB.

[0326] refer to Figure 1A , provides a compound of formula 201, wherein the variables L, X, Y, Z, R 20 、R 21 and n have been defined previously herein. Representative known compounds of formula 201 can be found in Figure 8 (The Chemical Abstracts Service (CAS) registration number for each known composition shown is provided) and in the Examples. Figure 1A As shown in step a of , 201 can be converted to a compound of formula 202 by protecting the hydroxyl group. Many hydroxyl protecting groups (abbreviated as "Pg") are known in the art, and many are discussed in Greene's "Protective Groups in Organic Synthesis", supra. Protecting groups can be acid-labile, base-labile, or otherwise unstable under specified conditions. For example, a protecting group can be silyl-based (e.g., tert-butyldimethylsilyl or triisopropylsilyl) and thus protected with fluoride ion (i.e., F - ) is removed. For example, for the conversion of (1) to (2), suitable conditions for this conversion can be found in Example 1, below (see: Scheme 1, step a).

[0327] Next, refer to Figure 1A As shown in step b, the compound of formula 202 can be converted to the brominated compound of formula 203. For example, the conversion can be carried out by treating 202 with N-bromosuccinimide, as described in Example 1, step b for the conversion of (2) to (3).

[0328] Reference again Figure 1A, the brominated compound of formula 203 can then be converted to the epoxide of formula 204, as illustrated in step c. For example, such conversion to 204 can be achieved by treating the brominated compound of formula 203 with an inorganic base (e.g., potassium carbonate), as described in Example 1, step c for the conversion of (3) to (4).

[0329] like Figure 1A As illustrated in step d, a compound of formula 204 can be converted to a compound of formula 205. For example, such conversion of 204 to 205 can be carried out by treating 204 with a mixture of sodium metaperiodate (NaIO4) and periodic acid (HIO4), as described for the conversion of (4) to (5a) and (5b) in Example 1, step d. As described in Example 1, step d, a portion of the tert-butyldimethylsilyl protecting groups are removed from the hydroxyl groups. Such deprotected impurities can be easily reprotected, as described in Example 1, step e (i.e., (5b) is converted to (5a)). Alternatively, the deprotected material (5b) can be removed by performing a purification step (e.g., chromatography). However, as described above, silyl-based protection is not the only option, and in fact, other (more stable) forms of hydroxyl protection may be more suitable for this process. In any case, as shown in Example 1, silyl protection will be sufficient to produce compounds such as Figure 1A , the desired bromo compound as described by compound 209 and exemplified by (9) in Example 1.

[0330] Next, if Figure 1A As illustrated in step f., compounds of formula 205 can be converted to novel compounds of formula 207 by treatment with sodium 2-chloro-2,2-difluoroacetate (6) and triphenylphosphine, as described in Example 1, step f for the conversion of (5) to (7). Compounds of formula 207 contain terminal difluoro groups, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein. Therefore, in some embodiments, the present application also relates to compounds of formula 207.

[0331]

[0332] Among them, L, X, Y, Z, R 20 、R 21 , n and Pg are as defined above.

[0333] Thus, the protecting group Pg of the compound of formula 207 can be removed to generate the compound of formula 208, such as Figure 1A, as described in step g. For example, 207 can be converted to 208 (for silyl-based protecting groups) by treating 207 with tetra-n-butylammonium fluoride (TBAF), as described in Example 1, step g for the conversion of (7) to (8). Compounds of formula 208 contain terminal difluoro groups, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein. Therefore, in some embodiments, the present application also relates to compounds of formula 208.

[0334]

[0335] Among them, L, X, Y, Z, R 20 、R 21 and n are as defined above.

[0336] Finally, the hydroxy compound of formula 208 can be converted into its bromo derivative 209, such as Figure 1A , as described in step h. For example, compounds of formula 208 can be converted to their bromides by treating 208 with phosphorus tribromide as described in Example 1, step h. for the conversion of (8) to (9). Compounds of formula 209 contain terminal difluoro groups, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein. Therefore, in some embodiments, the present application also relates to compounds of formula 209.

[0337]

[0338] Among them, L, X, Y, Z, R 20 、R 21 and n are as defined above.

[0339] Similarly and with reference Figure 1B , the hydroxy compound of general formula 208a can be converted into its bromide of general formula 209a. For example, the compound of general formula 208a can be converted into its bromine compound (i.e., 209a) by treating 208a with phosphorus tribromide as described in Example 1, step h for converting (8) to (9). The difference between the compound of general formula 208a and the compound of 208 is that the compound of general formula 208a encompasses the compound of general formula 208, but the compound of general formula 208a represents a larger group of compounds (at least they do not require dual terminal fluorine atoms). Several representative compounds of formula 208a can be found in Figure 8 middle.

[0340] In addition, reference Figure 1CThe hydroxy compound of formula 208b can be converted to its bromide of formula 209b. For example, the compound of formula 208b can be converted to its bromide (i.e., 209b) by treating 208b with phosphorus tribromide as described in Example 1, step h for converting (8) to (9). The compound of formula 208b differs from the compounds of formulas 208 and 208a in that the compound of formula 208b does not contain a terminal olefin. Several representative compounds of formula 208b can be found in Figure 8 middle.

[0341] refer to Figure 2A And the above Figure 1A The compounds of formula 211 can be prepared by Figure 2A The multi-step process described in is converted to compounds of general formula 219, which is similar to Figure 1A The process is almost identical in terms of scheme and is exemplified in Example 1, Scheme 1 and the description of the related conversion of (1) to (9). Figure 1A Description, reference examples and Figure 2A , which provides the necessary guidance for converting compounds of general formula 211 into compounds of general formula 219.

[0342] Compounds of formula 217 contain a terminal difluoro group, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein.

[0343]

[0344] Among them, L, X, Y, Z, R8, R9, R 20 , n and Pg are as defined above.

[0345] Compounds of formula 218 contain a terminal difluoro group, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein.

[0346]

[0347] Among them, L, X, Y, Z, R8, R9, R 20 and n are as defined above.

[0348] Compounds of formula 219 contain a terminal difluoro group, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein.

[0349]

[0350] Among them, L, X, Y, Z, R8, R9, R 20 and n are as defined above.

[0351] Similarly (as with Figure 1B Compared with), reference Figure 2B The compound of formula 218a can be converted to the compound of formula 219a by treatment with phosphorus tribromide as described in Example 1, step h for the conversion of (8) to (9). Figure 1C Compare) and refer to Figure 2C The compound of formula 218b can be converted to the compound of formula 219b by treatment with phosphorus tribromide as described in Example 1, step h for the conversion of (8) to (9). Representative compounds of formula 211, 218a or 218b can be found in Figure 8 middle.

[0352] refer to Figure 3A And the above Figure 1A (and Figure 2A ), the compound of formula 221 can be obtained by Figure 3A The multi-step process described in is converted to compounds of general formula 229, which is similar to Figure 1A (and Figure 2A ) is almost the same in terms of scheme and is converted from Example 1, Scheme 1 and the related (1) to the description example of (9). Therefore, according to the above Figure 1A Description, reference examples and Figure 3A , which provides the necessary guidance for converting compounds of general formula 221 into compounds of general formula 229.

[0353] Compounds of formula 227 contain a terminal difluoro group, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein. Therefore, in some embodiments, the present application also relates to compounds of formula 227.

[0354]

[0355] Among them, L, X, Y, Z, R8, R9, R 21 , n and Pg are as defined above.

[0356] Compounds of formula 228 contain a terminal difluoro group, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein.

[0357]

[0358] Among them, L, X, Y, Z, R8, R9, R21 and n are as defined above.

[0359] Compounds of formula 229 contain a terminal difluoro group, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein.

[0360]

[0361] Among them, L, X, Y, Z, R8, R9, R 21 and n are as defined above.

[0362] Similarly (as with Figure 1B and Figure 2B Compare) and refer to Figure 3B The compound of formula 228a can be converted to the compound of formula 229a by treatment with phosphorus tribromide as described in Example 1, step h for the conversion of (8) to (9). Figure 1C and Figure 2C Compare) and refer to Figure 3C The compound of formula 228b can be converted to the compound of formula 229b by treatment with phosphorus tribromide as described in Example 1, step h for the conversion of (8) to (9). Representative compounds of formula 221, 228a or 228b can be found in Figure 8 middle.

[0363] refer to Figure 4A And the above Figure 1A (and Figure 2A and Figure 3A ), the compound of formula 231 can be obtained by Figure 4A The multi-step process described in is converted to compounds of general formula 239, which is similar to Figure 1A (and Figure 2A & Figure 3A ) is almost the same in terms of scheme and is converted from Example 1, Scheme 1 and the related (1) to the description example of (9). Therefore, according to the above Figure 1A Description, with reference to the examples, Figure 4A The necessary guidance is provided for the conversion of compounds of general formula 231 into compounds of general formula 239.

[0364] Compounds of formula 237 contain a terminal difluoro group, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein.

[0365]

[0366] wherein L, X, Y, Z, R8, R9, n and Pg are as defined above.

[0367] Compounds of formula 238 contain terminal difluoro groups, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein.

[0368]

[0369] wherein L, X, Y, Z, R8, R9 and n are as defined above.

[0370] Compounds of formula 239 contain a terminal difluoro group, and these compounds are believed to have novel structures and are particularly useful for preparing therapeutic compounds as disclosed herein.

[0371]

[0372] wherein L, X, Y, Z, R8, R9 and n are as defined above.

[0373] Similarly (as with Figure 1B 、 Figure 2B and Figure 3B Compare) and refer to Figure 4B The compound of formula 238a can be converted to the compound of formula 239a by treatment with phosphorus tribromide as described in Example 1, step h for the conversion of (8) to (9). Figure 1C 、 Figure 2C and Figure 3C Compare) and refer to Figure 4C The compound of formula 238b can be converted to the compound of formula 239b by treatment with phosphorus tribromide, as described in Example 1, step h for the conversion of (8) to (9). Representative compounds of formula 231, 238a or 238b can be found in Figure 8 middle.

[0374] Additionally, refer to Figure 5A and 5B Compounds of formula 308a and 308b can be converted to compounds of formula 309a and 309b, respectively, by treating 308a or 308b with phosphorus tribromide, as described in Example 1, step h for the conversion of (8) to (9). Compounds of formula 308a include, for example, ether-containing alcohols, silyl ethers, polyethylene glycol (PEG), and other substituted alkyl groups terminated with ethers. Compounds of formula 308b include, for example, ether-containing alcohols, silyl ethers, polyethylene glycol (PEG), and other substituted alkyl groups terminated with trialkylsilyl moieties. Representative compounds of formula 308a and 308b can be found in Figure 8 middle.

[0375] The bromides represented by the general formula 209, 209a, 209b, 219, 219a, 219b, 229, 229a, 229b, 239, 239a, 239b, 309a and 309b discussed above (refer to Figure 1A 、 1B , 1C, 2A, 2B, 2C, 3A, 3B, 3C, 4A, 4B, 4C, 5A, and 5B) can be described as tail group intermediates and these tail group intermediates can be used in the processes described below for preparing therapeutic compounds disclosed herein. However, before doing so, the preparation of certain head group intermediates used in such processes will be described.

