Quinone, hydroquinone and naphthoquinone analogs of vatebenzoquinone for treatment of mitochondrial disorder diseases

Abstract

The present invention relates to quinone, hydroquinone and naphthoquinone analogs of vatebenzoquinone for the treatment of mitochondrial disorder diseases. Disclosed is a compound of formula C-D, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, where C is 11, and D is 13, 14, 19, or 20. The invention also discloses application of the compound, the pharmaceutically acceptable salt or the composition containing the compound and the pharmaceutically acceptable salt in preparation of medicines for treating or preventing Friedel's Ataxia, improving the expression level of ataxia, treating defects of complex I, reducing or inhibiting the activity of lipoxygenase-15 and reducing or inhibiting ferroptosis, and also discloses application of the compound, the pharmaceutically acceptable salt or the composition containing the compound and the pharmaceutically acceptable salt in preparation of medicines for treating or preventing Friedel's Ataxia, improving the expression level of ataxia, treating defects of complex I.

Description

Quinone, hydroquinone, and naphthoquinone analogs for treating mitochondrial disorders

[0001] This application is a divisional application of Chinese patent application filed on October 2, 2020, with application number 202080084283.6 and entitled "Quinone-, hydroquinone- and naphthoquinone-analogs of vatibenquinone for the treatment of mitochondrial abnormalities".

[0002] Cross-references to related applications

[0003] This application claims the benefit and priority of U.S. Provisional Application No. 62 / 911,069, filed October 4, 2019, and U.S. Provisional Application No. 62 / 991,525, filed March 18, 2020, the contents of each of the aforementioned U.S. Provisional Applications of any kind and all purposes, which are incorporated herein by reference in their entirety. Technical Field

[0004] This application generally relates to compositions and methods for the prevention, mitigation, and / or treatment of mitochondrial diseases (such as Friedrich's ataxia), and / or reducing the severity of such diseases. Furthermore, this application relates to: 1) methods for preparing novel therapeutic compounds and related intermediates (e.g., benzo[a]dihydropyran], quinones, hydroquinones, benzoquinones, and hydroxybenzoquinones), and / or 2) administering, alone or in combination with one or more other therapeutic agents, an effective amount of the novel compounds disclosed herein to a subject suffering from Friedrich's ataxia or other mitochondrial diseases. Background Technology

[0005] The following description is provided to aid the reader's understanding. The information provided or references cited are not to be considered prior art to the compositions and methods disclosed herein.

[0006] Friedreich's ataxia (FA) is a fatal, single-gene, autosomal recessive disorder caused by mutations in the gene encoding the nuclear protein ataxia. Tissues in both the peripheral and central nervous systems are affected in FA, including the dentate nucleus, Clark's column, spinocerebellar tract, and dorsal root ganglia. Progressive degeneration of these tissues leads to worsening ataxia, ultimately resulting in the loss of independent walking ability in most patients by their thirtieth year of life.

[0007] The FXN gene encodes the coagulin protein. Coagulin is an iron-binding protein responsible for forming iron-sulfur clusters. One consequence of coagulin deficiency is mitochondrial iron overload.

[0008] Conamin is a highly conserved iron-binding protein. Human conamin is synthesized as a 210-amino acid precursor, which is then introduced into the mitochondria via a mitochondrial-targeting signal contained at the N-terminus. The conamin precursor is subsequently cleaved into the mature 14 kDa protein (residues 81-210).

[0009] Coagulants bind Fe electrostatically. 2+ Ions and Fe 3+ Both ions act as iron chaperones during Fe-S cluster assembly. The chaperone binds directly 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 to synthesize sulfur-containing bioorganic derivatives, and Isu is a transient scaffold protein on which Fe-S clusters are assembled. The chaperone enhances the efficiency of Fe-S cluster formation, which is required to activate the mitochondrial Kreb cycle enzyme aconitase. The chaperone also plays a role in mitochondrial iron storage and heme biosynthesis by incorporating mitochondrial iron into protoporphyrin (PIX).

[0010] Loss of function of synergists leads to the 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 synergists protect dopaminergic neurons from MPTP-induced toxicity in a mouse model of Parkinson's disease.

[0011] Ferroprelation is an iron-dependent form of cell death, biochemically distinct from apoptosis, and typically accompanied by significant iron accumulation and lipid peroxidation. Ferroprelation-inducing factors can directly or indirectly affect glutathione peroxidase through various pathways, leading to decreased intracellular antioxidant capacity and accumulation of reactive oxygen species (ROS), ultimately resulting in oxidative cell death. Recent studies have shown that ferroprelation is closely related to the pathophysiology of various diseases, such as tumors, neurological disorders, ischemia-reperfusion injury, kidney injury, and hematological disorders. Decreased expression of FXN (a coagulant protein) is associated with mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. Recent research indicates that FXN, which regulates iron homeostasis and mitochondrial function, is a key regulator of ferroprelation. Therefore, ferroprelation has been identified as a therapeutic target for Friedrich's ataxia. As mentioned above, ferroprelation is associated with glutathione depletion and the production of lipid peroxides generated by lipoxygenases (such as lipoxygenase-15). Therefore, targeting lipoxygenase-15 provides a therapeutic target for Friedrich's ataxia.

[0012] Mitochondrial iron overload leads to impaired mitochondrial metabolism and a defective mitochondrial respiratory chain. This defective respiratory chain results in increased free radical generation and oxidative damage, which may be considered a mechanism impairing cell viability. Some evidence suggests that conamin may detoxify ROS by activating glutathione peroxidase and increasing thiols. (See Calabrese et al., Journal of the Neurological Sciences, 233(1): 145-162 (June 2005)).

[0013] Friedrich ataxia occurs when the FXN gene contains an amplified GAA triplet repeat sequence within the intron. The mutated FXN gene contains an amplified GAA triplet repeat sequence in its first intron; point mutations have also been detected in some lineages. Because the defect is located in an intron that is removed from the mRNA transcript between transcription and translation, the mutated FXN gene does not lead to the production of abnormal proteins. Instead, the mutation results in gene silencing, meaning it reduces gene transcription.

[0014] Symptoms typically begin between the ages of 5 and 15, although they can sometimes appear in adulthood. The first symptom is usually gait ataxia or difficulty walking. The ataxia gradually worsens and slowly spreads to the arms and trunk. Sensory loss is common in the extremities and may spread to other parts of the body. Other features include loss of tendon reflexes, especially in the knees and ankles. Most people with Friedrich's ataxia develop scoliosis, which usually requires surgical intervention. Articulation difficulties (slow speech and slurred speech) can develop and may gradually worsen. Many individuals with advanced Friedrich's ataxia experience hearing and vision loss.

[0015] Heart disease is often accompanied by Friedrich's ataxia, such as hypertrophic cardiomyopathy, myocardial fibrosis (the formation of fibrous material in the heart muscle), and heart failure. Arrhythmias, such as tachycardia (rapid heart rate) and cardiac block (impaired conduction of heartbeats within the heart), are also common. Other possible symptoms include chest pain, shortness of breath, and palpitations.

[0016] Many patients with Friedrich's ataxia experience a slow decline in visual acuity later in the disease. The most common ophthalmological manifestation of Friedrich's ataxia is optic neuropathy. In some cases, severe / catastrophic vision loss is experienced.

[0017] Approximately 20% of people with Friedrich's ataxia experience carbohydrate intolerance, and 10% develop diabetes. Most individuals with Friedrich's ataxia are prone to fatigue and find that they need more rest and take longer to recover from common illnesses such as colds and flu.

[0018] The rate of progression varies from person to person. Typically, patients are confined to wheelchairs for 10 to 20 years after the onset of the first symptoms, and in later stages of the disease, individuals may experience complete loss of mobility. Friedrich's ataxia can shorten life expectancy, and heart disease is the most common cause of death.

[0019] The five enzyme complexes of the oxidative phosphorylation (OXPHOS) system (i.e., complex I, complex II, complex III, complex IV, and complex V) are located in the mitochondrial membrane, and a deficiency in complex I, which leads to decreased levels (and reduced production) of adenosine triphosphate (ATP), is thought to be associated with Friedreich's ataxia. Indeed, it has been shown that reduced expression of complex I proteins in the cells of patients with Friedreich's ataxia increases the intracellular non-biologically available iron pool, leading to increased free radical generation, increased cellular oxidative damage, and decreased complex I activity, as well as the associated reduction in intracellular ATP production (Heidari et al., Complex I and ATP Content Deficiency in Lymphocytes from Friedreich's Ataxia, Can. J. Neurol. Sci. 2009: 36: 26-31).

[0020] There is no known cure for Friedrich's ataxia. Treatment typically involves managing the symptoms. Because patients with Friedrich's ataxia are at risk of heart disease, they are usually prescribed medications such as beta-blockers, ACE inhibitors, and / or diuretics. Since damage caused by oxidative stress is believed to be involved in the progression of Friedrich's ataxia, antioxidants such as vitamin E, idebenone, and coenzyme Q10 are often co-administered to people diagnosed with or suspected of having Friedrich's ataxia. These compounds have been used in various clinical trials.

[0021] Currently, EPI-743 (a benzoquinone compound, also known as vatiquinone) is in Phase 2 clinical trials, and a Phase 3 clinical trial for the treatment of refractory epilepsy has not yet been initiated. It has received Orphan Drug Designation and Fast Track status from the United States Food and Drug Administration (FDA). Vatiquinone is believed to reduce oxidative stress and improve mitochondrial function.

[0022] Omaveloxolone is a second-generation synthetic oleanane triterpenoid compound that is believed to exhibit antioxidant and anti-inflammatory activities. Omaveloxolone is currently in Phase 2 clinical development for the treatment of multiple indications, including Friedrich's ataxia, mitochondrial myopathy, and ophthalmic disorders / diseases.

[0023] Several other treatments for Friedrich's ataxia are currently undergoing clinical trials, but none have been approved by the FDA. Therefore, better drug candidates are still needed to address the needs of patients diagnosed with Friedrich's ataxia. Summary of the Invention

[0024] On one hand, a compound of formula EF or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof is provided, wherein E is 21 or 22:

[0025] And F is 13, 14, 15, 16, 17, 18, 19, or 20:

[0026] Where J is O, S, or NR 11 K does not exist or -(CR) 12 R 13 )-;L is -(CR 12 R 13 -; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each X is independently represented by the formula -(CR) 12 R 13 The group )-; each Y is independently absent or of the formula -(CR 12 R 13 The group is )-; each Z is independently of the formula -(CR 14The group R1, R2, and R3 are each independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; or R1 and R2 together form a five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring, a five-membered heteroaromatic ring, or a six-membered heterocyclic ring; each R8 and R9 are each independently H, D, F, Cl, Br, I, or C1-C4 alkyl; or R8 and R9 together form a three-membered, four-membered, five-membered, six-membered, or seven-membered carbon ring or heterocyclic ring; R 10 It is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy; R 11 It is H, D, or C1-C6 alkyl; R 12 R 13 and R 14 Each of these elements is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; R 20 Is it H, D, F or C1-C? 12 Alkyl; each R 21 Independently, it is H, D, F, Cl, Br, I, or a C1-C4 alkyl group; n is an integer from 0 to 12; and Indicates the connection point from E to F. Indicates the connection point from F to E; and further, the condition is: (i) Equations 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 form contains at least one fluorine atom; and / or (ii) R8 and R9 together form a ternary, quaternary, pentary, hexanal, or septial carbon ring or heterocycle. In any embodiment herein, it is possible that E is 21 and F is 13, 14, 19, or 20. In any embodiment herein, it is possible that E is 22 and F is 13, 14, 19, or 20. In any embodiment herein, it is possible that E is 21 and F is 15, 16, 17, or 18. In any embodiment herein, it is possible that E is 22 and F is 15, 16, 17, or 18. In any embodiment herein, it is possible that J is O. In any embodiment herein, it is possible that J is S. In any embodiment herein, it is possible that J is NR. 11 In any implementation herein, J may be O or NR. 11And K does not exist. In some implementations, 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))-, -(CF(OCF3))-, -(C(CH2))-, -(CD(OCD3))-, -(CF(OCF3))-, -(C(OCF3))-, -(C(CH2))-, -(CD(OCD3))-, -(C(OCF ... ))-, -(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, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-.In some implementations, 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 implementations, 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, -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, -CH2CH 2CH3, -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, 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(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 implementations, 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 five- or six-membered carbon ring or heterocycle. In some embodiments, E is 21A, 21B, 21C, 21D, 21E, or 21F.

[0027] Among them, R 16 and R 17 Each of these 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 18It is 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, -OC H(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, -CD2CD 2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, -OCH2CH2CH3, -O CH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2CF3 or -O CF(CF2CF3)2; and wherein, if W is C (carbon), then each of the R4, R5, R6 and R7 connected 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 wherein, if W is N (nitrogen), then each of the R4, R5, R6 and R7 connected thereto is independently absent or selected from H, D, methyl, ethyl, isopropyl and tert-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 wherein, if W is C (carbon), each of R4, R5, R6, and R7 connected thereto is independently selected from H, D, F, Cl, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -CH2CH3, and -CH(CH3)2; and wherein, if W is N (nitrogen), each of R4, R5, R6, and R7 connected thereto is independently absent or selected from H, D, methyl, and ethyl. In some implementations, each W is C, and each of R4, R5, R6, and R7 is independently H, D, Cl, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, or -OCF.

[0028] In any implementation thereof, it is possible that 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(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some implementations, 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.

[0029] In any embodiment described herein, it is possible that R8 and R9 together form a ternary, quaternary, pentaneous, hexanal, or heptaneous carbon ring or heterocycle, which may be 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47. , where # indicates the connection point where the carbocyclic or heterocyclic ring connects to the remainder of the compound. In any embodiment herein, it is possible that 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(C D3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CF2CF3, -CF(CF2CF3)2, -C(CH2CH3)3, -C(CD2CD3)3, -C(CF2CF3)3, -OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments, R 10 It is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2. In any embodiment herein, it is possible that R 11 It is H, methyl, or ethyl. In any embodiment described herein, it is possible that R... 12 R 13 Or R 14Each of these 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, R 12 R 13 Or R 14 Each of these is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -OCH2CH3. In any implementation herein, it is possible that R... 20 These are H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In any embodiment herein, it is possible that each R 21 Independently, n can be H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3. In any implementation herein, n may be 0, 1, 2, 3, or 4.

[0030] In some implementations, the compound is

[0031] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0032] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0033] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0034] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0035] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0036] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0037] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0038] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0039] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0040] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0041] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0042] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0043] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate and / or solvate thereof.

[0044] On one hand, a compound of formula CD or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof is provided, wherein C is 11 or 12:

[0045] And D is 13, 14, 15, 16, 17, 18, 19, or 20:

[0046] Wherein, J' is OH, SH, or NH-R 11 K does not exist or -(CR) 12 R 13 )-;L is -(CR 12 R 13 -; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy; and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each X is independently represented by the formula -(CR) 12 R 13 The group )-; each Y is independently absent or of the formula -(CR 12 R 13 The group is )-; each Z is independently of the formula -(CR 14The group R1, R2, and R3 are each independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; or R1 and R2 together form a five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring, a five-membered heteroaromatic ring, or a six-membered heterocyclic ring; each of R8 and R9 is independently H, D, F, Cl, Br, I, or a C1-C4 alkyl; or R8 and R9 together form a three-, four-, five-, six-, or seven-membered carbon ring or heterocyclic ring; R 10 It is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy; R 11 It is H, D, or C1-C6 alkyl; R 12 R 13 and R 14 Each of these elements is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; R 19 It is H, C1-C4 alkyl or benzyl; R 20 Is it H, D, F or C1-C? 12 Alkyl; each R 21 Independently, it is H, D, F, Cl, Br, I, or a C1-C4 alkyl group; n is an integer from 0 to 12, including the end value; and Indicates the connection point from C to D. Indicates the connection point from D to C; and further, the condition is: (i) Equations 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 contains at least one fluorine atom; and / or (ii) R8 and R9 together form a ternary, quaternary, pentary, hexanal or septial carbon ring or heterocycle.

[0047] In any embodiment described herein, it is possible that C is 11 and D is 13, 14, 19, or 20. In any embodiment described herein, it is possible that C is 12 and D is 13, 14, 19, or 20. In any embodiment described herein, it is possible that C is 11 and D is 15, 16, 17, or 18. In any embodiment described herein, it is possible that C is 12 and D is 15, 16, 17, or 18. In any embodiment described herein, it is possible that J' is OH. In any embodiment described herein, it is possible that J' is SH. In any embodiment described herein, it is possible that J' is NH-R. 11 In any embodiment described herein, J' may be OH or NH-R. 11And K does not exist. In some implementations, 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))-, -(CF(OCF3))-, -(C(CH2))-, -(CD(OCD3))-, -(CF(OCF3))-, -(C(OCF3))-, -(C(CH2))-, -(CD(OCD3))-, -(C(OCF ... ))-, -(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, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-.In some implementations, 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 implementations, 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, -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, -CH2CH 2CH3, -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, 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(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)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 five- or six-membered carbon ring or heterocycle. In some embodiments, C is 11A, 11B, 11C, 11D, 11E, or 11F.

[0048] Among them, R 16 and R 17 Each of these 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 18It is 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, -OC H(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, -CD2CD 2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, -OCH2CH2CH3, -O CH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2CF3 or -O CF(CF2CF3)2; and wherein, if W is C (carbon), then each of the R4, R5, R6 and R7 connected 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 wherein, if W is N (nitrogen), then each of the R4, R5, R6 and R7 connected thereto is independently absent or selected from H, D, methyl, ethyl, isopropyl and tert-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 wherein, if W is C (carbon), each of R4, R5, R6, and R7 connected thereto is independently H, D, F, Cl, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2; and wherein, if W is N (nitrogen), each of R4, R5, R6, and R7 connected thereto is independently absent or selected from H, D, methyl, and ethyl. In some implementations, each W is C (carbon) and each of R4, R5, R6 and R7 is independently H, D, Cl, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3 or -OCF3.

[0049] In any implementation thereof, it is possible that 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(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. In any embodiment herein, it is possible that R8 and R9 together form a ternary, quaternary, pentaneous, hexanal, or heptaneous carbocyclic or heterocyclic ring selected from the following: 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47. , where # indicates the connection point where the carbocyclic or heterocyclic ring is connected to the remainder of the compound.

[0050] In any implementation thereof, it is possible that 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, -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(C D3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CF2CF3, -CF(CF2CF3)2, -C(CH2CH3)3, -C(CD2CD3)3, -C(CF2CF3)3, -OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments, R 10 It is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2. In any embodiment herein, it is possible that R 11 It is H, methyl, or ethyl. In any embodiment described herein, it is possible that R... 12 R 13 Or R 14 Each of these 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, R 12 R 13 Or R 14Each of these is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -OCH2CH3. In any implementation herein, it is possible that R... 19 It is H. In any implementation herein, it is possible that R 19 Yes -CH3. In any implementation herein, it is possible that R 19 It is -CH2CH3. In any implementation herein, it is possible that R 19 It is -C(CH3)3. In any implementation herein, it is possible that R 19 It is an unsubstituted or substituted benzyl group. In any embodiment herein, it is possible that R 20 These are H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In any embodiment herein, it is possible that each R 21 Independently, n can be H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3. In any implementation herein, n may be 0, 1, 2, 3, or 4.

[0051] In some implementations, the compound is

[0052] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0053] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0054] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0055] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0056] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0057] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0058] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0059] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0060] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0061] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0062] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0063] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In some embodiments, the compound is

[0064] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate and / or solvate thereof.

[0065] In one respect, 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:

[0066] B is 5, 6, 7, or 8:

[0067] And H is 25:

[0068] Where J is O, S, or NR 11 K does not exist or is -(CR) 12 R 13 )-;L is -(CR 12 R 13 )-; Each Q is independently represented by the formula -(CR 12 R 13 The group is O or Si, provided that each O and each Si is not directly bonded to O or Si; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy; and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each X is independently represented by the formula -(CR) 12 R 13The group )-; each Y is independently absent or of the formula -(CR 12 R 13 The group is )-; each Z is independently of the formula -(CR 14 The group R1, R2, and R3 are each independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; or R1 and R2 together form a five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring, a heteroaromatic ring, or a six-membered heterocyclic ring; each of R8 and R9 is independently H, D, F, Cl, Br, I, or a C1-C4 alkyl; or R8 and R9 together form a three-, four-, five-, six-, or seven-membered carbon ring or heterocyclic ring; R 10 It is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy; R8', R9' and R 10 Each of the members in 'R8' is independently a C1-C4 alkyl group, or R8' and R9' together form a ternary, quaternary, pentaneous, hexanal, or heptaneous carbon ring or heterocycle; R 11 It is H, D, or C1-C6 alkyl; R 12 R 13 and R 14 Each of these elements is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; R 15 It is H, C1-C4 alkyl, or PG, where PG is a phenol protecting group; R 20 Is it H, D, F or C1-C? 12 Alkyl; each R 21 Independently, it is H, D, F, Cl, Br, I, or a C1-C4 alkyl group; n is an integer from 0 to 12, including the end value; p is an integer from 0 to 20, including the end value; and Indicates the connection point where A connects to B, or A connects to H, and Indicate the connection point where B is connected to A, or H is connected to A; and further, the condition is: (i) equations 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 form contains at least one fluorine atom; and / or (ii) R8 and R9 together form a ternary, quaternary, pentary, hexanal or septary carbon ring or heterocycle.

[0069] In any implementation herein, it is possible that A is 1 or 3 and B is 5 or 8. In any implementation herein, it is possible that A is 2 or 4 and B is 5 or 8. In any implementation herein, it is possible that A is 1 or 3 and B is 6 or 7. In any implementation herein, it is possible that A is 2 or 4 and B is 6 or 7. In any implementation herein, it is possible that J is 0. In any implementation herein, it is possible that J is S. In any implementation herein, it is possible that J is NR. 11 In any implementation herein, J may be O or NR. 11And K does not exist. In some implementations, 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))-, -(CF(OCF3))-, -(C(CH2))-, -(CD(OCD3))-, -(CF(OCF3))-, -(C(OCF3))-, -(C(CH2))-, -(CD(OCD3))-, -(C(OCF ... ))-, -(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, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-.In some implementations, 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 implementations, 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, -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, -CH2CH 2CH3, -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, 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(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 implementations, 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 five- or six-membered carbon ring or heterocycle. In some embodiments, A is 1A, 1B, 1C, 1D, 1E, 1F, 3A, 3B, 3C, 3D, 3E, or 3F.

