Quinone analogue, hydroquinone analogue and naphthoquinone analogue for treatment of mitochondrial disease

Abstract

To provide means for preventing, ameliorating and / or treating mitochondrial diseases such as Friedreich's ataxia and / or reducing the severity of such diseases.SOLUTION: The present disclosure provides therapeutic compositions (i.e., therapeutic agents) and methods of preventing or treating Friedreich's ataxia in a mammalian subject, reducing risk factors, signs and / or symptoms associated with Friedreich's ataxia (e.g., Complex I deficiency), and / or reducing the likelihood or severity of Friedreich's ataxia. The present disclosure further provides novel intermediates for the production of the therapeutic compositions and related reduced forms of the therapeutic compositions, which reduce forms may also be used as therapeutic agents (or prodrugs of the therapeutic agent(s)).SELECTED DRAWING: Figure 4

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 911,069, filed October 4, 2019, and U.S. Provisional Patent Application No. 62 / 991,525, filed March 18, 2020, each of which is incorporated herein by reference in its entirety for any purpose.

[0002] This 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. Additionally, this application relates to 1) methods for producing novel therapeutic compounds and related intermediates (e.g., chromans (benzodihydropyrans), quinones, hydroquinones, benzoquinones, and hydroxybenzoquinones), and / or 2) administering an effective amount of the novel compounds disclosed herein, alone or in combination with one or more other therapeutic agents, to a subject suffering from Friedreich's ataxia or other mitochondrial diseases. [Background technology]

[0003] introduction The following description is provided to aid the reader's understanding and is not an admission that the information provided or references cited are prior art to the compositions and methods disclosed herein. Friedreich's ataxia (FA) is a fatal, monogenic, autosomal recessive disorder caused by mutations in the gene encoding the nuclear-encoded mitochondrial protein frataxin. FA affects tissues of both the peripheral and central nervous systems, including the dentate nucleus, Clark's columns, spinocerebellar tracts, and dorsal root ganglia. Progressive degeneration of these tissues leads to worsening ataxia, with most patients losing the ability to walk independently by their 20s. The FXN gene encodes the protein frataxin, an iron-binding protein responsible for the formation of iron-sulfur clusters. One consequence of frataxin deficiency is mitochondrial iron overload.

[0004] Frataxin is a highly conserved iron-binding protein. Human frataxin is synthesized as a 210 amino acid precursor that is imported into mitochondria via a mitochondrial targeting signal contained in the N-terminus. The frataxin precursor is then cleaved to yield the mature 14 kDa protein (residues 81–210). Frataxin electrostatically binds both Fe2+ and Fe3+ ions and acts as an iron chaperone during Fe-S cluster assembly. Frataxin directly binds to the central Fe-S cluster assembly complex, which consists of the Nfs1 enzyme and the Isu scaffold protein. Nfs1 is a cysteine ​​desulfurase used in the synthesis of sulfur bioorganic derivatives, and Isu is a temporary scaffold protein onto which Fe-S clusters assemble. Frataxin increases the efficiency of Fe-S cluster formation, which is required for activating the mitochondrial Krebs cycle enzyme aconitase. Frataxin also plays a role in mitochondrial iron storage and heme biosynthesis through the incorporation of mitochondrial iron into protoporphyrin (PIX). Loss of frataxin function leads to disruption of 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 dopamine neuronal cells from MPTP-induced toxicity in a mouse model of Parkinson's disease.

[0005] Ferroptosis is a type of iron-dependent cell death that is biologically distinct from apoptosis. It is generally accompanied by the accumulation of large amounts of iron and lipid peroxidation during cell death. Ferroptosis-inducing factors directly or indirectly affect glutathione peroxidase through various pathways, leading to a decrease in antioxidant capacity and the accumulation of lipid reactive oxygen species (ROS) in cells, ultimately resulting in oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, including tumors, neurological disorders, ischemia-reperfusion injury, kidney injury, and hematological disorders. Decreased expression of frataxin (FXN) is associated with mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. Recent studies have shown that frataxin, 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 the production of lipid peroxides generated by lipoxygenase enzymes such as lipoxygenase-15. Thus, targeting lipoxygenase-15 provides a therapeutic target for Friedreich's ataxia. Mitochondrial iron overload leads to impaired mitochondrial metabolism and defects in the mitochondrial respiratory chain. Defects in the mitochondrial respiratory chain lead to increased free radical generation and oxidative damage, which may be a mechanism for impairing cell viability. Some evidence suggests that frataxin may detoxify ROS through activation of glutathione peroxidase and elevation of thiols (see, e.g., Calabrese et al., Journal of the Neurological Sciences, 233(1): 145-162 (June 2005)).

[0006] Friedreich's ataxia occurs when the FXN gene contains an amplified intronic GAA repeat. Mutant FXN genes contain an expansion of three GAA repeats in the first intron, and point mutations have also been detected in some families. Because the defect is located within the intron, it is removed from the mRNA transcript during transcription and translation, and the mutant FXN gene does not result in the production of an abnormal protein. Instead, the mutation results in gene silencing, i.e., the mutation reduces transcription of the gene. Symptoms typically begin between the ages of 5 and 15, but may appear in adults. The first symptom is usually gait ataxia or difficulty walking. The ataxia gradually worsens and slowly spreads to the arms and torso. There is often loss of sensation in the limbs, which may spread to other parts of the body. Other features include loss of tendon reflexes, particularly in the knees and ankles. Most patients with Friedreich's ataxia develop scoliosis, which often requires surgical intervention for treatment. Dysarthria (slow and slurred speech) develops and progressively worsens. Many patients with late-stage Friedreich's ataxia experience hearing and vision loss.

[0007] Heart disease is also often associated with Friedreich's ataxia, including hypertrophic cardiomyopathy, myocardial fibrosis (the formation of fibrous tissue in the heart muscle), and heart failure. Heart rhythm abnormalities, such as tachycardia (rapid heart rate) and heart block (impaired conduction of impulse waves within the heart), are also common. Other symptoms that may occur include chest pain, shortness of breath, and palpitations. Many patients with Friedreich's ataxia experience a slow decline in vision in the later stages of the disease. The most common ocular symptom of Friedreich's ataxia is optic neuropathy. Some suffer from severe / catastrophic vision loss. Approximately 20 percent of people with Friedreich's ataxia develop carbohydrate intolerance, and 10 percent develop diabetes. Most people with Friedreich's ataxia tire easily and require more rest and longer recovery times from common illnesses such as colds and flu. The rate of progression varies from person to person. Generally, patients become wheelchair-bound within 10 to 20 years after the first symptoms appear, and in the later stages of the disease, they can become severely disabled. Friedreich's ataxia is associated with a shortened life expectancy, and heart disease is the leading cause of death.

[0008] The five enzyme complexes of the oxidative phosphorylation (OXPHOS) system (i.e., complex I, complex II, complex III, complex IV, and complex V) reside in the mitochondrial membrane, and complex I deficiency, which results in reduced levels (and reduced production) of adenosine triphosphate (ATP), is thought to be associated with Friedreich's ataxia. Indeed, it has been suggested that reduced frataxin expression in cells from Friedreich's ataxia patients increases intracellular, non-bioavailable iron stores, thereby leading to increased free radical generation, increased oxidative damage to cells, and reduced complex I activity and associated reduced 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).

[0009] There is no known cure for Friedreich's ataxia. Generally, treatment involves treating symptoms. Because patients with Friedreich's ataxia are at risk of developing heart disease, these patients are prescribed medications such as beta-blockers, ACE inhibitors, and / or diuretics. Because damage caused by oxidative stress is thought to contribute to the progression of Friedreich's ataxia, patients diagnosed with or suspected of having Friedreich's ataxia are often given a combination of antioxidants, such as vitamin E, idebenone, and coenzyme Q10. These compounds are being used in various clinical trials. Recently, EPI-743 (a benzoquinone compound also known as vatiquinone) is in Phase 2 clinical trials, has not yet begun Phase 3 clinical trials for the treatment of intractable epilepsy, and has been granted orphan drug and fast track status by the U.S. Food and Drug Administration (FDA). Vatiquinone is thought to reduce oxidative stress and improve mitochondrial function. Omaveloxolone is a synthetic oleanatriterpenoid known to exhibit second-generation antioxidant and anti-inflammatory activity. Omaveloxolone is currently in Phase 2 clinical trials for the treatment of various indications, including Friedreich's ataxia, mitochondrial myopathies, and ophthalmologic conditions / diseases. Although several other therapies for the treatment of Friedreich's ataxia are currently in clinical trials, no drugs are FDA-approved. Thus, there remains a need for better drug candidates to address the needs of patients diagnosed with Friedreich's ataxia. Summary of the Invention

[0010] In one aspect, there are provided compounds of formula EF, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein E is 21 or 22: [ka] and F is 13, 14, 15, 16, 17, 18, 19 or 20: [ka] where J is O, S or NR 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13 )—; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each X independently represents a group of the formula -(CR 12 R 13 each Y is independently absent or a group of the formula -(CR 12 R 13 each Z is independently a group of the formula -(CR 14 )-; each of R1, R2, and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic ring or heteroaromatic ring, or a 6-membered heterocyclic ring; each R8 and R9 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl; or R8 and R9 together form a 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic ring; R 10 is H, D, F, Cl, Br, I, C-C alkyl or C-C alkoxy; R 11 is H, D or C1-C6 alkyl; R 12 , R 13 and R 14 each is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 20 is H, D, F or C1-C 12 alkyl; each R21 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl; n is an integer from 0 to 12; and *** indicates the point of attachment of E to F, and ** indicates the point of attachment of F to E; and further provided that (i) any of the formulae 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 in the formula (I) contains at least one fluorine atom; and / or (ii) R8 and R9 together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring. In any embodiment herein, E may be 21 and F may be 13, 14, 19, or 20. In any embodiment herein, E may be 22 and F may be 13, 14, 19, or 20. In any embodiment herein, E may be 21 and F may be 15, 16, 17, or 18. In any embodiment herein, E may be 22 and F may be 15, 16, 17, or 18. In any embodiment herein, J may be O. In any embodiment herein, J may be S. In any embodiment herein, J may be NR 11 In any embodiment herein, J may be O or NR 11and K may be absent. In some embodiments, each of K and L 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 of K and L is independently -(CH)-, -(CD)-, -(CF)-, -(CH(CH))-, -(CD(CD))-, -(CF(CF))-, -(C(CH))-, -(C(CD))-, -(C(CF))-, -(CH(OCH))-, -(CD(OCD))-, -(CF(OCF))-, or -(C(OCH))-. In some embodiments, each of K and L is independently -(CH)-, -(CD)-, -(CHF)-, -(CF)-, -(CH(CH))-, -(CF(CF))-, -(C(CH))-, or -(C(CF))-.In 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, each of R1, R2, and R3 is independently H, D, Cl, 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(C F3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OC D(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -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, -CH2CH2 CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF 2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, -OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2 , -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments, each of R1, R2, and R3 is independently H, D, Cl, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3), -C(CD3), -C(CF3), -OC(CH3), -OC(CD3), -OC(CF3), -CH2CH3, -OCH2CH3, or -CH(CH. 3)2. In some embodiments, each of R1, R2, and R3 is independently H, F, —CH3, —OCH3, —CH2F, —CHF2, —CF3, —OCF3, —C(CH3)3, —C(CF3)3, —CH2CH3, —OCH2CH3, or —CH(CH3)2. In some embodiments, J is O; each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-; and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments, 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 R1 and R2 together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments, E is 21A, 21B, 21C, 21D, 21E, or 21F: [ka] where R 16 and R 17 each is independently 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, -CH(CH3)2, -OCH(CH3)2, -C(CH3)3, or -O(CH3)3; and J" is O, S, or NR 18 where R 18is H, D, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R3 is H, D, Cl, 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, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -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, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF 2CH2CH3, -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, -OCF2CF2CF3 or -OCF(CF2CF3)2; and when W is C (carbon), Each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, and -CH(CH3)2, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently selected from absent, H, D, methyl, ethyl, isopropyl, and t-butyl.In some embodiments, 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 when W is C (carbon), then Each of R, R, R, and R bonded thereto is independently selected from H, D, F, Cl, -CH, -OCH, -CHF, -CHF, -CF, -OCF, -CHCH, and -CH(CH), and when W is N (nitrogen), each of R, R, R, and R bonded thereto is independently selected from H, D, methyl, and ethyl. In some embodiments, each W is C, and each of R, R, R, and R is independently H, D, Cl, F, -CH, -OCH, -CHF, -CHF, -CF, or -OCF.

[0011] In any embodiment herein, each of 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(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, It may also be -C(CD3)3, -C(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some embodiments, each of R8 and R9 may independently be 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(CH2CH3)2, -CF2CF2CF3, or -CF(CF2CF3)2.

[0012] In any embodiment herein, R and R together can be 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 or 47: [ka] In any embodiment herein, R 10is 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, -OCD(CD3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC(CD3) 3, -OC(CF3), -C(CH)(CF), -C(CH)(CF), -OC(CH)(CF), -OC(CH)(CF), -CHCHCH, -CH(CHCH), -CDCDCD, -CD(CDCD), -CFCFCF, -CF(CFCF), -C(CHCH), -C(CDCD), -C(CFCF), -OCHCHCH, -OCH(CHCH), -OCDCDCD, -OCD(CDCD), -OCFCFCF, or -OCF(CFCF). 10 is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2. In any embodiment herein, R 11 may be H, methyl or ethyl. In any embodiment herein, R 12 , R 13 or R 14 may independently be 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. 12 , R 13 or R 14is independently H, D, F, -CH, -OCH, -CD, -OCD, -CHF, -OCHF, -CHF, -OCHF, -CF, -OCF, -CHCH, or -OCHCH. 20 may be H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In any embodiment herein, each R 21 may independently be H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3. In any embodiment herein, n may be 0, 1, 2, 3, or 4.

[0013] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

[0014] In one aspect, there is provided a compound of formula CD, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein C is 11 or 12: [ka] and D is 13, 14, 15, 16, 17, 18, 19 or 20: [ka] where J' is OH, SH or NH-R 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13)—; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each X independently represents a group of the formula -(CR 12 R 13 each Y is independently absent or a group of the formula -(CR 12 R 13 each Z is independently a group of the formula -(CR 14 )-; each of R1, R2 and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy; or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic ring or heteroaromatic ring or a 6-membered heterocyclic ring; each of R8 and R9 is independently H, D, F, Cl, Br, I or C1-C4 alkyl; or R8 and R9 together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring; R 10 is H, D, F, Cl, Br, I, C-C alkyl or C-C alkoxy; R 11 is H, D or C1-C6 alkyl; R 12 , R 13 and R 14each is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 19 is H, C1-C4 alkyl or benzyl; R 20 is H, D, F, or C1-C 12 alkyl; each R 21 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl; n is an integer from 0 to 12, inclusive; and *** is the attachment point of C to D, and ** is the point of attachment of D to C; and further provided that (i) any of the formulae 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 the formula (ii) contains at least one fluorine atom; and / or (ii) R8 and R9 together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring.

[0015] In any embodiment herein, C may be 11 and D may be 13, 14, 19, or 20. In any embodiment herein, C may be 12 and D may be 13, 14, 19, or 20. In any embodiment herein, C may be 11 and D may be 15, 16, 17, or 18. In any embodiment herein, C may be 12 and D may be 15, 16, 17, or 18. In any embodiment herein, J' may be OH. In any embodiment herein, J' may be SH. In any embodiment herein, J' may be NH-R 11 In any embodiment herein, J' may be OH or NH-R 11and K may be absent. In some embodiments, each of K and L 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 of K and L is independently -(CH)-, -(CD)-, -(CF)-, -(CH(CH))-, -(CD(CD))-, -(CF(CF))-, -(C(CH))-, -(C(CD))-, -(C(CF))-, -(CH(OCH))-, -(CD(OCD))-, -(CF(OCF))-, or -(C(OCH))-. In some embodiments, each of K and L is independently -(CH)-, -(CD)-, -(CHF)-, -(CF)-, -(CH(CH))-, -(CF(CF))-, -(C(CH))-, or -(C(CF))-.In 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, each of R1, R2, and R3 is independently H, D, Cl, 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(C F3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OC D(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -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, -CH2CH2 CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF 2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, -OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2 , -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments, each of R1, R2, and R3 is independently 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, each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2.In some embodiments, J' is OH; each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-; and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments, R3 is H, D, Cl, F, -CH3, -OCH3, -CD3, -OCD3, -CF3, -OCF3, -C(CH3), -C(CD3), -C(CF3), -OC(CH3), -OC(CD3), -OC(CF3), -CH2CH3, -OCH2CH3, or -CH(CH3), and R1 and R2 together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments, C is 11A, 11B, 11C, 11D, 11E, or 11F: [ka] where R 16 and R 17 each is independently 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, -CH(CH3)2, -OCH(CH3)2, -C(CH3)3, or -O(CH3)3; and J" is OH, SH, or NH-R 18 where R 18is H, D, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R3 is H, D, Cl, 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, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -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, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -C F2CH2CH3, -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, -OCF2CF2CF3 or -OCF(CF2CF3)2; and when W is C (carbon), is selected from H, D, F, Cl, Br, I, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, and -CH(CH3)2; and when W is N (nitrogen), each of R4, R5, R6, and R7 attached thereto is independently selected from H, D, methyl, ethyl, isopropyl, and t-butyl.In some embodiments, 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 when W is C (carbon), wherein each of R, R, R, and R bonded thereto is independently H, D, F, Cl, -CH, -OCH, -CHF, -CHF, -CF, -OCF, -CHCH, or -CH(CH), and when W is N (nitrogen), each of R, R, R, and R bonded thereto is independently absent or selected from H, D, methyl, and ethyl. In some embodiments, each W is C (carbon), and each of R, R, R, and R is independently H, D, Cl, F, -CH, -OCH, -CHF, -CHF, -CF, or -OCF.

[0016] In any embodiment herein, each of 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(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, It may also be -C(CD3)3, -C(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some embodiments, each of R and R is independently H, F, -CH, -CHF, -CHF, -CF, -CHCH, -CH(CH), -CFCH, -CHCF, -CH(CF), -CFCF, -CF(CF), -C(CH), -C(CF), -CHCHCH, -CH(CHCH), -CFCFCF, or -CF(CFCF). In any embodiment herein, R and R together are 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47: [ka] wherein # indicates the point of attachment of the carbocyclic or heterocyclic ring to the remainder of the compound.

[0017] In any embodiment herein, R 10is 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, -OCD(CD3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC(CD3) 3, -OC(CF3), -C(CH)(CF), -C(CH)(CF), -OC(CH)(CF), -OC(CH)(CF), -CHCHCH, -CH(CHCH), -CDCDCD, -CD(CDCD), -CFCFCF, -CF(CFCF), -C(CHCH), -C(CDCD), -C(CFCF), -OCHCHCH, -OCH(CHCH), -OCDCDCD, -OCD(CDCD), -OCFCFCF, or -OCF(CFCF). 10 is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2. In any embodiment herein, R 11 may be H, methyl or ethyl. In any embodiment herein, R 12 , R 13 or R 14 may independently be 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. 12 , R 13 or R 14is independently H, D, F, -CH, -OCH, -CD, -OCD, -CHF, -OCHF, -CHF, -OCHF, -CF, -OCF, -CHCH, or -OCHCH. 19 may be H. In any embodiment herein, R 19 may be -CH3. In any embodiment herein, R 19 may be -CH2CH3. In any embodiment herein, R 19 may be —C(CH3)3. In any embodiment herein, R 19 may be an unsubstituted or substituted benzyl group. In any embodiment herein, R 20 may be H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In any embodiment herein, each R 21 may independently be H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3. In any embodiment herein, n may be 0, 1, 2, 3, or 4.

[0018] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

[0019] In one embodiment, a compound of formula AB, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, or a compound of formula AH, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein: A is 1, 2, 3 or 4: [ka] and B is 5, 6, 7 or 8: [ka] and H is 25: [ka] where J is O, S or NR 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13 )—; each Q independently represents a group of the formula —(CR 12 R 13 )- group, O, or Si, provided that each O and each Si is not directly bonded to an O or an S; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each X independently represents a group of the formula -(CR 12 R13 each Y is independently absent or a group of the formula -(CR 12 R 13 )-; each Z is independently a group of the formula -(CR 14 )-; each of R1, R2 and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy; or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic ring or heteroaromatic ring or a 6-membered heterocyclic ring; each of R8 and R9 is independently H, D, F, Cl, Br, I or C1-C4 alkyl; or R8 and R9 together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring; R 10 are H, D, F, Cl, Br, I, C-C alkyl or C-C alkoxy; R, R and R 10 each of R' is independently C1-C4 alkyl, or R8' and R9' together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R 11 is H, D or C1-C6 alkyl; R 12 , R 13 and R 14 each is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 15 is H, C1-C4 alkyl or PG, where PG is a phenol protecting group; R 20 is H, D, F or C1-C 12 alkyl; each R 21 are independently H, D, F, Cl, Br, I, or C1-C4 alkyl; n is an integer from 0 to 12, inclusive; p is an integer from 0 to 20, inclusive; and *** indicates the point of attachment A of A to B or to H, and ** indicates the point of attachment of B to A or H to A; provided further that (i) any of the formulae R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 12 , R 13 , R 14 , R 20 or R 21at least one group in the formula (ii) contains at least one fluorine atom; and / or (ii) R8 and R9 together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic ring or (ii) a heterocyclic ring.

[0020] In any embodiment herein, A may be 1 or 3 and B may be 5 or 8. In any embodiment herein, A may be 2 or 4 and B may be 5 or 8. In any embodiment herein, A may be 1 or 3 and B may be 6 or 7. In any embodiment herein, A may be 2 or 4 and B may be 6 or 7. In any embodiment herein, J may be O. In any embodiment herein, J may be S. In any embodiment herein, J is NR 11 In any embodiment herein, J may be O or NR 11and K may be absent. In some embodiments, each of K and L 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 of K and L is independently -(CH)-, -(CD)-, -(CF)-, -(CH(CH))-, -(CD(CD))-, -(CF(CF))-, -(C(CH))-, -(C(CD))-, -(C(CF))-, -(CH(OCH))-, -(CD(OCD))-, -(CF(OCF))-, or -(C(OCH))-. In some embodiments, each of K and L is independently -(CH)-, -(CD)-, -(CHF)-, -(CF)-, -(CH(CH))-, -(CF(CF))-, -(C(CH))-, or -(C(CF))-.In 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, each of R1, R2, and R3 is independently H, D, Cl, 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(C F3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OC D(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -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, -CH2CH2 CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF 2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, -OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2 , -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments, each of R1, R2, and R3 is independently 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, each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2.In some embodiments, J is O; each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-; and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments, 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 R1 and R2 together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments, A is 1A, 1B, 1C, 1D, 1E, 1F, 3A, 3B, 3C, 3D, 3E, or 3F: [ka] and R 16 and R 17 each is independently 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, -CH(CH3)2, -OCH(CH3)2, -C(CH3)3, or -O(CH3)3; and J" is O, S, or NR 18 where R 18is H, D, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R3 is H, D, Cl, 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, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -OCH(CF3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC(CD3)3, -OC(CF 3)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, -OCF2CF2CF3 or -OCF(CF2CF3)2; and when W is C (carbon), When W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently H, D, F, Cl, Br, I, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2; and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently selected from absent, H, D, methyl, ethyl, isopropyl, and t-butyl.In some embodiments, 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 when W is C (carbon), Each of R, R, R, and R bonded thereto is independently selected from H, D, F, Cl, -CH, -OCH, -CHF, -CHF, -CF, -OCF, -CHCH, and -CH(CH), and when W is N (nitrogen), each of R, R, R, and R bonded thereto is independently absent or selected from H, D, methyl, and ethyl. In some embodiments, each W is C (carbon), and each of R, R, R, and R is independently H, D, Cl, F, -CH, -OCH, -CHF, -CHF, -CF, or -OCF.

[0021] In any embodiment herein, each of 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(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, It may also be -C(CD3)3, -C(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some embodiments, each of 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(CH2CH3)2, -CF2CF2CF3, or -CF(CF2CF3)2.

[0022] In any embodiment herein, R8 and R9 together represent 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 and 47: [ka] wherein # indicates the point of attachment of the carbocyclic or heterocyclic ring to the remainder of the compound. 10is 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, -OCD(CD3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC(CD3) 3, -OC(CF3), -C(CH)(CF), -C(CH)(CF), -OC(CH)(CF), -OC(CH)(CF), -CHCHCH, -CH(CHCH), -CDCDCD, -CD(CDCD), -CFCFCF, -CF(CFCF), -C(CHCH), -C(CDCD), -C(CFCF), -OCHCHCH, -OCH(CHCH), -OCDCDCD, -OCD(CDCD), -OCFCFCF, or -OCF(CFCF). 10 is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2. In any embodiment herein, R 11 may be H, methyl or ethyl. In any embodiment herein, R 12 , R 13 or R 14 may independently be 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. 12 , R 13 or R 14is independently H, D, F, -CH, -OCH, -CD, -OCD, -CHF, -OCHF, -CHF, -OCHF, -CF, -OCF, -CHCH, or -OCHCH. 15 may be H. In any embodiment herein, R 15 may be -CH3. In any embodiment herein, R 15 may be a silyl-based phenol protecting group. In any embodiment herein, R 15 may be a triphenylmethyl-based phenol protecting group. In any embodiment herein, R 15 may be an unsubstituted or substituted benzyl group.

[0023] In any embodiment herein, R 20 may be H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In any embodiment herein, each R 21 may independently be H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3. In any embodiment herein, n may be 0, 1, 2, 3, or 4.

[0024] In one embodiment, there is provided a compound of formula EG, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein E is 21 or 22: [ka] and G is 23 or 24: [ka] where J is O, S or NR 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13 )—; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each Q independently represents a group of the formula -(CR 12 R 13 )- group, O, or Si, with the proviso that each O and each Si is not directly bonded to O or S; each of R1, R2, and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; each of R8', R9', and R 10R' is independently C1-C4 alkyl; or R8' and R9' together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R 11 is H, D or C1-C6 alkyl; R 12 and R 13 each is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 20 is H, D, F, or C1-C12 alkyl; p is an integer from 0 to 20, inclusive; and *** indicates the point of attachment of E to G, and ** indicates the point of attachment of G to E.

[0025] In any embodiment herein, E is 21, J is O, K is -CH2-, L is -CH2-, and each of R1, R2, and R3 may be independently selected from H, D, F, -CH3, -OCH3, and -OCF3. 20 The chiral center at the carbon to which is attached may be in the S configuration, or R 20 The chiral center at the carbon to which is attached may be in the R configuration. In any embodiment herein, each Q may be -CH2-, or at least one Q may be O and each other Q may be -CH2-. In some embodiments, the compound has the formula Compound M-0: [ka] wherein each of R1, R2, and R3 is independently H, F, —CH3, —OCH3, —CH2CH3, —OCH2CH3, or —OCF3; p′ is an integer from 1 to 9, inclusive; and p″ is an integer from 1 to 9, inclusive. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

[0026] In one aspect, there is provided a compound of formula CG, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein C is 11 or 12: [ka] and G is 23 or 24: [ka] where J' is OH, SH or NH-R 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13 )—; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each Q independently represents a group of the formula -(CR 12 R 13)- group, O, or Si, with the proviso that each O and each Si is not directly bonded to O or S; each of R1, R2, and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; each of R8', R9', and R 10 R' is independently C1-C4 alkyl; or R8' and R9' together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R 11 is H, D or C1-C6 alkyl; R 12 and R 13 each is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 20 is H, D, F, or C1-C12 alkyl; p is an integer from 0 to 20, inclusive; and *** indicates the point of attachment of E to G, and ** indicates the point of attachment of G to E. In some embodiments, C is 11, J' is OH, and R 19 is H, K is —CH—, L is —CH—, and each of R, R, and R is independently selected from H, D, F, —CH, —OCH, and —OCF.

[0027] In any embodiment herein, R 20 The chiral center at the carbon to which is attached may be in the S configuration, or R 20 The chiral center at the carbon to which is attached may be in the R configuration. In any embodiment herein, each Q may be -CH2-, or at least one Q may be O and each other Q may be -CH2-. In some embodiments, the compound has the formula Compound M-3: [ka] wherein each of R1, R2, and R3 is independently H, F, —CH3, —OCH3, —CH2CH3, —OCH2CH3, or —OCF3; p′ is an integer from 1 to 9, inclusive; and p″ is an integer from 1 to 9, inclusive. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

[0028] In one embodiment, compounds are provided that include a substituted quinone or hydroquinone head group to which is covalently attached an aliphatic tail group that includes at least one chiral center, at least one hydroxyl group, and at least one silicon atom. In one aspect, the present technology provides a method for treating or preventing signs or symptoms of Friedreich's ataxia or decreased frataxin levels or activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any aspect or embodiment of the present technology disclosed herein (hereinafter collectively referred to as "compounds" or "compounds" of the present technology) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, the subject may exhibit a decreased level of frataxin expression compared to a normal control subject. In any embodiment herein, the compound may be administered daily for six weeks or more. In any embodiment herein, the compound may be administered daily for twelve weeks or more. In any embodiment herein, the subject may have been diagnosed with Friedreich's ataxia. In some embodiments, Friedreich's ataxia may include one or more of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems. In any embodiment herein, the subject may be human. In any embodiment herein, the compound may be administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0029] In one aspect, the present technology provides a method for reducing mitochondrial iron in a mammalian subject having or suspected of having Friedreich's ataxia, comprising administering to the subject a therapeutically effective amount of a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, the mammalian subject may have reduced frataxin expression compared to a normal control subject. In any embodiment herein, the compound may be administered daily for six weeks or more. In any embodiment herein, the compound may be administered daily for twelve weeks or more. In any embodiment herein, the subject may have been diagnosed with Friedreich's ataxia. In some embodiments, Friedreich's ataxia includes one or more of muscle weakness, incoordination, impaired motor control, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems. In any embodiment herein, the subject may be human. In any embodiment herein, the compound may be administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0030] In one aspect, the present technology provides a method for treating Complex I deficiency in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, the compound may be administered daily for six weeks or more. In any embodiment herein, the compound may be administered daily for twelve weeks or more. In any embodiment herein, the subject may have been diagnosed with Friedreich's ataxia. In some embodiments, Friedreich's ataxia includes one or more of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems. In any embodiment herein, the subject may be human. In any embodiment herein, the compound may be administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0031] In one aspect, provided is a method for reducing or inhibiting lipoxygenase-15 activity in a mammalian subject having or suspected of having Friedreich's ataxia, comprising administering to the subject a therapeutically effective amount of a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, the compound may be administered daily for six weeks or more. In any embodiment herein, the compound may be administered daily for twelve weeks or more. In any embodiment herein, Friedreich's ataxia may include one or more of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems. In any embodiment herein, the subject may be human. In any embodiment herein, the compound may be administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0032] In one aspect, a method for reducing or inhibiting ferroptosis in a mammalian subject having or suspected of having Friedreich's ataxia is provided, comprising administering to the subject a therapeutically effective amount of a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, the compound may be administered daily for six weeks or more. In any embodiment herein, the compound may be administered daily for twelve weeks or more. In any embodiment herein, Friedreich's ataxia may include one or more of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems. In any embodiment herein, the subject may be human. In any embodiment herein, the compound may be administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0033] In one aspect, the present technology provides a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in treating or preventing Friedreich's ataxia in a subject in need thereof. In any embodiment herein, the compound may be effective for increasing or maintaining frataxin levels in a subject suspected of having Friedreich's ataxia. In any embodiment herein, the compound may be effective for inhibiting a decline in frataxin levels in a subject suspected of having Friedreich's ataxia. In any embodiment herein, the compound may be effective for treating one or more symptoms of Friedreich's ataxia selected from the group consisting of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems. In any embodiment herein, the compound may be effective when administered daily for six weeks or more. In any embodiment herein, the compound may be effective when administered daily for twelve weeks or more.