[0376] refer to Figure 6A The method for preparing the Grignard reagent of the protected head group intermediate of general formula 703a is described starting with a compound of general formula 700a, wherein the variables R1, R2 and R3 are as defined above. Representative compounds of formula 700a can be found in Figure 9 This process is exemplified in Examples 1 and 2 below for the production of Grignard reagents (13) and (20), respectively (see Schemes 2 and 3, respectively). Figure 6A , compounds of general formula 700a are brominated, for example, by treatment with bromine (as described in Examples 1 and 2, Schemes 2 and 3, step a), to produce brominated hydroquinone 701a. Compounds of general formula 701a are exemplified by (11) and (18) in the Examples. Next, the phenolic -OH group of the compound of general formula 701a is protected with a protecting group ("Pg"). Because the Grignard reaction is very basic, base-labile hydroxyl / phenoxy protecting groups are generally avoided. Therefore, acid-labile and / or Grignard-stable protecting groups can be used. Thus, compounds of general formula 701a can be converted to protected compounds of general formula 702a by treatment with an appropriate protecting group. In Examples 1 and 2, step b, a methoxymethyl ether (MOM) protecting group (prepared from chloromethyl methyl ether) is selected, to produce (12) and (19), respectively (see Schemes 2 and 3, respectively). The now appropriately protected compound of general formula 702a can be converted to a Grignard reagent of general formula 703a by reaction with magnesium in an anhydrous ether-based solvent. Grignard reagents of general formula 703a are exemplified by (13) and (20) in Examples 1 and 2, Step c, respectively (see Schemes 2 and 3, respectively).

[0377] Similarly, reference Figure 6C , Figure 6AThe process described in (i.e., steps ac) can be used to convert compounds of formula 700b to Grignard reagents of formula 703b. Grignard reagents of formula 703a and 703b (head group intermediates) can be reacted with bromides of formula 209, 209a, 209b, 219, 219a, 219b, 229, 229a, 229b, 239, 239a, 239b, 309a and 309b (tail group intermediates) (prepared as described above) to produce intermediates and therapeutic compounds described herein. This process is described in Figure 7A This is described in more detail below.

[0378] Alternatively, refer to Figure 6B , illustrates a scheme for producing lithiated compounds of formula 705a from compounds of formula 700a. This process is exemplified in Examples 3-9, Schemes 4-10, and the detailed description. Typically, the bisphenol of formula 700a is protected to produce a bis-protected (e.g., bis-methoxymethyl (MOM) protected or bis-THP (bis-tetra-hydropyranyl) derivative) derivative 704a, such as Figure 6C , as described in step a (see: Example 3, Scheme 4, step a). Compound 704a is exemplified by (24) in Examples 3-9. The diprotected derivative of formula 704a can be lithiated (e.g., by treatment with n-butyllithium as described in Example 3, Scheme 4, step b) to produce the lithiated intermediate 705a. Compound 705a is exemplified by (25) in Examples 3-9. Similarly and with reference to Figure 6D , Figure 6B The process described in (i.e., steps ab) can be used to convert compounds of formula 700b to lithiated intermediates of formula 705b. The lithiated intermediates of formula 705a and 705b (head group intermediates) can be reacted with bromides of formula 209, 209a, 209b, 219, 219a, 219b, 229, 229a, 229b, 239, 239a, 239b, 309a, and 309b (prepared as described above) (tail group intermediates) to produce intermediates for producing therapeutic compounds described herein. This process is described in detail in the following manner: Figure 7B This is described in more detail below.

[0379] refer to Figure 7A , describes a protocol for reacting the Grignard reagent 703a or the lithiated intermediate 705a ("head group intermediate") with one of the bromides of formula 209, 209a, 209b, 219, 219a, 219b, 229, 229a, 229b, 239, 239a, 239b, 309a, and 309b ("tail group intermediate") to produce a therapeutic agent of formula (707a) and quinone (708a). This process is exemplified in Examples 1-3. Again, refer to Figure 7A , one of the Grignard reagents (703a) or the lithiated intermediate (705a) is selected and reacted with one of the bromides selected from 209, 209a, 209b, 219, 219a, 219b, 229, 229a, 229b, 239, 239a, 239b, 309a, and 309b (209, 219, 229, and 239 are omitted to simplify the drawing, but will react as indicated), thereby producing a diprotected hydroquinone compound of formula 706a, as illustrated in step d', wherein V is a tail group of formula 3, 4, 5, 6, 7, 8, 9, 10, or 11 (or 12) as described above. The reaction can be carried out as described in Schemes 2-3, step d, Scheme 4, step c, and Schemes 5-9, step b, and the related examples. The compound of formula 706a is an example of a compound of formula CB described above. These doubly protected compounds of formula 706a can then be deprotected to produce compounds of formula 707a (also compounds of formula CB), as illustrated in Scheme 2-3, step e, Scheme 4, step d, and Scheme 5-9, step c, and the related Examples. Compounds of formula 707a are examples of compounds of formula CB described above. Finally, compounds of formula 707a can be converted to compounds of formula 708a, as illustrated in Scheme 2-3, step f, Scheme 4, step e, and Scheme 5-9, step d, and the related Examples. Compounds of formula 708a are examples of compounds of formula AB described above. Thus, Figure 8 Any of the specific alcohols listed can be used to produce Figure 1A 、 1B , 1C, 2A, 2B, 2C, 3A, 3B, 3C, 4A, 4B, 4C, 5A and 5B and their corresponding (tail group) bromides, which can then be reacted with Figure 9 The head group of any compound prepared by the method of the present invention is reacted with a Grignard reagent or a lithiation reagent to produce a specific therapeutic agent described by the general formula 707a or 708a, wherein the specific structure is selected from Figure 8 A specific alcohol selected from Figure 9 The present application considers Figure 8 and Figure 9 All possible combinations of reagents described in and produced according to the aforementioned methods.

[0380] Similarly and with reference Figure 7B, describes a protocol for reacting Grignard reagent 703b or lithiated intermediate 705b ("head group intermediate") with bromides of general formula 209, 209a, 209b, 219, 219a, 219b, 229, 229a, 229b, 239, 239a, 239b, 309a, and 309b ("tail group intermediate") (209, 219, 229, and 239 are omitted to simplify the drawing, but will react as indicated) to produce therapeutic agents of formula (707b) and quinone (708b). This process is exemplified in Examples 1-10. Again referring to Figure 7B , selecting one of the Grignard reagents (703b) or the lithiated intermediate (705b) and reacting with one of the bromides selected from 209, 209a, 209b, 219, 219a, 219b, 229, 229a, 229b, 239, 239a, 239b, 309a and 309b, thereby producing a double protected hydroquinone compound of formula 706b, as illustrated in step d', wherein V is a tail group of formula 3, 4, 5, 6, 7, 8, 9, 10 or 11 (or 12) as described above. The reaction can be carried out as described in Schemes 2-3, Step d, Scheme 4, Step c and Schemes 5-9, Step b and the related Examples. The compound of formula 706b is an example of a compound of formula CB above. These doubly protected compounds of Formula 706b can then be deprotected to produce compounds of Formula 707b, as illustrated in Scheme 2-3, step e, Scheme 4, step d, and Scheme 5-9, step c, and the related Examples. Compounds of Formula 707b are examples of compounds of Formula CB described above. Finally, compounds of Formula 707b can be converted to compounds of Formula 708b, as illustrated in Scheme 2-3, step f, Scheme 4, step e, and Scheme 5-9, step d, and the related Examples. Compounds of Formula 708b are examples of compounds of Formula AB described above.

[0381] Example

[0382] Example 1: Synthesis of 2-((2E,6E)-11,11-difluoro-3,7-dimethylundeca-2,6,10-trien-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione (Compound A)

[0383]

[0384] Option 1:

[0385]

[0386] 1) Synthesis of (5E,9E)-11-bromo-1,1-difluoro-5,9-dimethylundeca-1,5,9-triene (9)

[0387] Step a. Synthesis of tert-butyldimethyl(((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)oxy)silane (2)

[0388] To trans, trans-farnesol (1, 3.30g, 14.84mmol) and imidazole (1.52g, 22.26mmol) in anhydrous dichloromethane (DCM, 38mL) solution was added tert-butyldimethylsilyl chloride (TBSCl, 3.70g, 20.78mmol), and the reaction mixture was stirred at room temperature (rt) for 4 hours (hrs.). Then, the reaction mixture was diluted with DCM (22mL) and water (60mL), and stirred at room temperature for 15 minutes (min.). The aqueous phase was separated and the organic phase was washed with water (3x60mL) and brine (30mL), through anhydrous (anh.) Na2SO4 drying, and concentrated under reduced pressure. The crude product was passed through silica gel flash chromatography (SiO2, hexane-ethyl acetate (EtOAc, 5:1, R f (PR) 0.3)) to give 2 (4.75 g, 95%) as a colorless oil.

[0389] 1 H-NMR(300MHz, CDCl3)δ:5.36–5.27(m,1H),5.17–5.04(m,2H),4.20(d,J=6.8Hz,2H) ,2.16–1.91(m,8H),1.68(s,3H),1.63(s,3H),1.60(s,6H),0.91(s,9H),0.07(s,6H).

[0390] Step b. Synthesis of (6E,10E)-2-bromo-12-((tert-butyldimethylsilyl)oxy)-2,6,10-trimethyldodeca-6,10-dien-3-ol (3)

[0391] To a solution of 2 (4.75 g, 14.11 mmol) in tetrahydrofuran (THF, 160 mL) and H2O (77 mL) was added dropwise a solution of N-bromosuccinimide (2.76 g, 15.52 mmol) in THF (30 mL) at 0 ° C. After the reaction mixture was stirred at 0 ° C for 2 hours, the reaction mixture was quenched by adding Et2O (200 mL) and water (100 mL), and the resulting mixture was stirred at room temperature for 15 minutes. The organic phase was separated and the aqueous phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. After evaporating the solvent under reduced pressure, the crude product was purified by flash chromatography on a silica gel column (SiO2, hexane-EtOAc (3: 1, R fThe product was purified by HPLC (PR) 0.3) to afford 3 (3.90 g, 64%) as a colorless oil.

[0392] 1 H-NMR(300MHz, CDCl3)δ:5.36–5.25(m,1H),5.25–5.14(m,1H),4.19(d,J=6.3Hz,2H),3.97(dd,J=11.3,1.9Hz,1H),2.38–2.2 6(m,1H),2.19–1.90(m,7H),1.88–1.69(m,1H),1.62(s,3H),1.59(s,3H),1.34(s,3H),1.33(s,3H),0.90(s,9H),0.07(s,6H).

[0393] Step c. Synthesis of tert-butyl (((2E,6E)-9-(3,3-dimethyloxirane-2-yl)-3,7-dimethylnona-2,6-dien-1-yl)oxy)dimethylsilane (4)

[0394] To a solution of 3 (3.90 g, 9.0 mmol) in methanol (MeOH, 81 mL) was added KCO (2.49 g, 18.0 mmol), and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then quenched by adding water (100 mL), and the resulting aqueous phase was extracted with EtO (3x150 mL). The combined organic phases were washed with brine (80 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product 4 (3.0 g, 95%) as a colorless oil, which was used in the next step without further purification.