[0070] Among them, R 16 and R 17 Each of these 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 18It is 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, -O CH(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, -CD2C D2CD3, -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 wherein, if W is C (carbon), each of the R4, R5, R6 and R7 connected 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 wherein, if W is N (nitrogen), each of the R4, R5, R6 and R7 connected thereto is independently absent or selected from H, D, methyl, ethyl, isopropyl and tert-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 wherein, if W is C (carbon), each of R4, R5, R6, and R7 connected thereto is independently selected from H, D, F, Cl, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -CH2CH3, and -CH(CH3)2; and wherein, if W is N (nitrogen), each of R4, R5, R6, and R7 connected thereto is independently absent or selected from H, D, methyl, and ethyl. In some implementations, each W is C (carbon), and each of R4, R5, R6, and R7 is independently H, D, Cl, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, or -OCF3.

[0071] In any implementation thereof, it is possible that 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(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some implementations, 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.

[0072] In any embodiment described herein, it is possible that R8 and R9 together form a ternary, quaternary, pentaneous, hexanal, or heptaneous carbon ring or heterocycle selected from the following: 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47: , where # indicates the connection point where the carbocyclic or heterocyclic ring connects to the remainder of the compound. In any embodiment herein, it is possible that R 10 Is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, -CH(CH3)2, -CD2CD3, -CD(CD3)2, -CF2CH3, -CF(CH3)2, -CH2CF3, - CH(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -OCD2CD3, -OCD(CD3)2, -OCF2(CF3), -OCF(CF3)2, -OC(CH3)3, -OC( CD3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CF2C F3, -CF(CF2CF3)2, -C(CH2CH3)3, -C(CD2CD3)3, -C(CF2CF3)3, -OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments, R1 is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2. In any embodiment herein, it is possible that R... 11 It is H, methyl, or ethyl. In any embodiment described herein, it is possible that R... 12 R 13 Or R 14Each of these 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, R 12 R 13 Or R 14 Each of these is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -OCH2CH3. In any implementation herein, it is possible that R... 15 It is H. In any implementation herein, it is possible that R 15 Yes -CH3. In any implementation herein, it is possible that R 15 It is based on a silyl phenol protecting group. In any embodiment herein, it is possible that R 15 It is based on the phenol protecting group of triphenylmethyl. In any embodiment herein, it is possible that R 15 It is an unsubstituted or substituted benzyl group.

[0073] In any implementation thereof, it is possible that R 20 These are H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In any embodiment herein, it is possible that each R 21 Independently, n can be H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3. In any implementation herein, n may be 0, 1, 2, 3, or 4.

[0074] On one hand, compounds of formula EG or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates and / or solvates thereof are provided, wherein E is 21 or 22:

[0075] And G is 23 or 24:

[0076] Where J is O, S, or NR 11 K does not exist or -(CR) 12 R 13 )-;L is -(CR 12 R 13 -; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy; and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each Q is independently of the formula -(CR) 12 R 13 The R1, R2, and R3 groups are H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy groups, provided that each O and each Si is not directly bonded to O or Si; 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 five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring, a heteroaromatic ring, or a six-membered heterocyclic ring; each of R8', R9', and R 10 'Independently a C1-C4 alkyl group; or R8' and R9' together form a ternary, quaternary, pentaneous, hexanal, or heptaneous carbon ring or heterocycle; R 11 It is H, D, or C1-C6 alkyl; R 12 and R 13 Each of these elements is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; R 20 Is it H, D, F or C1-C? 12 Alkyl group; p is an integer from 0 to 20, including the end value; and Instruct E to connect to the connection point of G, and Indicates the connection point from which G connects to E.

[0077] In any embodiment described herein, it is possible that E is 21, J is O, K is -CH2-, L is -CH2-, and each of R1, R2, and R3 is independently selected from: H, D, F, -CH3, -OCH3, and -OCF3. In any embodiment described herein, it is possible that R is connected thereto. 20 The chiral center at the carbon atom is in the S configuration, or possibly, it is connected to an R atom. 20 The chiral center at the carbon atom is in the R configuration. In any embodiment herein, it is possible that each Q is -CH2-, or at least one Q is O and every other Q is -CH2-. In some embodiments, the compound is compound M-0 having the following formula:

[0078] In this context, 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...

[0079] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate and / or solvate thereof.

[0080] On one hand, a compound of formula CG or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof is provided, wherein C is 11 or 12:

[0081] And G is 23 or 24:

[0082] Wherein, J' is OH, SH, or NH-R 11 K does not exist or -(CR) 12 R 13 )-;L is -(CR 12 R 13 -; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each Q is independently of the formula -(CR) 12 R 13 The R1, R2, and R3 groups are H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy groups, provided that each O and each Si is not directly attached to O or Si; 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 five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring, a heteroaromatic ring, or a six-membered heterocyclic ring; each of R8', R9', and R 10 'Independently a C1-C4 alkyl group; or R8' and R9' together form a ternary, quaternary, pentaneous, hexanal, or heptaneous carbon ring or heterocycle; R 11 It is H, D, or C1-C6 alkyl; R 12 and R 13 Each of these elements is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; R 20 Is it H, D, F or C1-C? 12 Alkyl group; p is an integer from 0 to 20, including the end value; and Instruct E to connect to the connection point of G, and This indicates the connection point where G connects to E. In some implementations, C is 11, J' is OH, and R... 19 H is -CH2-, K is -CH2-, L is -CH2-, and each of R1, R2, and R3 is independently selected from: H, D, F, -CH3, -OCH3, and -OCF3.

[0083] In any implementation thereof, it is possible that an R is connected thereto. 20 The chiral center at the carbon atom is in the S configuration, or has an R atom attached to it. 20 The chiral center at the carbon atom is in the R configuration. In any embodiment herein, it is possible that each Q is -CH2-, or it is possible that at least one Q is O and every other Q is -CH2-. In some embodiments, the compound is of formula M-3:

[0084] In this context, 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...

[0085] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate and / or solvate thereof.

[0086] In one aspect, a compound is provided comprising a substituted quinone or hydroquinone head group, wherein an aliphatic tail group comprising at least one chiral center, at least one hydroxyl group and at least one silicon atom is covalently attached to the head group.

[0087] In one aspect, this technology provides a method for treating or preventing signs or symptoms of Friedrich's ataxia or reduced levels or activity of ataxin in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of any aspect or embodiment of this technology disclosed herein (hereinafter collectively referred to as "compounds of this technology," etc.) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, it is possible that the subject exhibits reduced ataxin expression levels compared to a normal control subject. In any embodiment herein, it is possible that the compound is administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the compound is administered daily for 12 weeks or longer. In any embodiment herein, it is possible that the subject has been diagnosed with Friedrich's ataxia. In some embodiments, Friedrich's ataxia includes one or more of muscle weakness, loss of coordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart disease. In any embodiment herein, it is possible that the subject is a human. In any of the embodiments described herein, it is possible that the compound is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, via the eye, intrathecally, intravenously, via iontophoresis, via mucosa, intravitreal, or intramuscularly.

[0088] In one aspect, this technology provides a method for reducing mitochondrial iron in mammalian subjects suffering from or suspected of suffering from Friedrich's ataxia, the method comprising administering to the subject a therapeutically effective amount of a compound of the technology or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, it is possible that the mammalian subject has reduced expression of ataxia proteins compared to a normal control subject. In any embodiment herein, it is possible that the compound is administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the compound is administered daily for 12 weeks or longer. In any embodiment herein, it is possible that the subject has been diagnosed with Friedrich's ataxia. In some embodiments, Friedrich's ataxia includes one or more of muscle weakness, loss of coordination, impaired motor control, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart disease. In any embodiment herein, it is possible that the subject is a human. In any of the embodiments described herein, it is possible that the compound is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, via the eye, intrathecally, intravenously, via iontophoresis, via mucosa, intravitreal, or intramuscularly.

[0089] In one aspect, this technology provides a method for treating a deficiency of Complex I in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the technology or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, it is possible that the compound is administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the compound is administered daily for 12 weeks or longer. In any embodiment herein, it is possible that the subject has been diagnosed with Friedrich's ataxia. In some embodiments, Friedrich's ataxia includes one or more of muscle weakness, loss of coordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart disease. In any embodiment herein, it is possible that the subject is a human. In any embodiment herein, it is possible that the compound is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, intraocularly, intrathecally, intravenously, via iontophoresis, via mucosa, intravitreal, or intramuscularly.

[0090] In one aspect, a method is provided for reducing or inhibiting lipoxygenase-15 activity in mammalian subjects suffering from or suspected of suffering from Friedrich's ataxia, the method comprising administering to the subject a therapeutically effective amount of a compound of the art or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, it is possible that the compound is administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the compound is administered daily for 12 weeks or longer. In any embodiment herein, it is possible that Friedrich's ataxia includes one or more of muscle weakness, loss of coordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart disease. In any embodiment herein, it is possible that the subject is a human. In any embodiment herein, it is possible that the compound is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, intraocularly, intrathecally, intraocularly, intrathecally, intravenously, via iontophoresis, via mucosa, intravitreal, or intramuscularly.

[0091] In one aspect, a method is provided for reducing or inhibiting ferroptosis in mammalian subjects suffering from or suspected of suffering from Friedrich's ataxia, the method comprising administering to the subject a therapeutically effective amount of a compound of the art or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, it is possible that the compound is administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the compound is administered daily for 12 weeks or longer. In any embodiment herein, it is possible that Friedrich's ataxia includes one or more of muscle weakness, loss of coordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart disease. In any embodiment herein, it is possible that the subject is a human. In any embodiment herein, it is possible that the compound is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, intraocularly, intrathecally, intraocularly, intrathecally, intravenously, via iontophoresis, via mucosa, intravitreal, or intramuscularly.

[0092] In one aspect, this technology provides compounds of the technology or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof for the treatment or prevention of Friedrich's ataxia in subjects of need. In any embodiment herein, it is possible that the compound effectively increases or maintains ataminin levels in subjects suspected of having Friedrich's ataxia. In any embodiment herein, it is possible that the compound effectively inhibits the decrease in ataminin levels in subjects suspected of having Friedrich's ataxia. In any embodiment herein, it is possible that the compound effectively treats one or more symptoms of Friedrich's ataxia selected from the group consisting of: muscle weakness, loss of coordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart disease. In any embodiment herein, it is possible that the compound is effective when administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the compound is effective when administered daily for 12 weeks or longer.

[0093] In one aspect, this technology provides compounds of the technology or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof for enhancing the expression levels of conaminins in desired subjects. In any embodiment herein, it is possible that the compound is effective when administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the compound is effective when administered daily for 12 weeks or longer.

[0094] In one aspect, this technology provides compounds of the technology or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof for treating complex I deficiency in subjects of need. In any embodiment herein, it is possible that the compound is effective when administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the compound is effective when administered daily for 12 weeks or longer. In any embodiment herein, it is possible that the compound effectively increases intracellular adenosine triphosphate (ATP) levels in tissues of subjects diagnosed with Friedrich's ataxia.

[0095] In one aspect, this technology provides compounds of the technology or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof for reducing or inhibiting lipoxygenase-15 activity in mammalian subjects with or suspected of having Friedrich's ataxia. In any embodiment herein, it is possible that the compound is effective when administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the compound is effective when administered daily for 12 weeks or longer.

[0096] In one aspect, this technology provides compounds of the technology or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof for reducing or inhibiting ferroptosis in mammalian subjects suffering from or suspected of suffering from Friedrich's ataxia. In any embodiment herein, it is possible that the compound is effective when administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the compound is effective when administered daily for 12 weeks or longer.

[0097] In one aspect, the use of the composition in the preparation of a medicament for the treatment or prevention of Friedrich's ataxia in subjects of need is provided, wherein the composition comprises a therapeutically effective amount of the compound of the art or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, it is possible that the medicament effectively increases or maintains ataminin levels in subjects suspected of having Friedrich's ataxia. In any embodiment herein, it is possible that the medicament effectively inhibits a decrease in ataminin levels in subjects suspected of having Friedrich's ataxia. In any embodiment herein, it is possible that the medicament effectively treats one or more symptoms of Friedrich's ataxia selected from the group consisting of: muscle weakness, loss of coordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart disease. In any embodiment herein, it is possible that the medicament is effective when administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the medicament is effective when administered daily for 12 weeks or longer.

[0098] In one aspect, the use of the composition in the preparation of a medicament for increasing the expression level of ataxia protein in mammalian subjects compared with normal control subjects is provided, wherein the composition comprises a therapeutically effective amount of the compound of the art or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, it is possible that the medicament is effective when administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the medicament is effective when administered daily for 12 weeks or longer. In any embodiment herein, it is possible that the medicament effectively increases the level of ataxia protein in subjects diagnosed with Friedrich's ataxia.

[0099] In one aspect, the use of the composition in the preparation of a medicament for treating complex I deficiency in mammalian subjects compared with normal control subjects is provided, wherein the composition comprises a therapeutically effective amount of the compound of the art or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, it is possible that the medicament is effective when administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the medicament is effective when administered daily for 12 weeks or longer. In any embodiment herein, it is possible that the medicament effectively increases intracellular adenosine triphosphate (ATP) levels in tissues of subjects diagnosed with Friedrich's ataxia.

[0100] In one aspect, the use of the composition in the preparation of a medicament for reducing or inhibiting lipoxygenase-15 activity in mammalian subjects suffering from or suspected of suffering from Friedrich's ataxia is provided, wherein the composition comprises a therapeutically effective amount of the compound of the art or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, it is possible that the medicament is effective when administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the medicament is effective when administered daily for 12 weeks or longer.

[0101] In one aspect, use of the composition in the preparation of a medicament for reducing or inhibiting ferroptosis in mammalian subjects suffering from or suspected of suffering from Friedrich's ataxia is provided, wherein the composition comprises a therapeutically effective amount of the compound of the art or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof. In any embodiment herein, it is possible that the medicament is effective when administered daily for 6 weeks or longer. In any embodiment herein, it is possible that the medicament is effective when administered daily for 12 weeks or longer. Attached Figure Description

[0102] Figure 1A is a diagram of a partial chemical scheme for producing the novel compositions disclosed herein.

[0103] Figure 1B is a continuation illustration of the chemical scheme shown in Figure 1A for producing the novel composition disclosed herein, wherein compound 216 (i.e., 216a) is the starting material for producing compound 226a.

[0104] Figure 1C is a continuation illustration of the chemical scheme shown in Figure 1A for producing novel compositions of formula I (and formulas Ia to Ih).

[0105] Figure 1D is a continuation illustration of the chemical scheme shown in Figure 1B, wherein compound 226a is converted into a composition of formula II (including formulas IIa to IId).

[0106] Figure 2A is a diagram of a partial chemical scheme for producing the novel compositions disclosed herein.

[0107] Figure 2B is a continuation illustration of the chemical scheme shown in Figure 2A for producing the novel composition disclosed herein, wherein compound 316 (i.e., 316a) is the starting material for producing compound 326a.

[0108] Figure 2C is a continuation of the chemical scheme shown in Figure 2A for producing novel compositions of Formula III (including Formulas IIIa to IIIh).

[0109] Figure 2D is a continuation illustration of the chemical scheme shown in Figure 2B, wherein compound 316a is converted into a composition of formula IV (including formulas IVa to IVd).

[0110] Figure 3 is a diagram of the chemical scheme used to produce the intermediate compound 203 used / disclosed herein.

[0111] Figure 4 is a diagram of the chemical schemes used to reduce certain therapeutic compositions disclosed herein.

[0112] Figure 5 is a graphical representation of the data obtained from analyzing the effects of the various compounds disclosed in this paper on cells obtained from patients confirmed to have Friedrich's ataxia.

[0113] Figure 6A is an illustration of various known heterocyclic compounds that can be used as starting materials in the methods for generating the novel compounds disclosed herein.

[0114] Figure 6B is an illustration of various known heterocyclic compounds that can be used as starting materials in the methods for generating novel compounds disclosed herein.

[0115] Figure 6C is an illustration of various known heterocyclic compounds that can be used as starting materials in the methods for generating the novel compounds disclosed herein.

[0116] Figure 7 is a bar chart summarizing the results obtained from the Nrf-2 activation assay, comparing the activity of omasorone with various novel compounds disclosed herein. Detailed Implementation

[0117] I. Chemical Definition: The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are determined according to the Periodic Table of the Elements, GAS edition, Handbook of Chemistry and Physics, 7Sh edition, inner cover. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th ed., 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 ed., Cambridge University Press, Cambridge, 1987.

[0118] The abbreviations used in this article have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are intended to conform to the standard rules of chemical valence known in the field of chemistry. When a range of values ​​is listed, it is intended to include every value and subrange within that range. For example, “C1-C6 alkyl” is intended to cover alkyl groups of 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. When a group or part is referred to as “substituted,” one or more hydrogen atoms of that group have been replaced by a substituent. Possible "substituents" include, for example, one or more: (i) deuterium (D), fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atoms (each of F, Cl, Br, and I individually is a "halogen," and F, Cl, Br, and I are collectively referred to as "halogens"); 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., -OR"), nitro (i.e., -NO2) groups, or amino groups (in the form of protected or unprotected groups). The form of the substituent (i.e., -NH2 or -NHPG, where PG is the protecting group) is chosen independently for each possible position for hydrogen atom substitution. Other substituents are considered, such as azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, nitro, sulfhydryl, imino, amide, phosphonate, hypophosphonate, carboxyl, silyl, ether, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. Unsubstituted groups or moieties are unsubstituted.

[0119] Some compounds of this application may exist in both non-solventized and solvated forms (including hydrated forms). For example, a solvated form may exist because it is difficult or impossible to remove all solvent from the synthesized compound. Generally, the solvated form is equivalent to the non-solventized form and is included within the scope of this application. Some compounds of this application may exist in various crystalline or amorphous forms. Some compounds of this application may exist in various tautomeric forms. Some compounds of this application may exist in various salt forms. In general, all physical forms are equivalent to the uses contemplated in this application and are intended to fall within the scope of the inventive compositions disclosed herein.

[0120] As used herein, “alkoxy” is an example of a heteroalkyl group and refers to an alkyl, cycloalkyl, heteroalkyl, or cycloheteralkyl group having the following general formula attached to a terminal oxygen: Wherein, R” is an alkyl, cycloalkyl, heteroalkyl, or cyclohexaalkyl group, and This indicates the bond that forms the attachment point between the alkoxy group and another compound or part. Each instance of an alkoxy group may independently be optionally unsubstituted (“unsubstituted alkoxy”) or substituted with one or more substituents (“substituted alkoxy”). For example, the substituent may be a halogen, such as fluorine. Some non-limiting examples of fluorine-substituted alkoxy groups used herein include: fluoromethoxy (“-OCH2F”), difluoromethoxy (“-OCHF2”), and trifluoromethoxy (“-OCF3”).

[0121] As used herein, "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-C2"). 20 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 12 carbon atoms (“C1-C1”). 12 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C1-C1”). 10 Alkyl group (“C1-C8 alkyl”). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1-C6 alkyl”). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1-C5 alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1-C4 alkyl”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms. Atom (“C1-C2 alkyl”). In some embodiments, the alkyl group has one carbon atom (“C1 alkyl”). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Higher alkyl groups (such as C1-C6 alkyl groups) 12 Additional examples of C7 include positive H+ (C7), positive S+ (C8), positive N+ (C9), and positive N+ (C9). 10 ), undecyl (C 11 ) and dodecyl (C 12Each example of an alkyl group may be independently and optionally unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (e.g., 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent) (“substituted alkyl”). For example, the substituents may be halogens, such as fluorine. Some non-limiting examples of substituted alkyl groups as used herein include: fluoromethyl (“-CH2F”), difluoromethyl (“-CHF2”), and trifluoromethyl (“-CF3”).

[0122] As used herein, "alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 12 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C"). 12 (Alkenyl group). In some embodiments, the alkenyl group has 1 to 10 carbon atoms ("C2-C"). 10 The alkenyl group has 2 to 8 carbon atoms (“C2-C8 alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C2-C6 alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C2-C5 alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C2-C4 alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C2-C3 alkenyl”). In some embodiments, the alkenyl group has 2 carbon atoms (“C2 alkenyl”). One or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). The C2-C4 alkenyl group... Examples include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. Examples of C2-C6 alkenyl groups include the above-mentioned C2-C4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl groups include heptenyl (C1), octenyl (C8), octtrienyl (C8), etc. Each example of an alkenyl group may independently and optionally be unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (e.g., 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 may be halogens, such as fluorine.

[0123] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds ("C2-C"). 12 The alkynyl group has 2 to 10 carbon atoms ("C2-C10"). In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C2-C10"). 10The alkynyl group has 2 to 8 carbon atoms (“C2-C8 alkynyl”). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C2-C6 alkynyl”). In some embodiments, the alkynyl group has 2 to 5 carbon atoms (“C2-C5 alkynyl”). In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C2-C4 alkynyl”). In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C2-C3 alkynyl”). In some embodiments, the alkynyl group has 2 carbon atoms (“C2 alkynyl”). One or more The carbon-carbon triple bond can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-C4 ynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. Each instance of an ynyl group can be independently and optionally unsubstituted (“unsubstituted ynyl”) or substituted by one or more substituents (e.g., 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent) (“substituted ynyl”). For example, the substituent can be a halogen, such as fluorine.

[0124] As used herein, “aprotic solvent” refers to an organic solvent that does not have 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).

[0125] As used herein, “aryl” (sometimes abbreviated as “Ar”) refers to a group (“C6-C”) that has a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) that provides 6 to 14 ring carbon atoms and zero heteroatoms in the aromatic ring system. 14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; such as phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 "Aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C"). 14 Aryl groups (e.g., anthracene groups) can be described as C6-C... 10A aryl group is a group of atoms that are not hydrogen atoms in the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may be independently and optionally unsubstituted (“unsubstituted aryl”) or substituted with one or more substituents (e.g., 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 substituents may be halogens, such as fluorine or chlorine. In some embodiments, the aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogens, azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl or protected hydroxyl (i.e., -OH or -OPG, where PG is a protecting group), alkoxy (i.e., -OR"), nitro, amino (in protected or unprotected form, i.e., -NH2 or -NHPG, where PG is a protecting group), mercapto, imino, amide, phosphonate, hypophosphonate, carbonyl, carboxyl, silyl, ether, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl, difluoromethyl and trifluoromethyl), cyano, etc. The aryl group is sometimes referred to as an aromatic group (or aromatic moiety).

[0126] As used herein, the term "arylalkyl" refers to an alkylene linkage connected to (C1-C2) via an alkylene linker. 20 Arylalkyl refers to an aryl or heteroaryl group (which may be substituted or unsubstituted) of an alkyl group (which may be substituted or unsubstituted). The term "arylalkyl" refers to a group that may be substituted or unsubstituted. The term "arylalkyl" also means compounds in which one or more methylene groups in the alkyl chain of the arylalkyl group may be replaced by heteroatoms such as O, N, P, Si, and S, and in which nitrogen, phosphorus, and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized by one or more linked alkyl and / or aryl groups. Arylalkyl includes, for example, benzyl (in substituted or unsubstituted form).