[0034] In one aspect, the present technology provides a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in increasing frataxin expression levels in a subject in need thereof. In any embodiment herein, the compound may be effective when administered daily for 6 weeks or more. In any embodiment herein, the compound may be effective when administered daily for 12 weeks or more.

[0035] In one aspect, the present technology provides a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in treating Complex I deficiency in a subject in need thereof. In any embodiment herein, the compound may be effective when administered daily for 6 weeks or more. In any embodiment herein, the compound may be effective when administered daily for 12 weeks or more. In any embodiment herein, the compound may be effective for increasing intracellular adenosine triphosphate (ATP) levels in tissues of a subject diagnosed with Friedreich's ataxia.

[0036] In one aspect, the present technology provides a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in reducing or inhibiting lipoxygenase-15 activity in a mammalian subject having or suspected of having Friedreich's ataxia. In any embodiment herein, the compound may be effective when administered daily for 6 weeks or more. In any embodiment herein, the compound may be effective when administered daily for 12 weeks or more.

[0037] In one aspect, the present technology provides a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in reducing or inhibiting ferroptosis in a mammalian subject having or suspected of having Friedreich's ataxia. In any embodiment herein, the compound may be effective when administered daily for 6 weeks or more. In any embodiment herein, the compound may be effective when administered daily for 12 weeks or more.

[0038] In one aspect, there is provided a use of a composition in the preparation of a medicament for treating or preventing Friedreich's ataxia in a subject in need thereof, wherein the composition comprises a therapeutically effective amount of a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, the medicament may be effective for increasing or maintaining frataxin levels in a subject suspected of having Friedreich's ataxia. In any embodiment herein, the medicament may be effective for inhibiting a decline in frataxin levels in a subject suspected of having Friedreich's ataxia. In any embodiment herein, the medicament may be effective for treating one or more symptoms of Friedreich's ataxia selected from the group consisting of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems. In any embodiment herein, the medicament may be effective when administered daily for six weeks or more. In any embodiment herein, the medicament may be effective when administered daily for twelve weeks or more.

[0039] In one aspect, there is provided a use of a composition in the preparation of a medicament for increasing frataxin expression levels in a mammalian subject compared to a normal control subject, wherein the composition comprises a therapeutically effective amount of a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, the medicament may be effective when administered daily for 6 weeks or more. In any embodiment herein, the medicament may be effective when administered daily for 12 weeks or more. In any embodiment herein, the medicament may be effective for increasing frataxin levels in a subject diagnosed with Friedreich's ataxia.

[0040] In one aspect, there is provided a use of a composition in the preparation of a medicament for treating Complex I deficiency in a mammalian subject compared to a normal control subject, wherein the composition comprises a therapeutically effective amount of a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, the medicament may be effective when administered daily for 6 weeks or more. In any embodiment herein, the medicament may be effective when administered daily for 12 weeks or more. In any embodiment herein, the medicament may be effective for increasing intracellular adenosine triphosphate (ATP) levels in tissues of a subject diagnosed with Friedreich's ataxia.

[0041] In one aspect, there is provided a use of a composition in the preparation of a medicament for reducing or inhibiting lipoxygenase-15 activity in a mammalian subject having or suspected of having Friedreich's ataxia, said composition comprising a therapeutically effective amount of a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, the medicament may be effective when administered daily for 6 weeks or more. In any embodiment herein, the medicament may be effective when administered daily for 12 weeks or more.

[0042] In one aspect, there is provided a use of a composition in the preparation of a medicament for reducing or inhibiting ferroptosis in a mammalian subject having or suspected of having Friedreich's ataxia, wherein the composition comprises a therapeutically effective amount of a compound of the present technology, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, the medicament may be effective when administered daily for 6 weeks or more. In any embodiment herein, the medicament may be effective when administered daily for 12 weeks or more. [Brief explanation of the drawings]

[0043] [Figure 1A]FIG. 1A illustrates a partial chemical scheme for the preparation of the novel compositions disclosed herein. [Figure 1B] FIG. 1B is a continuation of the chemical scheme shown in FIG. 1A for the preparation of the novel compositions disclosed herein, in which one form of compound 216 (i.e., 216a) is the starting material for the preparation of compound 226a. [Figure 1C] FIG. 1C is a continuation of the chemical scheme shown in FIG. 1A for the preparation of the novel compositions of Formula I (and Formulas Ia-Ih). [Figure 1D] FIG. 1D is a continuation of the chemical scheme shown in FIG. 1B, in which compound 226a is converted to compositions of Formula II (including Formulas IIa-IId). [Figure 2A] FIG. 2A is an illustration of a partial chemical scheme for the preparation of the novel compositions disclosed herein. [Figure 2B] FIG. 2B is a continuation of the chemical scheme shown in FIG. 2A for the preparation of the novel compositions disclosed herein, in which one form of compound 316 (i.e., 316a) is the starting material for the preparation of compound 326a. [Figure 2C] FIG. 2C is a continuation of the chemical scheme shown in FIG. 2A for the preparation of novel compositions of Formula III (including Formulas IIIa-IIIh). [Figure 2D] FIG. 2D is a continuation of the chemical scheme shown in FIG. 2B, in which compound 316a is converted to compositions of Formula IV (including Formulas IVa-IVd). [Figure 3] FIG. 3 shows a chemical scheme for the preparation of intermediate compound 203 used / disclosed herein. [Figure 4] FIG. 4 is an illustration of a chemical scheme for the reduction of certain therapeutic compositions disclosed herein. [Figure 5] FIG. 5 is a graphical representation of data obtained for an analysis of the effects of various compounds disclosed herein on cells obtained from a patient confirmed to have Friedreich's ataxia. [Figure 6A]FIG. 6A is an illustration of various known heterocycles that can be used as starting materials in the methods for making the novel compounds disclosed herein. [Figure 6B] FIG. 6B is an illustration of various known heterocycles that can be used as starting materials in the methods for making the novel compounds disclosed herein. [Figure 6C] FIG. 6C is an illustration of various known heterocycles that can be used as starting materials in the methods for making the novel compounds disclosed herein. [Figure 7] FIG. 7 is a bar graph summarizing the results obtained for the Nrf-2 activation assay, comparing the activity of obameloxolone with the activity of various novel compounds disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0044] I. Chemical definition: 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, 7th Ed. endpapers. Furthermore, 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.

[0045] Abbreviations used herein have their conventional meanings in the chemical and biological arts. Chemical structures and formulas depicted herein are intended to conform to standard rules of chemical valency known in the chemical arts. When a range of values ​​is recited, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" is intended to encompass 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 moiety is referred to as "substituted," one or more of the hydrogen atoms of the group is replaced with a substituent. Possible "substituents" include, for example, one or more of (i) deuterium (D), fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atoms (F, Cl, Br, and I are each individually a "halogen" and F, Cl, Br, and I are collectively referred to as "halogen"); or (ii) 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., i.e., -OR"), nitro (i.e., -NO2) group, or amino (protected or unprotected, i.e., -NH2 or -NHPG, where PG is a protecting group). Other substituents such as azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carboxyl, silyl, ether, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, and the like are also contemplated. A group or moiety that is not substituted is unsubstituted.

[0046] Certain compounds of the present application may exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvated forms may exist, for example, because it is difficult or impossible to remove all of the solvent from the compound after synthesis. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present application. Certain compounds of the present application may exist in multiple crystalline or amorphous forms. Compounds of the present application may exist in various tautomeric forms. Certain compounds of the present application may exist in various salt forms. In general, all physical forms are equivalent for the uses contemplated by the present application and are intended to be within the scope of the inventive compositions disclosed herein.

[0047] As used herein, an "alkoxy" is an example of a heteroalkyl group and has the general formula: [ka] wherein R″ is an alkyl, cycloalkyl, heteroalkyl, or cycloheteroalkyl group attached to a terminal oxygen of [ka] represents a bond that forms the point of attachment of the alkoxy group to another compound or moiety. The alkoxy group in each instance can independently be unsubstituted ("unsubstituted alkoxy") or substituted with one or more substituents ("substituted alkoxy"). For example, the substituents can be halogens such as fluorine. Some non-limiting examples of fluorine-substituted alkoxy groups used herein include fluoromethoxy ("-OCHF"), difluoromethoxy ("-OCHF"), and trifluoromethoxy ("-OCF").

[0048] As used herein, "alkyl" refers to the radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("C1-C 20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C-C 12In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C-C 10 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("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), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). 12 Further examples of aryl include n-heptyl (C7), n-octyl (C8), nonyl (C9), decyl (C 10 ), Undecyl (C 11 ) and dodecyl (C 12 ) and the like. Each example alkyl group independently can be optionally unsubstituted (an "unsubstituted alkyl") or substituted 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 (a "substituted alkyl"). For example, a substituent can be a halogen, such as fluorine. Some non-limiting examples of substituted alkyl groups as used herein include fluoromethyl ("-CHF"), difluoromethyl ("-CHF"), and trifluoromethyl ("-CF").

[0049] As used herein, "alkenyl" refers to a radical of a straight or branched chain 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, an alkenyl group has 1 to 10 carbon atoms ("C-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 intermediate (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C2-C4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C1), octenyl (C8), octacryenyl (C8), and the like. The alkenyl group in each example can independently be unsubstituted ("unsubstituted alkenyl") or substituted 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 ("substituted alkenyl"). For example, the substituents can be halogens such as fluorine.

[0050] As used herein, the term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds ("C2-C12 In some embodiments, an alkynyl group is an alkynyl group having 2 to 10 carbon atoms ("C-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"). The one or more carbon-carbon triple bonds can be intermediate (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. The alkynyl group in each example can independently be unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents; for example, with 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent ("substituted alkynyl"). For example, the substituent can be a halogen, such as fluorine.

[0051] As used herein, "aprotic solvent" refers to an organic solvent that has no OH or NH bonds. Non-limiting examples of aprotic solvents include acetonitrile (abbreviated as ACN or MeCN), tetrahydrofuran (THF), dioxane, dichloromethane (DCM), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[0052] As used herein, "aryl" (sometimes abbreviated as "Ar") refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and no heteroatoms, representing an aromatic ring system (e.g., "C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 Aryl groups include, for example, C-C 10

[0023] The term "membered" refers to a non-hydrogen ring atom in the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each example aryl group can independently be optionally unsubstituted ("unsubstituted aryl") or substituted 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 ("substituted aryl"). For example, the substituent can be a halogen, such as fluorine or chlorine. In some embodiments, the aromatic ring may be optionally substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl or protected hydroxyl (i.e., -OH or -OPG, where PG is a protecting group), alkoxy (i.e., -OR"), nitro, amino (protected or unprotected, i.e., -NH or -NHPG, where PG is a protecting group), sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl, difluoromethyl, and trifluoromethyl), cyano, and the like. An aryl group may also be referred to as an aromatic group (aromatic moiety).

[0053] As used herein, the term "arylalkyl" refers to a group of alkylene groups (C-C) 20) refers to the radical of an aryl or heteroaryl group (which may be substituted or unsubstituted) attached to an alkyl group (which may be substituted or unsubstituted). The term "arylalkyl" refers to groups which may be substituted or unsubstituted. The term "arylalkyl" also refers to compounds in which one or more methylene groups in the alkyl chain of the arylalkyl group may be replaced with heteroatoms such as O, N, P, Si, and S, the nitrogen, phosphorus, and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized with one or more attached alkyl and / or aryl groups. Arylalkyl groups include, for example, benzyl (substituted or unsubstituted).

[0054] As used herein, the term "arylheteroalkyl" refers to the radical of an aryl group bonded to an acyclic, stable straight or branched chain, or combination thereof, wherein the alkyl group contains at least one carbon atom 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, which aryl groups may be substituted or unsubstituted.

[0055] As used herein, the term "benzyl group" refers to a group of the formula: [ka] wherein 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). When each A1 is H, the benzyl group is unsubstituted. When at least one A1 is not H, the benzyl group is substituted.

[0056] As used herein, the term "carbocycle" or "carbocyclic ring" refers to a ring formed by linked carbon atoms. A carbocycle can independently be optionally unsubstituted (e.g., an "unsubstituted cycloalkyl") or substituted with one or more substituents (e.g., a "substituted cycloalkyl"). For example, the substituents can be halogen, such as fluorine. A cycloalkyl group comprises a carbocycle. An aryl group, such as benzene, comprises a carbocycle. A carbocycle can contain 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"). A carbocycle can be aromatic, and thus can contain 6 carbon atoms ("C6 carbocycle"), 10 carbon atoms ("C8 carbocycle"). 10 carbocyclic rings") or 14 carbon atoms ("C 14 carbocyclic rings).

[0057] As used herein, "chiral chromatography" refers to a chiral column (i.e., a chiral stationary phase) for the separation of racemic mixtures, and in some cases diastereomeric mixtures, with the goal of obtaining optically enriched or optically pure products from the chromatographic separation.

[0058] As used herein, "cycloalkyl" refers to a group having 3 to 12 ring carbon atoms ("C3-C 12In some embodiments, a cycloalkyl group has from 3 to 10 ring carbon atoms ("C3-C 10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C4-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 7 ring carbon atoms ("C5-C7 cycloalkyl"). In some embodiments, a cycloalkyl group has 6 to 7 ring carbon atoms ("C6-C7 cycloalkyl"). A cycloalkyl group can be described, for example, as a C4-C7 membered cycloalkyl, where "member" refers to a non-hydrogen ring atom in 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 aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), and cycloheptatrienyl (C7), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C 10 Cycloalkyl groups include, but are not limited to, the aforementioned C3-C7 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10As the above examples illustrate, in certain embodiments, a cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or comprises a fused, bridged, or spiro ring system, e.g., a bicyclic system ("bicyclic cycloalkyl"), which may be saturated or 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 ring systems in which a cycloalkyl ring, as defined above, is fused with one or more aryl groups and the point of attachment is on the cycloalkyl ring; in such cases, the number of carbons always refers to the number of carbons in the cycloalkyl ring system. The cycloalkyl group in each example can independently be optionally unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). For example, the substituents can be halogen, such as fluorine.

[0059] As used herein, "cycloheteroalkyl" refers to a cycloalkyl group radical containing at least one heteroatom selected from the group consisting of O, N, P, Si, and S (wherein the heteroatom replaces a carbon atom within the ring), and in which the nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized with an attached alkyl and / or aryl group. The heteroatoms O, N, P, S, and Si can be located at any position on the cycloheteroalkyl group, but typically each heteroatom is bonded to at least two carbon atoms of the cycloalkyl group.

[0060] As used herein, the term "heteroalkyl" refers to a radical of an acyclic, stable, straight or branched chain, or combination thereof, containing 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 are optionally oxidized, and the nitrogen heteroatom is optionally quaternized with an attached alkyl and / or aryl group. The heteroatom O, N, P, S, and Si can be located at any position in the heteroalkyl group, but generally each heteroatom is bonded to at least two carbon atoms of the radical 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)-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 may be consecutive, such as, for example, -CH2-NH-OCH3, -CH2CH2-SS-CH2CH3, and -CH2-O-Si(CH3)3. The heteroalkyl group in each instance can independently be unsubstituted (an "unsubstituted heteroalkyl") or substituted with one or more substituents; for example, with 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent (a "substituted heteroalkyl"). For example, the substituent can be a halogen, such as fluorine.

[0061] As used herein, the term "heteroaryl" refers to an aromatic heterocyclic radical containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. As used herein, the term "heteroaryl" refers to a group that may be substituted or unsubstituted. For example, the substituents may be halogens such as fluorine. The heteroaryl may be fused to one or two rings, such as a cycloalkyl, aryl, or second heteroaryl ring. The point of attachment of the heteroaryl to the molecule may be on the heteroaryl, cycloalkyl, heterocycloalkyl, or aryl ring, with the heteroaryl group being attached via a carbon atom or a heteroatom. Examples of heteroaryl groups include imidazolyl, furyl, pyrrolyl, thienyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, pyrazolyl, triazolyl, oxazolyl, tetrazolyl, benzimidazolyl, benzisothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl, or benzo(b)thienyl, each of which is optionally substituted.Heteroaromatic rings may be optionally substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl or protected hydroxyl (i.e., -OH or -OPG, where PG is a protecting group), alkoxy (i.e., -OR"), nitro, amino (protected or unprotected, i.e., -NH or -NHPG, where PG is a protecting group), sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, and the like. Heteroaryl groups are sometimes referred to as heteroaromatic groups (or moieties).

[0062] 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. For further evidence that the term "heterocyclic ring" is a well-established term in the field of organic chemistry, see Oxford Dictionary of Biochemistry and Molecular Biology, Oxford University Press, Oxford, 1997. A heterocyclic ring can be aliphatic (e.g., tetrahydrofuran) or aromatic (e.g., pyridine).

[0063] 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 in a specified ratio to the number of compound molecules in the hydrate.

[0064] As used herein, the term "pharmaceutically acceptable salts" refers to salts of therapeutically effective compounds that can be made from relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When 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. When 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. Salts derived from pharmaceutically acceptable organic bases include 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, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, polyamine resins, procaine, purine, theobromine, triethylamine (NEt3), trimethylamine, tripropylamine, tromethamine, and the like, for example, salts derived from organic bases in the protonated form (e.g., [HNEt3] +) are included. Salts derived from pharmaceutically acceptable inorganic acids include salts of boric acid, carbonic acid, hydrohalic acids (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 hydroxyl 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 hydroxyl acids (e.g., o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene acid, and benzoic acid). Examples of suitable salts include salts of hydroxynaphthalene-2-carboxylic acids (e.g., 3-hydroxynaphthalene-2-carboxylic acid and 3-hydroxynaphthalene-2-carboxylic acid), ascorbic acid, dicarboxylic acids (e.g., fumaric acid, maleic acid, oxalic acid and succinic acid), glucuronic acid, mandelic acid, mucic acid, nicotinic acid, orotic acid, pamoic acid, pantothenic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, edisylic acid, ethanesulfonic acid, isethionic acid, methanesulfonic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid and p-toluenesulfonic acid (PTSA)), xinaphoric acid, and the like. In some embodiments, the pharmaceutically acceptable counterion is selected from the group consisting of acetate, benzoate, besylate, bromide, camphorsulfonate, chloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, mesylate, methylsulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.In some embodiments, the salt is tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, maleate, trifluoroacetate, hydrochloride, or tosylate. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., Journal of Pharmaceutical 66: 1-19 (1977)). Certain compounds herein contain basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts, or exist in zwitterionic form. 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 the inventive compositions disclosed herein.

[0065] As used herein, the term "protecting group" or "PG" refers to a chemical group that reacts with and attaches (at least for a certain period of time) to a functional group within a molecule (e.g., -OH, -NH, or -SH) to prevent the functional group from participating in reactions of the molecule, and which can then be removed to regenerate said functional group. For further evidence that protecting group is a well-established term in the field of organic chemistry, see Oxford Dictionary of Biochemistry and Molecular Biology, Oxford University Press, Oxford, 1997. For further references examining the suitability of various protecting groups (e.g., hydroxyl or amine protecting groups (i.e., PGs)) for organic synthesis reactions, see Greene's Protective Groups in Organic Synthesis, 4th ed., 2007, John Wiley & Sons, Inc.

[0066] As used herein, the term "solvate" refers to a form of a compound that is associated with a solvent, usually by solvolysis. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. As used herein, the term "tautomer" refers to interconvertible forms of a particular compound structure that differ in the replacement of hydrogen atoms and electrons. Thus, the two structures are in equilibrium due to the shift of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they readily interconvert upon treatment with acid or base. Tautomeric forms can be relevant for achieving optimal chemical reactivity and biological activity of a desired compound.

[0067] II. Other Definitions: It should be understood that certain aspects, modes, embodiments, variations and features of the present technology are described below in varying degrees of detail to provide a substantial understanding of the present application. Definitions of certain terms as used herein are provided below. Unless otherwise specified, all technical and scientific terms used herein generally have the same meaning as commonly understood by one skilled in the art to which the present technology belongs. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. For example, reference to "a cell" includes a combination of two or more cells.

[0068] As used herein, "administration" of an agent (i.e., a therapeutic agent) to a subject includes any route of introducing or delivering a compound to a subject to perform its intended function. Administration may be by any suitable route, such as oral administration. Administration may be subcutaneous. Alternatively, administration may be topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ophthalmic, intrathecal, intracerebroventricular, iontophoretic, transmucosal, intravitreal, or intramuscular. Administration includes self-administration and administration by another.

[0069] 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 oil; and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, and urea. Additionally, auxiliary agents, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents can be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin, the entire contents of which are incorporated herein by reference. As used herein, the phrase "delayed onset" refers to delaying, preventing, or causing one or more symptoms of a disorder, condition, pathology, or indication in a statistical sample to occur more slowly than normal in a treated sample compared to an untreated control sample.

[0070] As used herein, the term "effective amount" refers to an amount sufficient to achieve a desired therapeutic and / or prophylactic effect, e.g., an amount that alleviates, improves, prevents, or delays the onset of physiological symptoms of a mitochondrial disease such as Friedreich's ataxia. For therapeutic or prophylactic applications, in some embodiments, the amount of the composition administered to a subject will vary depending on the type and severity of the disease and individual characteristics such as health, age, weight, and tolerance to drugs. In some embodiments, it will also vary depending on the extent, severity, and type of disease. Those skilled in the art will be able to determine the appropriate dosage depending on these and other factors. These compositions can also be administered in combination with one or more additional therapeutic compounds. 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 with one or more signs, symptoms, or risk factors of a mitochondrial disease, such as Friedreich's ataxia; for example, muscle weakness, particularly in the arms and legs, incoordination, impaired motor control, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, or a cardiac and / or ocular condition or disorder. For example, a "therapeutically effective amount" of a therapeutic compound includes a level at which the presence, frequency, or severity of one or more signs, symptoms, or risk factors of a mitochondrial disease, e.g., Friedreich's ataxia, is reduced or eliminated. In some embodiments, a therapeutically effective amount reduces or ameliorates the physiological effects of a mitochondrial disease (e.g., Friedreich's ataxia) and / or the risk factors for Friedreich's ataxia, and / or delays the progression or onset of a mitochondrial disease (e.g., Friedreich's ataxia).

[0071] As used herein, "inhibit" means to reduce by an objectively measurable amount or degree compared to a control. In one embodiment, inhibit means to reduce by at least a statistically significant amount compared to a control. In one embodiment, inhibit means to reduce by at least a 5 percent compared to a control. In various individual embodiments, inhibit means to reduce by at least a 2, 3, 4, 5, 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, 95, or 99 percent compared to a control.

[0072] As used herein, the term "concurrent" therapeutic use refers to the simultaneous, substantially simultaneous administration of at least two active ingredients by the same route. As used herein, the term "separate" therapeutic use refers to the simultaneous or substantially simultaneous administration of at least two active ingredients by different routes. As used herein, the term "sequential" therapeutic use refers to the administration of at least two active ingredients at different times, and the administration routes are the same or different. More specifically, sequential use refers to the complete administration of one of the active ingredients to begin the administration of one or more other active ingredients. Thus, it is possible to administer one of the active ingredients minutes, hours, or days before administering one or more other active ingredients. There is no simultaneous treatment within this definition. 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, horse, cow, or non-human primate. In certain embodiments, the subject is a human.

[0073] As used herein, the terms "treatment" or "palliative" refer to therapeutic treatment whose purpose is to relieve, alleviate, or slow (attenuate) the condition or disorder of interest. By way of non-limiting example, a subject is said to be successfully treated for a mitochondrial disease (e.g., Friedreich's ataxia) if, after receiving an effective amount of a compound of the present application (including a pharmaceutically acceptable salt thereof (e.g., hydrochloride, acetate, citrate, trifluoroacetate, benzoate, oxalate, or mesylate), stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate) in accordance with the methods described herein, the subject exhibits an observable and / or measurable reduction or absence of one or more signs and symptoms of the mitochondrial disease (e.g., Friedreich's ataxia), such as, but not limited to, muscle weakness, especially in the arms and legs, incoordination, impaired motor control, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, or a cardiac or ocular condition or disorder. It should also be recognized that the various treatment modalities for medical conditions as described are intended to mean "substantial," including complete treatment, but also less than complete treatment, in which some biologically or medically relevant result is achieved. Treating Friedreich's ataxia, as used herein, also refers to treating the signs and symptoms associated with decreased frataxin activity or frataxin expression levels that are characteristic of Friedreich's ataxia.

[0074] As used herein, "prevention" of a disease or condition, e.g., a mitochondrial disease such as Friedreich's ataxia, refers to a result in a statistical sample that shows a reduced occurrence of the disorder or condition in treated samples compared to untreated control samples, or a delayed onset of one or more symptoms of the disorder or condition compared to untreated control samples. Such prevention may also be referred to as prophylactic treatment. As used herein, preventing a mitochondrial disease (e.g., Friedreich's ataxia) includes preventing or delaying the onset of a mitochondrial disease (e.g., Friedreich's ataxia), preventing, delaying, or slowing its progression or development. As used herein, preventing Friedreich's ataxia also includes preventing the recurrence of one or more signs or symptoms of Friedreich's ataxia.

[0075] III. Chiral / Stereochemical Considerations: The compounds described herein may contain one or more asymmetric centers and, therefore, may exist in various isomeric forms, e.g., enantiomers and / or diastereomers (i.e., stereoisomers). Chiral centers in depicted structures (including claims) are indicated herein with an asterisk ( *) can be distinguished. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, 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 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers and / or as mixtures of various isomers.

[0076] Purity is a relative term in the sense that 100% purity is extremely difficult to achieve, and as used herein, a pure enantiomer compound is substantially free of the other enantiomer or stereoisomer of that compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. With respect to amino acids (usually described as "D" and "L" enantiomers), "D"-amino acids have the "R" configuration, and "L"-amino acids have the "S" configuration. In some embodiments, "substantially free" refers to (i) an aliquot of an "R" compound that contains less than 2% of the "S" form; or (ii) an aliquot of an "S" compound that contains less than 2% of the "R" form. The term "enantiomerically pure" or "pure enantiomer" indicates that a 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 particularly specified enantiomer (e.g., compared to other enantiomers). In certain embodiments, the masses are based on the phase masses of all enantiomers or stereoisomers of a compound.

[0077] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure "R" compound may contain, for example, about 90% excipients and about 10% of the enantiomerically pure "R" compound. In certain embodiments, the enantiomerically pure "R" compound in such a composition may contain, for example, at least about 95% by weight of the "R" compound and at most about 5% by weight of the "S" compound, relative to the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure "S" compound may contain, for example, about 90% excipients and about 10% of the enantiomerically pure "S" compound. In certain embodiments, the enantiomerically pure "S" compound in such a composition may contain, for example, at least about 95% by weight of the "S" compound and at most about 5% by weight of the "R" compound, relative to the total weight of the enantiomers of the compound. In certain embodiments, the active ingredient can be formulated with minor amounts or no excipients or carriers.

[0078] IV. Pharmaceutical Compositions, Routes of Administration, and Dosages: In certain embodiments, the present application is directed to pharmaceutical compositions. In some embodiments, the compositions comprise a therapeutic compound (i.e., a drug) and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises multiple compounds and a pharmaceutically acceptable carrier. The pharmaceutical composition can be a drug. In certain embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent other than the compound of the present application, which can be an agent useful in the treatment of a mitochondrial disease, such as Friedreich's ataxia. Pharmaceutical compositions can be prepared by combining one or more compounds of the present application with a pharmaceutically acceptable carrier and, optionally, one or more additional therapeutic agents.

[0079] As stated above, "effective amount" refers to any amount sufficient to achieve a desired biological effect. In conjunction with the teachings provided herein, by selecting from various active compounds and evaluating factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and mode of administration, one can design an effective preventative (i.e., prophylactic) or therapeutic regimen that is effective for ameliorating a particular subject's condition or disease without causing substantial undesired toxicity. The effective amount for a particular indication may vary depending on factors such as the disease or condition being treated, the particular compound of the present application being administered, the size of the subject, or the severity of the disease or condition. Effective amounts can be determined by methods known to physicians and clinicians during preclinical and clinical trials. Those skilled in the art can empirically determine effective amounts of particular compounds of the present application and / or other therapeutic agents without necessitating undue experimentation. A maximum dose, i.e., the highest safe dose according to any medical judgment, may be used. Multiple doses per day may be contemplated to achieve appropriate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by the patient's peak or sustained plasma levels of the drug. "Dose" and "dosage" are used interchangeably herein. A dose can be self-administered, administered by another person, or administered by a device (e.g., a pump).

[0080] Compounds for use in treatment or prevention can be tested in suitable animal model systems. Similarly, for in vivo testing, any animal model system known in the art can be used before administration to human subjects. Suitable animal model systems before testing in human subjects include, but are not limited to, rats, mice, chickens, cows, monkeys, and rabbits. Therapeutic compounds, and optionally other therapeutic agents, may be administered per se (pure) or in the form of pharmaceutically acceptable salts. When used in medicines, these salts should be pharmaceutically acceptable, although non-pharmaceutically acceptable salts may also be conveniently used to make these pharmaceutically acceptable salts. The pharmaceutical compositions of the present application comprise an effective amount of a therapeutic compound as described herein, optionally distributed in a pharmaceutically acceptable carrier. The components of these pharmaceutical compositions also are capable of being commingled with the compounds of the present application, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

[0081] The dosage, toxicity, and therapeutic efficacy of any therapeutic compound, composition (e.g., formulation or drug), other therapeutic agent, or mixture thereof can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compounds that exhibit high therapeutic indices are advantageous. Compounds that exhibit toxic side effects can also be used, but care must be taken to design delivery systems that target such compounds to the site of affected tissues in order to minimize potential damage to uninfected cells and thereby reduce side effects. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The dosage of such compounds can be within a range of circulating concentrations that include the ED50 with little or no toxicity. Dosages can vary within this range depending on the dosage form used and the route of administration utilized. For any compound used in these methods, the therapeutically effective dose can be initially estimated in cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can then be used to accurately determine useful doses in humans. Plasma levels can be measured, for example, by high performance liquid chromatography.

[0082] In some embodiments, an effective amount of a therapeutic compound disclosed herein sufficient to achieve a therapeutic or prophylactic effect can range from about 0.000001 mg / kilogram body weight / day to about 10,000 mg / kilogram body weight / day. Preferably, the dosage range is from about 0.0001 mg / kilogram body weight / day to about 100 mg / kilogram body weight / day. For example, dosages can range from 1 mg / kg body weight or 10 mg / kg body weight daily, every two days, or every three days, or from 1 to 10 mg / kg weekly, every two weeks, or every three weeks. In some embodiments, a single dose of a therapeutic compound disclosed herein ranges from 0.001 to 10,000 micrograms / kg body weight. In some embodiments, a therapeutic compound disclosed herein dissolved or suspended in a carrier ranges from 0.2 to 2000 milligrams per delivered milliliter. An exemplary treatment regimen may require administration once a day or once a week. In some cases, in treatment applications, relatively high dosages may be required for a relatively short period of time until the progression of the disease is reduced or stopped, or until the subject shows partial or complete improvement of the symptoms of the disease. Thereafter, the patient can be administered a prophylactic regimen.

[0083] In some embodiments, a therapeutically effective amount of a therapeutic compound disclosed herein is a compound present in a tissue at a concentration of 10 -12 ~10 -6 moles, e.g., about 10 -7 The concentration can be defined as a mole. This concentration may be delivered by a systemic dose of 0.001-100 mg / kg or the equivalent dose by body surface area. Dosing regimens are optimized to maintain therapeutic concentrations in target tissues, such as single daily or weekly administration, but also include continuous administration (e.g., oral, systemic, topical, subcutaneous, parenteral injection, or transdermal application). In some embodiments, intravenous or subcutaneous administration of a therapeutic compound may generally be from 0.01 μg / kg / day to 20 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of a therapeutic compound may generally be from 0.01 μg / kg / day to 100 μg / kg / day. In some embodiments, intravenous or subcutaneous administration of a therapeutic compound may generally be from 0.1 μg / kg / day to 1 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of a therapeutic compound may generally be from 10 μg / kg / day to 2 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of a therapeutic compound may generally be from 500 μg / kg / day to 5 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of a therapeutic compound may generally be from 1 mg / kg / day to 20 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of a therapeutic compound may generally be from 1 mg / kg / day to 10 mg / kg / day.