[0395] 1 H-NMR(300MHz, CDCl3)δ:5.34–5.27(m,1H),5.20–5.12(m,1H),4.19(d,J=6.3Hz,2H),2.70(t,J=6.2Hz,1H ),2.24–1.95(m,6H),1.73–1.51(m,2H),1.62(s,3H),1.30(s,3H),1.26(s,3H),0.90(s,9H),0.07(s,6H).

[0396] Step d. Synthesis of a mixture of (4E,8E)-10-((tert-butyldimethylsilyl)oxy)-4,8-dimethyldecan-4,8-dialdehyde (5a) and (4E,8E)-10-hydroxy-4,8-dimethyldecan-4,8-dialdehyde (5b)

[0397] A stirred mixture of 4 (3.0 g, 8.51 mmol), THF (54 mL) and water (10 mL) at 0°C was treated sequentially with NaIO (1.09 g, 5.10 mmol) and HIO (2.13 g, 9.36 mmol). The resulting mixture was stirred at 0°C for 10 minutes and then warmed to room temperature. After 1 hour, the reaction mixture was quenched by adding saturated NaHCO solution (100 mL) and the resulting mixture was stirred at room temperature for 5 minutes. The two-phase layers were separated and the aqueous layer was extracted with diethyl ether (3x200 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The crude mixture of 5a and 5b (2 g) was used in the next step without further purification.

[0398] Step e. Synthesis of (4E,8E)-10-((tert-butyldimethylsilyl)oxy)-4,8-dimethyldecan-4,8-dialdehyde (5a)

[0399] To the solution of the crude mixture of 5a and 5b (8.51mmol) and imidazoles (869mg, 12.77mmol) in anhydrous DCM (21mL) TBSCl (2.12g, 11.91mmol) is added, and the reaction mixture is stirred at room temperature for 4 hours. Then, reactant is diluted with DCM (19mL) and water (40mL) and stirred at room temperature for 15 minutes. The aqueous phase is separated, and the organic phase is washed with water (3x40mL) and salt solution (20mL), through anhydrous Na2SO4 is dried and concentrated under reduced pressure. The crude product is passed through silica gel flash chromatography (SiO2, hexane-EtOAc (4:1, R f (PR) 0.3)) to give 5a (2.52 g, 95% over 2 steps) as a colorless oil.

[0400] 1 H-NMR(300MHz, CDCl3)δ:9.75(t,J=1.9Hz,1H),5.34–5.24(m,1H),5.19–5.09(m,1H),4.18(d,J=6.3Hz, 2H), 2.55–2.45 (m, 2H), 2.31 (t, J = 7.4Hz, 2H), 2.16–1.95 (m, 4H), 1.61 (s, 6H), 0.90 (s, 9H), 0.07 (s, 6H).

[0401] Step f. Synthesis of tert-butyl (((2E,6E)-11,11-difluoro-3,7-dimethylundeca-2,6,10-trien-1-yl)oxy)dimethylsilane (7)

[0402] To a mixture of 5a (2.52 g, 8.11 mmol), 2-chloro-2,2-difluoroacetic acid sodium (6, 2.47 g, 16.22 mmol) and triphenylphosphine (PPh3, 4.25 g, 16.22 mmol) was added anhydrous N, N'-dimethylformamide (DMF, 16 mL) under argon, and the reaction mixture was stirred at 105 ° C for 2 hours. After cooling in an ice bath, water (20 mL) was slowly added. The resulting mixture was then diluted with water (80 mL) and Et2O (400 mL) and stirred at room temperature for 5 minutes. The aqueous phase was separated and the organic phase was washed with water (2x100 mL) and brine (100 mL). After drying over anhydrous Na2SO4, the volatile matter was removed under reduced pressure, and the crude product was purified by flash chromatography on a silica gel column (SiO2, hexane-EtOAc (20:1, R f The product was purified by HPLC (PR) 0.5) to afford 7 (1.58 g, 56% (excluding PPh3 impurity)) as a colorless oil.

[0403] 1 H-NMR(300MHz, CDCl3)δ:5.38–5.26(m,1H),5.18–5.08(m,1H),4.20(d,J=6.3Hz,2H),4.10(dtd, J=25.8,7.6,2.6Hz,1H),2.18–1.97(m,8H),1.63(s,3H),1.60(s,3H),0.91(s,9H),0.08(s,6H).

[0404] Step g. Synthesis of (2E,6E)-11,11-difluoro-3,7-dimethylundeca-2,6,10-trien-1-ol (8)

[0405] To a solution of 7 (1.58 g, 4.58 mmol) in anhydrous THF (7 mL) was added tetra-n-butylammonium fluoride (TBAF, 6.9 mL, 6.87 mmol, 1 M in THF). The reaction mixture was stirred at room temperature for 2 hours. After the reaction (TLC control) was completed, the reaction mixture was quenched by adding Et2O (25 mL) and water (25 mL), and the resulting mixture was stirred at room temperature for 5 minutes. Then, the organic phase was separated and the aqueous phase was extracted with Et2O (2 × 25 mL). The combined organic phases were washed with brine (25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (SiO2, hexane-EtOAc (4:1, R f The product was purified by HPLC (PR) 0.3) to afford 8 (905 mg, 86%) as a colorless oil.

[0406] 1H-NMR(300MHz, CDCl3)δ:5.48–5.34(m,1H),5.15–5.07(m,1H),4.15(d,J=6.8Hz, 2H),4.13–4.00(m,1H),2.20–1.96(m,8H),1.68(s,3H),1.59(s,3H),1.29(s,1H).

[0407] Step h. Synthesis of (5E,9E)-11-bromo-1,1-difluoro-5,9-dimethylundeca-1,5,9-triene (9)

[0408] To a cooled (0 ° C) solution of 8 (400 mg, 1.74 mmol) in anhydrous diethyl ether (Et2O, 6 mL) was added phosphorus tribromide (PBr3, 0.20 mL, 2.08 mmol, d = 2.85) dropwise, and the reaction mixture was stirred at 0 ° C for 1 hour (hr.). The reaction mixture was poured onto ice (2 g) and extracted with Et2O (3 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 9 (504 mg, 99%) as a light yellow oil.

[0409] 1 H-NMR(300MHz, CDCl3)δ:5.58–5.48(m,1H),5.13–5.04(m,1H),4.18–4.05( m,1H),4.02(d,J=8.4Hz,2H),2.18–1.98(m,8H),1.73(s,3H),1.59(s,3H).

[0410] 2) Synthesis of 2-((2E,6E)-11,11-difluoro-3,7-dimethylundeca-2,6,10-trien-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione (Compound A)

[0411] Option 2:

[0412]

[0413] Step a: Synthesis of 2-bromo-3,5,6-trimethylbenzene-1,4-diol (11)

[0414] To a solution of 2,3,5-trimethyl-benzene-1,4-diol (10, 1.52 mg, 10.0 mmol) in DCM (20 mL) was added a solution of bromine (1.60 g, 10.0 mmol) in DCM (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours, then quenched by adding water (40 mL) and extracted with DCM (20 mL). The organic phase was washed with 5% Na2S2O3 aqueous solution (20 mL) and brine (20 mL), dried over Na2SO4, filtered and evaporated to give 11 (2.24 g, 97%) as a brown solid, which was used without additional purification.

[0415] Step b: Synthesis of 1-bromo-2,5-bis(methoxymethoxy)-3,4,6-trimethylbenzene (12)

[0416] To a solution of 11 (2.24 g, 9.70 mmol) in anhydrous acetonitrile (MeCN, 40 mL) was added KCO(5.36 g, 38.8 mmol) and chloromethyl methyl ether (MOMCl, 2.2 mL, 29.1 mmol), and stirred at room temperature for 24 hours. EtOAc (100 mL) and water (100 mL) were added to the reaction mixture. The organic phase was separated and washed with salt water (40 mL) in addition, dried over NaSO, filtered and evaporated. The crude product was flash-chromatographically purified by silica gel column chromatography (SiO, hexane-EtOAc (5: 1, R f (PR) 0.3)) to give 12 (1.4 g, 48%) as a light yellow solid.

[0417] 1 H-NMR (300MHz, CDCl3) δ: 5.00 (s, 2H), 4.88 (s, 2H), 3.65 (s, 3H), 3.61 (s, 3H), 2.37 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H).

[0418] Steps c and d: Synthesis of 1-((2E,6E)-11,11-difluoro-3,7-dimethylundeca-2,6,10-trien-1-yl)-2,5-bis(methoxymethoxy)-3,4,6-trimethylbenzene (14)

[0419] 12 (326 mg, 1.02 mmol) was reacted with magnesium (49 mg, 2.05 mmol) in THF (4 mL) at 40 ° C in the presence of a pinch of iodine and 1,2-dibromoethane for one hour to form Grignard reagent 13 (completion of the reaction was confirmed by LC / MS). CuCl (68 mg, 0.682 mmol) was added to the cooled (0-5 ° C) reaction mixture, and the mixture was stirred at room temperature for 1 hour, followed by the dropwise addition of 9 (200 mg, 0.682 mmol, prepared as described above) in THF (2 mL). The reaction mixture was stirred for 16 hours, quenched by addition to saturated (sat.) aqueous (aq.) NHCl (5 mL), and extracted with EtO (15 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried over NaSO, filtered, and evaporated. The crude product was purified by flash column chromatography (SiO2, hexane-Et2O (5:1, R f The product was purified by HPLC (PR) 0.4) to afford 14 (212 mg, 69%, containing 10-15% impurities) as a colorless oil.

[0420] 1 H-NMR(300MHz, CDCl3)δ:5.12–5.00(m,2H),4.88(s,2H),4.86(s,2H),4.07(dtd,J=25.6,7.3,2.6Hz,1H),3.61(s ,3H),3.59(s,3H),3.38(d,J=6.2Hz,2H),2.19(s,6H),2.18(s,3H),2.15–1.94(m,8H),1.75(s,3H),1.56(s,3H).

[0421] Steps e and f: Synthesis of 2-((2E,6E)-11,11-difluoro-3,7-dimethylundeca-2,6,10-trien-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione (Compound A)

[0422] To a solution of 14 (212 mg, 0.468 mmol) in MeOH (8 mL) was added 7 drops of concentrated (conc.) hydrochloric acid (HCl) at room temperature and the reactants were stirred for 16 hours. After evaporation, crude hydroquinone, 2-((2E, 6E)-11,11-difluoro-3,7-dimethyl-11-carbon-2,6,10-triene-1-yl)-3,5,6-trimethylbenzene-1,4-diol (15) was dissolved in a mixture of isopropanol (i-PrOH, 2.3 mL) and water (0.12 mL) and treated with FeCl3 (304 mg, 1.87 mmol) at room temperature for 3 hours. Water (10 mL) and Et2O (10 mL) were added to the reaction mixture. The organic phase was separated and washed with brine (10 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified by flash column chromatography (SiO2, hexane-Et2O (5:1, R f (PR) 0.7)) to give 78 mg (46%) of compound A as a yellow oil (HPLC purity 96.4%).

[0423] 1 H-NMR(400MHz, CDCl3)δ:5.09–5.01(m,1H),4.99–4.89(m,1H),4.06(dtd,J=25.7,7.5,2.6Hz,1H ), 3.20 (d, J = 7.0Hz, 2H), 2.11–1.92 (m, 8H), 2.02 (s, 1H), 2.01 (s, 6H), 1.74 (s, 3H), 1.56 (s, 3H). MS(M+H + ):363.2.