[0127] As used herein, the term "arylhexaalkyl" refers to a group attached to an aryl group (which may be substituted or unsubstituted) of a noncyclic, stable, straight-chain or branched or combined alkyl group, wherein the alkyl group comprises at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein nitrogen, phosphorus and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized by one or more attached alkyl and / or aryl groups.

[0128] As used herein, the term "benzyl group" refers to a group of the following formula:

[0129] Each A1 is independently H, D, F, Cl, Br, I, -CH3, -OCH3, -CH2CH3, -OCH2CH3, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, nitrile (-C≡N), hydroxyl / phenol (i.e., -OH or -OPG, where PG is a protecting group), or nitro (-NO2). If each A1 is H, the benzyl group is unsubstituted. If at least one A1 is not H, the benzyl group is substituted.

[0130] As used herein, the term "carbocyclic ring" or "carbon ring" refers to a ring formed by linked carbon atoms. A carbocyclic ring may be independently and optionally unsubstituted (e.g., "unsubstituted cycloalkyl") or substituted with one or more substituents (e.g., "substituted cycloalkyl"). For example, the substituent may be halogen, such as fluorine. Cycloalkyl groups contain carbocyclic rings. Aryl groups (such as benzene) contain carbocyclic rings. Carbocyclic rings may contain 3 carbon atoms ("C3 carbon ring"), 4 carbon atoms ("C4 carbon ring"), 5 carbon atoms ("C5 carbon ring"), 6 carbon atoms ("C6 carbon ring"), 7 carbon atoms ("C7 carbon ring"), or 8 carbon atoms ("C8 carbon ring"). Carbocyclic rings may be aromatic and therefore contain 6 carbon atoms ("C6 carbon ring"), 10 carbon atoms ("C8 carbon ring"), or 10 carbon atoms ("C7 carbon ring"). 10 Carbon ring ("C") or 14 carbon atoms ("C") 14 Carbon rings).

[0131] As used herein, "chiral chromatography" refers to the use of a chiral column (i.e., a chiral stationary phase) to separate racemic and sometimes diastereomeric mixtures in order to obtain optically enriched or optically pure products from chromatographic separation.

[0132] As used herein, “cycloalkyl” refers to a non-aromatic cyclic hydrocarbon group having 3 to 12 ring carbon atoms (“C3-C…”). 12 Cycloalkyl group (“C3-C4”). In some embodiments, the cycloalkyl group has 3 to 10 cyclic carbon atoms (“C3-C4”). 10The cycloalkyl group (“C3-C8 cycloalkyl”) is used in some embodiments. In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms (“C4-C6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms (“C5-C6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 7 ring carbon atoms (“C5-C7 cycloalkyl”). In some embodiments, the cycloalkyl group has 6 to 7 ring carbon atoms (“C6-C7 cycloalkyl”). The cycloalkyl group can be described as such as C4... -C7 membered cycloalkyl, wherein the term "membered" refers to a non-hydrogen ring atom within this 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), etc. Exemplary C3-C7 cycloalkyl groups include, but are not limited to, the previously mentioned C3-C6 cycloalkyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), and cyclohepttrienyl (C7), bicyclo[2.1.1]hexyl (C6), bicyclo[3.1.1]heptyl (C7), etc. Exemplary C3-C 10 Cycloalkyl groups include, but are not limited to, the previously mentioned C3-C7 cycloalkyl groups, as well as cyclononyl (C9), cyclononenyl (C9), and cyclodecyl (C9). 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl (C 10 As shown in the preceding examples, in some embodiments, the cycloalkyl group is monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic cycloalkyl”), and may be saturated or may be partially unsaturated. Non-limiting examples of bicyclic cycloalkyl groups include 1-ethylbicyclo[1.1.1]pentane, 1-ethylbicyclo[2.2.2]octane, and (3r,5r,7r)-1-ethyladamantane. “Cycloalkyl” also includes cyclic systems in which the cycloalkyl ring as defined above is fused with one or more aryl groups, wherein the bonding point is on the cycloalkyl ring, and in this case, the carbon number continues to indicate the number of carbons in the cycloalkyl ring system. Each example of a cycloalkyl group may independently be optionally unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). For example, the substituent may be a halogen, such as fluorine.

[0133] As used herein, “cyclohexaalkyl” refers to a cycloalkyl group containing at least one heteroatom selected from the group consisting of O, N, P, Si, and S (wherein the heteroatom substitutes for a carbon atom in the ring), and wherein nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized by an attached alkyl and / or aryl group. One or more heteroatoms O, N, P, S, and Si may be located at any position on the cyclohexaalkyl group, but typically each heteroatom is attached to at least two carbon atoms of the cycloalkyl group.

[0134] As used herein, the term "heteroalkyl" refers to a non-cyclic, stable, straight-chain or branched group or combination thereof, comprising at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized by an attached alkyl and / or aryl group. One or more heteroatoms O, N, P, S, and Si may be located at any position on the heteroalkyl group, but typically each heteroatom is attached to at least two carbon atoms of the group. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-CH2-P(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. At most two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3, -CH2CH2-SS-CH2CH3, and -CH2-O-Si(CH3)3. Each instance of a heteroalkyl group may be independently and optionally unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (e.g., 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent) (“substituted heteroalkyl”). For example, the substituents may be halogens, such as fluorine.

[0135] As used herein, the term "heteroaryl" refers to an aromatic heterocyclic group comprising one, two, three, or four heteroatoms selected from nitrogen, sulfur, and oxygen, independent of the other atoms. As used herein, the term "heteroaryl" refers to a group that may or may not be substituted. For example, the substituent can be a halogen, such as fluorine. Heteroaryl groups can be fused to one or two rings, such as cycloalkyl, aryl, or second heteroaryl rings. The connection point of the heteroaryl group to the molecule can be on a heteroaryl, cycloalkyl, heterocycloalkyl, or aryl ring, and the heteroaryl group can be linked by a carbon atom or a heteroatom. Examples of heteroaryl groups include imidazolyl, furanyl, pyrrolyl, thiophene, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indazole, benzoxazolyl, benzoisoxazolyl, benzofuranyl, benzothiazolyl, indolazidyl, imidazopyridyl, pyrazolyl, triazolyl, oxazolyl, tetrazolyl, benzoimidazolyl, benzoisothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indole, tetrahydroindole, azaindole, imidazopyridyl, quinazolinyl, purine, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, or benzo(b)thiaphene, each of which may optionally be substituted. Aromatic heterocycles can be substituted at one or more ring positions by one or more substituents, such as halogens, azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl or protected hydroxyl (i.e., -OH or -OPG, where PG is the protecting group), alkoxy (i.e., -OR"), nitro, amino (in protected or unprotected form, i.e., -NH2 or -NHPG, where PG is the protecting group), mercapto, imino, amide, phosphonate, hypophosphonate, carbonyl, carboxyl, silyl, ether, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. Heteroaromatic groups are sometimes referred to as heteroaromatic groups (or moiety).

[0136] 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. See also: Oxford Dictionary of Biochemistry and Molecular Biology, Oxford University Press, Oxford, 1997, as evidence that the term "heterocyclic ring" is a recognized term in organic chemistry. Heterocyclic rings can be aliphatic (e.g., tetrahydrofuran) or aromatic (e.g., pyridine).

[0137] As used herein, the term "hydrate" refers to a compound associated with water. The number of water molecules in a hydrate of a compound may (or may not) be in a certain proportion to the number of compound molecules in the hydrate.

[0138] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a therapeutically active compound that can be prepared using a relatively non-toxic acid or base, depending on the specific substituent found on the compound described herein. When the compounds of this 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 (pure base or base in a suitable inert solvent). When the compounds of this 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 (pure acid or acid in a suitable inert solvent). Salts derived from pharmaceutically acceptable inorganic bases include ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, and zinc salts, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl reduced glucosamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine (NEt3), trimethylamine, tripropylamine, tromethamine, etc., where the salts include protonated forms of organic bases (such as [HNEt3]). +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, aminosulfonic acid, and sulfuric acid. Salts derived from pharmaceutically acceptable organic acids include salts of the following substances: aliphatic hydroxy acids (e.g., citric acid, gluconic acid, glycolic acid, lactic acid, lactobionic acid, malic acid, and tartaric acid), aliphatic monocarboxylic acids (e.g., acetic acid, butyric acid, formic acid, propionic acid, and trifluoroacetic acid), amino acids (e.g., aspartic acid and glutamic acid), aromatic carboxylic acids (e.g., benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, gentian acid, hippuric acid, and triphenylacetic acid), aromatic hydroxy acids (e.g., o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-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, mucoic acid, nicotinic acid, orotic acid, and pamoic acid. Pantothenic acid, sulfonic acid (such as benzenesulfonic acid, camphorsulfonic acid, edisyl sulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid and p-toluenesulfonic acid (PTSA)), xinafoic acid, etc. In some embodiments, pharmaceutically acceptable balancing ions are selected from the group consisting of: acetate, benzoate, benzenesulfonate, bromide, camphorsulfonate, chloride, theophylline, citrate, ethanedisulfonate, fumarate, gluconate, glucuronate, hippurate, iodide, hydroxyethylsulfonate, lactate, lacturonate, lauryl sulfate, malate, maleate, methanesulfonate, methyl sulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, dihydroxynaphthyl acid, phosphate, polygalacturonic acid, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate. In some embodiments, the salt is a tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, maleate, trifluoroacetate, hydrochloride, or toluenesulfonate. Salts of amino acids such as arginine salts are also included, as well as salts of organic acids such as glucuronic acid or galacturonic acid (see Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of this application contain both basic and acidic functional groups, allowing the compounds to be converted into base or acid addition salts, or to 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 compositions of the invention disclosed herein.

[0139] As used herein, the term “protecting group” or “PG” refers to a chemical group that reacts with and binds (at least for a period of time) to a functional group (such as -OH, -NH2, or -SH) in a molecule to prevent that functional group from participating in the molecule’s reaction, but which can subsequently be removed to regenerate the functional group. See also: Oxford Dictionary of Biochemistry and Molecular Biology, Oxford University Press, Oxford, 1997. This serves as evidence that protecting groups are a recognized term in organic chemistry. Further reference is Greene's Protective Groups in Organic Synthesis, 4th Edition, 2007, John Wiley & Sons, Inc., which is considered the primary reference for studying the suitability of various protecting groups (such as hydroxyl or amino protecting groups (i.e., PG)) for organic synthetic reactions.

[0140] As used herein, the term "solvent" refers to a compound that typically associates with a solvent via a solvent decomposition reaction. This physical association can include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc.

[0141] As used herein, the term "tautomer" refers to a compound that exhibits interchangeable forms of a specific compound structure with different shifts in hydrogen atoms and electrons. Thus, two structures can reach equilibrium through the movement of π electrons and atoms (typically H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with acids or bases. The tautomer form may be relevant to obtaining optimal chemical reactivity and biological activity of the target compound.

[0142] II. Other definitions:

[0143] It should be understood that certain aspects, modes, implementations, variations, and features of this technology are described below with varying degrees of detail in order to provide a substantial understanding of this application. Definitions of certain terms used as in this specification are provided below. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this technology pertains.

[0144] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless otherwise expressly stated. For example, a reference to “cell” includes a combination of two or more cells, and so on.

[0145] As used herein, “administering” or “administration” refers to the administration of an agent (i.e., a therapeutic agent) or drug to a subject, encompassing any route by which a compound is introduced or delivered to the subject to perform its intended function. Administration can be performed via any suitable route, such as oral administration. Administration can be subcutaneous. Alternatively, administration can be performed locally, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, via the eye, intrathecally, intraventricularly, via iontophoresis, via mucosa, intravitreal, or intramuscularly. Administration includes both self-administration and administration by another person.

[0146] As used herein, the terms “carrier” and “pharmaceutically acceptable carrier” refer to a diluent, adjuvant, excipient, or medium that is administered or formulated with a compound 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, urea, etc. Additionally, adjuvants, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described at Remington's Pharmaceutical Sciences, EW Martin, which is incorporated herein by reference in its entirety.

[0147] As used in this article, the phrase “delayed onset of…” means that, in a statistical sample, one or more symptoms, signs, disorders, or indications of illness occur more slowly than normal in a treated sample, relative to an untreated control sample.

[0148] As used herein, the term "effective amount" refers to an amount sufficient to achieve the desired therapeutic and / or preventative effect, such as reducing, improving, preventing, or delaying the onset of physiological symptoms of mitochondrial diseases (such as Friedrich's ataxia). In the context of therapeutic or preventative applications, in some embodiments, the amount of composition administered to the subject will depend on the type and severity of the disease and individual characteristics such as general health status, age, sex, weight, and tolerance to the drug. In some embodiments, it also depends on the degree, severity, and type of the disease. A skilled technician will be able to determine the appropriate dosage based on these and other factors. The composition may 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 may be administered to a subject having one or more signs, symptoms, or risk factors for a mitochondrial disease such as Friedrich's ataxia; for example, muscle weakness, particularly weakness of the arm and leg muscles, loss of coordination, impaired motor control, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, cardiac and / or ophthalmic disorders or conditions. For example, a "therapeuticly effective amount" of a therapeutic compound includes reducing or eliminating the level of presence, frequency, or severity of one or more signs, symptoms, or risk factors for a mitochondrial disease (such as Friedrich's ataxia). In some embodiments, the therapeutically effective amount reduces or improves the physiological effects of mitochondrial diseases (such as Friedrich's ataxia) and / or risk factors for Friedrich's ataxia, and / or delays the progression or onset of mitochondrial diseases (such as Friedrich's ataxia).

[0149] As used herein, “inhibit” or “inhibiting” means a reduction in an objectively measurable amount or degree compared to a control. In one embodiment, inhibition or inhibiting means a reduction in at least a statistically significant amount compared to a control. In one embodiment, inhibition or inhibiting means a reduction of at least 5% compared to a control. In various individual embodiments, inhibition or inhibiting means a reduction of at least 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 33%, 40%, 50%, 60%, 67%, 70%, 75%, 80%, 90%, 95%, or 99% compared to a control.

[0150] As used herein, the term “simultaneous” therapeutic use refers to the application of at least two active ingredients via the same route and simultaneously or substantially simultaneously.

[0151] As used in this article, the term “single” therapeutic use refers to the simultaneous or substantially simultaneous administration of at least two active ingredients via different routes.

[0152] As used herein, the term "sequential" therapeutic use refers to the administration of at least two active ingredients at different times, via the same or different routes of administration. More specifically, sequential use means the complete administration of one active ingredient before the administration of another or more other active ingredients. Thus, one active ingredient may be administered over minutes, hours, or days, followed by the administration of one or more other active ingredients. Simultaneous treatment does not exist under this definition.

[0153] As used herein, “object” refers to a living animal. In various embodiments, the object is a mammal. In various embodiments, the object is a non-human mammal, including but not limited to mice, rats, hamsters, guinea pigs, rabbits, sheep, goats, cats, dogs, pigs, horses, cattle, or non-human primates. In some embodiments, the object is a human.

[0154] As used herein, the terms “treating” or “treatment” or “alleviation” refer to therapeutic treatment in which the goal is to reduce, alleviate, or slow down (relieve) a target pathological condition or symptom. By way of example, but not limitation, if, after receiving an effective amount of the compound of this application (including its pharmaceutically acceptable salts (such as hydrochloride, acetate, citrate, trifluoroacetate, benzoate, oxalate, or methanesulfonate), stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates) according to the methods described herein, the subject exhibits a reduction or absence of one or more observable and / or measurable signs and symptoms of mitochondrial disease (such as Friedrich's ataxia) (such as, but not limited to, muscle weakness, especially weakness of the arm and leg muscles, loss of coordination, impaired motor control, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, heart and / or eye diseases or conditions), then the subject's mitochondrial disease (such as Friedrich's ataxia) is successfully “treated”. It should also be understood that the various treatment modalities for the medical conditions described are intended to represent “basically” all but less than all treatments, in which some biological or medically relevant outcomes are achieved. As used herein, treatment of Friedrich’s ataxia also refers to the treatment of signs and symptoms associated with the reduced activity or expression levels of ataminants specific to Friedrich’s ataxia.

[0155] As used herein, “prevention” or “preventing” of a disease or disorder, such as a mitochondrial disease (e.g., Friedrich's ataxia), refers to a result in a statistically significant reduction in the incidence of the disease or disorder in a treated sample compared to an untreated control sample, or a delayed onset of one or more symptoms of the disease or disorder compared to an untreated control sample. Such prevention is sometimes referred to as prophylactic treatment. As used herein, prevention of mitochondrial diseases (e.g., Friedrich's ataxia) includes preventing or delaying the onset of mitochondrial diseases (e.g., Friedrich's ataxia), preventing, delaying, or slowing the development or progression of mitochondrial diseases (e.g., Friedrich's ataxia). As used herein, prevention of Friedrich's ataxia also includes preventing the recurrence of one or more signs or symptoms of Friedrich's ataxia.

[0156] III. Chiral / Stereochemical Considerations: The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of isomeric forms, such as enantiomers and / or diastereomers (i.e., stereoisomers). The chiral centers in the structures shown (including those in the claims) may be indicated herein by using an asterisk (…). The compounds described herein may be identified by means of enantiomers, diastereomers, or geometric isomers, or may be mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers may be separated from the mixture 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 may 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, New York, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (edited by EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure of this application further includes the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0157] As used herein, a pure enantiomer is substantially free of other enantiomerizations or stereoisomers of the compound (i.e., enantiomeric excess); because purity is a relative term, achieving 100% purity is, in a sense, very difficult. In other words, the “S” form of the compound is substantially free of the “R” form, and therefore enantiomeric excess of the “R” form. Regarding amino acids (more commonly described as “D” and “L” enantiomers), it should be understood that for “D”-amino acids, the configuration is “R”, and for “L”-amino acids, the configuration is “S”. In some embodiments, “substantially free” means: (i) an aliquot containing less than 2% of the “S” form of the “R” form compound; or (ii) an aliquot containing less than 2% of the “R” form of the “S” form compound. The terms "enantiomer-pure" or "pure enantiomer" mean that a compound contains more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight (e.g., compared with other enantiomers). In some embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0158] 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" type compound may comprise, for example, about 90% excipients and about 10% enantiomerically pure "R" type compound. In some embodiments, the enantiomerically pure "R" type compound in such compositions may, for example, comprise at least about 95% by weight of the "R" type compound and at most about 5% by weight of the "S" type compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure "S" type compound may comprise, for example, about 90% excipients and about 10% enantiomerically pure "S" type compound. In some embodiments, the enantiomerically pure "S" type compound in such compositions may, for example, comprise at least about 95% by weight of the "S" type compound and at most about 5% by weight of the "R" type compound, based on the total weight of the enantiomers of the compound. In some implementations, the active ingredient may be formulated with little or no excipients or carriers.

[0159] IV. Drug composition, route of administration and administration: In some embodiments, this application relates to pharmaceutical compositions. In some embodiments, the composition comprises a therapeutic compound (i.e., an agent) and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises multiple compounds and a pharmaceutically acceptable carrier. The pharmaceutical composition may be a pharmaceutical agent.

[0160] In some embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent besides the compounds of this application. This at least one additional therapeutic agent may be an agent that can be used to treat mitochondrial diseases, such as Friedrich's ataxia.

[0161] The pharmaceutical composition can be prepared by combining one or more compounds of this application with a pharmaceutically acceptable carrier and optionally one or more additional therapeutic agents.

[0162] As stated above, “effective amount” means any amount sufficient to achieve the desired biological effect. In conjunction with the teachings provided herein, effective preventative (i.e., prophylactic) or therapeutic treatment regimens can be planned by selecting from a variety of active compounds and weighting factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and administration mode. These regimens do not cause substantial undesirable toxicity but are still effective in treating the disease or ailment of a particular subject. The effective amount for any particular indication can vary depending on factors such as the disease or ailment being treated, the specific compound of this application being administered, the size of the subject, or the severity of the disease or ailment. The effective amount can be determined during preclinical and clinical trials using methods familiar to physicians and clinicians. Those skilled in the art can empirically determine the effective amount of a particular compound and / or other therapeutic agent of this application without excessive experimentation. A maximum dose, i.e., the highest safe dose based on some medical judgment, can be used. Multiple daily doses can be considered to achieve appropriate systemic compound levels. Appropriate systemic levels can be determined, for example, by measuring the patient’s peak or sustained plasma levels. “Dose” and “dosage” are used interchangeably herein. The dosage can be administered by oneself, by others, or through a device (such as a pump).

[0163] The use of compounds 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 prior to administration to human subjects. Suitable animal model systems include, but are not limited to, rats, mice, chickens, cattle, monkeys, rabbits, etc., prior to testing in human subjects.

[0164] Therapeutic compounds and optional other therapeutic agents may be administered either on their own (pure) or in the form of pharmaceutically acceptable salts. When used in a medicine, the salt should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may be suitably used to prepare their pharmaceutically acceptable salts.

[0165] The pharmaceutical compositions of this application contain an effective amount of the therapeutic compound as described herein and may optionally be dispensed into a pharmaceutically acceptable carrier. The components of the pharmaceutical composition may also be blended with and mixed with the compounds of this application in a manner that does not significantly impair the desired efficacy.

[0166] The dosage, toxicity, and therapeutic efficacy of any therapeutic compound, composition (such as a formulation or drug), other therapeutic agent, or mixture thereof can be determined by standard pharmaceutical procedures in cell cultures or laboratory animals, such as those used to determine the LD50 (the dose that is lethal to 50% of the population) and ED50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD50 / ED50. Compounds exhibiting a high therapeutic index are advantageous. While compounds exhibiting toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of the affected tissue to minimize potential damage to uninfected cells and thus reduce side effects.

[0167] Data obtained from cell culture assays and animal studies can be used to establish dose ranges for human use. Doses of such compounds can be obtained within a range of circulating concentrations, including the ED50, with little or no toxicity. The dose can vary within this range depending on the dosage form and route of administration used. For any compound used in this method, the therapeutically effective dose can be initially estimated from cell culture assays. Doses can be established in animal models to achieve a range of circulating plasma concentrations, including the IC50 (i.e., the concentration of the test compound at which half-maximal inhibition of symptoms is achieved) determined in cell cultures. This information can be used to accurately determine the useful dose in humans. For example, plasma levels can be measured by high-performance liquid chromatography.

[0168] In some embodiments, the effective amount of the therapeutic compound disclosed herein sufficient to achieve a therapeutic or preventative effect can range from about 0.000001 mg per kg body weight per day to about 10,000 mg per kg body weight per day. Suitably, the dosage range is from about 0.0001 mg per kg body weight per day to about 100 mg per kg body weight per day. For example, the dosage can be 1 mg / kg body weight or 10 mg / kg body weight per day, every two days or every three days, or from 1 mg / kg to 10 mg / kg per week, every two weeks or every three weeks. In some embodiments, the single dose range of the therapeutic compound disclosed herein is from 0.001 micrograms to 10,000 micrograms per kg body weight. In some embodiments, the therapeutic compound disclosed herein dissolved or suspended in a carrier ranges from 0.2 micrograms to 2000 micrograms per delivered milliliter.