[0084] Generally, the daily oral dose of the compound for a human subject is about 0.01 micrograms / kg / day to 100 milligrams / kg / day. One or more oral doses per day in the range of 0.01 to 50 milligrams / kg are expected to produce therapeutic results. The dosage may be adjusted appropriately to achieve the desired local or systemic drug levels depending on the mode of administration. For example, intravenous administration is expected to require a dose one to several orders of magnitude lower per day. If the subject does not respond adequately to such doses, higher doses (or higher effective doses via a different, more localized delivery route) can be used, as tolerated by the patient. Multiple doses per day may be contemplated to achieve adequate systemic levels of the compound. For use in treatment, an effective amount of the compound can be administered to a subject by any method that delivers the compound to the desired surface. Administration of the pharmaceutical composition can be achieved by any means known to those skilled in the art. Routes of administration include, but are not limited to, oral administration, topical administration, intranasal administration, systemic administration, intravenous administration, subcutaneous administration, intraperitoneal administration, intradermal administration, intraocular administration, ophthalmic administration, intrathecal administration, intraventricular administration, iontophoretic administration, transmucosal administration, intravitreal administration, or intramuscular administration. Administration includes self-administration, administration by another person, and administration by a device.

[0085] The therapeutic compounds disclosed herein can be delivered to a subject as a formulation or medicament (i.e., a pharmaceutical composition). Formulations and medicaments can be prepared, for example, by dissolving or suspending a therapeutic compound 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 as a pharmaceutically acceptable solution, which typically contains pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. The pharmaceutical composition (e.g., formulation or agent) may contain a carrier, which may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thiomerasol, and the like. Glutathione and other antioxidants can be included to prevent oxidation. It is often advantageous to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0086] Solutions or suspensions (e.g., formulations or medicaments) used for parenteral, intradermal, subcutaneous, or intraocular application may contain the following components: a sterile diluent such as water for injection, saline solution, hydrogenated oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvent; an antibacterial agent such as benzyl alcohol or methylparaben; 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 dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be enclosed in glass or plastic ampoules, disposable syringes, or multiple-dose vials. For convenience to the patient or treating physician, dosage formulations can be provided alone or in kits containing all the necessary equipment (e.g., vials of drug, vials of diluent, syringes, and needles) for a course of treatment (e.g., 7 or more days of treatment).

[0087] 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. For intravenous and other parenteral routes of administration, the compounds or pharmaceutical compositions of the present application can be formulated as lyophilized preparations, as lyophilized preparations of liposome-intercalated or liposome-encapsulated active compounds, as lipid complexes in aqueous suspension, or as salt complexes. Lyophilized preparations are generally reconstituted with a suitable aqueous solution, e.g., sterile water or physiological saline, immediately prior to administration.

[0088] Pharmaceutical compositions (e.g., formulations or medicaments) suitable for injectable use can 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™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). Compositions for administration by injection are generally sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Sterile injectable solutions (e.g., formulations or drugs) can be prepared by blending the required amount of the active compound in a suitable solvent with one or a combination of the ingredients listed above, followed by filtration and sterilization, if necessary. Generally, dispersions are prepared by blending the active compound into a sterile vehicle containing a basic dispersion medium and the other ingredients required from those listed 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 yield a powder of the active ingredient and any additional desired ingredients from the previously sterilized and sterilized solution. Therapeutic compounds or pharmaceutical compositions, when it is desirable to deliver them systemically, can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion (e.g., by IV injection or via a pump to meter the dose over a predetermined period of time). Injectable preparations can be presented in unit dosage form, e.g., in ampoules or multi-dose containers, with an added preservative. These compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0089] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compound in water-soluble form. Furthermore, suspensions of therapeutic compounds 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 allow for the preparation of highly concentrated solutions.

[0090] For oral administration, these compounds can be readily formulated by combining the active compound with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by the subject to be treated. Tablets, pills, capsules, troches, and the like may contain any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel®, or cornstarch; lubricants such as magnesium stearate or stearates; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavor. Pharmaceutical preparations for oral use can be prepared as solid excipients, optionally by grinding the resulting mixture and, if desired, adding suitable additives, followed by processing the granulated mixture into tablets or dragee cores. Suitable excipients are, in particular, sugars including lactose, sucrose, mannitol, or sorbitol; fillers such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or cellulose preparations such as polyvinylpyrrolidone (PVP). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, e.g., sodium alginate, can be added. Optionally, oral preparations can also be formulated in saline or a buffer, such as EDTA to neutralize internal acidity, or can be administered without a carrier.

[0091] Oral dosage forms of one or more of the components described above are also specifically contemplated. One or more of the components may be chemically modified to facilitate effective oral delivery of the derivative. Generally, contemplated chemical modifications involve the attachment of at least one moiety to the component molecule itself, where the moiety (a) inhibits acid hydrolysis; and (b) enables uptake from the stomach or intestine into the bloodstream. Increased overall stability and increased circulation time of one or more components in the body are also desirable. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, 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 can be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane.For pharmaceutical applications, as indicated above, polyethylene glycol (PEG) moieties of various molecular weights are suitable.

[0092] For a particular therapeutic compound or pharmaceutical composition, the preferred location of release may be the stomach, the small intestine (the duodenum, jejunum, or ileum), or the large intestine. Those skilled in the art have available formulations that will not dissolve in the stomach but will release the substance in the duodenum or elsewhere in the intestine. Preferably, this release avoids the deleterious effects of the stomach environment, either by protection of the compound (or derivative) or by release of the bioactive substance beyond the stomach environment, such as the intestine. Tablets may also be coated with a coating or mixture of coatings, which are not intended to protect against the stomach. This may include sugar coatings or coatings that make the tablet easier to swallow. Capsules may consist of a hard coating (e.g., gelatin) for delivery of dry therapeutic agents (e.g., powder); for liquid forms, a soft gelatin coating may be used. The coating material for cachets may be sticky starch or other edible paper. Pills, lozenges, molded tablets, or moulded tablets may be used.

[0093] The therapeutic compound or pharmaceutical composition may be included in the formulation as fine multiparticulates in the form of granules or pellets having a particle size of about 1-2 mm. Formulations of material for capsule administration may be present as powders, lightly compressed plugs, or even tablets. The therapeutic compound or pharmaceutical composition may be prepared by compression. Coloring and flavoring agents may all be included. For example, the therapeutic compound or pharmaceutical composition may be dispensed and then contained within a food product, such as a refrigerated beverage, which may further contain coloring and flavoring agents. Formulations or medicaments containing therapeutic compounds, other therapeutic agents, or mixtures thereof can be diluted or bulked with inert materials. These diluents can include carbohydrates, particularly mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, and starch. Certain inorganic salts, including calcium triphosphate, magnesium carbonate, and sodium chloride, may also be used as bulking agents. Some commercially available diluents are Fast-Flo®, Emdex®, Starch 1500®, Emcompress®, and Avicel®.

[0094] To provide a solid dosage form, a disintegrant may be included in the pharmaceutical composition. Materials used as disintegrants include, but are not limited to, starch, including commercially available disintegrants based on starch Explotab. Sodium starch glycolate, Amberlite®, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethylcellulose, 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, including powdered gums such as agar, Karaya, or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants. Binders can be used to hold the therapeutic agent and form a hard tablet and include materials derived from natural products such as acacia, tragacanth, 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.

[0095] Antifriction agents may be included in the formulation of the therapeutic agent to prevent sticking during the compounding process. Lubricants may be used as a layer between the therapeutic agent and the die wall and 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 glycol (PEG) of various molecular weights, and Carbowax™ 4000 and 6000 may also be used. Glidants may be added to improve the flowability of the drug during formulation and to aid rearrangement during compression. Glidants may include starch, talc, pyrogenic silica, and hydrated silicoaluminate.

[0096] To aid in the dissolution of the therapeutic compound or pharmaceutical composition into the aqueous environment, surfactants are used as wetting agents. Surfactants may be added as surfactants. Surfactants may include anionic surfactants such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic surfactants may be used, including benzalkonium chloride and benzethonium chloride. Potential nonionic surfactants that may be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glycerol monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants may be present in the formulation of the compounds of the present application either alone or as a mixture in various ratios. Orally usable pharmaceutical compositions may include push-fit capsules made of gelatin and soft-shell capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules may 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 optionally, stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. Microsphere formulations for oral administration are also available. Such microspheres are well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

[0097] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For topical administration, the therapeutic compounds as disclosed herein may be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well known in the art. For administration of a therapeutic compound or pharmaceutical composition by inhalation for use in accordance with the present application, it can conveniently be delivered in the form of an aerosol spray from a pressurized pack or nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In some embodiments, the formulation, medicament, or therapeutic compound can be delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Such methods include those described in U.S. Pat. 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. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the therapeutic compound and a suitable powder base, such as lactose or starch.

[0098] Nasal delivery of the therapeutic compounds or pharmaceutical compositions of the present application is also contemplated. Nasal delivery allows the therapeutic compounds or pharmaceutical compositions of the present application to pass into the bloodstream immediately after administration to the nasal cavity, without the need for product deposition in the lungs. Formulations for nasal delivery include those involving dextran or cyclodextran. For nasal administration, a useful device is a small, hard bottle fitted with a metered-dose sprayer. In one embodiment, the metered dose is delivered by drawing the solution pharmaceutical composition into a chamber of a defined volume, the chamber containing an orifice sized to aerosolize 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 certain embodiments, the chamber is a piston configuration. Such devices are commercially available. Alternatively, a plastic squeeze bottle is used with a hole or opening sized to aerosolize the aerosol formulation by forming a spray when squeezed. The opening is usually found at the top of the bottle, which is generally tapered to partially fit into the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler provides a metered dose of the aerosol formulation for administration of a metered dose of the therapeutic compound or pharmaceutical composition. Alternatively, the therapeutic compounds or pharmaceutical compositions may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0099] Also contemplated herein is pulmonary delivery of the therapeutic compounds or pharmaceutical compositions disclosed herein, where the compound, formulation, or agent is delivered to the lungs of a mammal upon inhalation and can travel through the lung epithelial lining into the bloodstream. Other reports of 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 (α1-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 herein 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 herein by reference.

[0100] Contemplated for use in the practice of this technology are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including, but not limited to, nebulizers, metered dose inhalers, and dry powder inhalers, all of which are known to those skilled in the art. Some specific examples of commercially available devices suitable for practicing this technique are the Ultravent™ nebulizer manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II® nebulizer manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin® metered dose inhaler manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler® powder inhaler manufactured by Fisons Corp., Bedford, Mass. All such devices require the use of formulations suitable for delivery of the therapeutic compounds, formulations, and medicaments of the present application. Generally, each formulation will be specific to the type of device used and may include the use of an appropriate propellant material in addition to conventional diluents, adjuvants, and / or carriers useful in therapy. The use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is also contemplated. The chemically modified compounds of the present application may also be prepared into different formulations and medicaments depending on the type of chemical modification or the type of device used.

[0101] Formulations suitable for use with either jet or ultrasonic nebulizers may contain a therapeutic compound (or derivative) of the present application dissolved in water at a concentration of about 0.1 to 25 mg of the bioactive compound of the present application per mL of solution. The formulation may also contain a buffer and a simple sugar (e.g., for inhibitor stabilization and tonicity adjustment). Nebulizer formulations may also contain a soluble ... The compound of the present invention is introduced to the surface of the derivative (as a result of atomization of the solution). A surfactant may also be included to reduce or prevent aggregation. Formulations for use in metered-dose inhalers generally comprise a fine powder containing the compound (or derivative) of the present application suspended in a propellant with the aid of a surfactant. The propellant may be any conventional substance used for this purpose, such as a chlorofluorocarbon, hydrochlorofluorocarbon, hydrofluorocarbon, or hydrocarbon (including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane), or a combination thereof. Suitable surfactants include sorbitan trioleate and soybean lecithin. Oleic acid may also be useful as a surfactant. The formulations dispensed from the powder inhaler device may comprise a fine dry powder containing the therapeutic compound (or derivative) of the present application, and may include a bulking agent such as lactose, sorbitol, sucrose, or mannitol in an amount to facilitate dispersion of the powder from the device, e.g., 50-90% of the formulation mass. The therapeutic compound or pharmaceutical composition (or derivative) of the present application may advantageously be prepared in a particulate form with a mean particle size of less than 10 micrometers (μm), most preferably 0.5-5 μm, for most efficient delivery to the deep lung layers.

[0102] For ophthalmic or intraocular indications, any suitable mode of delivering a therapeutic compound or pharmaceutical composition to the eye or the area adjacent to the eye can be used. For ophthalmic formulations, see generally Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, NY (1993) and Havener, WH, Ocular Pharmacology, CV Mosby Co., St. Louis (1983). Non-limiting examples of pharmaceutical compositions suitable for administration within or adjacent to the eye include, but are not limited to, ocular inserts, mini-tablets, and topical formulations 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.

[0103] Eye drops comprise sterile liquid formulations that can be administered 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 preservatives. In some embodiments, the optimal pH of the eye drops is approximately 7.4, which is the same as the pH of tears. In situ gels are viscous liquids that exhibit the ability to undergo a sol-to-gel transition, influenced by external factors such as appropriate pH, temperature, and the presence of electrolytes. This property results in slowed drug efflux from the ocular surface and increased bioavailability of the active ingredient. Polymers commonly used in in situ gel formulations include, but are not limited to, gellan gum, poloxamer, silicone-containing formulations, and cellulose acetate phthalate. In some embodiments, therapeutic compounds are formulated into in situ gels (as pharmaceutical compositions).

[0104] For topical ophthalmic administration, the therapeutic compound or pharmaceutical composition may be formulated as a solution, gel, ointment, cream, suspension, etc., as is well known in the art. An ointment is a semi-solid dosage form for external application, such as topical use on the eye or skin. In some embodiments, the ointment comprises a solid or semi-solid hydrocarbon base with a melting or softening point close to human core body temperature. In some embodiments, the ointment applied to the eye breaks down into small droplets, which remain in the conjunctival sac for a longer period of time, thereby increasing bioavailability. Ocular inserts are solid or semi-solid dosage forms that lack the drawbacks of conventional ophthalmic drug forms. They are less susceptible to defense mechanisms such as nasolacrimal outflow, exhibit the ability to remain in the conjunctival sac for extended periods, and are more stable than conventional dosage forms. Ocular inserts 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 disclosed herein and one or more polymeric materials. These polymeric materials include, but are not limited to, methylcellulose and its derivatives (e.g., hydroxypropylmethylcellulose (HPMC)), ethylcellulose, polyvinylpyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethylchitosan, gelatin, and various mixtures of the aforementioned polymers. The ocular insert may also comprise silica.

[0105] Minitablets are biodegradable, solid drug forms that convert to a gel after application to the conjunctival sac, thereby extending the contact period between the active ingredient (i.e., a therapeutic compound disclosed herein) and the ocular surface and increasing the bioavailability of the therapeutic compound. Advantages of minitablets include ease of application to the conjunctival sac, resistance to defense mechanisms such as lacrimal outflow or nasolacrimal drainage, longer contact with the cornea due to the presence of a mucoadhesive polymer, and sustained release of the active ingredient from the formulation at the application site due to swelling of the carrier outer layer. Minitablets may contain one or more therapeutic compounds disclosed herein and one or more polymers. Non-limiting examples of polymers suitable for use in minitablet formulations include cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose, ethylcellulose, acrylates (e.g., polyacrylic acid and its crosslinked forms), Carbopol® or carbomer, chitosan, and starch (e.g., drum-dried waxy corn starch). In some embodiments, the mini-tablets further comprise one or more excipients, non-limiting examples of which include mannitol and magnesium stearate.

[0106] Ophthalmic or intraocular preparations and medicaments may contain non-toxic auxiliary substances such as antimicrobial ingredients that are not harmful in use, e.g., thimerosal, benzalkonium chloride, methyl and propylparabens, benzyldodecinium bromide, benzyl alcohol, or phenylethanol; buffer ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffer; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylenesorbitan monopalmitate, ethylenediaminetetraacetic acid, etc. In some embodiments, the viscosity of the ophthalmic formulation containing one or more therapeutic compounds is increased to improve contact with the cornea and bioavailability in the eye. Viscosity can be increased by adding a high molecular weight hydrophilic polymer that does not diffuse through biological membranes and forms a three-dimensional network in water. Non-limiting examples of such polymers include polyvinyl alcohol, poloxamer, hyaluronic acid, carbomer, and polysaccharides, cellulose derivatives, gellan gum, and xanthan gum. 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 depot formulation, such as a controlled release formulation. Such controlled release formulations can include particles, such as microparticles or nanoparticles.

[0107] The therapeutic compounds or pharmaceutical compositions 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. In addition to the formulations described above, the therapeutic compounds may also be formulated as a depot preparation. Such long-acting pharmaceutical compositions may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. Suitable liquid or solid pharmaceutical depot forms may be, for example, aqueous or saline solutions for inhalation, microencapsulated, cochleated, coated on fine gold particles, contained in liposomes, nebulized, aerosolized, pellets for skin implantation, or dried into sharp objects to be scraped on the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, and formulations with sustained release of active compounds, where formulation excipients and additives and / or adjuvants, such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers, are commonly used as described above. Pharmaceutical compositions may be suitable for use in various drug delivery systems. For a brief review of drug delivery methods, see Langer R, Science 249:1527-33 (1990) Langer, Science 249: 1527-1533, 1990.

[0108] The therapeutic compound or pharmaceutical composition may be provided in particles. Particle, as used herein, refers to nanoparticles or microparticles (or in some cases larger particles) that may consist, in whole or in part, of the compound of the present application or other therapeutic agents, as described above. These particles may contain a therapeutic agent within a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent may also be dispersed within the particle. The therapeutic agent may also be adsorbed within the particle. These particles may have any dimensional release rate, including zero-order, first-order, second-order, delayed, sustained, immediate, and any combination thereof. In addition to the therapeutic agent, the particles may contain any of the materials commonly used in the pharmaceutical and medical arts, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable materials, or combinations thereof. The particles may also be microcapsules containing the compound of the present application in solution or in a semi-solid state. The particles may be of virtually any shape.

[0109] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering therapeutic agents. Such polymers can be natural or synthetic. The polymer is selected based on the desired period of release. Bioadhesive polymers of particular interest include the bioerodible polymers described in Sawhney HS et al. (1993) Macromolecules 26:581-7, which is incorporated herein by reference. These include polyhyaluronic acid, casein, gelatin, glutin, 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).

[0110] The therapeutic compound or other therapeutic agent, or a mixture thereof, may be formulated in a carrier system. The carrier may be a colloidal system. The colloidal system may be a liposome, i.e., a phospholipid bilayer vehicle. In one embodiment, the therapeutic compound or other therapeutic agent, or a mixture thereof, may be encapsulated in a liposome while maintaining the integrity of the therapeutic compound or other therapeutic agent, or a mixture thereof. Those skilled in the art will recognize that there are various methods for preparing 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, active agents may also be loaded into particles prepared from pharmaceutically acceptable components, including, but not limited to, soluble, insoluble, permeable, impermeable, biodegradable or gastroretentive polymers or liposomes, including, but not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles and viral vector systems.

[0111] The carrier can also be a polymer, e.g., a biodegradable, biocompatible polymer matrix. In one embodiment, a therapeutic compound or other therapeutic agent, or a mixture thereof, can be embedded in the polymer matrix while maintaining the integrity of the composition. The polymer can be a nanoparticle that encapsulates the therapeutic agent or agent. The polymer can be natural, such as a polypeptide, protein, or polysaccharide, or synthetic, such as a poly-α-hydroxy acid. Examples include carriers made from collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharides, fibrin, gelatin, and combinations thereof. In one embodiment, the polymer is polylactic acid (PLA) or polylactic / glycolic acid (PLGA). Polymer matrices can be prepared and isolated in various forms and sizes, including microspheres and nanospheres. Polymer formulations can result in extended duration of therapeutic effect (see Reddy, Ann. Pharmacother., 34(7-8):915-923 (2000)). Polymeric formulations for human growth hormone (hGH) are being used in clinical trials (see Kozarich and Rich, Chemical Biology, 2:548-552 (1998)). Examples of polymeric microsphere sustained-release formulations are described in PCT Publication WO 99 / 15154 (Tracy, et al.), U.S. Patent Nos. 5,674,534 and 5,716,644 (also known as 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 a polymer matrix containing particles of erythropoietin that are stabilized against aggregation by salt.

[0112] In some embodiments, the therapeutic compound or other therapeutic agent, or mixtures thereof, are prepared with carriers that protect the therapeutic compound or other therapeutic agent, or mixtures thereof, against rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Such formulations can be prepared using known techniques. These materials are also commercially available, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to specific cells using monoclonal antibodies against 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. Pat. No. 4,522,811.

[0113] The therapeutic compound may be contained in a controlled release system. The term "controlled release" refers to any drug-containing formulation in which the manner and characteristics of drug release from the formulation are controlled. This refers to immediate release formulations as well as non-immediate release formulations, including, but not limited to, sustained release and delayed release formulations. The term "sustained release" (also called "extended release") is used in its conventional sense to refer to a drug formulation that provides sustained release of drug over an extended period of time, preferably, but not necessarily, resulting in substantially constant blood levels of drug over an extended period of time. The term "delayed release" is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of drug therefrom. "Delayed release" may or may not include release of drug over an extended period of time, and therefore may or may not be "sustained release."

[0114] The use of long-term sustained release implants may be particularly suitable for the treatment of chronic conditions. The term "implant" is intended to include a single composition (such as a mesh) or a composition comprising multiple components (e.g., a fiber mesh composed of several individual pieces of mesh material), or multiple individual compositions that reside locally to provide a long-term sustained release resulting from the aggregation of the multiple compositions. "Long-term" release, as used herein, means that the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 2 days. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 7 days. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 14 days. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 30 days. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 60 days. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 90 days. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 180 days. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least one year. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 15-30 days. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 30-60 days. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 60-90 days. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 90-120 days. In some embodiments, the implant is constructed and configured to deliver therapeutic or prophylactic levels of the active ingredient for at least 120-180 days.In some embodiments, long-term sustained release implants are known to those skilled in the art and include any of the release systems described above. In some embodiments, such implants can be administered surgically. In some embodiments, such implants can be administered topically or by injection.

[0115] It will be appreciated by those skilled in the relevant art that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the technology contained herein, in view of the information known to those skilled in the art, and may be made without departing from the scope of the present application or any embodiment thereof.

[0116] V. Compounds and Compositions Useful for Treating Mitochondrial Diseases (e.g., Friedreich's Ataxia) and Intermediates Related Thereto (a) Therapeutic compound In some embodiments, the present application provides novel compounds and compositions useful for treating mitochondrial diseases, such as Friedreich's ataxia, in mammalian subjects. The compounds and compositions (e.g., pharmaceutical preparations) may be formulated in any manner suitable for administration to a subject. For example, the compounds and compositions may be formulated as tablets, in a solution for subcutaneous injection, in a solution for intravenous injection, or in a gel, cream, or drops for topical or intraocular application. In some embodiments, the compounds and compositions may be used to prepare medicaments.

[0117] In some embodiments, the present application relates to compounds represented by formula EF, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein E is 21 or 22: [ka] and F is 13, 14, 15, 16, 17, 18, 19 or 20: [ka] where J is O, S or NR 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13 )—; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each X independently represents a group of the formula -(CR 12 R 13 each Y is independently absent or a group of the formula -(CR 12 R 13 each Z is independently a group of the formula -(CR 14 )-; each of R1, R2, and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic ring or heteroaromatic ring, or a 6-membered heterocyclic ring; each R8 and R9 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl; or R8 and R9 together form a 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic ring; R 10is H, D, F, Cl, Br, I, C-C alkyl or C-C alkoxy; R 11 is H, D, or C-C alkyl; each R 12 , R 13 and R 14 are independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 20 is H, D, F or C1-C 12 alkyl; each R 21 is H, D, F, Cl, Br, I, or C1-C4 alkyl; n is an integer from 0 to 12 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12); and *** indicates the point of attachment of E to F, and ** indicates the point of attachment of F to E; and further provided that (i) any of the formulae 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 in the formula (I) contains at least one fluorine atom; and / or (ii) R8 and R9 together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring. In some embodiments, at least one of R8 and R9 is fluorine or a substituted C1-C4 alkyl group containing at least one fluorine. In some embodiments, each of R8 and R9 is independently fluorine or a substituted C1-C4 alkyl group containing at least one fluorine. In some embodiments, each of R8 and R9 is fluorine. In some embodiments, R8, R9, and R 10 Each of R, R and R is fluorine. 10 are each independently fluorine or a substituted C1-C4 alkyl group containing at least one fluorine.

[0118] As used herein, in compounds such as those of formula EF, aromatic groups such as 21 and 22 may be referred to as "head" groups, and aliphatic groups such as 13, 14, 15, 16, 17, 18, 19, and 20 may be referred to as "tail" groups. Thus, the therapeutic compounds disclosed herein (not just compounds of formula EF) generally comprise an aromatic "head" group covalently bonded to an aliphatic "tail" group, where the aromatic head group is a quinone or hydroquinone. The quinone (or reduced hydroquinone) may be a substituted benzoquinone ring, naphthoquinone ring, or other aromatic ring.

[0119] Any combination of 21 and 22 with 13, 14, 15, 16, 17, 18, 19, or 20 is acceptable. In some embodiments, E is 21 and F is 13, 14, 19, or 20. In some embodiments, E is 22 and F is 13, 14, 19, or 20. In some embodiments, E is 21 and F is 15, 16, 17, or 18; in some embodiments, E is 22 and F is 15, 16, 17, or 18. In some embodiments, E is 21 and F is 13. In some embodiments, E is 21 and F is 14. In some embodiments, E is 21 and F is 15. In some embodiments, E is 21 and F is 16. In some embodiments, E is 21 and F is 17. In some embodiments, E is 21 and F is 18. In some embodiments, E is 21 and F is 19. In some embodiments, E is 21 and F is 20. In some embodiments, E is 22 and F is 13. In some embodiments, E is 22 and F is 14. In some embodiments, E is 22 and F is 15. In some embodiments, E is 22 and F is 16. In some embodiments, E is 22 and F is 17. In some embodiments, E is 22 and F is 18. In some embodiments, E is 22 and F is 19. In some embodiments, E is 22 and F is 20.

[0120] The atom or group represented by J is O, S, or NR 11 In some embodiments, J is O (oxygen). In some embodiments, J is S (sulfur). In some embodiments, J is NR 11 where R 11 is defined above. In some embodiments, J is O or NR 11 and K does not exist.

[0121] In some embodiments, the groups represented by K and L are each independently —(CH)—, —(CD)—, —(CHF)—, —(CF)—, —(CH(CH))—, —(CD(CD))—, —(CF(CH))—, —(CH(CF))—, —(CF(CF))—, —(C(CH))—, —(C(CD))—, —(C(CF)), —(CH(OCH))—, —(CD(OCD))—, —(CF(OCH))—, —(CH(OCF))—, —CF(OC F3))-, -(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, K is absent and L is selected from the group consisting of -(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 of K and L 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, K is absent and L is -(CH)-, -(CD)-, -(CF)-, -(CH(CH))-, -(CD(CD))-, -(CF(CF))-, -(C(CH))-, -(C(CD))-, -(C(CF))-, -(CH(OCH))-, -(CD(OCD))-, -(CF(OCF))-, or -(C(OCH))-. In some embodiments, each of K and L is independently -(CH)-, -(CD)-, -(CHF)-, -(CF)-, -(CH(CH))-, -(CF(CF))-, -(C(CH))-, or -(C(CF))-. In some embodiments, K is not present and L is -(CH)-, -(CD)-, -(CHF)-, -(CF)-, -(CH(CH))-, -(CF(CF))-, -(C(CH))-, or -(C(CF)). In some embodiments, each of K and L is independently -(CH)-, -(CD)-, -(CHF)-, or -(CF). In some embodiments, K is not present and L is -(CH)-, -(CD)-, -(CHF)-, or -(CF). In some embodiments, each of K and L is -(CH). In some embodiments, K is not present and L is -(CH). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, each of K and L is -(CF2)-. In some embodiments, K is absent and L is -(CF2)-.

[0122] In some embodiments of the compound represented by EF, E is 21 and each of R1, R2, and R3 is independently H, D, Cl, 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, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -OCH(CF3)2, -OCF2(CF3), -OCF(CF3)2, -O C(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, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments of the compound represented by EF, E is 21 and each of R1, R2, and R3 is independently 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 of the compound represented by EF, E is 21 and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments of the compound represented by EF, E is 21 and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, or -OCF3. In some embodiments of the compound represented by EF, E is 21 and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CF3, or -OCF3. In some embodiments of the compound represented by EF, E is 21 and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, or -CF3. In some embodiments of the compound represented by EF, E is 21 and each of R1, R2, and R3 is independently -CH3. In some embodiments of the compound represented by EF, E is 21 and each of R1, R2, and R3 is independently H. In some embodiments of the compound represented by EF, E is 21 and each of R1, R2, and R3 is independently H or -CH3. In some embodiments of the compound represented by EF, E is 21 and each of R1, R2, and R3 is independently H or -OCH3. In some embodiments of the compound represented by EF, E is 21 and each of R1, R2, and R3 is independently H, -CH3, or -OCH3. In some embodiments of the compound represented by EF, E is 21, each of R1 and R2 is -OCH3, and R3 is -CH3. In some embodiments of the compound represented by EF, E is 21, each of R1 and R2 is -CH3, and R3 is H. In some embodiments of the compound represented by EF, E is 21, each of R1 and R2 is -OCH3, and R3 is H. In some embodiments of the compound represented by EF, E is 21, and at least one of R1, R2, and R3 is F.

[0123] In some embodiments of the compound represented by EF, E is 21, J is O, and each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-; and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments of the compound represented by EF, E is 21, J is O, each of K and L is independently -(CH)-, -(CD)-, -(CHF)-, or -(CF), and each of R, R, and R is independently H, F, -CH, -OCH, -CHF, -CHF, -CF, or -OCF. In some embodiments of the compound represented by EF, E is 21, J is O, each of K and L is independently -(CH), -(CD), -(CHF), or -(CF), and each of R, R, and R is independently H, F, -CH, -OCH, -CF, or -OCF. In some embodiments of the compound represented by EF, E is 21, J is O; each of K and L is -(CH)-; and each of R1, R2, and R3 is -CH. In some embodiments of the compound represented by EF, E is 21, J is O; each of K and L is -(CH)-; and each of R1, R2, and R3 is H. In some embodiments of the compound represented by EF, E is 21, J is O; each of K and L is -(CH)-; and each of R1, R2, and R3 is CH. In some embodiments of the compound represented by EF, E is 21, J is O; each of K and L is -(CH)-; and each of R1, R2, and R3 is independently H or -CH. In some embodiments of the compounds represented by EF, E is 21, J is O; each of K and L is —(CH 2 )—; and each of R 1 , R 2 , and R 3 is independently H or —OCH 3 .In some embodiments of the compound represented by EF, E is 21, J is O; each of K and L is -(CH)-; and each of R, R, and R is independently H, -CH, or -OCH. In some embodiments of the compound represented by EF, E is 21, J is O; each of K and L is -(CH)-; each of R and R is -OCH, and R is -CH. In some embodiments of the compound represented by EF, E is 21, J is O; each of K and L is -(CH)-; each of R and R is -OCH, and R is H. In some embodiments of the compound represented by EF, E is 21, J is O; each of K and L is -(CH)-; each of R and R is -CH, and R is H. In some embodiments of the compound represented by EF, E is 21, J is O; each of K and L is —(CH)—; each of R and R is —OCH, and R is H. In some embodiments of the compound represented by EF, E is 21, J is O; each of K and L is —(CH)—; and at least one of R, R, and R is F.