[0424] Example 2: Synthesis of 2-((2E,6E)-11,11-difluoro-3,7-dimethylundeca-2,6,10-trien-1-yl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione (Compound B)

[0425]

[0426] Option 3:

[0427]

[0428] Step a: Synthesis of 2-bromo-5,6-dimethoxy-3-methylbenzene-1,4-diol (18)

[0429] To a solution of 2,3-dimethoxy-5-methyl-benzene-1,4-diol (17,822 mg, 4.46 mmol) in DCM (10 mL) was added a solution of bromine (714 mg, 4.46 mmol) in DCM (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours, then quenched in water (20 mL) and extracted with DCM (10 mL). The organic phase was washed with 5% Na2S2O3 aqueous solution (10 mL) and brine (10 mL), dried over Na2SO4, filtered and evaporated to give 18 (1.17 g, 99%) as a yellow solid, which was used without additional purification.

[0430] 1 H-NMR (300MHz, CDCl3) δ: 5.49 (s, 1H), 5.46 (s, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 2.29 (s, 3H).

[0431] Step b: Synthesis of 1-bromo-3,4-dimethoxy-2,5-bis(methoxymethoxy)-6-methylbenzene (19)

[0432] To a solution of 18 (1.17 g, 4.46 mmol) in anhydrous MeCN (22 mL) was added KCO(2.47 g, 17.84 mmol) and MOMCl (1.0 mL, 13.38 mmol), and the reactant was stirred at room temperature for 24 hours. EtOAc (50 mL) and water (50 mL) were added to the reaction mixture. The organic phase was separated and washed with salt water (20 mL) in addition, at NaSO, it was dried, filtered and evaporated. The crude product was purified by flash column chromatography (SiO, hexane-EtOAc (5: 1, R f The product was purified by HPLC (PR) 0.3) to afford 19 (862 mg, 55%) as a colorless solid.

[0433] 1 H-NMR (300MHz, CDCl3) δ: 5.14 (s, 2H), 5.06 (s, 2H), 3.87 (s, 6H), 3.67 (s, 3H), 3.59 (s, 3H), 2.36 (s, 3H).

[0434] Steps c and d: Synthesis of 1-((2E,6E)-11,11-difluoro-3,7-dimethylundeca-2,6,10-trien-1-yl)-3,4-dimethoxy-2,5-bis(methoxymethoxy)-6-methylbenzene (21)

[0435] Compound 19 (358 mg, 1.02 mmol) was reacted with magnesium (49 mg, 2.05 mmol) in THF (4 mL) at ambient temperature in the presence of a pinch of iodine and 1,2-dibromoethane for 2 hours to form Grignard reagent 20 (completion of the reaction was confirmed by LC / MS). CuCl (68 mg, 0.682 mmol) was added to the cooled (0-5 ° C) reaction mixture, and the mixture was stirred at room temperature for 1 hour, followed by the dropwise addition of 9 (200 mg, 0.682 mmol) in THF (2 mL). The reaction mixture was stirred for 16 hours, quenched by the addition of saturated aqueous NH4Cl (5 mL), and extracted with Et2O (15 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified by flash column chromatography (SiO2, hexane-Et2O (5:1, R f The product was purified by HPLC (PR) 0.4) to afford 21 (269 mg, 81%, containing 10-15% impurities) as a colorless oil.

[0436] 1 H-NMR(300MHz, CDCl3)δ:5.11–5.02(m,2H),5.05(s,2H),5.04(s,2H),4.07(dtd,J=26.0,7.3,2.8Hz,1H),3.86(s ,6H),3.59(s,3H),3.58(s,3H),3.37(d,J=6.3Hz,2H),2.17(s,3H),2.15–1.94(m,8H),1.75(s,3H),1.57(s,3H).

[0437] Steps e and f: Synthesis of 2-((2E,6E)-11,11-difluoro-3,7-dimethylundeca-2,6,10-trien-1-yl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione (Compound B)

[0438] To a solution of 21 (269 mg, 0.555 mmol) in MeOH (10 mL) was added 8 drops of concentrated HCl at room temperature, and the reactants were stirred for 16 hours. After evaporation, crude hydroquinone, 2-((2E, 6E)-11,11-difluoro-3,7-dimethyl-11-carbon-2,6,10-triene-1-yl)-5,6-dimethoxy-3-methylbenzene-1,4-diol (22) was dissolved in a mixture of i-PrOH (2.8 mL) and water (0.14 mL) and treated with FeCl3 (360 mg, 2.22 mmol) at room temperature for 3 hours. Water (10 mL) and Et2O (10 mL) were added to the reaction mixture. The organic phase was separated and washed with brine (10 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified by flash column chromatography (SiO2, hexane-Et2O (5:1, R f (PR) 0.3)) to give 110 mg (50%) of compound B as a reddish-orange oil (HPLC purity 99.2%).

[0439] 1 H-NMR(400MHz, CDCl3)δ:5.09–5.00(m,1H),4.98–4.88(m,1H),4.07(dtd,J=25.7,7.5,2.6Hz,1H),3.9 9(s,3H),3.97(s,3H),3.18(d,J=7.0Hz,2H),2.10–1.94(m,8H),2.01(s,3H),1.73(s,3H),1.56(s,3H). MS(M+H + ):395.3.

[0440] Example 3: Synthesis of 2,3-dimethoxy-5-methyl-6-(10,10,10-trifluorodecyl)cyclohexa-2,5-diene-1,4-dione (Compound C)

[0441]

[0442] Option 4:

[0443]

[0444] Step a: Synthesis of 2,2'-((2,3-dimethoxy-5-methyl-1,4-phenylene)bis(oxy))bis(tetrahydro-2H-pyran) (24)

[0445] To a solution of 2,3-dimethoxy-5-methylbenzene-1,4-diol (17,970mg, 11.52mmol) and 3,4-dihydropyran (3.16mL, 34.56mmol, d=0.920) in anhydrous DCM (9mL) was added pyridinium p-toluenesulfonate (29mg, 0.115mmol), and the mixture was stirred at room temperature for 48 hours. EtOAc (20mL) was added to the reaction mixture and first washed with saturated NaHCO3 aqueous solution (20mL), then washed with brine (20mL). The organic phase was separated, dried over Na2SO4, dried and evaporated. The crude product was purified by flash column chromatography (SiO2, hexane-EtOAc (4:1, R f The product was purified by HPLC (PR) 0.3) to afford 24 (2.56 g, 63%) as a colorless oil.

[0446] 1 H-NMR(300MHz, CDCl3)δ:6.69(d,J=2.1Hz,1H),5.34(q,J=3.3Hz,1H),5.12(t,J=3.6Hz,1H),4.16–4.06(m,1H),4.06– 3.90(m,1H),3.87(s,3H),3.86(d,J=2.8Hz,3H),3.67–3.50(m,2H),2.25(s,3H),2.06–1.83(m,6H),1.74–1.51(m,6H).

[0447] Steps b and c: Synthesis of 2,2'-((2,3-dimethoxy-5-methyl-6-(10,10,10-trifluorodecyl)-1,4-phenylene)bis(oxy))bis(tetrahydro-2H-pyran) (27)

[0448] To a solution of 24 (556 mg, 1.578 mmol) in anhydrous THF (14 mL) was added n-butyl lithium (n-BuLi, 1.03 mL, 2.367 mmol, 2.3 M in hexane) at 0 ° C. The solution was allowed to warm to room temperature and stirred for 1 hour. The mixture was recooled to 0 ° C and treated with hexamethylphosphoramide (HMPA, 0.41 mL, 2.367 mmol, d = 1.03), and then 10-bromo-1,1,1,-trifluorodecane (26,521 mg, 1.893 mmol) dissolved in THF (2 mL) was added. The solution was allowed to warm to room temperature and stirred for 24 hours. The reaction was quenched by adding saturated NH4Cl aqueous solution and then extracted with EtOAc (20 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, hexane-Et2O (4:1, R fThe product was purified by HPLC (PR) 0.3) to afford 27 (298 mg, 35%) as a colorless oil.

[0449] 1 H-NMR(300MHz, CDCl3)δ:5.18–5.07(m,2H),4.20–4.00(m,2H),3.84(s,3H),3.82(d,J=1.4Hz,3H), 3.61–3.50(m,2H),2.81–2.47(m,2H),2.21(d,J=1.4Hz,3H),2.13–1.85(m,8H),1.71–1.22(m,20H).

[0450] Steps d and e: Synthesis of 2,3-dimethoxy-5-methyl-6-(10,10,10-trifluorodecyl)cyclohexa-2,5-diene-1,4-dione (Compound C)

[0451] To a solution of 27 (298 mg, 0.545 mmol) in MeOH (10 mL) was added 8 drops of concentrated HCl at room temperature, and the reactants were stirred for 16 hours. After evaporation, crude hydroquinone, 2,3-dimethoxy-5-methyl-6-(10,10,10-trifluorodecyl)benzene-1,4-diol (28) was dissolved in a mixture of i-PrOH (2.7 mL) and water (0.14 mL) and treated with FeCl3 (354 mg, 2.18 mmol) at room temperature for 3 hours. Water (10 mL) and Et2O (10 mL) were added to the reaction mixture. The organic phase was separated and washed with brine (10 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified by flash column chromatography (SiO2, hexane-Et2O (5:1, R f (PR) 0.3)) to give 115 mg (56%) of compound C as a reddish-orange oil (HPLC purity 96.9%).

[0452] 1 H-NMR(400MHz, CDCl3)δ:3.98(s,3H),3.98(s,3H),2.47–2.40(m,2H),2.11–1.97(m,2H),2.00(s,3H),1.59–1.47(m,2H),1.41–1.25(m,12H). MS(M+H + ):377.3.

[0453] Compound D (CAS# 55486-00-5) was purchased from Cayman Chemical Company, Ann Arbor, Michigan 21027. LCMS analysis confirmed identity and approximately 98% purity. Compound D was used as received without purification.

[0454]

[0455] Example 4: Synthesis of 2,3-dimethoxy-5-methyl-6-(6,6,6-trifluorohexyl)cyclohexa-2,5-diene-1,4-dione (Compound E)

[0456]

[0457] Option 5:

[0458]

[0459] Steps a and b: Synthesis of 2,2'-((2,3-dimethoxy-5-methyl-6-(6,6,6-trifluorohexyl)-1,4-phenylene)bis(oxy))bis(tetrahydro-2H-pyran) (30).

[0460] To a solution of 24 (801 mg, 2.3 mmol) in anhydrous hexane (3.8 mL) was added anhydrous N, N, N', N'-tetramethylethylenediamine (TMEDA) (0.37 mL, 2.5 mmol, d = 0.775) at 0 ° C under a gentle argon stream, followed by dropwise addition of n-BuLi (1.5 mL, 3.5 mmol, 2.3 M in hexane). The solution was allowed to warm to room temperature and stirred for 30 minutes, and the formation of a yellow precipitate was observed. Anhydrous THF (5 mL) was added to the mixture, and the reaction mixture was cooled to 0 ° C (orange solution). Anhydrous HMPA (0.43 mL, 2.5 mmol, d = 1.03) and a solution of 6-bromo-1,1,1-trifluorohexane (29,767 g, 3.5 mmol) (dissolved in anhydrous THF (5 mL)) were quickly added to the reaction mixture. The solution was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched by adding saturated aqueous NH4Cl solution, then extracted with EtOAc (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, hexane-Et2O (4:1, R f The product was purified by HPLC (PR) 0.3) to give 30 (630 mg, 56%). The material was used in the next reaction without further purification.