[0169] Exemplary treatment regimens may require daily or weekly administration. In therapeutic applications, relatively high doses are sometimes necessary at relatively short intervals until disease progression decreases or ceases, or until the subject shows partial or complete improvement in disease symptoms. Afterward, a prophylactic regimen may be administered to the patient.

[0170] In some embodiments, the therapeutically effective amount of the therapeutic compound disclosed herein may be defined as 10 kilometres present at the target tissue. -12 moles up to 10 -6 Moore, as about 10 -7 The concentration of the compound in moles. This concentration can be delivered via a systemic dose from 0.001 mg / kg to 100 mg / kg or an equivalent dose calculated based on body surface area. Dosing regimens will be optimized to maintain therapeutic concentrations at the target tissue, such as by administration once daily or weekly, but also including continuous administration (e.g., oral, systemic, local, subcutaneous, parenteral infusion, or transdermal application).

[0171] In some embodiments, the intravenous or subcutaneous administration of the therapeutic compound may typically be from 0.01 μg / kg / day to 20 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the therapeutic compound may typically be from 0.01 μg / kg / day to 100 μg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the therapeutic compound may typically be from 0.1 μg / kg / day to 1 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the therapeutic compound may typically be from 10 μg / kg / day to 2 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the therapeutic compound may typically be from 500 μg / kg / day to 5 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the therapeutic compound may typically be from 1 mg / kg / day to 20 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the therapeutic compound may typically be from 1 mg / kg / day to 10 mg / kg / day.

[0172] Typically, for human subjects, the daily oral dose of the compound ranges from approximately 0.01 μg / kg to 100 mg / kg daily. The expected range of oral doses from 0.01 mg / kg to 50 mg / kg, administered once or multiple times daily, will produce therapeutic results. Depending on the administration method, the dose may be appropriately adjusted to achieve the desired local or systemic drug levels. For example, intravenous administration is expected to be a lower dose, ranging from one to several orders of magnitude daily. If the response in the subject is insufficient at such doses, even higher doses (or more effective doses via different, more local routes of delivery) may be used, within the limits of patient tolerance. Multiple daily doses may be considered to achieve suitable systemic compound levels.

[0173] For use in therapy, an effective amount of the compound can be administered to the subject by any mode of delivery of the compound to the desired surface. The administration of the pharmaceutical composition can be accomplished by any method known to those skilled in the art. Routes of administration include, but are not limited to, oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, intraocular, intrathecal, intraocular, intrathecal, intraventricular, iontophoresis, transmucosal, intravitreal, or intramuscular administration. Administration includes self-administration, administration by another person, and device administration.

[0174] The therapeutic compounds disclosed herein can be delivered to a subject in the form of a formulation or a pharmaceutical (i.e., a pharmaceutical composition). Formulations and pharmaceuticals can be prepared, for example, by dissolving or suspending the therapeutic compounds disclosed herein in water or a carrier (i.e., a pharmaceutically acceptable carrier). For example, the formulations and pharmaceuticals of this application can be administered as pharmaceutically acceptable solutions, which may conventionally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0175] Pharmaceutical compositions (e.g., formulations or drugs) may contain a carrier, which may be a solvent or dispersion medium, such as containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. For example, appropriate flowability can be maintained by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. Microbial action can be prevented by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, ascorbic acid, thiomerasol, etc.). Glutathione and other antioxidants may be included to prevent oxidation. In many cases, including isotonic agents in the composition is advantageous, such as sugars, polyols such as mannitol, sorbitol, or sodium chloride. The absorption of injectable compositions can be prolonged by including agents that delay absorption (e.g., aluminum monostearate or gelatin) in the composition.

[0176] Solutions or suspensions (e.g., formulations or drugs) intended for parenteral, intradermal, subcutaneous, or intraocular application may include the following components: sterile diluents, such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate, or phosphate; and agents for tonication, such as sodium chloride or dextrose. pH may be adjusted using acids or bases (such as hydrochloric acid or sodium hydroxide). Parenteral formulations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. For the convenience of patients or treating physicians, the formulation may be provided individually or in a kit containing all necessary equipment (e.g., vials, diluent vials, syringes, and needles) during the course of treatment (e.g., 7 days or longer).

[0177] Systemic formulations include those designed for administration by injection (such as subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), as well as those designed for administration via the skin, oral mucosa, or lungs.

[0178] For intravenous and other parenteral routes of administration, the compounds or pharmaceutical compositions of this application may be formulated as lyophilized formulations, lyophilized formulations of liposome-intercalated or liposome-encapsulated active compounds, lipid complexes in aqueous suspensions, or salt complexes. Lyophilized formulations are typically reconstituted in a suitable aqueous solution, such as sterile water or saline, shortly before administration.

[0179] Suitable pharmaceutical compositions (e.g., formulations or drugs) for injectable use may include sterile aqueous solutions (in the case of water solubility) or dispersions, and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, and CREMOPHOR EL. TM (BASF, Parsippony, New Jersey) or phosphate-buffered saline (PBS). Compositions intended for injection are typically sterile and should be fluid to the extent easily injectable. They should be stable under manufacturing and storage conditions and must be protected against contamination by microorganisms such as bacteria and fungi.

[0180] Sterile injectable solutions (e.g., formulations or pharmaceuticals) can be prepared by incorporating the desired amount of an active compound with one or a combination of the ingredients listed above (as needed) into a suitable solvent, followed by filtration and sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile medium containing a base dispersion medium and any other desired ingredients from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, typical preparation methods include vacuum drying and freeze-drying, which can produce a powder containing the active ingredient plus any additional desired ingredients from a previously sterile filtered solution.

[0181] When systemic delivery is required, therapeutic compounds or pharmaceutical compositions can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion (e.g., by IV injection or via pump for metered administration over a specified time). Injectable formulations may be present in unit dosage forms, such as in ampoules or multi-dose containers, with added preservatives. Compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous media and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants.

[0182] Pharmaceutical compositions for parenteral administration comprise aqueous solutions of the active compound in a water-soluble form. Alternatively, suspensions of the therapeutic compound can be prepared as suitable oily injectable suspensions. Suitable lipophilic solvents or mediators include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or reagents that increase the solubility of the therapeutic compound to allow for the preparation of highly concentrated solutions.

[0183] For oral administration, compounds can be readily formulated by combining one or more active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of this application to be formulated into tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, liquids, suspensions, etc., for oral administration to a subject to treatment. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, Primogel®, or corn starch; lubricants, such as magnesium stearate or stearates; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

[0184] Pharmaceutical formulations for oral use can be obtained as solid excipients, optionally by grinding the resulting mixture and processing the granular mixture after adding suitable excipients (if desired) to obtain tablets or sugar-coated pellet cores. Suitable excipients are particularly fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose formulations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrants, such as croscarmellose, agar, or alginate or its salts, such as sodium alginate, can be added. Optionally, oral formulations can also be formulated in saline or buffer solutions (such as EDTA for neutralizing internal acidic conditions) or can be administered without any carrier.

[0185] Oral dosage forms of one or more of the above components have also been specifically considered. One or more components can be chemically modified to make oral delivery of the derivatives effective. Typically, the chemical modifications considered involve attaching at least one moiety to the component molecule itself, wherein the moiety allows (a) inhibition of acid hydrolysis; and (b) absorption from the stomach or intestine into the bloodstream. It is also desirable to increase the overall stability of one or more components and to increase the in vivo circulation time. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. (Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, edited by Hocenberg and Roberts, Wiley-Interscience, New York, 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. As specified above, polyethylene glycol (PEG) moieties of various molecular weights are suitable for pharmaceutical applications.

[0186] For a particular therapeutic compound or pharmaceutical composition, the preferred site of release may be the stomach, small intestine (duodenum, jejunum, or ileum), or large intestine. Those skilled in the art have available formulations that do not dissolve in the stomach but release the material in the duodenum or other parts of the intestine. Preferably, release will avoid the harmful effects of the gastric environment by protecting the compound (or derivative) of this application or by releasing the bioactive material outside the gastric environment (such as in the intestine).

[0187] Coatings or coating mixtures can also be used on tablets, not intended to protect them from stomach irritation. This can include sugar coatings or coatings that make the tablets easier to swallow. Capsules can consist of a hard shell (such as gelatin) for delivering dry therapeutic agents (such as powders); for liquid forms, a soft gelatin shell can be used. The shell material for flat capsules can be thick starch or other edible paper. For pills, lozenges, molded tablets, or tablet grinders, wet aggregation techniques can be used.

[0188] Therapeutic compounds or pharmaceutical compositions can be contained in formulations as fine, multi-particulate forms, in the form of granules or pellets with a particle size of about 1 mm to 2 mm. Formulations for materials used in capsule administration can also be powders, light-pressed tablets, or even tablets. Therapeutic compounds or pharmaceutical compositions can be prepared by compression. Colorants and flavorings can both be included. For example, therapeutic compounds or pharmaceutical compositions can be formulated and then further contained in edible products, such as frozen beverages containing colorants and flavorings.

[0189] Diluents can be used to dilute or increase the volume of formulations or pharmaceuticals containing therapeutic compounds, other therapeutic agents, or mixtures thereof with inert materials. These diluents may include carbohydrates, particularly mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextran, and starch. Certain inorganic salts may also be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents are Fast-Flo®, Emdex®, STARCH 1500®, Emcompress®, and Avicel®.

[0190] Disintegrants can be included in pharmaceutical compositions to provide a solid dosage form. Materials used as disintegrants include, but are not limited to, starch, including the commercially available starch-based disintegrant Explotab. Sodium starch glycolate, Amberlite®, sodium carboxymethyl cellulose, hyperbranched starch, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge, and bentonite can also be used. Another form of disintegrant is an insoluble cation exchange resin. Powdered adhesives can be used as both disintegrants and binders, and these may include powdered adhesives such as agar, sycamore gum, or tragacanth gum. Alginic acid and its sodium salts can also be used as disintegrants.

[0191] Binders can be used to hold therapeutic agents together to form hard tablets and include materials derived from natural products such as gum arabic, tragacanth, starch, and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) can both be used in alcoholic solutions to granulate therapeutic agents.

[0192] Anti-friction agents can be included in the formulation of the therapeutic agent to prevent adhesion during formulation. Lubricants can be used as a layer between the therapeutic agent and the mold wall, and these can 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 can also be used. TM 4000 and Carbowax TM 6000.

[0193] Gliding agents can be added, which improve the flow properties of the drug during formulation and facilitate rearrangement during compression. Gliding agents may include starch, talc, pyrolytic silica, and hydrated aluminosilicates.

[0194] To facilitate the dissolution of therapeutic compounds or pharmaceutical compositions in an aqueous environment, surfactants may be added as wetting agents. Surfactants may include anionic detergents such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate. Cationic detergents that may be used include benzalkonium chloride and benzyl chloride. Potential nonionic detergents that may be included as surfactants in formulations include polidocanol 400, polyethylene glycol (40) stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glyceryl monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants may be present alone or as mixtures in different proportions in formulations of the compounds or derivatives of this application.

[0195] Orally applicable pharmaceutical compositions include push-in capsules made of gelatin and soft-sealable capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-in capsules may contain the active ingredient blended with fillers such as lactose, binders such as starch, and / or lubricants 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 oil, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres are well defined in the art. All formulations intended for oral administration should be administered at a dosage appropriate for such administration.

[0196] For oral administration, the composition may be in the form of tablets or lozenges formulated in a conventional manner.

[0197] For topical application, therapeutic compounds such as those disclosed herein can be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art.

[0198] For therapeutic compounds or pharmaceutical compositions administered by inhalation according to this application, they can be conveniently delivered from a pressurized package or nebulizer in the form of an aerosol spray using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In some embodiments, the formulation, pharmaceutical product, or therapeutic compound can be delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant (such as a gas, such as carbon dioxide), or a nebulizer. Such methods include those described in U.S. Patent No. 6,468,798. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a measured amount. Capsules and cartridges, such as gelatin, for use with inhalers or blowpipes can be formulated as a powder mixture containing a therapeutic compound and a suitable powder matrix such as lactose or starch.

[0199] Nasal delivery of the therapeutic compounds or pharmaceutical compositions of this application is also considered. Nasal delivery allows the therapeutic compounds or pharmaceutical compositions of this application to pass directly into the bloodstream after administration to the nose, without depositing the product in the lungs. Formulations for nasal delivery include those having dextran or cyclodextrin.

[0200] For nasal administration, a useful device is a small, rigid bottle with a metered-dose nebulizer. In one embodiment, a metered dose is delivered by inhaling the pharmaceutical composition of the present application into a chamber of a defined volume having orifices sized to atomize the aerosol formulation into an aerosol when the liquid within the chamber is compressed. The chamber is compressed to administer the therapeutic compound or pharmaceutical composition. In a particular embodiment, the chamber is arranged in a piston configuration. Such devices are commercially available.

[0201] Alternatively, plastic squeeze bottles with orifices or openings sized to atomize the aerosol formulation upon extrusion. The openings are typically located at the top of the bottle, and the top is usually tapered to partially fit the nasal passage for effective administration of the aerosol formulation. Preferably, the nasal inhaler will provide a measured amount of the aerosol formulation for administering a measured dose of a therapeutic compound or pharmaceutical composition.

[0202] Alternatively, the therapeutic compound or pharmaceutical composition may be in powder form and may be reconstituted with a suitable medium (e.g., sterile, pyrogen-free water) prior to use.

[0203] This article also considers the pulmonary delivery of the therapeutic compounds or pharmaceutical compositions disclosed herein. Compounds, formulations, or drugs can be delivered to the lungs of mammals upon inhalation and cross the pulmonary epithelium to enter the bloodstream. Other reports on inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13 (Supplement 5):143-146 (1989) (endothelin-1); Hubbard et al., Annals Int Med 3:206-212 (1989) (α1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (α-1-protease); 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, JImmunol 140:3482-3488 (Interferon-γ and tumor necrosis factor-α) and Platz et al., U.S. Patent No. 5,284,656 (Granocyte colony-stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of a drug to produce a systemic effect is described in U.S. Patent No. 5,451,569 to Wong et al., issued September 19, 1995 (incorporated by reference).

[0204] Consider the use of a wide range of mechanical devices designed for the transpulmonary delivery of therapeutic products in the practice of this technology, including but not limited to nebulizers, metered-dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0205] Some specific examples of commercially available devices suitable for this technical practice are Ultravent devices manufactured by Mallinckrodt, Inc., St. Louis, Missouri. TMNebulizers; Acorn II® nebulizer manufactured by Marquest Medical Products, Englewood, Colorado; Ventolin® metered-dose inhaler manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and Spinhaler® powder inhaler manufactured by Fisons Corp., Bedford, Mass.

[0206] All such devices require formulations suitable for dispensing the therapeutic compounds, formulations, and drugs of this application. Typically, each formulation is specific to the type of device used and involves the use of appropriate propellant materials in addition to the commonly used diluents, adjuvants, and / or carriers in therapy. Furthermore, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is considered. The chemically modified compounds of this application can also be formulated into different formulations and drugs depending on the type of chemical modification or the type of device used. Formulations suitable for use with jet or ultrasonic nebulizers may contain the therapeutic compound (or derivative) of this application dissolved in water at a concentration of about 0.1 mg to 25 mg of the bioactive compound of this application per mL of solution. The formulation may also contain buffers and monosaccharides (e.g., for inhibitor stabilization and osmotic pressure regulation). Nebulizer formulations may also contain surfactants to reduce or prevent surface-induced aggregation of the compounds of this application caused by atomization of the solution during aerosol formation.

[0207] Formulations used with metered-dose inhaler devices may typically comprise finely ground powder containing the compound (or derivative thereof) of this application suspended in the propellant by means of a surfactant. The propellant may be any conventional material used for this purpose, such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, or hydrocarbons, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soybean lecithin. Oleic acid may also be used as a surfactant.

[0208] Formulations dispensed from a powder inhaler device may include finely ground dry powder containing the therapeutic compound (or derivative) of this application, and may also contain a swelling agent, such as lactose, sorbitol, sucrose, or mannitol, in an amount that facilitates powder dispersion from the device (e.g., 50% to 90% by weight of the formulation). The therapeutic compound or pharmaceutical composition (or derivative) of this application may advantageously be prepared in the form of particles with an average particle size of less than 10 micrometers (μm), most preferably 0.5 μm to 5 μm, for most efficient delivery to deep lungs.

[0209] For ocular or intraocular indications, any suitable mode of delivery of the therapeutic compound or pharmaceutical composition to the eye or area near the eye may be used. For ocular preparations, see generally Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York (1993), and also Havener, WH, Ocular Pharmacology, CV Mosby Co., St. Louis (1983). Non-limiting examples of pharmaceutical compositions suitable for application to the eye or area near the eye include, but are not limited to, ophthalmic inserts, mini-tablets, and topical preparations such as eye drops, ointments, and in-situ gels. In one embodiment, a contact lens is 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 the therapeutic compound or pharmaceutical composition applied to the eye.

[0210] Eye drops may comprise a sterile liquid formulation that can be applied directly to the eye. In some embodiments, the eye drops comprise at least one therapeutic compound disclosed herein and may also comprise one or more preservatives. In some embodiments, the optimal pH of the eye drops is equal to the pH of the tear film, which is about 7.4.

[0211] In-situ gels are viscous liquids that, when influenced by external factors such as appropriate pH, temperature, and the presence of electrolytes, exhibit the ability to undergo a sol-to-gel transition. This property results in slower drug excretion from the ocular surface and increased bioavailability of the active ingredient. Commonly used polymers 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 as in-situ gels (as pharmaceutical compositions).

[0212] For topical ocular application, therapeutic compounds or pharmaceutical compositions may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is known in the art. Ointments are semi-solid dosage forms for external use (such as for topical application to the eyes or skin). In some embodiments, ointments comprise a solid or semi-solid hydrocarbon matrix with a melting or softening point close to the core temperature of the human body. In some embodiments, ointments applied to the eyes break down into droplets that remain in the conjunctival sac for a longer period of time, thereby increasing bioavailability.

[0213] Ophthalmic inlays are solid or semi-solid dosage forms that do not have the disadvantages of traditional ophthalmic drug forms. They are less susceptible to defense mechanisms, such as outflow through the nasolacrimal duct, exhibit the ability to remain in the conjunctival sac for a longer period of time, and are more stable than conventional dosage forms. They also have advantages such as accurate administration of one or more therapeutic compounds, slow release of one or more therapeutic compounds at a constant rate, and limitation of systemic absorption of one or more therapeutic compounds. In some embodiments, ophthalmic inlays comprise one or more therapeutic compounds as disclosed herein and one or more polymeric materials. Polymeric materials may include, but are not limited to, methylcellulose and its derivatives (such as hydroxypropyl methylcellulose (HPMC)), ethylcellulose, polyvinylpyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethyl chitosan, gelatin, and various mixtures of the above polymers. Ophthalmic inlays may comprise silica.

[0214] Mini-tablets are a biodegradable solid pharmaceutical form that transforms into a gel upon application to the conjunctival sac, thereby prolonging the contact time between the active ingredient (i.e., the therapeutic compounds disclosed herein) and the ocular surface, which in turn increases the bioavailability of the therapeutic compound. Advantages of mini-tablets include ease of application to the conjunctival sac, resistance to defense mechanisms such as tearing or outflow through the nasolacrimal duct, longer contact with the cornea due to the presence of mucosal adhesion polymers, and gradual release of the active ingredient from the formulation at the application site due to the expansion of the outer carrier layer. Mini-tablets may comprise one or more of the therapeutic compounds disclosed herein and one or more polymers. Non-limiting examples of polymers suitable for mini-tablet formulations include cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose, ethyl cellulose, acrylics (e.g., polyacrylic acid and its cross-linked forms), Carbopol® or carbomer, chitosan, and starches (e.g., drum-dried waxy corn starch). In some embodiments, mini-tablets also comprise one or more excipients. Non-limiting examples of excipients include mannitol and magnesium stearate.

[0215] Ophthalmic or intraocular preparations and drugs may contain non-toxic excipients, such as antibacterial components that are harmless during use, such as thimerosal, benzalkonium chloride, methylparaben and propylparaben, benzyl dimethyl dodecyl ammonium bromide, benzyl alcohol or phenylethanol; buffering agents, such as sodium chloride, sodium borate, sodium acetate, sodium citrate or gluconate buffers; and other conventional ingredients, such as sorbitol monolaurate, triethanolamine, polyoxyethylene sorbitol monopalmitate, ethylenediaminetetraacetic acid, etc.

[0216] In some embodiments, the viscosity of ophthalmic formulations 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 high-molecular-weight hydrophilic polymers that do not diffuse across biological membranes and form 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.

[0217] In some embodiments, the ophthalmic formulation can be injected into the eye, for example, as a sol-gel. In some embodiments, the ophthalmic formulation is a reservoir-type formulation, such as a controlled-release formulation. Such controlled-release formulations may contain particles, such as micron-sized particles or nanoparticles.

[0218] Therapeutic compounds or pharmaceutical compositions may also be formulated into rectal or vaginal compositions, such as suppositories or retention enemas, containing conventional suppository bases, such as cocoa butter or other glycerides.

[0219] In addition to the formulations described above, therapeutic compounds can also be formulated into reservoir-type formulations. Such long-acting pharmaceutical compositions can be formulated with suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or can be formulated as slightly soluble derivatives, such as slightly soluble salts.

[0220] Suitable liquid or solid drug reservoir forms may be, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated on microscopic gold particles, contained in liposomes, in spray form, aerosol, granules for implantation in the skin, or dried onto sharp objects to be inserted into the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or formulations with sustained release of the active compound, wherein excipients and additives and / or adjuvants, such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers, are typically used as described above. Pharmaceutical compositions are suitable for a variety of drug delivery systems. For a brief description of methods for drug delivery, see Langer R, Science 249:1527-33 (1990).

[0221] Therapeutic compounds or pharmaceutical compositions may be provided in particles. As used herein, particles refer to nanoparticles or microparticles (or, in some cases, larger particles), which may consist wholly or partially of the compounds of this application or one or more other therapeutic agents as described herein. Particles may contain one or more therapeutic agents in a core surrounded by a coating (including, but not limited to, enteric coating). One or more therapeutic agents may also be dispersed throughout the particle. One or more therapeutic agents may also be adsorbed into the particle. Particles may have any level of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to one or more therapeutic agents, particles may include any of those materials conventionally used in the pharmaceutical and medical fields, including but not limited to erosive, non-erosive, biodegradable, or non-biodegradable materials or combinations thereof. Particles may be microcapsules containing the compounds of this application in solution or semi-solid form. Particles may be virtually any shape.