[0124] In some embodiments of the compound represented by EF, E is 21, R is H, D, Cl, F, -CH, -OCH, -CD, -OCD, -CF, -OCF, -C(CH), -C(CD), -C(CF), -OC(CH), -OC(CD), -OC(CF), -CHCH, -OCHCH, or -CH(CH), and R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by EF, E is 21, (i) R is H, F, -CH, or -OCH, and (ii) R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by EF, E is 21, (i) R is H; and (ii) R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by EF, E is 21, (i) R is —CH; and (ii) R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by EF, E is 21, (i) R is —OCH; and (ii) R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by EF, E is 21, (i) R is F; and (ii) R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring.

[0125] In some embodiments of EF, R1 and R2 of 21 together form 21A, 21B, 21C, 21D, 21E, or 21F: [ka] where R 16 and R 17are each independently 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, -CH(CH3)2, -OCH(CH3)2, -C(CH3)3, or -O(CH3)3; and J" is O, S, or NR 18 where R 18 is H, D, —CH, —CHF, —CHF, or —CF. In some embodiments, R 16 and R 17 are each independently H, D, Cl, F, —CH, —OCH, —CD, —OCD, —CHF, —CHF, —CF, or —OCF. In some embodiments, R 16 and R 17 are each independently H, D, F, or -CH. In some embodiments, R 16 and R 17 is H. In some embodiments, R 16 and R 17 is F. In some embodiments, R 16 and R 17 is —CH3. In some embodiments, R 18 is H or -CH3.

[0126] In some embodiments of the compound represented by EF, E is 22 and R3 is H, D, Cl, 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), -C(CD3), -C(CF3), -OCH 2CH3, -OCH(CH3)2, -OCD2CD3, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -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, -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, -OCF2CF2CF3 or -OCF(CF2CF3)2; and W is C (carbon). When W is N (nitrogen), each of R4, R5, R6, and R7 attached thereto is independently H, D, F, Cl, Br, I, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2; and when W is N (nitrogen), each of R4, R5, R6, and R7 attached thereto is independently selected from absent, H, D, methyl, ethyl, isopropyl, or t-butyl. [ka] For each instance, the bond between each W is a single bond. [ka] In some embodiments, R is H, D, Cl, F, -CH, -OCH, -CD, -OCD, -CHF, -CHF, -CF, -OCF, -C(CH), -C(CD), -C(CF), -OC(CH), -OC(CD), -OC(CF), -CHCH, -OCHCH, or -CH(CH); and when W is C (carbon), and each of R, R, R, and R bonded thereto is independently H, D, F, Cl, -CH, -OCH, -CHF, -CHF, -CF, -OCF, -CHCH, or -CH(CH). When W is N (nitrogen), each of R, R, R, and R bonded thereto is independently absent or selected from H, D, methyl, and ethyl. In some embodiments, each W is C (carbon), and each of R, R, R, and R is independently H, D, Cl, F, -CH, -OCH, -CHF, -CHF, -CF, or -OCF. In some embodiments, each W is C (carbon), and each of R, R, R, and R is independently H, D, Cl, F, -CH, or -OCH. In some embodiments, each W is C (carbon) and each of R, R, R, and R is independently H, -CH, or -OCH. In some embodiments, each W is C (carbon) and each of R, R, R, and R is H. In some embodiments, each W is C (carbon) and each of R, R, R, and R is -CH.

[0127] In some embodiments of compound EF, each of 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(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, -CD2CD2CD3, -CD( It can be CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some embodiments of compound EF, each of R8 and R9 can independently be 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(CH2CH3)2, -CF2CF2CF3, or -CF(CF2CF3)2. In some embodiments of compound EF, each of R8 and R9 can independently be H, F, -CH3, -CH2F, -CHF2, or -CF3.

[0128] In some embodiments of compound EF, each of R and R can independently be a C-C alkyl group. The alkyl group can be substituted, for example, with one or more fluorine atoms. For example, the alkyl group can be fluoromethyl, difluoromethyl, or trifluoromethyl.

[0129] In some embodiments of compound EF, R and R together can form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring. For example, the 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring is 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47: [ka] where # indicates the point of attachment of the carbocyclic or heterocyclic ring to the remainder of the compound. In some embodiments, the 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring can include one or more fluorine substitutions. In some embodiments, the 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring can include one or more deuterium substitutions.

[0130] In some embodiments of compound EF, 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, -C H(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OCD(CD3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC(CD 3)3, -OC(CF3), -C(CH)(CF), -C(CH)(CF), -OC(CH)(CF), -OC(CH)(CF), -CHCHCH, -CH(CHCH), -CDCDCD, -CD(CDCD), -CFCFCF, -CF(CFCF), -C(CHCH), -C(CDCD), -C(CFCF), -OCHCHCH, -OCH(CHCH), -OCDCDCD, -OCD(CDCD), -OCFCFCF, or -OCF(CFCF). In some embodiments of compound EF, R 10 is H, D, F, —CH, —OCH, —CD, —OCD, —CHF, —OCHF, —CHF, —OCHF, —CF, —OCF, —CHCH, or —CH(CH). In some embodiments of compound EF, R 10 is H, D, F, —CH, —CHF, —CHF, or —CF. In some embodiments of compound EF, R 10is H, D, or F. In some embodiments of compound EF, R 10 is —CH or —CF. In some embodiments of compound EF, R 10 is —H or —CH. In some embodiments of compound EF, R 10 is H. In some embodiments of compound EF, R 10 is —CH3. In some embodiments of compound EF, R 10 is F. In some embodiments of compound EF, R 10 does not exist. In some embodiments of compound EF, R 11 is H, methyl, or ethyl. In some embodiments of compound EF, R 11 is H. In some embodiments of compound EF, R 11 is methyl. In some embodiments of compound EF, R 11 is ethyl.

[0131] In some embodiments of compound EF, R 12 , R 13 or R 14 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 EF, R 12 , R 13 or R 14 is independently H, D, F, —CH, —OCH, —CD, —OCD, —CHF, —OCHF, —CHF, —OCHF, —CF, or —OCF. In some embodiments of compound EF, R 12 , R 13 or R 14 is independently H, D, F, —CH, —CD, or —CF. In some embodiments of compound EF, R 12 , R13 or R 14 is independently H, D, or F. In some embodiments of compound EF, R 12 , R 13 or R 14 is independently H, F, or —CH. In some embodiments of compound EF, R 12 , R 13 or R 14 is H. In some embodiments of compound EF, R 12 , R 13 or R 14 is D. In some embodiments of compound EF, R 12 , R 13 or R 14 In each case, F.

[0132] In some embodiments of compound EF, R 20 is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In some embodiments of compound EF, R 20 is H, D, F, -CH, -CD, -CHF, -CHF, -CF, -CHCH, -CHCH, -CHCHCH, -CH(CH), or -C(CH). In some embodiments of compound EF, R 20 is H, D, F, —CH, —CD, —CHF, —CHF, or —CF. In some embodiments of compound EF, R 20 is H, D, F, —CH, —CD, —CHF, —CHF, or —CF. In some embodiments of compound EF, R 20 is —CH 3 , —CD 3 , —CH 2 F, —CHF 2 , or —CF 3 . In some embodiments of compound EF, R20 is H. In some embodiments of compound EF, R 20 is —CH3. In some embodiments of compound EF, R 20 is —CF. In some embodiments of compound EF, R 20 is F.

[0133] In some embodiments of compound EF, each R 21 is independently H, D, F, -CH, -CD, -CHF, -CHF, -CF, -CHCH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, or -C(CH). In some embodiments of compound EF, each R 21 is independently H, D, F, -CH, -CD, -CHF, -CHF, or -CF. In some embodiments of compound EF, each R 21 is independently H, —CH or —CF. In some embodiments of compound EF, each R 21 is —CH 3 . In some embodiments of compound EF, each R 21 is H. In some embodiments of compound EF, each R 21 is -CF3.

[0134] In some embodiments of Compound EF, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments of Compound EF, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of Compound EF, n is 0, 1, 2, 3, or 4. In some embodiments of Compound EF, n is 0. In some embodiments of Compound EF, n is 1. In some embodiments of Compound EF, n is 2. In some embodiments of Compound EF, n is 3. In some embodiments of Compound EF, n is 4. In some embodiments of Compound EF, n is 5. In some embodiments of Compound EF, n is 6. In some embodiments of Compound EF, n is 7. In some embodiments of Compound EF, n is 8. In some embodiments of Compound EF, n is 9. In some embodiments of Compound EF, n is 10. In some embodiments of Compound EF, n is 11. In some embodiments of Compound EF, n is 12.

[0135] Some embodiments of Compound EF have the formula referred to herein as Compound A. [ka] Some embodiments of Compound EF have the formula referred to herein as Compound B. [ka] Some embodiments of Compound EF have the formula referred to herein as Compound C. [ka] Some embodiments of Compound EF have the formula referred to herein as Compound D. [ka] Some embodiments of Compound EF have the formula referred to herein as Compound E. [ka] Some embodiments of Compound EF have the formula referred to herein as Compound F. [ka] Some embodiments of compound EF have the formula referred to herein as compound G. [ka] Some embodiments of Compound EF have the formula referred to herein as Compound H. [ka] Some embodiments of Compound EF have the formula referred to herein as Compound I. [ka] Some embodiments of Compound EF have the formula referred to herein as Compound J. [ka] Some embodiments of Compound EF have the formula referred to herein as Compound K. [ka] Some embodiments of Compound EF have the formula referred to herein as Compound L. [ka] Some embodiments of Compound EF have the formula referred to herein as Compound N. [ka]

[0136] As shown in Examples 17 and 18 below, certain compounds disclosed herein exhibit a high degree of potency in the BSO assay (Example 17) and the rotenone ATP assay (Example 18). More specifically, for some of the compounds disclosed herein, the potency and efficacy are similar to or greater than that of vatiquinone in ameliorating the effects of Friedreich's ataxia in a cell-based assay (see Example 17; BSO assay). Similarly, some of the compounds disclosed herein are also effective in rescuing cells that exhibit induction of complex I deficiency in the rotenone ATP assay (Example 18). In many cases, the compounds disclosed herein have moderate to good activity in both the BSO assay and the rotenone ATP assay (see Examples 17 and 18 and Table 2). In comparison, while several currently available therapeutic agents, such as batiquinone, idebenone, or omaveloxolone, may exhibit good or moderate activity in one or the other of the BSO assay or the rotenone ATP assay (see Table 2 below), none of them are active in both assays, suggesting that the compounds disclosed herein may exhibit unique mechanisms of action and, therefore, may be superior therapeutic agents compared to compounds currently being evaluated in clinical trials as therapeutic agents for the treatment of certain mitochondrial diseases (e.g., Friedreich's ataxia). Thus, it is believed that the therapeutic compounds disclosed herein are proven to be superior agents for the treatment of certain mitochondrial diseases, such as Friedreich's ataxia. The aforementioned compounds can be used in the preparation of compositions, such as medicaments. Thus, the compounds or compositions can be used in the treatment and / or prevention of mitochondrial diseases, such as Friedreich's ataxia.

[0137] As further demonstrated by Examples 19-22 (in combination with Examples 17 and 18), compounds disclosed herein protect cells from BSO-induced ferroptosis; demonstrate the unique ability to protect cells from RSL3-induced ferroptosis; and exhibit complex I bypass activity. No prior art compound appears to possess this unique combination of properties that would be therapeutically valuable in treating mitochondrial diseases such as Friedreich's ataxia.

[0138] (b) Intermediates for therapeutic drugs In addition to the novel agents provided herein for the treatment of Friedreich's ataxia, novel intermediates to the novel agents are also provided. In some embodiments, these intermediates are compounds of formula AB: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, where A is 1, 2, 3, or 4: [ka] and B is 5, 6, 7 or 8 [ka] where J is O, S or NR 11 and K is absent or -(CR 12 R 13 )- and L is -(CR 12 R 13 )—, and each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond), each X independently represents a group of the formula -(CR 12 R 13 )—, and each Y is independently absent or a group of the formula —(CR 12 R 13 )-, and each Z is independently a group of the formula -(CR 14 )-, wherein each of R, R, and R is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; or R and R together form a 5-membered carbocyclic, 5-membered heterocyclic, 5-membered aromatic or heteroaromatic, or 6-membered heterocyclic ring, and each R and R is independently H, D, F, Cl, Br, I, or C-C alkyl; or R and R together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, and R 10 is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, and R 11 is H, D or C1-C6 alkyl, and R 12 , R 13 and R 14 is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; 15is H, -CH3, -CH2CH3 or PG, where PG is a phenol protecting group, R 20 is H, D, F or C1-C 12 alkyl, and each R 21 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl; n is an integer from 0 to 12, inclusive; and *** indicates the point of attachment of A to B, and ** indicates the point of attachment of C to D; provided further that (i) any of the formulae 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 in the formula (I) contains at least one fluorine atom; and / or (ii) R8 and R9 together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring. In some embodiments, at least one of R8 and R9 is fluorine or a substituted C1-C4 alkyl group containing at least one fluorine. In some embodiments, each of R8 and R9 is independently fluorine or a substituted C1-C4 alkyl group containing at least one fluorine. In some embodiments, each of R8 and R9 is fluorine. In some embodiments, R8, R9, and R 10 Each of R, R and R is fluorine. 10 Each of is independently fluorine or a substituted C1-C4 alkyl group containing at least one fluorine. In some embodiments of AB, R 15 is H.

[0139] Any combination of 1, 2, 3, and 4 with 5, 6, 7, or 8 is possible. In some embodiments, A is 1 and B is 5, 6, 7, or 8. In some embodiments, A is 2 and B is 5, 6, 7, or 8. In some embodiments, A is 3 and B is 5, 6, 7, or 8. In some embodiments, A is 4 and B is 5, 6, 7, or 8. 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 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 3 and B is 5. In some embodiments, A is 3 and B is 6. In some embodiments, A is 3 and B is 7. In some embodiments, A is 3 and B is 8. In some embodiments, A is 4 and B is 5. In some embodiments, A is 4 and B is 6. In some embodiments, A is 4 and B is 7. In some embodiments, A is 4 and B is 8.

[0140] The atom or group represented by J is O, S, or NR 11 In some embodiments, J is O (oxygen). In some embodiments, J is S (sulfur). In some embodiments, J is NR 11 where R 11 is defined below. In some embodiments, J is O or NR 11 and K does not exist.

[0141] In some embodiments, the groups represented by K and L are each independently —(CH)—, —(CD)—, —(CHF)—, —(CF)—, —(CH(CH))—, —(CD(CD))—, —(CF(CH))—, —(CH(CF))—, —(CF(CF))—, —(C(CH))—, —(C(CD))—, —(C(CF)), —(CH(OCH))—, —(CD(OCD))—, —(CF(OCH))—, —(CH(OCF))—, —CF(OC F3))-, -(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, K is absent and L is selected from the group consisting of -(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 of K and L 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, K is absent and L is -(CH)-, -(CD)-, -(CF)-, -(CH(CH))-, -(CD(CD))-, -(CF(CF))-, -(C(CH))-, -(C(CD))-, -(C(CF))-, -(CH(OCH))-, -(CD(OCD))-, -(CF(OCF))-, or -(C(OCH))-. In some embodiments, each of K and L is independently -(CH)-, -(CD)-, -(CHF)-, -(CF)-, -(CH(CH))-, -(CF(CF))-, -(C(CH))-, or -(C(CF))-. In some embodiments, K is not present and L is -(CH)-, -(CD)-, -(CHF)-, -(CF)-, -(CH(CH))-, -(CF(CF))-, -(C(CH))-, or -(C(CF)). In some embodiments, each of K and L is independently -(CH)-, -(CD)-, -(CHF)-, or -(CF). In some embodiments, K is not present and L is -(CH)-, -(CD)-, -(CHF)-, or -(CF). In some embodiments, each of K and L is -(CH). In some embodiments, K is not present and L is -(CH). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, each of K and L is -(CF2)-. In some embodiments, K is absent and L is -(CF2)-.

[0142] In some embodiments of the compound represented by AB, A is 1 or 3 and each of R, R, and R is independently H, D, Cl, F, —CH, —OCH, —CD, —OCD, —CHF, —OCHF, —CHF, —OCHF, —CF, —OCF, —CHCH, —CH(CH), —CDCD, —CD(CD), —CFCH, CF(C H3)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, -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, -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(CD2CD 3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments of the compound represented by AB, A is 1 or 3 and each of R1, R2, and R3 is independently 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 of the compound represented by AB, A is 1 or 3 and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments of the compound represented by AB, A is 1 or 3 and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, or -OCF3. In some embodiments of the compound represented by AB, A is 1 or 3 and each of R1, R2, and R3 is independently H, F, -CH3, -CF3, -OCH3, or -OCF3. In some embodiments of the compound represented by AB, A is 1 or 3 and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, or -CF3. In some embodiments of the compound represented by AB, A is 1 or 3 and each of R1, R2, and R3 is independently -CH3. In some embodiments of the compound represented by AB, A is 1 or 3 and each of R1, R2, and R3 is independently H. In some embodiments of the compound represented by AB, A is 1 or 3 and each of R1, R2, and R3 is independently H or -CH3. In some embodiments of the compound represented by AB, A is 1 or 3 and each of R1, R2, and R3 is independently H or -OCH3. In some embodiments of the compound represented by AB, A is 1 or 3 and each of R1, R2, and R3 is independently H, -CH3, or -OCH3. In some embodiments of the compound represented by AB, A is 1 or 3, each of R1 and R2 is -OCH3, and R3 is -CH3. In some embodiments of the compound represented by AB, A is 1 or 3, each of R1 and R2 is -OCH3, and R3 is H. In some embodiments of the compound represented by AB, A is 1 or 3, each of R1 and R2 is -CH3, and R3 is H. In some embodiments of the compound represented by AB, A is 1 or 3, each of R1 and R2 is -OCH3, and R3 is H.In some embodiments of the compounds represented by AB, A is 1 or 3 and at least one of R 1 , R 2 , and R 3 is F.

[0143] In some embodiments of the compound represented by AB, A is 1 or 3, J is O, and each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-; and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments of the compound represented by AB, A is 1 or 3, J is O, each of K and L is independently -(CH)-, -(CD)-, -(CHF)-, or -(CF), and each of R, R, and R is independently H, F, -CH, -OCH, -CHF, -CHF, -CF, or -OCF. In some embodiments of the compound represented by AB, A is 1 or 3, J is O, each of K and L is independently -(CH), -(CD), -(CHF), or -(CF), and each of R, R, and R is independently H, F, -CH, -OCH, -CF, or -OCF. In some embodiments of the compound represented by AB, A is 1 or 3, J is O; each of K and L is -(CH)-; and each of R, R, and R is -CH. In some embodiments of the compound represented by AB, A is 1 or 3, J is O; each of K and L is -(CH)-; and each of R, R, and R is H. In some embodiments of the compound represented by AB, A is 1 or 3, J is O; each of K and L is -(CH)-; each of R and R is -OCH, and R is -CH. In some embodiments of the compound represented by AB, A is 1 or 3, J is O; each of K and L is -(CH)-; and each of R, R, and R is independently H or -OCH.In some embodiments of the compound represented by AB, A is 1 or 3, J is O; each of K and L is -(CH)-; and each of R, R, and R is independently H, -CH, or -OCH. In some embodiments of the compound represented by AB, A is 1 or 3, J is O; each of K and L is -(CH)-; each of R and R is -OCH, and R is -CH. In some embodiments of the compound represented by AB, A is 1 or 3, J is O; each of K and L is -(CH)-; each of R and R is -OCH, and R is -CH. In some embodiments of the compound represented by AB, A is 1 or 3, J is O; each of K and L is -(CH)-; each of R and R is -CH, and R is H. In some embodiments of the compound represented by AB, A is 1 or 3, J is O; each of K and L is —(CH)—; each of R and R is —OCH, and R is H. In some embodiments of the compound represented by AB, A is 1 or 3, each of K and L is —(CH)—, and at least one of R, R, and R is F.

[0144] In some embodiments of the compound represented by AB, A is 1 or 3, R is H, D, Cl, F, -CH, -OCH, -CD, -OCD, -CF, -OCF, -C(CH), -C(CD), -C(CF), -OC(CH), -OC(CD), -OC(CF), -CHCH, -OCHCH, or -CH(CH), and R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by AB, A is 1 or 3, (i) R is H, F, -CH, or -OCH, and (ii) R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by AB, A is 1 or 3, (i) R is H; and (ii) R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by AB, A is 1 or 3, (i) R is —CH; and (ii) R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by AB, A is 1 or 3, (i) R is —OCH; and (ii) R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by AB, A is 1 or 3, (i) R is F; and (ii) R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring.

[0145] In some embodiments, one or three of R and R together form 1A, 1B, 1C, 1D, 1E, 1F, 3A, 3B, 3C, 3D, 3E, or 3F: [ka] where R 16 and R 17each is independently 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, -CH(CH3)2, -OCH(CH3)2, -C(CH3)3, or -O(CH3)3; and J" is O, S, or NR 18 where R 18 is H, D, —CH, —CHF, —CHF, or —CF. In some embodiments, R 16 and R 17 are each independently H, D, Cl, F, —CH, —OCH, —CD, —OCD, —CHF, —CHF, —CF, or —OCF. In some embodiments, R 16 and R 17 are each independently H, D, F, or -CH. In some embodiments, R 16 and R 17 is H. In some embodiments, R 16 and R 17 is F. In some embodiments, R 16 and R 17 is —CH3. In some embodiments, R 18 is H or -CH3.

[0146] In some embodiments of the compound represented by AB, where A is 2 or 4, R is H, D, Cl, F, —CH, —OCH, —CD, —OCD, —CHF, —OCHF, —CHF, —OCHF, —CF, —OCF, —CHCH, —CH(CH), —CDCD, —CD(CD), —CFCH, —CF(CH), —CHCF, —CH(CF), —CFCF, —CF(CF), —C(CH), —C(CD), —C(CF). , -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -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, -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, -OCF2CF2CF3 or -OCF(CF2CF3)2; and W is C(Carbon When W is N (nitrogen), then each of R4, R5, R6, and R7 bonded thereto is independently H, D, F, Cl, Br, I, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2; and when W is N (nitrogen), then each of R4, R5, R6, and R7 bonded thereto is independently absent or selected from H, D, methyl, ethyl, isopropyl, and t-butyl. [ka] For each instance, the bond between each W is a single bond. [ka] In some embodiments, 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 when W is C (carbon), Each of R, R, R, and R bonded thereto is independently H, D, F, Cl, -CH, -OCH, -CHF, -CHF, -CF, -OCF, -CHCH, or -CH(CH); and when W is N (nitrogen), each of R, R, R, and R bonded thereto is independently absent or selected from H, D, methyl, and ethyl. In some embodiments, each W is C (carbon), and each of R, R, R, and R is independently H, D, Cl, F, -CH, -OCH, -CHF, -CHF, -CF, or -OCF. In some embodiments, each W is C (carbon), and each of R, R, R, and R is independently H, D, Cl, F, -CH, or -OCH. In some embodiments, each W is C (carbon) and each of R, R, R, and R is independently H, -CH, or -OCH. In some embodiments, each W is C (carbon) and each of R, R, R, and R is H. In some embodiments, each W is C (carbon) and each of R, R, R, and R is -CH.

[0147] In some embodiments of compound AB, each of R and R is independently H, D, F, Cl, Br, I, -CH, -CD, -CHF, -CHF, -CF, -CHCH, -CH(CH), -CDCD, -CD(CD), -CFCH, -CF(CH), -CHCF, -CH(CF), -CFCF, -CF(CF), -C(CH). , -C(CD3)3, -C(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD( It can be CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some embodiments of compound AB, each of R8 and R9 can independently be 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(CH2CH3)2, -CF2CF2CF3, or -CF(CF2CF3)2. In some embodiments of compound AB, each of R8 and R9 can independently be H, F, -CH3, -CH2F, -CHF2, or -CF3.

[0148] In some embodiments of compound AB, each of R and R can independently be a C-C alkyl group. The alkyl group can be substituted, for example, with one or more fluorine atoms. For example, the alkyl group can be fluoromethyl, difluoromethyl, or trifluoromethyl.

[0149] In some embodiments of compound AB, R and R together can be a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring. For example, the 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring is 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47: [ka] where # indicates the point of attachment of the carbocyclic or heterocyclic ring to the remainder of the compound. In some embodiments, the 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring can include one or more fluorine substitutions. In some embodiments, the 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring can include one or more deuterium substitutions.

[0150] 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, -C H(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OCD(CD3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC(CD 3)3, -OC(CF3), -C(CH)(CF), -C(CH)(CF), -OC(CH)(CF), -OC(CH)(CF), -CHCHCH, -CH(CHCH), -CDCDCD, -CD(CDCD), -CFCFCF, -CF(CFCF), -C(CHCH), -C(CDCD), -C(CFCF), -OCHCHCH, -OCH(CHCH), -OCDCDCD, -OCD(CDCD), -OCFCFCF, or -OCF(CFCF). In some embodiments of compound AB, R 10 is H, D, F, —CH, —OCH, —CD, —OCD, —CHF, —OCHF, —CHF, —OCHF, —CF, —OCF, —CHCH, or —CH(CH). In some embodiments of compound AB, R 10 is H, D, F, —CH, —CHF, —CHF, or —CF. In some embodiments of compound AB, R 10is H, D, or F. In some embodiments of compound AB, R 10 is —CH or —CF. In some embodiments of compound AB, R 10 is H or —CH. In some embodiments of compound AB, R 10 is H. In some embodiments of compound AB, R 10 is —CH3. In some embodiments of compound AB, R 10 does not exist.

[0151] In some embodiments of compound AB, R 11 is H, methyl, or ethyl. In some embodiments of compound AB, R 11 is H. In some embodiments of compound AB, R 11 is methyl. In some embodiments of compound AB, R 11 is ethyl.

[0152] In some embodiments of compound AB, R 12 , R 13 or R 14 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 is independently H, D, F, —CH, —OCH, —CD, —OCD, —CHF, —OCHF, —CHF, —OCHF, —CF, or —OCF. In some embodiments of compound AB, R 12 , R 13 or R 14 is independently H, D, F, —CH, —CD, or —CF. In some embodiments of compound AB, R 12 , R 13or R 14 is independently H, D, or F. In some embodiments of compound AB, R 12 , R 13 or R 14 is independently H, F, or —CH. In some embodiments of compound AB, R 12 , R 13 or R 14 is H. In some embodiments of compound AB, R 12 , R 13 or R 14 is D. In some embodiments of compound AB, R 12 , R 13 or R 14 In each case, F.

[0153] Atom or group R 15 may vary depending on the starting material and the desired product. For example, R 15 When R is a C1-C4 alkyl group, it is generally intended that this group remain in the final product, since such groups are not easily removed. 15 is methyl, ethyl, isopropyl, or t-butyl. In some embodiments, R 15 is —CH 3 . Thus, if a product (intermediate or therapeutic) bearing an alkyl group is desired, the starting material will generally contain an alkyl group. In some embodiments, R 15 is H (unprotected phenol). In some embodiments, R 15In some embodiments, the protecting group (PG), which temporarily protects the phenol during chemical synthesis, is ultimately removed to regenerate the unprotected phenol. For example, in some embodiments, the protecting group can be a triphenylmethyl-based protecting group. In some embodiments, triphenylmethyl-based protecting groups include triphenylmethyl-, 4-monomethyl-triphenylmethyl-, 4,4'-dimethyl-triphenylmethyl-, 4,4',4"-trimethyl-triphenylmethyl, 4-monomethoxy-triphenylmethyl-, 4,4'-dimethoxy-triphenylmethyl-, or 4,4',4"-trimethoxy-triphenylmethyl-. Triphenylmethyl-based protecting groups can generally be removed in the presence of a medium to strong acid. In some embodiments, the protecting group may be a silyl-based protecting group. Silyl protecting groups generally contain a silicon atom to which two to three (preferably three) alkyl groups are attached. Some non-limiting examples of silyl protecting groups include trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), and triisopropylsilyl (TIPS). Silyl protecting groups can generally be removed in the presence of fluoride ions. In some embodiments, R 15 is a substituted or unsubstituted benzyl group. In some embodiments, the benzyl group can remain in the therapeutic agent. In some embodiments, the benzyl group is used as a protecting group and can be removed, for example, by hydrogenation or treatment with strong acid.

[0154] 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, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In some embodiments of compound AB, R 20 is H, D, F, -CH, -CD, -CHF, -CHF, -CF, -CHCH, -CHCH, -CHCHCH, -CH(CH), or -C(CH). In some embodiments of compound AB, R 20 is H, D, F, —CH, —CD, —CHF, —CHF, or —CF. In some embodiments of compound AB, R 20 is H, D, F, —CH, —CD, —CHF, —CHF, or —CF. In some embodiments of compound AB, R 20 is —CH 3 , —CD 3 , —CH 2 F, —CHF 2 , or —CF 3 . In some embodiments of compound AB, R 20 is H. In some embodiments of compound AB, R 20 is —CH3. In some embodiments of compound AB, R 20 is —CF. In some embodiments of compound AB, R 20 is F.

[0155] In some embodiments of compound AB, each R 21 is independently H, D, F, -CH, -CD, -CHF, -CHF, -CF, -CHCH, -CHCH, -CH(CH), -CHCHCHCH, or -C(CH). 21 is independently H, D, F, —CH, —CD, —CHF, —CHF, or —CF. In some embodiments of compound AB, each R 21is independently H, —CH or —CF. In some embodiments of compound AB, each R 21 is —CH 3 . In some embodiments of compound AB, each R 21 is H. In some embodiments of compound AB, each R 21 is -CF3.

[0156] 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 0. In some embodiments of Compound AB, n is 1. 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.

[0157] In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has. In some embodiments of compound AB, the compound has the formula: [ka] It has.

[0158] (a) Other Derivatives / Therapeutic Agents In some embodiments, the present application further provides therapeutic compounds of formula CD (defined below), which can be prepared by reduction of a therapeutic compound of formula EF. Because other compounds with a hydroquinone structure, such as vitamin E, have been clinically associated with 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), such reduced compounds of the formula EF may also be suitable for use in treating mitochondrial diseases such as Friedreich's ataxia or other ataxias (e.g., ataxia associated with vitamin E deficiency (AVED)). For example, therapeutic compounds of formula CD (below) may be considered therapeutic agents themselves, or alternatively, may be considered prodrug forms of therapeutic agents of formula EF. Specifically, therapeutic compounds of formula EF are believed to be active in affecting in vivo concentrations of reactive oxygen species (ROS) (e.g., inner and outer mitochondrial concentrations) and may in fact actively cycle between reduced (compounds of formula CD) and oxidized (compounds of formula EF) forms in vivo. Compounds of formula EF can be converted to compounds of formula CD, for example, as described below in Examples 8 and 9. Additionally, compounds of formula CD were shown to be effective as lipoxygenase-15 (LO-15) inhibitors in Example 22.

[0159] Thus, in some embodiments, the present application further provides novel compounds of formula CD, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein C is 11 or 12: [ka] and D is 13, 14, 15, 16, 17, 18, 19 or 20: [ka] where J' is OH, SH or NH-R 11 and K is absent or -(CR 12 R 13 )- and L is -(CR 12 R 13 )—, and each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond), each X independently represents a group of the formula -(CR 12 R 13)—, and each Y is independently absent or a group of the formula —(CR 12 R 13 )-, and each Z is independently a group of the formula -(CR 14 )-, and each of R1, R2, and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; or R1 and R2 together form a 5-membered carbocyclic, 5-membered heterocyclic, 5-membered aromatic or heteroaromatic, or 6-membered heterocyclic ring, and each R8 and R9 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl; or R8 and R9 together are a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, and R 10 is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, and R 11 is H, D or C1-C6 alkyl, and R 12 , R 13 and R 14 is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; 19 is H, C1-C4 alkyl or benzyl (substituted or unsubstituted), and R 20 is H, D, F or C1-C 12 alkyl, and each R 21 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl; n is an integer from 0 to 12, inclusive; and *** indicates the point of attachment of C to D, and ** indicates the point of attachment of C to D; provided further that (i) any of the formulae R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 12 , R 13 , R 14 , R 20 or R 21at least one group in the formula (I) contains at least one fluorine atom; and / or (ii) R8 and R9 together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring. In some embodiments, at least one of R8 and R9 is fluorine or a substituted C1-C4 alkyl group containing at least one fluorine. In some embodiments, each of R8 and R9 is independently fluorine or a substituted C1-C4 alkyl group containing at least one fluorine. In some embodiments, each of R8 and R9 is fluorine. In some embodiments, R8, R9, and R 10 Each of R, R and R is fluorine. 10 is independently a fluorine or a substituted C-C alkyl group containing at least one fluorine. 19 is H.