[0461] Steps c and d: Synthesis of 2,3-dimethoxy-5-methyl-6-(6,6,6-trifluorohexyl)cyclohexa-2,5-diene-1,4-dione (Compound E)

[0462] Note: The product is light sensitive, therefore the reaction and product isolation should be performed in the dark.To a solution of 30 (630 mg, 1.28 mmol) in methanol (21 mL) was added 0.21 mL of concentrated hydrochloric acid at room temperature, and the mixture was stirred for 16 hours. After evaporation, crude hydroquinone (2,3-dimethoxy-5-methyl-6-(6,6,6-trifluorohexyl)benzene-1,4-diol (31)) was dissolved in a mixture of i-PrOH (6.9 mL) and water (0.34 mL) and treated with FeCl3 (892 mg, 5.5 mmol) at room temperature for 3 hours. Water (20 mL) and Et2O (40 mL) were added to the reaction mixture. The organic phase was separated and washed with brine (20 mL), dried over Na2SO4, filtered and evaporated. The crude product was first purified by flash column chromatography (SiO2, hexane-Et2O (5:1, R f The product was purified by reverse phase flash chromatography (KP-C-18-HS, ​​(MeCN / MeOH, 70 / 30) / H2O) to give compound E (205 mg, 49%, HPLC purity 96.23%).

[0463] 1 H-NMR(400MHz, CDCl3)δ:3.99(s,3H),3.99(s,3H),2.48–2.45(m,2H),2.13–2.03(m,2H),2.01(s,3H),1.62–1.57(m,2H),1.44–1.41(m,4H).

[0464] Example 5: Synthesis of 2-(6,6-difluorohexyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione (Compound F)

[0465]

[0466] Option 6:

[0467]

[0468] Steps a and b: Synthesis of 2,2'-((2-(6,6-difluorohexyl)-5,6-dimethoxy-3-methyl-1,4-phenylene)bis(oxy))bis(tetrahydro-2H-pyran) (33)

[0469] To a solution of 24 (1.0 g, 2.83 mmol) in anhydrous hexane (10 mL) was first added TMEDA (0.46 mL, 3.12 mmol, d = 0.775) at 0 ° C under a gentle argon stream, followed by dropwise addition of n-BuLi (1.8 mL, 4.25 mmol, 2.3 M in hexane). The solution was allowed to warm to room temperature and stirred for 30 minutes. The formation of a yellow precipitate was observed. The mixture was recooled to 0 ° C and treated with HMPA (0.74 mL, 4.255 mmol, d = 1.03), followed by addition of 6-bromo-1,1-difluorohexane (32, 0.68 g, 3.4 mmol) dissolved in THF (4 mL). The solution was allowed to warm to room temperature and stirred for 4 hours. The reactant was quenched by adding a saturated NH4Cl aqueous solution, then extracted with EtOAc (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO 2 , hexane-Et 2 O (25:1) to afford 33 (317 mg, 23%) as a colorless oil. This material was used in the next reaction without further purification.

[0470] 1 H-NMR (400MHz, CDCl3) δ: 5.80 (tt; J = 57.0; 4.5Hz; 1H), 5.13–5.11 (m, 2H), 4.15–4.04 (m, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.5 9–3.52(m,2H),2.77–2.70(m,1H),2.61–2.55(m,1H),2.21(s,3H),2.01–1.78(m,8H),1.67–1.57(m,6H),1.53–1.41(m,6H).

[0471] Steps c and d: Synthesis of 2-(6,6-difluorohexyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione (Compound F)

[0472] Note: The product is light sensitive, therefore the reaction and product isolation should be performed in the dark.To a solution of 33 (0.31 g, 0.66 mmol) in methanol (15 mL) was added 10 drops of concentrated hydrochloric acid at room temperature, and the mixture was stirred for 16 hours. After evaporation, crude hydroquinone (2-(6,6-difluorohexyl)-5,6-dimethoxy-3-methylbenzene-1,4-diol (34)) was dissolved in a mixture of i-PrOH (5 mL) and water (0.3 mL) and treated with FeCl3 (520 mg) at room temperature for 3 hours. Water (10 mL) and Et2O (250 mL) were added to the reaction mixture. The organic phase was separated and washed with brine (70 mL), dried over Na2SO4, filtered and evaporated. The crude product was first purified by flash column chromatography (SiO2, hexane-Et2O (25:1) and then repurified by reverse phase flash chromatography ((MeCN / MeOH) / H2O; 70-85%) to give compound F (61 mg, 30%, HPLC purity 99.62%).

[0473] 1 H-NMR (400MHz, CDCl3) δ: 5.79 (tt; J = 57.0; 4.5Hz; 1H), 3.99 (s, 3H), 3.99 (s ,3H),2.48–2.44(m,2H),2.01(s,3H),1.89–1.75(m,2H),1.50–1.39(m,6H).

[0474] Example 6: Synthesis of 2-(6-fluorohexyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione (Compound G)

[0475]

[0476] Option 7:

[0477]

[0478] Steps a and b: Synthesis of 2,2'-((2-(6-fluorohexyl)-5,6-dimethoxy-3-methyl-1,4-phenylene)bis(oxy))bis(tetrahydro-2H-pyran) (36)

[0479] To a solution of 24 (1.0 g, 2.83 mmol) in anhydrous hexane (10 mL) was first added TMEDA (0.46 mL, 3.12 mmol, d = 0.775) at 0 ° C under a gentle argon stream, followed by dropwise addition of n-BuLi (1.8 mL, 4.25 mmol, 2.3 M in hexane). The solution was allowed to warm to room temperature and stirred for 30 minutes. The formation of a yellow precipitate was observed. The mixture was recooled to 0 ° C and treated with HMPA (0.41 mL, 2.367 mmol, d = 1.03), followed by addition of 1-bromo-6-fluorohexane (35, 0.62 g, 3.4 mmol) dissolved in THF (4 mL). The solution was allowed to warm to room temperature and stirred for 4 hours. The reactant was quenched by adding a saturated NH4Cl aqueous solution, then extracted with EtOAc (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO 2 , hexane-Et 2 O (23:1)) to afford 36 (350 mg, 27%) as a colorless oil. This material was used in the next reaction without further purification.

[0480] 1 H-NMR(400MHz, CDCl3)δ:5.13–5.11(m,2H),4.52–4.48(m,1H),4.40–4.37(m,1H),4.14–4.05(m,2H),3.82(s ,3H),3.81(s,3H),3.59–3.53(m,2H),2.21(s,3H),2.01–1.89(m,6H),1.76–1.58(m,9H),1.52–1.41(m,6H).

[0481] Steps c and d: Synthesis of 2-(6-fluorohexyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione (Compound G)

[0482] Note: The product is light sensitive, therefore the reaction and product isolation should be performed in the dark. To a solution of 36 (0.35 g, 0.77 mmol) in methanol (15 mL) was added 8 drops of concentrated hydrochloric acid at room temperature, and the mixture was stirred for 16 hours. After evaporation, crude hydroquinone (2-(6-fluorohexyl)-5,6-dimethoxy-3-methylbenzene-1,4-diol (37)) was dissolved in a mixture of i-PrOH (3 mL) and water (0.2 mL) and treated with FeCl3 (415 mg) at room temperature for 3 hours. Water (10 mL) and Et2O (100 mL) were added to the reaction mixture. The organic phase was separated and washed with brine (50 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified by flash column chromatography (SiO2, hexane-Et2O (5:1) to obtain compound G (133 mg, 60%, HPLC purity 98.0%).

[0483] 1 H-NMR(400MHz, CDCl3)δ:4.51–4.48(m,1H),4.39–4.36(m,1H),3.98(s,3H),3.9 8(s,3H),2.48–2.44(m,2H),2.01(s,3H),1.75–1.63(m,2H),1.46–1.36(m,6H).

[0484] Example 7: Synthesis of 2-heptyl-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione (Compound H)

[0485]

[0486] Option 8:

[0487]

[0488] Steps a and b: Synthesis of 2,2'-((2-heptyl-5,6-dimethoxy-3-methyl-1,4-phenylene)bis(oxy))bis(tetrahydro-2H-pyran) (39)

[0489] To a solution of 24 (1.0 g, 2.83 mmol) in anhydrous hexane (10 mL) was first added TMEDA (0.46 mL, 3.12 mmol, d = 0.775) at 0 ° C under a gentle argon stream, followed by dropwise addition of n-BuLi (1.8 mL, 4.25 mmol, 2.3 M in hexane). The solution was allowed to warm to room temperature and stirred for 30 minutes. The formation of a yellow precipitate was observed. The mixture was recooled to 0 ° C and treated with HMPA (0.41 mL, 2.367 mmol, d = 1.03), followed by addition of 1-bromoheptane (38, 0.74 ml, 3.4 mmol) dissolved in THF (4 mL). The solution was allowed to warm to room temperature and stirred for 4 hours. The reactants were quenched by adding saturated NH4Cl aqueous solution, then extracted with EtOAc (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO 2 , hexane-Et 2 O (20:1) to afford 39 (310 mg, 24%) as a colorless oil. This material was used in the next reaction without further purification.

[0490] 1H-NMR(400MHz, CDCl3)δ:5.15–5.11(m,2H),4.16–4.07(m,2H),3.82(s,3H),3.81(s,3H),3.60–3.54(m,2H),2.74–2.67(m,1H) ,2.60–2.53(m,1H),2.21(s,3H),2.01–1.89(m,5H),1.69–1.59(m,5H),1.52–1.44(m,2H),1.41–1.24(m,8H),0.9–0.87(m,3H).

[0491] Steps c and d: Synthesis of 2-heptyl-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione (Compound H)

[0492] Note: The product is light sensitive, therefore the reaction and product isolation should be performed in the dark. To a solution of 39 (0.31 g, 0.69 mmol) in methanol (15 mL) was added 8 drops of concentrated hydrochloric acid at room temperature, and the mixture was stirred for 16 hours. After evaporation, crude hydroquinone (2-heptyl-5,6-dimethoxy-3-methylbenzene-1,4-diol (40)) was dissolved in a mixture of i-PrOH (3 mL) and water (0.2 mL) and treated with FeCl3 (430 mg) for 3 hours. Water (10 mL) and Et2O (200 mL) were added to the reaction mixture. The organic phase was separated and washed with brine (70 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified by flash column chromatography (SiO2, hexane-Et2O (5:1) to obtain compound H (140 mg, 72%, HPLC purity 98.8%).

[0493] 1 H-NMR (400MHz, CDCl3) δ: 3.99 (s, 3H), 3.98 (s, 3H), 2.46–2.43 (m, 2H), 2.01 (s, 3H), 1.40–1.27 (m, 10H), 0.89–0.86 (m, 3H).