[0222] Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for delivering one or more therapeutic agents. Such polymers can be natural or synthetic. The polymer is selected based on the desired release time period. Bioadhesive polymers of particular interest include bio-erosive hydrogels described in Sawhney HS et al. (1993) Macromolecules 26:581-7 (the teachings of which are incorporated herein by reference). These include polyhyaluronic acid, casein, gelatin, gelatin protein, polyanhydride, 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(laurate methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), and poly(ε-caprolactone).

[0223] Therapeutic compounds or other therapeutic agents, or mixtures thereof, may be formulated in a carrier system. The carrier may be a colloidal system. The colloidal system may be a liposome, a phospholipid bilayer medium. In one embodiment, the therapeutic compound or other therapeutic agent, or mixture thereof, may be encapsulated in a liposome while maintaining the integrity of the therapeutic compound or other therapeutic agent, or mixture thereof. Those skilled in the art will understand that various methods exist for preparing liposomes. (See Lichtenberg et al., MethodsBiochem. Anal., 33:337-462 (1988); Anselem et al., Liposome Technology, CRC Press (1993)). Liposome 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 ingredients, including but not limited to soluble, insoluble, permeable, impermeable, biodegradable, or gastric-retention polymers or liposomes. Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles, and viral vector systems.

[0224] The carrier can also be a polymer, such as 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 nanoparticles encapsulating one or more therapeutic agents. The polymer can be natural, such as peptides, proteins, or polysaccharides, or synthetic, such as polyalphahydroxy acids. Examples include carriers made from collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharides, fibroin, gelatin, and combinations thereof. In one embodiment, the polymer is polylactic acid (PLA) or polylactic acid / glycolic acid (PLGA). The polymer matrix can be prepared and separated in a variety of forms and sizes, including microspheres and nanospheres. Polymer formulations can result in prolonged duration of therapeutic effect. (See Reddy, Ann. Pharmacother., 34(7-8):915-923 (2000)). Polymer formulations for human growth hormone (hGH) have been used in clinical trials. (See Kozarich and Rich, Chemical Biology, 2:548-552 (1998)).

[0225] Examples of sustained-release formulations of polymer microspheres are described in PCT Publication WO 99 / 15154 (Tracy et al.), U.S. Patent Nos. 5,674,534 and 5,716,644 (both 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 erythropoietin particles stabilized by salt to prevent aggregation.

[0226] In some embodiments, a therapeutic compound or other therapeutic agent, or a mixture thereof, is prepared together with a carrier that protects the therapeutic compound, other therapeutic agent, or mixture thereof from rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Such formulations can be prepared using known techniques. The material is also commercially available, such as from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting specific cells, containing 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. Patent No. 4,522,811.

[0227] One or more therapeutic compounds may be included in a controlled-release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and distribution of the drug from the formulation are controlled. This refers to both immediate and non-immediate release formulations, where non-immediate release formulations include, but are not limited to, sustained-release and delayed-release formulations. The term "sustained release" (also known as "extended release") is used in its conventional sense to refer to a drug formulation that provides a gradual release of the drug over an extended period of time and preferably, but not necessarily, results in a substantially constant blood drug level over the 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 the administration of the formulation and the release of the drug from the formulation. "Delayed release" may or may not involve a gradual release of the drug over an extended period of time, and therefore may or may not be "sustained release."

[0228] The use of long-term sustained-release implants is 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 fibrous mesh consisting of several individual mesh sheets) or multiple individual compositions wherein the multiple components remain localized and provide a long-term sustained release resulting from the aggregate of the multiple compositions. As used herein, "long-term" release means that the implant is constructed and positioned to deliver a therapeutic or prophylactic level of active ingredient for at least 2 days. In some embodiments, the implant is constructed and positioned to deliver a therapeutic or prophylactic level of active ingredient for at least 7 days. In some embodiments, the implant is constructed and positioned to deliver a therapeutic or prophylactic level of active ingredient for at least 14 days. In some embodiments, the implant is constructed and positioned to deliver a therapeutic or prophylactic level of active ingredient for at least 30 days. In some embodiments, the implant is constructed and positioned to deliver a therapeutic or prophylactic level of active ingredient for at least 60 days. In some embodiments, the implant is constructed and positioned to deliver a therapeutic or prophylactic level of active ingredient for at least 90 days. In some embodiments, the implant is constructed and placed to deliver a therapeutic or prophylactic level of active ingredient for at least 180 days. In some embodiments, the implant is constructed and placed to deliver a therapeutic or prophylactic level of active ingredient for at least one year. In some embodiments, the implant is constructed and placed to deliver a therapeutic or prophylactic level of active ingredient for 15-30 days. In some embodiments, the implant is constructed and placed to deliver a therapeutic or prophylactic level of active ingredient for 30-60 days. In some embodiments, the implant is constructed and placed to deliver a therapeutic or prophylactic level of active ingredient for 60-90 days. In some embodiments, the implant is constructed and placed to deliver a therapeutic or prophylactic level of active ingredient for 90-120 days. In some embodiments, the implant is constructed and placed to deliver a therapeutic or prophylactic level of active ingredient for 120-180 days. In some embodiments, long-term continuous-release implants are well known to those skilled in the art and include some 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.

[0229] Those skilled in the art will understand that, given the information known to them, other suitable modifications and revisions to the compositions and methods described herein will be apparent from the description of the art contained herein and may be made without departing from the scope of this application or any of its embodiments.

[0230] V. Compounds and compositions thereof that can be used to treat mitochondrial diseases (such as Friedrich's ataxia) and their interactions Intermediate body of the closed

[0231] (a) Therapeutic compounds

[0232] In some embodiments, this application provides novel compounds and compositions that can be used to treat mitochondrial diseases such as Friedrich's ataxia in mammalian subjects. The compounds and compositions (e.g., formulations) can be formulated in any manner suitable for administration to a subject. The compounds and compositions can, for example, be formulated as tablets, solutions for subcutaneous injection, solutions for intravenous injection, or gels, creams, or drops for topical or intraocular application. In some embodiments, the compounds and compositions can be used to prepare pharmaceuticals.

[0233] In some embodiments, this 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:

[0234] And F is 13, 14, 15, 16, 17, 18, 19, or 20:

[0235] Where J is O, S, or NR 11 K does not exist or -(CR) 12 R 13 )-;L is -(CR 12 R 13 -; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if it is a single bond, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each X is independently represented by the formula -(CR) 12 R 13 The group )-; each Y is independently absent or of the formula -(CR 12 R 13 The group is )-; each Z is independently of the formula -(CR 14The group R1, R2, and R3 are each independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; or R1 and R2 together form a five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring, a heteroaromatic ring, or a six-membered heterocyclic ring; each R8 and R9 are independently H, D, F, Cl, Br, I, or C1-C4 alkyl; or R8 and R9 together form a three-membered, four-membered, five-membered, six-membered, or seven-membered carbon ring or heterocyclic ring; R 10 It is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy; R 11 It is H, D, or C1-C6 alkyl; each R 12 R 13 and R 14 Independently, it is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy; R 20 Is it H, D, F or C1-C? 12 Alkyl; each R 21 It is H, D, F, Cl, Br, I, or a C1-C4 alkyl group; 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 connection point from E to F. Indicates the connection point from F to E; and further, the condition is: (i) Equations 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 R8 and R9 contains at least one fluorine atom; and / or (ii) R8 and R9 together form a ternary, quaternary, pentary, hexanal, or septary carbon ring or heterocycle. In some embodiments, at least one of R8 and R9 is fluorine or a substituted C1-C4 alkyl group containing at least one fluorine atom. In some embodiments, each of R8 and R9 is independently fluorine or a substituted C1-C4 alkyl group containing at least one fluorine atom. In some embodiments, each of R8 and R9 is fluorine. In some embodiments, R8, R9, and R9 are... 10 Each of these is fluorine. In some embodiments, R8, R9, and R... 10 Each of them is independently fluorine or a substituted C1-C4 alkyl group containing at least one fluorine.

[0236] As used herein, in compounds such as those of formula EF, aromatic groups such as 21 and 22 are sometimes referred to as “head” groups, and aliphatic groups such as 13, 14, 15, 16, 17, 18, 19, and 20 are referred to as “tail” groups. Therefore, the therapeutic compounds disclosed herein (not only those of formula EF) generally contain an aromatic “head” group covalently linked to an aliphatic “tail” group, wherein the aromatic head group is a quinone or hydroquinone. The quinone (or hydroquinone in its reduced form) may be a substituted benzoquinone ring, naphthoquinone ring, or other aromatic ring.

[0237] Any combination of 21 and 22 with 13, 14, 15, 16, 17, 18, 19, or 20 is permitted. 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.

[0238] The atom or group represented by J can be 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 As defined above. In some implementations, J is O or NR. 11 And K does not exist.

[0239] In some embodiments, the groups represented by K and L can each be 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(OC))-, -(C ... 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 implementations, K is absent and 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 implementations, 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 -(CH2)-, -(CD2)-, -(CF2)-, -(CH(CH3))-, -(CD(CD3))-, -(CF(CF3))-, -(C(CH3)2)-, -(C(CD3)2)-, -(C(CF3)2)-, -(CH(OCH3))-, -(CD(OCD3))-, -(CF(OCF3))-, or -(C(OCH3)2)-. In some embodiments, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-. In some embodiments, K is absent and L is -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-. In some embodiments, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, or -(CF2)-. In some embodiments, K is absent and L is -(CH2)-, -(CD2)-, -(CHF)-, or -(CF2)-. In some embodiments, each of K and L is -(CH2)-. In some embodiments, K is absent and L is -(CH2)-. In some embodiments, each of K and L is -(CD2)-. In some embodiments, K is absent and L is -(CD2)-. In some embodiments, each of K and L is -(CF2)-. In some implementations, K is absent and L is -(CF2)-.

[0240] In some embodiments of the compound represented by EF, wherein 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, -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(CD2 CD3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments of the compound represented by EF, wherein 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(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments of the compound represented by EF, wherein 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 -CH3. In some embodiments of the compound represented by EF, E is 21, and each of R1, R2, and R3 is 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.

[0241] In some embodiments of the compound represented by EF, wherein 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, wherein E is 21, J is O, and 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 EF, wherein E is 21, J is O, K, and L, and 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 EF, wherein E is 21, J is O; each of K and L is -(CH2)-; and each of R1, R2, and R3 is -CH3. In some embodiments of the compound represented by EF, wherein E is 21, J is O; each of K and L is -(CH2)-; and each of R1, R2, and R3 is H. In some embodiments of the compound represented by EF, wherein E is 21, J is O; each of K and L is -(CH2)-; and each of R1, R2, and R3 is CH3. In some embodiments of the compound represented by EF, wherein E is 21, J is O; 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 EF, wherein E is 21, 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 EF, wherein E is 21, J is O; 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 EF, wherein E is 21, J is O; each of K and L is -(CH2)-; each of R1 and R2 is -OCH3 and R3 is -CH3.In some embodiments of the compound represented by EF, wherein E is 21, J is O; each of K and L is -(CH2)-; each of R1 and R2 is -OCH3 and R3 is H. In some embodiments of the compound represented by EF, wherein E is 21, J is O; each of K and L is -(CH2)-; each of R1 and R2 is -CH3 and R3 is H. In some embodiments of the compound represented by EF, wherein E is 21, J is O; each of K and L is -(CH2)-; each of R1 and R2 is -OCH3 and R3 is H. In some embodiments of the compound represented by EF, wherein E is 21, J is O; each of K and L is -(CH2)- and at least one of R1, R2, and R3 is F.

[0242] In some embodiments of the compound represented by EF, wherein E is 21, 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 five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by EF, wherein E is 21, (i) R3 is H, F, -CH3, or -OCH3, and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by EF, wherein E is 21, (i) R3 is H; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by EF, E is 21, (i) R3 is -CH3; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by EF, E is 21, (i) R3 is -OCH3; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by EF, E is 21, (i) R3 is F; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle.

[0243] In some embodiments of EF, R1 and R2 of 21 together form a heterocyclic ring, as shown in 21A, 21B, 21C, 21D, 21E, or 21F: .

[0244] Among them, R 16 and R 17Each of these 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 It is H, D, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R 16 and R 17 Each can be independently H, D, Cl, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, or -OCF3. In some embodiments, R 16 and R 17 Each can be independently H, D, F, or -CH3. In some implementations, R 16 and R 17 It is H. In some implementations, R 16 and R 17 It is F. In some implementations, R 16 and R 17 It is -CH3. In some implementations, R 18 It is H or -CH3.

[0245] In some embodiments of the compound represented by EF, where 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)3, -C(CD3)3, -C(CF3)3 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, -OCH2CH 2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2C F3 or -OCF(CF2CF3)2; and wherein, if W is C (carbon), then each of R4, R5, R6 and R7 connected 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 wherein, if W is N (nitrogen), then each of R4, R5, R6 and R7 connected thereto is independently absent or selected from H, D, methyl, ethyl, isopropyl or tert-butyl. In some embodiments, for For each instance, the key between each W is a single key. In some implementations, for For each instance, the key between each W is a double key. 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 wherein, if W is C (carbon), each of R4, R5, R6, and R7 connected thereto is independently H, D, F, Cl, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2; and wherein, if W is N (nitrogen), each of R4, R5, R6, and R7 connected thereto is independently absent or selected from H, D, methyl, and ethyl. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is independently H, D, Cl, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, or -OCF3. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is independently H, -CH3, or -OCH3. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is H. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is -CH3.

[0246] In some embodiments of compound EF, each of R8 and R9 may 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, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some embodiments of compound EF, 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. In some embodiments of compound EF, each of R8 and R9 may independently be H, F, -CH3, -CH2F, -CHF2, or -CF3.

[0247] In some embodiments of compound EF, each of R8 and R9 may be an independent C1-C4 alkyl group. The alkyl group may, for example, be substituted with one or more fluorine atoms. For example, the alkyl group may be fluoromethyl, difluoromethyl, or trifluoromethyl.

[0248] In some embodiments of compound EF, R8 and R9 together can form a ternary, quaternary, pentaneary, hexanal, or heptaneary carbon ring or heterocycle. For example, the ternary, quaternary, pentaneary, hexanal, or heptaneary carbon ring or heterocycle can be 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47.

[0249] The # symbol indicates the connection point where the carbocyclic or heterocyclic ring connects to the remainder of the compound. In some embodiments, the ternary, quaternary, pentaneary, hexanal, or heptaneous carbocyclic or heterocyclic ring may contain one or more fluorine substitutions. In some embodiments, the ternary, quaternary, pentaneary, hexanal, or heptaneous carbocyclic or heterocyclic ring may contain one or more deuterium substitutions.

[0250] 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(C D3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CF2CF3, -CF(CF2CF3)2, -C(CH2CH3)3, -C(CD2CD3)3, -C(CF2CF3)3, -OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments of compound EF, R 10 It is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2. In some embodiments of compound EF, R 10 It is H, D, F, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments of compound EF, R 10 It is H, D, or F. In some embodiments of compound EF, R 10 It is -CH3 or -CF3. In some embodiments of compound EF, R 10 It is -H or -CH3. In some embodiments of compound EF, R 10It is H. In some embodiments of compound EF, R 10 It is -CH3. In some embodiments of compound EF, R 10 It is F. In some embodiments of compound EF, R 10 It does not exist.

[0251] In some embodiments of compound EF, R 11 It is H, methyl, or ethyl. In some embodiments of compound EF, R 11 It is H. In some embodiments of compound EF, R 11 It is a methyl group. In some embodiments of compound EF, R 11 It is an ethyl group.

[0252] In some embodiments of compound EF, R 12 R 13 Or R 14 Each instance 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 Each instance is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, or -OCF3. In some embodiments of compound EF, R 12 R 13 Or R 14 Each instance is independently H, D, F, -CH3, -CD3, or -CF3. In some embodiments of compound EF, R 12 R 13 Or R 14 Each instance is independently H, D, or F. In some embodiments of compound EF, R 12 R 13 Or R 14 Each instance is independently H, F, or -CH3. In some embodiments of compound EF, R 12 R 13 Or R 14 Each instance is H. In some embodiments of compound EF, R12 R 13 Or R 14 Each instance is D. In some embodiments of compound EF, R 12 R 13 Or R 14 Each instance of is F.

[0253] In some embodiments of compound EF, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In some embodiments of compound EF, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3. In some embodiments of compound EF, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound EF, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound EF, R 20 It is -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound EF, R 20 It is H. In some embodiments of compound EF, R 20 It is -CH3. In some embodiments of compound EF, R 20 It is -CF3. In some embodiments of compound EF, R 20 It is F.

[0254] In some embodiments of compound EF, each R 21 Independently, it is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3. In some embodiments of compound EF, each R21 Independently, it is H, D, F, -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound EF, each R... 21 Independently H, -CH3, or -CF3. In some embodiments of compound EF, each R 21 It is -CH3. In some embodiments of compound EF, each R 21 It is H. In some embodiments of compound EF, each R 21 It is -CF3.

[0255] 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.

[0256] In some embodiments of compound EF, it has the formula referred to herein as compound A:

[0257] In some embodiments of compound EF, it has the formula referred to herein as compound B:

[0258] In some embodiments of compound EF, it has the formula referred to herein as compound C:

[0259] In some embodiments of compound EF, it has the formula referred to herein as compound D:

[0260] In some embodiments of compound EF, it has the formula referred to herein as compound E:

[0261] In some embodiments of compound EF, it has the formula referred to herein as compound F:

[0262] In some embodiments of compound EF, it has the formula referred to herein as compound G:

[0263] In some embodiments of compound EF, it has the formula referred to herein as compound H:

[0264] In some embodiments of compound EF, it has the formula referred to herein as compound I:

[0265] In some embodiments of compound EF, it has the formula referred to herein as compound J:

[0266] In some embodiments of compound EF, it has the formula referred to herein as compound K:

[0267] In some embodiments of compound EF, it has the formula referred to herein as compound L:

[0268] In some embodiments of compound EF, it has the formula referred to herein as compound N:

[0269] As shown in Examples 17 and 18 below, certain compounds disclosed herein exhibit high potency in the BSO assay (Example 17) and the rotenone ATP assay (Example 18). More specifically, for several compounds disclosed herein, in cell-based assays, their potency and efficacy are similar to or greater than that of vatibenone in improving Friedrich's ataxia (see: Example 17; BSO assay). Similarly, several compounds disclosed herein also effectively rescued cells exhibiting induced complex I deficiency in the rotenone ATP assay (Example 18). In many cases, the compounds disclosed herein showed high potency in the BSO assay. andThe rotenone ATP assays all showed considerable to good activity (see Examples 17 and 18, and Table 2). By comparison, while several currently available therapeutic agents, such as vatibenone, idebenone, or omasolone, exhibit good or considerable activity in one or the other of the BSO assay or the rotenone ATP assay (see Table 2 below), none of them were active in both assays, indicating that the compounds disclosed herein exhibit a unique mechanism of action and are therefore superior therapeutic agents compared to those currently evaluated in clinical trials as treatments for certain mitochondrial diseases such as Friedrich's ataxia. Therefore, it is believed that the therapeutic compounds disclosed herein will prove to be superior agents for the treatment of certain mitochondrial diseases such as Friedrich's ataxia. The compounds mentioned above can be used to prepare compositions, such as pharmaceuticals. These compounds or compositions can therefore be used to treat and / or prevent mitochondrial diseases such as Friedrich's ataxia.

[0270] As further illustrated in Examples 19 to 22 (in conjunction with Examples 17 and 18), the compounds disclosed herein exhibit a unique ability to protect cells from BSO-induced ferroptosis; and to protect cells from RSL3-induced ferroptosis. and It exhibits complex I bypass activity. No existing compound appears to possess this unique combination of properties with therapeutic value in treating mitochondrial diseases such as Friedrich's ataxia.

[0271] (b) Intermediates for therapeutic agents

[0272] In addition to the novel agents for treating Friedrich's ataxia provided herein, novel intermediates of said novel agents are also provided. In some embodiments, those intermediates are compounds of formula AB, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein A is 1, 2, 3, or 4:

[0273] And B is 5, 6, 7, or 8:

[0274] Where J is O, S, or NR 11 K does not exist or -(CR) 12 R 13 )-, L is -(CR 12 R 13 -, each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond), each X is independently represented by the formula -(CR). 12 R 13 The group )-, each Y is independently absent or of the formula -(CR 12 R 13 The group is )-, each Z independently is of the formula -(CR 14 The R1, R2, and R3 groups are each independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; or R1 and R2 together form a five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring, a heteroaromatic ring, or a six-membered heterocyclic ring, and each R8 and R9 is independently H, D, F, Cl, Br, I, or a C1-C4 alkyl; or R8 and R9 together form a three-membered, four-membered, five-membered, six-membered, or seven-membered carbon ring or heterocyclic ring, R 10 It is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, R 11 It is H, D or C1-C6 alkyl, R 12 R 13 and R 14 Each instance is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, R 15 It is H, -CH3, -CH2CH3, or PG, where PG is a phenol protecting group, and R... 20 Is it H, D, F or C1-C? 12 Alkyl, each R 21 Independently, it is H, D, F, Cl, Br, I or C1-C4 alkyl, n is an integer from 0 to 12, including the end value, and Indicates the connection point from A to B. Indicate the connection point from C to D; and further, the condition is: (i) Equations 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 comprises at least one fluorine atom; and / or (ii) R8 and R9 together form a ternary, quaternary, pentary, hexanal, or septary carbon ring or heterocycle. In some embodiments, at least one of R8 and R9 is fluorine or a substituted C1-C4 alkyl group comprising at least one fluorine atom. In some embodiments, each of R8 and R9 is independently fluorine or a substituted C1-C4 alkyl group comprising at least one fluorine atom. In some embodiments, each of R8 and R9 is fluorine. In some embodiments, R8, R9, and R9 are... 10 Each of these is fluorine. In some embodiments, R8, R9, and R... 10 Each of these is independently fluorine or a substituted C1-C4 alkyl group containing at least one fluorine. In some embodiments of AB, R 15 It is H.

[0275] Any combination of 1, 2, 3, and 4 with 5, 6, 7, or 8 is permitted. 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 implementations, A is 4 and B is 5. In some implementations, A is 4 and B is 6. In some implementations, A is 4 and B is 7. In some implementations, A is 4 and B is 8.

[0276] The atom or group represented by J can be 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 Defined below. In some implementations, J is O or NR. 11 And K does not exist.