[0160] Any combination of 11 and 12 with 13, 14, 15, 16, 17, 18, 19, or 20 is acceptable. In some embodiments, C is 12 and D is 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, C is 11 and D is 13, 14, 19, or 20. In some embodiments, C is 12 and D is 13, 14, 19, or 20. In some embodiments, C is 11 and D is 15, 16, 17, or 18. In some embodiments, C is 12 and D is 13, 14, 19, or 20. In some embodiments, C is 12 and D is 15, 16, 17, or 18. In some embodiments, C is 11 and D is 13. In some embodiments, C is 11 and D is 14. In some embodiments, C is 11 and D is 15. In some embodiments, C is 11 and D is 16. In some embodiments, C is 11 and D is 17. In some embodiments, C is 11 and D is 18. In some embodiments, C is 11 and D is 19. In some embodiments, C is 11 and D is 20. In some embodiments, C is 12 and D is 13. In some embodiments, C is 12 and D is 14. In some embodiments, C is 12 and D is 15. In some embodiments, C is 12 and D is 16. In some embodiments, C is 12 and D is 17. In some embodiments, C is 12 and D is 18. In some embodiments, C is 12 and D is 19. In some embodiments, C is 12 and D is 20.

[0161] The atom or group represented by J' is OH, SH, or NH-R 11 In some embodiments, J' is OH. In some embodiments, J' is S. In some embodiments, J' is NH-R 11 where R 11 is defined above. In some embodiments, J' is OH or NH-R 11 and K does not exist.

[0162] In some embodiments, the groups represented by K and L are each independently —(CH)—, —(CD)—, —(CHF)—, —(CF)—, —(CH(CH))—, —(CD(CD))—, —(CF(CH))—, —(CH(CF))—, —(CF(CF))—, —(C(CH))—, —(C(CD))—, —(C(CF)), —(CH(OCH))—, —(CD(OCD))—, —(CF(OCH))—, —(CH(OCF))—, —CF(OC F3))-, -(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, K is absent and L is selected from the group consisting of -(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 of K and L 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, K is absent and L is -(CH)-, -(CD)-, -(CF)-, -(CH(CH))-, -(CD(CD))-, -(CF(CF))-, -(C(CH))-, -(C(CD))-, -(C(CF))-, -(CH(OCH))-, -(CD(OCD))-, -(CF(OCF))-, or -(C(OCH))-. In some embodiments, each of K and L is independently -(CH)-, -(CD)-, -(CHF)-, -(CF)-, -(CH(CH))-, -(CF(CF))-, -(C(CH))-, or -(C(CF))-. In some embodiments, K is not present and L is -(CH)-, -(CD)-, -(CHF)-, -(CF)-, -(CH(CH))-, -(CF(CF))-, -(C(CH))-, or -(C(CF)). In some embodiments, each of K and L is independently -(CH)-, -(CD)-, -(CHF)-, or -(CF). In some embodiments, K is not present and L is -(CH)-, -(CD)-, -(CHF)-, or -(CF). In some embodiments, each of K and L is -(CH). In some embodiments, K is not present and L is -(CH). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, K is not present and L is -(CD). In some embodiments, each of K and L is -(CF2)-. In some embodiments, K is absent and L is -(CF2)-.

[0163] In some embodiments of the compound represented by CD, C is 11 and each of R1, R2, and R3 is independently H, D, Cl, 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, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -OCH(CF3)2, -OCF2(CF3), -OCF(CF3)2, -O C(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, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments of the compound represented by CD, C is 11 and each of R1, R2, and R3 is independently 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 of the compound represented by CD, C is 11 and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments of the compound represented by CD, C is 11 and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, or -OCF3. In some embodiments of the compound represented by CD, C is 11 and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CF3, or -OCF3. In some embodiments of the compound represented by CD, C is 11 and each of R1, R2, and R3 is independently H, F, —CH3, —OCH3, or —CF3. In some embodiments of the compound represented by CD, C is 11 and each of R1, R2, and R3 is independently —CH3. In some embodiments of the compound represented by CD, C is 11 and each of R1, R2, and R3 is independently H. In some embodiments of the compound represented by CD, C is 11 and each of R1, R2, and R3 is independently H or —CH3. In some embodiments of the compound represented by CD, C is 11 and each of R1, R2, and R3 is independently H or —OCH3. In some embodiments of the compound represented by CD, C is 11 and each of R1, R2, and R3 is independently H, —CH3, or —OCH3. In some embodiments of the compound represented by CD, C is 11, each of R1 and R2 is -OCH3, and R3 is -CH3. In some embodiments of the compound represented by CD, C is 11, each of R1 and R2 is -CH3, and R3 is H. In some embodiments of the compound represented by CD, C is 11, each of R1 and R2 is -OCH3, and R3 is H. In some embodiments of the compound represented by CD, C is 11, and at least one of R1, R2, and R3 is F.

[0164] In some embodiments of the compound represented by CD, C is 11, J' is OH, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-; and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -C(CH3)3, -C(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments of the compound represented by CD, C is 11, J' is OH, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, or -(CF2)-; and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, or -OCF3. In some embodiments of the compound represented by CD, C is 11, J' is OH, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, or -(CF2)-; and each of R1, R2, and R3 is independently H, F, -CH3, -OCH3, -CF3, or -OCF3. In some embodiments of the compound represented by CD, C is 11, J' is OH; each of K and L is -(CH2)-; and each of R1, R2, and R3 is -CH3. In some embodiments of the compound represented by CD, C is 11, J' is OH; each of K and L is -(CH2)-; and each of R1, R2, and R3 is independently H or -CH3. In some embodiments of the compound represented by CD, C is 11, J is O; each of K and L is -(CH2)-; and each of R1, R2, and R3 is independently H or -OCH3. In some embodiments of the compound represented by CD, C is 11, J' is OH; each of K and L is -(CH2)-; and each of R1, R2, and R3 is independently H, -CH3, or -OCH3.In some embodiments of the compound represented by CD, C is 11, J' is OH; each of K and L is -(CH2)-, and each of R1 and R2 is -OCH3, and R3 is -CH3. In some embodiments of the compound represented by CD, C is 11, J' is OH; each of K and L is -(CH2)-, and each of R1 and R2 is -OCH3, and R3 is H. In some embodiments of the compound represented by CD, C is 11, J' is OH; each of K and L is -(CH2)-, and each of R1 and R2 is -CH3, and R3 is H. In some embodiments of the compound represented by CD, C is 11, J' is OH; each of K and L is -(CH2)-, and each of R1 and R2 is -OCH3, and R3 is H. In some embodiments of the compounds represented by CD, C is 11, J' is OH; each of K and L is -(CH2)-, and at least one of R1, R2, and R3 is F.

[0165] In some embodiments of the compound represented by CD, C is 11, R is H, D, Cl, F, -CH, -OCH, -CD, -OCD, -CF, -OCF, -C(CH), -C(CD), -C(CF), -OC(CH), -OC(CD), -OC(CF), -CHCH, -OCHCH, or -CH(CH), and R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by CD, C is 11, (i) R is H, F, -CH, or -OCH, and (ii) R and R together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by CD, C is 11, (i) R3 is H; and (ii) R1 and R2 together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by CD, C is 11, (i) R3 is —CH3; and (ii) R1 and R2 together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by CD, C is 11, (i) R3 is —OCH3; and (ii) R1 and R2 together form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments of the compound represented by CD, C is 11, (i) R3 is F; and (ii) R1 and R2 together form a 5- or 6-membered carbocyclic or heterocyclic ring.

[0166] In some embodiments, R and R together form 11A, 11B, 11C, 11D, 11E, or 11F: [ka] where R 16 and R 17are each independently 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, -CH(CH3)2, -OCH(CH3)2, -C(CH3)3, or -O(CH3)3; and J" is OH, SH, or NH-R 18 where R 18 is H, D, —CH, —CHF, —CHF, or —CF. In some embodiments, R 16 and R 17 are each independently H, D, Cl, F, —CH, —OCH, —CD, —OCD, —CHF, —CHF, —CF, or —OCF. In some embodiments, R 16 and R 17 are each independently H, D, F, or -CH. In some embodiments, R 16 and R 17 is H. In some embodiments, R 16 and R 17 is F. In some embodiments, R 16 and R 17 is —CH3. In some embodiments, R 18 is H or -CH3.

[0167] In some embodiments of the compound represented by CD, C is 12 and R3 is H, D, Cl, 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), -C(CD3), -C(CF3), -OCH 2CH3, -OCH(CH3)2, -OCD2CD3, -OCD(CD3)2, -OCF2CH3, -OCF(CH3)2, -OCH2CF3, -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, -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, -OCF2CF2CF3 or -OCF(CF2CF3)2; and W is C (carbon) and when W is N (nitrogen), each of R4, R5, R6, and R7 attached thereto is independently H, D, F, Cl, Br, I, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2; and when W is N (nitrogen), each of R4, R5, R6, and R7 attached thereto is independently absent or selected from H, D, methyl, ethyl, isopropyl, and t-butyl. In some embodiments, [ka] For each instance, the bond between each W is a single bond. [ka] In some embodiments, R is H, D, Cl, F, -CH, -OCH, -CD, -OCD, -CHF, -CHF, -CF, -OCF, -C(CH), -C(CD), -C(CF), -OC(CH), -OC(CD), -OC(CF), -CHCH, -OCHCH, or -CH(CH); and when W is C (carbon), and each of R, R, R, and R bonded thereto is independently H, D, F, Cl, -CH, -OCH, -CHF, -CHF, -CF, -OCF, -CHCH, or -CH(CH); and when W is N (nitrogen), each of R, R, R, and R bonded thereto is independently absent or selected from H, D, methyl, and ethyl. In some embodiments, each W is C (carbon), and each of R, R, R, and R is independently H, D, Cl, F, -CH, -OCH, -CHF, -CHF, -CF, or -OCF. In some embodiments, each W is C (carbon), and each of R, R, R, and R is independently H, D, Cl, F, -CH, or -OCH. In some embodiments, each W is C (carbon) and each of R, R, R, and R is independently H, -CH, or -OCH. In some embodiments, each W is C (carbon) and each of R, R, R, and R is H. In some embodiments, each W is C (carbon) and each of R, R, R, and R is -CH.

[0168] In some embodiments of compound CD, each of R8 and R9 can independently be 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(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, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2C. In some embodiments of Compound CD, each of R and R can independently be H, F, -CH, -CHF, -CHF, -CF, -CHCH, -CH(CH), -CFCH, -CHCF, -CH(CF), -CFCF, -CF(CF), -C(CH), -C(CF), -CHCHCH, -CH(CHCH), -CFCFCF, or -CF(CFCF). In some embodiments of Compound CD, each of R and R can independently be H, F, -CH, -CHF, -CHF, or -CF.

[0169] In some embodiments of Compound CD, each of R and R can independently be a C-C alkyl group. The alkyl group can be substituted, for example, with one or more fluorine atoms. For example, the alkyl group can be fluoromethyl, difluoromethyl, or trifluoromethyl.

[0170] In some embodiments of Compound CD, R and R together can form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring. For example, the 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring is 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47: [ka] where # indicates the point of attachment of the carbocyclic or heterocyclic ring to the remainder of the compound. In some embodiments, the 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring can include one or more fluorine substitutions. In some embodiments, the 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring can include one or more deuterium substitutions.

[0171] In some embodiments of Compound CD, 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, -C H(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OCD(CD3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC(CD 3)3, -OC(CF3), -C(CH)2(CF), -C(CH)(CF3), -OC(CH3)2(CF), -OC(CH3)(CF3), -CH2CH2CH3, -CH(CH2CH3), -CD2CD2CD3, -CD(CD2CD3), -CF2CF2CF3, -CF(CF2CF3), -C(CH2CH3), -C(CD2CD3), -C(CF2CF3), -OCH2CH2CH3, -OCH(CH2CH3), -OCD2CD2CD3, -OCD(CD2CD3), -OCF2CF2CF3, or -OCF(CF2CF3). In some embodiments of compound CD, R 10 is H, D, F, —CH, —OCH, —CD, —OCD, —CHF, —OCHF, —CHF, —OCHF, —CF, —OCF, —CHCH, or —CH(CH). In some embodiments of compound CD, R 10 is H, D, F, —CH, —CHF, —CHF, or —CF. In some embodiments of compound CD, R 10 is H, D, or F. In some embodiments of compound CD, R10 is —CH or —CF. In some embodiments of compound CD, R 10 is H or —CH. In some embodiments of compound CD, R 10 is H. In some embodiments of compound EF, R 10 is —CH3. In some embodiments of compound CD, R 10 does not exist.

[0172] In some embodiments of Compound CD, R 11 is H, methyl, or ethyl. In some embodiments of compound CD, R 11 is H. In some embodiments of compound CD, R 11 is methyl. In some embodiments of compound CD, R 11 is ethyl.

[0173] In some embodiments of Compound CD, R 12 , R 13 or R 14 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 CD, R 12 , R 13 or R 14 is independently H, D, F, —CH, —OCH, —CD, —OCD, —CHF, —OCHF, —CHF, —OCHF, —CF, or —OCF. In some embodiments of compound CD, R 12 , R 13 or R 14 is independently H, D, F, —CH, —CD, or —CF. In some embodiments of compound CD, R 12 , R 13 or R 14is independently H, D, or F. In some embodiments of compound CD, R 12 , R 13 or R 14 is independently H, F, or —CH. In some embodiments of compound CD, R 12 , R 13 or R 14 is H. In some embodiments of compound CD, R 12 , R 13 or R 14 is D. In some embodiments of compound CD, R 12 , R 13 or R 14 In each case, F.

[0174] In some embodiments, R 19 is H. In some embodiments, R 19 is C1-C4 alkyl. For example, R 19 can be methyl, or R 19 can be ethyl, or R 19 can be isopropyl, or R 19 can be tert-butyl. In some embodiments, R 19 can be benzyl (substituted or unsubstituted). For example, in some embodiments, R 19 is the expression: [ka] wherein each A1 is independently H, D, F, Cl, Br, I, -CH3, -OCH3, CH2CH3, -OCH2CH3, trichloromethyl, or trifluoromethyl.

[0175] In some embodiments of Compound CD, R 20is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In some embodiments of compound CD, R 20 is H, D, F, -CH, -CD, -CHF, -CHF, -CF, -CHCH, -CHCH, -CH(CH), or -C(CH). In some embodiments of compound CD, R 20 is H, D, F, —CH, —CD, —CHF, —CHF, or —CF. In some embodiments of compound CD, R 20 is H, D, F, —CH, —CD, —CHF, —CHF, or —CF. In some embodiments of compound CD, R 20 is —CH 3 , —CD 3 , —CH 2 F, —CHF 2 , or —CF 3 . In some embodiments of compound CD, R 20 is H. In some embodiments of compound CD, R 20 is —CH3. In some embodiments of compound EF, R 20 is —CF. In some embodiments of compound CD, R 20 is F.

[0176] In some embodiments of Compound CD, each R 21 is independently H, D, F, -CH, -CD, -CHF, -CHF, -CF, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, or -C(CH). In some embodiments of compound CD, each R 21 is independently H, D, F, —CH, —CD, —CHF, —CHF, or —CF. In some embodiments of compound CD, each R 21is independently H, —CH or —CF. In some embodiments of compound CD, each R 21 is —CH 3 . In some embodiments of compound CD, each R 21 is H. In some embodiments of compound CD, each R 21 is -CF3.

[0177] In some embodiments of Compound CD, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments of Compound CD, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of Compound CD, n is 0, 1, 2, 3, or 4. In some embodiments of Compound CD, n is 0. In some embodiments of Compound CD, n is 1. In some embodiments of Compound CD, n is 2. In some embodiments of Compound CD, n is 3. In some embodiments of Compound CD, n is 4. In some embodiments of Compound CD, n is 5. In some embodiments of Compound CD, n is 6. In some embodiments of Compound CD, n is 7. In some embodiments of Compound CD, n is 8. In some embodiments of Compound CD, n is 9. In some embodiments of Compound CD, n is 10. In some embodiments of Compound CD, n is 11. In some embodiments of Compound CD, n is 12.

[0178] Some embodiments of Compound CD have the formula referred to herein as Compound A-2. [ka] Some embodiments of Compound CD have the formula referred to herein as Compound B-2. [ka] Some embodiments of Compound CD have the formula referred to herein as Compound C-2. [ka] Some embodiments of Compound CD have the formula referred to herein as Compound D-2. [ka] Some embodiments of Compound CD have the formula referred to herein as Compound E-2. [ka] Some embodiments of Compound CD have the formula referred to herein as Compound F-2. [ka] Some embodiments of Compound CD have the formula referred to herein as Compound G-2. [ka] Some embodiments of Compound CD have the formula referred to herein as Compound H-2. [ka] Some embodiments of Compound CD have the formula referred to herein as Compound I-2. [ka] Some embodiments of Compound CD have the formula referred to herein as Compound J-2. [ka] Some embodiments of Compound CD have the formula referred to herein as Compound K-2. [ka] Some embodiments of compound CD have the formula referred to herein as compound L-2. [ka] Some embodiments of Compound CD have the formula referred to herein as Compound N-2. [ka]

[0179] In some embodiments, the present application further provides therapeutic compounds comprising a substituted quinone head group to which is covalently attached an aliphatic tail group comprising at least one chiral center, at least one hydroxyl group, and at least one silicon atom. In some embodiments, such compounds can have the formula EG, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein E is 21 or 22: [ka] and G is 23 or 24: [ka] where J is O, S or NR 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13 )—; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each Q independently represents a group of the formula -(CR 12 R 13 )- group, O, or Si, provided that each O and each Si is not directly bonded to an O or an S; each of R1, R2, and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy, or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; R8', R9', and R 10 each of R' is independently C1-C4 alkyl, or R8' and R9' together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R 11 is H, D or C1-C6 alkyl; R 12 and R 13 each is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 20 is H, D, F or C1-C 12 alkyl; p is an integer from 0 to 20, inclusive; and *** indicates the point of attachment of E to G, and ** indicates the point of attachment of G to E. In some embodiments, R8′, R9′ and R 10Each of ' is independently methyl or ethyl.

[0180] In some embodiments, E is 21, J is O, K is —(CH)—, L is —(CH)—, and each of R, R, and R is independently selected from H, D, F, —CH, —OCH, and —OCF; each of R, R, and R 10 ' is independently methyl or ethyl, and R 20 is C1-C4 alkyl. In some embodiments, each of R1, R2, and R3 is independently H, -CH3, or -OCH3. In some embodiments, each of R1, R2, and R3 is independently H or -CH3. In some embodiments, each of R1, R2, and R3 is -CH3.

[0181] In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O and each other Q is -(CH2)-. In some embodiments, at least one Q is Si and each other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O and the remaining Q' are -(CH2)-.

[0182] In some embodiments, EG is compound M-0 or M-0′: [ka] wherein each of R1, R2, and R3 is independently H, F, —CH3, —OCH3, —CH2CH3, —OCH2CH3, or —OCF3; p' is an integer from 1 to 9, inclusive; and tp" is an integer from 1 to 9, inclusive. In some embodiments, each of R1, R2, and R3 is independently H, —CH3, or —OCH3. In some embodiments, each of R1, R2, and R3 is independently H or —CH3. In some embodiments, each of R1, R2, and R3 is —CH3. In some embodiments, each of p' and p" is independently an integer from 1 to 4, inclusive.

[0183] In some embodiments, EG is compound M or compound M': [ka] is.

[0184] In some embodiments, the present application further provides a therapeutic compound comprising a substituted hydroquinone head group having covalently attached thereto an aliphatic tail group comprising at least one chiral center, at least one hydroxyl group, and at least one silicon atom. Thus, in some embodiments, the present application further provides a therapeutic compound or intermediate of formula CG, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein C is 11 or 12: [ka] and G is 23 or 24: [ka] where J' is OH, SH, or NH-R 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13 )—; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each Q independently represents a group of the formula -(CR 12 R 13 )- group, O, or Si, provided that each O and each Si is not directly bonded to an O or an S; each of R1, R2, and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy, or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; R8', R9', and R 10 each of R' is independently C1-C4 alkyl, or R8' and R9' together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R 11 is H, D or C1-C6 alkyl; R 12 and R 13 each is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 19 is H, C1-C4 alkyl or benzyl (substituted or unsubstituted); R 20 is H, D, F or C1-C 12 alkyl; p is an integer from 0 to 20, inclusive; and*** indicates the point of attachment of C to G, and ** indicates the point of attachment of G to C. In some embodiments, R8′, R9′ and R 10 Each of ' is independently methyl or ethyl.

[0185] In some embodiments, C is 11, J' is OH, K is -(CH2)-, L is -(CH2)-, each of R1, R2, and R3 is independently selected from H, D, F, -CH3, -OCH3, and -OCF3, and R8', R9', and R 10 each ' is independently methyl or ethyl; R 19 is H, and R 20 is C1-C4 alkyl. In some embodiments, each of R1, R2, and R3 is independently H, -CH3, or -OCH3. In some embodiments, each of R1, R2, and R3 is independently H or -CH3. In some embodiments, each of R1, R2, and R3 is -CH3.

[0186] In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O and each other Q is -(CH2)-. In some embodiments, at least one Q is Si and each other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O and the remaining Q' are -(CH2)-.

[0187] In some embodiments, CG is compound M-3 or compound M-3′: [ka] wherein each of R1, R2, and R3 is independently H, F, —CH3, —OCH3, —CH2CH3, —OCH2CH3, or OCF3; p' is an integer from 1 to 9, inclusive; and p" is an integer from 1 to 9, inclusive. In some embodiments, each of R1, R2, and R3 is independently H, —CH3, or —OCH3. In some embodiments, each of R1, R2, and R3 is independently H or —CH3. In some embodiments, each of R1, R2, and R3 is —CH3. In some embodiments, each of p' and p" is independently an integer from 1 to 4, inclusive.

[0188] In some embodiments, CG is compound M-2 or M-2′: [ka] is.

[0189] In some embodiments, the present application further provides a therapeutic compound or therapeutic compound intermediate comprising a precursor of an aromatic quinone or hydroquinone head group to which is attached a precursor of an aliphatic tail group comprising at least one chiral center, at least one hydroxyl group, and at least one silicon atom. In some embodiments, the present application relates to a compound of formula AH, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein A is 1, 2, 3, or 4: [ka] and H is 25: [ka] where J is O, S or NR 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13 )—; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each Q independently represents a group of the formula -(CR 12 R 13 )- group, O, or Si, provided that each O and each Si is not directly bonded to an O or an S; each of R1, R2, and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy, or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; R8', R9', and R 10 each of R' is independently C1-C4 alkyl, or R8' and R9' together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R 11 is H, D or C1-C6 alkyl; R 12 and R 13 each is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 15 is H, C1-C4 alkyl or PG, where PG is a phenol protecting group; R 20 is H, D, F or C1-C 12alkyl; p is an integer from 0 to 20, inclusive; and *** indicates the point of attachment of A to H, and ** indicates the point of attachment of H to A. In some embodiments, R8′, R9′ and R 10 Each of ' is independently methyl or ethyl.

[0190] In some embodiments, A is 1 or 3, J is O, K is —(CH)—, L is —(CH)—, and each of R, R, and R is independently selected from H, D, F, —CH, —OCH, and —OCF; 10 ' is independently methyl or ethyl, and R 15 is H or PG. In some embodiments, each of R1, R2, and R3 is independently H, —CH3, or —OCH3. In some embodiments, each of R1, R2, and R3 is independently H or —CH3. In some embodiments, each of R1, R2, and R3 is —CH3.

[0191] In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O and each other Q is -(CH2)-. In some embodiments, at least one Q is Si and each other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O and the remaining Q' are -(CH2)-.

[0192] In some embodiments, AH is compound M-4 or M-4′: [ka] wherein each of R1, R2, and R3 is independently H, F, —CH3, —OCH3, —CH2CH3, —OCH2CH3, or OCF3; p' is an integer from 1 to 9, inclusive; and p" is an integer from 1 to 9, inclusive. In some embodiments, each of R1, R2, and R3 is independently H, —CH3, or —OCH3. In some embodiments, each of R1, R2, and R3 is independently H or —CH3. In some embodiments, each of R1, R2, and R3 is —CH3. In some embodiments, each of p' and p" is independently an integer from 1 to 4, inclusive.

[0193] In some embodiments, AH is compound M-5 or M-5′: [ka] is.

[0194] In some embodiments, the present application further provides a therapeutic compound of formula EI, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein E is 21 or 22: [ka] and I is 26 or 27: [ka] where J is O, S or NR 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13 )—; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each Q independently represents a group of the formula -(CR 12 R 13 )- group, O, or Si, with the proviso that each O and each Si is not directly bonded to O or S; each of R1, R2, and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy, or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; each of R8", R9", and R 10 are independently H, F, or C1-C4 alkyl, provided that R8", R9", and R 10 " at least one of them is F;R 11 is H, D or C1-C6 alkyl; R 12 and R 13 each is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 20 is H, D, F or C1-C 12 alkyl; p is an integer from 0 to 20, inclusive; and *** is the attachment point of E to I, and ** is the point of attachment of I to E. In some embodiments, R, R and R 10At least one of R, R and R is F. In some embodiments, at least one of R, R and R is F. 10 Each of R, R and R is independently H or F. In some embodiments, R, R and R 10 " is F.

[0195] In some embodiments, E is 21, J is O, K is —(CH)—, L is —(CH)—, each of R, R, and R is independently selected from H, D, F, —CH, —OCH, and —OCF; and each of R, R, and R 10 " are independently H or F, and R 20 is C1-C4 alkyl. In some embodiments, each of R1, R2, and R3 is independently H, -CH3, or -OCH3. In some embodiments, each of R1, R2, and R3 is independently H or -CH3. In some embodiments, each of R1, R2, and R3 is -CH3.

[0196] In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O and each other Q is -(CH2)-. In some embodiments, at least one Q is Si and each other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O and the remaining Q' are -(CH2)-.

[0197] In some embodiments, EI is compound N-0 or N-0′: [ka] wherein each of R1, R2, and R3 is independently H, F, —CH3, —OCH3, —CH2CH3, —OCH2CH3, or —OCF3; Q is —(CH2)—, O, or Si; p' is an integer from 0 to 9, inclusive; and p" is an integer from 0 to 9, inclusive. In some embodiments, Q is —(CH2)—. In some embodiments, each of R1, R2, and R3 is independently H, —CH3, or —OCH3. In some embodiments, each of R1, R2, and R3 is independently H or —CH3. In some embodiments, each of R1, R2, and R3 is —CH3. In some embodiments, each of p' and p" is independently an integer from 0 to 4, inclusive.

[0198] In some embodiments, EI is compound N or compound N′: [ka] is.

[0199] In some embodiments, the present application further provides a therapeutic compound or intermediate of formula CI, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein C is 11 or 12: [ka] and I is 26 or 27: [ka] where J' is OH, SH or NH-R 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13 )—; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each Q independently represents a group of the formula -(CR 12 R 13 )- group, O, or Si, with the proviso that each O and each Si is not directly bonded to O or S; each of R1, R2, and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy, or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; each of R8", R9", and R 10 are independently H, F, or C1-C4 alkyl, provided that R8", R9", and R 10 " at least one of them is F;R 11 is H, D or C1-C6 alkyl; R 12 and R 13 each is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 19 is H, C1-C4 alkyl or benzyl (substituted or unsubstituted); R 20 is H, D, F or C1-C 12 alkyl; p is an integer from 0 to 20, inclusive; and *** indicates the point of attachment of C to I, and **indicates the point of attachment of I to C. In some embodiments, R8", R9" and R 10 Each of R, R and R is independently H or F. In some embodiments, R, R and R 10 At least one of R, R and R is F. In some embodiments, at least one of R, R and R is F. 10 " is F.

[0200] In some embodiments, C is 11, J' is OH, K is -(CH2)-, L is -(CH2)-, each of R1, R2, and R3 is independently selected from H, D, F, -CH3, -OCH3, and -OCF3, and each of R8", R9", and R 10 " are independently H or F, and R 19 is H and R 20 is C1-C4 alkyl. In some embodiments, each of R1, R2, and R3 is independently H, -CH3, or -OCH3. In some embodiments, each of R1, R2, and R3 is independently H or -CH3. In some embodiments, each of R1, R2, and R3 is -CH3.

[0201] In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O and each other Q is -(CH2)-. In some embodiments, at least one Q is Si and each other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O and the remaining Q' are -(CH2)-.

[0202] In some embodiments, CI is compound N-3 or N-3': [ka] wherein each of R1, R2, and R3 is independently H, F, —CH3, —OCH3, —CH2CH3, —OCH2CH3, or OCF3; Q is —(CH2)—, O, or Si; p' is an integer from 0 to 9, inclusive; and p" is an integer from 0 to 9, inclusive. In some embodiments, Q is —(CH2)—. In some embodiments, each of R1, R2, and R3 is independently H, —CH3, or —OCH3. In some embodiments, each of R1, R2, and R3 is independently H or —CH3. In some embodiments, each of R1, R2, and R3 is —CH3. In some embodiments, each of p' and p" is independently an integer from 0 to 4, inclusive.

[0203] In some embodiments, CG is compound N-2 or N-2′: [ka] is.

[0204] In some embodiments, the present application further provides a therapeutic compound or intermediate of formula AU, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein A is 1, 2, 3, or 4: [ka] and U is 28: [ka] where J is O, S or NR 11 and K is absent or -(CR 12 R 13 )-; L is -(CR 12 R 13 )—; each W is independently C (carbon) or N (nitrogen), where: [ka] For each use of, the bond between each W may be a single bond or a double bond, with the further proviso that, in the case of a single bond, each C (carbon) atom has a hydrogen atom bonded thereto in addition to one of R4, R5, R6, or R7, and in each case, each of R4, R5, R6, and R7 bonded thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and when W is N (nitrogen), each of R4, R5, R6, and R7 bonded thereto is independently absent ( [ka] is a double bond), or is selected from H, D and C1-C6 alkyl ( [ka] is a single bond; each Q independently represents a group of the formula -(CR 12 R 13 )- group, O, or Si, with the proviso that each O and each Si is not directly bonded to O or S; each of R1, R2, and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy, or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; each of R8", R9", and R 10 are independently H, F, or C1-C4 alkyl, provided that R8", R9", and R 10 " at least one of them is F;R 11 is H, D or C1-C6 alkyl; R 12 and R 13 each is independently H, D, F, Cl, Br, I, C-C alkyl, or C-C alkoxy; R 15 is H, C1-C4 alkyl or PG, where PG is a phenol protecting group; R 20 is H, D, F or C1-C 12 alkyl; p is an integer from 0 to 20, inclusive; and *** indicates the point of attachment of A to U, and **indicates the point of attachment of U to A. In some embodiments, R8", R9", and R 10 Each of R, R and R is independently H or F. In some embodiments, R, R and R 10 At least one of R, R and R is F. In some embodiments, at least one of R, R and R is F. 10 " is F.

[0205] In some embodiments, A is 1 or 3, J is O, K is —(CH)—, L is —(CH)—, and each of R, R, and R is independently selected from H, D, F, —CH, —OCH, and —OCF; and each of R, R, and R 10 " are independently H or F, and R 15 is H or PG. In some embodiments, each of R1, R2, and R3 is independently H, —CH3, or —OCH3. In some embodiments, each of R1, R2, and R3 is independently H or —CH3. In some embodiments, each of R1, R2, and R3 is —CH3. In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O and each other Q is -(CH2)-. In some embodiments, at least one Q is Si and each other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O and the remaining Q' are -(CH2)-.