[0494] Example 8: Synthesis of 2,3-dimethoxy-5-methyl-6-(4,4,4-trifluorobutyl)cyclohexa-2,5-diene-1,4-dione (Compound I)

[0495]

[0496] Option 9:

[0497]

[0498] Steps a and b. Synthesis of 2,2'-((2,3-dimethoxy-5-methyl-6-(4,4,4-trifluorobutyl)-1,4-phenylene)bis(oxy))bis(tetrahydro-2H-pyran) (42)

[0499] To a solution of 24 (801 mg, 2.3 mmol) in anhydrous hexane (3.8 mL) was added anhydrous TMEDA (0.37 mL, 2.5 mmol, d = 0.775) at 0 ° C under a gentle argon stream, and then n-BuLi (1.5 mL, 3.5 mmol, 2.3 M in hexane) was added dropwise. The solution was allowed to warm to room temperature and stirred for 30 minutes. The formation of a yellow precipitate was observed. Anhydrous THF (5 mL) was added to the mixture, and the reaction mixture was cooled to 0 ° C (orange solution). Anhydrous HMPA (0.43 mL, 2.5 mmol, d = 1.03) and a solution of 4-bromo-1,1,1-trifluorobutane (41,668 g, 3.5 mmol) (dissolved in anhydrous THF (5 mL)) were quickly added to the reaction mixture. The solution was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched by adding saturated NH4Cl aqueous solution, then extracted with EtOAc (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, hexane-Et2O (4:1, R f The product was purified by HPLC (PR) 0.3) to afford 42 (441 mg, 39%). This material was used in the next reaction without further purification.

[0500] Steps c and d: Synthesis of 2,3-dimethoxy-5-methyl-6-(4,4,4-trifluorobutyl)cyclohexa-2,5-diene-1,4-dione (Compound I)

[0501] Note: The product is light sensitive, therefore the reaction and product isolation should be performed in the dark. To a solution of 42 (441 mg, 0.95 mmol) in methanol (15 mL) was added 0.15 mL of concentrated hydrochloric acid at room temperature and stirred for 16 hours. After evaporation, crude hydroquinone (2,3-dimethoxy-5-methyl-6-(4,4,4-trifluorobutyl) benzene-1,4-diol (43)) was dissolved in a mixture of i-PrOH (5.0 mL) and water (0.26 mL) and treated with FeCl3 (662 mg, 4.08 mmol) for 3 hours. Water (20 mL) and Et2O (40 mL) were added to the reaction mixture. The organic phase was separated and washed with brine (20 mL) and dried over Na2SO4, filtered and evaporated. The crude product was first purified by flash column chromatography (SiO2, hexane-Et2O (5:1, R fThe obtained product was purified by reverse phase flash chromatography (KP-C-18-HS, ​​(MeCN / MeOH, 70 / 30) / H2O) to afford compound I (66 mg, 24%, HPLC purity 95.66%) as a reddish orange oil.

[0502] 1 H-NMR (400MHz, CDCl3) δ: 4.00 (s, 3H), 3.99 (s, 3H), 2.56–2.52 (m, 2H), 2.20–2.07 (m, 2H), 2.03 (s, 3H), 1.71–1.63 (m, 2H).

[0503] Example 9: Synthesis of 2-(4-fluorobutyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione (Compound J)

[0504]

[0505] Option 10:

[0506]

[0507] Steps a and b: Synthesis of 2,2'-((2-(4-fluorobutyl)-5,6-dimethoxy-3-methyl-1,4-phenylene)bis(oxy))bis(tetrahydro-2H-pyran) (45)

[0508] To a solution of 24 (1.0 g, 2.83 mmol) in anhydrous hexane (10 mL) was first added TMEDA (0.46 mL, 3.12 mmol, d = 0.775) at 0 ° C under a gentle argon stream, followed by the dropwise addition of n-BuLi (1.8 mL, 4.25 mmol, 2.3 M in hexane). The solution was allowed to warm to room temperature and stirred for 30 minutes. The formation of a yellow precipitate was observed. The mixture was recooled to 0 ° C and treated with HMPA (0.74 mL, 4.255 mmol, d = 1.03), followed by the addition of 1-bromo-4-fluorobutane (44, 0.74 mL, 4.2 mmol) in THF (5 mL). The solution was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched by the addition of saturated NH4Cl aqueous solution, then extracted with EtOAc (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO 2 , hexane-Et 2 O (25:1) to afford 45 (250 mg, 21%) as a colorless oil. This material was used in the next reaction without further purification.

[0509] Steps c and d: Synthesis of 2-(4-fluorobutyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione (Compound J)

[0510] Note: The product is light sensitive, therefore the reaction and product isolation should be performed in the dark. To a solution of 45 (0.25 g, 0.58 mmol) in methanol (10 mL) was added 7 drops of concentrated hydrochloric acid at room temperature, and the mixture was stirred for 16 hours. After evaporation, the crude hydroquinone (2-(4-fluorobutyl)-5,6-dimethoxy-3-methylbenzene-1,4-diol (46)) was dissolved in a mixture of i-PrOH (4 mL) and water (0.2 mL) and treated with FeCl3 (420 mg) for 3 hours. Water (10 mL) and Et2O (250 mL) were added to the reaction mixture. The organic phase was separated and washed with brine (70 mL), dried over Na2SO4, filtered and evaporated. The crude product was first purified by flash column chromatography (SiO2, hexane-Et2O (30:1) and then purified by reverse phase flash chromatography ((MeCN / MeOH) / H2O; 65-75%) to give compound J (48 mg, 32%, HPLC purity 99.4%).

[0511] 1 H-NMR (400MHz, CDCl3) δ: 4.52 (t; J = 5.9Hz; 1H), 4.40 (t; J = 5.9Hz; 1H), 3.99 (s, 3H), 3.99(s,3H),2.53–2.49(m,2H),2.03(s,3H),1.81–1.68(m,2H),1.57–1.49(m,2H).

[0512] Example 10: Synthesis of 2,3-dimethoxy-5-methyl-6-(3-(trimethylsilyl)propyl)cyclohexa-2,5-diene-1,4-dione (Compound K)

[0513]

[0514] Option 11:

[0515]

[0516] Steps a and b: Synthesis of (3-(3,4-dimethoxy-6-methyl-2,5-bis((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propyl)trimethylsilane (48)

[0517] To a solution of 24 (1.0 g, 2.83 mmol) in anhydrous hexane (10 mL) was first added TMEDA (0.46 ml, 3.12 mmol, d = 0.775) at 0 ° C under a gentle argon stream, followed by dropwise addition of n-BuLi (1.8 mL, 4.25 mmol, 2.3 M in hexane). The solution was allowed to warm to room temperature and stirred for 30 minutes. The formation of a yellow precipitate was observed. The mixture was recooled to 0 ° C and treated with HMPA (0.74 mL, 4.255 mmol, d = 1.03), followed by addition of (3-iodopropyl)trimethylsilane (47, 0.82 g, 3.4 mmol) dissolved in THF (4 mL). The solution was allowed to warm to room temperature and stirred for 4 hours. The reactants were quenched by adding saturated NH4Cl aqueous solution, then extracted with EtOAc (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO 2 , hexane-Et 2 O (20:1) to afford 48 (510 mg, 39%) as a colorless oil. This material was used in the next reaction without further purification.

[0518] Steps c and d: Synthesis of 2,3-dimethoxy-5-methyl-6-(3-(trimethylsilyl)propyl)cyclohexa-2,5-diene-1,4-dione (Compound K)

[0519] Note: The product is light sensitive, therefore the reaction and product isolation should be performed in the dark. To a solution of 48 (0.31 g, 0.66 mmol) in methanol (15 mL) was added 10 drops of concentrated hydrochloric acid and stirred for 16 hours at room temperature. After evaporation, crude hydroquinone (2,3-dimethoxy-5-methyl-6-(3-(trimethylsilyl)propyl)benzene-1,4-diol (49)) was dissolved in a mixture of i-PrOH (5 mL) and water (0.3 mL) and treated with FeCl3 (530 mg) for 3 hours. Water (10 mL) and Et2O (250 mL) were added to the reaction mixture. The organic phase was separated and washed with brine (70 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified by flash column chromatography (SiO2, hexane-Et2O (25:1) and further purified by reverse phase flash chromatography ((MeCN / MeOH) / H2O; 65-75%) to give compound K (241 mg, 74%, HPLC purity 99.44%).

[0520] 1 H-NMR (400MHz, CDCl3) δ: 3.99 (s, 3H), 3.98 (s, 3H), 2.49–2.46 (m, 2H), 2.01 (s, 3H), 1.44–1.36 (m, 2H), 0.58–0.53 (m, 2H), -0.03 (s, 9H).

[0521] Example 11A: Preparation of Reduced Form of Compound C (Prophetic)

[0522] Compound C (20 mg) was dissolved in a mixture of MeOH / THF (1 mL+1 mL) under an argon atmosphere. NaBH (3 mg) was then added, and the reaction mixture was stirred at room temperature for 1 hour. Next, the reaction mixture was quenched by adding Et O (30 mL) and aqueous NH Cl (10 mL) while stirring for 2 minutes at room temperature. The aqueous phase was separated, and the organic phase was washed with salt water (10 mL), over anhydrous Na SO dried and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 28 (i.e., the reduced form of compound C - the compound can also be isolated from Example 3 as 28).

[0523] Example 11B: Preparation of Reduced Form of Vatiquinone ("Vatiquinone-R")

[0524] Option 12:

[0525]

[0526] Vatiquinone (20 mg) was dissolved in a mixture of MeOH / THF (1 mL + 1 mL) under an argon atmosphere. NaBH (3 mg) was then added, and the reaction mixture was stirred at room temperature for 1 hour. Next, the reaction mixture was quenched by adding Et O (30 mL) and aqueous NH Cl (10 mL) while stirring at room temperature for 2 minutes. The aqueous phase was separated, and the organic phase was washed with brine (10 mL), dried over anhydrous Na SO and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 0.015 g (74% yield) of reduced vatiquinone (vatiquinone-R).

[0527] 1 H-NMR (CDCl3, 400MHz): δ = 5.17-5.08 (m, 3H), 2.74-2.71 (m, 2H), 2.19-2.16 (m ,9H),2.11-1.96(m,11H),1.71-1.68(m,5H),1.62-1.56(m,11H),1.25(s,4H).

[0528] 13C-NMR (101MHz, Chloroform-d) δ = 145.9, 145.5, 136.1, 135.3, 131.4, 125.9, 124.5, 124.2, 124.0, 121.8, 120. 7,119.1,74.0,41.9,41.0,40.0,30.5,26.9,26.7,26.7,25.8,23.0,20.7,17.8,16.2,16.2,12.5,12.4,12.2.

[0529] HRMS,[M+H]:C 29 H 47 O3 (calculated value: 443.3525). Found: 443.3516.

[0530] Example 12: Bandin-Deficient Fibroblast Viability Assay ("BSO Assay")

[0531] Reference: Matthias L. Jauslin, Thomas Wirth, Thomas Meier and Fabrice Schoumacher, Acellular model for Friederichs Ataxia reveals small-moleculeglutathione peroxidase mimetics as novel treatment strategy, Human Molecular Genetics, 2002, Volume 11 (24): 3055-3063.

[0532] This example is used to evaluate the potential efficacy of various novel compositions for the treatment of Friedreich's ataxia (FA or FRDA) - essentially as described in the reference cited above (Matthias et al.) This data can be used to select candidates for further testing, including animal studies for the development of active therapeutics.