[0277] In some embodiments, the groups represented by K and L can each be 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(OC))-, -(C ... 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 implementations, K is absent and 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 implementations, 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 -(CH2)-, -(CD2)-, -(CF2)-, -(CH(CH3))-, -(CD(CD3))-, -(CF(CF3))-, -(C(CH3)2)-, -(C(CD3)2)-, -(C(CF3)2)-, -(CH(OCH3))-, -(CD(OCD3))-, -(CF(OCF3))-, or -(C(OCH3)2)-. In some embodiments, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-. In some embodiments, K is absent and L is -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-. In some embodiments, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, or -(CF2)-. In some embodiments, K is absent and L is -(CH2)-, -(CD2)-, -(CHF)-, or -(CF2)-. In some embodiments, each of K and L is -(CH2)-. In some embodiments, K is absent and L is -(CH2)-. In some embodiments, each of K and L is -(CD2)-. In some embodiments, K is absent and L is -(CD2)-. In some embodiments, each of K and L is -(CF2)-. In some implementations, K is absent and L is -(CF2)-.

[0278] In some embodiments of the compound represented by AB, where A is 1 or 3, 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, -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(CD2 CD3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments of the compounds represented by AB, wherein 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(CF3)3, -CH2CH3, -OCH2CH3, or -CH(CH3)2. In some embodiments of the compounds represented by AB, wherein 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 -CH3. In some embodiments of the compound represented by AB, A is 1 or 3, and each of R1, R2, and R3 is 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 compound represented by AB, A is 1 or 3, and at least one of R1, R2, and R3 is F.

[0279] In some embodiments of the compound represented by AB, wherein 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 compounds represented by AB, A is 1 or 3, J is O, and 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 compounds represented by AB, A is 1 or 3, J is O, K, and L, and 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 AB, A is 1 or 3, J is O; each of K and L is -(CH2)-; and each of R1, R2, and R3 is -CH3. In some embodiments of the compound represented by AB, A is 1 or 3, J is O; each of K and L is -(CH2)-; and each of R1, R2, and R3 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 -(CH2)-; 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, 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 AB, A is 1 or 3, J is O; 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 AB, A is 1 or 3, J is O; each of K and L is -(CH2)-; 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, J is O; each of K and L is -(CH2)-; 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, J is O; each of K and L is -(CH2)-; 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, J is O; each of K and L is -(CH2)-; 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 K and L is -(CH2)- and at least one of R1, R2, and R3 is F.

[0280] In some embodiments of the compound represented by AB, wherein A is 1 or 3, 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 five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by AB, wherein A is 1 or 3, (i) R3 is H, F, -CH3, or -OCH3, and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by AB, wherein A is 1 or 3, (i) R3 is H; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by AB, wherein A is 1 or 3, (i) R3 is -CH3; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by AB, wherein A is 1 or 3, (i) R3 is -OCH3; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by AB, wherein A is 1 or 3, (i) R3 is F; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle.

[0281] In some implementations, R1 and R2 of 1 or 3 together form a heterocyclic ring, as indicated in 1A, 1B, 1C, 1D, 1E, 1F, 3A, 3B, 3C, 3D, 3E, or 3F:

[0282] Among them, R 16 and R 17 Each of these 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 It is H, D, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R 16 and R 17 Each can be independently H, D, Cl, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, or -OCF3. In some embodiments, R 16 and R 17 Each can be independently H, D, F, or -CH3. In some implementations, R 16 and R 17 It is H. In some implementations, R 16 and R 17 It is F. In some implementations, R 16 and R 17 It is -CH3. In some implementations, R 18 It is H or -CH3.

[0283] In some embodiments of the compound represented by AB, where A is 2 or 4, 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)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(CH2CH 3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CH2CH3, -CF(CH2CH3)2, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3, -CF(CF2CF3)2, -OCH2C H2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2C F3 or -OCF(CF2CF3)2; and wherein, if W is C (carbon), then each of R4, R5, R6 and R7 connected 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 wherein, if W is N (nitrogen), then each of R4, R5, R6 and R7 connected thereto is independently absent or selected from H, D, methyl, ethyl, isopropyl and tert-butyl. In some embodiments, for For each instance, the key between each W is a single key. In some implementations, for For each instance, the key between each W is a double key. 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 wherein, if W is C (carbon), then each of R4, R5, R6, and R7 connected thereto is independently H, D, F, Cl, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2; and wherein, if W is N (nitrogen), then each of R4, R5, R6, and R7 connected thereto is independently absent or selected from H, D, methyl, and ethyl. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is independently H, D, Cl, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, or -OCF3. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is independently H, -CH3, or -OCH3. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is H. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is -CH3.

[0284] In some embodiments of compound AB, each of R8 and R9 may 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, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some embodiments of compound AB, 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. In some embodiments of compound AB, each of R8 and R9 may independently be H, F, -CH3, -CH2F, -CHF2, or -CF3.

[0285] In some embodiments of compound AB, each of R8 and R9 may independently be a C1-C4 alkyl group. The alkyl group may, for example, be substituted with one or more fluorine atoms. For example, the alkyl group may be fluoromethyl, difluoromethyl, or trifluoromethyl.

[0286] In some embodiments of compound AB, R8 and R9 together can form a ternary, quaternary, pentaneary, hexanal, or heptaneary carbon ring or heterocycle. For example, the ternary, quaternary, pentaneary, hexanal, or heptaneary carbon ring or heterocycle can be 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47.

[0287] The # symbol indicates the connection point where the carbocyclic or heterocyclic ring connects to the remainder of the compound. In some embodiments, the ternary, quaternary, pentaneary, hexanal, or heptaneous carbocyclic or heterocyclic ring may contain one or more fluorine substitutions. In some embodiments, the ternary, quaternary, pentaneary, hexanal, or heptaneous carbocyclic or heterocyclic ring may contain one or more deuterium substitutions.

[0288] 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(C D3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CF2CF3, -CF(CF2CF3)2, -C(CH2CH3)3, -C(CD2CD3)3, -C(CF2CF3)3, -OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments of compound AB, R 10 It is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2. In some embodiments of compound AB, R 10 It is H, D, F, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments of compound AB, R 10 It is H, D, or F. In some embodiments of compound AB, R 10 It is -CH3 or -CF3. In some embodiments of compound AB, R 10 It is H or -CH3. In some embodiments of compound AB, R 10It is H. In some embodiments of compound AB, R 10 It is -CH3. In some embodiments of compound AB, R 10 It does not exist.

[0289] In some embodiments of compound AB, R 11 It is H, methyl, or ethyl. In some embodiments of compound AB, R 11 It is H. In some embodiments of compound AB, R 11 It is a methyl group. In some embodiments of compound AB, R... 11 It is an ethyl group.

[0290] In some embodiments of compound AB, R 12 R 13 Or R 14 Each instance is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH(CH2CH3)2, -C(CH3)3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2CH3, -OCH(CH2CH3)2, or -OC(CH3)3. In some embodiments of compound AB, R 12 R 13 Or R 14 Each instance is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, or -OCF3. In some embodiments of compound AB, R 12 R 13 Or R 14 Each instance is independently H, D, F, -CH3, -CD3, or -CF3. In some embodiments of compound AB, R 12 R 13 Or R 14 Each instance is independently H, D, or F. In some embodiments of compound AB, R 12 R 13 Or R 14 Each instance is independently H, F, or -CH3. In some embodiments of compound AB, R 12 R 13 Or R 14 Each instance is H. In some embodiments of compound AB, R 12 R 13 Or R14 Each instance is D. In some embodiments of compound AB, R 12 R 13 Or R 14 Each instance of is F.

[0291] Atom or group R 15 It can be changed depending on the starting materials and the desired product. For example, if R 15 If it is a C1-C4 alkyl group, then this group is generally intended to be retained in the final product because such groups are not easily removed. In some embodiments, R 15 It is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, R 15 It is -CH3. Therefore, if a product (intermediate or therapeutic agent) with an alkyl group is desired, the starting material will typically contain an alkyl group.

[0292] In some implementations, R 15 It is H (unprotected phenol).

[0293] In some implementations, R 15 The protecting group (PG) temporarily protects phenol during chemical synthesis but is eventually removed to regenerate unprotected phenol. For example, in some embodiments, the protecting group may be a triphenylmethyl-based protecting group. In some embodiments, triphenylmethyl-based protecting groups may include: triphenylmethyl-based protecting groups, 4-monomethyl-triphenylmethyl-based protecting groups, 4,4'-dimethyl-triphenylmethyl-based protecting groups, 4,4',4”-trimethyl-triphenylmethyl-based protecting groups, 4-monomethoxy-triphenylmethyl-based protecting groups, 4,4'-dimethoxy-triphenylmethyl-based protecting groups, or 4,4',4”-trimethoxy-triphenylmethyl-based protecting groups. Triphenylmethyl-based protecting groups can generally be removed in the presence of moderate to strong acids.

[0294] In some embodiments, the protecting group may be a silyl-based protecting group. A silyl protecting group typically comprises a silicon atom with two to three (preferably three) alkyl groups attached thereto. Some non-limiting examples of silyl protecting groups include trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), and triisopropylsilyl (TIPS). Silyyl protecting groups can generally be removed in the presence of fluoride ions.

[0295] In some implementations, R 15It is a substituted or unsubstituted benzyl group. In some embodiments, the benzyl group may be retained intact in the therapeutic agent. In some embodiments, the benzyl group serves as a protecting group and can be removed, for example, by hydrogenation or treatment with a strong acid.

[0296] In some embodiments of compound AB, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In some embodiments of compound AB, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3. In some embodiments of compound AB, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound AB, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound AB, R 20 It is -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound AB, R 20 It is H. In some embodiments of compound AB, R 20 It is -CH3. In some embodiments of compound AB, R 20 It is -CF3. In some embodiments of compound AB, R 20 It is F.

[0297] In some embodiments of compound AB, each R 21 Independently, it is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3. In some embodiments of compound AB, each R 21Independently, it is H, D, F, -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound AB, each R... 21 Independently H, -CH3, or -CF3. In some embodiments of compound AB, each R 21 It is -CH3. In some embodiments of compound AB, each R 21 It is H. In some embodiments of compound AB, each R 21 It is -CF3.

[0298] 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.

[0299] In some embodiments of compound AB, the following formula is used: .

[0300] In some embodiments of compound AB, the following formula is used: .

[0301] In some embodiments of compound AB, the following formula is used: .

[0302] In some embodiments of compound AB, the following formula is used: .

[0303] In some embodiments of compound AB, the following formula is used: .

[0304] In some embodiments of compound AB, the following formula is used: .

[0305] In some embodiments of compound AB, the following formula is used: .

[0306] In some embodiments of compound AB, the following formula is used: .

[0307] In some embodiments of compound AB, the following formula is used: .

[0308] In some embodiments of compound AB, the following formula is used: .

[0309] In some embodiments of compound AB, the following formula is used: .

[0310] In some embodiments of compound AB, the following formula is used: .

[0311] In some embodiments of compound AB, the following formula is used: .

[0312] (c) Other derivatives / therapeutic agents

[0313] In some embodiments, this application also provides therapeutic compounds of formula CD (defined below) which can be prepared by reducing therapeutic compounds of formula EF. This reduced form of the formula EF compound is also considered suitable for treating mitochondrial diseases, such as Friedreich's ataxia or other ataxias (such as ataxia with vitamin E deficiency (AVED)), because other compounds having a hydroquinone structure (such as vitamin E) have also been shown to be 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). For example, the therapeutic compound of formula CD (hereinafter) is believed to be a therapeutic agent itself or, alternatively, a prodrug form of a therapeutic agent of formula EF. Specifically, the therapeutic compound of formula EF is believed to be active in in vivo influencing the concentration of reactive oxygen species (ROS) (e.g., internal and external mitochondrial concentrations) and can actually actively cycle in vivo between its reduced form (compound of formula CD) and its oxidized form (compound of formula EF). The compound of formula EF can, for example, be converted to the compound of formula CD, as described below in Examples 8 and 9. Furthermore, the compound of formula CD showed efficacy as a lipoxygenase-15 (LO-15) inhibitor in Example 22.

[0314] Therefore, in some embodiments, this application also provides novel compounds of formula CD or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates and / or solvates thereof, wherein C is 11 or 12:

[0315] And D is 13, 14, 15, 16, 17, 18, 19, or 20:

[0316] Wherein, J' is OH, SH, or NH-R11 K does not exist or -(CR) 12 R 13 )-, L is -(CR 12 R 13 -, each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond), each X is independently represented by the formula -(CR). 12 R 13 The group )-, each Y is independently absent or of the formula -(CR 12 R 13 The group is )-, each Z independently is of the formula -(CR 14 The R1, R2, and R3 groups are each independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; or R1 and R2 together form a five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring, or a five-membered heteroaromatic ring, or a six-membered heterocyclic ring, and each R8 and R9 is independently H, D, F, Cl, Br, I, or a C1-C4 alkyl; or R8 and R9 together form a three-membered, four-membered, five-membered, six-membered, or seven-membered carbon ring or heterocyclic ring, R 10 It is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, R 11 It is H, D or C1-C6 alkyl, R 12 R 13 and R 14 Each instance is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, R 19 It is H, C1-C4 alkyl or benzyl (substituted or unsubstituted), R 20 Is it H, D, F or C1-C? 12 Alkyl, each R 21 Independently, it is H, D, F, Cl, Br, I or C1-C4 alkyl, n is an integer from 0 to 12, including the end value, and Indicates the connection point from C to D, and Indicate the connection point from C to D; and further, the condition is: (i) Equations 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 comprises at least one fluorine atom; and / or (ii) R8 and R9 together form a ternary, quaternary, pentary, hexanal, or septary carbon ring or heterocycle. In some embodiments, at least one of R8 and R9 is fluorine or a substituted C1-C4 alkyl group comprising at least one fluorine atom. In some embodiments, each of R8 and R9 is independently fluorine or a substituted C1-C4 alkyl group comprising at least one fluorine atom. In some embodiments, each of R8 and R9 is fluorine. In some embodiments, R8, R9, and R9 are... 10 Each of these is fluorine. In some embodiments, R8, R9, and R... 10 Each of these is independently fluorine or a substituted C1-C4 alkyl group containing at least one fluorine. In some embodiments of EF, R 19 It is H.

[0317] Any combination of 11 and 12 with 13, 14, 15, 16, 17, 18, 19, or 20 is permitted. 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.

[0318] The atom or group represented by J' can be 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 Defined below. In some embodiments, J' is OH or NH-R. 11 And K does not exist.

[0319] In some embodiments, the groups represented by K and L can each be 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(OC))-, -(C ... 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 implementations, K is absent, and 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 implementations, 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 -(CH2)-, -(CD2)-, -(CF2)-, -(CH(CH3))-, -(CD(CD3))-, -(CF(CF3))-, -(C(CH3)2)-, -(C(CD3)2)-, -(C(CF3)2)-, -(CH(OCH3))-, -(CD(OCD3))-, -(CF(OCF3))-, or -(C(OCH3)2)-. In some embodiments, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-. In some embodiments, K is absent, and L is -(CH2)-, -(CD2)-, -(CHF)-, -(CF2)-, -(CH(CH3))-, -(CF(CF3))-, -(C(CH3)2)-, or -(C(CF3)2)-. In some embodiments, each of K and L is independently -(CH2)-, -(CD2)-, -(CHF)-, or -(CF2)-. In some embodiments, K is absent, and L is -(CH2)-, -(CD2)-, -(CHF)-, or -(CF2)-. In some embodiments, each of K and L is -(CH2)-. In some embodiments, K is absent, and L is -(CH2)-. In some embodiments, each of K and L is -(CD2)-. In some embodiments, K is absent, and L is -(CD2)-. In some implementations, each of K and L is -(CF2)-. In some implementations, K is absent, and L is -(CF2)-.

[0320] In some embodiments of the compound represented by CD, wherein 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, -C H2CF3, -CH(CF3)2, -CF2CF3, -CF(CF3)2, -C(CH3)3, -C(CD3)3, -C(CF3)3, -OCH2CH3, -OCH(CH3)2, -O CD2CD3, -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(CD2 CD3)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(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 -CH3. In some embodiments of the compound represented by CD, C is 11, and each of R1, R2, and R3 is 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.

[0321] In some embodiments of the compound represented by CD, C is 11, J' is OH, 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 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 compound 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.

[0322] In some embodiments of the compound represented by CD, C is 11, 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 five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by CD, C is 11, (i) R3 is H, F, -CH3, or -OCH3, and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by CD, C is 11, (i) R3 is H; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by CD, C is 11, (i) R3 is -CH3; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by CD, C is 11, (i) R3 is -OCH3; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle. In some embodiments of the compound represented by CD, C is 11, (i) R3 is F; and (ii) R1 and R2 together form a five- or six-membered carbon ring or heterocycle.

[0323] In some embodiments, R1 and R2 of 11 together form a heterocyclic ring, as shown in 11A, 11B, 11C, 11D, 11E, or 11F:

[0324] Among them, R 16 and R 17Each of these elements 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 18 It is H, D, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R 16 and R 17 Each can be independently H, D, Cl, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, or -OCF3. In some embodiments, R 16 and R 17 Each can be independently H, D, F, or -CH3. In some implementations, R 16 and R 17 It is H. In some implementations, R 16 and R 17 It is F. In some implementations, R 16 and R 17 It is -CH3. In some implementations, R 18 It is H or -CH3.

[0325] In some embodiments of the compound represented by CD, where C is 12, 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 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, -OCH2CH 2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CH2CH3, -OCF(CH2CH3)2, -OCH2CF2CF3, -OCH(CF2CF3)2, -OCF2CF2C F3 or -OCF(CF2CF3)2; and wherein, if W is C (carbon), then each of R4, R5, R6 and R7 connected 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 wherein, if W is N (nitrogen), then each of R4, R5, R6 and R7 connected thereto is independently absent or selected from H, D, methyl, ethyl, isopropyl and tert-butyl. In some embodiments, for For each instance, the key between each W is a single key. In some implementations, for For each instance, the key between each W is a double key. 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 wherein, if W is C (carbon), then each of R4, R5, R6, and R7 connected thereto is independently H, D, F, Cl, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2; and wherein, if W is N (nitrogen), then each of R4, R5, R6, and R7 connected thereto is independently absent or selected from H, D, methyl, and ethyl. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is independently H, D, Cl, F, -CH3, -OCH3, -CH2F, -CHF2, -CF3, or -OCF3. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is independently H, -CH3, or -OCH3. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is H. In some embodiments, each W is C (carbon), and each of R4, R5, R6, and R7 is -CH3.

[0326] In some embodiments of compound CD, each of R8 and R9 may 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, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2. In some embodiments of compound CD, 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. In some embodiments of compound CD, each of R8 and R9 may independently be H, F, -CH3, -CH2F, -CHF2, or -CF3.

[0327] In some embodiments of compound CD, each of R8 and R9 may independently be a C1-C4 alkyl group. The alkyl group may, for example, be substituted with one or more fluorine atoms. For example, the alkyl group may be fluoromethyl, difluoromethyl, or trifluoromethyl.

[0328] In some embodiments of compound CD, R8 and R9 together can form a ternary, quaternary, pentaneary, hexanal, or heptaneary carbon ring or heterocycle. For example, the ternary, quaternary, pentaneary, hexanal, or heptaneary carbon ring or heterocycle can be 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47.

[0329] The # symbol indicates the connection point where the carbocyclic or heterocyclic ring connects to the remainder of the compound. In some embodiments, the ternary, quaternary, pentaneary, hexanal, or heptaneous carbocyclic or heterocyclic ring may contain one or more fluorine substitutions. In some embodiments, the ternary, quaternary, pentaneary, hexanal, or heptaneous carbocyclic or heterocyclic ring may contain one or more deuterium substitutions.

[0330] 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(C D3)3, -OC(CF3)3, -C(CH3)2(CF3), -C(CH3)(CF3)2, -OC(CH3)2(CF3), -OC(CH3)(CF3)2, -CH2CH2CH3, -CH(CH2CH3)2, -CD2CD2CD3, -CD(CD2CD3)2, -CF2CF2CF3, -CF(CF2CF3)2, -C(CH2CH3)3, -C(CD2CD3)3, -C(CF2CF3)3, -OCH2CH2CH3, -OCH(CH2CH3)2, -OCD2CD2CD3, -OCD(CD2CD3)2, -OCF2CF2CF3 or -OCF(CF2CF3)2. In some embodiments of compound CD, R 10 It is H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -OCF3, -CH2CH3, or -CH(CH3)2. In some embodiments of compound CD, R 10 It is H, D, F, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments of compound CD, R 10 It is H, D, or F. In some embodiments of compound CD, R 10 It is -CH3 or -CF3. In some embodiments of compound CD, R 10 It is H or -CH3. In some embodiments of compound CD, R 10It is H. In some embodiments of compound EF, R 10 It is -CH3. In some embodiments of compound CD, R 10 It does not exist.

[0331] In some embodiments of compound CD, R 11 It is H, methyl, or ethyl. In some embodiments of compound CD, R 11 It is H. In some embodiments of compound CD, R 11 It is a methyl group. In some embodiments of compound CD, R 11 It is an ethyl group.

[0332] In some embodiments of compound CD, R 12 R 13 Or R 14 Each instance 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 Each instance is independently H, D, F, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, or -OCF3. In some embodiments of compound CD, R 12 R 13 Or R 14 Each instance is independently H, D, F, -CH3, -CD3, or -CF3. In some embodiments of compound CD, R 12 R 13 Or R 14 Each instance is independently H, D, or F. In some embodiments of compound CD, R 12 R 13 Or R 14 Each instance is independently H, F, or -CH3. In some embodiments of compound CD, R 12 R 13 Or R 14 Each instance is H. In some embodiments of compound CD, R 12 R 13 Or R14 Each instance is D. In some embodiments of compound CD, R 12 R 13 Or R 14 Each instance of is F.

[0333] In some implementations, R 19 It is H. In some implementations, R 19 It is a C1-C4 alkyl group. For example, R 19 It can be methyl, or R 19 It can be ethyl, or R 19 It can be isopropyl, or R 19 It can be tert-butyl. In some implementations, R 19 It can be benzyl (substituted or unsubstituted). For example, in some embodiments, R 19 It is a group of the following formula:

[0334] Each A1 is independently H, D, F, Cl, Br, I, -CH3, -OCH3, CH2CH3, -OCH2CH3, trichloromethyl, or trifluoromethyl.

[0335] In some embodiments of compound CD, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3. In some embodiments of compound CD, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3. In some embodiments of compound CD, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound CD, R 20 It is H, D, F, -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound CD, R 20It is -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound CD, R 20 It is H. In some embodiments of compound CD, R 20 It is -CH3. In some embodiments of compound EF, R 20 It is -CF3. In some embodiments of compound CD, R 20 It is F.

[0336] In some embodiments of compound CD, each R 21 Independently, it is H, D, F, -CH3, -CD3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3. In some embodiments of compound CD, each R 21 Independently, it is H, D, F, -CH3, -CD3, -CH2F, -CHF2, or -CF3. In some embodiments of compound CD, each R 21 Independently H, -CH3, or -CF3. In some embodiments of compound CD, each R 21 It is -CH3. In some embodiments of compound CD, each R 21 It is H. In some embodiments of compound CD, each R 21 It is -CF3.