[0206] In some embodiments, AH is compound N-4 or compound N-4′: [ka] wherein each of R1, R2, and R3 is independently H, F, —CH3, —OCH3, —CH2CH3, —OCH2CH3, or OCF3; Q is —(CH2)—, O, or Si; p' is an integer from 0 to 9, inclusive; and p" is an integer from 0 to 9, inclusive. In some embodiments, Q is —(CH2)—. In some embodiments, each of R1, R2, and R3 is independently H, —CH3, or —OCH3. In some embodiments, each of R1, R2, and R3 is independently H or —CH3. In some embodiments, each of R1, R2, and R3 is —CH3. In some embodiments, each of p' and p" is independently an integer from 0 to 4, inclusive. In some embodiments, AU is compound 104 or compound 104': [ka] is.

[0207] VI. Methods for Making Therapeutic Compounds and Related Intermediates In some embodiments, the present application relates to methods for preparing the novel compositions disclosed herein. Suitable methods are generally shown in Figures 1A, 1B, 1C, 1D, 2A, 2B, 2C, 2D, and 3. Specific examples of the use of the general methodology for the preparation of specific novel compounds can be found in Examples 1-7 and 9-10, below. The schematics shown in Figures 1A, 1B, 1C, 1D, 2A, 2B, 2C, and 2D and the following description are closely related to Scheme 2 (below) and the related description in Example 1. The schematic shown in Figure 3 and the following description of the preparation of compounds of formula 203 are closely related to the description in Scheme 1 (below) and Example 1. A general method for the reduction of therapeutic compounds of general formula IO to other therapeutic compounds of general formula I-OR can be found in Figure 4 and Examples 9 and 10.

[0208] Referring to Figure 1A, a compound of formula 204 is provided. Representative known compounds of formula 204 can be found in Figures 6A, 6B, and 6C (a Chemical Abstracts Service (CAS) Registry Number is provided for each known compound shown). The asterisk shown in the compound of formula 204 (and for all other compounds shown in the figures) identifies a chiral center. If available, a stereochemically pure compound of formula 204 (i.e., a pure enantiomer of 204 or 205, if it is the starting material as described below) can be used in the methods described herein, although this is neither a requirement nor a limitation. A racemic mixture of 204 (or 205) can be used because the process generates diastereomers in steps d and e (described below) that can be separated by chromatographic (or other) techniques, including the examples described herein.

[0209] In the compound of formula 204, J, K, L, R, R, R and R 20 is as defined above. In some embodiments, R 30 is H. In some embodiments, the phenol may be (temporarily) 30 is a protecting group PG) or with a more permanent group such as methyl, ethyl, isopropyl or tert-butyl ether (in this case R 30 may be a C1-C6 alkyl group). In these cases, R 30 represents a phenol protecting group. If all phenols are protected, it is not necessary to perform step b. (below) to obtain compounds of formula 206.

[0210] The carboxylic acid compound of formula 204 can be converted to an ester of formula 205 under suitable conditions. The conversion of a carboxylic acid to an ester is a well-known chemical method. Any suitable method known in the art may be used to accomplish this conversion of a carboxylic acid to an ester, but the method described in step a. of Scheme 2 in Example 1 is particularly illustrated. As described in step a. of Scheme 2 in Example 1, methyl ester (5) is generated by heating (4) in methanol in the presence of p-toluenesulfonic acid (PTSA), thereby obtaining (5). Higher esters can be prepared by using an appropriate alternative alcohol or by applying other methods known in the art. Alternatively, referring to Figure 1A, an ester compound of formula 205 is provided. As can be seen from Figures 6A, 6B, and 6C, various esters of formula 205 are commercially known and / or available.

[0211] In the compound of formula 205, J, K, L, R1, R2, R3, R 20 and R 30 is as defined above. The group R 31 represents any C1-C6 alkyl or benzyl group, but is generally methyl, ethyl, or benzyl. 30 When is not H, the compound of formula 205 is the same as the compound of formula 206, described below.

[0212] Referring to FIG. 1A, a compound of formula 205 (wherein R 30It can be seen that phenol (wherein is H) can be converted to a compound of formula 206 by protection of the exocyclic phenol. Any suitable method known in the art can be used to accomplish this conversion of a phenol to a protected phenol, but the method described in step b. of Scheme 2 in Example 1 is particularly illustrated. In step b. of Example 1, the phenol of (5) is alkylated with benzyl bromide in DMF (as solvent) in the presence of KCO (as base) at room temperature, thereby producing the benzyl ether (6). Any benzyl halide can be used to generate a substituted or unsubstituted benzyl protecting group attached to the phenol. Generally, the protection reaction proceeds in a dry aprotic solvent in the presence of a base (inorganic or organic). However, any suitable protecting group and any suitable conditions can be used. For example, the phenol can be protected with a triphenylmethyl-based protecting group, for example, by using triphenylmethyl chloride and similar conditions. Alternatively, the phenol can be protected with a silyl-based protecting group, for example, by using tert-butyldimethylsilyl chloride and similar conditions. In some embodiments, the phenol can optionally be reacted with a reagent to produce a more permanent modification, such as, for example, methyl iodide, ethyl iodide, or isopropyl iodide, thereby producing a methyl ether, ethyl ether, or isopropyl ether, respectively.

[0213] In the compound of formula 206, J, K, L, R1, R2, R3, R 20 and R 31 is as defined above. The group R 32 represents any phenol protecting group (e.g., a C1-C4 alkyl group, a triphenylmethyl protecting group, a silyl protecting group, or a benzyl protecting group), while R 32 is not hydrogen (H).

[0214] Referring to FIG. 1A, it can be seen that compounds of formula 206 can be converted to compounds of formula 207 by converting the ester group back to a carboxylic acid (a process known as ester saponification). Ester saponification is a well-known chemical method. Any suitable method known in the art may be used to accomplish this conversion of an ester to a carboxylic acid, but the method described in step c. of Scheme 2 in Example 1 is particularly illustrated. Generally, this method involves treating the ester in water or a mixture of water and a water-miscible organic solvent (e.g., methanol, ethanol, tetrahydrofuran, and / or acetonitrile) with a strong base such as sodium hydroxide, potassium hydroxide, or lithium hydroxide for a period of time necessary to saponify the ester, followed by neutralization with an acid (typically a strong acid such as hydrochloric acid) to generate the carboxylic acid from the carboxylate anion. Depending on the nature of the starting materials, the reaction can be carried out at low, room, or elevated temperatures. In compounds of formula 207, J, K, L, R, R, R, R, and R are independently selected from the group consisting of carboxylic acid, ... 20 and R 32 is as defined above.

[0215] With reference to FIG. 1A, it can be seen that a compound of formula 207 can be converted to a compound of formula 209, for example, by conversion of the acid group to a mixed anhydride. The formation of mixed anhydrides is a well-known chemical method. Any suitable method known in the art may be used to accomplish this conversion of a carboxylic acid to a mixed anhydride, but in particular the method set forth in step d. of Scheme 2 in Example 1 is illustrated. Generally, this conversion is carried out by reacting a (inorganic or organic) base and an acid chloride (shown as a compound of formula 208 (FIG. 1A), where R 33 is any alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylheteroalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, or heteroaryl group known in the art; and is shown as 8 in Scheme 2. This reaction can be carried out at low temperatures (e.g., −30° C.). In the compound of Formula 209, J, K, L, R, R, R, R 20 and R 32is as defined above. In general, R 33 is a bulky group such as t-butyl or adamantyl. Mixed anhydrides tend to be unstable (especially susceptible to hydrolysis in the presence of water), and are generally (although not necessarily) used directly in subsequent reactions without isolation or purification.

[0216] Referring to Figure 1A, it can be seen that the compound of formula 209 can be converted to the diastereomer of formula 211a or 211b by reaction with the appropriate chiral oxazolidin-2-one (in Figure 1A, the compound of formula 210 is shown). Any suitable method known in the art can be used to effect this conversion, but in particular the method described in steps d and e of Scheme 2 in Example 1 is shown. Generally, as shown in Example 1, the mixed anhydride can be reacted with n-butyllithium ( n In the compounds of formula 211a and 211b, J, K, L, R, R, R 20 and R 32 is as defined above. While a mixture of stereoisomers can be used to proceed to the next step, the use of chiral compound 210 produces diastereoisomers that can be separated by chromatography (or other methods). Because therapeutic agents are generally stereochemically pure, this mixture is often chromatographically separated to produce isolated compounds of formula 211a and formula 211b, although this is neither a requirement nor a limitation. Thus, the products of the next reaction are stereochemically pure or stereochemical mixtures (even if not purified in the next reaction) based on the nature of the starting materials. When stereochemical mixtures are obtained, these compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if stereochemically pure products are desired.

[0217] 1A, it can be seen that compounds of formula 211a and / or 211b can be converted to compounds of formula 212 by conversion of the amide to an alcohol. Any suitable method known in the art can be used to accomplish this conversion, but the method described in step f. of Scheme 2 in Example 1 is particularly illustrated. Generally, as seen in Example 1, stereochemically pure 11b can be produced by treatment with lithium aluminum hydride (LiH) under anhydrous conditions at low temperature in an aprotic solvent to generate alcohol 12. In compounds of formula 212, J, K, L, R1, R2, R3, R 20 and R 32 is as defined above. Compounds of formula 212 can be stereochemically pure or stereochemically mixed. If a stereochemically mixed compound, these compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired.

[0218] 1A, it can be seen that compounds of formula 212 can be converted to compounds of formula 213 by reaction of the alcohol group with trifluoromethanesulfonic anhydride (or other groups that render the alcohol derivative susceptible to nucleophilic attack, such as tosyl). Any suitable method known in the art can be used to accomplish this conversion, but the method described in step g of Scheme 2 in Example 1 is particularly illustrated. Generally, as seen in Example 1, 12 can be converted to 13 by treatment with trifluoromethanesulfonic anhydride and pyridine in DCM at low temperature (e.g., 0°C). In compounds of 213, the groups of formula J, K, L, R, R, R, R 20 and R 32is as defined above, and "OTf" refers to a trifluoromethanesulfonyl-protected hydroxyl group. Compounds of Formula 213 can be stereochemically pure or stereochemically mixed. If a stereochemically mixed compound, these compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired.

[0219] Referring to Figure 1A, it can be seen that a compound of formula 213 can be converted to a compound of formula 214 by reaction with a compound of formula 203. The compound of formula 203 can be purchased from an available source or can be prepared as described below with reference to Figure 3 and the associated description of Scheme 1 and Example 1. Any suitable method known in the art can be used to effect this conversion, but in particular the method described in step h. of Scheme 2 in Example 1 is illustrated. Generally, as seen in Example 1, this reaction involves dissolving or suspending (3) and hexamethylphosphoramide in an aprotic solvent (e.g., THF) at low temperature (e.g., -78°C), followed by: n This is accomplished by adding BuLi dropwise followed by trifluoromethane sulfonate (13). In the compound of formula 214, J, K, L, R, R, R, R 20 and R 32 is as defined above. In compounds of formula 214, the group B' is a group of formula: [ka] wherein X, Y, R, R, R 21 is as defined above, n' is 0 to 11 inclusive, and # indicates the point of attachment. [ka] Each bond appearing as is either a single bond or a double bond. [ka] is a double bond, each Z' is Z as defined above, and R 10 ' does not exist. [ka] is a single bond, then each Z' is X as defined above, and R 10 ' is R as defined above 10 The abbreviation Ph refers to a phenyl group (the complete structure of 203 is shown in Figure 3). Compounds of formula 214 can be stereochemically pure or stereochemical mixtures. If stereochemical mixtures, these compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired.

[0220] Referring to Figure 1A, it can be seen that a compound of formula 214 can be converted to a compound of formula 215. Any suitable method known in the art can be used to effect this conversion, but in particular the method described in step i. of Scheme 2 in Example 1 is illustrated. Generally, as seen in Example 1, treatment of (14) with lithium triethylborohydride in the presence of a palladium catalyst (e.g., bis[(diphenylphosphino)ferrocene]palladium(II) chloride provides (15). This reaction can be carried out in an aprotic solvent (e.g., THF) at low temperature (e.g., 0°C). In the compound of formula 215, [ka] Each bond, n, J, K, L, X, Y, Z', R1, R2, R3, R8, R9, R 10 ', R 20 , R 21 and R 32is as defined above. Compounds of Formula 215 can be stereochemically pure or stereochemically mixed. If a stereochemically mixed compound, these compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired.

[0221] Referring to FIG. 1A, compounds of formula 215 are those containing a group R 32 It can be seen that the compound of formula 216 can be converted by removal of R, thereby regenerating the unprotected phenol (-OH). 32 The stringent conditions used to remove R 32 It depends on the nature of R 32 When R is alkyl, it is generally removed and thus the compound of formula 215 is not converted to the compound of formula 216. 32 When R is a silyl protecting group, it can generally be removed by treatment in the presence of fluoride ions, such as treatment with tetra-n-butylammonium fluoride (TBAF). 32 When is a triphenylmethyl-based protecting group, it can generally be removed by treatment with an acid such as dichloroacetic acid, trichloroacetic acid, or trifluoroacetic acid (neat or diluted in a compatible organic solvent such as DCM). Other phenol protecting groups, methods for their preparation (i.e., protection of the phenol) and deprotection (regeneration of the phenol from the protected phenol) are well known to those skilled in the art.

[0222] In the compound shown in Example 1, the group R 32 is benzyl. Any suitable method known in the art may be used to accomplish this removal of the benzyl group, particularly the method described in step j. of Scheme 2 in Example 1. Generally, (15) is reacted with a suspension of lithium (metal) in n-propylamine in an aprotic solvent such as diethyl ether to give (16). The reaction can be quenched by adding saturated aqueous ammonium chloride and an alcohol (e.g., methanol). In compounds of formula 216, [ka] Each bond shown as n, J, K, L, X, Y, Z', R1, R2, R3, R8, R9, R 10 ', R 20 and R 21 is as defined above. Compounds of Formula 216 can be stereochemically pure or a stereochemical mixture. If a stereochemical mixture, the compound can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired.

[0223] In some embodiments, in the compound of Formula 216, R and R are H and R 10 ' is not present. The preparation of compounds of this structure generally follows from the availability of a suitable alcohol of formula 201, as shown in Figure 3 and described in more detail below with respect to the preparation of compounds of formula 203 (as described above in the preparation of compounds of formula 214). 10 The species of compounds of formula 216 where ' is absent is shown in Figure 1B and identified as compounds of formula 216a. Because the availability of compounds of formula 201 may be limited, the method described in Figure 1B represents an alternative approach to the preparation of compounds having the desired groups R8 and R9 (which are not H) from starting materials where R8 and R9 are H.

[0224] Referring to Figure 1B, compounds of formula 216a are provided. Compounds of this formula can be prepared as described above and shown in Figure 1A. The asterisk shown in the compound of formula 216a (and all other compounds shown in Figure 1B) identifies the chiral center. If available, stereochemically pure compounds of formula 216a (i.e., pure enantiomers of 216a) can be used in the methods described herein, but this is not a requirement or limitation. Racemic mixtures of 216a can be used, but generally these products are also mixtures of stereochemically impure compounds. In the case of stereochemical mixtures, the compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired. In compounds of formula 216a, [ka] Each bond shown as n, J, K, L, X, Y, Z, Z', R1, R2, R3, R 20 and R 21 is as defined above.

[0225] Referring to Figure 1B, it can be seen that a compound of formula 216a can be converted to a compound of formula 217a by protection of the exocyclic phenol. Any suitable method known in the art can be used to accomplish this conversion of a phenol to a protected phenol, but the method described in step k. of Scheme 2 of Example 1 is particularly illustrated. In step k. of Example 1, the phenol of (16) was protected using tert-butyldimethylsilyl chloride in DMF (as solvent) in the presence of imidazole (as base), thereby producing the more tert-butyldimethylsilyl protected product (17). Generally, this protection reaction proceeds in a dry aprotic solvent (e.g., DMF) in the presence of a base (inorganic or organic). However, any suitable protecting group and any suitable conditions can be used. For example, a phenol can be protected with a (substituted or unsubstituted) benzyl protecting group, for example, by using (substituted or unsubstituted) benzyl chloride and similar conditions (e.g., those described above for the preparation of compound 206). Alternatively, the phenol can be protected with a triphenylmethyl-based protecting group, for example, by use of triphenylmethyl chloride and similar conditions. In some embodiments, the phenol can optionally (but not preferably) be reacted with a reagent that produces a more permanent modification, such as methyl iodide, ethyl iodide, or isopropyl iodide, thereby producing a methyl ether, ethyl ether, or isopropyl ether, respectively.

[0226] If available, a stereochemically pure compound of formula 216a (i.e., a pure enantiomer of 216a) can be used in the methods described herein, although this is neither a requirement nor a limitation. While racemic mixtures of 216a can be used, the product (i.e., 217a) will generally also be a mixture of stereochemically impure compounds. In the case of a stereochemical mixture, the compound can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired. In compounds of formula 217a, [ka] Each bond, n, J, K, L, X, Y, Z, Z', R1, R2, R3, R 20 and R 21 is as defined above. In the compound of formula 217a, the group R 34 represents any phenol protecting group (e.g., a C1-C4 alkyl group, a triphenylmethyl protecting group, a silyl protecting group, or a benzyl protecting group), while R 34 is not hydrogen (H). For example, R 34 can be a silyl protecting group such as tert-butyldimethylsilyl.

[0227] Referring to Figure 1B, it can be seen that compounds of formula 217a can be converted to compounds of formula 218a. Any suitable method known in the art can be used to accomplish this conversion, particularly the method described in step 1 of Scheme 2 in Example 1. Generally, as seen in Example 1, compound 17 is treated with N-bromosuccinimide in a mixture of organic solvent (e.g., THF) and water at low temperature (e.g., 0°C) to yield 18. However, any suitable conditions can be used. If available, a stereochemically pure compound of formula 217a (i.e., a pure enantiomer of 217a) can be used in the methods described herein, although this is neither a requirement nor a limitation. While a racemic mixture of 217a can be used, the product 218a is generally also a mixture of stereochemically impure compounds. In the case of a stereochemical mixture, the compound can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired. In the compound of formula 218a: [ka] Each bond, n, J, K, L, X, Y, Z, Z', R1, R2, R3, R 20 , R 21 and R 34 is as defined above.

[0228] Referring to Figure 1B, it can be seen that compounds of formula 218a can be converted to epoxide compounds of formula 219a by treatment with a base. Any suitable method known in the art can be used to accomplish this conversion, particularly the method described in step m of Scheme 2 in Example 1. Generally, as seen in Example 1, compound 18 is reacted at low temperature (e.g., 0°C) in the presence of an inorganic base such as sodium carbonate, potassium carbonate, or cesium carbonate in an alcohol such as methanol or ethanol (or an aqueous mixture of alcohols) to afford epoxide 19. However, any suitable conditions can be used. If available, stereochemically pure compounds of formula 218a (i.e., pure enantiomers of 218a) can be used in the methods described herein, although this is neither a requirement nor a limitation. Racemic mixtures of 218a can be used, but these products 219a are generally also stereochemically impure mixtures. In the case of stereochemical mixtures, the compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired. [ka] Each bond, n, J, K, L, X, Y, Z, Z', R1, R2, R3, R 20 , R 21 and R 34 is as defined above.

[0229] Referring to Figure 1B, it can be seen that compounds of formula 219a can be converted to aldehydes of formula 220a by treatment with an oxidizing agent such as sodium periodate. Any suitable method known in the art can be used to accomplish this conversion, with particular reference to the method described in step n of Scheme 2 in Example 1. Generally, as shown in Example 1, epoxide 19 is treated with sodium periodate and periodic acid in water or a mixture of water and an organic solvent at low temperature (e.g., 0°C) to afford 20. However, any suitable conditions can be used. If available, stereochemically pure compounds of formula 219a (i.e., pure enantiomers of 219a) can be used in the methods described herein, although this is neither a requirement nor a limitation. Racemic mixtures of 219a can be used, but these products 220a are generally also stereochemically impure mixtures. In the case of stereochemical mixtures, the compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired. [ka] Each bond, n, J, K, L, X, Y, Z, Z', R1, R2, R3, R 20 , R 21 and R 34 is as defined above.

[0230] Referring to Figure 1B, it can be seen that aldehydes of formula 220a can be converted to alcohols of formula 221a by treatment with a reducing agent such as sodium borohydride. Any suitable method known in the art can be used to accomplish this conversion, with particular reference to the method described in step o of Scheme 2 in Example 1. Generally, as shown in Example 1, aldehyde 20 is treated with sodium borohydride in an alcohol (e.g., ethanol) or a mixture of water and alcohol at low temperature (e.g., 0°C) to afford alcohol 21. However, any suitable conditions can be used. If available, stereochemically pure compounds of formula 220a (i.e., pure enantiomers of 220a) can be used in the methods described herein, although this is neither a requirement nor a limitation. Racemic mixtures of 220a can be used, but generally these products 221a are also stereochemically impure mixtures. In the case of stereochemical mixtures, the compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired. [ka] Each bond, n, J, K, L, X, Y, Z', R1, R2, R3, R 20 , R 21 and R 34 is as defined above.

[0231] Referring to Figure 1B, it can be seen that alcohols of formula 221a can be converted to iodides of formula 222a by treatment with imidazole and iodine. Any suitable method known in the art can be used to accomplish this conversion, with particular reference to the method described in step p. of Scheme 2 in Example 1. Generally, as shown in Example 1, alcohol 21 is treated with triphenylphosphine, imidazole, and iodine in an aprotic solvent (e.g., DCM) at room temperature to afford iodide 22. However, any suitable conditions can be used. If available, stereochemically pure compounds of formula 221a (i.e., pure enantiomers of 221a) can be used in the methods described herein, although this is neither a requirement nor a limitation. Racemic mixtures of 221a can be used, but generally these products 222a are also stereochemically impure mixtures. In the case of stereochemical mixtures, the compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired. [ka] Each bond, n, J, K, L, X, Y, Z', R1, R2, R3, R 20 , R 21 and R 34 is as defined above.

[0232] Referring to Figure 1B, it can be seen that the iodide of formula 222a can be converted to the triphenylphosphonium iodide salt of formula 223a by treatment with a large excess of triphenylphosphine. Any suitable method known in the art can be used to accomplish this conversion, but the method described in step q of Scheme 2 in Example 1 is particularly illustrated. Generally, as shown in Example 1, treatment of iodide 22 with a large excess of triphenylphosphine in an aprotic solvent (e.g., ACN) at elevated temperature (e.g., 85°C) affords triphenylphosphonium iodide salt 23. However, any suitable conditions can be used. If available, a stereochemically pure compound of formula 222a (i.e., a pure enantiomer of 222a) can be used in the methods described herein, but this is neither a requirement nor a limitation. Racemic mixtures of 222a can be used, but generally these products (223a) are also stereochemically impure mixtures. In the case of stereochemical mixtures, the compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired. [ka] Each bond, n, J, K, L, X, Y, Z', R1, R2, R3, R 20 , R 21 and R 34 is as defined above.

[0233] Referring to Figure 1B, it can be seen that the triphenylphosphonium iodide salt of Formula 223a can be converted to a compound of Formula 225a by treating it with hexamethyldisilylazide, followed by the addition of a compound of Formula 224. In the compound of Formula 224, R' can embody any of the definitions of R shown above, and R' can embody any of the definitions of R shown above, with the proviso that R and R cannot both be H (to regenerate compound 216a; the starting material for this method is shown in Figure 1B). Any suitable method known in the art can be used to effect this conversion, particularly the method described in step r. of Scheme 2 of Example 1, or (ii) step a. of Scheme 3 of Example 2. Generally, as shown in Example 1, step r, triphenylphosphonium iodide salt (23) is treated with hexamethyldisilazide and ketone (24) in an aprotic solvent (e.g., THF) at low temperature (e.g., −78° C.) to give compound (25). However, any suitable conditions can be used. If available, a stereochemically pure compound of formula 223a (i.e., a pure enantiomer of 223a) can be used in the methods described herein, but this is neither a requirement nor a limitation. While racemic mixtures of 223a can be used, these products (225a) are generally also stereochemically impure mixtures. In the case of stereochemical mixtures, the compound can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired. In compounds of formula 225a, [ka] Each bond represented as n, J, K, L, X, Y, Z, Z', R1, R2, R3, R8', R9', R 20 , R 21 and R 34 is as defined above. Furthermore, it should be noted that compounds in which both R and R are fluorine can be produced by essentially following the simplified procedure set forth in Example 3 below.

[0234] Referring to FIG. 1B, compounds of formula 225a contain a phenol protecting group R 34 It can be seen that removal of R can convert to the compound of formula 226a, thereby regenerating the unprotected phenol (-OH). 34 The stringent conditions used to remove R 34 It depends on the nature of R 34 When R is alkyl, it is generally not removed and therefore the compound of formula 225a is not converted to the compound of formula 226a. 34 When R is a silyl protecting group, it can generally be removed by treatment in the presence of fluoride ions, such as treatment with tetra-n-butylammonium fluoride (TBAF). 34 When R is a triphenylmethyl-based protecting group, it can generally be removed by treatment with an acid such as dichloroacetic acid, trichloroacetic acid, or trifluoroacetic acid (neat or diluted in a compatible organic solvent such as DCM). 34 When is a benzyl protecting group, it can generally be removed as described in Example 1, Scheme 2, step j.

[0235] Any suitable method known in the art may be used to effect this conversion of 225a to 226a, but the method described in step s. of Scheme 2 in Example 1 is particularly useful for removing the tert-butyldimethylsilyl group. Generally, as shown in step s. of Example 1, the protected compound 25 is treated with tetra-n-butylammonium fluoride (TBAF) in an aprotic solvent (e.g., THF) at room temperature to yield the deprotected compound 26. However, any suitable conditions can be used. If available, a stereochemically pure compound of formula 225a (i.e., a pure enantiomer of 225a) can be used in the methods described herein, although this is neither a requirement nor a limitation. While racemic mixtures of 225a can be used, these products 226a are generally also stereochemically impure mixtures. In the case of stereochemical mixtures, the compound can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, if applicable) if a stereochemically pure product is desired. In the compound of formula 226a: [ka] Each bond represented as n, J, K, L, X, Y, Z, Z', R1, R2, R3, R8', R9', R 20 , and R 21 is as defined above. Furthermore, it should be noted that compounds in which both R and R are fluorine can be produced by essentially following the simplified procedure set forth in Example 3 below.

[0236] The compound of general formula 216 (the product of the process shown in FIG. 1A) and the compound of general formula 226a (the product of the process shown in FIG. 1B) have the groups Z, R8′, and R9′ of compound 216 compared to the groups Z, R8′, and R9′ of compound 226a. [ka] , Z', R8, R9, R 10' differ in structure. Thus, compounds 216 and 226a can be converted to therapeutically active compounds of formula I or formula II, respectively, by following the methods shown in Figures 1C and 1D, respectively.

[0237] Any suitable method known in the art may be used to accomplish the conversion of 216 to a compound of Formula I and 226a to a compound of Formula II, with particular reference to the method described in step t. of Scheme 2 in Example 1. Generally, as shown in step t. of Example 1, treatment of unprotected phenolic compound (26) in an aprotic solvent (e.g., isopropyl acetate) with cerium(IV) ammonium nitrate at room temperature provides the therapeutic agent (Compound A), which is isolated after quenching the reaction at low temperature (e.g., 0°C), extraction, and column chromatography. However, any suitable conditions can be used. If available, stereochemically pure compounds of formula 216 or 226a (i.e., pure enantiomers of 216 or 226a, respectively) can be used in the methods described herein, although this is neither a requirement nor a limitation. While racemic mixtures of 216 or 226a can be used, these products (Formula I or II) are generally also stereochemically impure mixtures. In the case of stereochemical mixtures, the compounds can optionally be purified by appropriate means (eg, chromatography or chiral chromatography, if applicable) if stereochemically pure products are desired.

[0238] In some embodiments, a compound of Formula I can exist as Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, or Formula Ih (all as shown in Figure 1C). In some embodiments, a compound of Formula II can exist as Formula IIa, Formula IIb, Formula IIc, or Formula IId (all as shown in Figure 1D). With respect to all of the compounds of Formula I, Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, or Formula Ih shown in Figure 1C and Formula IIa, Formula IIb, Formula IIc, or Formula IId shown in Figure 1D, [ka] Each bond represented as n, J, K, L, X, Y, Z, Z', R1, R2, R3, R8, R9, R 10 , R8', R9', R 10 ', R 20 , and R 21 is as defined above.

[0239] In some embodiments below, the groups represented by R1 and R2 can form a 6-membered carbocyclic or heterocyclic ring, thereby forming a compound of formula 204, as shown in Figure 1A: [ka] Instead of starting with, the starting material can be a compound of formula 304 as shown in Figure 2A: [ka] During the ceremony, [ka] Each bond represented by each W, as well as groups J, K, L, R3, R4, R5, R6, R7, R 20 and R 30 As shown in Figure 2A, compounds of formula 304 can be converted to compounds of formula 316 by a multi-step process similar to that shown in Figure 1A, differing only in the nature of (and therefore substitution of) the carbocyclic or heterocyclic ring formed by R1 and R2, as described above for the conversion of compounds of formula 204 to compounds of formula 216: [ka] Similarly, as shown in FIG. 2B, a compound of formula 316a: [ka] can be converted to a compound of formula 326a by a multi-step process similar to that shown in FIG. 1B, differing only in the nature of (and therefore substitution of) the carbocyclic or heterocyclic ring formed by R1 and R2, as described above for the conversion of a compound of formula 216a to a compound of formula 226a: [ka] As shown in Figure 2C, compounds of Formula 316 can be converted to compounds of Formula III, including compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, and IIIh, by methods similar to those shown in Figure 1C, differing only in the nature of (and therefore substitution of) the carbocyclic or heterocyclic ring formed by R1 and R2, as described above for the conversion of compounds of Formula 216 to compounds of Formula I: [ka] Further, as shown in Figure 2D, compounds of Formula 326a can be converted to compounds of Formula IV, including compounds of Formulas IVa, IVb, IVc, and IVd, by methods similar to those shown in Figure 1D, differing only in the nature of (and therefore substitution of) the carbocyclic or heterocyclic ring formed by R1 and R2, as described above for the conversion of compounds of Formula 226a to compounds of Formula II: [ka] For the avoidance of doubt, the suffix "x" as used in any of Figures 2A, 2B, 2C or 2D can be converted to [ka] Each bond is represented as [ka] Each bond represented by each W, n, and groups B', J, K, L, X, Y, Z, Z', R3, R4, R5, R6, R7, R8, R9, R 10 , R8', R9', R 10 ', R 20 , R 21 , R 30 , R 31 , R 32 , R 33 and R 34is any of the forms previously defined.

[0240] As described above, the compound of formula 203: [ka] is useful, for example, in the preparation of compounds of formula 214 (FIG. 1A) or 314 (FIG. 2A), wherein [ka] Each bond, n, X, Y, Z', R8, R9, R 10 ' and R 21 is as defined above. Such compounds of formula 203 are commercially available or can be prepared for use in the methods described herein.

[0241] For example, and with reference to Figure 3, compounds of formula 203 can be prepared in a two-step process starting from an alcohol of formula 201. More specifically, with reference to Figure 3, it can be ...