[0533] introduction:

[0534] This assay utilizes frataxin-deficient fibroblasts (i.e., fibroblasts from Friedreich's Ataxia (FRDA) patient material) as a means of measuring cell viability by determining how well a compound of interest can potentially inhibit / delay / prevent L-buthionine-sulfoxamine-induced (BSO-induced) cell death in both diseased and control (healthy) cells.

[0535] Test product:

[0536] Stock solutions of the test articles (and control compounds) were prepared in dimethyl sulfoxide (10 mM DMSO). Working stock solutions (2x concentrated) were prepared on the day of the experiment in the respective cell culture medium to be used for the assay (detailed culture medium description below). A list of the compounds used as test articles in this Example 12 is shown in Table 1 below.

[0537] Determination experiment:

[0538] Patient-derived frataxin-deficient fibroblast cell lines were obtained from the Coriell Institute. More specifically, the following cell line / DNA sample was obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research: GM03665. To evaluate the importance of individual growth conditions on the susceptibility of cells to BSO toxicity, cells were grown in:

[0539] MEM (Sigma-Aldrich) 15% fetal bovine serum (FBS), without growth factors;

[0540] MEM (Sigma-Aldrich) 15% FBS, containing growth factors (Cat. No. 100-18B, recombinant human FGF-basic (154 a.a.) and Cat. No. AF-100-15, animal-free recombinant human EGF, from Peprotech);

[0541] MEM199 / MEM EBS (Bioconcept Ltd.) 10% FBS, insulin 10 μg / ml, L-glutamine 2 mM, containing growth factors (Cat. No. 100-18B, recombinant human FGF-basic (154 a.a.) and Cat. No. AF-100-15, animal-free recombinant human EGF, from Peprotech).

[0542] For the experiment, fibroblasts (from all growth conditions) were seeded (100 μL (3×10^3 cells / well) in MEM199 / MEM EBS medium 10% FBS, insulin 10 μg / mL, L-glutamine 2 mM and growth factors) on 96-well plates and allowed to grow on the plates for 24 hours. After 24 hours, the medium was removed and the target test compound (100 μL, 2x concentrated stock solution) was added to the 96-well plate (final DMSO concentration did not exceed 0.5%) and incubated for 24 hours. L-buthionine-sulfoxamine (BSO, from Acros Organics, Cat. No. 235520010) (100 μL, 2x concentrated stock solution) was then added to final concentrations ranging from 1 to 10 mM. The test compound and BSO were dissolved in MEM199 / MEM EBS medium 10% FBS, insulin 10g / mL, l-glutamine 2mM and growth factors. Cell viability was monitored and determined after 24 hours or 48 hours using the MTT (thiazolyl blue tetrazolium bromide) assay. For the MTT assay, the culture medium was removed and 100 μL of MTT 1mg / mL was added, incubated at +37°C for 2 hours, then the culture medium was removed and 100 μL of isopropanol was added to dissolve the precipitate. Absorption was measured at wavelengths of 570 (OD570) and 650 (OD650) nm. Control cells (vehicle instead of BSO and compound) and vehicle controls (with BSO, but vehicle instead of test compound) were treated in the same manner as cells treated with BSO and compound. All cell culture media contained 100 U / mL of penicillin and streptomycin each.

[0543] calculate :

[0544] Absorption readings are processed as follows: Value Δ =value OD570 -value OD650 , and the values ​​obtained were used to calculate cell viability as % of the viability of control cells (ie, no BSO, no compound, vehicle only).

[0545] Repeated experiments :

[0546] Unless otherwise indicated in Table 1, all samples were run in at least 3 replicates for the test compound and in at least 8 replicates for the control (i.e., control (no BSO, no compound) and vehicle control (i.e., with BSO, no compound). The exact N for each data point is indicated in the figure / table legends. The results for the tested compounds (test articles and controls) are listed in Table 1 below.

[0547] discuss:

[0548] This is a cell-based assay that measures the cytotoxicity caused by oxidative stress following depletion of endogenous glutathione defense mechanisms. The cells were primary Friedrich's ataxia (FA) patient fibroblasts incubated for 48 hours in BSO, an inhibitor of gamma-glutamyl synthetase (an enzyme required for glutathione production). Compared to healthy control fibroblasts, FA patient fibroblasts are more susceptible to BSO-induced cell death because the loss of tarazol and subsequent cytoplasmic iron accumulation accelerate ROS-driven lipid peroxidation. In the assay, cells were pretreated with decreasing doses of the drug from 250 nM to 6.125 nM one day before adding BSO at a fixed dose of 10 mM. After 48 hours, cytotoxicity was measured using the MTT assay and reported as a percentage of the MTT absorbance normalized to cells grown in medium without BSO for 48 hours. Unless otherwise stated, each data point was performed in triplicate wells of a 96-well plate. The data obtained are presented in Table 1 below. In summary, all compounds tested (i.e., compounds A, A, and K), except compound J, were protective against BSO-induced cell death in the assay, although in all cases the protective effects of the tested compounds were inferior to those of valtiquinone. The best tested compounds were compounds A and C. Omavirolone was roughly comparable in protective effect to valtiquinone, but idebenone was not truly very protective in this assay.

[0549] Example 13: Rotenone ATP Assay (Complex I Bypass Assay)

[0550] introduction :

[0551] This assay is adapted from Haefeli RH, Erb M, Gemperli AC, Robay D, Courdier Fruh I, et al. (2011) NQO1-Dependent Redox Cycling of Idebenone: Effects on Cellular Redox Potential and Energy Levels. PLoS ONE 6(3):e17963. HepG2 human hepatoma cells were incubated with the electron transport chain complex I toxin rotenone + / - target compounds, and the corresponding effects on ATP synthesis were measured using a bioluminescent substrate. This assay can be used to identify compounds that can "bypass" rotenone-induced complex I arrest, which significantly impairs mitochondrial respiration and results in a net decrease in ATP generated from endogenous substrates.

[0552] Test product:

[0553] Stock solutions of the test articles (see Table 1 below for a list of test articles examined using this assay) were prepared in dimethyl sulfoxide (DMSO, 10 mM). Working stock solutions were prepared on the day of the experiment in glucose-free, serum-free Dulbecco's modified Eagle's medium (DMEM) supplemented with 50 micromolar rotenone.

[0554] Determination experiment :

[0555] Briefly, HepG2 cells were plated at 25,000 cells per well in low glucose (1 g / L) DMEM medium + 10% fetal bovine serum and incubated for 24 hours. The next day, the culture medium was decanted and subsequently replaced with glucose-free / serum-free DMEM supplemented with 50 micromolar rotenone and the target compound. Serial dilutions of the compound were prepared in 3-fold dilutions starting from 25 micromolar. The cells were incubated in a humidified tissue culture incubator for 60 minutes. After incubation, ATP levels were quantified using a bioluminescent assay (Promega TiterMax Glo Assay kit) and read on a standard microplate reader.

[0556] calculate :

[0557] ATP bioluminescence was plotted against the logarithm of the target compound and the data were used to generate EC50 values. Curve fitting was performed using a sigmoidal dose-response curve fitting function (GraphPad Prism software).

[0558] Repeated experiments :

[0559] EC50 values ​​were derived from 7-point dose-response curves performed with n=3 technical replicates per dose. The robustness of the curve fit was assessed as a quality control measure, with a successful curve fit requiring an R-squared value of at least 0.80. Target compounds that demonstrated an increase in ATP bioluminescence relative to vehicle control were validated in independent biological replicates with n=3 technical replicates per dose.

[0560] discuss :

[0561] This assay is a direct measure of the ability of a target compound to restore ATP production under conditions that inhibit Complex I of the mitochondrial electron transport chain. Since most ATP produced via the electron transport chain is believed to come from Complex I activity, significant impairment of Complex I function can have extremely serious biological consequences. Notably, Complex I mutations are believed to drive the pathophysiology of a variety of mitochondrial diseases, including Leigh syndrome and Leber's Hereditary Optic Neuropathy (LHON), and reduced Complex I activity and resulting attenuation of ATP production have been shown in neurodegenerative diseases, including Frisch's ataxia, Parkinson's disease, and Huntington's disease. The data are presented in Table 1 below. In short, most compounds were tested in the rotenone oxygraph assay rather than this assay, but only idebenone was active among omaviron, idebenone, and vartiquinone. Compounds B and C were also tested and exhibited Complex I bypass activity comparable to idebenone.

[0562] Example 14: RSL-3 Toxicity Assay (RSL-3 Assay)

[0563] This assay was adapted from: Hinman, A., Holst, CR, Latham, JC, Bruegger, JJ, Ulas, G., McCusker, KP, Amagata, A., Davis, D., Hoff, KG, Kahn-Kirby ,AH,Kim,V.,Kosaka,Y.,Lee,E.,Malone,SA,Mei,JJ,Richards,SJ,Rivera,V.,Miller,G.,Trimmer,JK,Shrader,WD,“Vitamin Ehydroquinone is an endogenous regulator of ferroptosisvia redox control of 15-lipoxygenase”, (2018) PLoS ONE 13(8):e0201369. This assay was designed to determine whether the novel compounds disclosed herein exhibit a protective effect when fibroblasts from patients with Friedreich's ataxia are subjected to the toxic effects of RSL-3, a known inducer of a regulated cell death process catalyzed by iron and lipid peroxidation, known as ferroptosis.

[0564] Briefly, GM03665 cells (Coriell Institute) were seeded at 2x10^4 cells / mL (100 μL or 2x10^3 cells / well) in DMEM cell culture medium containing 10% fetal bovine serum and 1% penicillin-streptomycin (Pen-Strep) antibiotic mixture in 96-well plates (Sarstedt). The cells were incubated overnight at 37°C in a humidified atmosphere containing 5% CO2 to allow the cells to attach to the culture plates. The test compound was prepared as a DMSO stock solution (10 mM) and serially diluted in cell culture medium to obtain a 2x working solution. The cell culture medium was discarded and 50 μL of the test compound solution or cell culture medium containing the vehicle (for control wells) was added. Within 15 minutes, a 2x working solution (4 μM) of 1S,3R-RSL-3 (CAS#1219810-16-8, Sigma-Aldrich) was added (diluted from a 5 mM DMSO stock solution in cell culture medium). The final reaction volume was 100 μL, and the final DMSO concentration in the reaction was kept below 0.2% (v / v) and equal in all wells. The final RSL-3 concentration was 2 μM, and the final concentration of the test compound in the reaction was up to 1000 nM. Cell viability was assessed using the MTT test after 24 hours of incubation. A 1 mg / mL MTT (Sigma-Aldrich) solution in n 1X PBS (pH = 7,4) was prepared 1 hour before the assay and filtered through a Filtropur S 0.2 filter (Sarstedt). The cell culture medium containing the test compound was discarded and 100 μL of MTT solution was added. The plate was incubated at +37°C for 2 hours. Thereafter, the MTT solution was removed and 100 μL of isopropanol was added to dissolve the precipitate. The absorbance at 570 and 650 nm was measured using a Hidex Sense microplate reader. The data obtained were analyzed using GraphPadPrism software to calculate the EC reported in Table 1 below. 50 value.