[0337] 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.

[0338] In some embodiments of compound CD, it has the formula referred to herein as compound A-2: .

[0339] In some embodiments of compound CD, it has the formula referred to herein as compound B-2: .

[0340] In some embodiments of compound CD, it has the formula referred to herein as compound C-2: .

[0341] In some embodiments of compound CD, it has the formula referred to herein as compound D-2: .

[0342] In some embodiments of compound CD, it has the formula referred to herein as compound E-2: .

[0343] In some embodiments of compound CD, it has the formula referred to herein as compound F-2: .

[0344] In some embodiments of compound CD, it has the formula referred to herein as compound G-2: .

[0345] In some embodiments of compound CD, it has the formula referred to herein as compound H-2: .

[0346] In some embodiments of compound CD, it has the formula referred to herein as compound I-2: .

[0347] In some embodiments of compound CD, it has the formula referred to herein as compound J-2: .

[0348] In some embodiments of compound CD, it has the formula referred to herein as compound K-2: .

[0349] In some embodiments of compound CD, it has the formula referred to herein as compound L-2: .

[0350] In some embodiments of compound CD, it has the formula referred to herein as compound N-2: .

[0351] In some embodiments, this application also provides therapeutic compounds comprising a substituted quinone head group, with an aliphatic tail group comprising at least one chiral center, at least one hydroxyl group, and at least one silicon atom covalently linked to the head group. In some embodiments, such compounds may have formula EG or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein E is 21 or 22.

[0352] And G is 23 or 24:

[0353] Where J is O, S, or NR 11 K does not exist or -(CR) 12 R 13 )-;L is -(CR 12 R 13 -; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently nonexistent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each Q is independently of the formula -(CR) 12 R 13 The group R1, R2, and R3 is H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy, provided that each O and each Si is not directly bonded to O or Si; 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 five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring, a heteroaromatic ring, or a six-membered heterocyclic ring; R8', R9', and R 10 Each of the following is independently a C1-C4 alkyl group; or R8' and R9' together form a ternary, quaternary, pentagonal, hexavalent, or septagonal carbon ring or heterocycle; R 11 It is H, D, or C1-C6 alkyl; R 12 and R 13 Each of these elements is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; R 20Is it H, D, F or C1-C? 12 Alkyl group; p is an integer from 0 to 20, including the end value; and Instruct E to connect to the connection point of G, and The connection point indicating the connection between G and E. In some implementations, R8', R9', and R... 10 Each of the elements in ' is independently either methyl or ethyl.

[0354] In some implementations, E is 21, J is O, K is -(CH2)-, L is -(CH2)-, and 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 'Independently methyl or ethyl, and R 20 It is a C1-C4 alkyl group. 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.

[0355] In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O, and every other Q is -(CH2)-. In some embodiments, at least one Q is Si, and every other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O, and the remaining Qs are -(CH2)-.

[0356] In some embodiments, EG is compound M-0 or compound M-0': .

[0357] In this embodiment, 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 of end values), and p” is an integer from 1 to 9 (inclusive of end values). 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 of end values.

[0358] In some embodiments, EG is compound M or compound M': .

[0359] In some embodiments, this application also provides therapeutic compounds comprising a substituted hydroquinone head group, with an aliphatic tail group comprising at least one chiral center, at least one hydroxyl group, and at least one silicon atom covalently linked to the head group. Therefore, in some embodiments, this application also provides therapeutic compounds or intermediates of formula CG, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein C is 11 or 12.

[0360] And G is 23 or 24:

[0361] Wherein, J' is OH, SH, or NH-R 11 K does not exist or -(CR) 12 R 13 )-;L is -(CR 12 R 13 -; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each Q is independently of the formula -(CR) 12 R 13 The group R1, R2, and R3 is H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy, provided that each O and each Si is not directly bonded to O or Si; 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 five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring, a heteroaromatic ring, or a six-membered heterocyclic ring; R8', R9', and R 10 Each of the following is independently a C1-C4 alkyl group; or R8' and R9' together form a ternary, quaternary, pentagonal, hexavalent, or septagonal carbon ring or heterocycle; R 11 It is H, D, or C1-C6 alkyl; R 12 and R 13 Each of these elements is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; R19 It is H, C1-C4 alkyl, or benzyl (substituted or unsubstituted); R 20 Is it H, D, F or C1-C? 12 Alkyl group; p is an integer from 0 to 20, including the end value; and Instructs C to connect to the connection point of G, and The connection point indicating the connection between G and C. In some implementations, R8', R9', and R... 10 Each of the elements in ' is independently either methyl or ethyl.

[0362] In some embodiments, C is 11, J' is OH, K is -(CH2)-, L is -(CH2)-, and each of R1, R2, and R3 is independently selected from: H, D, F, -CH3, -OCH3, and -OCF3, and R8', R9', and R 10 Each of the elements in ' is independently either methyl or ethyl, R 19 It is H, and R 20 It is a C1-C4 alkyl group. 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.

[0363] In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O, and every other Q is -(CH2)-. In some embodiments, at least one Q is Si, and every other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O, and the remaining Qs are -(CH2)-.

[0364] In some embodiments, CG is compound M-3 or compound M-3':

[0365] In this embodiment, 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 of end values), and p” is an integer from 1 to 9 (inclusive of end values). 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 of end values.

[0366] In some embodiments, CG is compound M-2 or compound M-2': .

[0367] In some embodiments, this application also provides a therapeutic compound or an intermediate of a therapeutic compound comprising a precursor of an aromatic quinone or hydroquinone head group, wherein an aliphatic tail group comprising at least one chiral center, at least one hydroxyl group, and at least one silicon atom is attached to the precursor of the head group. In some embodiments, this application relates to compounds of formula AH or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein A is 1, 2, 3, or 4:

[0368] And H is 25:

[0369] Where J is O, S, or NR 11 K does not exist or -(CR) 12 R 13 )-;L is -(CR 12 R 13 -; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each Q is independently of the formula -(CR) 12 R 13 The group R1, R2, and R3 is H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy, provided that each O and each Si is not directly bonded to O or Si; 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 five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring, a heteroaromatic ring, or a six-membered heterocyclic ring; R8', R9', and R 10 Each of the elements in R8' is independently a C1-C4 alkyl group, or R8' and R9' together form a ternary, quaternary, pentagonal, hexavalent, or septagonal carbon ring or heterocycle; R 11 It is H, D, or C1-C6 alkyl; R12 and R 13 Each of these elements is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; R 15 It is H, C1-C4 alkyl, or PG, where PG is a phenol protecting group; R 20 Is it H, D, F or C1-C? 12 Alkyl group; p is an integer from 0 to 20, including the end value; and Indicates the connection point from A to H, and This indicates the connection point where H is connected to A. In some implementations, R8', R9', and R... 10 Each of the elements in ' is independently either methyl or ethyl.

[0370] In some implementations, A is 1 or 3, J is O, K is -(CH2)-, L is -(CH2)-, and 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 'Independently methyl or ethyl, and R 15 It 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.

[0371] In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O, and every other Q is -(CH2)-. In some embodiments, at least one Q is Si, and every other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O, and the remaining Qs are -(CH2)-.

[0372] In some embodiments, AH is compound M-4 or compound M-4':

[0373] In this embodiment, 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 of end values), and p” is an integer from 1 to 9 (inclusive of end values). 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 of end values.

[0374] In some embodiments, AH is compound M-5 or M-5': .

[0375] In some embodiments, this application also provides therapeutic compounds of formula EI or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein E is 21 or 22:

[0376] And I is 26 or 27:

[0377] Where J is O, S, or NR 11 K does not exist or -(CR) 12 R 13 )-;L is -(CR 12 R 13 -; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each Q is independently of the formula -(CR) 12 R 13The R1, R2, and R3 groups are H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, or R1 and R2 together form a five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring or a heteroaromatic ring, or a six-membered heterocyclic ring; each R8”, R9”, and R 10 "Independently H, F, or C1-C4 alkyl, however the condition is R8", R9", and R 10 At least one of them is F; R 11 It is H, D, or C1-C6 alkyl; R 12 and R 13 Each of these elements is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; R 20 Is it H, D, F or C1-C? 12 Alkyl group; p is an integer from 0 to 20, including the end value; and Indicates that E is connected to the connection point of I, and This indicates the connection point from I to E. In some implementations, R8", R9", and R 10 At least one of R8", R9", and R is F. In some implementations, R8", R9", and R 10 Each of the letters in the alphabet is independently H or F. In some implementations, R8", R9", and R 10 Each of them is F.

[0378] In some implementations, E is 21, J is O, K is -(CH2)-, L is -(CH2)-, and 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 "Independently H or F, and R" 20 It is a C1-C4 alkyl group. 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.

[0379] In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O, and every other Q is -(CH2)-. In some embodiments, at least one Q is Si, and every other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O, and the remaining Qs are -(CH2)-.

[0380] In some embodiments, EI is compound N-0 or compound N-0':

[0381] In this embodiment, 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 an independent integer from 0 to 4, inclusive.

[0382] In some embodiments, EI is compound N or compound N': .

[0383] In some embodiments, this application also provides a therapeutic compound or intermediate of formula C1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein C is 11 or 12:

[0384] And I is 26 or 27:

[0385] Wherein, J' is OH, SH, or NH-R 11 K does not exist or -(CR) 12 R 13 )-;L is -(CR 12 R 13 -; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each Q is independently of the formula -(CR) 12 R 13 The R1, R2, and R3 groups are H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, or R1 and R2 together form a five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring or a heteroaromatic ring, or a six-membered heterocyclic ring; each R8”, R9”, and R 10 "Independently H, F, or C1-C4 alkyl, however the condition is R8", R9", and R 10 At least one of them is F; R 11 It is H, D, or C1-C6 alkyl; R 12 and R 13 Each of these elements is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; R 19 It is H, C1-C4 alkyl, or benzyl (substituted or unsubstituted); R 20 Is it H, D, F or C1-C? 12 Alkyl group; p is an integer from 0 to 20, including the end value; and Indicates that C is connected to the connection point of I, and Indicates the connection point from I to C. In some implementations, R8", R9", and R 10 Each of the letters in the alphabet is independently H or F. In some implementations, R8", R9", and R 10 At least one of R8", R9", and R is F. In some implementations, R8", R9", and R 10 Each of them is F.

[0386] In some embodiments, C is 11, J' is OH, K is -(CH2)-, L is -(CH2)-, and 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 "Independently H or F, R" 19 It is H, and R 20 It is a C1-C4 alkyl group. 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.

[0387] In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O, and every other Q is -(CH2)-. In some embodiments, at least one Q is Si, and every other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O, and the remaining Qs are -(CH2)-.

[0388] In some embodiments, CI is compound N-3 or compound N-3':

[0389] In this embodiment, 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 an independent integer from 0 to 4, inclusive.

[0390] In some embodiments, CG is compound N-2 or compound N-2': .

[0391] In some embodiments, this application also provides therapeutic compounds or intermediates of formula AU, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein A is 1, 2, 3, or 4:

[0392] And U is 28:

[0393] Where J is O, S, or NR 11 K does not exist or -(CR) 12 R 13 )-;L is -(CR 12 R 13 -; each W is independently C (carbon) or N (nitrogen), and wherein, for each used The bonds between each W can be single or double bonds, and further, if they are single bonds, then each C (carbon) atom will have a hydrogen atom bonded to it in addition to one of R4, R5, R6, or R7, and in any case, each of R4, R5, R6, and R7 bonded to each C (carbon) atom is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl, and C1-C6 alkoxy, and if W is N (nitrogen), then each of R4, R5, R6, and R7 bonded to it is independently absent (if...). (is a double bond) or selected from H, D and C1-C6 alkyl groups (if It is a single bond); each Q is independently of the formula -(CR) 12 R 13 The R1, R2, and R3 groups are H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, or R1 and R2 together form a five-membered carbon ring, a five-membered heterocyclic ring, a five-membered aromatic ring or a heteroaromatic ring, or a six-membered heterocyclic ring; each R8”, R9”, and R 10 "Independently H, F, or C1-C4 alkyl, however the condition is R8", R9", and R 10 At least one of them is F; R 11 It is H, D, or C1-C6 alkyl; R 12 and R 13 Each of these elements is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy; R 15 It is H, C1-C4 alkyl, or PG, where PG is a phenol protecting group; R 20 Is it H, D, F or C1-C? 12 Alkyl group; p is an integer from 0 to 20, including the end value; and Indicates the connection point of A to U, and This indicates the connection point where U connects to A. In some implementations, R8", R9", and R... 10 Each of the letters in the alphabet is independently H or F. In some implementations, R8", R9", and R 10 At least one of R8", R9", and R is F. In some implementations, R8", R9", and R 10 Each of them is F.

[0394] In some implementations, A is 1 or 3, J is O, K is -(CH2)-, L is -(CH2)-, and 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 "Independently H or F, and R"15 It 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.

[0395] In some embodiments, each Q is -(CH2)-. In some embodiments, at least one Q is O, and every other Q is -(CH2)-. In some embodiments, at least one Q is Si, and every other Q is -(CH2)-. In some embodiments, only one Q is O. In some embodiments, only one Q is O, and the remaining Qs are -(CH2)-.

[0396] In some embodiments, AH is compound N-4 or compound N-4':

[0397] In this embodiment, 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 an independent integer from 0 to 4, inclusive.

[0398] In some embodiments, AU is compound 104 or compound 104': .

[0399] VI. Methods for preparing therapeutic compounds and related intermediates

[0400] In some embodiments, this application relates to methods for generating the novel compositions disclosed herein. Suitable methods are generally illustrated in Figures 1A, 1B, 1C, 1D, 2A, 2B, 2C, 2D, and 3. Specific examples of generating certain novel compounds using general methods can be seen in Examples 1 to 7 and Examples 9 to 10 below. The general descriptions and following descriptions present in Figures 1A, 1B, 1C, 1D, 2A, 2B, 2C, and 2D are very consistent with the relevant descriptions in Scheme 2 (below) and Example 1. The general descriptions present in Figure 3 and the following descriptions for generating compounds of formula 203 are very consistent with the relevant descriptions in Scheme 1 (below) and Example 1. General methods for reducing therapeutic compounds of general formula 10 to other therapeutic compounds of general formula I-OR can be seen in Figure 4 and Examples 9 and 10.

[0401] Referring to Figure 1A, compounds of formula 204 are provided. Representative known compounds of formula 204 can be seen in Figures 6A, 6B, and 6C (a Chemical Abstracts Service (CAS) registration number is provided for each known composition shown). The asterisks shown in the compounds of formula 204 (and for all other compounds shown in the figures) indicate chiral centers. Stereochemically pure compounds of formula 204 (i.e., pure enantiomers of 204 or 205 if the starting material is mentioned below) can be used in the processes described herein—but this is not a requirement or limitation. Racemic mixtures of 204 (or 205) can be used because the process is... Steps d and e (The following discussion) produces diastereomers that can be separated by chromatography (or other) techniques, as included in the examples discussed herein.

[0402] In the compound of formula 204, J, K, L, R1, R2, R3 and R 20 As defined above. In some implementations, R 30 It is H. In some embodiments, phenol has been protected (either temporarily or, in this case, R) 30 It is either protected by a protecting group (PG), or protected by a more permanent group such as methyl, ethyl, isopropyl, or tert-butyl ether (in which case, R...). 30 It can be a C1-C6 alkyl group). In those cases, R 30 This represents the phenol protecting group. In cases where the phenol is already protected, step b. (hereinafter) is not required to obtain the compound of formula 206.

[0403] The carboxylic acid compound of formula 204 can be converted into an ester of formula 205 under suitable conditions. The conversion of carboxylic acids to esters is a well-known chemical reaction. Any suitable method known in the art can be used to achieve this conversion, but specifically, the method under scheme 2 in Example 1... Step a. The methods discussed herein are exemplary. For example, under scheme 2 of embodiment 1... step a. As discussed herein, methyl ester (5) is prepared by heating (4) in methanol in the presence of p-toluenesulfonic acid (PTSA) to obtain (5). Higher esters can be prepared by using suitable alternative alcohols or by applying other processes well known in the art. Alternatively, ester compounds of formula 205 are provided with reference to Figure 1A. As can be seen from Figures 6A, 6B and 6C, various esters of formula 205 are commercially known and / or available.

[0404] In the compound of formula 205, J, K, L, R1, R2, R3, R 20 and R 30 As defined above. Group R 31 Represents any C1-C6 alkyl or benzyl group, but will typically be methyl, ethyl, or benzyl. If R 30 If it is not H, then the compound of formula 205 is synonymous with the compound of formula 206, as discussed below.

[0405] Referring to Figure 1A, it can be seen that the compound of formula 205 (where R) 30 H) can be converted to a compound of formula 206 by protection of an exocyclic phenol. Any suitable method known in the art can be used to achieve this conversion of phenol to a protected phenol, but in particular, the method under scheme 2 in Example 1... Step b. The methods discussed are exemplary. In Example 1 Step b. In the presence of K₂CO₃ (as a base), benzyl bromide in DMF (as a solvent) is used at room temperature to alkylate (5) phenol, thereby producing a benzyl ether (6). Any benzyl halide can be used to generate a substituted or unsubstituted benzyl protecting group attached to phenol. Typically, the protection reaction is carried out in a dry aprotic solvent in the presence of an (inorganic or organic) base. However, any suitable protecting group and any suitable conditions can be used. For example, phenol can be protected with a triphenylmethyl-based protecting group using, for example, triphenylmethyl chloride and similar conditions. Alternatively, phenol can be protected with a silyl-based protecting group using, for example, tert-butyldimethylsilyl chloride and similar conditions. In some embodiments, phenol may optionally be reacted with an agent that produces a more persistent modification (such as, for example, methyl iodide, ethyl iodide, or isopropyl iodide) to produce a methyl ether, ethyl ether, or isopropyl ether, respectively.

[0406] In the compound of formula 206, J, K, L, R1, R2, R3, R 20 and R 31 As defined above. Group R 32 Represents any phenol protecting group (such as C1-C4 alkyl groups, triphenylmethyl-based protecting groups, silyl protecting groups, or benzyl protecting groups), but R 32 It is not hydrogen (H).

[0407] Referring to Figure 1A, it can be seen that the compound of formula 206 can be converted into the compound of formula 207 by converting the ester group back into a carboxylic acid (a process known as ester saponification). Ester saponification is a well-known chemical reaction. This conversion from ester to carboxylic acid can be achieved using any suitable method known in the art, but specifically, under scheme 2 in Example 1... step c. The method discussed herein is exemplary. Typically, the process involves treating the ester in water or a mixture of water and water-miscible organic solvents (such as methanol, ethanol, tetrahydrofuran, and / or acetonitrile) with a strong base (such as sodium hydroxide, potassium hydroxide, or lithium hydroxide) for a sustained period of time necessary for saponification, followed by neutralization with an acid (typically a strong acid, such as hydrochloric acid) to generate a carboxylic acid from the carboxylate anion. Depending on the nature of the starting materials, the reaction can be carried out at low temperatures, room temperature, or high temperatures. In the compounds of formula 207, J, K, L, R1, R2, R3, R... 20 and R 32 As defined above.

[0408] Referring to Figure 1A, it can be seen that the compound of formula 207 can be converted into the compound of formula 209, for example, by converting the acid group to a mixed anhydride. The formation of a mixed anhydride is a well-known chemical reaction. Any suitable method known in the art can be used to achieve this conversion of carboxylic acids to mixed anhydrides, but particularly, under scheme 2 of Example 1. Step d. The method discussed herein is exemplary. Typically, this transformation can be achieved through the reaction of an (inorganic or organic) base with an acyl chloride (shown as a compound of formula 208 in Figure 1A), where R... 33 The reaction is carried out by treating a carboxylic acid (7) in a dry aprotic solvent (such as THF) in the presence of any alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylheteroalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, or heteroaryl group known in the art; and represented as 8 in Scheme 2). The reaction can be carried out at a reduced temperature (e.g., -30°C). In the compounds of formula 209, J, K, L, R1, R2, R3, R... 20 and R 32 As defined above. Typically, R 33These are bulky groups, such as tert-butyl or adamantyl. Because mixed anhydrides tend to be unstable (especially prone to hydrolysis in the presence of any water), they are often (but not necessarily) used directly in subsequent reactions without separation or purification.

[0409] Referring to Figure 1A, it can be seen that the compound of formula 209 can be converted into a diastereomer of formula 211a or 211b by reacting with a suitable chiral oxazolidinyl-2-one (in Figure 1A, the compound of formula 210 is exemplary). This conversion can be achieved using any suitable method known in the art, but particularly under scheme 2 in Example 1. Step d, Step e. The methods discussed herein are exemplary. Typically, as provided in Example 1, a mixture of acid anhydrides and oxazolidin-2-one is reacted in n-butyllithium (… n The reaction is further carried out in anhydrous conditions and at reduced temperatures (e.g., -78°C) in an aprotic solvent in the presence of BuLi. In the compounds of formulas 211a and 211b, J, K, L, R1, R2, R3, R... 20 and R 32 As defined above. While mixtures of stereoisomers may be used in subsequent steps, chiral compound 210 is used to produce diastereomers that can be separated by chromatography (or other means). Since therapeutic agents are typically stereochemically pure, mixtures are most often separated chromatographically to produce separated compounds of formula 211a and 211b, but this is not a requirement or limitation. The process can produce stereochemically pure compounds or stereochemical mixtures. Therefore, based on the nature of the starting materials, the products of subsequent reactions will be stereochemically pure or stereochemical mixtures (unless purified in subsequent reactions). If a stereochemical mixture is obtained, and a stereochemically pure product is required, the compound may optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate).

[0410] Referring to Figure 1A, it can be seen that compounds of formula 211a and / or formula 211b can be converted into compounds of formula 212 by converting the amide to an alcohol. This conversion can be achieved using any suitable method known in the art, but specifically, under scheme 2 in Example 1. Step f. The methods discussed herein are exemplary. Typically, as seen in Example 1, stereochemically pure 11b can be treated with lithium aluminum hydride (LiH) in an anhydrous condition and at reduced temperatures in an aprotic solvent to produce alcohol (12). In the compounds of formula 212, J, K, L, R1, R2, R3, R... 20 and R 32As defined above, the compound of Formula 212 may be stereochemically pure or a stereochemical mixture. If it is a stereochemical mixture, and a stereochemically pure product is required, the compound may optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate).