Claims

1. A compound of formula EF, During the ceremony, E is 21 or 22: 【Chemistry 1】 and F is 13, 14, 15, 16, 17, 18, 19 or 20: 【Chemistry 2】 where: J is O, S or N-R 11 and K is absent or -(CR 12 R 13 ) and L is -(CR 12 R 13 )- and; Each W is independently C (carbon) or N (nitrogen), where: 【Transformation 3】 For each use of R, the bond between each W may be a single bond or a double bond, provided that in the case of a single bond, each C (carbon) atom is bonded to R 4 , R 5 , R 6 or R 7 and in each case, R 4 , R 5 , R 6 and R 7 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl and C 1 -C 6 When W is N (nitrogen), R bonded thereto is selected from alkoxy. 4 , R 5 , R 6 and R 7 Each of these does not exist independently ( 【Chemistry 4】 is a double bond), or H, D and C 1 -C 6 alkyl ( 【Transformation 5】 is a single bond); Each X independently represents a group of the formula -(CR 12 R 13 )- group; Each Y is independently absent or a group of the formula -(CR 12 R 13 )- group; Each Z independently represents a group of the formula -(CR 14 )- group; R 1 , R 2 and R 3 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 alkoxy; or R 1 and R 2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; Each R 8 and R 9 are each independently H, D, F, Cl, Br, I, or C 1 -C 4 alkyl; or R 8 and R 9 together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R 10 are H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 is alkoxy; R 11 is H, D or C 1 -C 6 is alkyl; R 12 , R 13 and R 14 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 is alkoxy; R 20 is H, D, F or C 1 -C 12 is alkyl; Each R 21 are independently H, D, F, Cl, Br, I, or C 1 -C 4 is alkyl; n is an integer from 0 to 12; and *** indicates the point of attachment of E to F, ** indicates the point of attachment of F to E; Further, provided that (i) formula R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 20 Or R 21 at least one group of R 8 and R 9 together form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring, or Pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof.

2. 2. The compound of claim 1, wherein E is 21 and F is 13, 14, 19, or 20.

3. 2. The compound of claim 1, wherein E is 22 and F is 13, 14, 19, or 20.

4. 2. The compound of claim 1, wherein E is 21 and F is 15, 16, 17, or 18.

5. 2. The compound of claim 1, wherein E is 22 and F is 15, 16, 17, or 18.

6. The compound of any one of claims 1 to 5, wherein J is O.

7. The compound of any one of claims 1 to 5, wherein J is S.

8. J is N-R 11 The compound according to any one of claims 1 to 5,

9. J is O or N-R 11 and K is absent.

10. Each of K and L is independently —(CH 2 )—, —(CD 2 )—, —(CHF)—, —(CF 2 )—, —(CH(CH 3 ))—, —(CD(CD 3 ))—, —(CF(CH 3 ))—, —(CH(CF 3 ))—, —(CF(CF 3 ))—, —(C(CH 3 )) 2 —, —(C(CD 3 )) 2 —, —(C(CF 3 )) 2 , —(CH(OCH 3 ))—, —(CD(OCD 3 ))—, —(CF(OCH 3 ))—, —(CH(OCF 3 ))—, —(CF(OCF 3 ))—, —(C(OCH 3 )) 2 —, —(C(OCD 3 )) 2 —, —(C(OCF 3 )) 2 , —(C(CH 3 )(CF 3 ))—, —(C(CD 3 )(CF 3 ))—, —(CH(CH 2 CH 3 ))—, —(CD(CD 2 CD 3 ))—, —(CF(CH 2 CH 3 ))—, —(CH(CH 2 CF 3 ))—, —(CH(CF 2 CF 3 ))—, —(CF(CF 2 CF 3 ))—, —(C(CH 2 CH 3 )) 2 —, —(C(CD 2 CD 3 )) 2 )— or —(C(CF 2 CF 3 )) 2 9. The compound according to claim 1, wherein

11. K and L each independently represent -(CH 2 ) -, -(CD 2 ) -, -(CF 2 )-,-(CH(CH 3 ))-,-(CD(CD 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 ) -, -(C(CD 3 ) 2 ) -, -(C(CF 3 ) 2 )-,-(CH(OCH 3 ))-,-(CD(OCD 3 )) -, -(CF(OCF 3 ))- or -(C(OCH 3 ) 2 11. The compound according to claim 10, wherein:

12. K and L each independently represent -(CH 2 ) -, -(CD 2 )-,-(CHF)-,-(CF 2 )-,-(CH(CH 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 )-or-(C(CF 3 ) 2 11. The compound according to claim 10, wherein:

13. L is -(CH 2 ), -(CD 2 ), -(CHF), -(CF 2 ), -(CH(CH 3 )), -(CD(CD 3 )), -(CF(CH 3 )), -(CH(CF 3 )), -(CF(CF 3 )), -(C(CH 3 )) 2 ), -(C(CD 3 ))<ooo0173>), -(C(CF 3 )) 2 ), -(CH(OCH 3 )), -(CD(OCD 3 )), -(CF(OCH 3 )), -(CH(OCF 3 )), -(CF(OCF 3 )), -(C(OCH 3 )) 2 ), -(C(OCD 3 )) 2 ), -(C(OCF 3 )) 2 ), -(C(CH 3 )(CF 3 )), -(C(CD 3 )(CF 3 )), -(CH(CH 2 CH 3 )), -(CD(CD 2 CD 3 )), -(CF(CH 2 CH 3 )), -(CH(CH 2 CF 3 )), -(CH(CF 2 CF 3 )), -(CF(CF 2 CF 3 )), -(C(CH 2 CH 3 ))) 2 ), -(C(CD 2 CD 3 )) 2 ), or -(C(CF 2 CF 3 )) 2 10. The compound of claim 9, wherein:

14. L is -(CH 2 ) -, -(CD 2 ) -, -(CF 2 )-,-(CH(CH 3 ))-,-(CD(CD 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 ) -, -(C(CD 3 ) 2 ) -, -(C(CF 3 ) 2 )-,-(CH(OCH 3 ))-,-(CD(OCD 3 )) -, -(CF(OCF 3 ))- or -(C(OCH 3 ) 2 14. The compound of claim 13, wherein:

15. L is -(CH 2 ) -, -(CD 2 )-,-(CHF)-,-(CF 2 )-,-(CH(CH 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 )-or-(C(CF 3 ) 2 14. The compound of claim 13, wherein:

16. R 1 、R 2 and R 3 each independently is H, D, Cl, F, -CH 3 、-OCH 3 、-CD 3 、-OCD 3 、-CH 2 F、-OCH 2 F、-CHF 2 、-OCHF 2 、-CF 3 、-OCF 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CD 2 CD 3 、-CD(CD 3 ) 2 、-CF 2 CH 3 、CF(CH 3 ) 2 、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CF​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ 2 、-OC(CH 3 ) 3 、-OC(CD 3 ) 3 、-OC(CF 3 ) 3 、-C(CH 3 ) 2 (CF 3 ),-C(CH 3 )(CF 3 ) 2 、-OC(CH 3 ) 2 (CF 3 ),-OC(CH 3 )(CF 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 2 CH 3 ) 2 、-CD 2 CD 2 CD 3 、-CD(CD 2 CD 3 ) 2 、-CF 2 CH 2 CH 3 、-CF(CH 2 CH 3 ) 2 、-CH 2 CF 2 CF 3 、-CH(CF 2 CF 3 ) 2 、-CF 2 CF 2 CF 3 、-CF(CF 2 CF 3 ) 2 、-OCH 2 CH 2 CH 3 、-OCH(CH 2 CH 3 ) 2 、-OCD 2 CD 2 CD 3 、-OCD(CD 2 CD 3 ) 2 、-OCF 2 CH 2 CH 3 , -OCF(CH 2 CH 3 ) 2 , -OCH 2 CF 2 CF 3 , -OCH(CF 2 CF 3 ) 2 , -OCF 2 CF 2 CF 3 or -OCF(CF 2 CF 3 ) 2 5. The compound of claim 1, 2, or 4, wherein:

17. R 1 , R 2 and R 3 each independently represents H, D, Cl, F, —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 or -CH(CH 3 ) 2 5. The compound of claim 1, 2, or 4, wherein:

18. R 1 , R 2 and R 3 each independently represents H, F, or —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 or -CH(CH 3 ) 2 5. The compound of claim 1, 2, or 4, wherein:

19. J is O; and each of K and L is independently —(CH 2 ) -, -(CD 2 )-,-(CHF)-,-(CF 2 )-,-(CH(CH 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 )-or-(C(CF 3 ) 2 )-; R 1 , R 2 and R 3 each independently represents H, F, or —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 or -CH(CH 3 ) 2 5. The compound of claim 1, 2, or 4, wherein:

20. R 3 is H, D, Cl, F, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 , or -CH(CH 3 ) 2 and R 1 and R 2 5. The compound of claim 1, 2, or 4, wherein together form a 5- or 6-membered carbocyclic or heterocyclic ring.

21. E is 21A, 21B, 21C, 21D, 21E or 21F: 【Transformation 6】 wherein R 16 and R 17 each independently represents H, D, Cl, F, —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 , -CH(CH 3 ) 2 , -OCH(CH 3 ) 2 , -C(CH 3 ) 3 or -O(CH 3 ) 3 and J" is O, S, or N-R 18 where R 18 is H, D, -CH 3 , -CH 2 F, -CHF 2 or -CF 3 21. The compound of claim 20, wherein:

22. R 3 がH、D、Cl、F、-CH 3 、-OCH 3 、-CD 3 、-OCD 3 、-CH 2 F-OCH 2 F-CHF 2 、-OCHF 2 、-CF 3 、-OCF 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CD 2 CD 3 、-CD(CD 3 ) 2 、-CF 2 CH 3 、CF(CH 3 ) 2 、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CF 3 、-CF(CF 3 ) 2 、-C(CH 3 ) 3 、-C(CD 3 ) 3 、-C(CF 3 ) 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-OCD 2 CD 3 、-OCD(CD 3 ) 2 、-OCF 2 CH 3 、-OCF(CH 3 ) 2 、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 (CF 3 ),-OCF(CF 3 ) 2 、-OC(CH 3 ) 3 、-OC(CD 3 ) 3 、-OC(CF 3 ) 3 、-C(CH 3 ) 2 (CF 3 ),-C(CH 3 )(CF 3 ) 2 、-OC(CH 3 ) 2 (CF 3 ),-OC(CH 3 )(CF 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 2 CH 3 ) 2 、-CD 2 CD 2 CD 3 、-CD(CD 2 CD 3 ) 2 、-CF 2 CH 2 CH 3 、-CF(CH 2 CH 3 ) 2 、-CH 2 CF 2 CF 3 、-CH(CF 2 CF 3 ) 2 、-CF 2 CF 2 CF 3 、-CF(CF 2 CF 3 ) 2 、-OCH 2 CH 2 CH 3 、-OCH(CH 2 CH 3 ) 2 、-OCD 2 CD 2 CD 3 、-OCD(CD 2 CD 3 ) 2 、-OCF 2 CH 2 CH 3 , -OCF(CH 2 CH 3 ) 2 , -OCH 2 CF 2 CF 3 , -OCH(CF 2 CF 3 ) 2 , -OCF 2 CF 2 CF 3 or -OCF(CF 2 CF 3 ) 2 and when W is C (carbon), R bonded thereto 4 , R 5 , R 6 and R 7 each independently represents H, D, F, Cl, Br, I, or —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 , and -CH(CH 3 ) 2 and when W is N (nitrogen), R bonded thereto is 4 , R 5 , R 6 and R 7 6. The compound of claim 1, 3, or 5, wherein each of is independently absent or selected from H, D, methyl, ethyl, isopropyl, and t-butyl.

23. R 3 is H, D, Cl, F, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 , or -CH(CH 3 ) 2 and when W is C (carbon), R 4 , R 5 , R 6 and R 7 each independently represents H, D, F, Cl, —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 , and -CH(CH 3 ) 2 and when W is N (nitrogen), R bonded thereto is 4 , R 5 , R 6 and R 7 6. The compound of claim 1, 3, or 5, wherein each of is independently absent or selected from H, D, methyl, and ethyl.

24. Each W is C, and R 4 , R 5 , R 6 and R 7 each independently represents H, D, Cl, F, —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 or -OCF.

25. R 8 and R 9 each independently is H, D, F, Cl, Br, I, -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 2 CD 3 , -CD(CD 3 ) 2 , -CF 2 CH 3 , -CF(CH 3 ) 2 , -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CF 3 , -CF(CF 3 ) 2 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -C(CH 3 ) 2 (CF 3 ), -C(CH 3 )(CF 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -CD 2 CD 2 CD 3 , -CD(CD 2 CD 3 ) 2 , -CF 2 CH 2 CH 3 , -CF(CH 2 CH 3 ) 2 , -CH 2 CF 2 CF 3 , -CH(CF 2 CF 3 ) 2 , -CF 2 CF 2 CF 3 or -CF(CF 2 CF 3 ) 2 The compound according to any one of claims 1 to 24,

26. R 8 and R 9 each independently represents H, F, or —CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 2 CH 3 , -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CF 3 , -CF(CF 3 ) 2 , -C(CH 3 ) 3 , -C(CF 3 ) 3 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -CF 2 CF 2 CF 3 or -CF(CF 2 CF 3 ) 2 26. The compound of claim 25, wherein:

27. R 8 and R 9 together 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 or 47: 【Transformation 7】 25. The compound according to any one of claims 1 to 24, wherein the compound forms a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring, which may be:

28. R 10 がH、D、F、-CH 3 、-OCH 3 、-CD 3 、-OCD 3 、-CH 2 F-OCH 2 F-CHF 2 、-OCHF 2 、-CF 3 、-OCF 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CD 2 CD 3 、-CD(CD 3 ) 2 、-CF 2 CH 3 、CF(CH 3 ) 2 、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CF 3 、-CF(CF 3 ) 2 、-C(CH 3 ) 3 、-C(CD 3 ) 3 、-C(CF 3 ) 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-OCD 2 CD 3 、-OCD(CD 3 ) 2 、-OCF 2 (CF 3 ),-OCF(CF 3 ) 2 、-OC(CH 3 ) 3 、-OC(CD 3 ) 3 、-OC(CF 3 ) 3 、-C(CH 3 ) 2 (CF 3 ),-C(CH 3 ) (CF 3 ) 2 , -OC(CH 3 ) 2 (CF 3 ), —OC(CH 3 ) (CF 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -CD 2 CD 2 CD 3 , -CD (CD 2 CD 3 ) 2 , -CF 2 CF 2 CF 3 , -CF(CF 2 CF 3 ) 2 , -C(CH 2 CH 3 ) 3 , -C(CD 2 CD 3 ) 3 , -C(CF 2 CF 3 ) 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 2 CH 3 ) 2 , -OCD 2 CD 2 CD 3 , -OCD (CD 2 CD 3 ) 2 , -OCF 2 CF 2 CF 3 or -OCF(CF 2 CF 3 ) 2 The compound according to any one of claims 1 to 27,

29. R 10 is H, D, F, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 or -CH(CH 3 ) 2 29. The compound of claim 28, wherein:

30. R 11 The compound of any one of claims 1 to 29, wherein is H, methyl or ethyl.

31. R 12 , R 13 or R 14 each independently represents H, D, F, or —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH 2 CH 3 , -OCH(CH 2 CH 3 ) 2 or -OC(CH 3 ) 3 The compound according to any one of claims 1 to 30,

32. R 12 , R 13 or R 14 each independently represents H, D, F, or —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 or -OCH 2 CH 3 32. The compound of claim 31 , wherein:

33. R 20 is H, D, F, -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 unchanged CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 The compound according to any one of claims 1 to 32,

34. Each R 21 are independently H, D, F, -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 or -C(CH 3 ) 3 The compound according to any one of claims 1 to 33,

35. 35. The compound of any one of claims 1 to 34, wherein n is 0, 1, 2, 3 or 4.

36. The compound 【Transformation 8】 2. The compound of claim 1, wherein:

37. The compound 【Chemistry 9】 2. The compound of claim 1, wherein:

38. The compound 【Chemistry 10】 2. The compound of claim 1, wherein:

39. The compound 【Chemistry 11】 2. The compound of claim 1, wherein:

40. The compound 【Chemistry 12】 2. The compound of claim 1, wherein:

41. The compound 【Chemistry 13】 2. The compound of claim 1, wherein:

42. The compound 【Chemistry 14】 2. The compound of claim 1, wherein:

43. The compound 【Chemistry 15】 2. The compound of claim 1, wherein:

44. The compound 【Chemistry 16】 2. The compound of claim 1, wherein:

45. The compound 【Chemistry 17】 2. The compound of claim 1, wherein:

46. The compound [Chemistry 18] 2. The compound of claim 1, wherein:

47. The compound 【Chemistry 19】 2. The compound of claim 1, wherein:

48. The compound 【Chemistry 20】 2. The compound of claim 1, wherein:

49. A compound of formula CD, During the ceremony, C is 11 or 12: 【Chemistry 21】 and D is 13, 14, 15, 16, 17, 18, 19 or 20: 【Chemistry 22】 where: J' is OH, SH or NH-R 11 and K is absent or -(CR 12 R 13 )- and; L is -(CR 12 R 13 )- and; Each W is independently C (carbon) or N (nitrogen), where: 【Chemistry 23】 For each use of R, the bond between each W may be a single bond or a double bond, provided that in the case of a single bond, each C (carbon) atom is bonded to R 4 , R 5 , R 6 or R 7 and in each case, R 4 , R 5 , R 6 and R 7 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl and C 1 -C 6 When W is N (nitrogen), R bonded thereto is selected from alkoxy. 4 , R 5 , R 6 and R 7 Each of these does not exist independently ( 【Chemistry 24】 is a double bond) or H, D and C 1 -C 6 alkyl ( 【Chemistry 25】 is a single bond); Each X independently represents a group of the formula -(CR 12 R 13 )- group; Each Y is independently absent or a group of the formula -(CR 12 R 13 )- group; Each Z independently represents a group of the formula -(CR 14 )- group; R 1 , R 2 and R 3 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 alkoxy; or R 1 and R 2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; R 8 and R 9 are each independently H, D, F, Cl, Br, I, or C. 1 -C 4 alkyl; or R 8 and R 9 together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R 10 are H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 is alkoxy; R 11 is H, D or C 1 -C 6 is alkyl; R 12 , R 13 and R 14 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 is alkoxy; R 19 is H, C 1 -C 4 alkyl or benzyl; R 20 is H, D, F, or C 1 -C 12 is alkyl; Each R 21 are independently H, D, F, Cl, Br, I, or C 1 -C 4 is alkyl; n is an integer from 0 to 12, inclusive; and *** indicates the point of attachment of C to D, and ** indicates the point of attachment of D to C; Further, provided that (i) formula R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 20 Or R 21 at least one group of R 8 and R 9 together form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring, or or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

50. 50. The compound of claim 49, wherein C is 11 and D is 13, 14, 19 or 20.

51. 50. The compound of claim 49, wherein C is 12 and D is 13, 14, 19 or 20.

52. 50. The compound of claim 49, wherein C is 11 and D is 15, 16, 17, or 18.

53. 50. The compound of claim 49, wherein C is 12 and D is 15, 16, 17, or 18.

54. 54. The compound of any one of claims 49 to 53, wherein J' is OH.

55. 54. The compound of any one of claims 49 to 53, wherein J' is SH.

56. J' is NH-R 11 The compound according to any one of claims 49 to 53, wherein

57. J' is OH or NH-R 11 and K is absent.

58. Each of K and L is independently —(CH 2 )—, —(CD 2 )—, —(CHF)—, —(CF 2 )—, —(CH(CH 3 ))—, —(CD(CD 3 ))—, —(CF(CH 3 ))—, —(CH(CF 3 ))—, —(CF(CF 3 ))—, —(C(CH 3 )) 2 —, —(C(CD 3 )) 2 —, —(C(CF 3 )) 2 —, —(CH(OCH 3 ))—, —(CD(OCD 3 ))—, —(CF(OCH 3 ))—, —(CH(OCF 3 ))—, —(CF(OCF 3 ))—, —(C(OCH 3 )) 2 —, —(C(OCD 3 )) 2 —, —(C(OCF 3 )) 2 —, —(C(CH 3 )(CF 3 ))—, —(C(CD 3 )(CF 3 ))—, —(CH(CH 2 CH 3 ))—, —(CD(CD 2 CD 3 ))—, —(CF(CH 2 CH 3 ))—, —(CH(CH 2 CF 3 ))—, —(CH(CF 2 CF 3 ))—, —(CF(CF 2 CF 3 ))—, —(C(CH 2 CH 3 )) 2 —, —(C(CD 2 CD 3 )) 2 )— or —(C(CF 2 CF 3 )) 2 57. The compound according to any one of claims 49 to 56, wherein:

59. K and L each independently represent -(CH 2 ) -, -(CD 2 ) -, -(CF 2 )-,-(CH(CH 3 ))-,-(CD(CD 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 ) -, -(C(CD 3 ) 2 ) -, -(C(CF 3 ) 2 )-,-(CH(OCH 3 ))-,-(CD(OCD 3 )) -, -(CF(OCF 3 ))- or -(C(OCH 3 ) 2 )-.

60. K and L each independently represent -(CH 2 ) -, -(CD 2 )-,-(CHF)-,-(CF 2 )-,-(CH(CH 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 )-or-(C(CF 3 ) 2 )-.

61. L is -(CH 2 ), -(CD 2 ), -(CHF), -(CF 2 ), -(CH(CH 3 )), -(CD(CD 3 )), -(CF(CH 3 )), -(CH(CF 3 )), -(CF(CF 3 )), -(C(CH 3 )) 2 ), -(C(CD 3 )) 2 ), -(C(CF 3 )) 2 ), -(CH(OCH 3 )), -(CD(OCD 3 )), -(CF(OCH 3 )), -(CH(OCF 3 [[ID=3^{6}]])), -(CF(OCF 3 )), -(C(OCH 3 )) 2 ), -(C(OCD 3 )) 2 ), -(C(OCF 3 )) 2 ), -(C(CH 3 )(CF<00012^{9}1>[[ID=5^{4}]])), -(C(CD 3 )(CF 3 )), -(CH(CH 2 CH 3 )), -(CD(CD 2 CD 3 )), -(CF(CH 2 CH 3 )), -(CH(CH 2 CF 3 )), -(CH(CF 2 CF 3 )), -(CF(CF 2 CF 3 )), -(C(CH 2 CH 3 )) 2 ), -(C(CD 2 CD 3 )) 2 ), or -(C(CF 2 CF 3 )) 2 58. The compound of claim 57, wherein:

62. L is -(CH 2 ) -, -(CD 2 ) -, -(CF 2 )-,-(CH(CH 3 ))-,-(CD(CD 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 ) -, -(C(CD 3 ) 2 ) -, -(C(CF 3 ) 2 )-,-(CH(OCH 3 ))-,-(CD(OCD 3 )) -, -(CF(OCF 3 ))- or -(C(OCH 3 ) 2 62. The compound of claim 61, wherein:

63. L is -(CH 2 ) -, -(CD 2 )-,-(CHF)-,-(CF 2 )-,-(CH(CH 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 )-or-(C(CF 3 ) 2 62. The compound of claim 61, wherein:

64. R 1 、R 2 and R 3 each independently is H, D, Cl, F, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 2 CD 3 , -CD(CD 3 ) 2 , -CF 2 CH 3 , CF(CH 3 ) 2 , -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CF 3 , -CF(CF 3 ) 2 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCD 2 CD 3 , -OCD(CD 3 ) 2 , -OCF 2 CH 3 , -OCF(CH 3 ) 2 , -OCH 2 CF 3 , -OCH(CF 3 ) 2 , -OCF 2 (CF 3 ), -OCF(CF 3 ) 2 、-OC(CH 3 ) 3 、-OC(CD 3 ) 3 、-OC(CF 3 ) 3 、-C(CH 3 ) 2 (CF 3 ),-C(CH 3 )(CF 3 ) 2 、-OC(CH 3 ) 2 (CF 3 ),-OC(CH 3 )(CF 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 2 CH 3 ) 2 、-CD 2 CD 2 CD 3 、-CD(CD 2 CD 3 ) 2 、-CF 2 CH 2 CH 3 、-CF(CH 2 CH 3 ) 2 、-CH 2 CF 2 CF 3 、-CH(CF 2 CF 3 ) 2 、-CF 2 CF 2 CF 3 、-CF(CF 2 CF 3 ) 2 、-OCH 2 CH 2 CH 3 、-OCH(CH 2 CH 3 ) 2 、-OCD 2 CD 2 CD 3 、-OCD(CD 2 CD 3 ) 2 、-OCF 2 CH 2 CH 3 , -OCF(CH 2 CH 3 ) 2 , -OCH 2 CF 2 CF 3 , -OCH(CF 2 CF 3 ) 2 , -OCF 2 CF 2 CF 3 or -OCF(CF 2 CF 3 ) 2 53. The compound of claim 49, 50, or 52, wherein:

65. R 1 , R 2 and R 3 each independently represents H, D, Cl, F, —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 or -CH(CH 3 ) 2 53. The compound of claim 49, 50, or 52, wherein:

66. R 1 , R 2 and R 3 each independently represents H, F, or —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 or -CH(CH 3 ) 2 53. The compound of claim 49, 50, or 52, wherein:

67. J' is OH; and each of K and L is independently -(CH 2 ) -, -(CD 2 )-,-(CHF)-,-(CF 2 )-,-(CH(CH 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 )-or-(C(CF 3 ) 2 ) -; and R 1 , R 2 and R 3 each independently represents H, F, or —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 or -CH(CH 3 ) 2 53. The compound of claim 49, 50, or 52, wherein:

68. R 3 is H, D, Cl, F, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 , or -CH(CH 3 ) 2 and R 1 and R 2 53. The compound of claim 49, 50, or 52, wherein together form a 5- or 6-membered carbocyclic or heterocyclic ring.

69. C is 11A, 11B, 11C, 11D, 11E or 11F: 【Chemistry 26】 wherein R 16 and R 17 each independently represents H, D, Cl, F, —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 , -CH(CH 3 ) 2 , -OCH(CH 3 ) 2 , -C(CH 3 ) 3 or -O(CH 3 ) 3 and J″ is OH, SH, or NH—R 18 where R 18 is H, D, -CH 3 , -CH 2 F, -CHF 2 or -CF 3 69. The compound of claim 68, wherein:

70. R 3 がH、D、Cl、F、-CH 3 、-OCH 3 、-CD 3 、-OCD 3 、-CH 2 F-OCH 2 F-CHF 2 、-OCHF 2 、-CF 3 、-OCF 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CD 2 CD 3 、-CD(CD 3 ) 2 、-CF 2 CH 3 、CF(CH 3 ) 2 、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CF 3 、-CF(CF 3 ) 2 、-C(CH 3 ) 3 、-C(CD 3 ) 3 、-C(CF 3 ) 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-OCD 2 CD 3 、-OCD(CD 3 ) 2 、-OCF 2 CH 3 、-OCF(CH 3 ) 2 、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 (CF 3 ),-OCF(CF 3 ) 2 、-OC(CH 3 ) 3 、-OC(CD 3 ) 3 、-OC(CF 3 ) 3 、-C(CH 3 ) 2 (CF 3 ),-C(CH 3 )(CF 3 ) 2 、-OC(CH 3 ) 2 (CF 3 ),-OC(CH 3 )(CF 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 2 CH 3 ) 2 、-CD 2 CD 2 CD 3 、-CD(CD 2 CD 3 ) 2 、-CF 2 CH 2 CH 3 、-CF(CH 2 CH 3 ) 2 、-CH 2 CF 2 CF 3 、-CH(CF 2 CF 3 ) 2 、-CF 2 CF 2 CF 3 、-CF(CF 2 CF 3 ) 2 、-OCH 2 CH 2 CH 3 、-OCH(CH 2 CH 3 ) 2 、-OCD 2 CD 2 CD 3 、-OCD(CD 2 CD 3 ) 2 、-OCF 2 CH 2 CH 3 , -OCF(CH 2 CH 3 ) 2 , -OCH 2 CF 2 CF 3 , -OCH(CF 2 CF 3 ) 2 , -OCF 2 CF 2 CF 3 or -OCF(CF 2 CF 3 ) 2 and when W is C (carbon), R bonded thereto 4 , R 5 , R 6 and R 7 each independently represents H, D, F, Cl, Br, I, or —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 , and -CH(CH 3 ) 2 and when W is N (nitrogen), R bonded thereto is 4 , R 5 , R 6 and R 7 54. The compound of claim 49, 51, or 53, wherein each of is independently absent or selected from H, D, methyl, ethyl, isopropyl, and t-butyl.

71. R 3 is H, D, Cl, F, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 , or -CH(CH 3 ) 2 and when W is C (carbon), R bonded thereto 4 , R 5 , R 6 and R 7 each independently represents H, D, F, Cl, —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 and when W is N (nitrogen), R bonded thereto 4 , R 5 , R 6 and R 7 54. The compound of claim 49, 51, or 53, wherein each of is independently absent or selected from H, D, methyl, and ethyl.

72. Each W is C (carbon), and R 4 , R 5 , R 6 and R 7 each independently represents H, D, Cl, F, —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 or -OCF 3 72. The compound of claim 71, wherein:

73. R 8 and R 9 each independently represents H, D, F, Cl, Br, I, -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 2 CD 3 , -CD(CD 3 ) 2 , -CF 2 CH 3 , -CF(CH 3 ) 2 , -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CF 3 , -CF(CF 3 ) 2 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -C(CH 3 ) 2 (CF 3 ), -C(CH 3 )(CF 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -CD 2 CD 2 CD 3 , -CD(CD 2 CD 3 ) 2 , -CF 2 CH 2 CH 3 , -CF(CH 2 CH 3 ) 2 , -CH 2 CF 2 CF 3 , -CH(CF 2 CF 3 ) 2 , -CF 2 CF 2 CF 3 or -CF(CF 2 CF 3 ) 2 73. The compound according to any one of claims 49 to 72, wherein

74. R 8 and R 9 each independently represents H, F, or —CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 2 CH 3 , -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CF 3 , -CF(CF 3 ) 2 , -C(CH 3 ) 3 , -C(CF 3 ) 3 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -CF 2 CF 2 CF 3 or -CF(CF 2 CF 3 ) 2 74. The compound of claim 73, wherein:

75. R 8 and R 9 together 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 and 47: 【Chemistry 27】 73. The compound of any one of claims 49 to 72, wherein the compound forms a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring selected from the group consisting of:

76. R 10 がH、D、F、-CH 3 、-OCH 3 、-CD 3 、-OCD 3 、-CH 2 F-OCH 2 F-CHF 2 、-OCHF 2 、-CF 3 、-OCF 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CD 2 CD 3 、-CD(CD 3 ) 2 、-CF 2 CH 3 、CF(CH 3 ) 2 、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CF 3 、-CF(CF 3 ) 2 、-C(CH 3 ) 3 、-C(CD 3 ) 3 、-C(CF 3 ) 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-OCD 2 CD 3 、-OCD(CD 3 ) 2 、-OCF 2 (CF 3 ),-OCF(CF 3 ) 2 、-OC(CH 3 ) 3 、-OC(CD 3 ) 3 、-OC(CF 3 ) 3 、-C(CH 3 ) 2 (CF 3 ),-C(CH 3 ) (CF 3 ) 2 , -OC(CH 3 ) 2 (CF 3 ), —OC(CH 3 ) (CF 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -CD 2 CD 2 CD 3 , -CD (CD 2 CD 3 ) 2 , -CF 2 CF 2 CF 3 , -CF(CF 2 CF 3 ) 2 , -C(CH 2 CH 3 ) 3 , -C(CD 2 CD 3 ) 3 , -C(CF 2 CF 3 ) 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 2 CH 3 ) 2 , -OCD 2 CD 2 CD 3 , -OCD (CD 2 CD 3 ) 2 , -OCF 2 CF 2 CF 3 or -OCF(CF 2 CF 3 ) 2 The compound according to any one of claims 49 to 75,

77. R 10 is H, D, F, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 or -CH(CH 3 ) 2 77. The compound of claim 76, wherein:

78. R 11 is H, methyl or ethyl.

79. R 12 , R 13 or R 14 each independently represents H, D, F, or —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH 2 CH 3 , -OCH(CH 2 CH 3 ) 2 or -OC(CH 3 ) 3 The compound according to any one of claims 49 to 78, wherein

80. R 12 , R 13 or R 14 each independently represents H, D, F, or —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 or -OCH 2 CH 3 80. The compound of claim 79, wherein:

81. R 19 The compound of any one of claims 49 to 80, wherein is H.

82. R 19 Ga-CH 3 The compound according to any one of claims 49 to 80, wherein

83. R 19 Ga-CH 2 CH 3 The compound according to any one of claims 49 to 80, wherein

84. R 19 -C(CH 3 ) 3 The compound according to any one of claims 49 to 80, wherein

85. R 19 The compound of any one of claims 49 to 80, wherein is an unsubstituted or substituted benzyl group.

86. R 20 is H, D, F, -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 The compound according to any one of claims 49 to 85,

87. Each R 21 are independently H, D, F, -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 or -C(CH 3 ) 3 87. The compound according to any one of claims 49 to 86, wherein

88. 88. The compound of any one of claims 49 to 87, wherein n is 0, 1, 2, 3, or 4.