[0565] Compounds A and B, as well as idebenone, were not tested in this assay. The data presented in Table 1 indicate that omaviron was inactive in this assay, but valeronone was active. Of the tested compounds, C-H, only compound J was essentially inactive, although none of the tested compounds were as active as valeronone. In summary, valeronone and compounds C-I and K were found to have a protective effect on Friedreich's ataxia fibroblasts when exposed to the toxic effects of RSL-3.

[0566] Discussion - Both BSO and RSL-3 are frequently used to induce a regulated cell death pathway called ferroptosis. Ferroptosis is thought to require the combined activity of iron-catalyzed oxidative stress and lipid peroxidation and has been described in cell and animal models of a variety of neurodegenerative diseases, including Friedreich's ataxia, Huntington's disease, Parkinson's disease, and Alzheimer's disease. Compounds that are active in both assays should theoretically have strong anti-ferroptosis activity. Surprisingly, the reference compound omaviron showed anti-ferroptosis activity in the BSO assay, but not in the RSL-3 assay. These data suggest that the downstream mechanisms of ferroptosis can be differentially regulated based on the experimental insult, and some compounds, such as omaviron, may be ineffective in all cases. Notably, when BSO or RSL3 were used as the initiating stimulus, the results for compounds CI and K were favorable in inhibiting ferroptotic cell death, thereby distinguishing these compounds from omaviron and idebenone.

[0567] Example 15: Rotenone Oximeter Assay (High-Resolution Respirometry of Intact HepG2 Cells)

[0568] An Oximeter-2k (O2k, OROBOROS INSTRUMENTS, Austria) was used to measure respiration in intact cells. Respirometry was performed in Dulbecco's Modified Eagle Medium (DMEM) high glucose without supplements. All experiments were performed at 37°C.

[0569] HepG2 cells (ATCC collection code HB-8065 TM ) in 10cm 2 Cells were cultured in DMEM high glucose medium supplemented with 10% fetal bovine serum (FBS), 100 units / mL penicillin, and 100 μg / mL streptomycin in culture dishes until approximately 90% confluence was achieved. Immediately before respirometry, cells were washed with medium without FBS, trypsinized, and resuspended in DMEM high glucose without FBS.

[0570] The final concentration of intact cells in the O2k chamber was 0.5·10 6 After respiration stabilizes, rotenone, a complex I inhibitor, is added at a final concentration of 1 μM to inhibit electron flux through complex I. Then, the test compound is added at a final concentration of 10 μM, and changes in intact cell respiration rate are monitored. An increase in respiratory rate indicates that complex I bypass is occurring.

[0571] The data presented in Table 1 indicate that all compounds CK were active in this assay, although compound J was the least active. Compounds BC were active in the rotenone ATP assay. Vasquinone and omaviron were inactive in both this assay and the rotenone ATP assay—thus indicating that vasquinone and omaviron do not possess Complex I bypassing ability. Idebenone was active in this assay (and scored the highest), but was only very weakly active in the BSO assay—specifically, even at the highest dose evaluated (3 μM), an EC50 could not be calculated because 50% rescue was achieved. In summary, all of the new test compounds tested in this assay (except compound A—which was not tested in any Complex I bypassing assay) were found to exhibit rather potent, marginal Complex I bypassing activity.

[0572] Both the BSO assay (or RSL-3 assay) and either of the complex I bypass assays (i.e., the rotenone ATP assay or the rotenone ATP assay) were evaluated. Discussion of the significance of high scores in the ketone oxygraph assay:

[0573] Compounds active in both the BSO (or RSL-3) ferroptosis assay and the Complex I bypass assay (i.e., the rotenone ATP assay or the rotenone oxygraph assay) are considered to have unique and potent polypharmacology. or have the ability to bypass BSO-induced cell death (vatiquinone, omaviron) or to restore ATP production when inhibiting complex I (idebenone). However, none of these benchmark compounds have Two types Significantly, the present invention has discovered and characterized a number of compounds with dual activities (e.g., compounds BI and K (and, given the trends in the data in Table 1, it is expected that their closely related analogs, such as compounds M, N, O, P, and Q, will have similar polypharmacology)), and it is believed that these compounds will provide better efficacy than therapeutic approaches targeting one pathway alone in indications where ferroptosis / lipid peroxidation-driven cell death coexists with impaired bioenergetics due to dysfunctional Complex I activity (e.g., Friedreich's ataxia).

[0574]

[0575]

[0576] Example 16: Determination of log D ("LogD") at pH 7.4

[0577] The octanol / buffer distribution coefficient ("LogD") at pH 7.4 can be measured as follows. A phosphate buffer at pH 7.4 was prepared by combining 50 mL of a 0.2 M KH2PO4 solution with 150 mL of distilled HO and then adjusting to pH 7.4 with 10 N NaOH. In triplicate incubations of each target compound, 15 μL of a 10 mM solution of the compound in DMSO was added to a test tube containing 0.75 mL of n-octanol and 0.75 mL of pH 7.4 phosphate buffer. These samples were gently mixed on a tabletop rotator for 1 hour at room temperature (23°C). The tubes were then removed from the rotator and the aqueous and organic phases were separated for 1 hour. The concentrations of the compound (both ionized and non-ionized) for each incubation and the log D values ​​calculated therefrom were determined, with the final log D for a specific compound being the average log D of the three log D values.

[0578] Equivalent solutions

[0579] The application should not be limited to the specific embodiments described in this application, and the embodiments are intended to be a single illustration of the individual aspects of the technology. Many modifications and variations of the technology can be made without departing from its spirit and scope, which will be obvious to those skilled in the art. Functionally equivalent methods and instruments within the scope of the technology, in addition to those listed herein, will be obvious to those skilled in the art from the above description. Such modifications and variations are intended to fall within the scope of the appended claims. The application is only limited by the terms of the appended claims and the full scope of equivalents granted by such claims. It should be understood that the application is not limited to specific methods, reagents, compounds, compositions or biological systems, which may of course be different. It should also be understood that the terms used herein are only used to describe the purpose of specific embodiments and are not intended to be limited.

[0580] In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0581] As will be understood by those skilled in the art, for any and all purposes, particularly in providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be readily identified as fully descriptive and enables the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, and so forth. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, a middle third, and an upper third, and so forth. As will also be understood by those skilled in the art, all language such as "at most," "at least," "greater than," "less than," and the like includes the referenced number and refers to a range that can subsequently be broken down into the subranges discussed above. Finally, as will be understood by those skilled in the art, a range includes each individual member. Thus, for example, a group consisting of 1-3 cells refers to groups consisting of 1, 2, or 3 cells. Similarly, a group consisting of 1-5 cells refers to groups consisting of 1, 2, 3, 4, or 5 cells, and so forth.

[0582] All patents, patent applications, provisional applications, and publications mentioned or cited herein, including all figures and tables, are incorporated by reference in their entirety to the extent they do not conflict with the explicit teachings of this specification. Other embodiments are set forth in the following claims.

Claims

1. A compound having the formula of Compound K, or a pharmaceutically acceptable salt or tautomer thereof:

2. A compound having the formula of Compound C, or a pharmaceutically acceptable salt or tautomer thereof:

3. A compound having the formula of Compound E, or a pharmaceutically acceptable salt or tautomer thereof:

4. A compound having the formula of Compound F, or a pharmaceutically acceptable salt or tautomer thereof:

5. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or tautomer thereof, in the preparation of a medicament for treating or preventing Friedreich's ataxia or signs or symptoms of decreased tataxin levels or activity in a subject in need thereof.

6. The use according to claim 5, wherein The subject exhibits reduced expression levels of frataxin compared to normal control subjects.

7. The use according to claim 5 or 6, wherein The compound is administered daily for 6 weeks or longer.

8. The use according to claim 5 or 6, wherein The compound is administered daily for 12 weeks or longer.

9. The use according to claim 5 or 6, wherein The subject has been diagnosed with Friedreich's ataxia.

10. The use according to claim 9, wherein The symptoms of Friedreich's ataxia include one or more of the following: muscle weakness, loss of coordination, impaired vision, impaired hearing, slurred speech, spinal curvature, diabetes, and a heart condition.

11. The use according to claim 5 or 6, wherein The subject is a human.

12. The use according to claim 5 or 6, wherein The compounds are administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

13. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or tautomer thereof, in the preparation of a medicament for reducing mitochondrial iron in a mammalian subject having or suspected of having Friedreich's ataxia.

14. The use according to claim 13, wherein The mammalian subject has decreased expression of frataxin compared to a normal control subject.

15. The use according to claim 13 or 14, wherein The compound is administered daily for 6 weeks or longer.

16. The use according to claim 13 or 14, wherein The compound is administered daily for 12 weeks or longer.

17. The use according to claim 13 or 14, wherein The subject has been diagnosed with Friedreich's ataxia.

18. The use according to claim 17, wherein The Friedreich's ataxia includes one or more of the following: muscle weakness, loss of coordination, impaired motor control, impaired vision, impaired hearing, slurred speech, spinal curvature, diabetes, and a heart condition.

19. The use according to claim 13 or 14, wherein The subject is a human.

20. The use according to claim 13 or 14, wherein The compounds are administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

21. Use of a compound or composition for the preparation of a medicament for treating or preventing Friedreich's ataxia in a subject in need thereof, wherein: The compound or composition comprises a therapeutically effective amount of the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or tautomer thereof.

22. The use according to claim 21, wherein The agent is effective to increase or maintain the level of ataxin in a subject suspected of having Friedreich's ataxia.

23. The use according to claim 21, wherein The agent is effective in inhibiting a decrease in ataxin levels in a subject suspected of having Friedreich's ataxia.

24. The use according to any one of claims 21 to 23, wherein The agent is effective in treating one or more symptoms of Friedreich's ataxia selected from the group consisting of muscle weakness, loss of coordination, impaired vision, impaired hearing, slurred speech, spinal curvature, diabetes, and a heart condition.

25. The use according to any one of claims 21 to 23, wherein The agent is effective when administered daily for 6 weeks or longer.

26. The use according to any one of claims 21 to 23, wherein The agent is effective when administered daily for 12 weeks or longer.

27. Use of a compound or composition for the preparation of a medicament for increasing the level of frataxin expression in a mammalian subject compared to a normal control subject, wherein: The compound or composition comprises a therapeutically effective amount of the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or tautomer thereof.

28. The use according to claim 27, wherein The agent is effective when administered daily for 6 weeks or longer.

29. The use according to claim 27, wherein The agent is effective when administered daily for 12 weeks or longer.

30. The use according to any one of claims 27 to 29, wherein The agent is effective to increase the level of ataxin in a subject diagnosed with Friedreich's ataxia.

31. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or tautomer thereof, in the preparation of a medicament for reducing or inhibiting ferroptosis in a mammalian subject having or suspected of having Friedreich's ataxia.

32. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or tautomer thereof, in the preparation of a medicament for treating Complex I deficiency in a mammalian subject in need thereof, wherein The compounds had calculated LogDs ranging from 2 to 7, inclusive.

33. A composition prepared by dissolving the compound of any one of claims 1 to 4 in a solvent.

34. A preparation or medicament comprising the composition of claim 33.

35. A formulation or medicament comprising a compound as claimed in any one of claims 1 to 4.

36. Use of the composition of claim 33, the formulation or the medicament of claim 34 or 35 in the preparation of a medicament for treating one or more symptoms of Friedreich's ataxia in a subject.

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