[0411] Referring to Figure 1A, it can be seen that the compound of formula 212 can be converted into the compound of formula 213 by reacting the alcohol group with trifluoromethanesulfonic anhydride (or other groups that subject the alcohol derivative to nucleophilic attachment, such as toluenesulfonyl)). This conversion can be achieved using any suitable method known in the art, but particularly under scheme 2 in Example 1. step g. The methods discussed are exemplary. Typically, as seen in Example 1, (12) can be converted to (13) by treatment in a DCM at a reduced temperature (e.g., 0°C) with trifluoromethanesulfonic anhydride and pyridine. In the compounds of formula 213, J, K, L, R1, R2, R3, R 20 and R 32 As defined above, and “OTf” refers to the hydroxyl group protected by the trifluoromethanesulfonyl group. Compounds of Formula 213 can be stereochemically pure or stereochemical mixtures. If it is a stereochemical mixture, and a stereochemically pure product is required, the compound may optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate).

[0412] Referring to Figure 1A, it can be seen that the compound of formula 213 can be converted into the compound of formula 214 by reacting with the compound of formula 203. The compound of formula 203 can be purchased from available sources or produced as described below with reference to Figure 3 and the relevant discussion in Scheme 1 and Example 1. This conversion can be achieved using any suitable method known in the art, but specifically, under Scheme 2 in Example 1. Step h. The method discussed herein is exemplary. Typically, as seen in Example 1, (3) and hexamethylphosphoramide are dissolved or suspended in an aprotic solvent (such as THF) at a reduced temperature (e.g., -78°C), and then added dropwise. n BuLi, then trifluoromethanesulfonate (13) is added dropwise to carry out the reaction. In the compound of formula 214, J, K, L, R1, R2, R3, R 20 and R 32 As defined above. In the compound of formula 214, group B' has the following formula:

[0413] Among them, X, Y, R8, R9, R 21 As defined above, n' is 0 to 11 (inclusive), and # indicates a connection point. Each is represented as... The key is either a single key or a double key. If If it is a double bond, then each Z' is Z as defined above and R 10 'Does not exist.' If If it 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 phenyl (the complete structure of 203 is shown in Figure 3). Compounds of Formula 214 can be stereochemically pure or a stereochemical mixture. If it is a stereochemical mixture, and a stereochemically pure product is required, the compound can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate).

[0414] Referring to Figure 1A, it can be seen that the compound of formula 214 can be converted into the compound of formula 215. This conversion can be achieved using any suitable method known in the art, but particularly, under scheme 2 in Example 1... Step i. The method discussed herein is exemplary. Typically, as seen in Example 1, (14) is treated with lithium triethylborohydride in the presence of a palladium catalyst (e.g., bis[(diphenylphosphino)ferrocene]palladium(II) chloride) to obtain (15). This reaction can be carried out in an aprotic solvent (e.g., THF) at a reduced temperature (e.g., 0°C). In the compounds of formula 215, each is represented as The keys, n, J, K, L, X, Y, Z', R1, R2, R3, R8, R9, R 10 '、R 20 R 21 and R 32 As defined above, the compound of Formula 215 may be stereochemically pure or contain a mixture of stereochemicals. If it is a mixture of stereochemicals, and a stereochemically pure product is required, the compound may optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate).

[0415] Referring to Figure 1A, it can be seen that the compound of formula 215 can be obtained by removing the R group. 32 This regenerates unprotected phenol (-OH) into a compound of formula 216. Used for removing R... 32 The exact conditions will depend on R 32 The property of R. If R 32 If it is an alkyl group, it is usually not removed, and therefore the compound of formula 215 is not converted into the compound of formula 216. If R 32 If the protecting group is based on silyl groups, it can usually be removed by treatment in the presence of fluoride ions, such as by treatment with tetrabutylammonium fluoride (TBAF). If R 32If the protecting group is based on triphenylmethyl, it can usually be removed by treatment with an acid (such as dichloroacetic acid, trichloroacetic acid, or trifluoroacetic acid (pure or diluted in a compatible organic solvent such as DCM)). Other phenol protecting groups, their generation methods (i.e., protection of phenol), and deprotection (regeneration of phenol from protected phenol) are well known to those skilled in the art.

[0416] In the compound shown in Example 1, the group R 32 It is benzyl. The removal of the benzyl group can be achieved using any suitable method known in the art, but specifically, under scheme 2 in Example 1. Step j. The method discussed in the text is exemplary. Typically, in an aprotic solvent such as diethyl ether, treatment with a suspension of lithium (metal) in n-propylamine (15) yields (16). This reaction can be quenched by adding saturated aqueous ammonium chloride and an alcohol (such as methanol). In the compounds of formula 216, each is represented as The keys, n, J, K, L, X, Y, Z', R1, R2, R3, R8, R9, R 10 '、R 20 and R 21 As defined above, the compound of Formula 216 may be stereochemically pure or a stereochemical mixture. If it is a stereochemical mixture, and a stereochemically pure product is required, the compound may optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate).

[0417] In some embodiments, in the compound of formula 216, R8 and R9 are H and R 10 'Does not exist.' The preparation of compounds with this structure is usually achieved by the availability of a suitable alcohol of formula 201, as shown in Figure 3 and discussed in more detail below regarding the preparation of compounds of formula 203 (as discussed above in the preparation of compounds of formula 214). Where R8 and R9 are H and R 10 The types of compounds of formula 216 that do not exist are shown in Figure 1B and are identified as compounds of formula 216a. Since the availability of compounds of formula 201 may be limited, the method described in Figure 1B shows an alternative method for generating compounds with desired groups R8 and R9 (not H) from starting materials in which R8 and R9 are H.

[0418] Referring to Figure 1B, compounds of formula 216a are provided. These compounds can be prepared as described above and as shown in Figure 1A. The asterisks shown in the compounds of formula 216a (and all other compounds shown in Figure 1B) indicate chiral centers. Stereochemically pure compounds of formula 216a (i.e., pure enantiomers of 216a) can be used in the processes described herein, if available—but this is not a requirement or limitation. Racemic mixtures of 216a can be used, but typically the products will also be mixtures of stereochemically impure compounds. If a stereochemical mixture is required, the compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate). In the compounds of formula 216a, each is represented as... The keys, n, J, K, L, X, Y, Z, Z', R1, R2, R3, R 20 and R 21 As defined above.

[0419] Referring to Figure 1B, it can be seen that the compound of formula 216a can be converted to the compound of formula 217a through the protection of an exocyclic phenol. Any suitable method known in the art can be used to achieve this conversion of phenol to a protected phenol, but in particular, the method under scheme 2 in Example 1... Step k. The methods discussed are exemplary. In Example 1 Step k. In this embodiment, tert-butyldimethylsilyl chloride in DMF (as solvent) in the presence of imidazole (as base) is used to protect (16) phenol, thereby producing a tert-butyldimethylsilyl-protected product (17). Typically, the protection reaction is carried out in a dry aprotic solvent (such as DMF) in the presence of an (inorganic or organic) base. However, any suitable protecting group and any suitable conditions can be used. For example, phenol can be protected with a (substituted or unsubstituted) benzyl protecting group by using, for example, (substituted or unsubstituted) benzyl chloride and similar conditions (such as those described above for producing compound 206). Alternatively, phenol can be protected with a triphenylmethyl-based protecting group by using, for example, triphenylmethyl chloride and similar conditions. In some embodiments, phenol may optionally (but not preferably) react with an agent that produces a more persistent modification (such as methyl iodide, ethyl iodide, or isopropyl iodide) to produce a methyl ether, ethyl ether, or isopropyl ether, respectively.

[0420] If available, stereochemically pure compounds of formula 216a (i.e., pure enantiomers of 216a) can be used in the processes described herein—but this is not a requirement or limitation. Racemic mixtures of 216a can be used, but typically the product (i.e., 217a) will also be a mixture of stereochemically impure compounds. If a stereochemical mixture is required, the compounds can optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate). In compounds of formula 217a, each is represented as The keys, n, J, K, L, X, Y, Z, Z', R1, R2, R3, R 20 and R 21 As defined above. In compounds of formula 217a, the group R 34 Represents any phenol protecting group (e.g., C1-C4 alkyl group, triphenylmethyl-based protecting group, silyl protecting group, or benzyl protecting group), but R 34 Not hydrogen (H). For example, R 34 It can be based on a silyl-based protecting group, such as tert-butyldimethylsilyl.

[0421] Referring to Figure 1B, it can be seen that the compound of formula 217a can be converted into the compound of formula 218a. This conversion can be achieved using any suitable method known in the art, but particularly, under scheme 2 in Example 1. Step 1. The methods discussed herein are exemplary. Typically, as seen in Example 1, compound (17) can be treated with N-bromosuccinimide at a reduced temperature (e.g., 0°C) in a mixture of an organic solvent (e.g., THF) and water to produce (18). However, any suitable conditions may be used. Stereochemically pure compounds of formula 217a (i.e., pure enantiomers of 217a) may be used in the processes described herein—but this is not a requirement or limitation. Racemic mixtures of 217a may be used, but typically the product (218a) will also be a mixture of stereochemically impure compounds. If a stereochemical mixture is desired, the compounds may optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate). In the compounds of formula 218a, each is represented as The keys, n, J, K, L, X, Y, Z, Z', R1, R2, R3, R 20 R 21 and R 34 As defined above.

[0422] Referring to Figure 1B, it can be seen that the compound of formula 218a can be converted into the epoxy compound of formula 219a by treatment with a base. This conversion can be achieved using any suitable method known in the art, but particularly under scheme 2 in Example 1. Step m. The methods discussed herein are exemplary. Generally, as seen in Example 1, compound (18) can be reacted in an alcohol such as methanol or ethanol (or an aqueous mixture of alcohols) at a reduced temperature (e.g., 0°C) in the presence of an inorganic base such as sodium carbonate, potassium carbonate, or cesium carbonate to give the epoxide (19). However, any suitable conditions may be used. Stereochemically pure compounds of formula 218a (i.e., pure enantiomers of 218a) may be used in the processes described herein—but this is not a requirement or limitation. Racemic mixtures of 218a may be used, but generally the product (219a) will also be a mixture of stereochemically impure compounds. If a stereochemical mixture is required, the compounds may optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate). In the compounds of formula 219a, each is represented as The keys, n, J, K, L, X, Y, Z, Z', R1, R2, R3, R 20 R 21 and R 34 As defined above.

[0423] Referring to Figure 1B, it can be seen that the compound of formula 219a can be converted into the aldehyde of formula 220a by treatment with an oxidizing agent such as sodium periodate. This conversion can be achieved using any suitable method known in the art, but specifically, under scheme 2 in Example 1. Step n. The methods discussed herein are exemplary. Typically, and as shown in Example 1, the epoxide (19) is treated with sodium periodate and periodic acid in water or a mixture of water and an organic solvent at a reduced temperature (e.g., 0°C) to obtain (20). However, any suitable conditions may be used. Stereochemically pure compounds of formula 219a (i.e., pure enantiomers of 219a) may be used in the processes described herein if available—but this is not a requirement or limitation. Racemic mixtures of 219a may be used, but typically the product (220a) will also be a mixture of stereochemically impure compounds. If a stereochemical mixture is required, the compounds may optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate). In the compounds of formula 220a, each is represented as The keys, n, J, K, L, X, Y, Z, Z', R1, R2, R3, R 20 R 21 and R 34 As defined above.

[0424] Referring to Figure 1B, it can be seen that the aldehyde of formula 220a can be converted into an alcohol of formula 221a by treatment with a reducing agent such as sodium borohydride. This conversion can be achieved using any suitable method known in the art, but particularly under scheme 2 in Example 1. Step o. The methods discussed herein are exemplary. Typically, as shown in Example 1, the aldehyde (20) is treated with sodium borohydride in an alcohol (such as ethanol) or a mixture of water and alcohol at a reduced temperature (such as 0°C) to give the alcohol (21). However, any suitable conditions may be used. Stereochemically pure compounds of formula 220a (i.e., pure enantiomers of 220a) may be used in the processes described herein if available—but this is not a requirement or limitation. Racemic mixtures of 220a may be used, but typically the product (221a) will also be a mixture of stereochemically impure compounds. If a stereochemical mixture is required, the compounds may optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate). In the compounds of formula 221a, each is represented as The keys, n, J, K, L, X, Y, Z', R1, R2, R3, R 20 R 21 and R 34 As defined above.

[0425] Referring to Figure 1B, it can be seen that the alcohol of formula 221a can be converted to the iodide of formula 222a by treatment with imidazole and iodine. This conversion can be achieved using any suitable method known in the art, but specifically, under scheme 2 in Example 1. Step p. The methods discussed herein are exemplary. Typically, as shown in Example 1, alcohol (21) can be treated at room temperature in an aprotic solvent (such as DCM) with triphenylphosphine, imidazole, and iodine to obtain iodide (22). However, any suitable conditions may be used. Stereochemically pure compounds of formula 221a (i.e., pure enantiomers of 221a) may be used in the processes described herein—but this is not a requirement or limitation. Racemic mixtures of 221a may be used, but typically the product (222a) will also be a mixture of stereochemically impure compounds. If a stereochemical mixture is required, the compounds may optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate). In the compounds of formula 222a, each is represented as The keys, n, J, K, L, X, Y, Z', R1, R2, R3, R 20 R 21 and R 34 As defined above.

[0426] Referring to Figure 1B, it can be seen that the iodide of formula 222a can be converted to the triphenylphosphine iodide salt of formula 223a by treatment with an excess of triphenylphosphine. This conversion can be achieved using any suitable method known in the art, but specifically, under scheme 2 in Example 1. Step q. The methods discussed herein are exemplary. Typically, as illustrated in Example 1, the iodide (22) can be treated with an excess of triphenylphosphine in an aprotic solvent (such as ACN) at elevated temperatures (e.g., 85°C) to yield triphenylphosphine iodide (23). However, any suitable conditions may be used. Stereochemically pure compounds of formula 222a (i.e., pure enantiomers of 222a) may be used in the processes described herein—but this is not a requirement or limitation. Racemic mixtures of 222a may be used, but typically the product (223a) will also be a mixture of stereochemically impure compounds. If a stereochemical mixture is required, the compounds may optionally be purified by appropriate means (e.g., chromatography or chiral chromatography, as appropriate). In the compounds of formula 223a, each is represented as The keys, n, J, K, L, X, Y, Z', R1, R2, R3, R 20 R 21 a...

Claims

1. A compound of formula CD, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein, C is 11: And D is 13, 14, 19, or 20: Where J' is OH or SH; K is -(CR) 12 R 13 )-;L is -(CR 12 R 13 )-; Each X is independently represented by the formula -(CR 12 R 13 The group )-; each Y is independently absent or of the formula -(CR 12 R 13 The group is )-; each Z is independently of the formula -(CR 14 The group is -; each of R1, R2 and R3 is independently a C1-C6 alkyl group; each of R8 and R9 is independently 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, -CH2CF2CF3, -CH(CF2CF3)2, -CF2CF2CF3 or -CF(CF2CF3)2; R 10 It is F, Cl, Br, or I; R 12 R 13 and R 14 Each of them is independently H or D; R 20 It is C1-C 12 Alkyl; each R 21 Independently, it is H, D, or C1-C4 alkyl; n is an integer from 0 to 12; and Indicates the connection point from C to D. The connection point from which D is connected to C is indicated; and further, at least one group in formulas R8 and R9 contains at least one fluorine atom.

2. The compound of claim 1, wherein, D is 19 or 20.

3. The compound according to claim 1 or 2, wherein, J' is OH.

4. The compound according to claim 1 or 2, wherein, J' is SH.

5. The compound of claim 1, wherein, Each of K and L is independently -(CH2)- or -(CD2)-.

6. The compound of claim 1, wherein, Each of R1, R2, and R3 is independently -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, or -CH(CH2CH3)2.

7. The compound of claim 1, wherein, Each of R1, R2, and R3 is independently -CH3, -C(CH3)3, -CH2CH3, or -CH(CH3)2.

8. The compound of claim 1, wherein, J' is OH; each of K and L is independently -(CH2)- or -(CD2)-; and each of R1, R2 and R3 is independently -CH3, -C(CH3)3, -CH2CH3 or -CH(CH3)2.

9. The compound according to claim 1 or 2, wherein, R3 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3 or -CH(CH2CH3)2.

10. The compound of claim 1 or 2, wherein, R3 is -CH3, -C(CH3)3, -CH2CH3 or -CH(CH3)2.

11. The compound of claim 1, wherein, Each of R8 and R9 is independently 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.

12. The compound of claim 1, wherein, R 10 It is F.

13. The compound of claim 1, wherein, R 20 z-CH3,-CH2CH3,-CH2CH2CH3,-CH(CH3)2,-C(CH3)3,-CH2CH2CH2CH3,-CH2CH2CH2CH2CH2CH3,-CH2CH2CH2CH2CH2CH2CH3,-CH2CH2CH2CH2CH2CH2CH2CH3,-CH2CH2CH2CH2CH2CH2CH2CH2CH3,-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3 or-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3.

14. The compound of claim 1, wherein, Each R 21 It can be independently H, D, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3 or -C(CH3)3.

15. The compound of claim 1, wherein, n is 0, 1, 2, 3 or 4.

16. The compound of claim 1, wherein, The compound is Or its pharmaceutically acceptable salts and / or stereoisomers.

17. The compound of claim 1, wherein, The compound is Or its pharmaceutically acceptable salts and / or stereoisomers.

18. The compound of claim 1, wherein, The compound is Or its pharmaceutically acceptable salt.

19. The compound of claim 1, wherein, The compound is Or its pharmaceutically acceptable salt.

20. The compound of claim 1, wherein, The compound is Or its pharmaceutically acceptable salt.

21. The compound of claim 1, wherein, The compound is Or its pharmaceutically acceptable salt.

22. The compound of claim 1, wherein, The compound is Or its pharmaceutically acceptable salt.

23. The compound of claim 1, wherein, The compound is Or its pharmaceutically acceptable salt.

24. The compound of claim 1, wherein, The compound is Or its pharmaceutically acceptable salts and / or stereoisomers.

25. Use of any compound of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment or prevention of Friedrich's ataxia in a subject of need.

26. The use as described in claim 25, wherein, The compound effectively increases or maintains ataxia levels in subjects suspected of having Friedrich's ataxia.

27. The use as described in claim 25, wherein, The compound effectively inhibits the decrease in ataxia levels in subjects suspected of having Friedrich's ataxia.

28. The use as claimed in any one of claims 25 to 27, wherein, The compound is effective in treating one or more symptoms of Friedrich's ataxia selected from the group consisting of: muscle weakness, loss of coordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart disease.

29. The use as described in claim 25, wherein, The compound is effective when applied daily for 6 weeks or longer.

30. The use as described in claim 25, wherein, The compound is effective when applied daily for 12 weeks or longer.

31. Use of the compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for increasing the expression level of a conamin in a desired subject.

32. The use as described in claim 31, wherein, The compound is effective when applied daily for 6 weeks or longer.

33. The use as described in claim 31 or 32, wherein, The compound is effective when applied daily for 12 weeks or longer.

34. Use of the compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a deficiency of complex I in a subject of need.

35. The use as described in claim 34, wherein, The compound is effective when applied daily for 6 weeks or longer.

36. The use as described in claim 34 or 35, wherein, The compound is effective when applied daily for 12 weeks or longer.

37. The use as described in claim 34, wherein, The compound effectively increases intracellular adenosine triphosphate (ATP) levels in tissues of individuals diagnosed with Friedrich's ataxia.

38. Use of any compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for reducing or inhibiting the activity of lipoxygenase-15 in mammalian subjects suffering from or suspected of suffering from Friedrich's ataxia.

39. The use as described in claim 38, wherein, The compound is effective when applied daily for 6 weeks or longer.

40. The use as described in claim 38 or 39, wherein, The compound is effective when applied daily for 12 weeks or longer.

41. Use of any compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for reducing or inhibiting ferroptosis in mammalian subjects suffering from or suspected of suffering from Friedrich's ataxia.

42. The use as described in claim 41, wherein, The compound is effective when applied daily for 6 weeks or longer.

43. The use as described in claim 41 or 42, wherein, The compound is effective when applied daily for 12 weeks or longer.

44. Use of the composition in the preparation of a medicament for the treatment or prevention of Friedrich's ataxia in persons in need, wherein, The composition comprises a therapeutically effective amount of the compound as described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

45. The use as described in claim 44, wherein, The drug effectively increases or maintains ataxia levels in subjects suspected of having Friedrich's ataxia.

46. ​​The use as described in claim 44, wherein, The drug effectively inhibits the decrease in ataxia levels in individuals suspected of having Friedrich's ataxia.

47. The use as described in any one of claims 44 to 46, wherein, The drug is effective in treating one or more symptoms of Friedrich's ataxia selected from the following groups: muscle weakness, loss of coordination, visual impairment, hearing impairment, slurred speech, scoliosis, diabetes, and heart disease.

48. The use as described in claim 44, wherein, The drug is effective when administered daily for 6 weeks or longer.

49. The use as described in claim 44, wherein, The drug is effective when administered daily for 12 weeks or longer.

50. Use of the composition in the preparation of a medicament for increasing the expression level of a conamin in mammalian subjects compared with normal controls, wherein, The composition comprises a therapeutically effective amount of the compound as described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

51. The use as described in claim 50, wherein, The drug is effective when administered daily for 6 weeks or longer.

52. The use as described in claim 50 or 51, wherein, The drug is effective when administered daily for 12 weeks or longer.

53. The use as described in claim 50, wherein, The drug effectively increases ataxia levels in individuals diagnosed with Friedrich's ataxia.

54. Use of the composition in the preparation of a medicament for treating complex I deficiency in mammalian subjects compared with normal controls, wherein, The composition comprises a therapeutically effective amount of the compound as described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

55. The use as described in claim 54, wherein, The drug is effective when administered daily for 6 weeks or longer.

56. The use as described in claim 54 or 55, wherein, The drug is effective when administered daily for 12 weeks or longer.

57. The use as described in claim 54, wherein, The drug effectively increases intracellular adenosine triphosphate (ATP) levels in the tissues of individuals diagnosed with Friedrich's ataxia.

58. Use of the composition in the preparation of a medicament for reducing or inhibiting the activity of lipoxygenase-15 in mammalian subjects with or suspected of having Friedrich's ataxia, wherein, The composition comprises a therapeutically effective amount of the compound as described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

59. The use as described in claim 58, wherein, The drug is effective when administered daily for 6 weeks or longer.

60. The use as described in claim 58 or 59, wherein, The drug is effective when administered daily for 12 weeks or longer.

61. Use of the composition in the preparation of a medicament for reducing or inhibiting ferroptosis in mammalian subjects suffering from or suspected of suffering from Friedrich's ataxia, wherein, The composition comprises a therapeutically effective amount of the compound as described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

62. The use as described in claim 61, wherein, The drug is effective when administered daily for 6 weeks or longer.

63. The use as described in claim 61 or 62, wherein, The drug is effective when administered daily for 12 weeks or longer.

Images