89. The compound 【Chemistry 28】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

90. The compound 【Chemistry 29】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

91. The compound 【Transformation 30】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

92. The compound 【Chemistry 31】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

93. The compound 【Chemistry 32】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

94. The compound 【Transformation 33】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

95. The compound 【Transformation 34】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

96. The compound 【Chemistry 35】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

97. The compound 【Transformation 36】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

98. The compound 【Chemistry 37】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

99. The compound 【Transformation 38】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

100. The compound 【Chemistry 39】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

101. The compound 【Chemistry 40】 50. The compound of claim 49, which is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

102. A compound of formula A-B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, or a compound of formula A-H, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, During the ceremony, A is 1, 2, 3 or 4: 【Chemistry 41】 and B is 5, 6, 7 or 8: 【Chemistry 42】 and And H is 25: 【Chemistry 43】 where: J is O, S or N-R 11 and K is absent or -(CR 12 R 13 )- and; L is -(CR 12 R 13 )- and; Each Q independently represents a group of the formula -(CR 12 R 13 )- group, O or Si, provided that each O and each Si is not directly bonded to an O or S; Each W is independently C (carbon) or N (nitrogen), where: 【Chemistry 44】 For each use of R, the bond between each W may be a single bond or a double bond, provided that in the case of a single bond, each C (carbon) atom is bonded to R 4 , R 5 , R 6 or R 7 and in each case, R 4 , R 5 , R 6 and R 7 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl and C 1 -C 6 When W is N (nitrogen), R bonded thereto is selected from alkoxy. 4 , R 5 , R 6 and R 7 Each of these does not exist independently ( 【Chemistry 45】 is a double bond), or H, D and C 1 -C 6 alkyl ( 【Chemistry 46】 is a single bond); Each X independently represents a group of the formula -(CR 12 R 13 )- group; Each Y is independently absent or a group of the formula -(CR 12 R 13 )- group; Each Z independently represents a group of the formula -(CR 14 )- group; R 1 , R 2 and R 3 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 alkoxy; or R 1 and R 2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; R 8 and R 9 are each independently H, D, F, Cl, Br, I, or C. 1 -C 4 alkyl; or R 8 and R 9 together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R 10 are H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 is alkoxy; R 8 ', R 9 ' and R 10 Each of ' is independently 1 -C 4 alkyl, or R 8 ' and R 9 ' together with a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R 11 is H, D or C 1 -C 6 is alkyl; R 12 , R 13 and R 14 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 is alkoxy; R 15 is H, C 1 -C 4 alkyl or PG, where PG is a phenol protecting group; R 20 is H, D, F or C 1 -C 12 is alkyl; Each R 21 are independently H, D, F, Cl, Br, I, or C 1 -C 4 is alkyl; n is an integer from 0 to 12, inclusive; p is an integer from 0 to 20, inclusive; and *** indicates the point of attachment of A to B or to H, and ** indicates the point of attachment of B to A or H to A; Further, provided that (i) formula R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 20 or R 21 at least one group of R 8 and R 9 together form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring, The compound, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

103. 103. The compound of claim 102, wherein A is 1 or 3 and B is 5 or 8.

104. 103. The compound of claim 102, wherein A is 2 or 4 and B is 5 or 8.

105. 103. The compound of claim 102, wherein A is 1 or 3 and B is 6 or 7.

106. 103. The compound of claim 102, wherein A is 2 or 4 and B is 6 or 7.

107. 107. The compound of any one of claims 102 to 106, wherein J is O.

108. 107. The compound of any one of claims 102 to 106, wherein J is S.

109. J is N-R 11 The compound according to any one of claims 102 to 106,

110. J is O or N-R 11 and K is absent.

111. Each of K and L is independently, -(CH 2 ), -(CD 2 ), -(CHF)-, -(CF 2 ), -(CH(CH 3 )), -(CD(CD 3 )), -(CF(CH 3 )), -(CH(CF 3 )), -(CF(CF 3 )), -(C(CH 3 )) 2 ), -(C(CD 3 )) 2 ), -(C(CF 3 )) 2 ), -(CH(OCH 3 )), -(CD(OCD 3 )), -(CF(OCH 3 )), -(CH(OCF 3 )), -(CF(OCF 3 )), -(C(OCH 3 [[ID=四十]])) 2 ), -(C(OCD 3 )) 2 ), -(C(OCF 3 )) 2 ), -(C(CH 3 )(CF 3 )), -(C(CD 3 )(CF 3 )), -(CH(CH 2 CH 3 )), -(CD(CD 2 CD 3 )), -(CF(CH 2 CH 3 )), -(CH(CH 2 CF 3 )), -(CH(CF 2 CF 3 )), -(CF(CF 2 CF 3 )), -(C(CH 2 CH​​​​​​​​​​​​​​ 2 110. The compound according to any one of claims 102 to 109, wherein

112. K and L each independently represent -(CH 2 ) -, -(CD 2 ) -, -(CF 2 )-,-(CH(CH 3 ))-,-(CD(CD 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 ) -, -(C(CD 3 ) 2 ) -, -(C(CF 3 ) 2 )-,-(CH(OCH 3 ))-,-(CD(OCD 3 )) -, -(CF(OCF 3 ))- or -(C(OCH 3 ) 2 )-. The compound of claim 111.

113. K and L each independently represent -(CH 2 ) -, -(CD 2 )-,-(CHF)-,-(CF 2 )-,-(CH(CH 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 )-or-(C(CF 3 ) 2 )-. The compound of claim 111.

114. L is -(CH 2 ), -(CD 2 ), -(CHF), -(CF 2 ), -(CH(CH 3 )), -(CD(CD 3 )), -(CF(CH 3 )), -(CH(CF<0002...)), -(CF(CF 3 )), -(C(CH 3 )) 2 ), -(C(CD 3 )) 2 ), -(C(CF 3 )) 2 ), -(CH(OCH 3 )), -(CD(OCD 3 )), -(CF(OCH 3 )), -(CH(OCF 3 )), -(CF(OCF 3 )), -(C(OCH 3 )) 2 ), -(C(OCD 3 )) 2 ), -(C(OCF 3 )) 2 ), -(C(CH 3 )(CF 3 )), -(C(CD 3 )(CF 3 )), -(CH(CH 2 CH 3 )), -(CD(CD 2 CD 3 )), -(CF(CH 2 CH 3 )), -(CH(CH 2 CF 3 )), -(CH(CF 2 CF 3 )), -(CF(CF 2 CF 3 )), -(C(CH 2 CH 3 )) 2 ), -(C(CD 2 CD 3 )) 2 ), or -(C(CF 2 CF 3 )) 2 )-. The compound of claim 110.

115. L is -(CH 2 ) -, -(CD 2 ) -, -(CF 2 )-,-(CH(CH 3 ))-,-(CD(CD 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 ) -, -(C(CD 3 ) 2 ) -, -(C(CF 3 ) 2 )-,-(CH(OCH 3 ))-,-(CD(OCD 3 )) -, -(CF(OCF 3 ))- or -(C(OCH 3 ) 2 )-. The compound of claim 114.

116. L is -(CH 2 ) -, -(CD 2 )-,-(CHF)-,-(CF 2 )-,-(CH(CH 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 )-or-(C(CF 3 ) 2 )-. The compound of claim 114.

117. R 1 、R 2 and R 3 each independently is H, D, Cl, F, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 2 CD 3 , -CD(CD 3 ) 2 , -CF 2 [[ID=۴۴]]CH 3 , CF(CH 3 ) 2 , -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CF 3 , -CF(CF 3 ) 2 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCD 2 CD 3 , -OCD(CD 3 ) 2 , -OCF 2 CH 3 , -OCF(CH 3 ) 2 , -OCH 2 CF 3 , -OCH(CF 3 ) 2 , -OCF 2 (CF 3 ), -OCF(CF 3 ) 2 、-OC(CH 3 ) 3 、-OC(CD 3 ) 3 、-OC(CF 3 ) 3 、-C(CH 3 ) 2 (CF 3 ),-C(CH 3 )(CF 3 ) 2 、-OC(CH 3 ) 2 (CF 3 ),-OC(CH 3 )(CF 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 2 CH 3 ) 2 、-CD 2 CD 2 CD 3 、-CD(CD 2 CD 3 ) 2 、-CF 2 CH 2 CH 3 、-CF(CH 2 CH 3 ) 2 、-CH 2 CF 2 CF 3 、-CH(CF 2 CF 3 ) 2 、-CF 2 CF 2 CF 3 、-CF(CF 2 CF 3 ) 2 、-OCH 2 CH 2 CH 3 、-OCH(CH 2 CH 3 ) 2 、-OCD 2 CD 2 CD 3 、-OCD(CD 2 CD 3 ) 2 、-OCF 2 CH 2 CH 3 , -OCF(CH 2 CH 3 ) 2 , -OCH 2 CF 2 CF 3 , -OCH(CF 2 CF 3 ) 2 , -OCF 2 CF 2 CF 3 or -OCF(CF 2 CF 3 ) 2 106. The compound of claim 102, 103, or 105, wherein:

118. R 1 , R 2 and R 3 each independently represents H, D, Cl, F, —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 or -CH(CH 3 ) 2 106. The compound of claim 102, 103, or 105, wherein:

119. R 1 , R 2 and R 3 each independently represents H, F, or —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 or -CH(CH 3 ) 2 106. The compound of claim 102, 103, or 105, wherein:

120. J is O; and each of K and L is independently —(CH 2 ) -, -(CD 2 )-,-(CHF)-,-(CF 2 )-,-(CH(CH 3 ))-,-(CF(CF 3 ))-,-(C(CH 3 ) 2 )-or-(C(CF 3 ) 2 )-; and R 1 , R 2 and R 3 each independently represents H, F, or —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 or -CH(CH 3 ) 2 106. The compound of claim 102, 103, or 105, wherein:

121. R 3 is H, D, Cl, F, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 , or -CH(CH 3 ) 2 and R 1 and R 2 106. The compound of claim 102, 103, or 105, wherein together form a 5- or 6-membered carbocyclic or heterocyclic ring.

122. A is 1A, 1B, 1C, 1D, 1E, 1F, 3A, 3B, 3C, 3D, 3E or 3F: 【Chemistry 47】 and R 16 and R 17 each independently represents H, D, Cl, F, —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 , -CH(CH 3 ) 2 , -OCH(CH 3 ) 2 , -C(CH 3 ) 3 or -O(CH 3 ) 3 and J" is O, S, or N-R 18 where R 18 is H, D, -CH 3 , -CH 2 F, -CHF 2 or -CF 3 122. The compound of claim 121, wherein:

123. R 3 がH、D、Cl、F、-CH 3 、-OCH 3 、-CD 3 、-OCD 3 、-CH 2 F-OCH 2 F-CHF 2 、-OCHF 2 、-CF 3 、-OCF 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CD 2 CD 3 、-CD(CD 3 ) 2 、-CF 2 CH 3 、CF(CH 3 ) 2 、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CF 3 、-CF(CF 3 ) 2 、-C(CH 3 ) 3 、-C(CD 3 ) 3 、-C(CF 3 ) 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-OCD 2 CD 3 、-OCD(CD 3 ) 2 、-OCF 2 CH 3 、-OCF(CH 3 ) 2 、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 (CF 3 ),-OCF(CF 3 ) 2 、-OC(CH 3 ) 3 、-OC(CD 3 ) 3 、-OC(CF 3 ) 3 、-C(CH 3 ) 2 (CF 3 ),-C(CH 3 )(CF 3 ) 2 、-OC(CH 3 ) 2 (CF 3 ),-OC(CH 3 )(CF 3 ) 2 、-CH 2 CH 2 CH 3 、-CH(CH 2 CH 3 ) 2 、-CD 2 CD 2 CD 3 、-CD(CD 2 CD 3 ) 2 、-CF 2 CH 2 CH 3 、-CF(CH 2 CH 3 ) 2 、-CH 2 CF 2 CF 3 、-CH(CF 2 CF 3 ) 2 、-CF 2 CF 2 CF 3 、-CF(CF 2 CF 3 ) 2 、-OCH 2 CH 2 CH 3 、-OCH(CH 2 CH 3 ) 2 、-OCD 2 CD 2 CD 3 、-OCD(CD 2 CD 3 ) 2 、-OCF 2 CH 2 CH 3 , -OCF(CH 2 CH 3 ) 2 , -OCH 2 CF 2 CF 3 , -OCH(CF 2 CF 3 ) 2 , -OCF 2 CF 2 CF 3 or -OCF(CF 2 CF 3 ) 2 and when W is C (carbon), R bonded thereto 4 , R 5 , R 6 and R 7 each independently represents H, D, F, Cl, Br, I, or —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 and when W is N (nitrogen), R bonded thereto 4 , R 5 , R 6 and R 7 107. The compound of claim 102, 104, or 106, wherein each of is independently absent or selected from H, D, methyl, ethyl, isopropyl, and t-butyl.

124. R 3 is H, D, Cl, F, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -OC(CH 3 ) 3 , -OC(CD 3 ) 3 , -OC(CF 3 ) 3 , -CH 2 CH 3 , -OCH 2 CH 3 , or -CH(CH 3 ) 2 and when W is C (carbon), R bonded thereto 4 , R 5 , R 6 and R 7 each independently represents H, D, F, Cl, —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 , and -CH(CH 3 ) 2 and when W is N (nitrogen), R bonded thereto is 4 , R 5 , R 6 and R 7 107. The compound of claim 102, 104, or 106, wherein each of is independently absent or selected from H, D, methyl, and ethyl.

125. Each W is C (carbon), and R 4 , R 5 , R 6 and R 7 each independently represents H, D, Cl, F, —CH 3 , -OCH 3 , -CH 2 F, -CHF 2 , -CF 3 or -OCF 3 125. The compound of claim 124, wherein:

126. R 8 and R 9 each independently is H, D, F, Cl, Br, I, -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 2 CD 3 , -CD(CD 3 ) 2 , -CF 2 CH 3 , -CF(CH 3 ) 2 , -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CF 3 , -CF(CF 3 ) 2 , -C(CH 3 ) 3 , -C(CD 3 ) 3 , -C(CF 3 ) 3 , -C(CH 3 ) 2 (CF 3 ), -C(CH 3 )(CF 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -CD 2 CD 2 CD 3 , -CD(CD 2 CD 3 ) 2 , -CF 2 CH 2 CH 3 , -CF(CH 2 CH 3 ) 2 , -CH 2 CF 2 CF 3 , -CH(CF 2 CF 3 ) 2 , -CF 2 CF 2 CF 3 or -CF(CF 2 CF 3 ) 2 The compound according to any one of claims 102 to 125,

127. R 8 and R 9 each independently represents H, F, or —CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 2 CH 3 , -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CF 3 , -CF(CF 3 ) 2 , -C(CH 3 ) 3 , -C(CF 3 ) 3 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -CF 2 CF 2 CF 3 or -CF(CF 2 CF 3 ) 2 127. The compound of claim 126, wherein:

128. R 8 and R 9 together 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 and 47: 【Chemistry 48】 126. The compound of any one of claims 102 to 125, wherein the compound forms a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring selected from the group consisting of:

129. R 10 がH、D、F、-CH 3 、-OCH 3 、-CD 3 、-OCD 3 、-CH 2 F-OCH 2 F-CHF 2 、-OCHF 2 、-CF 3 、-OCF 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CD 2 CD 3 、-CD(CD 3 ) 2 、-CF 2 CH 3 、-CF(CH 3 ) 2 、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CF 3 、-CF(CF 3 ) 2 、-C(CH 3 ) 3 、-C(CD 3 ) 3 、-C(CF 3 ) 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-OCD 2 CD 3 、-OCD(CD 3 ) 2 、-OCF 2 (CF 3 ),-OCF(CF 3 ) 2 、-OC(CH 3 ) 3 、-OC(CD 3 ) 3 、-OC(CF 3 ) 3 、-C(CH 3 ) 2 (CF 3 ),-C(CH 3 ) (CF 3 ) 2 , -OC(CH 3 ) 2 (CF 3 ), —OC(CH 3 ) (CF 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -CD 2 CD 2 CD 3 , -CD (CD 2 CD 3 ) 2 , -CF 2 CF 2 CF 3 , -CF(CF 2 CF 3 ) 2 , -C(CH 2 CH 3 ) 3 , -C(CD 2 CD 3 ) 3 , -C(CF 2 CF 3 ) 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 2 CH 3 ) 2 , -OCD 2 CD 2 CD 3 , -OCD (CD 2 CD 3 ) 2 , -OCF 2 CF 2 CF 3 or -OCF(CF 2 CF 3 ) 2 The compound according to any one of claims 102 to 128,

130. R 10 is H, D, F, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 or -CH(CH 3 ) 2 130. The compound of claim 129, wherein:

131. R 11 is H, methyl or ethyl.

132. R 12 , R 13 or R 14 each independently represents H, D, F, or —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH 2 CH 3 , -OCH(CH 2 CH 3 ) 2 or -OC(CH 3 ) 3 The compound according to any one of claims 102 to 131,

133. R 12 , R 13 or R 14 each independently represents H, D, F, or —CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -OCH 2 F, -CHF 2 , -OCHF 2 , -CF 3 , -OCF 3 , -CH 2 CH 3 or -OCH 2 CH 3 133. The compound of claim 132, wherein:

134. R 15 The compound of any one of claims 102 to 133, wherein is H.

135. R 15 Ga-CH 3 The compound according to any one of claims 102 to 134,

136. R 15 is a silyl-based phenol protecting group.

137. R 15 is a triphenylmethyl-based phenol protecting group.

138. R 15 is an unsubstituted or substituted benzyl group.

139. R 20 is H, D, F, -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ 3 The compound according to any one of claims 102 to 138,

140. Each R 21 are independently H, D, F, -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 or -C(CH 3 ) 3 The compound according to any one of claims 102 to 139,

141. 141. The compound of any one of claims 102 to 140, wherein n is 0, 1, 2, 3, or 4.

142. A compound of formula E-G, During the ceremony, E is 21 or 22: 【Chemistry 49】 and G is 23 or 24: [Transformation 50] wherein: J is O, S or N-R 11 and K is absent or -(CR 12 R 13 )- and; L is -(CR 12 R 13 )- and; Each W is independently C (carbon) or N (nitrogen), where: 【Chemistry 51】 For each use of R, the bond between each W may be a single bond or a double bond, provided that in the case of a single bond, each C (carbon) atom is bonded to R 4 , R 5 , R 6 or R 7 and in each case, R 4 , R 5 , R 6 and R 7 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl and C 1 -C 6 When W is N (nitrogen), R bonded thereto is selected from alkoxy. 4 , R 5 , R 6 and R 7 Each of these does not exist independently ( 【Chemistry 52】 is a double bond), or H, D and C 1 -C 6 alkyl ( 【Chemistry 53】 is a single bond); Each Q independently represents a group of the formula -(CR 12 R 13 )—, O, or Si, provided that each O and each Si is not directly bonded to an O or S; R 1 , R 2 and R 3 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 alkoxy; or R 1 and R 2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; Each R 8 ', R 9 ' and R 10 ' is independently, C 1 -C 4 alkyl; or R 8 ' and R 9 ' together form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R 11 is H, D or C 1 -C 6 is alkyl; R 12 and R 13 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 is alkoxy; R 20 is H, D, F or C 1 -C1 2 is alkyl; p is an integer from 0 to 20, inclusive; and *** indicates the point of attachment of E to G, and ** indicates the point of attachment of G to E, or Pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof.

143. E is 21, J is O, and K is —CH 2 - and L is -CH 2 - and R 1 , R 2 and R 3 each independently represents H, D, F, or —CH 3 , -OCH 3 and -OCF 3 143. The compound of claim 142, selected from:

144. R 20 144. The compound of claim 142 or 143, wherein the chiral center at the carbon to which is attached is S.

145. R 20 144. The compound of claim 142 or 143, wherein the chiral center at the carbon to which is attached is R.

146. Each Q is -CH 2 The compound according to any one of claims 142 to 145, wherein

147. At least one Q is O and each other Q is —CH 2 The compound according to any one of claims 142 to 145, wherein

148. The compound has the formula Compound M-0: 【Chemistry 54】 wherein R 1 , R 2 and R 3 each independently represents H, F, or —CH 3 , -OCH 3 , -CH 2 CH 3 , -OCH 2 CH 3 , or -OCF 3 and p" is an integer from 1 to 9, inclusive.

149. The compound is 【Transformation 55】 149. The compound of claim 147 or 148, wherein:

150. A compound of formula C-G, During the ceremony, C is 11 or 12: 【Transformation 56】 and G is 23 or 24: 【Chemistry 57】 where: J' is OH, SH or NH-R 11 and K is absent or -(CR 12 R 13 )- and; L is -(CR 12 R 13 )- and; Each W is independently C (carbon) or N (nitrogen), where: 【Transformation 58】 For each use of R, the bond between each W may be a single bond or a double bond, provided that in the case of a single bond, each C (carbon) atom is bonded to R 4 , R 5 , R 6 or R 7 and in each case, R 4 , R 5 , R 6 and R 7 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl and C 1 -C 6 When W is N (nitrogen), R bonded thereto is selected from alkoxy. 4 , R 5 , R 6 and R 7 Each of these does not exist independently ( 【Chemistry 59】 is a double bond), or H, D and C 1 -C 6 alkyl ( 【Transformation 60】 is a single bond); Each Q independently represents a group of the formula -(CR 12 R 13 )—, O, or Si, provided that each O and each Si is not directly bonded to an O or S; R 1 , R 2 and R 3 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 alkoxy; or R 1 and R 2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring; Each R 8 ', R 9 ' and R 10 ' is independently, C 1 -C 4 alkyl; or R 8 ' and R 9 ' together form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring; R 11 is H, D or C 1 -C 6 is alkyl; R 12 and R 13 each independently represents H, D, F, Cl, Br, I, C 1 -C 6 Alkyl or C 1 -C 6 is alkoxy; R 20 is H, D, F or C 1 -C1 2 is alkyl; p is an integer from 0 to 20, inclusive; and *** indicates the point of attachment of E to G, and ** indicates the point of attachment of G to E, or Pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof.

151. C is 11, J' is OH, and R 19 is H and K is -CH 2 - and L is -CH 2 - and R 1 , R 2 and R 3 each independently represents H, D, F, or —CH 3 , -OCH 3 and -OCF 3 151. The compound of claim 150, selected from:

152. R 20 152. The compound of claim 150 or 151, wherein the chiral center at the carbon to which is attached is in the S configuration.

153. R 20 152. The compound of claim 150 or 151, wherein the chiral center at the carbon to which is attached is in the R configuration.

154. Each Q is -CH 2 The compound according to any one of claims 150 to 153, wherein

155. At least one Q is O and each other Q is —CH 2 The compound according to any one of claims 150 to 153, wherein

156. The compound has the formula Compound M-3: 【Chemistry 61】 wherein R 1 , R 2 and R 3 each independently represents H, F, or —CH 3 , -OCH 3 , -CH 2 CH 3 , -OCH 2 CH 3 , or -OCF 3 156. The compound of claim 155, wherein p' is an integer from 1 to 9, inclusive, and p" is an integer from 1 to 9, inclusive.

157. The compound 【Transformation 62】 157. The compound of claim 155 or 156, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein:

158. A compound comprising a substituted quinone or hydroquinone head group to which is covalently attached an aliphatic tail group comprising at least one chiral center, at least one hydroxyl group, and at least one silicon atom.

159. 159. A method for treating or preventing signs or symptoms of Friedreich's ataxia or decreased frataxin levels or activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 158 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

160. 160. The method of claim 159, wherein the subject exhibits a reduced level of frataxin expression compared to a normal control subject.

161. 161. The method of claim 159 or 160, wherein the compound is administered daily for 6 weeks or more.

162. 162. The method of any one of claims 159-161, wherein the compound is administered daily for 12 weeks or more.

163. 163. The method of any one of claims 159 to 162, wherein the subject has been diagnosed with Friedreich's ataxia.

164. 164. The method of claim 163, wherein the Friedreich's ataxia comprises one or more of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems.

165. 165. The method of any one of claims 159 to 164, wherein the subject is a human.

166. 166. The method of any one of claims 159-165, wherein the compound is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intraventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

167. 159. A method for reducing mitochondrial iron in a mammalian subject having or suspected of having Friedreich's ataxia, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

168. The method of claim 167, wherein the mammalian subject has reduced frataxin expression compared to a normal control subject.

169. 169. The method of claim 167 or 168, wherein the compound is administered daily for 6 weeks or more.

170. 170. The method of any one of claims 167-169, wherein the compound is administered daily for 12 weeks or more.

171. 171. The method of any one of claims 167 to 170, wherein the subject has been diagnosed with Friedreich's ataxia.

172. 172. The method of claim 171, wherein the Friedreich's ataxia comprises one or more of muscle weakness, incoordination, impaired motor control, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems.

173. The method of any one of claims 167 to 172, wherein the subject is a human.

174. 174. The method of any one of claims 167-173, wherein the compound is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intraventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

175. 159. A method for treating Complex I deficiency in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

176. 176. The method of claim 175, wherein the compound is administered daily for 6 weeks or more.

177. 177. The method of claim 175 or 176, wherein the compound is administered daily for 12 weeks or more.

178. 178. The method of any one of claims 175 to 177, wherein the subject has been diagnosed with Friedreich's ataxia.

179. 179. The method of claim 178, wherein the Friedreich's ataxia comprises one or more of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems.

180. 180. The method of any one of claims 175 to 179, wherein the subject is a human.

181. 181. The method of any one of claims 175-180, wherein the compound is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmologically, intrathecally, intraventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

182. 159. A method for reducing or inhibiting lipoxygenase-15 activity in a mammalian subject having or suspected of having Friedreich's ataxia, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

183. 183. The method of claim 182, wherein the compound is administered daily for 6 weeks or more.

184. 184. The method of claim 182 or 183, wherein the compound is administered daily for 12 weeks or more.

185. 185. The method of any one of claims 182-184, wherein the Friedreich's ataxia comprises one or more of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems.

186. The method of any one of claims 182 to 185, wherein the subject is a human.

187. 187. The method of any one of claims 182-186, wherein the compound is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intraventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

188. 159. A method for reducing or inhibiting ferroptosis in a mammalian subject having or suspected of having Friedreich's ataxia, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

189. 189. The method of claim 188, wherein the compound is administered daily for 6 weeks or more.

190. 190. The method of claim 188 or 189, wherein the compound is administered daily for 12 weeks or more.

191. 191. The method of any one of claims 188-190, wherein the Friedreich's ataxia comprises one or more of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems.

192. The method of any one of claims 188 to 191, wherein the subject is a human.

193. 193. The method of any one of claims 188-192, wherein the compound is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intraventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

194. 159. A compound according to any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in the treatment or prevention of Friedreich's ataxia in a subject in need thereof.

195. 195. The compound of claim 194, wherein the compound is effective for increasing or maintaining frataxin levels in a subject suspected of having Friedreich's ataxia.

196. 195. The compound of claim 194, wherein the compound is effective to inhibit a decrease in frataxin levels in a subject suspected of having Friedreich's ataxia.

197. 197. The compound of any one of claims 194 to 196, wherein the compound is effective for treating one or more symptoms of Friedreich's ataxia selected from the group consisting of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems.

198. 198. The compound of any one of claims 194-197, wherein the compound is effective when administered daily for six weeks or more.

199. 200. The compound of any one of claims 194-198, wherein the compound is effective when administered daily for 12 weeks or more.

200. 159. A compound according to any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in increasing frataxin expression levels in a subject in need thereof.

201. 201. The compound of claim 200, wherein the compound is effective when administered daily for six weeks or more.

202. 202. The compound of claim 200 or 201, wherein the compound is effective when administered daily for 12 weeks or more.

203. 159. A compound according to any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in treating Complex I deficiency in a subject in need thereof.

204. 204. The compound of claim 203, wherein the compound is effective when administered daily for six weeks or more.

205. 205. The compound of claim 203 or 204, wherein the compound is effective when administered daily for 12 weeks or more.

206. The compound of claims 203-205, wherein the compound is effective to increase intracellular adenosine triphosphate (ATP) levels in tissue of a subject diagnosed with Friedreich's ataxia.

207. 159. A compound according to any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in reducing or inhibiting lipoxygenase-15 activity in a mammalian subject having or suspected of having Friedreich's ataxia.

208. 208. The compound of claim 207, wherein the compound is effective when administered daily for 6 weeks or more.

209. 209. The compound of any one of claims 207 or 208, wherein the compound is effective when administered daily for 12 weeks or more.

210. 159. A compound according to any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in reducing or inhibiting ferroptosis in a mammalian subject having or suspected of having Friedreich's ataxia.

211. 211. The compound of claim 210, wherein the compound is effective when administered daily for six weeks or more.

212. 212. The compound of any one of claims 210 or 211, wherein the compound is effective when administered daily for 12 weeks or more.

213. 159. Use of a composition in the preparation of a medicament for treating or preventing Friedreich's ataxia in a subject in need thereof, said composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

214. The use of claim 213, wherein the agent is effective to increase or maintain frataxin levels in a subject suspected of having Friedreich's ataxia.

215. The use of claim 213, wherein the agent is effective to inhibit the decline of frataxin levels in a subject suspected of having Friedreich's ataxia.

216. 216. The use of any one of claims 213 to 215, wherein the medicament is effective for treating one or more symptoms of Friedreich's ataxia selected from the group consisting of muscle weakness, incoordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart problems.

217. 217. The compound of any one of claims 213 to 216, wherein the medicament is effective when administered daily for six weeks or more.

218. 218. The compound of any one of claims 213 to 217, wherein the medicament is effective when administered daily for 12 weeks or more.

219. 159. Use of a composition in the preparation of a medicament for increasing frataxin expression levels in a mammalian subject compared to a normal control subject, said composition comprising a therapeutically effective amount of any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

220. 220. The use of claim 219, wherein the agent is effective when administered daily for 6 weeks or more.

221. 221. The use of claim 219 or 220, wherein the agent is effective when administered daily for 12 weeks or more.

222. 222. The use of any one of claims 219 to 221, wherein the medicament is effective to increase frataxin levels in a subject diagnosed with Friedreich's ataxia.

223. 159. Use of a composition in the preparation of a medicament for treating Complex I deficiency in a mammalian subject relative to a normal control subject, said composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

224. 224. The use of claim 223, wherein the agent is effective when administered daily for 6 weeks or more.

225. 225. The use of claim 223 or 224, wherein the agent is effective when administered daily for 12 weeks or more.

226. 226. The use of any one of claims 223 to 225, wherein the agent is effective to increase intracellular adenosine triphosphate (ATP) levels in tissue of a subject diagnosed with Friedreich's ataxia.

227. 159. Use of a composition in the preparation of a medicament for reducing or inhibiting lipoxygenase-15 activity in a mammalian subject having or suspected of having Friedreich's ataxia, the composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

228. 228. The use of claim 227, wherein the agent is effective when administered daily for 6 weeks or more.

229. 229. The use of claim 227 or 228, wherein the agent is effective when administered daily for 12 weeks or more.

230. 159. Use of a composition in the preparation of a medicament for reducing or inhibiting ferroptosis in a mammalian subject having or suspected of having Friedreich's ataxia, the composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 158, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof.

231. 231. The use of claim 230, wherein the agent is effective when administered daily for 6 weeks or more.

232. 232. The use of claim 230 or 231, wherein the agent is effective when administered daily for 12 weeks or more.

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